Head Neck

RO/Head-neck
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Contents
Articles
Radiation Oncology/Epidemiology/Worldwide 1
Radiation Oncology/Cancer epidemiology 2
Radiation Oncology/Epidemiology/Most commons 3
Radiation Oncology/Epidemiology/Survival 4
Radiation Oncology/Staging 5
Radiation Oncology/CNS 10
Radiation Oncology/Pilocytic Astrocytoma 14
Radiation Oncology/Optic Pathway Glioma 15
Radiation Oncology/Brainstem Glioma 19
Radiation Oncology/CNS/Low grade glioma 21
Radiation Oncology/CNS/Anaplastic glioma 25
Radiation Oncology/CNS/High grade glioma/Overview 28
Radiation Oncology/CNS/High grade glioma/Adjuvant therapy 31
Radiation Oncology/CNS/High grade glioma/Recurrence 44
Radiation Oncology/CNS/Germinoma 45
Radiation Oncology/CNS/Ependymoma 48
Radiation Oncology/CNS/Choroid Plexus 52
Radiation Oncology/Medulloblastoma/Staging 53
Radiation Oncology/Medulloblastoma/Overview 54
Radiation Oncology/Medulloblastoma/Therapy 56
Radiation Oncology/Medulloblastoma/Protons 66
Radiation Oncology/Peds/CNS PNET 67
Radiation Oncology/CNS/Pineal 70
Radiation Oncology/Peds/ATRT 77
Radiation Oncology/Retinoblastoma 78
Radiation Oncology/CNS/Acoustic neuroma 84
Radiation Oncology/CNS/Pituitary adenoma 89
Radiation Oncology/CNS/Trigeminal neuralgia/Overview 90
Radiation Oncology/CNS/Trigeminal neuralgia/Treatment 94
Radiation Oncology/CNS/Trigeminal neuralgia/Retreatment 103
Radiation Oncology/CNS/Sphenopalatine neuralgia 106
Radiation Oncology/CNS/Cluster Headaches 106
Radiation Oncology/CNS/Arteriovenous malformation 108
Radiation Oncology/CNS/Cavernous malformation 111
Radiation Oncology/Paraganglioma 111
Radiation Oncology/CNS/Cancer pain 116
Radiation Oncology/Chordoma 116
Radiation Oncology/Head & Neck/General 122
Radiation Oncology/Head & Neck/Post-op 140
Radiation Oncology/Head & Neck/Nasopharynx/Staging 154
Radiation Oncology/Head & Neck/Nasopharynx/Overview 156
Radiation Oncology/Head & Neck/Nasopharynx/Early Stage 159
Radiation Oncology/Head & Neck/Nasopharynx/Advanced Stage 162
Radiation Oncology/Head & Neck/Larynx/Staging 171
Radiation Oncology/Head & Neck/Larynx/Overview 173
Radiation Oncology/Head & Neck/Larynx/Supraglottis 178
Radiation Oncology/Head & Neck/Larynx/Glottis 181
Radiation Oncology/Head & Neck/Hypopharynx 186
Radiation Oncology/Head & Neck/Oral cavity 191
Radiation Oncology/Head & Neck/Oropharynx 195
Radiation Oncology/Head & Neck/Sinonasal/Staging 203
Radiation Oncology/Head & Neck/Sinonasal/Overview 205
Radiation Oncology/Head & Neck/Sinonasal/Maxillary sinus 209
Radiation Oncology/Head & Neck/Sinonasal/Ethmoid sinuses 212
Radiation Oncology/Head & Neck/Protons 214
Radiation Oncology/Head & Neck/Salivary gland 216
Radiation Oncology/Thyroid/Workup 224
Radiation Oncology/Thyroid/Papillary and follicular 225
Radiation Oncology/Thyroid/Medullary 230
Radiation Oncology/Thyroid/Hurthle cell 232
Radiation Oncology/Thyroid/Anaplastic 233
Radiation Oncology/Head & Neck/Recurrent 235
Radiation Oncology/Head & Neck/Palliation 238
Radiation Oncology/Head & Neck/Second Primary 238
Radiation Oncology/Melanoma/Mucosal 241
Radiation Oncology/Head & Neck/IMRT 243
Radiation Oncology/Head & Neck/Brachytherapy 244
Radiation Oncology/HN-supportive care 244
References
Article Sources and Contributors 247
Image Sources, Licenses and Contributors 249
Article Licenses
License 250
Radiation Oncology/Epidemiology/Worldwide 1
Radiation Oncology/Epidemiology/Worldwide
• Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
• Global cancer statistics: 2002 [1] 1999 [2]
Summary
• In 2002, there were estimated to be 10.9 million new cases of cancer, 6.7 million deaths, and 24.6 million persons
living with cancer.
Incidence
• 1st - Lung - 1.35 million (in 2002)
• 2nd - Breast - 1.15 million (in 2002)
• 3rd - Colon and rectum - 1.02 million cases (in 2002)
• 4th - Stomach - 934,000 cases (in 2002)
• 5th - Liver - 626,000 (in 2002)
• 9th - Bladder - 357,000 (in 2002)
Incidence - Women
• 1st - Breast - 1.15 million (in 2002)
• 2nd - Cervix
Deaths
• 1st - Lung - 1.18 million (in 2002)
• 2nd - Stomach - 700,000 (in 2002)
• 3rd - Liver - 598,000 (in 2002)
• 4th - Colon and rectum - 529,000 (in 2002)
• 5th - Breast - 411,000 (in 2002)
• -?- - Bladder - 145,000 (in 2002)
Deaths - Women
• 1st - Breast - 411,000 (in 2002)
• 2nd - Cervix
References
[1] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?CMD=search& DB=pubmed& term=15761078
[2] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?CMD=search& DB=pubmed& term=10200776
Radiation Oncology/Cancer epidemiology 2
Radiation Oncology/Cancer epidemiology

This page is for articles pertaining to general cancer epidemiology, such as the role of smoking in causing cancer,
etc. This page should not be used to list the most common cancers. That should be done separately.
• British Doctors Study (1951 - )
• PMID 1009386 — "Mortality in relation to smoking: 20 years' observations on male British doctors." Doll R et
al. Br Med J. 1976 Dec 25;2(6051):1525-36.
• 34,440 men. Followed for 20 years. Ratio of death for smokers under age 70 was 2:1. Lung cancer incidence
fell as smoking decreased.
• This is the first study to establish a causal relationship between smoking and a number of cancers and heart
disease.
Obesity
• American Cancer Society Prevention Study II
• PMID 12711737 — "Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S.
adults." Calle EE et al. N Engl J Med. 2003 Apr 24;348(17):1625-38.
• Cohort study. 900,000 adults. 16 years follow-up.
• RR for breast cancer associated with increasing body-mass index > 25. For men, RR of any cancer was 1.52
for BMI > 25. For women, RR was 1.62 for BMI > 25. BMI also associated with higher rates of death due to
cancers of the esophagus, colon and rectum, liver, gallbladder, pancreas, kidney, non-Hodgkin's lymphoma,
multiple myeloma.
• Iowa Women's Health Study
• PMID 8419667 — "Body fat distribution and 5-year risk of death in older women." Folsom AR et al. JAMA.
1993 Jan 27;269(4):483-7.
• Cohort study. 21,707 women. Follow-up 7 years.
• Increased breast cancer mortality with increased waist-hip ratio.
Smoking
Lung Cancer:
• PMID 16189363, 2005 — "Effect of smoking reduction on lung cancer." Godtfredsen NS et al. JAMA. 2005 Sep
28;294(12):1505-10.
Radiation Oncology/Epidemiology/Most commons 3
Radiation Oncology/Epidemiology/Most
commons
See also: Epidemiology in USA and → Worldwide epidemiology
By demographic
• Men age 15-35: most common is testicular
Gynecologic
• Most common gynecologic malignancy: 1) endometrial (46%), 2) ovarian, 3) cervical (16%)
Endometrial makes up only 6.3% of malignancies in women.
• Deaths: Endometrial, 6500/yr (24%)
• In 1930s, cervical was the most common cause of cancer death in women.
Gastrointestinal
• 6% - Esophagus - 14,550 cases, 13,770 deaths (in 2006)
• ?% - Gastric - 21,700 cases, 12,800 deaths (in 2001).
• 1 - 4% - Non-Hodgkin lymphoma
• 0.1 - 3% - GIST
Pediatric cancers
12,000 cases/yr
• 6th most common (under age 15) - osteosarcoma - 400/yr
• Bone tumors: 1st - osteosarcoma, 2nd - Ewing's
• Most common extracranial solid malignancy - Neuroblastoma
• Most common malignancy of infants - Neuroblastoma
• 4% (of pediatric malignancies) - Rhabdomyosarcoma
Radiation Oncology/Epidemiology/Survival
Cancer Survival Data

Disease Median 1-year OS 2-year OS 5-year OS 10-year OS
OS
→ Chordoma
Overall (SEER data) 6.3 years 68% 40%
Glioma
→ Low Grade (WHO II)
RT alone (EORTC 22844) ~6 years 59%
RT alone (NCCTG) ~9 years 94% 72%
Observation (EORTC 22845) 7.4 years 66%
High Grade (WHO III)
RT alone (RTOG 9402) 4.7 years 46%
RT alone (EORTC 26951) 3.4 years 37%
High Grade (WHO IV)
Observation (BTCG 69-01) 3.2 months
RT alone (BTCG 69-01) 8.1 months
Pancreas
Resectable
Surgery only (CONKO-001) 1.7 years 9%
Adjuvant 5FU/RT (GITSG 9173) 1.7 years 42%
Adjuvant 5FU/RT/Chemo (ESPAC-1) 1.7 years
Adjuvant GEM-RT/5-FU/GEM (RTOG 9704) 1.7 years
Adjuvant GEM (CONKO-001) 1.9 years 21%
Unresectable
No treatment ~4 months
Palliative bypass 6-7 months
RT/5-FU (FFCD-SFRO) 9 months 32%
RT/GEM (ECOG E4201) 11 months
GEM (FFCD-SFRO) 13 months 53%
RT/GEM (Taipei) 14 months 56% 15%
RT/TNFerade(PACT) 1.4 years 71%
Prostate
Early Stage (cT1-T2)
Watchful waiting (SPCG-4) 86%
Surgery (SPCG-4) 91%

NSCLC
Early Stage Operable
Surgery (Stage I) composite 65%
Surgery (Stage I) Brazil 95%
Conventional RT (Stage I) composite 20%
SBRT (Stage I) Japan 83%
Surgery (Stage II) 45%
Spinal Cord Compression
RT Alone (Patchell) 3 months
Surgery + RT (Patchell) 4 months
Radiation Oncology/Staging
See also: AJCC staging (discusses the various staging editions)

The purpose of this page is to provide a quick comparison of the stages that are used for various malignancies. It is
not meant to go into detail of what constitutes each stage. For that information, see the article on each specific
malignancy.
This page uses the lastest AJCC 6th edition from 2002.
Note: should move this information into table form
Notes: M-stage not listed unless it is different than the commonly used M0 or M1.
For simplicity, N(1-3) means N-stage can be N0 or N1-3. However, N(0-1) means N-stage is N0 or N1. These
schemes are different but easier to remember.
All sites also contain T0 (no tumor) but this isn't listed below. Many sites contain Tis and Stage 0 but these aren't
listed below.
The headings below are per the AJCC Cancer Staging Handbook and do not necessarily follow the Table of Contents
organization of this wikibook.
See also: TNM by organ categories [1] - excellent web-based staging guide
Head and Neck

Note: Overall staging the same for all except nasopharynx and thyroid.
N-stage is the same for all (except the above 2). T-stage is similar for all subsites, with only minor differences.
• Overall staging: I (T1 N0) - II (T2 N0) - III (T3 N0, T1-3 N1) - IVA (T4a, N2) IVB (T4b, N3) IVC (M1)
• Lip and → Oral Cavity - I - II - III - IVA IVB IVC
T(T1-4 and T4a, T4b), N(N1, N2a N2b N2c, N3)
• → Pharynx (except nasopharynx) - I - II - III - IVA IVB IVC
• Larynx - I - II - III - IVA IVB IVC
supraglottis and subglottis: T(T1, T2, T3, T4a T4b)
glottis: T(T1a T1b, T2, T3, T4a T4b)
for all: N(N1, N2a N2b N2c, N3)

• Nasal cavity - I - II - III - IVA IVB IVC
• → Salivary glands - I - II - III - IVA IVB IVC
• Nasopharynx - I - II - III - IVA IVB IVC
T(T1, T2a T2b, T3, T4), N(N1, N2, N3a N3b)
I (T1 N0) - IIA (T2a N0) IIB (T1-2 N1, T2b N0) - III (T3 N0-2, T1-3 N2) - IVA (T4 N0-2) IVB (N3) IVC
(M1)
• Thyroid
Overall stage: papillary or follicular: (Under 45 years) I - II. (45 yrs+) I - II - III - IVA IVB IVC
Overall stage: medullary: I - II - III - IVA IVB IVC
Overall stage: anaplastic: IVA IVB IVC
T(T1-4 and T4a, T4b), N(N1a and N1b). Anaplastic is T4a or T4b only.
Gastrointestinal
• Note: These sites (the next 6) are all different with no pattern.
• Esophagus - I - IIA IIB - III - IVA IVB
T(1-4), N(0-1), M(0, 1a 1b) - M1a not applicable for midthoracic primary tumors
I (T1 N0) - IIA (T2-3 N0) IIB (T1-2 N1) - III (T3N1 or T4) - IVA (M1a) IVB (M1b)
• Stomach - IA IB - II - IIIA IIIB - IV
T(T1, T2a T2b, T3, T4), N(1-3)
IA (T1N0) IB (T1N1, T2N0) - II (T1N2, T2N1, T3N0) - IIIA (T2N2, T3N1, T4N0) IIIB (T3N2) - IV
(T4N1-3, N3, M1)
Mnemonic - IA add to 1, IB add to 2, II - 3, IIIA - 4, IIIB - 5
• Small intestine - I - II - III - IV
T(1-4), N(0-1)
I (T1-2 N0) - II (T3-4 N0) - III (N1) - IV (M1)
• Colon and rectum - I - IIA IIB - IIIA IIIB IIIC - IV
T(1-4), N(1-2)
I (T1-2 N0) - IIA (T3 N0) IIB (T4 N0) - IIIA (T1-2 N1) IIIB (T3-4 N1) IIIC (N2) - IV (M1)
• Anal canal - I - II - IIIA IIIB - IV
T(1-4), N(1-3)
I (T1 N0) - II (T2-3 N0) - IIIA (T1-3 N1, T4 N0) IIIB (T4 N1, N2-3) - IV (M1)
• Liver (includes intrahepatic bile ducts) - I - II - IIIA IIIB IIIC - IV
T(1-4), N(0-1)
I (T1 N0) - II (T2 N0) - IIIA (T3 N0) IIIB (T4 N0) IIIC (N1) - IV (M1)
• Note: The following (GB, bile duct, ampulla, pancreas) have same overall staging. The only difference is that GB
has T1a and T1b.
• Gallbladder - IA IB - IIA IIB - III - IV
T(1a 1b, 2, 3, 4), N(0-1)
IA (T1 N0) IB (T2 N0) - IIA (T3 N0) IIB (T1-3 N1) - III (T4) - IV (M1)
• Extrahepatic bile ducts - IA IB - IIA IIB - III - IV

T(1-4), N(0-1)
• Ampulla of Vater - IA IB - IIA IIB - III - IV
T(1-4), N(0-1)
• Pancreas - IA IB - IIA IIB - III - IV
T(1-4), N(0-1)
Lung
• Lung - IA IB - IIA IIB - IIIA IIIB - IV
T(1-4), N(1-3)
IA (T1 N0) IB (T2 N0) - IIA (T1 N1) IIB (T2 N1, T3 N0) - IIIA (T3 N1-2, T1-3 N2) IIIB (T4, N3) - IV
(M1)
• Pleural mesothelioma - IA IB - II - III - IV
T(T1a T1b, T2, T3, T4), N(1-3)
IA (T1a N0) IB (T1b N0) - II (T2 N0) - III (T1-2 N1-2, T3 N0-2) - IV (T4, N3, M1)
Musculoskeletal
• Bone - IA IB - IIA IIB - III - IVA IVB
T(1-3), N(0-1), M(1a, 1b). Grade is also used to determine stage.
IA (T1 N0, Low grade) IB (T2 N0, Low grade) - IIA (T1 N0, High grade) IIB (T2 N0, High grade) - III (T3
N0) - IVA (M1a) IVB (N1, M1b)
• Soft tissue sarcoma - I - II - III - IV
T(1a 1b, 2a 2b), N(0-1). Grade is also used to determine stage.
I (Low grade N0) - II (High grade T1a/b-T2a N0) - III (High grade T2b N0) - IV (N1, M1)
Skin
• Carcinoma of the skin - I - II - III - IV
T(1-4), N(0-1)
I (T1 N0) - II (T2-3 N0) - III (T4, N1) - IV (M1)
• Melanoma - Clinical node staging: IA IB - IIA IIB - III - IV - Pathologic node staging: IIIA IIIB IIIC
T(1a 1b, 2a 2b, 3a 3b, 4a 4b), N(1a 1b, 2a 2b 2c, 3), M(1a 1b 1c). Note: all M1 are the same overall stage.
Clinical - IA (T1a N0) IB (T2a, T1b N0) - IIA (T3a, T2b N0) IIB (T4a, T3b N0) IIC (T4b N0) - III (N+) - IV
(M1)
Pathologic - IIIA (N1a or N2a with no ulceration T1-4a) IIIB (N1b or N2b with no ulceration T1-4a, or N1a
or N2a with ulceration T1-4b, or any N2c) IIIC (N1b or N2b with ulceration T1-4b, or any N3)
Hint: ulceration always upstages by one
Breast
• Breast - I - IIA IIB - IIIA IIIB IIIC - IV
T(1mic 1a 1b 1c, 2, 3, 4a 4b 4c 4d), N(1mi 1a 1b 1c, 2a 2b, 3a 3b 3c). Note: all subtypes of a stage are the
same overall stage.
I (T1 N0) - IIA (T1 N1, T2 N0) IIB (T2 N1, T3 N0) - IIIA (N2, T3 N1) IIIB (T4) IIIC (N3) - IV (M1)
Gynecologic
In all, T-stage parallels the FIGO stage, except there is no T4b (Stage IVB is M1), and in cases where the FIGO
stage includes node-positive disease as a distinct stage (e.g. uterine corpus Stage IIIC). Except for vulvar, N+ makes
the overall stage the highest Stage III stage. There is no T4 (and thus no IVA) for ovary and fallopian tube.
N-stage changes the FIGO stage in most, but only in vulvar cancer is there N1 vs N2.
• Vulva - IA IB - II - III - IVA IVB (FIGO staging)
T(1a 1b, 2, 3, 4), N(1-2). N1 is III, N2 is Stage IVA.
• Vagina - I - II - III - IVA IVB (FIGO staging)
T(1-4), N(0-1). N+ is Stage III.
• Cervix - IA1 IA2 IB1 IB2 - IIA IIB - IIIA IIIB - IVA IVB (FIGO staging)
T(1a1 1a2 1b1 1b2, 2a 2b, 3a 3b, 4), N(0-1). N+ is Stage IIIB in AJCC only, not used in FIGO stage.
• Uterine corpus - IA IB IC - IIA IIB - IIIA IIIB IIIC - IVA IVB (FIGO staging)
T(1a 1b 1c, 2a 2b, 3a 3b, 4), N(0-1). N+ is IIIC (no other way to be Stage IIIC).
• Ovary - IA IB IC - IIA IIB IIC - IIIA IIIB IIIC - IV (FIGO staging)
T(1a 1b 1c, 2a 2b 2c, 3a 3b 3c), N(0-1). N+ is IIIC.
• Fallopian tube - IA IB IC - IIA IIB IIC - IIIA IIIB IIIC - IV (FIGO staging)
T(1a 1b 1c, 2a 2b 2c, 3a 3b 3c), N(0-1). N+ is IIIC.
• Gestational trophoblastic tumors - IA IB - IIA IIB - IIIA IIIB - IVA IVB (FIGO staging)
T(1-2), N stage is not used, M(1a 1b). Risk group (high or low or unknown) is also used in staging.
Genitourinary
• Penis - I - II - III - IV
T(Ta, 1-4), N(1-3)
I (T1 N0) - II (T1 N1, T2 N0-1) - III (T1-2 N2, T3 N0-2) - IV (T4, N3, M1)
• Prostate - I - II - III - IV
T(1a 1b 1c, 2a 2b 2c, 3a 3b, 4), N(0-1), M1(1a 1b 1c). Grade is also used for T1a tumors. Note: all M1 are the
same overall stage.
I (T1a N0 G1) - II (T1a G2-4, T1b-1c, T2) - III (T3 N0) - IV (T4, N1, M1)
• Testis - IA IB IS - IIA IIB IIC - IIIA IIIB IIIC (there is no Stage IV)
T(1-4), N(1-3), M(1a 1b -- affects stage), S(1-3)
IA (T1 N0 M0 S0) IB (T2-4 N0 M0 S0) IS (Any T N0 M0 S1-3) - IIA (Any T N1 M0 S0-1) IIB (Any T N2
M0 S0-1) IIC (Any T N3 M0 S0-1) - IIIA (Any T Any N M1a S0-1) IIIB (S2 and N1-3 or M1a) IIIC (S3 and
N1-3 or M1a, or M1b)
• Kidney - I - II - III - IV
T(1a 1b, 2, 3a 3b 3c, 4), N(1-2). Substage does not change overall stage.
I (T1 N0) - II (T2 N0) - III (T3, N1) - IV (T4, N2, M1)
• Renal pelvis and ureter - I - II - III - IV

T(1-4), N(1-3). Note: all N+ are the same overall stage.
I (T1 N0) - II (T2 N0) - III (T3 N0) - IV (T4, N+, M1)
• Bladder - 0a 0is - I - II - III - IV
T(Ta Tis T1, 2a 2b, 3a 3b, 4a 4b), N(1-3). Substages 4a and 4b change overall stage but T2 and T3 substages
do not. All N+ (N1-3) is the same overall stage.
I (T1 N0) - II (T2 N0) - III (T3 N0, T4a N0) - IV (T4b, N+, M1)
• Urethra - 0a 0is - I - II - III - IV
T(Ta Tis, 1-4), N(1-2)
I (T1 N0) - II (T2 N0) - III (T1-3 N1, T3 N0) - IV (T4, N2, M1)
Ophthalmic sites
Most of these sites are rarely used, so I won't do them.
• → Retinoblastoma - No AJCC stage grouping
Clinical: T(1a 1b, 2a 2b 2c, 3, 4), N(1-2), M(1a 1b)
Pathologic: T(1, 2a 2b 2c, 3a 3b 3c, 4), N(0-1)
Central nervous system

No AJCC staging system
Lymphoid malignancies
TNM does not apply.
• Lymphoma - Ann Arbor Stage: I - II - III - IV with modifiers.
• Multiple myeloma - Durie-Salmon staging: IA IB - IIA IIB - IIIA IIIB.
References
[1] http:/ / cancerstaging. blogspot. com
Radiation Oncology/CNS
Clinical Sections
Introduction
Adult:
• Glioma
• Meningioma
• Primary CNS Lymphoma
• → Pineal Gland Tumors
• Metastatic to brain
• CSF involvement
• Spine
• Miscellaneous CNS Tumors
Pediatric:
• Craniopharyngioma
• Glioma:
• → Optic Pathway Glioma
• → Brainstem Glioma
• → Pilocytic Astrocytoma
• → Germinoma
• → Ependymoma
• → Choroid Plexus Tumor
• Medulloblastoma
• → CNS PNET
• → Pineal Gland tumors
• → Atypical Teratoid Rhabdoid Tumor (AT/RT)
• → Retinoblastoma
Benign:
• → Acoustic Neuroma (Vestibular Schwannoma)
• → Pituitary Adenoma
• Trigeminal Neuralgia
• → Sphenopalatine Neuralgia
• → Chronic Cluster Headaches
• → Arteriovenous Malformation (AVM)
• → Cavernous Malformation
• Glomus Jugulare (Paraganglioma)
• → Cancer pain
Proton therapy
2007 WHO Classification [1]

Neuroepithelial Tumors
• Astrocytic Tumors
• → Pilocytic astrocytoma 9421/1
• Pilomyxoid astrocytoma 9425/3
• Subependymal giant cell astrocytoma 9384/1
• Pleomorphic xanthoastrocytoma 9424/3
• → Diffuse astrocytoma 9400/3
• Fibrillary astrocytoma 9420/3
• Protoplasmic astrocytoma 9410/3
• Gemistocytic astrocytoma 9411/3
• Anaplastic astrocytoma 9401/3
• Glioblastoma 9440/3
• Giant cell glioblastoma 9441/3
• Gliosarcoma 9442/3
• Gliomatosis cerebri 9381/3
• Oligodendroglial tumours
• → Oligodendroglioma 9450/3
• Anaplastic oligodendroglioma 9451/3
• Oligoastrocytic tumours
• → Oligoastrocytoma 9382/3
• Anaplastic oligoastrocytoma 9382/3
• Ependymal tumours
• → Subependymoma (WHO Grade 1) 9383/1
• → Myxopapillary ependymoma (WHO Grade 1) 9394/1
• → Ependymoma (WHO Grade 2) 9391/3
• Cellular 9391/3
• Papillary 9393/3
• Clear cell 9391/3
• Tanycytic 9391/3
• → Anaplastic ependymoma (WHO Grade 3) 9392/3
• Choroid plexus tumours
• → Choroid plexus papilloma 9390/0
• Atypical choroid plexus papilloma 9390/1*
• → Choroid plexus carcinoma 9390/3
• Other neuroepithelial tumours
• Astroblastoma 9430/3
• Chordoid glioma of the third ventricle 9444/1
• Angiocentric glioma 9431/1*
• Neuronal and mixed neuronal-glial tumours
• Dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos) 9493/0
• Desmoplastic infantile astrocytoma/ganglioglioma 9412/1
• Dysembryoplastic neuroepithelial tumour 9413/0
• Gangliocytoma 9492/0
• Ganglioglioma 9505/1
• Anaplastic ganglioglioma 9505/3
• Papillary glioneuronal tumor 9509/1*
• Rosette-forming glioneuronal tumour of the fourth ventricle 9509/1*
• Central neurocytoma 9506/1
• Extraventricular neurocytoma 9506/1*
• Cerebellar liponeurocytoma 9506/1*
• Paraganglioma of the filum terminale 8680/1
Tumours of the pineal region
• → Pineocytoma 9361/1
• → Pineal parenchymal tumour of intermediate differentiation 9362/3
• → Pineoblastoma 9362/3
• → Papillary tumour of the pineal region 9395/3*
Embryonal tumours
• Medulloblastoma 9470/3
• Desmoplastic/nodular medulloblastoma 9471/3
• Medulloblastoma with extensive nodularity 9471/3*
• Anaplastic medulloblastoma 9474/3*
• Large cell medulloblastoma 9474/3
• → CNS primitive neuroectodermal tumours (PNETs)
• CNS PNET, NOS 9473/3
• CNS neuroblastoma 9500/3
• CNS ganglioneuroblastoma 9490/3
• Medulloepithelioma 9501/3
• Ependymoblastoma 9392/3
• → Atypical teratoid / rhabdoid tumour 9508/3
Tumors of the Cranial and Paraspinal Nerves
• Schwannoma (Neurilemoma, neurinoma) 9560/0
• Cellular 9560/0
• Plexiform 9560/0
• Melanotic 9560/0
• Neurofibroma 9540/0
• Plexiform 9550/0
• Perineurioma 9571/0
• Intraneural perineurioma 9571/0
• Soft tissue perineurioma 9571/0
• Malignant peripheral nerve sheath tumour (MPNST) 9540/3
• Epithelioid 9540/3
• MPNST with divergent mesenchymal and / or epithelial differentiation 9540/3
• Melanotic 9540/3
Tumors of the Meninges
• Tumours of meningothelial cells
• Meningioma 9530/0
• Mesenchymal tumours
• Lipoma 8850/0
• Angiolipoma 8861/0
• Hibernoma 8880/0
• Liposarcoma (intracranial) 8850/3
• Solitary fibrous tumour 8815/0
• Fibrosarcoma 8810/3
• Malignant fibrous histiocytoma 8830/3
• Leiomyoma 8890/0
• Leiomyosarcoma 8890/3
• Rhabdomyoma 8900/0
• Rhabdomyosarcoma 8900/3
• Chondroma 9220/0
• Chondrosarcoma 9220/3
• Osteoma 9180/0
• Osteosarcoma 9180/3
• Osteochondroma 9210/0
• Haemangioma 9120/0
• Epithelioid haemangioendothelioma 9133/1
• Haemangiopericytoma 9150/1
• Angiosarcoma 9120/3
• Kaposi sarcoma 9140/3
• Primary melanocytic lesions
• Diffuse melanocytosis 8728/0
• Melanocytoma 8728/1
• Malignant melanoma 8720/3
• Meningeal melanomatosis 8728/3
• Other neoplasms related to the meninges
• Haemangioblastoma 9161/1
Lymphomas and Hematopoietic Neoplasms
• Malignant lymphomas 9590/3
• Plasmacytoma 9731/3
• Granulocytic sarcoma 9930/3
Germ Cell Tumors
• → Germinoma 9064/3
• Embryonal carcinoma 9070/3
• Yolk sac tumour 9071/3
• Choriocarcinoma 9100/3
• Teratoma 9080/1
• Mature 9080/0
• Immature 9080/3
• Teratoma with malignant transformation 9084/3
• Mixed germ cell tumours 9085/3
Tumors of the Sellar Region
• Craniopharyngioma 9350/1
• Adamantinomatous 9351/1
• Papillary 9352/1
• Granular cell tumour 9582/0
• Pituicytoma 9432/1*
• Spindle cell oncocytoma of the adenohypophysis 8291/0*
Metastatic Tumors
References
[1] http:/ / www. blackwell-synergy. com/ doi/ pdf/ 10. 1111/ j. 1750-3639. 2007. 00084. x
Radiation Oncology/Pilocytic Astrocytoma

Pilocytic Astrocytoma
Juvenile Pilocytic Astrocytoma

• WHO Grade I tumors
• Well-circumscribed, enhancing lesions typically located in the cerebellum; many are → Optic Pathway Gliomas
• Surgical resection alone results in favorable outcome, with 10-year OS >80%
Proton Therapy
• Loma Linda; 2002 (1991-1997) PMID 11977386 -- "Conformal proton radiation therapy for pediatric low-grade
astrocytomas." (Hug EB, Strahlenther Onkol. 2002 Jan;178(1):10-7.)
• Retrospective. 27 patients, progressive or recurrent low-grade astrocytoma. Fractionated proton therapy
50.4-63 CGE in 1.8 CGE/fx. Mean F/U 3.3 years
• Outcome: LC 78%, OS 85%
• Toxicity: well tolerated; Moyamoya disease in one child with NF1; 6 patients with optic pathway tumors
maintained/improved their vision
• Conclusion: Proton RT is safe and efficacious; longer term follow-up needed
Adult Pilocytic Astrocytoma

• Uncommon
• Clinical presentation includes visual disturbances, seizures, and headaches. Papilledema common
• Favorable prognosis both in terms of survival and neurologic function
• Most remain stable after resection (gross or subtotal) only, and need no adjuvant RT with close follow-up
• It may be reasonable to offer RT in unresectable disease, especially if causing neurologic symptoms
• 10 year OS 95%
• Intergroup NCCTG/RTOG (1986-1994)
• Prospective. 20 adults with supratentorial pilocytic astrocytoma. If gross total (n=11) or subtotal (n=6)
resection, observation. If biopsy only (n=3), RT 50.4 Gy to 2-cm edema margin
• 10 years; 2004 PMID 15001258 -- "Adult patients with supratentorial pilocytic astrocytomas: a prospective
multicenter clinical trial." (Brown PD, Int J Radiat Oncol Biol Phys. 2004 Mar 15;58(4):1153-60.) Median F/U
Radiation Oncology/Pilocytic Astrocytoma 15
10 years
• 10-year outcome: 95% alive. 1 patient died of unknown cause 2.1 years after enrollment; 1 patient
progressed 1 month after enrollment and was salvaged with P-32 followed 1.5 years later by RT, now
without evidence of progression at 9 years
• Conclusion: Favorable prognosis; don't need RT after gross total or subtotal resection
Radiation Oncology/Optic Pathway Glioma

Optic Pathway Glioma
Epidemiology
• Low grade astrocytic tumors
• Prevalence
• 2% of cerebral gliomas
• 5% of childhood brain tumors
• 90% in children <20 years, 75% in <10 year olds; 10% in adults
• Associated with neurofibromatosis
• 30% of OPG patients have NF1 stigmata
• Up to 25% of NF1 patients develop OPG (most common CNS tumor in NF1)
• Location
• Anterior (orbital, infracanalicular, prechiasmal) - common in prepubertal children
• Posterior (chiasm, hypothalamus, anterior 3rd ventricle) - common in adolescents
Treatment
• Optimal management of optic pathway gliomas is controversial
• Patient age
• Tumor location
• Presence of NF1
• Children should probably be managed with observation and close follow-up, if possible
• Adults should be managed aggressively
• Non-surgical treatment algorithm as per PMID 16411210
• <3 years or 3-10 with unresectable lesion
• Observe until radiographic or symptomatic progression
• Packer regimen (carboplatin/vincristine); if no progression, observe; if progression, RT
• >10 years
• Proton RT if available, else stereotactic/conformal RT; if no progression, observe; if progression, protocol
Surgery
• No consensus regarding optimal timing
• Likely benefit:
• Obstructive hydrocephalus
• Single nerve involvement causing progressive disfiguring proptosis or blindness
• Possible benefit: delaying RT in young children
• Probable contra-indication:
• Diffuse chiasmal involvement/broadly infiltrative disease
• NF patients
Chemotherapy
• No consensus; most are treated under Low Grade Glioma guidelines
• UCSF study demonstrated activity of nitrosurea-based chemo (TPDCV)
• George Washington study (Packer) demonstrated good outcomes with carboplatin/vincristine (now the most
"standard" chemo)
• French trial showed good long-term control, while avoiding RT
• Children's Oncology Group trial CCG A9952 ongoing (essentially randomizing UCSF and GW protocols)
Ongoing
• CCG A9952 - Protocol link [1] -- "Phase III Randomized Study of Carboplatin and Vincristine Versus
Thioguanine, Procarbazine, Lomustine, and Vincristine in Children With Progressive Low Grade Astrocytoma"
• Closed. Results not yet reported (04/07)
Published
• French Society of Pediatric Oncology, 2003 (1990-1998) PMID 14673044 -- "Progression-free survival in
children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy--results
of the first French prospective study for the French Society of Pediatric Oncology." (Laithier V, J Clin Oncol.
2003 Dec 15;21(24):4572-8.)
• Prospective. 85 children with progressive optic pathway tumors. Chemo: alternating procarbazine/carboplatin,
etoposide/cisplatin, and vincristine/cyclophosphamide every 3 weeks. At relapse, 2nd line chemo before RT
• 5-year outcomes: PFS 34%, OS 89%. RT-free survival 61%
• Prognostic factors: age <1, NF1 associated with disease progression
• Conclusion: RT can be avoided with prolonged chemotherapy, without compromising OS or visual function
• Royal Marsden, 2003 (UK) PMID 12892235 -- "Tolerance of nitrosurea-based multiagent chemotherapy regime
for low-grade pediatric gliomas." (Lancaster DL, J Neurooncol. 2003 Jul;63(3):289-94.)
• Prospective. 10 children with low-grade gliomas, initially treated with carboplatin/vincristine, second line with
TPCV
• Conclusion: TPCV is appropriate as second line therapy
• George Washington, 1997 PMID 9126887 -- "Carboplatin and vincristine chemotherapy for children with newly
diagnosed progressive low-grade gliomas." (Packer RJ, J Neurosurg. 1997 May;86(5):747-54.)
• Prospective. 78 children with progressive low-grade glioma (12 brainstem gliomas). Concurrent
carboplatin/vincristine. Median F/U 2.5 years
• 3-year PFS: 68%. No difference between NF1+ and NF1-. Objective response 56%
• Prognostic factors: only age (<3 yo 74% vs. >3 yo 39%, SS)
• UCSF, 1991 (1983-1989) PMID 1901597 -- "Management of chiasmal and hypothalamic gliomas of infancy and
childhood with chemotherapy." (Petronio J, J Neurosurg. 1991 May;74(5):701-8.)
• Retrospective. 19 children with chiasmal/hypothalamic gliomas. 12 treated immediately for progressive

symptoms, 7 deferred. Chemo: TPDCV
• Median time to progression: not reached at 20 months. No tumor-related deaths. Initial response/stabilization
15/18 patients
• Salvage: RT
• Conclusion: TPDCV allows RT to be deferred until progression of disease.
Radiation
• Most favorable outcomes reported for 45-56 Gy, in 1.8 Gy/fx
• Suggestion that posterior location tumors have worse outcomes
• Proton RT is being explored
• Harvard, 2005 (1992-1998) PMID 15667955 -- "Stereotactic radiotherapy for localized low-grade gliomas in
children: final results of a prospective trial." (Marcus K, Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):374-9.)
• Prospective. 50 patients with localized low-grade glioma. RT for progression on/after chemo or surgery.
Median F/U 6.9 years
• RT: Removable head frame. 2-mm margin. Mean dose 52.2 Gy in 1.8 Gy/fx. Target delineation via CT/MRI
fusion
• 5-year outcome: PFS 83%, OS 98%; 6 patients with in-field progression, no marginal failures
• Conclusion: stereotactic RT excellent local control, with limited margins
• Heidelberg, 2005 (Germany) (1990-2003) PMID 15936565 -- "Fractionated stereotactic radiotherapy of optic
pathway gliomas: tolerance and long-term outcome." (Combs SE, Int J Radiat Oncol Biol Phys. 2005 Jul
1;62(3):814-9.)
• Retrospective. 15 patients. Median dose 52.2 Gy (45.2-57.6) in 1.8 Gy/fx. Median F/U 8 years
• 5-year outcome: PFS 72%, OS 90%. No second malignancies
• Conclusion: Good control, normal brain sparing. Longer f/u needed
• Institut Curie, 1991 (1970-1986) PMID 1907959 -- "Chiasmal gliomas: results of irradiation management in 57
patients and review of literature." (Bataini JP, Int J Radiat Oncol Biol Phys. 1991 Aug;21(3):615-23.)
• Retrospective. 57 patients, 37% chiasm, 63% extended to hypothalamus/posteriorly. RT 40-60 Gy. Mean F/U
7.5 years
• 5-year (and 10-year) OS: 84%; response: CR 15%, PR 46%, SD 22%
• Conclusion: RT effective in cases of rapidly developing visual, neurological, or endocrine symptoms
• Neurological Institute, Columbia University, 1956 PMID 13323290 -- "The value of radiation therapy in the
management of glioma of the optic nerves and chiasm." (Taveras JM, Radiology. 1956 Apr;66(4):518-28.)
• Retrospective. 34 patients treated with RT
• Survival: 23/34 at time of publication
• Landmark study. Results deemed exceptional. Launched RT as a management strategy
RT Complications
• Manchester/London, 2006 PMID 16735710 -- "Second primary tumors in neurofibromatosis 1 patients treated
for optic glioma: substantial risks after radiotherapy." (Sharif S, J Clin Oncol. 2006 Jun 1;24(16):2570-5.)
• Retrospective. 58/80 NF1 patients with OPG. 18/58 RT alone or in combination. Dose 25-50 Gy
• Second CNS tumor: RT 9/18 (50%) developed 12 second tumors in 308 person-years of F/U; No RT 8/40
(20%) developed 9 second tumors in 721 person-years of F/U. RR 3 (SS). Median time-to-diagnosis 12 years.
Risk of MPNST was increased RR 5.3 (SS) over non-OPG NF1 controls
• Conclusion: Significantly increased 2nd CNS cancer risk in NF1 patients with OPG; RT should be used only if
absolutely necessary
• Toronto, 1993 (1971-1990) PMID 8315466 -- "Moyamoya phenomenon after radiation for optic glioma." (Kestle
JR, J Neurosurg. 1993 Jul;79(1):32-5.)
• Retrospective. 47 patients with OPG treated.
• Moyamoya phenomenon: 0/19 no RT; 5/28 with RT; 2/23 NF1- vs. 3/5 NF1+ (SS)
• Conclusion: High incidence of moyamoya in patients with NF1 and cranial RT
• Note: Moyamoya disease is a progressive chronic cerebrovascular disease seen mainly in Asia characterized
by bilateral stenosis/occlusion of the arteries in the circle of Willis with an unknown etiology that here used to
describe post-radiation changes to the vascular system
Review
• 2006 PMID 16411210 -- "Optic pathway gliomas." (Jahraus CD, Pediatr Blood Cancer. 2006 May
1;46(5):586-96.)
References
[1] http:/ / www. cancer. gov/ clinicaltrials/ COG-A9952
Radiation Oncology/Brainstem Glioma

Epidemiology
• 10-20% CNS tumors in children
• 5% CNS tumors in adults
Subtypes
Diffuse brainstem glioma

• Usually located in the pons.
• Generally high grade (WHO III/IV).
• Locally invasive.
• Universally poor prognosis (median survival <1 yr).
• 80% brainstem gliomas.
Focal brainstem glioma

• Located in medulla or midbrain.
• Low grade.
• Well circumscribed without local infiltration or edema.
• Significant proportion can have long term survival.
• 15-20% brainstem gliomas.
Anatomy
Brainstem Glioma
Treatment
• Diffuse brainstem glioma - treated with steroids and RT/temodar like a high grade astrocytoma.
• Hyperfractionation has been extensively studied and does not appear to benefit.
• Focal brainstem glioma
• Tectal glioma treated with CSF diversion and observation.
• Tegmental glioma treated with surgical resection.
• Dorsal exophytic focal brainstem glioma treated with surgical resection.
• Medullary focal brainstem glioma often treated with RT.
Radiation Therapy for Diffuse Brainstem Glioma

• Nijmegen, Netherlands; 2009 PMID 18990510 -- "The role of hypofractionation radiotherapy for diffuse
intrinsic brainstem glioma in children: a pilot study." (Janssens GO, Int J Radiat Oncol Biol Phys. 2009 Mar
1;73(3):722-6. Epub 2008 Nov 5.)
• Prospective. 9 children, diffuse brainstem glioma. RT 39/13. Mean F/U 15 months
• Outcome: Median OS 8.6 months, median TTP 4.9 months; both comparable to "standard" regimens
• Toxicity: No Grade 3-4
• Conclusion: Radical hypofractionation feasible, offers quick relief with minimal overall treatment time
• Harvard; 2003 (1990-96) - PMID 12654425 -- Marcus KJ et al. "A phase I trial of etanidazole and
hyperfractionated radiotherapy in children with diffuse brainstem glioma." Int J Radiat Oncol Biol Phys. 2003
Apr 1;55(5):1182-5.
• 18 pts w/ brainstem glioma tx'd w/ etanidazole + hyperfractionated RT on dose escalation protocol. (66 Gy in
1.5 BID to 1st 3 pts, 63 Gy in 1.5 BID to next 15).
• 3 grade 3 toxicities (skin, 1 vomiting)
• Median survival 8.5 mo
• Conclusion: dose limiting toxicity of etanidazole in childhood pt was rash (compared to adults when it is
peripheral neurophathy).
• POG 9239, 1999 (1992-97) - PMID 10192340 -- Mandell LR et al. "There is no role for hyperfractionated
radiotherapy in the management of children with newly diagnosed diffuse intrinsic brainstem tumors: results of a
Pediatric Oncology Group phase III trial comparing conventional vs. hyperfractionated radiotherapy." Int J Radiat
Oncol Biol Phys. 1999 Mar 15;43(5):959-64.
• 130 pts w/ diffuse brainstem glioma tx'd w/ concurrent cisplatin and randomized to hyperfractionated RT (117
cGy BID to 70.2 Gy) vs conventional RT (180 cGy qD to 54 Gy).
• OS at 1 yr was 30.9% (conventional) vs 27% (HF); OS at 2 yrs was 7.1% (conventional) vs 6.7% (HF)
• Median time to progression was 6 mo's (conventional) vs 5 mo's (HF).
• Conclusion: no benefit to hyperfractionated RT for diffuse brainstem glioma.
Radiation Oncology/CNS/Low grade glioma

Adult low grade gliomas
Overview
• Relatively slow-growing primary brain tumors
• Account for ~10% of primary CNS tumors in USA
• Median age at diagnosis is 40's for adult tumors, and teens for pilocytic astrocytoma
• Heterogenous clinical presentation ranging from seizure only to functional deficits
• Classified as Grade I or Grade II by WHO; common histologic subtypes include astrocytomas,
oligodendrogliomas, and mixed oligoastrocytomas.
• Anaplastic transformation to high grade is common, in 70-80% patients
• Surgery is typically first option
• RT may be offered as adjuvant or as salvage; while time-to-progression and control of seizures is better with
adjuvant RT, there is no difference in overall survival
• There does not seem a strong dose response between 45 and 65 Gy based on two randomized trails (EORTC
22844 compared 45 Gy vs. 59.4 Gy, INTERGROUP compared 50.4 Gy vs. 64.8 Gy); as a result, NCCN
recommends 45 - 54 Gy as a reasonable dose
• 5-year overall survival is 60-70%, while progression-free survival is 40-50%
Prognostic Factors
1p/19q fusion or deletion
• NCCTG Trials; 2006 PMID 17047046 -- "A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q
and predicts a better prognosis of patients with oligodendroglioma." (Jenkins RB, Cancer Res. 2006 Oct
15;66(20):9852-61.)
• 119 patients enrolled on 2 low-grade glioma NCCTG trials. Translocation t(1;19) evaluated by FISH
• Fusion prevalence: oligodendroglioma 55%, mixed oligoastrocytoma 47%, astrocytoma 0%
• Median OS: all patients - fusion/deletion 11.9 years vs. no fusion 8.1 years (SS); oligodendroglioma only -
fusion/deletion 13.0 years vs. no fusion 9.1 years (SS)
• Conclusion: t(1;19) mediates combined 1p/19q deletion, and is associated with superior OS and PFS in
low-grade gliomas
Prognostic Grouping
• EORTC 22844/22845
• 2002 PMID 11956268, "Prognostic factors for survival in adult patients with cerebral low-grade glioma."
(Pignatti F et al. J Clin Oncol. 2002 Apr 15;20(8):2076-84.)
• EORTC 22844 (construction set = 322 patients) and EORTC 22845 (validation set = 288 patients)
• Poor prognosis: Age >= 40, astrocytoma histology, tumor >= 6 cm, tumor crosses midline, neurologic deficits
prior to surgery; no impact from extent of surgery
• Model:
Risk Factors Risk Score Median

Group OS
Astrocytoma histology
Low risk 0-2 7.8 years
Age >=40
High risk 3-5 3.7 years
Tumor >=6 cm
Tumor crossing
midline
Neurologic deficit
Adjuvant RT Dose
• EORTC 22844 (1985-1991)
• Randomized. 343 patients. Age 16-65. Included astrocytoma, oligodendroglioma, mixed oligoastrocytoma.
Excluded completely excised pilocytic astrocytoma. Surgery first. Randomized to low dose 45 Gy vs high dose
59.4 Gy at 1.8 Gy/fx. RT technique: 2 cm margin around enhancing tumor to 45 Gy, reduced field 1 cm
margin to 54 Gy and minimal margin to 59.4 Gy.
• 5-years; 1996 PMID 8948338, 1996 — "A randomized trial on dose-response in radiation therapy of
low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study
22844." Karim AB et al. Int J Radiat Oncol Biol Phys. 1996 Oct 1;36(3):549-56. Median F/U 6.2 years
• 5-year outcome: No difference in OS (58% vs 59%) or PFS (47% vs 50%)
• Predictors: Age, size, neurologic status, amount of surgery
• Conclusion: No dose response above 45 Gy
• Quality of life; 1998 PMID 10023313 -- "Quality of life after radiation therapy of cerebral low-grade gliomas
of the adult: results of a randomised phase III trial on dose response (EORTC trial 22844). EORTC
Radiotherapy Co-operative Group." (Kiebert GM, Eur J Cancer. 1998 Nov;34(12):1902-9.)
• Questionnaire, 47 items
• Outcome: high RT group had more fatigue/malaise, emotional functioning
• Conclusion: 45/25 schedule better
• Intergroup NCCTG/RTOG/ECOG (1986-1994)
• Randomized. 203 patients. Age >18. Included low grade astrocytoma, oligodendroglioma, or mixed
oligoastrocytoma; pilocytic astrocytomas were excluded. Randomized to 50.4 Gy vs 64.8 Gy. RT technique: 2
cm margin around preoperative tumor volume, 1 cm margin for boost after 50.4 Gy.
• 5-years; 2002 PMID 11980997 — "Prospective randomized trial of low- versus high-dose radiation therapy in
adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment
Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study." (Shaw E et al. J Clin
Oncol. 2002 May 1;20(9):2267-76.) Median F/U 6.4 years
• 5-year outcome: OS low dose 72% vs. high dose 65% (NS); time-to-progression 58% vs. 52% (NS). Failure
within field 92%
• Toxicity: more often and more severely in high dose arm (2.5% vs 5%)
• Poor prognosis: astrocytoma, age >40, tumor >=5 cm (5-year OS if <40 and oligodendroglioma 82% vs.
>40 and astrocytoma 32%)
• Conclusion: No benefit for higher RT dose
• MMSE Cognitive; 2003 PMID 12829670 -- "Effects of radiotherapy on cognitive function in patients with
low-grade glioma measured by the folstein mini-mental state examination." (Brown PD, J Clin Oncol. 2003 Jul
1;21(13):2519-24.)
• Prospective. 203 patients evaluated with Mini-Mental State Examination at baseline and follow-up. Median
F/U 7.4 years
• 7.4-year outcome: Stable MMSE in 95% patients without tumor progression. If abnormal baseline MMSE,
experienced significant improvement after treatment
• Conclusion: Most patients had stable neurocognitive status on MMSE after RT
• Full Cognitive; 2005 PMID 15964709 -- "Cognitive function after radiotherapy for supratentorial low-grade
glioma: a North Central Cancer Treatment Group prospective study." (Laack NN, Int J Radiat Oncol Biol
Phys. 2005 Nov 15;63(4):1175-83.)
• Subset. 20 patients (10 low dose, 10 high dose) treated at Mayo Clinic. Evaluated with extensive battery of
tests at baseline, and then every 1.5 years. Median F/U 3 years
• Outcome: baseline scores below average compared with age-specific norms. No changes in cognitive
performance regardless of stratification (dose, age, location, type, or resection)
• Conclusion: Cognitive function stable after RT
Early vs Delayed Radiotherapy

• EORTC 22845 (1986-1997)
• Randomized. 314 patients. Age 16-65. Supratentorial low grade astrocytoma, low grade oligoastrocytoma, or
low grade oligodendroglioma. Excluded small completely resected → pilocytic astrocytomas, → optic nerve
gliomas, brainstem gliomas, third ventricle gliomas, and infratentorial gliomas. Surgery first. Randomized to
early radiotherapy with 54 Gy (1.8 Gy/fx) vs delayed radiotherapy until the time of progression. CT with
contrast every 4 months until progression. Technique: preop CT + 2 cm margins to 45 Gy, reduced field to 1
cm after 45 Gy.
• 2005 PMID 16168780 — "Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma
and oligodendroglioma in adults: the EORTC 22845 randomised trial." (van den Bent MJ et al. The Lancet
Volume 366, Issue 9490, 17 September 2005, Pages 985-990.) Median F/U 7.8 years
• Outcome: Median PFS early RT 5.3 yrs vs delayed RT 3.4 yrs (SS). 5-year PFS 55% vs. 35% (SS). Median
OS 7.4 vs 7.2 yrs (NS). 65% of pts in control group received RT at progression, 4% in early RT received
salvage RT. At 1 yr, better control of seizures in early RT group (25% vs. 41%, SS).
• After progression: survival early RT 1.0 years vs. delayed RT 3.4 years (SS). ~70% transformed to high
grade tumors, regardless if they had RT or not. Most recurrences within field
• Toxicity (compared at 1 year for patients still tumor free at 2 years): No difference in cognitive deficit, focal
deficit, performance status, or headaches.
• Conclusion: Early RT lengthens PFS and controls seizures, but doesn't impact OS
• Comment: tumor planning off CT, central path showed 26% were high grade tumors but balanced between
arms, no QoL analysis. Lack of OS difference likely due to effectiveness of salvage RT
RT +/- Chemotherapy
• RTOG 98-02 / INT (1998-2002) -- RT +/- PCV
• Randomized arm + observation arm. 362 patients, WHO Grade II supratentorial astrocytoma,
oligoastrocytoma, or oligodendroglioma
• High risk LGG (age >=40 or STR/bx; 251 patients): Arm 1) RT 54/30 alone vs. Arm 2) RT + PCV x6
cycles. RT given T2 + 2 cm block-edge margin
• Low risk LGG (age <40 and GTR; 111 patients): Observation only
• 4-years; 2006 ASCO Abstract 1500 [1] (slides + video) — "Initial report of Radiation Therapy Oncology
Group (RTOG) 9802: Prospective studies in adult low-grade glioma (LGG)." Shaw EG et al. Journal of
Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement),
2006: 1500. Median F/U 4 years
• Outcome:
• High risk: 5-year OS RT 61% vs. RT + PCV 70% (NS); PFS 39% vs. 61% (NS)
• Low risk: 5-year OS 94%; PFS 50%
• Toxicity: Grade 3-4 RT 9% vs. RT + PCV 67%. No treatment deaths
• Conclusion: Poor 5-year PFS in all 3 arms; no survival advantage for adding adjuvant PCV in high risk
patients
• 6-years; 2008 ASCO Abstract 2006 [2] -- "Final report of Radiation Therapy Oncology Group (RTOG)
protocol 9802: Radiation therapy (RT) versus RT + procarbazine, CCNU, and vincristine (PCV) chemotherapy
for adult low-grade glioma (LGG)." (Shaw EG, J Clin Oncol 26: 2008 (May 20 suppl; abstr 2006)) Median
F/U 5.9 years
• High risk outcome: 5-year OS RT 63% vs. RT + PCV 72% (NS); PFS 46% vs. 63% (p=0.06). In years 0-2
no difference, beyond 2 years significant benefit for RT+PCV. HR for death 0.52, for PFS 0.45
• Conclusion: PFS but not OS were improved with addition of PCV. Beyond 2 years, OS advantage, and
decreased risk of death by 48%
• RTOG 04-24 (Ongoing)
• Phase II. High risk LGG (at least 3 risk factors: age >=40, tumor diameter >=6cm, tumor crossing midline,
astrocytoma subtype, pre-op neurologic deficit). RT + Temozolomide. Comparison will be to historical
EORTC patient population
Observation
• RTOG 98-02 (1998-2002) -- RT +/- PCV
• Randomized arm + observation arm. (see above). 362 patients, WHO Grade II supratentorial astrocytoma,
oligoastrocytoma, or oligodendroglioma. Low risk LGG (age <40 and GTR; 111 patients): Observation only
• 2006 ASCO Abstract 1500 [1] (slides + video) — "Initial report of Radiation Therapy Oncology Group
(RTOG) 9802: Prospective studies in adult low-grade glioma (LGG)." Shaw EG et al. Journal of Clinical
Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006:
1500. Median F/U 4 years
• Outcome: Low risk 5-year OS 94%; PFS 50%
• Conclusion: Poor 5-year PFS
Optic Pathway Glioma

• Please see the → Optic Pathway Glioma chapter
References
[1] http:/ / www. asco. org/ portal/ site/ ASCO/ menuitem. 34d60f5624ba07fd506fe310ee37a01d/
?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD& vmview=abst_detail_view& confID=40& abstractID=30611
[2] http:/ / www. asco. org/ ASCO/ Abstracts+ & + Virtual+ Meeting/ Abstracts?& vmview=abst_detail_view& confID=55& abstractID=32096
Radiation Oncology/CNS/Anaplastic glioma

Anaplastic Glioma (WHO Grade III)
Overview
• Includes anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), and anaplastic oligoastrocytoma
(AOA)
• Management typically follows that of WHO Grade IV glioblastoma, particularly for anaplastic astrocytoma.
However, several trials are specific to WHO Grade III histologies, particularly AO and AOA
Prognosis
• RTOG RPA; 1993 (1974-1989) - PMID 8478956 — "Recursive partitioning analysis of prognostic factors in
three Radiation Therapy Oncology Group malignant glioma trials." Curran WJ et al. J Natl Cancer Inst. 1993 May
5;85(9):704-10.
• Analysis of RTOG 74-01 / ECOG 1374, RTOG 79-18, and RTOG 83-02. 1578 pts included.
RPA Stages For Anaplastic Astrocytoma WHO Grade III (No TMZ)
Stage Characteristics Median Survival 1-year OS 2-year OS
(mo)
I Age <50, normal MS 59 90% 76%
II Age >=50, KPS >=70, Symptoms >3 mo 37 85% 68%
III Age <50, abnormal MS 18 70% 35%
IV Age>=50, KPS>=70, Symptoms <=3 11 45% 15%

mo
V Age>=50, KPS<70 and normal MS 9 30% 6%
VI Age >=50, KPS <70, abnormal MS 5 20% 4%
Adjuvant RT vs. Chemotherapy

• NOA-04 (Germany)(1999-2005) -- RT 54-60 Gy vs. PCV vs. temozolomide
• Randomized. 318 patients, supratentorial WHO Grade III glioma. Arm 1) RT 54-60 Gy in 6 weeks vs. Arm 2)
CCN 110 mg/m2, vincristine 2 mg, procarbazine 60 mg/m2 x4 cycles vs. Arm 3) Temozolomide 200 mg/m2
x8 cycles. Primary endpoint time-to-failure
• 2008 ASCO Abstract [1] -- "Randomized phase III study of sequential radiochemotherapy of oligoastrocytic
tumors of WHO-grade III with PCV or temozolomide: NOA-04." (Wick Wolfgang W. J Clin Oncol 26: 2008
(May 20 suppl; abstr LBA2007))
• Outcome: median TTF RT 3.6 years vs. PCV/Temodar 3.6 years (NS), median OS 5+ years vs. 5+ years
(NS)
• Predictors: oligo component (oligodendroglioma or oligoastrocytoma), LOH 1p/19q , MGMT+
• Toxicity: Grade 3-4 hematologic significantly higher for PCV than temozolomide
• Conclusion: No difference in TTF between RT and chemotherapy (PCV or temozolomide)
Adjuvant RT +/- Chemotherapy

• EORTC 26951 (1996-2002) -- RT +/- adjuvant PCV
• Randomized. 368 patients. AO and AOA (>25% oligodendroglial elements). Median age 49. Surgery followed
by RT within 6 weeks 59.4/33, then Arm 1) observation vs. Arm 2) PCV (procarbazine 60, lomustine 110,
vincristine 1.4) x6 cycles. Adjuvant PCV discontinued in 38%; 80% of RT arm received chemo at progression.
RT PTV1 = T2 + 2.5cm to 45/25, then PTV2 = T1 + 1.5cm to 59.4/33. Primary endpoint OS
• 5-years; 2006 PMID 16782911 — "Adjuvant procarbazine, lomustine, and vincristine improves
progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and
oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III
trial." (Van den Bent MJ et al. J Clin Oncol. 2006 Jun 20;24(18):2715-22.). Median F/U 5 years
• Outcome: median OS RT+PCV 3.4 years vs RT 2.6 years (NS); PFS: 1.9 years vs 1.1 years (SS)
• 1p/19q Analysis: Combined deletion in 25%; 5-year OS 74%; 5-year OS RT+PCV 74% vs. RT 75% (NS);
PFS 69% vs. 50% (NS). Comparison of 5-year OS 1p/19q deleted 74% vs. 1p/19qWT ~30%
• Conclusion: Adjuvant PCV does not prolong OS, but improves PFS. Patients with 1p/19q deletion have
significantly better outcome, though not impacted by addition of PCV
• QoL; 2007 PMID 18089866 -- "Health-related quality of life in patients treated for anaplastic
oligodendroglioma with adjuvant chemotherapy: results of a European Organisation for Research and
Treatment of Cancer randomized clinical trial." (Taphoorn MJ, J Clin Oncol. 2007 Dec 20;25(36):5723-30.)
• Health-related QoL assessed, baseline 78% patients, at 2.5 years post treatment 55%
• Outcome: baseline: considerable impairment in both groups. PCV group worse appetite, drowsiness, N/V
during and shortly after chemo. No long-term difference
• Conclusion: No long term difference in QoL after PCV
• RTOG 9402 / INT 0149 (1994-2002) -- Sequential PCV -> RT vs. RT alone
• Randomized. 289 patients with supratentorial AO and AOA (>25% oligodendroglioma component), KPS
>=60. Randomized to PCV x4 cycles prior to RT vs RT alone after maximal surgical resection. Arm 1) PCV
(procarbazine, CCNU, vincristine) x4 cycles followed by RT vs. Arm 2) RT alone. RT given 59.4/33/ PTV1 =
T2 + 2cm, PTV2 = T1 + 1cm
• 2006 PMID 16782910 — "Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone
for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402."
(Cairncross G, J Clin Oncol. 2006 Jun 20;24(18):2707-14.) Median F/U 5.1 years
• Outcome: Median OS PCV->RT 4.9 years vs. RT 4.7 years (NS). PFS 2.6 years vs. 1.7 years (SS).
• Toxicity: Grade 3-4 induction PCV 65%, RT after PCV 8% vs. RT alone 5%
• Chromosomes: LOH 1p/19q combined in 46%, AO 57% vs. AOA 14% (SS). Lower risk of tumor
progression PFS 4.0 v 1.3 years(SS), and median OS not-reached vs. 2.8 years (SS). No effect of treatment
on survival
• Conclusion: No impact on survival. Improved PFS but at significant toxicity cost. Patients with 1p/19q
deletion have significantly improved outcome
• EORTC 26882 (1988-2000) -- RT +/- adjuvant BCNU/DBD
• Randomized. Stopped early due to slow accrual. 193/212 patients, anaplastic astrocytoma. Two cohorts: 58
anaplastic astrocytoma patients from original EORTC 26882 cohort + 135 patients from extended accrual
focusing on AA only. Arm 1) RT alone vs. Arm 2) RT + concurrent BCNU/DBD followed by adjuvant
BCNU/DBD x1 year. RT 60/30. Primary endpoint OS.
• 2008 PMID 18248979 -- "Adjuvant dibromodulcitol and BCNU chemotherapy in anaplastic astrocytoma:
results of a randomised European Organisation for Research and Treatment of Cancer phase III study (EORTC
study 26882)." (Hildebrand J, Eur J Cancer. 2008 Jun;44(9):1210-6. Epub 2008 Jan 14.)
• Pathology: At central path review, 53% of AA cases couldn't be confirmed. AA 35%, AOA 8%, AO 2%,
GBM 25%, low grade glioma 23%, other diagnosis 7%
• Outcome: median OS RT 2.0 years vs. RT + BCNU/DBD 2.3 years (NS), no difference in PFS
• Conclusion: No benefit in OS or PFS with addition of BCNU/DBD
Proton Therapy
• Harvard; 2001 (1993-1996) PMID 11516862 -- "Dose-escalation with proton/photon irradiation for
Daumas-Duport lower-grade glioma: results of an institutional phase I/II trial." (Fitzek MM, Int J Radiat Oncol
Biol Phys. 2001 Sep 1;51(1):131-7.)
• Phase I/II. Closed early due to toxicity without meaningful benefit. 20 patients (Daumas-Duport Grade 2 in 7,
Grade 3-4 in 13). Dose 68.2 CGE in Grade 2 and 79.7 CGE in Grade 3, conventional fractionation. Median
proton dose 84% depending on cyclotron availability, photons 3D-CRT. Median age 36 years. Median
time-to-RT 2.9 months. Median F/U 5 years for alive patients
• Outcome: 5-year OS Grade 2 71%, Grade 3 23%. New gado enhancement in 16/20 patients, 14/16 had
specimen (50% radiation necrosis, some with tumor recurrence). Most recurrences in high dose area
• Conclusion: Dose escalation failed to improve outcome relative to published series; significant rate of radiation
necrosis
Other
Does more aggressive treatment negatively impact survival?
• PMID 2689399, 1989 — "Radiation Therapy Oncology Group (RTOG) survival data on anaplastic astrocytomas
of the brain: does a more aggressive form of treatment adversely impact survival?" Laramore GE et al. Int J
Radiat Oncol Biol Phys. 1989 Dec;17(6):1351-6.
• With data from several RTOG trials, compared 47 pts treated with photons alone, 78 with photons + chemo,
and 38 photons + neutron boost.
• Median survival 3.0, 2.3, and 1.7 years, with decreasing survival with more aggressive treatment.
• PMID 1659173, 1991 — "Long-term survival in treated anaplastic astrocytomas. A report of combined
RTOG/ECOG studies." Fischbach AJ et al. Am J Clin Oncol. 1991 Oct;14(5):365-70.
• Similar study as above (Laramore), looking at mostly the same trials, reaching the same conclusion.
References
[1] http:/ / www. asco. org/ ASCO/ Abstracts+ %26+ Virtual+ Meeting/ Abstracts?& vmview=abst_detail_view& confID=55&
abstractID=31187
Radiation Oncology/CNS/High grade glioma/

Overview
Glioblastoma and High Grade Gliomas Overview
Pathology
• University of Calgary, 2007 PMID 17696644 -- "The p75 Neurotrophin Receptor Is a Central Regulator of
Glioma Invasion" (Johnston AL, PLoS Biol 5(8): e212, 2007)
• Glioma mouse model. p75 neurotrophin receptror (p75NTR) identified as critical regulator of glioma invasion.
This invasion is neurotrophin dependent, resulting in cytoskeletal changes
Prognosis
• EORTC Online Nomogram [1]
• EORTC 26981 / NCIC
• For trial details please see the → adjuvant therapy page
• RTOG RPA Validation; 2006 PMID 16735709 -- Radiotherapy and temozolomide for newly diagnosed
glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized
trial. (Mirimanoff RO, J Clin Oncol. 2006 Jun 1;24(16):2563-9.)
• Evaluation of predictive power of RPA in the trial. RPA adapted to EORTC as below
• Conclusion: RPA retains its prognostic significance overall, as well as in treatment arms
Adapted RPA Stages For Malignant Gliomas (Survival With-Temozolomide)

Stage Characteristics Median OS 2-year OS p-value vs.
control
III Age <50, PS 0 21 vs. 15 mo 43% vs. p<0.0001

20%
IV Age <50, PS 1-2 16 vs. 13 mo 28% vs. p<0.01

Age >=50, Surgery, MMSE >=27 11%
V Age >=50, Biopsy only or MMSE <27 10 vs. 9 mo 17% vs. 6% p=0.05
• Nomogram; 2008 PMID 18082451 -- "Nomograms for predicting survival of patients with newly diagnosed
glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3." (Gorlia T, Lancet
Oncol. 2008 Jan;9(1):29-38. Epub 2007 Dec 21.)
• Subanalysis. 573 patients. Modeling done on 1) intent-to-treat (n=573), 2) RT + TMZ group (n=287), and
3) RT + TMZ group with MGMT status s/p resection (n=103)
• Nomograms: Developed to predict median and 2-year OS. Available at EORTC GBM Calculator [2] web
page
• Conclusion: MGMT promoter methylation status, age, performance status, extent of resection, and MMSE
are suggested as eligibility or stratification factors for future trials
• Comment (editorial): More accurate than RTOG RPA class. For patients with MGMT status, age was not
statistically significant in multivariate setting, only MGMT status, PS, and MMSE. Still considered an
exploratory analysis
• RTOG RPA; 1993 (1974-1989) - PMID 8478956 — "Recursive partitioning analysis of prognostic factors in
three Radiation Therapy Oncology Group malignant glioma trials." Curran WJ et al. J Natl Cancer Inst. 1993 May
5;85(9):704-10.
• Analysis of RTOG 74-01 / ECOG 1374, RTOG 79-18, and RTOG 83-02. 1578 pts included.
• Age <50 or >=50 was most significant determinant of survival.
RPA Stages For GBM WHO Grade IV (No TMZ)

Stage Characteristics Median Survival 1-year OS 2-year OS
(mo)
III Age <50, KPS 90-100 18 70% 35%
IV Age <50, KPS <90 or 11 45% 15%

Age >=50, surgical resection, good neurologic function
V Age >=50, KPS >=70, surgical resection, unable to work or 9 30% 6%

Age >= 50, KPS >= 70, biopsy only and RT dose > 54.4 or
Age >=50, KPS <70 and normal MS
VI Age >=50, KPS >=70, biopsy only and RT dose <=54.4 Gy 5 20% 4%
or
Age >=50, KPS <70, abnormal MS
• Abstract update of this study combined groups 5&6 into a single risk group.
• RTOG Validation; 1998 PMID 9422557 -- "Validation and predictive power of Radiation Therapy Oncology
Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG
90-06." (Scott CB, Int J Radiat Oncol Biol Phys. 1998 Jan 1;40(1):51-5.)
• Validation of RPA classification using new dataset (RTOG 90-06)
• Outcome: Median OS and 2-year OS within 95% confidence interval; all classes but Class II statistically
distinct (p<0.0001)
• Conclusion: Validation of RPA classes, useful as historical controls for future Phase II trials
Biologic markers for prognosis

• Duke; 2005 PMID 16282174 -- "Glioblastoma multiforme and the epidermal growth factor receptor." (Friedman
HS, N Engl J Med. 2005 Nov 10;353(19):1997-9.)
• EGFR gene amplification
• EGFR gene mutations (most common is EGFRvIII, a constitutively active mutated form)
• Loss of PTEN tumor suppressor
• Overexpression of PDGFR α
• Mutated p53
• Loss of heterozygosity for chromosomes 1p and 19q, first identified in anaplastic oligodendrogliomas.
• MGMT repair gene
MGMT
• O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme depleted by daily treatment with
temozolomide.
• The MGMT gene on chromosome 10q26. The gene product removes alkyl groups from the O6 position of
guanine, an important site of DNA methylation by DNA alkylating agents. *High levels of MGMT in tumors
create resistance to this type of chemotherapy.
• Low levels of MGMT in tumor is associated with longer survival in patients with GBM receiving
nitrosourea-based chemotherapy.
• Silencing of the MGMT gene by methylation of its promoter is associated with better survival.
• EORTC / NCI Canada; 2005 - PMID 15758010 — "MGMT Gene Silencing and Benefit from Temozolomide in
Glioblastoma." Hegi ME et al. NEJM 352:997-1003, 2005.
• Analyzed MGMT methylation in pts from the EORTC / NCI Canada trial. 206 pts could be analyzed. 44% had
detectable MGMT promoter methylation by PCR. There is a 55% decrease (HR 0.45) in death in the
methylated group. Median survival 18.2 months vs 12.2 months. There was a benefit to RT+Temodar vs RT
alone for the methylated group (HR=0.51) but there was only a trend for the unmethylated group. 2-year OS
for methylated was 46% (RT+Temodar), 23% (RT alone); for non-methylated 13.8% and 2%. Median survival
for methylated was 21.7 m (RT+Temodar), ? (RT); for non-methylated, 12.7 m (RT+T), 11.8 m (RT).
• For methylated, (RT+Temodar) 2-year OS 46% , 23% (RT alone)
• Conclusion: Most of the benefit of Temodar is in the subgroup of patients with a methylated MGMT promoter.
Cancer biology
Radiobiology:
• Birmingham, 2007 (UK) PMID 17324531 -- "Estimation of radiobiologic parameters and equivalent radiation
dose of cytotoxic chemotherapy in malignant glioma." (Jones B, Int J Radiat Oncol Biol Phys. 2007 Jun
1;68(2):441-8.)
• Median tumor a/b 9.3; median cellular doubling time 39.5 days
• Temozolomide: median equivalent BED 11 Gy (9.1 Gy in 2 Gy/fx)
Radioresistance:
• Duke, 2006 - PMID 17051156 — "Glioma stem cells promote radioresistance by preferential activation of the
DNA damage response." Bao S et al. Nature. 2006 Dec 7;444(7120):756-60.
Treatment overview
• Surgery is the primary treatment modality. Patients who are not surgical candidates and have only diagnostic
biopsy have extremely poor outcomes
• Post-op EBRT is standard therapy
• Dose to 60 Gy in 30 fractions (dose intensification via escalation and fractionation not successful so far)
• For patients >60, RT 40/15 appears comparable to 60/30
• For patients >70 and KPS >=70, RT 50/28 GY provides modest survival benefit (median 29 weeks vs. 17
weeks) without reducing QOL or cognition over supportive care only
• For patients >70 and poor KPS, supportive care alone may be reasonable
• Addition of temozolomide to post-op RT is now effectively the standard of care
Surgery
Review
• Singapore, 2007 PMID 17549284 -- "The Role of Surgery in High-grade Glioma - Is Surgical Resection
Justified? A Review of the Current Knowledge." (Pang BC, Ann Acad Med Singapore. 2007 May;36(5):358-6.)
References
[1] http:/ / www. eortc. be/ tools/ gbmcalculator/
[2] http:/ / www. eortc. be/ tools/ gbmcalculator

Adjuvant therapy
High Grade Gliomas Adjuvant Therapy
Radiation
RT vs. supportive care

• BTCG 69-01 and 1981 SGSG study demonstrated significant (doubled) survival with RT over supportive care,
and resulted in RT becoming a standard component of treatment
• 2002 Review PMID 12242114 -- "Radiotherapy for newly diagnosed malignant glioma in adults: a systematic
review." (Laperriere N, Radiother Oncol. 2002 Sep;64(3):259-73.)
• Pooling of 6 randomized trials: significant survival benefit to post-op RT over supportive care (RR for 1-year
mortality 0.81)
• SGSG, 1981 -- "Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the
value of postoperative irradiation and lack of potentiation of bleomycin on survival time: a prospective
multicenter trial of the Scandinavian Glioblastoma Study Group." (Kristiansen K, Cancer. 1981 Feb
15;47(4):649-52.)
• Randomized. 118 patients Grade III/IV randomized post-op to 1) 45 Gy WBRT + bleomycin, 2) 45 Gy
WBRT, 3) support care
• Median OS: 10.8 mo vs. 10.8 mo vs. 5.2 mo (SS)
• Conclusion: RT dramatically better than supportive treatment. No effect of bleomycin
• BTSG 69-01 -- BCNU vs RT vs RT + BCNU vs Observation
• Randomized, 4 arms. 303 patients, anaplastic gliomas, treated with surgery and steroids. Arm 1) BCNU alone,
Arm 2) RT alone, Arm 3) RT + BCNU, Arm 4) best supportive care. BCNU was given on days 1-3 q6-8 wks.
RT was 50-60 Gy to whole brain.
• 1978 PMID 355604 — "Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A
cooperative clinical trial." (Walker MD, J Neurosurg. 1978 Sep;49(3):333-43.)
• Outcome: median OS OBS 3.2 months vs. BCNU 4.2 months vs. RT 8.1 months vs. RT + BCNU 8.0
months (SS)
• Toxicity: Acceptable thrombocytopenia and leukopenia
• Note: This trial established first evidence for post-op RT over supportive management
In the Elderly:
• France (Association of French-Speaking Neuro-Oncologists), 2007 (2001-2005) - PMID 17632898 --
"Radiotherapy for Glioblastoma in the Elderly." Keime-Guibert F et al. New Engl J Med. 2007 Apr
12;356(15):1527-1535.
• Randomized. Surgery and randomized to RT or supportive care.
• 85 pts. Pts age 70 or older, GBM or AA, KPS >=70. Surgery was biopsy only in 50%. Supportive care
included steroids and antiepileptics. RT was 50 Gy at 180 cGy/fx to CTV (enhancing tumor + 2 cm). Trial
discontinued after interim analysis.
• Median f/u 21 wks. 90% of pts were dead by 21 wks. 53% reduction in death for pts in RT group; MS
benefit of 12 wks (29.1 vs 16.9 wks). PFS 14.9 wks vs 5.4 wks. No significant difference in quality of life
or neuropsychiatric measures between groups; both parameters declined over time.
• Conclusion: RT in elderly pts results in modest improvement in survival without adversely affecting QOL.
WBRT vs. Limited-Volume RT

• Currently using regional fields (RTOG description):
• First 46 Gy/23 fxs: the treatment volume should include the volume of contrast enhancing lesion and
surrounding edema on pre-operative CT/MRI scan plus a 2 centimeter margin. If no edema is present, the
margin should be 2.5 cm.
• Boost 14 Gy/7 fxs: the tumor volume should include the contrast enhancing lesion (without edema) on the
pre-surgery MRI/CT scan plus a 2.5 centimeter margin.
• Comparable outcomes to WBRT
• 80-90% recurrence is local (within 2cm of enhancing tumor on CT)
• avoidance of neurotoxicity associated with WBRT
• WBRT may be recommended for multifocal disease, but it is rare, and failure typically within original disease
• MD Anderson, 1991 - PMID 1851573 -- Outcome and patterns of failure following limited-volume irradiation
for malignant astrocytomas. (Garden AS, Radiother Oncol. 1991 Feb;20(2):99-110.)
• Retrospective. 60 patients with GBM (39) or AA (21) treated between 1982-1986.
• RT: 53 treated with limited-volume, 7 WBRT
• Same results limited-volume and WBRT
• BTCG 80-01, 1989 - PMID 2661738 -- Randomized trial of three chemotherapy regimens and two radiotherapy
regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor
Cooperative Group Trial 8001. (Shapiro WR, J Neurosurg. 1989 Jul;71(1):1-9.)
• Randomized. 571 patients to 3 chemo regiments.
• RT patients accrued 1982-1983: WBRT 60.2 Gy
• RT patients accrued 1982-1983: randomized to WBRT 60.2 Gy or WBRT 43 Gy + 17.2 Gy cone-down boost
• Conclusion: no difference in survival. WBRT + boost as effective as WBRT
Margins
• Tubingen (Germany), 1994 - PMID 8184112 -- Malignant glioma: patterns of failure following individually
tailored limited volume irradiation. (Hess CF, Radiother Oncol. 1994 Feb;30(2):146-9.)
• Retrospective. 66 patients. RT: 60 Gy, with CTV = GTV + 2cm
• 86% recurrences in treated volume
• Conclusion: Limited fields appropriate
• Duke, 1989 - PMID 2557310 -- Radiation therapy treatment planning in supratentorial glioblastoma multiforme:
an analysis based on post-mortem topographic anatomy with CT correlations. (Halperin EC, Int J Radiat Oncol
Biol Phys. 1989 Dec;17(6):1347-50.)
• 15 patients with GBM, compared biopsy with CT scans, and treatment fields
• In 9/11 cases, contrast enhancing area + 1cm margin would have missed tumor
• In 5/11 cases, contrast enhancing area + edema + 1cm margin would have missed tumor
• Need contrast enhancing area + edema + 3cm margin to cover tumor (based on the 11 patients)
• Tumor tracked along nerve pathways, and frequently crossed corpus callosum
• MSKCC, 1989 - PMID 2542195 -- Patterns of failure following treatment for glioblastoma multiforme and
anaplastic astrocytoma. (Wallner KE, Int J Radiat Oncol Biol Phys. 1989 Jun;16(6):1405-9.)
• Retrospective. 34 CT scans reviewed (GBM 25, AA 9); treated 1983-1987
• Recurrence: 78% within 2.0 cm of presurgical tumor margin, defined as enhancing edge of tumor on CT. Only
1/34 (initially near midline) recurred in contralateral hemisphere
• Conclusion: partial brain irradiation appropriate
• PMID 3033172 -- Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. (Kelly PJ,
J Neurosurg. 1987 Jun;66(6):865-74.)
• 40 patients with untreated glial neoplasms, serial bx (195 biopsy specimens) with CT and MRI
• contrast enhancement most often corresponded to tumor tissue without intervening parenchyma
• hypodensity corresponded to parenchyma infiltrated by isolated tumor cells or in some instances to tumor
tissue in low-grade gliomas or to simple edema
• isolated tumor cell infiltration extended at least as far as T2 prolongation on magnetic resonance images.
• PMID 6252514 -- Assumptions in the radiotherapy of glioblastoma. (Hochberg FH, Neurology. 1980
Sep;30(9):907-11.)
• 35 CT scans evaluated and compared with autopsies
• Gross and microscopic tumor extent (within 2-cm margin) defined in 29/35 patients. 4 missed due to
subependymal spread
• Multicentricity in only 4% untreated and 6% treated patients, and all lesions identified on CT
• Recurrence within 2-cm margin in 90%. External recurrences identified on CT
CT/MRI fusion
• Michigan, 1992 - PMID 1429103 -- The clinical utility of magnetic resonance imaging in 3-dimensional
treatment planning of brain neoplasms. (Thornton AF, Int J Radiat Oncol Biol Phys. 1992;24(4):767-75.)
• MRI T1 comparable to CT tumor volume; MRI T2 comparable to CT edema
• Need to look at both modalities: 43% of fused volume seen on both studies; 37% seen only on MRI, 21% seen
only on CT
Dose Determination
• Current recommendation is 60 Gy in 30 fractions
• For patients >60, can consider 40 Gy in 15 fractions (or 45 Gy in 15 fractions, as is more common in the U.S.)
• Cross Cancer Inst (Canada), 2004 - PMID 15051755 -- Abbreviated course of radiation therapy in older
patients with glioblastoma multiforme: a prospective randomized clinical trial. (Roa W, J Clin Oncol. 2004 May
1;22(9):1583-8.)
• Randomized. 100 patients >60 years to 1) RT 60/30 over 6 weeks, or 2) 40/15 to PTV1 over 3 weeks. Standard
RTOG fields
• Median OS: 5.1 mo vs. 5.6 months (NS). Fewer patients on 40/15 required corticosteroids
• Conclusion: reasonable treatment option for older patients
• RTOG 98-03, 1998-2003 ASTRO Abstract [1] -- Phase I/II Conformal Three-Dimensional Radiation Therapy
Dose Escalation Study in Patients with Supratentorial Glioblastoma Multiforme: Report of the Radiation Therapy
Oncology Group 98-03 Protocol. (Werner-Wasik, ASTRO 2004, Abstract 2769)
• Phase I/II. 209 patients, entered to 3D-CRT dose escalation 66 Gy, 72 Gy, 78 Gy or 84 Gy. Stratified by tumor
volume. Also looking at effect of omitting treatment to edema volume
• RT PTV1: GTV + 15mm + 3mm to 46 Gy in 2 Gy/fx
• RT PTV2: GTV + 3mm boost to 66 Gy, 72 Gy, 78 Gy or 84 Gy in 2 Gy/fx
• Conclusion: Dose escalation feasible, no DLT so far.
• Michigan 2002 - PMID 11896114 -- Survival and failure patterns of high-grade gliomas after three-dimensional
conformal radiotherapy. (Chan JL, J Clin Oncol. 2002 Mar 15;20(6):1635-42.)
• Retrospective. 34 patients treated to 90 Gy using 3D-CRT. Median f/u 11.7 months
• Recurrence: 78% central, 13% in-field, 9% marginal, 0% distal. Median OS 11.7 months, 1-year OS 47%,
2-year OS 13%
• Conclusion: continued local failure
• MRC BR2,1991 - PMID 1654987 -- A Medical Research Council trial of two radiotherapy doses in the treatment
of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party. (Bleehen NM, Br J
Cancer. 1991 Oct;64(4):769-74.)
• Randomized. 474 patients to post-op 45 Gy in 20 fx vs. 60 Gy in 30 fxs using 1:2 randomization
• RT Arm 1: 45 Gy/20 fx to all known and potential tumor volume (focal fields)
• RT Arm 2: 40 Gy/20 fx as Arm 1 + 20 Gy/10 fx to GTV + 1 cm
• Median OS: 9 mo vs. 12 mo (SS); no additional acute RT toxicity
• RTOG 74-01 / ECOG 1374, 1988 - PMID 3281031, — "Combined modality approach to treatment of malignant
gliomas--re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation
Therapy Oncology Group and the Eastern Cooperative Oncology Group." (Nelson DF et al. NCI Monogr.
1988;(6):279-84.)
• Randomized. High grade glioma. 1) 60 Gy whole brain vs 2)60 Gy + 10 Gy boost vs 3)60 Gy + BCNU vs 4)60
Gy + CCNU + DTIC
• Median OS: 60 Gy WBRT 9.3 months vs. 60 Gy WBRT + 10 Gy boost 8.2 months (NS)
• BTSG PMID 231022 -- An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. (Walker
MD, Int J Radiat Oncol Biol Phys. 1979 Oct;5(10):1725-31.)
• Median OS: no RT 18 weeks vs. 50 Gy 28 weeks vs. 55 Gy 36 weeks vs. 60 Gy 42 weeks
• MRC Meta-analysis, 2002: PMID 11937180 — "Chemotherapy in adult high-grade glioma: a systematic review
and meta-analysis of individual patient data from 12 randomised trials." Stewart LA. Lancet. 2002 Mar
23;359(9311):1011-8.
• Meta-analysis, 12 trials, 3004 pts. Looking primarily at chemo, but some RT analysis
• Trials with RT 60 Gy vs. RT <60 Gy: HR 0.88 vs. HR 0.77 (p=0.1). No difference.
See further discussion in Chemotherapy section
Hyperfractionation
• RTOG 94-11, 1994-1995 - PMID 11121633 -- Phase II, two-arm RTOG trial (94-11) of
bischloroethyl-nitrosourea plus accelerated hyperfractionated radiotherapy (64.0 or 70.4 Gy) based on tumor
volume (> 20 or < or = 20 cm(2), respectively) in the treatment of newly-diagnosed radiosurgery-ineligible
glioblastoma multiforme patients. (Coughlin C, Int J Radiat Oncol Biol Phys. 2000 Dec 1;48(5):1351-8.)
• Phase II. 108 patients from 26 institutions. Patients assigned to RT arm based on tumor mass (20 cm3), +
BCNU
• RT: Arm A (>20 cm3): 64 Gy given 1.6 Gy/fx BID (BED comparable to 60/20) vs. Arm B (<20 cm3): 70.4 Gy
given 1.6 Gy/fx BID
• Overall MS: 9.1 mo and 11.0. Comparable with prior RTOG data. Toxicities tolerable.
• Conclusion: shorter RT time with comparable outcome
• RTOG 90-06, 1996 - No PMID, No survival benefit of hyperfractionated radiotherapy (RT) to 72 Gy and
carmustine versus standard RT and carmustine for malignant glioma patients: Preliminary results of RTOG
90-06 (Curran WJ, Proc Am Soc Clin Oncol. 1996. 15:154 Abstract)
• Randomized to 72 Gy in 1.2 Gy/fx BID + carmustine vs. standard RT + carmustine
• No difference
• Patients <50 years old had decreased survival with HF RT compared with standard RT; it is speculated they
lived longer to suffer from the increased treatment toxicity
• RTOG 83-02 (1983-89)
• Phase I/II. AA + GBM. Dose-escalation of hyperfractionated RT or accelerated HF RT with BCNU.
• 786 pts. HF (1.2 Gy BID to 64.8, 72, 76.8, or 81.6 Gy) or AHF (1.6 Gy twice daily to doses of 48 or 54.4 Gy).
All received BCNU.
• PMID 8608540, 1996 — "Final report of a phase I/II trial of hyperfractionated and accelerated
hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas.
Radiation Therapy Oncology Group Study 83-02." Werner-Wasik M et al. Cancer. 1996 Apr
15;77(8):1535-43.
• Mean OS 9.6 - 11 months for GBM. No difference in survival according to assigned dose.
• For AA pts, better survival with lower HF doses (64.8 - 72). For GBM, better survival with higher HF doses
(78.6 - 81.6).
• PMID 1451073, 1992 — "A randomized trial of accelerated hyperfractionated radiation therapy and
bis-chloroethyl nitrosourea for malignant glioma. A preliminary report of Radiation Therapy Oncology Group
83-02." Curran WJ Jr et al. Cancer. 1992 Dec 15;70(12):2909-17.
• PMID 8380567, 1993 — "Hyperfractionated radiation therapy and bis-chlorethyl nitrosourea in the treatment
of malignant glioma--possible advantage observed at 72.0 Gy in 1.2 Gy B.I.D. fractions: report of the
Radiation Therapy Oncology Group Protocol 8302." Nelson DF et al. Int J Radiat Oncol Biol Phys. 1993 Jan
15;25(2):193-207.
• Comment: led to 72 Gy being used in RTOG 90-06. Led to further dose escalation using AHF in 94-11.
• BTCG 77-02, 1989 (1978-80) - PMID 2542193 — "Results of a randomized trial comparing BCNU plus
radiotherapy, streptozotocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following
misonidazole plus radiotherapy in the postoperative treatment of malignant glioma." Deutsch M et al. Int J Radiat
Oncol Biol Phys. 1989 Jun;16(6):1389-96.
• 603 pts. All pts had surgery. RT was whole brain (60 Gy in 30-35 fx except arm 3). Arm 1: RT+BCNU IV x 3
days, repeat q8wk. Arm 2: RT+strep IV q week x 6 weeks then 2 week rest, repeat q8w. Arm 3:
HF-RT+BCNU. 1.1 Gy BID x 60 fx = 66 Gy. Arm 4: RT+miso then BCNU. Miso 2x/week 4-6 hr before RT.
After RT, BCNU q8weeks.
• Conclusion: No difference in survival among groups. (60/30 vs. 66/60 1.2 Gy BID)
Short course palliative RT

May be considered as palliation for poor prognosis patients
45 Gy in 15 fractions WB:OR
3 Gy x 17 = 51 Gy
• Johns Hopkins (1975-93) - PMID 9212001, 1997 — "Short course radiotherapy is an appropriate option for
most malignant glioma patients." (Kleinberg L, Int J Radiat Oncol Biol Phys. 1997 Apr 1;38(1):31-6.)
• Retrospective. 219 pts with GBM or AA treated: 3 Gy x 10 initially to large field (often whole brain), 2 week
break, followed by 3 Gy x 7 conedown boost, total of 51 Gy over 5.5 weeks. Chemotherapy in 29%
(nitrosourea).
• Median survival by RTOG RPA class: I - 68 m, II - 57 m, III - 22 m, IV - 13 m, V - 8 m, VI - 5 m. For each
RPA group, similar survival as in pts treated aggressively on prior RTOG studies.
• Conclusion: The short regimen is an appropriate treatment option for most malignant glioma patients. Do not
recommend this treatment for favorable prognosis pts (RPA class 1-3) because only few pts from those groups
included (21%).
3 Gy x 10 = 30 Gy
• Canada - PMID 8040031, 1994 — "A prospective study of short-course radiotherapy in poor prognosis
glioblastoma multiforme." (Bauman GS, Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):835-9.)
• 29 pts, GBM, with age >= 65 or KPS <= 50
• Tumor stable or improved in 60% of pts at 1 month evaluation. Median survival 6 months. (Historical results
for similar patients treated with full dose RT: 10 months; supportive care only: 1 month). Survival advantage
for full dose RT for pts with KPS > 50.
• Conclusion: Elderly pts with a low pretreatment KPS <= 50 may be treated adequately with short, palliative
RT
Radiosurgery
• RTOG 93-05
• 203 pts. GBM. All pts had surgery. Randomized to postoperative 1) SRS followed by EBRT 60 Gy + BCNU
(q8w x 6), or 2) EBRT + BCNU, no SRS. SRS dose 16-24 Gy, based on size.
• 2004, PMID 15465203 — "Randomized comparison of stereotactic radiosurgery followed by conventional
radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma
multiforme: report of Radiation Therapy Oncology Group 93-05 protocol." Souhami L et al. Int J Radiat Oncol
Biol Phys. 2004 Nov 1;60(3):853-60.
• Median f/u 5 yrs. MS 13.5 m (SRS) vs 13.6 m
• Conclusion: no difference in survival
Reviews:
• ASTRO review, 2005 - PMID 16111571 — "The American Society for Therapeutic Radiology and Oncology
(ASTRO) evidence-based review of the role of radiosurgery for malignant glioma." Tsao MN et al. Int J Radiat
Oncol Biol Phys. 2005 Sep 1;63(1):47-55.
• Conclusion: "For patients with malignant glioma, there is Level I-III (I=randomized trial, II=controlled trial,
III=opinion) evidence that the use of radiosurgery boost followed by external beam radiotherapy and BCNU
does not confer benefit in terms of overall survival, local brain control, or quality of life as compared with
external beam radiotherapy and BCNU. The use of radiosurgery boost is associated with increased toxicity.
For patients with malignant glioma, there is insufficient evidence regarding the benefits/harms of using
radiosurgery at the time of progression or recurrence. There is also insufficient evidence regarding the
benefits/harms in the use of stereotactic fractionated radiation therapy for patients with newly diagnosed or
progressive/recurrent malignant glioma."
Proton Therapy
• Harvard
• 1999 PMID 10433313 -- "Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for
glioblastoma multiforme: results of a phase II prospective trial." (Fitzek MM, J Neurosurg. 1999
Aug;91(2):251-60.)
• Phase II. 23 patients, GBM, residual <60 ml, KPS >=70. Dose escalation with mixed photon/proton beam to
90 CGE
• Outcome: 2-year OS 34%, median OS 20 months which was 5-11 months higher than historical
RTOG/MRC control. Tumor regrowth in areas of 60-70 Gy; only 1 recurrence in 90 Gy volume
• Conclusion: Dose of 90 CGE prevented central recurrence in almost all cases
• 1992 PMID 1310962 -- "Comparative treatment planning: proton vs. x-ray beams against glioblastoma
multiforme." (Tatsuzaki H, Int J Radiat Oncol Biol Phys. 1992;22(2):265-73.)
• Treatment planning. 90 CGE dose. 3D-CRT vs proton comparison
• Outcome: Protons less non-target brain than photon, especially in deep-seated structures. V70 was 175 ml
for photon vs 94 ml for proton plans
• Conclusion: For subpopulation of patients, 90 CGE could be delivered
• 1990 (1973-1987) PMID 2165739 -- "Fractionated proton radiation therapy of cranial and intracranial tumors."
(Austin-Seymour M, Am J Clin Oncol. 1990 Aug;13(4):327-30.)
• Retrospective. 144 patients (chordoma/chondrosarcoma 110, meningioma 13, craniopharyngioma 12,
glioma 9). Glioma were intermediate/high grade. Median dose >71 CGE (62.8-79.4)
• Outcome: No patient with high grade glioma survived
• Conclusion: Moderate dose proton therapy doesn't make a meaningful contribution to management of high
grade glioma
Carbon Ion Therapy

• Chiba; 2007 (1994-2002) PMID 17459607 -- "Phase I/II clinical trial of carbon ion radiotherapy for malignant
gliomas: combined X-ray radiotherapy, chemotherapy, and carbon ion radiotherapy." (Mizoe JE, Int J Radiat
Oncol Biol Phys. 2007 Oct 1;69(2):390-6. Epub 2007 Apr 24.)
• Phase I/II. 48 patients, malignant glioma (AA 16, GBM 32). Photons 50/25 + carbon ion dose escalation 16.8/8
-> 18.4/8 -> 20/8 -> 22.4/8 -> 24.8/8 GyE. Chemotherapy ACNU
• Outcome: median OS GBM: low dose 7 months vs. intermediate dose 19 months vs. high dose 26 months.
Median OS AA: 15 months vs. 35 months vs. 56 months
• Toxicity: No Grade 3+, Grade 2 clinical 8%, Grade 2 radiographic 8%
• Conclusion: Combined therapy shows potential efficacy; improved survival with higher carbon dose
Treatment toxicity
Please see the Brain Treatment Toxicity section
Chemotherapy
• RT/Temozolomide: 2-year OS benefit 26.5% vs 10.4%, median surival +2 months
• RT/other chemo: 2-year OS benefit: 20% vs. 15%, median survival +2 months (12-trial meta-analysis)
• MRC Meta-analysis, 2002: PMID 11937180 — "Chemotherapy in adult high-grade glioma: a systematic review
and meta-analysis of individual patient data from 12 randomised trials." Stewart LA. Lancet. 2002 Mar
23;359(9311):1011-8.
• Meta-analysis, 12 trials, 3004 pts.
• 15% decrease in risk of death. 1-year survival increase of 6% and 2 month increase in median survival.
See further discussion in Dose determination section
• 1993: PMID 8453582 — "Meta-analysis of radiation therapy with and without adjuvant chemotherapy for
malignant gliomas in adults." Fine HA et al. Cancer. 1993 Apr 15;71(8):2585-97.
• Meta-analysis, 16 trials, 3000 pts. Compared radiation alone vs radiation + chemo for high-grade astrocytomas
and GBM.
• Increase in survival of 10% at 1 year, 8.6% at 2 yrs. Survival benefit is earlier for AA than for GBM.
Temozolomide
• An oral alkylating agent.
• Standard of care as concurrent chemotherapy with conventional RT
• Neoadjuvant TMZ does not appear to be beneficial
• Largest benefit for TMZ is in patients with low MGMT expression, but since there is nothing else to give patients
with high MGMT expression, they are also treated with TMZ
• Marseille, 2007 PMID 17442989 -- "Correlation between O6-methylguanine-DNA methyltransferase and
survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide." (Chinot
OL, J Clin Oncol. 2007 Apr 20;25(12):1470-5.)
• Phase II. 29 patients. Induction dose-dense TMZ (7-days on/7-days off) x4 cycles, then conventional RT.
• Outcome: Median PFS 4 months, median OS 6.1 months.
• Stratified by MGMT: PFS low expression 5.5 months vs. high expression 1.9 months (SS); OS 16 months vs. 5
months (SS)
• Toxicity (Grade 3-4): thrombocytopenia 20%, neutropenia 17%
• Conclusion: Induction dose-dense TMZ inferior to standard concomitant RT + TMZ
• Greece (2000-2002) -- RT vs. RT + TMZ
• Randomized, Phase II. 130 patients with GBM, KPS >=60. Surgery. Arm 1) RT 60/30 vs. Arm 3) Same RT +
concurrent TMZ 75 mg/m2 1 hour prior to RT, then adjuvant TMZ 150 mg/m2 x6 cycles. RT CTV1=T2 + 2
cm margin to 46/23, CTV2=T1 + 2.5 cm margin to 60/30
• 2005 PMID 15800329 -- "Randomized phase II study of temozolomide and radiotherapy compared with
radiotherapy alone in newly diagnosed glioblastoma multiforme." (Athanassiou H, J Clin Oncol. 2005 Apr
1;23(10):2372-7.)
• Outcome: Median TTP RT 5.2 months vs. RT + TMZ 10.8 months (SS); 1-year PFS 37% vs. 8% (SS).
Median OS 8 months vs. 13 months (SS); 1-year OS 16% vs. 56% (SS)
• Toxicity: Grade 3+4 leukopenia 3%, thrombocytopenia 5%. One death from sepsis
• Conclusion: TMZ combined with RT more effective than RT alone
• EORTC / NCIC 26981-22981/CE.3 (2000-2002) -- RT vs. RT + TMZ

• Randomized. 573 patients with GBM, s/p biopsy or surgery (GTR 40%). Arm 1) RT alone vs Arm 2) RT with
concurrent daily temozolomide (T) 7 days/wk followed by six cycles of adjuvant T given 5 days monthly. RT
given 60/30, CTV = GTV + 2-3 cm margin. Temozolomide dose was 75 mg/m2 concurrent and 150-200
mg/m2 adjuvant.
• 2-years; 2005 PMID 15758009 — "Radiotherapy plus Concomitant and Adjuvant Temozolomide for
Glioblastoma." (Stupp R, New Engl J Med 352(10):987-996, 2005.) Median F/U 2.3 years
• Outcome: median OS RT 12.1 months vs. RT + T 14.6 months (SS); 2-year OS 10% vs. 26% (SS). On
subgroup analysis, no benefit if biopsy only or if PS = 2.
• Toxicity: Grade 3-4 toxicity 7%
• Conclusion: Addition of temozolomide resulted in clinically meaningful and statistically significant survival
benefit, with minimal toxicity
• 5-years; 2009 PMID 19269895; "Effects of radiotherapy with concomitant and adjuvant temozolomide versus
radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the
EORTC-NCIC trial." (Stupp R, Lancet Oncol. 2009 May;10(5):459-66.) >5yr med fu
• Outcome: Median OS RT 12.1 mo vs RT + TMZ 12.1 mo (SS). 2-year OS 11% vs. 27%; 5-year OS 2% vs.
10%. Benefit in all subgroups, including 60-70 year old (10.9 months vs. 11.8 months). Benefit it RPA III
14.8 mo vs. 18.7 mo
• MGMT: Methylation strongest predictor of outcome: methylated 23.4 mo vs. unmethylated 12.6 mo (SS)
• Salvage: Second surgery 24%, repeat RT 5%, salvage chemo 54%, supportive care only 39%
• Conclusion: Benefits of adjuvant TMZ lasted through 5 years, though few patients survive that long
Overall Survival
Follow up XRT & Temodar XRT
Median 14.6 mo 12.1

OS mo
2 years 27.2% 10.9%
3 years 16.0% 4.4%
4 years 12.1% 3.0%
5 years 9.8% 1.9%
• Please see the → overview section for discussion of MGMT promoter status and other prognostic variables
from this trial
BCNU (Carmustine)
• CNS Cancer Consortium (1988-1991) -- Concurrent Mitomycin C
• Randomized. 2x2 design. 377 patients (69% GBM). Arm 1) RT alone vs. Arm 2) RT + mitomycin C. Then
randomized Arm 1) BCNU vs. Arm 2) BCNU + 6-MP. RT 61.2 Gy
• 1996 PMID 8598355 -- "A phase III randomized prospective trial of external beam radiotherapy, mitomycin C,
carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain. CNS Cancer
Consortium." (Halperin EC, Int J Radiat Oncol Biol Phys. 1996 Mar 1;34(4):793-802.)
• Outcome: median OS initial randomization both arms 10.8 months (NS). Median OS second randomization
BCNU 11.4 months vs. BCNU/6-MP 9.3 months (NS). Significantly fewer patients terminanted RT in RT
only group compared with concurrent mitomycin C
• Conclusion: No benefit for mitomycin C, more patients terminated therapy. No benefit for adding 6-MP to
BCNU
• BTCG 80-01 - PMID 2661738 -- "Randomized trial of three chemotherapy regimens and two radiotherapy
regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor
Cooperative Group Trial 8001." (Shapiro WR, J Neurosurg. 1989 Jul;71(1):1-9.)
• Randomized. 571 patients to 3 chemo regiments (BCNU, BCNU/procarbazine,
BCNU/hydroxyurea/procarbazine/VM-26).
• RT patients accrued 1982-1983: WBRT 60.2 Gy
• RT patients accrued 1982-1983: randomized to WBRT 60.2 Gy or WBRT 43 Gy + 17.2 Gy cone-down boost
• Conclusion: no difference in survival. WBRT + boost as effective as WBRT
• BTCG 77-02, 1989 (1978-80) - PMID 2542193 — "Results of a randomized trial comparing BCNU plus
radiotherapy, streptozotocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following
misonidazole plus radiotherapy in the postoperative treatment of malignant glioma." Deutsch M et al. Int J Radiat
Oncol Biol Phys. 1989 Jun;16(6):1389-96.
• 603 pts. All pts had surgery. RT was whole brain (60 Gy in 30-35 fx except arm 3). Arm 1: RT+BCNU IV x 3
days, repeat q8wk. Arm 2: RT+strep IV q week x 6 weeks then 2 week rest, repeat q8w. Arm 3:
HF-RT+BCNU. 1.1 Gy BID x 60 fx = 66 Gy. Arm 4: RT+miso then BCNU. Miso 2x/week 4-6 hr before RT.
After RT, BCNU q8weeks.
• No difference in survival among groups.
• BTCG 75-01, 1983 -- PMID 6337710 -- "Comparisons of carmustine, procarbazine, and high-dose
methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma." (Green SB,
Cancer Treat Rep. 1983 Feb;67(2):121-32.)
• Randomized. 690 patients post-op to 60 Gy RT and 1) BCNU, 2) Medrol, 3) Procarbazine, 4) BCNU + Medrol
• Medrol alone not good. BCNU + Medrol not good in poor prognosis. Other groups comparable.
• RTOG 74-01 / ECOG 1374, 1988 - PMID 3281031, — "Combined modality approach to treatment of malignant
gliomas--re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation
Therapy Oncology Group and the Eastern Cooperative Oncology Group." Nelson DF et al. NCI Monogr.
1988;(6):279-84.
• Randomized. High grade glioma. 1) 60 Gy whole brain vs 2)60 Gy + 10 Gy boost vs 3)60 Gy + BCNU vs 4)60
Gy + CCNU + DTIC
• No difference in survival. For pts age > 60, no benefit for chemo. For age 40-60, benefit for BCNU
• BTCG 72-01 - PMID 7001230, 1980 — "Randomized comparisons of radiotherapy and nitrosoureas for the
treatment of malignant glioma after surgery." (Walker MD et al. N Engl J Med. 1980 Dec 4;303(23):1323-9.)
• 467 pts. HGG. After surgery, randomized to MeCCNU (semustine), RT, BCNU (carmustine) + RT, or
MeCCNU + RT.
• RT +/- BCNU/MeCCNU significantly better than MeCCNU alone. RT alone comparable to RT+BCNU or
RT+MeCCNU.
• NCCTG 93-72-52 / SWOG 9503 (1994-99) - PMID 16921039, 2006 — "Phase III trial of carmustine and
cisplatin compared with carmustine alone and standard radiation therapy or accelerated radiation therapy in
patients with glioblastoma multiforme: North Central Cancer Treatment Group 93-72-52 and Southwest
Oncology Group 9503 Trials." Buckner JC et al. J Clin Oncol. 2006 Aug 20;24(24):3871-9.
• 401 pts. 4 arm (2x2): BCNU vs BCNU + cisplatin, accelerated RT (ART) vs standard RT (SRT).
• Chemotherapy weekly, concurrent with RT x 8 weeks. RT 64.8 Gy / 1.8 / 48 d (SRT) or 48 Gy / 1.2 Gy BID /
15 d (ART).
• Worse toxicity with BCNU + cisplatin. No SS difference in survival at 2 yrs.
• Conclusion: no improvement in survival
BCNU wafers (Gliadel)

• Meta-Analysis; 2007 (UK) PMID 17999840 -- "The effectiveness and cost-effectiveness of carmustine implants
and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic
evaluation." (Garside R, Health Technol Assess. 2007 Nov;11(45):iii-iv, ix-221.)
• Meta-analysis, Markov modeling for effectiveness and cost-effectiveness. BCNU: 2 RCT and 2 observations
studies
• Outcome: No difference in OS, but unpublished long-term follow-up suggests significant survival benefit
based on very few patients at risk. No difference in PFS. Subgroup analysis for WHO Grade IV no significant
OS benefit.
• Cost estimate: Surgery + RT is ~£17,000. BCNU additional £6,600, for 0.122 QALYs. Incremental
cost-effectiveness ratio (ICER) £54,500/QALY. Assuming pay threshold £30,000, BCNU wafer not cost
effective in 89% simulations; in 15% simulations BCNU wafer did more harm than good
• Conclusion: BCNU wafers survival benefit not proven in Grade III, and not present in Grade IV. The
intervention will likely not be considered cost-effective by NHS
• Multinational (1997-99) -- placebo vs. BCNU wafer
• Randomized. 14 countries. 240 patients, malignant gliomas (86% GBM). At primary surgical resection, Arm
1) placebo vs. Arm 2) BCNU wafers. All patients received RT 55-60 Gy.
• 2003 PMID 12672279 — "A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU)
wafers (Gliadel wafers) in patients with primary malignant glioma." (Westphal M, Neuro-oncol. 2003
Apr;5(2):79-88.)
• Outcome: median OS placebo 11.6 vs. BCNU wafer 13.9 months (SS); 29% reduction in risk of death.
BCNU also improved time to KPS decline and neuroperformance measures decline.
• Toxicity: comparable, except CSF leak 1% vs. 5%, intracranial HTN 2% vs. 9%
• Conclusion: Local chemotherapy with BCNU wafers is well tolerated and offers a survival benefit to
patients with newly diagnosed malignant glioma
• Comment (PMID 17999840 above): Published analysis was stratified by country. Per-protocol unstratified
analysis of data (submitted to FDA) reveals no OS advantage (p=0.08). Further updated data (submitted to
FDA) reveals OS advantage (p=0.02) but this is driven by few patients, mostly Grade III, with long survival.
There is no difference in 1 or 2 year OS.
• Turku University (Finland)(1992-1993) -- placebo vs. BCNU wafer
• Randomized. 32/100 planned patients with high grade (Grade III-IV) glioma. Closed prematurely as
carmustine became unobtainable. Arm 1) Surgery + placebo vs. Arm 2) Surgery + carmustine polymer
• 1997 PMID 9218294 -- "Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a
randomized double-blind study." (Valtonen S, Neurosurgery. 1997 Jul;41(1):44-8; discussion 48-9.)
• Outcome: median OS placebo 9.2 months vs. 13.4 months (SS); for GBM 9.2 months vs. 12.3 months (SS).
At end of study, 6% vs. 31% alive
• Conclusion: Locally applied carmustine polymer at time of primary surgery has benefit on survival
Phase II Protocols
• Thessaloniki, 2006 (Greece) PMID 17214326 -- "Post-operative combined radiation and chemotherapy with
temozolomide and irinotecan in patients with high-grade astrocytic tumors. A phase II study with biomarker
evaluation." (Fountzilas G, Anticancer Res. 2006 Nov-Dec;26(6C):4675-86.)
• Phase II. 45 patients (38 GBM, 7 AA) treated with RT 60 Gy + TMZ + irinotecan. 22 patients completed 6
cycles. Medium F/U 50 months
• Toxicity: Neutropenia 37%, N/V 66%, diarrhea 31%, infection 44%. 5/45 fatal vaso-occlusive disease
• Survival: overall 12.8 months, progression-free 7.7 months
• Conclusion: too toxic
• RTOG 94-17 (1995-97) - Tirapazamine
• 124 pts. GBM. Phase II. RT 60 Gy + tirapazamine (3x/week x 12). Two dose levels.
• 2000: PMID 10715295 — "Single-arm, open-label phase II study of intravenously administered tirapazamine
and radiation therapy for glioblastoma multiforme." (Del Rowe J, J Clin Oncol. 2000 Mar;18(6):1254-9.)
• For summary, see results presented in chart below (Summary - ASCO Abstract 2002, Seiferheld)
• Conclusion: "Survival in the population treated with radiation and tirapazamine was equivalent to the control
population."
• RTOG 86-12 - IUdR
• "Survival improvement in anaplastic astrocytoma, combining external radiation with halogenated pyrimidines:
final report of RTOG 86-12, Phase I-II study."
• PMID 8407393 (1993), PMID 8985039 (1996)
• Summary ASCO Abstract [2] -- Five years of glioblastoma multiforme(GBM) phase II trials at the Radiation
Therapy Oncology Group (RTOG). (Seiferheld W, ASCO Abstracts, 2002)
• Conclusion: "None of the experimental agents from these studies demonstrated statistically significant
improvement in survival from the historical control after adjusting for RPA class. On the other hand, it is
important to realize that several of the studies exhibited survival similar to the historical control, and with
fewer life-threatening toxicities. These results question the standard practice of concurrent BCNU for GBM
patients."
RTOG Phase 2 Trials

Trial Agent N MOS (Observed) MOS (Expected) p-value
94-17 Tirapazamine 53 10.8 10.8 NS

(159mg/m2)
94-17 Tirapazamine 68 9.5 9.7 NS

(260mg/m2)
95-13 Topotecan 79 9.3 10.1 NS
96-02 Paclitaxel 61 9.7 9.6 NS
97-10 ß-Interferon 60 13.2 10.2 NS
98-06 Thalidomide 89 10.0 9.5 NS

Trials that failed

• Dose escalation > 60 Gy - Michigan, RTOG 74-01
• Accel. hyperfract - RTOG
• Radiosurgery - RTOG 93-05
• Brachytherapy - NCI-Canada, BTSG
• Proton boost - MGH
• BCNU
• Hyperfract (72 Gy) - RTOG 83-02, 90-06, BTCG 77-02
• Neoadj. chemo - ECOG
• Boron neutron capture (BNC)
Trials to add
RTOG trials to add:
• 7611 - neutron boost
• 7918 - WBRT + (BCNU vs misonidazole and BCNU)
• 8007 - neutron boost
• 8409 - WBRT + AZQ (aziridinylbenzoquinone)
Review
• Multi-institutional; 2008 PMID 18712283 -- "Radiation therapy of pathologically confirmed newly diagnosed
glioblastoma in adults." (Buatti J, J Neurooncol. 2008 Sep;89(3):313-37. Epub 2008 Aug 20.)
References
[1] http:/ / www. rtog. org/ abstracts/ astroaccptlist. html#Werner-Wasik
[2] http:/ / www. rtog. org/ abstracts/ asco. html

Recurrence
High Grade Glioma: Recurrences
Epidemiology
• Rotterdam, 2007 (2000-2005) ASCO Abstract [1] -- "The incidence of pseudo-progression in a cohort of
malignant glioma patients treated with chemo-radiation with temozolomide." (Taal W, Journal of Clinical
Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2009)
• Retrospective. 65 patients with malignant glioma, treated with RT/TMZ followed by TMZ x6 cycles
• Outcome: 35% (23) patients had MRI signs of progression after end of RT, with clinical deterioration in 18%
(12). In 12/23 stabilization/improvement of symptoms on continued TMZ. No impact of dexamethasone dose
• Conclusion: Up to 50% of patients may suffer from pseudo-progression; should continue TMZ
Salvage RT
• Review; 2007 PMID 17760992 -- "Radiotherapeutic alternatives for previously irradiated recurrent gliomas."
(Combs SE, BMC Cancer. 2007 Aug 30;7(1):167)
• Michigan, 2002 (1996-99) - PMID 11896114 — "Survival and failure patterns of high-grade gliomas after
three-dimensional conformal radiotherapy." Chan JL et al. J Clin Oncol. 2002 Mar 15;20(6):1635-42.
• Retrospective. 34 pts. Pts with HGG treated to 90 Gy using IMRT. Defined recurrences as central (>95% of
volume in high dose region), in-field(80% to 95%), marginal (20% to 80%), and distant (<20%). For planning,
used GTV=enhancing tumor (no edema). PTV1=0.5 cm margin, PTV2=1.5 cm, PTV3=2.5 cm. 90 Gy
prescribed to PTV1, 70 Gy to PTV2, 60 Gy to PTV3.
• 67% had recurrence. 78% were central, 13% in-field, 9%, 0% distant.
• Conclusion: predominant treatment failure is local/central. This suggests that close margins in conformal
treatment do not increase the risk of marginal or distant recurrences.
Salvage chemotherapy
• Duke, 2007 (2005-2006) PMID 17947719 -- "Bevacizumab plus irinotecan in recurrent glioblastoma
multiforme." (Vredenburgh JJ, J Clin Oncol. 2007 Oct 20;25(30):4722-9.)
• Phase II. 35 patients. Initial regimen bevacizumab 10 mg/kg with irinotecan. Then bevacizumab 15 mg/kg and
irinotecan
• Outcome: 6-month PFS 46%, OS 77%. Response rate 95% and significant improvements in cognitive and
functional status
• Toxicity: 1 CNS hemorrhage, 4 thromboembolic events
• Conclusion: Bevacizumab/irinotecan effective for recurrent disease, with moderate toxicity
References
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Radiation Oncology/CNS/Germinoma
CNS Germinoma
Overview
• Rare primary CNS tumor
• Typical age at presentation is early teens
• Mainly located in midline structures
• Can be M+ in as much as 24% histologically verified cases; Disease outside of CSF is very rare
• Bifocal germinomas (synchronous suprasellar and pineal tumors) regarded as M+ in USA but M0 in Europe
• Natural spread believed to be along subependymal lining of 3rd and 4th ventricles, leading to intraventricular
relapse before spinal dissemination
• Very sensitive to both radiation and chemotherapy
Location
• Pineal gland, suprasellar region, basal ganglia, hypothalamus
Pineal Gland Germinoma

Suprasellar Germinoma
Treatment
• Treatment of M0 disease is somewhat controversial. Historically craniospinal RT was the gold standard, but with
local control >99% and 10-year survival rates >90%, limiting side-effects is essential.
• There is now a movement toward WBRT, and further to tumor + ventricles only. Isolated spinal relapse appears
comparable between CSI and whole-brain RT or whole-ventricular RT with neoadjuvant chemo
• Focal RT of primary tumor alone appears associated with significantly higher overall and isolated spinal relapse
• M+ disease continues to be treated with CSI
• Attempts at treatment with chemotherapy alone have resulted in ~50% relapses and ~10% treatment-related
mortality; which is much worse than RT alone. This is currently not recommended
• Dose to primary disease is typically 40-45 Gy, and to subclinical disease 20-24 Gy
• Review PMID 15992700 -- "Radiotherapy of localised intracranial germinoma: time to sever historical ties?"
(Rogers SJ, Lancet Oncol. 2005 Jul;6(7):509-19.)
• Reviewed 20 studies since 1988. 788 patients. 66% cases histologically confirmed, 12/20 series 100%
confirmation. Median F/U 6.4 years
• CSI: local control 99.7%; relapses 3.8% but half of them outside CS axis; isolated spinal relapse 1%
• WBRT or Whole-ventricular RT+boost: both comparable. local control 97%; relapses 8%; isolated spinal
relapse 3%
• Focal: local control 93%; relapses 23%; isolated spinal relapses 11%
• Conclusion: Whole-ventricular RT + boost should replace craniospinal RT in completely staged localized
intracranial germinomas
Treatment of relapses: Chemotherapy.
Studies
• Seoul; 2008 (1981-2003) PMID 18514777 -- "Upfront chemotherapy and involved-field radiotherapy results in
more relapses than extended radiotherapy for intracranial germinomas: modification in radiotherapy volume
might be needed." (Eom KY, Int J Radiat Oncol Biol Phys. 2008 Jul 1;71(3):667-71.)
• Retrospective. 81 patients with tissue-confirmed intracranial germinoma. 39 RT only (all CSI), 42 chemo-RT
(size depended on tumor extent, ranging from tumor only to CSI). Median F/U 5.7 years
• Outcome: 5-year OS RT 100% vs. chemo-RT 93%; 5-year RFS RT 100% vs. 88% (SS). 4 relapses in
chemo-RT group (3 in brain and 1 in spine)
• Toxicity: same proportion return to school (NS), hormonal therapy RT 69% vs. chemo-RT 38%
• Conclusion: Better quality of life in chemo-RT but worse relapse compared with RT alone. Primary tumor RT
not sufficient, suggest at least inclusion of ventricles
• POG 9530 (1997-1999) -- response-based RT
• Phase II. 12 germinoma patients (and 14 NGGCT patients and/or elevated AFP/bHCG - not further discussed
here). Age >3 years. 5 resected, 7 bx. Germinoma treated with cisplatin/etoposide and
vincristine/cyclophosphamide x4 cycles. If CR, primary site RT 30.6 Gy; if PR primary site RT 50.4 Gy with
2cm margin (3D-CRT) or 0.5cm margin (SRT). If disseminated disease and CR, CSI 30.6 Gy; if PR CSI 36 Gy
• 2007 PMID 16598761 -- "Pre-radiation chemotherapy with response-based radiation therapy in children with
central nervous system germ cell tumors: a report from the Children's Oncology Group." (Kretschmar C,
Pediatr Blood Cancer. 2007 Mar;48(3):285-91.)
• Outcome: 11/12 progression-free at median 5.5 years, 1/12 refused RT, failed at 10 months, RT salvage,
progression-free at 4.8 years
• Conclusion: Response (91%) and survival encouraging
• Toronto; 2006 (1995-2004) PMID 16530340 -- "Limited-field radiation for bifocal germinoma." (Lafay-Cousin
L, Int J Radiat Oncol Biol Phys. 2006 Jun 1;65(2):486-92.)
• Retrospective. 6 patients with bifocal germinoma (pineal + suprasellar). All with diabetes insipidus at
presentation. Treated with chemo followed by limited-field RT (whole ventricle 24-40 Gy +/- boost). Median
F/U 4 years
• Outcome: 100% complete remission
• Conclusion: Bifocal germinoma can be considered locoregional rather than metastatic disease
• MAKEI 83/86/89, 1983-93 (German) - MAKEI = Maligue Keimzelltümoren (malignant germ cell tumors)
• Prospective, non-randomized. Goal: dose reduction. 60 pts. Germinomas. Three trials: 83(pilot) and two
successive trials. Biopsy only (no resection)
• In MAKEI 83/86 (11 pts), RT to 36 Gy to craniospinal axis + 14 Gy boost to tumor (total 50 Gy, at 1.8-2
Gy/fx). In MAKEI 89 (49 pts), 30 Gy (CSI) + 15 Gy (total 34 Gy at 1.5 Gy/fx).
• PMID 10561326, 1999 — "Radiation therapy for intracranial germinoma: results of the German cooperative
prospective trials MAKEI 83/86/89." Bamberg M et al. J Clin Oncol. 1999 Aug;17(8):2585-92.
• Mean f/u 59 mos. CR in all pts. 5-yr RFS 91%, OS 93%
• Conclusion: dose reduction is feasible.
• SIOP CNS GCT 96
• CSI 24 Gy
• MSKCC; 1996 PMID 8918487 -- "Chemotherapy without irradiation--a novel approach for newly diagnosed
CNS germ cell tumors: results of an international cooperative trial. The First International Central Nervous
System Germ Cell Tumor Study." (Balmaceda C, J Clin Oncol. 1996 Nov;14(11):2908-15.)
• Prospective. 68/71 patients (45 germinoma, 26 NGGCTs). Chemo carboplatin, etoposide, bleomycin x4 cycles.
If CR, 2 more cycles. If PR, 2 more cycles intensified by cyclophosphamide.
• Outcome: CR rate germinomas 86%, NGGCT 78%. 2-year OS germinoma 84%, NGGCT 62%
• Toxicity: 7/71 patients (10%)
• Conclusion: Chemo-only regimens should be used only in setting of clinical trials
• Seoul; 1996 (Korea)(1980-1996) PMID 8850422 -- "Radiotherapy of intracranial germinomas." (Huh SJ,
Radiother Oncol. 1996 Jan;38(1):19-23.)
• Retrospective. 32 patients, confirmed intracranial germinomas (14 suprasellar, 12 basal/thalamus, 4 pineal, 2
multiple). CSI in 29 patients. RT tumor bed 54 Gy, whole-brain 36 Gy, spinal axis 24 Gy
• Outcome: 5-year OS 97%, 10-year OS 97%; 1 death with persistent tumor 2 months after RT; no intracranial
or spinal recurrence
• Toxicity: 1 severe intellectual deterioration, 3 vertebral growth impairment
• Conclusion: Excellent result with RT alone
Radiation Oncology/CNS/Ependymoma
Epidemiology
• 5-10% of pediatric brain tumors
• Primarily in infants and children <5 years
• Approximately 200 pediatric cases per year in USA
Location
• Glial tumors that arise from ependymal lining of the ventricular system
• May occur anywhere in the ventricular system or spinal canal
• 90% are in the brain
• 1/3 supratentorial
• 2/3 infratentorial, many arising from the 4th ventricle
• Up to 50% may infiltrate into the brainstem
• 10% in the spine
• Myxopapillary ependymomas are found almost exclusively in the conus and filum terminale and are the most
common spinal tumors in this location.
• Location differs with age:
• In young children: 90% intracranial, typically roof of 4th ventricle
• In adolescents/adults: 75% spinal canal
Patterns of spread
• Spread is primarily local
• In 50% of pts with posterior fossa tumors, a "tongue" of tumor may extend through the foramen magnum well
into the cervical region
• Risk of leptomeningeal seeding is 5-10%
Presentation
• Since majority occur in 4th ventricle, symptoms are related to obstruction and subsequently increased intracranial
pressure
• In spinal ependymomas, presentation is typically with sensory deficits (compared with astrocytomas, which tend
to present with pain and motor symptoms)
Workup
• MRI of brain and spine: typically well-circumscribed, with displacement rather than invasion of brain
parenchyma
• CSF cytology
Pathology
• Myxopapillary ependymoma (WHO grade I)
• Subependymoma (WHO grade I)
• Ependymoma (WHO grade II)
• Cellular
• Papillary
• Clear cell
• Tanycytic
• Anaplastic ependymoma (WHO grade III)
Treatment Overview
• No randomized studies
• Surgery is primary management
• Adjuvant RT is considered standard of care, although highly selected series report good outcomes with surgery
alone
• Because recurrences tend to be local, RT is typically GTV plus 1-1.5 cm margin (per Perez, 4th edition)
• 5-year OS 50-65%, PFS 25-45%
• Recurrences typically local; median time to failure 1-2 years. About 20% isolated distant recurrences
Surgery
• Extent of surgery most important predictor of outcome
• 5-year OS with GTR: 70-80%
• 5-year OS with STR: 25-45%
• Gross total resection (GTR) achievable depending on location, overall 30-50%:
• Supratentorial lesions: GTR ~80%
• Infratentorial lesions: GTR "lower" rate (per Perez, 4th edition), BNI rate 70%
• Spinal lesions: GTR close to 100%
• Barrow Neurological Institute; 2005 (1983-2002) PMID 15871504 -- "Is gross-total resection sufficient
treatment for posterior fossa ependymomas?" (Rogers L, J Neurosurg. 2005 Apr;102(4):629-36.)
• Retrospective. Posterior fossas ependymomas, no subependymomas or CNS dissemination. GTR in 71%. RT
in 13/32 GTR and 12/13 STR. RT fields CSI + boost (n=6), rest posterior fossa or localized fields. Median F/U
5.5 years
• Local control: Median LC: GTR alone 6.6 years vs. GTR+RT not yet reached; 10-year LC: GTR alone 50%
vs. GTR+RT 100% (SS) vs. STR+RT 36% (SS), GTR alone comparable to STR+RT
• 10-year OS: GTR alone 67% vs. GTR+RT 83% vs. STR+RT 43% (all NS)
• Conclusion: Adjuvant RT significantly improves control after GTR
• BI Medical Center, NYC; 1998 PMID 9755311 -- "Treatment of intracranial ependymoma by surgery alone."
(Hukin J, Pediatr Neurosurg. 1998 Jul;29(1):40-5.)
• Prospective. 10 patients. Children >3 years, s/p GTR
• Outcome: 7 free of disease, 3 recurred (2 salvaged with surgery and RT). No deaths. Overall median PFS 4
years, and OS 4.2 years
• Conclusion: Deferral of RT after GTR of supratentorial ependymoma safe; recurrence salvageable
Radiation
Role of post-operative RT:
• Historically, ependymoma was believed to disseminate throughout the neuraxis, and CSI became the standard
management approach
• However, more recent retrospective studies have shown that failure is primarily local in >90%
• Benefit for post-operative RT is based on retrospective studies. 5-yr EFS 45% vs 0% and 51-70% vs 13% PFS.
Dose response:
Evidence of a dose response above 45-50 Gy.
RT volume:
No evidence of need for extended-field or craniospinal radiation.
CTV margin around resection cavity is generally 1 cm.
Hyperfractionation:
In one study (POG 9132), HF RT produced better event-free survival for pts with incomplete resection. Dose was
69.6 Gy at 1.2 Gy BID.
Subependymoma
• Uncommon variant of ependymal tumors
• Histologically clusters of ependymal cells in an astrocyte-based matrix
• Clinically slow growing, with extremely low Ki-67
• Many discovered incidentally at autopsy
• Clinically symptomatic tumors present with CSF obstruction
• Gross total resection alone frequently leads to cure, but perioperative mortality can be high
• Role of adjuvant RT is not clear
Anaplastic Ependymoma
• HIT-SKK87 and HIT-SKK92 (1987-1992, 1992-1997)
• HIT-SKK87: Low-risk (complete resection, M0) and age <2.5 received maintenance chemo only until RT at 3
years or progression. High-risk (subtotal resction, M+) and age 2.5-3 induction chemo / maintence chemo until
RT at 3 years or progression
• HIT-SKK92: Post-op chemo x3 cycles first, then if CR no RT. If PR and <18 months, then more chemo, if PR
and >18 months, then RT.
• RT given as CSI 35.2/22 Gy + 20/10 Gy boost; if no residual disease, reduced to CSI 24 Gy + PF boost to 55
Gy
• 2005 PMID 16300848 -- "Role of radiotherapy in anaplastic ependymoma in children under age of 3 years:
results of the prospective German brain tumor trials HIT-SKK 87 and 92." (Timmermann B, Radiother Oncol.
2005 Dec;77(3):278-85.)
• Total 34 children enrolled. No RT given in 13 children, preventive RT in 9, salvage RT in 12
• 3-year outcomes: PFS 27%, OS 56%. Positive predictive factors: higher age, M0, GTR, RT. If no RT, only
3/13 survived
• Conclusion: Delaying RT jeopardized survival. Predominant failure primary tumor site; RT of neuraxis should
be omitted in localized disease
Spine Ependymoma
• Rare tumors
• Gross total resection (~50%) leads to long-term control in >90%
• Subtotal resection can recur in 50-70% without adjuvant therapy; with adjuvant RT local control 60-100%
• RT dose seems to show a threshold effect, with worse control <45 Gy. However, radiation myelopathy becomes
concerning >55 Gy, and with pediatric patients possibly as low as 40 Gy
• Field size is unclear, but commonly is +/- 2 vertebral bodies. In sacrum, need to cover nerve roots, so inferior
edge at S4/S5 and lateral edges to SI joints
• Kaiser Permanente; 2007 (USA) PMID 17689025 -- "Outcomes in treatment for intradural spinal cord
ependymomas." (Volpp PB, Int J Radiat Oncol Biol Phys. 2007 Nov 15;69(4):1199-204. Epub 2007 Aug 6.)
• Retrospective. 23 patients (17 surgery alone, 5 surgery + RT, surgery + RT + chemo). Mean RT dose 45 Gy
• Outcome: 9-year OS 64%, LC 96%
• Recurrences: surgery alone: 12% recurred (1/17 locally, 1/17 distally). CMT 33% recurrence (both
out-of-field)
• Conclusion: En block total resection primary treatment, RT reserved for unfavorable characteristics (residual
tumor, anaplastic features, piecemeal resection)
Reviews
• PMID 15049020, 2004 — "Review of radiotherapy dose and volume for intracranial ependymoma." Taylor RE.
Pediatr Blood Cancer. 2004 May;42(5):457-60.
Radiation Oncology/CNS/Choroid Plexus

Epidemiology
• 0.5% intracranial neoplasms
• 10-20% intracranial neoplasms in <1 y/o
• 70% of choroid plexus tumors occur in pts <2 y/o
Histology
• Choroid plexus papillomas are WHO grade I.
• Choroid plexus carcinomas are WHO grade III.
• 80% of choroid plexus tumrs are papillomas.
Patterns of Spread
• Most common site is 4th ventricle.
• As high as 44% of choroid plexus carcinomas can have CSF seeding.
• CSF seeding rare for choroid plexus papilloma.
Treatment
Surgical Excision
• Johns Hopkins, 2002 (1985-2000) PMID 12125972 -- "Is there a requirement for adjuvant therapy for choroid
plexus carcinoma that has been completely resected?" (Fitzpatrick et al., J Neurooncol. 2002; 57(2):123-6.)
• 75 cases of choroid plexus carcinoma described in literature. 37 had GTR, 38 had STR
• 84% survival if GTR vs 18% if STR
• Long term survival was seen in pts who received GTR and no further tx; numbers were small.
Adjuvant Radiotherapy
• Indications for adjuvant RT
• positive margins
• positive neuraxis staging
• WHO grade III
• Indications for CSI
• positive margins
• positive neuraxis staging
Radiation Oncology/CNS/Choroid Plexus 53
Deferred Radiation in Young Children

• Baby POG I (1986-90)
• Prospective. 198 children < 3 yrs (132 < 2 yrs, 66 age 2-3 yrs), bx proven malignant brain tumors (low-grade
astro excluded), treated with maximal surgery, postop chemo (CTX/VCR followed by cis/etopo) for 2 yrs (if
age < 2 at dx) or 1 yr (age 2-3) or until disease progression, followed by RT.
• Histologies: 8 pts w/ choroid plexus tumors included in Baby POG I
• 1993 PMID 8388548 -- "Postoperative chemotherapy and delayed radiation in children less than three years of
age with malignant brain tumors." (Duffner et al., N Engl J Med. 1993; 328(24):1725-31)
• CR to chemo PFS comparable those with GTR PFS
• 1995 PMID 7619719 -- "Postoperative chemotherapy and delayed radiation in infants and very young children
with choroid plexus carcinomas. The Pediatric Oncology Group." (Duffner et al., Pediatr Neurosurg. 1995;
22(4):189-96.)
• 8 pts w/ choroid plexus carcinoma tx'd w/ surg, prolonged chemo, delayed RT.
• Results suggest this approach may allow prolonged DFS in young pts.
Radiation Oncology/Medulloblastoma/Staging
Medulloblastoma Staging
Modified Chang's Staging

T Stage
• T1 - tumor <3 cm in diameter
• T2 - tumor ≥3 cm in diameter
• T3a - tumor >3 cm and with extension into Aqueduct of Sylvius or foramen of Luschka
• T3b - tumor >3 cm and with unequivocal extension into brainstem
• T4 - tumor >3 cm with extension past Aqueduct of Sylvius or down past foramen magnum
M Stage
• M0 - No evidence of gross subarachnoid or hematogenous metastasis
• M1 - microscopic tumors cells found in CSF
• M2 - gross nodular seeding intracranially beyond the primary site (in cerebellar/cerebral subarachnoid space or in
third or lateral ventricle)
• M3 - gross nodular seeding in spinal subarachnoid space
• M4 - metastasis outside cerebrospinal axis
Radiation Oncology/Medulloblastoma/Staging 54
Risk Stratification
• Standard (Average) Risk (66%)
• >3 years old
• <1.5 cm2 residual disease after resection
• M0 by craniospinal MRI and CSF
• High Risk (34%)
• <3 years old
• Subtotal resection, >1.5 cm2 residual tumor
• M+; leptomeningeal seeding
• Location outside of posterior fossa (PNET)
Radiation Oncology/Medulloblastoma/Overview
Medulloblastoma Overview
Epidemiology
• Most common malignant brain tumor of childhood (20% of CNS tumors in children <19 years old; glial #1). 550
cases in the US
• Median age of presentation is 5-7 years old. 75% medulloblastomas occur in children <15 years old.
• Slight male predominance.
• Highest risk of CSF+ at presentation (30-35%)
Clinical Presentation
• Increased intracranial pressure: Headaches, nausea, vomiting
• Cranial nerve deficits
• Ataxic gait
• In infants: loss of milestones, increased head circumference, head tilt due to CN IV palsy
• Clinical exam: papilledema, nystagmus, CN abnormalities (VI most common -> "setting sun" sign with
downward gaze)
• 50-75% have <3 months of symptoms; prolonged symptoms duration multiplies probability of favourable
treatment outcome of basic disease
Radiographic
• Plain films: often invisible
• CT: hyperdense on unenhanced study, enhances with contrast, can appear homogenous
• MRI: hyperintense on T1, heterogenous on T2, often compresses 4th ventricle
• Get imaging before starting steroids
• Pre-op MRI brain and spinal cord (post-op spine can give false positives)
• Post-op MRI brain within 48 hours
• Pre-op CSF before surgery if safe (no increased ICP), else 10-14 days after surgery to avoid false-positive
findings from surgical debris
• If advanced, metastatic work-up
Histology
• "Small round blue cell"; classified as primitive neuroectodermal tumor (PNET)
• Medulloblast are derived from cerebellar granule cells, through activation of Sonic Hedgehog Pathway, likely
from external granluar layer of the cerebellum
• Genetics: Loss of 17p, 10q, 16q, chromosome 11; excess of 17q, chromosome 7
Prognostic Factors
• Clinically poor prognosis: Age <3 years, M2-4 disease, unresectable or subtotal resection
• Clinically better prognosis: Age >5-7 years, M0 disease (no metastasis), tumor is not visible on the postoperative
image
• Histologically poor prognosis: Large-cell anaplastic (LCA) variant, diploid DNA, LOH 17p, p53 mutation and
expression, low TrkC (tyrosine kinase that mediates neuronal differentiation; 4.8x risk of death), MYC mRNA
(c-myc/MYCC) expression, w:http://en.wikipedia.org/wiki/ERBB2|HER2-neu positive (ErbB2+),
HER2+/HER4+ coexpression
• Histologically better prognosis: Desmoplastic variant, high TrkC expression, ErbB2-, β-catenin (beta-catenin)
nucleopositivity
A combination from two factors (--/++) is examined as an independent factor
Anatomy
• Posterior Fossa borders
• Anterior: clivus and posterior clinoid
• Posterior: calvarium
• Superior: tentorium
• Inferior: occipital bone
• Lateral: portions of temporal, occipital, parietal bones
Natural History
• Dissemination: CSF seeding, intracranial, subarachnoid space, mets outside CNS <5%
• Most recurrences within two years, at the site of primary tumor (50%)
• Medulloblastoma tends to follow Collins' law (see PMID 9213055), which defines the period of risk for
recurrence as the patient's age at diagnosis + 9 months of gestation. According to Collin's law, if a patient has no
evidence of recurrence within this time period, he is considered cured (e.g. a 3 year old with medulloblastoma is
cured when his disease free interval reaches 3 years + 9 months). The premise is that if this tumor was present in
utero, then gestation+age determines rate of growth for it to become clinically evident. Therefore, if there is
residual disease after treatment, it should become clinically evident again within the same time-frame
• 10-year survival for all stages: 40-50%
• For today considerable part of survivors is living 20-25 years and more from the moment of primary treatment
Radiation Oncology/Medulloblastoma/Therapy
Medulloblastoma Therapy
Treatment Overview
Surgery
• Major goals of surgery are to achieve an oncologic resection and to restore normal flow of CSF
• Complete resection (GTR/R0) results in significantly better prognosis
• Insufficient as single modality (1/61 patients survived 3 years in Cushing's original paper)
Radiation
• Radiation therapy is delivered to the entire craniospinal axis (deferred if <3 years old).
• Dose of RT based upon risk stratification grouping:
• High risk patients treated with 36 Gy CSI (craniospinal irradiation) with concurrent vincristine
• Standard risk patients treated with 23.4 Gy CSI with concurrent vincristine
• Posterior fossa boost to 54-56 Gy
Chemotherapy
• Chemotherapy is standard adjuvant therapy for all risk groups
• Chemotherapy can also be given for younger patients in order to delay RT as the toxicity profile for patients <3
y/o who get CSI is worse than for older children.
Radiation doses (full/fraction) and chemotherapy regimes (pre/post, agents) are varied in concrete protocols
Overview
• SIOP I and CCG 942 demonstrated no benefit of adding chemo to standard CSI 36 Gy, though on subgroup
analysis advanced stage did benefit
• Standard risk group
• French SFOP group attempted to reduce RT volume by not irradiating supratentorium, but results very
disastrous. <20% EFS at 6 years, with 9/13 failures in supratentorium. CSI is necessary, despite long-term
toxicity
• Based on these results, POG 8631/CCG 923 attempted to lower CSI alone dose to 23.4 Gy, but had to be
stopped early after showing higher failure rate (67% vs. 52%)
• SIOP II in standard risk patients also attempted to lower CSI dose from 35 Gy to 25 Gy, and add adjuvant
chemo. Neither worked, with patients getting post-op adjuvant chemo and low dose CSI doing particularly
badly. High risk patients were randomized to +/- adjuvant chemo, standard 35 Gy CSI and additional chemo.
Adjuvant chemo didn't work here either. 5-year EFS 68% for standard CSI
• Most standard risk patients were nevertheless treated with adjuvant chemotherapy despite evidence of benefit.
PNET 3 study published in 2006 finally demonstrated benefit to EFS (5-year 74% vs. 60%), but no difference
in OS. Unfortunately, it also demonstrated a significantly worse health status in survivors treated with CSI +
adjuvant chemo compared to CSI alone
• German trial HIT 91 evaluated post-op chemo -> RT vs. post-op RT -> chemo. At 3 years, EFS was better for
immediate RT followed by chemo
• Meanwhile, CCG 9892 was a single-arm pilot study in standard risk patients evaluating concurrent vincristine
and low dose CSI 23.4 Gy, followed by CCNU/vincristine/cisplatin. 80% PFS at 5 years was as good as
historical control with CSI 35 Gy
• Based on these results, low dose CSI 23.4 Gy with concurrent vincristine became standard in CCG study
A9961, and randomization was between two different chemo arms (CCNU-based vs.
cyclophosphamide-based). 5-year EFS was 81%, and there was no difference between the arms
• High risk group
• Since both SIOP I and CCG 942 demonstrated benefit for chemo in advanced stage disease, efforts have been
aimed at determining correct sequence and drugs
• German trial HIT 91 evaluated post-op chemo -> RT vs. post-op RT -> chemo. At 3 years, EFS was better for
immediate RT followed by chemo
• POG 9031 similarly randomized patients to pre-RT vs. post-RT chemotherapy. Results at 2 years reported in
abstract form showed no difference in outcome
• Infants (<3 years old)
• Baby POG I trial attempted to delay RT by 1-2 years of intensive chemotherapy. In children with GTR, CSI of
24 Gy and PF boost of 50 Gy was used. 5-year EFS for this subgroup was 69%, and comparable to standard
risk older children. However, many children failed early, with overall 5-year EFS 32% and OS 40%
• At the same time, CCG tried a different approach with 8 drugs in one day (8-in-1), and delaying RT. This
approach did not work as well as Baby POG I, probably due to lesser intensity chemo
• Two trials, a German and French, have both evaluated eliminating RT altogether in young patients. They have
both shown it is possible in children with gross total resection (GTR/R0), without metastatic disease. The
neuropsychological outcomes of these children were favorable when compared to those receiving RT
• to be continued...
CSI +/- chemo

• CCG A9961 (1996-2000) PMID 16943538 "Phase III study of craniospinal radiation therapy followed by
adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma" Packer et al. JCO 24(25):4204-8,
2006.
• Randomized. 421 patients, standard risk. Treated with reduced dose RT (23.4 Gy CSI + 55.8 Gy to posterior
fossa) and concurrent vincristine, and then randomized to adjuvant: 1) CCNU, cisplatin and vincristine or 2)
cyclophosphamide, cisplatin, vincristine. Median F/U 5 years
• 5-year outcome: EFS 81%, OS 86%. No difference by chemo arm
• Prognostic factors: anaplasia OS 75% vs. 89% (SS)
• Relapse: posterior fossa alone 32%, disseminated alone 40%, PF+disseminated 25%
• Toxicity: 25% with delayed onset mutism, hypotonia, cerebellar deficits, supranuclear CN deficits, extreme
irritability, and/or emotional lability. ~50% residual deficits at 1 year
• Conclusion: Reduced dose CSI with chemo can be done safely to avoid toxicities of higher dose RT
• PNET 3 (1992-2000)
• Study closed early due to lack of accrual in RT alone arm Randomized. 179/217 standard risk patients
(including M1). Treated with neoadjuvant chemo (vincristine/etoposide/carboplatin/cyclophosphamide) vs. RT
alone (CSI 35 Gy + 20 Gy posterior fossa boost). Median F/U 5.4 years.
• 2003 PMID 12697884 -- "Results of a randomized study of preradiation chemotherapy versus radiotherapy
alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom
Children's Cancer Study Group PNET-3 Study." (Taylor RE, J Clin Oncol. 2003 Apr 15;21(8):1581-91.)
• 5-year outcome: OS 70% (NS), EFS chemo-RT 74% vs. RT alone 60% (SS)
• Conclusion: improved EFS with addition of chemo, no impact on survival
• 2007 PMID 17878477 -- "Reduction of health status 7 years after addition of chemotherapy to craniospinal
irradiation for medulloblastoma: a follow-up study in PNET 3 trial survivors on behalf of the CCLG (formerly
UKCCSG)" (Bull KS, J Clin Oncol. 2007 Sep 20;25(27):4239-45.)
• Prospective analysis. 73% of patients assessed. Evaluated health status (HUI3 Index [1]: vision, hearing,
speech, ambulation, dexterity, emotion, cognition and pain), behavior, and quality of life. Mean F/U 7.2
years
• Outcome: health status significantly worse in CSI+chemo arm, trend to poorer outcomes in behavior and
quality of life. Also significantly worse physical restrictions, with significantly more therapeutic and
educational support
• Conclusion: Addition of chemo to CSI leads to significant decrease in health status
• CCG 9892 PMID 10561268 "Treatment of children with medulloblastomas with reduced-dose craniospinal
radiation therapy and adjuvant chemotherapy" Packer et al. JCO 17(7):2127-36, 1999
• Pilot study evaluating reduced dose (23.4 Gy) CSI w/ concurrent vincristine as alternative to 35 Gy for
standard risk patients. Post fossa boosted to 55.8
• PFS 86% at 3 yrs, 79% at 5 yrs
• This study served as the basis for CCG A9961 reduced CSI dose
• SIOP II (1984-1989) PMID 7623725 "Prospective randomised trial of chemotherapy given before radiotherapy
in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of
Paediatric Oncology (GPO)" Bailey et al. Med Pediatr Onc 25(3):166-78, 1995
• Randomized. 364 patients. SIOP I low risk (total/subtotal resection, no brain stem invasion, M0) randomized
to +/- adjuvant chemo (vincristine, methotrexate, procarbazine), and then randomized to standard CSI 35 Gy
vs. reduced CSI 25 Gy. Boost posterior fossa to 55 Gy. High risk randomized to +/- adjuvant chemo, then
standard CSI and additional post-RT chemo
• Outcome: No advantage to pre-RT chemo. Standard CSI 35 Gy for low risk pts increased EFS (68% vs 55%).
Low risk patients with adjuvant chemo and CSI 25 Gy did particularly badly
• Conclusion: No benefit to adjuvant chemo. Standard dose of CSI is 35 Gy
• SIOP I PMID 2141512 -- "Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the
International Society of Paediatric Oncology (SIOP I)." (Tait DM, Eur J Cancer. 1990 Apr;26(4):464-9.)
• Randomized. 286 patients, 15 countries. Treated with CSI, randomized to +/- chemo (concurrent vincristine,
then CCNU/vincristine maintenance)
• Survival: 5-year 53%, 10-year 45%. No difference between arms
• Subgroup benefit: subtotal surgery, brainstem involvement, T3-T4 disease
• CCG 942 PMID 2319316 -- "The treatment of medulloblastoma. Results of a prospective randomized trial of
radiation therapy with and without CCNU, vincristine, and prednisone." (Evans AE, J Neurosurg. 1990
Apr;72(4):572-82.)
• Randomized. 233 patients. CSI +/- chemo (CCNU, vincristine, prednisone)

• 5-year outcomes: EFS chemo-RT 59% vs. RT alone 50% (NS); OS 65% for both (NS)
• Subgroup benefit: large tumors (EFS chemo-RT 48% vs. RT alone 0%)
• Conclusion: no benefit for chemo in low stage, subgroup benefit for advanced stage
CSI + adjuvant chemo alternatives

• CCG 921 (1986-1992) -- vincristine/lomustine/prednisone (VCP) vs. 8-in-1
• Randomized. 427 children <21 years, with medulloblastoma, pineoblastoma, ependymoblastoma, central
neuroblastoma, PNET, or malignant ependymoma, with unfavorable features. For ST-PNET required M+
staging. Children age >1.5 years (n=328) received post-op CSI with Arm A) vincristine, lomustine, prednisone
vs. Arm B) 8-in-1 (cisplatin, procarbazine, lomustine, vincristine, cyclophosphamide, methylprednisolone,
hydroxyurea, cytarabine). RT: age >3 received CSI 36 Gy, boost to 50.4-54 Gy spine mets and 54 Gy primary
brain site; age <3 received CSI 23.4 Gy with boost to 45 Gy. Children age <1.5 years (n=99) were not
randomized and received only Arm B
• 1999 PMID 10071274 -- "Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for
medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study."
(Zeltzer PM, J Clin Oncol. 1999 Mar;17(3):832-45.) Median F/U 7.0 years
• Subset analysis. 203 patients with medulloblastoma. Median OS 8-in-1 55% vs. VCP 54% (NS); PFS 63%
vs. 45% (SS)
• Prognostic factors: age <3 (who received lower CSI dose); if >3 y/o then M stage (PFS M0 70% vs. M1
57% vs. M2+ 40%, SS); if M0 tumors, then residual (PFS <1.5 cm2 78% vs. >1.5 cm2 54%)
• Conclusion: VCP + XRT superior; if <3 years (with reduced RT) had lowest survival
Pre-RT vs. Post-RT Chemo

• POG 9031 (1990-1996)
• Randomized. 226 patients with high risk disease (residual >1.5 cm3, T3b or T4, or M1-M3). Treated with
upfront chemo x3 cycles (cisplatin/etoposide) followed by CSI followed by chemo
(vincristine/cyclophosphamide) vs. upfront CSI, followedy by cisplatin/etoposide, followed by
vincristine/etoposide. RT CSI 35.2/22 + boost PF 18/10 Gy (53.2 Gy) if M0-M1 and CSI 40.0/25 + boost PF
14.4/8 Gy (54.4 Gy) if M2-M3. Spinal or brain mets boosted to 44.8 Gy
• RT QA, 2006 PMID 16413699 -- "Radiotherapy in pediatric medulloblastoma: quality assessment of Pediatric
Oncology Group Trial 9031." (Miralbell R, Int J Radiat Oncol Biol Phys. 2006 Apr 1;64(5):1325-30.)
• 5-year outcome: EFS 68%, OS 75%
• Major deviations: brain 26%, spine 7%, posterior fossa boost 40%, primary tumor bed 17%
• Conclusion: no correlation between major treatment deviations and negative outcome
• 2000 ASTRO Abstract 134 -- "Outcome for children with high stage medulloblastoma: Results of the pediatric
oncology group 9031" (Tarbell NJ, International Journal of Radiation Oncology*Biology*Physics, Volume 48,
Issue 3, Supplement 1, 2000, Page 179). Median F/U 4.5 years
• 2-year outcome: EFS pre-RT chemo 78% vs. post-RT chemo 80%; OS 83% vs. 90% (NS)
• Conclusion: No difference at 2 years; OS favorable compared to historical controls
• German HIT 88/89 and HIT 91 (1991-97)
• Pilot (HIT 88/89) followed by randomized (HIT 91). Trial enrolled pts with supratentorial PNET,
medulloblastoma, and anaplastic ependymomas. All treated with extensive resection. In HIT 88/89, pts treated
postoperatively with chemo x2 cycles (Ifosfamide, etoposide, MTX, cisplatin, cytarabine) -> RT (CSI 35.2 Gy
+ PF boost 20 Gy). In HIT 91, randomized to 1) chemo -> RT (same as HIT 88/89) or 2) immediate RT (35.2
+ 20) followed by maintenance chemo x8 cycles (CCNU, cisplatin, vincristine).

• Medullo prognostics, 2007 PMID 17473196 -- "Prognostic relevance of clinical and biological risk factors in
childhood medulloblastoma: results of patients treated in the prospective multicenter trial HIT'91." (Rutkowski
S, Clin Cancer Res. 2007 May 1;13(9):2651-7.)
• Formalin-fixed paraffin-embedded tumor samples analyzed, c-myc DNA, N-myc DNA, c-myc mRNA, and
trkC mRNA
• Risk groups identified based on trkC mRNA and c-myc mRNA
• Favorable group (incl. 2 patiens M+): high trkC and low c-myc mRNA: 7-year EFS 100%
• Intermediate group: everyone not in favorable/unfavorable - 7-year EFS 65%
• Unfavorable group: M+ and low trkC and high c-myc mRNA: 7-year EFS 33%
• Medullo outcomes, 2000 PMID 10661332 -- "Postoperative neoadjuvant chemotherapy before radiotherapy as
compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of
medulloblastoma in childhood: results of the German prospective randomized trial HIT '91." (Kortmann RD,
Int J Radiat Oncol Biol Phys. 2000 Jan 15;46(2):269-79.)
• Subset report of 158 medulloblastoma patients (137 randomized). Median F/U 2.5 years
• 3-year outcome: RFS RT->chemo 78% vs. chemo->RT 65% (SS), but no difference if age 3-6 years
• Negative prognosis: M2/3 disease, age <8 years. M1 not a bad prognostic factor
• Conclusion: RT upfront with maintenance chemo more effective. Neoadjuvant chemo caused higher RT
myelotoxicity, and more RT interruptions
• Pilot HIT 88/89 PMID 9743957 -- "Preradiation chemotherapy of children and young adults with malignant
brain tumors: results of the German pilot trial HIT'88/'89." (Kuhl J, Klin Padiatr. 1998
Jul-Aug;210(4):227-33.)
• RT delayed median 23 weeks
• 5-year OS: medulloblastoma 57%, ependymoma 62%, malignant glioma 36%, ST PNET 30%
• Conclusion: Well tolerated and efficacious. Based on this, HIT 91 developed
Chemotherapy to Delay XRT

• CCG 921 (1986-1992) -- vincristine/lomustine/prednisone vs. 8-in-1
• Infants; 1994 PMID 8040673 — "Survival of infants with primitive neuroectodermal tumors or malignant
ependymomas of the CNS treated with eight drugs in 1 day: a report from the Childrens Cancer Group."
(Geyer JR et al. J Clin Oncol. 1994 Aug;12(8):1607-15.)
• Infant (<1.5 year) subset of 82 children (46 posterior fossa, 15 ependymoma, 11 nonpineal ST-PNET, 8
pineoblastoma, 2 ATRT. Received Arm B only (8-in-1), RT omitted in most cases
• 3-year PFS: ST PNET 55% vs. medullo 22% vs. ependymoma 22% vs. pineoblastoma 0%. Median
time-to-progression 6 months
• Conclusion: OS is poor, a subset remained disease-free with chemo only
• Comment: Results inferior compared to Baby POG, probably due to less intensive chemo, but ~20%
long-term survivors with chemo only
• Infants failures; 2005 PMID 16007595 -- "Patterns of treatment failure in infants with primitive
neuroectodermal tumors who were treated on CCG-921: a phase III combined modality study." (Hong TS,
Pediatr Blood Cancer. 2005 Oct 15;45(5):676-82.)
• Infant (<1.5 years) subset of 65 patients (19 supratentorial, 46 posterior fossa.)
• Outcome: 5-year relapse rate M0 64% vs. M+ 71%. ST-PNET subset M0 64% vs. M+ 100%. Relapses
within 2 years
• Conclusion: Despite aggresive chemo, infents have high rates of treatment failure
• Baby POG I (1986-90)
• Histologies: medulloblastoma 31%, ependymoma 24%, PNET 18%, malignant glioma 9%, brain-stem glioma
7%, other 9%. 27% M+. GTR in 38% of cases.
• RT for medullo, PNETs, anaplastic ependymoma, or subarachnoid seeding CSI 35.2 Gy + boost to primary to
54 Gy. RT for ependymoma, gliomas local to 54 Gy. If no residual disease after chemo, reduced RT to CSI 24
Gy and primary site 50 Gy. Infants <2 years 90% of dose
• Response rate: best in medulloblastoma, glioma, ependymoma. Poor/no response in brain-stem gliomas and
embryonal tumors
• Conclusion: Chemo effective in infancy. If GTF, chemo alone provided excellent control. No clinically
important neurotoxicity. However, cannot recommend for embryonal tumors
• 10-years, 1999 PMID 11554387 — "The treatment of malignant brain tumors in infants and very young
children: an update of the Pediatric Oncology Group experience." (Duffner PK et al. Neuro-oncol. 1999
Apr;1(2):152-61.)
• Medullo: GTR 38%, 62% R+; of these 48% CR/PR to chemo. 5-year PFS 32%, OS 40%. Progression
typically <6 mo, none >2 years. No difference if RT delayed by 1 or 2 years
• Medullo: For children with GTR and M0, treated with CSI 24 Gy + 30 Gy PF boost. 5-year OS 69%
(comparable to older standard risk children)
• Medullo conclusion: chemo allowed for a delay in RT in children with GTR and possibly CR to chemo, which
allows for avoidance of the toxicity of irradiating CNS in very young
• CCG, 8-in-1
• Children < 18 months. Included medulloblastoma (56%), ependymoma (18%), ST PNET (12%),
pineoblastoma (10%), ATRT (2%). Eight drugs in 1 day: vincristine, carmustine, procarbazine, hydroxyurea,
cisplatin, cytarabine, prednisone, and cyclophosphamide. Planned for delayed RT but was omitted in most
cases.
• 1994: PMID 8040673 — "Survival of infants with primitive neuroectodermal tumors or malignant
ependymomas of the CNS treated with eight drugs in 1 day: a report from the Childrens Cancer Group." Geyer
JR et al. J Clin Oncol. 1994 Aug;12(8):1607-15.
• Results inferior compared to Baby POG, probably due to less intensive chemo, but ~20% long-term
survivors with chemo only
• St. Jude's Patterns of Failure Study PMID 9300735, Hartsell et al. "Patterns of failure in children with
medulloblastoma: effects of preirradiation chemotherapy" Int J Radiat Oncol Biol Phys. 1997; 39(1): 15-24
• 53 pts tx'd w/ pre-RT chemotherapy (if <3, received chemo then delayed CSI; if >3 w/ advanced dz, received
chemo followed by CSI)
• 23% rate of failure w/ delayed xrt; site of failure most commonly posterior fossa; salvage possible in 50% of
failures
• Conclusion: In M0 pts who get chemo followed by delayed CSI, risk of neuraxis failure increases w/ duration
of chemo.
Postoperative chemotherapy alone

• German Pediatric Brain Tumor Study Group, 2005 (1992-1997) - PMID 15758008 — "Treatment of Early
Childhood Medulloblastoma by Postoperative Chemotherapy Alone." (Rutkowski S et al. New Engl J Med
352:978-986, 2005. )
• Prospective. 43 children <3, 28% had M2-M3 disease. Treated at 31 different centers. Treatment was
maximum surgical removal of the tumor, with confirmation by MRI or CT. Intraventricular reservoir
(Ommaya) for MTX. Chemotherapy started in 2-4 weeks, consisting of three 2-month cycles of
cyclophosphamide, methotrexate (intraventricular and intravenous) with leucovorin, vincristine, carboplatin,
and etoposide, divided into four administrations per cycle, with one week between each cycle. Methotrexate
was intraventricular and intravenous. Treatment stopped after 3rd cycle. If not a complete response, then went
on to XRT or other treatment.
• 5-yr OS and PFS was 66% and 58%; GTR 93% and 82% vs. STR 56% and 50% vs. M2/M3 38% and 33%.
• Remission (no RT): 14/17 (82%) with GTR; 21/31 (68%) with M0-M1; 3/12 (25%) with M2-M3 . Response
rate to chemo was 62% in pts with measurable disease. Higher general intelligence in pts who did not receive
XRT (compared to pts from prior trials).
• Conclusion: Post-op chemo alone is promising in young children without mets
• Baby Brain French Society of Paediatric Oncology, SFOP, 2005 (1990-2002) - PMID 16054568 —
"Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young
children." Grill J et al. Lancet Oncol. 2005 Aug;6(8):573-80.
• 79 pts. Age < 5. Combination chemotherapy (does not include MTX), 3 courses in 7 cycles. Carboplatin,
procarbazine, etoposide, cisplatin, vincristine, cyclophosphamide. Classified as R0M0 (no residual disease, no
mets), R1M0 (radiologic residual disease) or RXM+ (mets).
• Median f/u 6.8 yrs. For R0M0: 5-yr OS 73%, PFS 29% if gross total section and 0% for subtotal resection. For
R1M0: 5-yr OS 41%, PFS 6%. For RXM+: 5-yr OS 13%, PFS 13%.
• Post-op chemotherapy alone can be used for children with complete resection but not those with metastatic
disease or incompletely resected tumor.
RT Technique
• CSI
• Daily fractions: 1.6-1.8 | 2*1.0 Gy, 5 days a week up to 18-40 Gy (18-25 Gy for AR only)
• Posterior Fossa boost
• Daily fractions: 1.8-2.0 | 2*1.0 Gy, 5 days a week up to 54-60 Gy | 36-40 & 55-68 (tumor bed) Gy
• Upper border 1 cm above the mid-point between the occiput and vertex
• Anterior border at the posterior clinoid
• Posterior border at the inner table of the skull
• Inferior border at the C2-C3 junction
• Plain film determination:
• Line drawn from foramen magnum to skull vertex is bisected with a perpendicular line
• A point X is identified on the perpendicular line at one-third of the distance from the back of the skull
• A line that connects the posterior clinoid process, X, and the internal occipital protuberance defines the
superior border of the posterior fossa
• Extent should be determined on MRI; plain films estimates as above not very good
• Posterior fossa may not require full boost; a multi-institutional prospective study showed 5% PF failure rate
with CSI 23.4 Gy, PF 36 Gy, and tumor bed boost 55.8 Gy
• RT should be delivered in <=50 days (limit in PNET-3 protocol), otherwise negative impact on EFS and OS
• Adjuvant vincristine chemotherapy may be administered during radiotherapy for a total of eight doses (weekly)
• Multi-Institutional; 2008 (1996-2003) PMID 17892918 -- "Multi-institution prospective trial of reduced-dose
craniospinal irradiation (23.4 gy) followed by conformal posterior fossa (36 gy) and primary site irradiation (55.8
gy) and dose-intensive chemotherapy for average-risk medulloblastoma." (Merchant TE, Int J Radiat Oncol Biol
Phys. 2008 Mar 1;70(3):782-7. Epub 2007 Sep 24.)
• Prospective. 4 institutions in US and Australia. 86 patients, average-risk MB, treated with risk-adapted RT. RT
technique: CSI 23.4 Gy, conformal posterior fossa RT 36 Gy, primary site (GTV + 2cm + 0.5cm) RT 55.8 Gy.
Chemo (cyclophosphamide, cisplatin, vincristine) 6 weeks after RT x4 cycles. Median F/U 5.1 years
• Outcome: 5-year EFS 83%, posterior fossa failure 5%
• RT dosimetry: 13% reduction in volume of PF receiving >55 Gy; reductions to temporal lobes, cochleae,
hypothalamus significant
• Conclusion: Irradiation of less than entire PF results in disease control comparable to that after treating entire
PF
• St. Bartholomew's, 2004 (UK) PMID 15447964 -- "A comparison of conventional, conformal and
intensity-modulated coplanar radiotherapy plans for posterior fossa treatment." (Breen SL, Br J Radiol. 2004
Sep;77(921):768-74.)
• Goal: sparing of cochlea to reduce ototoxicity, particularly when RT given concurrently with cisplatin. 2D
(opposed laterals) vs. 3D-CRT (2 wedged posterior obliques) vs. IMRT (4F coplanar)
• Conclusion: 3D-CRT superior to both 2D and IMRT
• POG 8631/CCG 923 (1986-1990) -- CSI 36 Gy vs. CSI 23.4 Gy
• 2000, PMID 10944134 -- "Low-stage medulloblastoma: final analysis of trial comparing standard-dose with
reduced-dose neuraxis irradiation." (Thomas PR, J Clin Oncol. 2000 Aug;18(16):3004-11.)
• Randomized. 126 patients, low risk (>3 years, complete resection T1-T2, later also T3a, M0) standard CSI
36(20*1.8) vs. reduced CSI 23.4(13*1.8); both followed by posterior fossa boost to 54(30*1.8) Gy. Study
closed prematurely due to high relapse in reduced arm
• 5-year EFS: standard CSI 67% vs. reduced CSI 52% (p=0.080)
8-year EFS: standard CSI 67% vs. reduced CSI 52% (p=0.141)
These data confirm the original one-sided conclusions but suggest that differences are less marked with time
• Conclusion: Reduced CSI 23.4 alone is insufficient; may need concurrent chemo
• SIOP II (1984-1989) -- CSI 35 Gy vs. CSI 25 Gy; also +/- adjuvant chemo
• Randomized. 364 patients. SIOP I low risk (total/subtotal resection, no brain stem invasion, M0) randomized
to +/- adjuvant chemo (vincristine, methotrexate, procarbazine), and then randomized to standard CSI 35 Gy
vs. reduced CSI 25 Gy. Boost posterior fossa to 55 Gy. High risk randomized to +/- adjuvant chemo, then
standard CSI and additional post-RT chemo
• 1995 PMID 7623725 "Prospective randomised trial of chemotherapy given before radiotherapy in childhood
medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric
Oncology (GPO)" Bailey et al. Med Pediatr Onc 25(3):166-78, 1995
• Outcome: No advantage to pre-RT chemo. Standard CSI 35 Gy for low risk pts increased EFS (68% vs
55%). Low risk patients with adjuvant chemo and CSI 25 Gy did particularly badly
• Conclusion: No benefit to adjuvant chemo. Standard dose of CSI is 35 Gy
• RT Review, 2004 PMID 15001263 -- "Impact of radiotherapy parameters on outcome in the International
Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 study of
preradiotherapy chemotherapy for M0-M1 medulloblastoma." (Taylor RE, Int J Radiat Oncol Biol Phys. 2004
Mar 15;58(4):1184-93.)
• Assessed accuracy of cribriform fossa, skull base, and PF field in 179/217 patients. Planning films reviewed
in 131/179 patients.
• Target deviation: 1) cribriform fossa: <3-mm margin between shielding edge and cribriform fossa; 2) skull
base: <8-mm margin between shielding edge and skull base; and PF: >5-mm discrepancy between field
edge and protocol definition.
• 3-year outcome: OS RT <=50 days 84% vs. RT >50 days 71% (SS), EFS 78% vs. 54% (SS)
• RT QA: 44% had 1+ deviations. PF recurrence in 34% with targeting deviation (and 54% with sup/ant/post
deviation) vs. 16% without (SS)
• Conclusion: RT should be delivered <50 days, and attention to PF field placement is important
• U Penn, 1995 PMID 7753996 -- "Posterior fossa: analysis of a popular technique for estimating the location in
children with medulloblastoma." (Solit DB, Radiology. 1995 Jun;195(3):697-8.)
• 10 patients. Compared standard method for identifying posterior fossa on plain films vs. MRI
• Conclusion: Underestimated volume in all 10 cases in some areas, but also significantly overestimated volume
in different areas
• SFOP M4, 1992 PMID 1512166 -- "M4 protocol for cerebellar medulloblastoma: supratentorial radiotherapy
may not be avoided." (Bouffet E, Int J Radiat Oncol Biol Phys. 1992;24(1):79-85.)
• Prospective. Surgical resection and risk-adapted post-op chemo ("8-in-1" + MTX). RT only to posterior fossa
(54 Gy) and spinal axis (36 Gy), supratentorium spared. Mean F/U 6 years
• 6-year outcome: DFS 18%; progression in 9/13 supratentorial
• Conclusion: Entire neuroaxis (CSI) needs to be treated, despite long-term toxicity
Toxicity considerations
• Also please see Pituitary toxicity
• Surgery: Posterior Fossa Syndrome: difficulty swallowing, mutism, truncal ataxia, emotional lability (occurs
12-24 hours postop; can take months and RT should not be delayed)
• Chemo: infertility, bone marrow tolerance, ototoxicity, poor CNS penetration
• RT: ototoxicity; endocrine and neurocognitive dysfunctions (long-term effects of CSI)
• Full posterior fossa RT results in 5 point IQ drop per year for <7 year old and -0.8 points for >7 year old
• The supratentorial radiation dose is the principal risk factor associated with impaired intellectual outcome. An
approximate 8-point per year decline for children treated with 36 Gy. One can forecast final IQ score based on
the initial IQ score, dose of irradiation, and age at time of irradiation PMID 1517781
• Even with the reduced radiation dose side effects can still be substantial. An average loss in IQ scores of over 4
points per year for the first 3 years after treatment by 23.4 Gy. In younger children (or those with a higher
baseline IQ score at the start of treatment) this loss was even more severe PMID 11481352
• The dose of radiotherapy applied to the brain strongly influences later verbal and non-verbal skills in children
with medulloblastoma. Verbal fluency, immediate word list recall, block design, and fine motricity of the
dominant hand were significantly lower in children irradiated at the standard doses than in those irradiated at
reduced doses PMID 11104345
• Neurocognitive development and outcome of children with cerebellar tumors diagnosed in infancy is very
positive among those who were treated with surgery and chemotherapy. However, those who received CRT as
part of their treatment are likely to have neurocognitive and psychosocial deficits that require remediational
interventions PMID 10550145
Adult
More rarely, medulloblastoma may present in older patients.
PMID 16189725
References:
1. Levin VA, Vestnys PS, Edwards MS, et al.: Improvement in survival produced by sequential therapies in the
treatment of recurrent medulloblastoma. Cancer 51(8): 1364-1370, 1983.
2. Carrie C, Lasset C, Alapetite C, et al.: Multivariate analysis of prognostic factors in adult patients with
medulloblastoma: retrospective study of 156 patients. Cancer 74(8): 2352-2360, 1994.
3. Allen JC, Bloom J, Ertel I, et al.: Brain tumors in children: current cooperative and institutional chemotherapy
trials in newly diagnosed and recurrent disease. Seminars in Oncology 13(1): 110-122, 1986.
References
[1] http:/ / www. healthutilities. com/ hui3. htm
Radiation Oncology/Medulloblastoma/Protons
Proton Therapy in Medulloblastoma
Clinical Data
• Loma Linda; 2004 (2001-2003) PMID 15701271 -- "Reducing toxicity from craniospinal irradiation: using
proton beams to treat medulloblastoma in young children." (Yuh GE, Cancer J. 2004 Nov-Dec;10(6):386-90.)
• Retrospective. 3 children, M2-M3 medulloblastoma, treated with CSI. 36 CGE + 18 CGE PF boost. Cranium -
opposed lateral fields. Spine - three matched PA fields
• Outcome: Substantially reduced dose to cochlea and vertebral bodies; virtually no exit dose through thorax,
abdomen, and pelvis.
• Toxicity: acute side effect mild
• Conclusion: Successful reduction of normal tissue irradiation
Treatment Planning
• PSI
• 2nd cancers; 2002 PMID 12377335 -- "Potential reduction of the incidence of radiation-induced second
cancers by using proton beams in the treatment of pediatric tumors." (Miralbell R, Int J Radiat Oncol Biol
Phys. 2002 Nov 1;54(3):824-9.)
• Treatment planning. 2 children, parameningeal rhabdomyosarcoma and medulloblastoma. Conventional
photon vs. IMRT vs PT vs IMPT. Secondary cancer incidence estimated
• Outcome: RMS: protons reduced expected incidence by > 2x over photons; MB protons reduced expected
incidence by 8-15x over photons
• Conclusion: Potential for significant reduction in secondary cancers with proton therapy
• Supratentorial; 1997 PMID 9231669 -- "Potential role of proton therapy in the treatment of pediatric
medulloblastoma/primitive neuroectodermal tumors: reduction of the supratentorial target volume." (Miralbell
R, Int J Radiat Oncol Biol Phys. 1997 Jun 1;38(3):477-84.)
• Treatment planning. 3 year old child with medulloblastoma. Photon whole brain (conventional 2 field) vs.
hand-optimized photon brain (6 fields) vs. IMRT (9 fields) vs. proton (3 fields). Whole brain 30 Gy +
posterior fossa/ventricle boost 10 Gy.
• Outcome: both optimized photon plans only slightly worse than proton plan
• Conclusion: Decrease in morbidity can be expected from protons and optimized photon plans compared to
whole brain irradiation
• Craniospinal; 1997 PMID 9240650 -- "Potential role of proton therapy in the treatment of pediatric
medulloblastoma/primitive neuro-ectodermal tumors: spinal theca irradiation." (Miralbell R, Int J Radiat Oncol
Biol Phys. 1997 Jul 1;38(4):805-11.)
• Treatment planning. 2 year old child with neuroblastoma, undergoing CSI. Single posterior 6 MV photon
field vs. single posterior 100 MeV proton field, 30 Gy
• Outcome: Target (spinal dural sac) coverage comparable. Vertebral body V50% photons 100% vs. protons
20%. Heart dose V60% photons 60% vs. protons 0%
• Conclusion: Potential role for proton therapy in decreasing OAR dose during CSI irradiation
Economics
• Sweden; 2005 PMID 15637691 -- "Cost-effectiveness of proton radiation in the treatment of childhood
medulloblastoma." (Lundkvist J, Cancer. 2005 Feb 15;103(4):793-801.)
• Markov simulation, children age 5 followed for tumor control and adverse events
• Outcome: Proton therapy 23,600 cost saving, 0.68 additional QALY per patient. Biggest benefit due to
reduction in IQ and GHD loss
• Conclusion: Proton therapy can be cost-effective and cost-saving compared with conventional RT
Radiation Oncology/Peds/CNS PNET

> Radiation Oncology/Peds/Brain tumors

Supratentorial PNETs
• Account for <5% of pediatric CNS tumors
• Patients typically present with symptoms related to increased ICP
• Embyonal tumor composed of undifferentiated/poorly differentiated neuroepithelial cells, which can differentiate
along neuronal, astrocytic, ependymal, muscular, or melanotic lines
• Distinct neuronal differentiation = cerebral neuroblastoma
• Ganglion cells present = ganglioneuroblastoma
• Arising in pineal region = → pineoblastoma
• Typically more aggressive nature compared to medulloblastoma (infratentorial PNET), with rapid progression
• German HIT trials: 3-year PFS ST-PNET PFS 49% vs standard-risk medulloblastoma 78% on same protocol
• CCG 921 trial: 5-year PFS ST-PNET M0 53% vs. medulloblastoma M0 71%; M+ 29% vs. 52% on same
protocol
• Different genetic alterations in ST PNET vs. medulloblastoma
• May occur anywhere in the CNS
• Historically treated on same protocols as medulloblastoma; treatment strategy now comparable to high-risk
medulloblastoma
• Historically, POG has viewed PNET and medulloblastoma as different entities, while CCG was reporting them
together
• Based on German HIT 87/92 trials, RT cannot be eliminated in young (<3 years) patients, even with intense
chemotherapy, and delay should be <6 months. Similarly, in CCG and POG protocols, infants treated with only
chemotherapy tended to progress and die of the disease
Poor prognostic factors:
• Disseminated disease at diagnosis (M+)
• Young age <3
• Non-cerebellar (medulloblastoma), non-pineal (pineoblastoma) primary
Studies
• CCG 99701 (Ongoing)
• Phase I/II. Feasibility of concurrent/maintenance chemotherapy. Central primitive embryonic tumors (PNET,
ATRT, Medulloblastoma, Ependymoblastoma, Medullomyoblastoma, Spongioblastoma, Medulloepithelioma,
Neuroblastoma, Pineoblastoma). No M4 disease. RT CSI 36/20 followed by tumor boost to 53-58.6 Gy in 1.8
Gy/fx, with concurrent carboplatin/ vincristine, followed by maintenance vincristine/ cyclophosphamide or
cisplatin/ vincristine/ cyclophosphamide
• HIT-SKK87 and HIT-SKK92 (1987-1992, 1992-1997)
• HIT-SKK87: Low-risk (complete resection, M0) and age <2.5 received maintenance chemo only until RT at 3
years or progression. High-risk (subtotal resction, M+) and age 2.5-3 induction chemo / maintence chemo until
RT at 3 years or progression
• HIT-SKK92: Post-op chemo x3 cycles first, then if CR no RT. If PR and <18 months, then more chemo, if PR
and >18 months, then RT.
• RT given as CSI 35.2/22 Gy + 20/10 Gy boost; if no residual disease, reduced to CSI 24 Gy + PF boost to 55
Gy
• 2006 PMID 16575007 -- "Role of radiotherapy in supratentorial primitive neuroectodermal tumor in young
children: results of the German HIT-SKK87 and HIT-SKK92 trials." (Timmermann B, J Clin Oncol. 2006 Apr
1;24(10):1554-60.)
• Total 29 children enrolled on both. No RT given in 15 children.
• 3-year outcomes: OS 17% and PFS 15%. RT only positive predictive factor
• Conclusion: Outcomes unsatisfactory. Omission of RT jeopardizes survival, even when intensive chemo given.
Suggest limiting delay of RT to maximum 6 months
• German HIT 88/89 and HIT 91 (1991-97)
• Pilot (HIT 88/89) followed by randomized (HIT 91). Trial enrolled pts with supratentorial PNET,
medulloblastoma, and anaplastic ependymomas. All treated with extensive resection. In HIT 88/89, pts treated
postoperatively with chemo x2 cycles (Ifosfamide, etoposide, MTX, cisplatin, cytarabine) -> RT (CSI 35.2 Gy
+ PF boost 20 Gy). In HIT 91, randomized to 1) immediate RT (35.2 + 20) followed by maintenance chemo x8
cycles (CCNU, cisplatin, vincristine), or 2) chemo -> RT (same as HIT 88/89).
• ST PNET subset, 2002 PMID 11821469, 2002 — "Role of radiotherapy in the treatment of supratentorial
primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT
88/89 and 91." (Timmermann M et al. J Clin Oncol. 2002 Feb 1;20(3):842-9.)
• Subset analysis of 63 children with ST PNET. 67% incomplete resection. 7 children RT to tumor site only,
2 children no RT, 15 children major RT violations. Median F/U 2.6 years
• 3-yr OS 48.4%. Progression in 38 pts, LR in 27 pts. 3-year PFS correct RT 49% vs. major protocol violation
RT 7%
• Conclusion: Preirradiation chemo increases risk of recurrence. Volume should encompass whole CNS to 35
Gy with boost to at least 54 Gy
• Pilot HIT 88/89 PMID 9743957 -- "Preradiation chemotherapy of children and young adults with malignant
brain tumors: results of the German pilot trial HIT'88/'89." (Kuhl J, Klin Padiatr. 1998
Jul-Aug;210(4):227-33.)
• RT delayed median 23 weeks
• 5-year OS: medulloblastoma 57%, ependymoma 62%, malignant glioma 36%, ST PNET 30%
• Conclusion: Well tolerated and efficacious. Based on this, HIT 91 developed
• CCG 921 (1986-1992)
• Infants failures; 2005 PMID 16007595 -- "Patterns of treatment failure in infants with primitive
neuroectodermal tumors who were treated on CCG-921: a phase III combined modality study." (Hong TS,
Pediatr Blood Cancer. 2005 Oct 15;45(5):676-82.)
• Infant (<1.5 years) subset of 65 patients (19 supratentorial, 46 posterior fossa.)
• Outcome: 5-year relapse rate M0 64% vs. M+ 71%. ST-PNET subset M0 64% vs. M+ 100%. Relapses
within 2 years
• Conclusion: despite aggresive chemo, infents have high rates of treatment failure
• Older kids failures; 2004 PMID 15337557 -- "Patterns of failure in supratentorial primitive neuroectodermal
tumors treated in Children's Cancer Group Study 921, a phase III combined modality study." (Hong TS, Int J
Radiat Oncol Biol Phys. 2004 Sep 1;60(1):204-13.)
• ST-PNET subset of 44 patients, age >1.5 years. Compared to medulloblastoma treated on same protocol
• Outcome: 3-year PFS M0 53% vs. M+ 14% (SS); 5-year relapse rate 47% vs. 71%. Worse relapse rate
compared to medulloblastoma: M0 47% vs. 29%, M+ 71% vs. 48%
• Pattern of failure: M0 11% in spine; M+ 43% in spine
• Time-course: 80% within 2 years
• Conclusion: High rate of failure, M+ patients doing particularly poorly
• 3-years; 1995 PMID 7602359 -- "Prognostic factors and treatment results for supratentorial primitive
neuroectodermal tumors in children using radiation and chemotherapy: a Childrens Cancer Group randomized
trial." (Cohen BH, J Clin Oncol. 1995 Jul;13(7):1687-96.)
• ST-PNET subset of 55 patients, age >1.5 years.
• Outcome: 3-year OS 57%, PFS 45%; pineal PNET better at 73% and 61% (SS); stage M0 PFS 50% vs. M+
0%. No difference between chemo arms
• Toxicity: 8-in-1 arm worse
• Conclusion: No difference between chemo arms; M0 and pineal site better outcome
• Infants; 1994 PMID 8040673 — "Survival of infants with primitive neuroectodermal tumors or malignant
ependymomas of the CNS treated with eight drugs in 1 day: a report from the Childrens Cancer Group."
(Geyer JR et al. J Clin Oncol. 1994 Aug;12(8):1607-15.)
• Infant (<1.5 year) subset of 82 children (46 posterior fossa, 15 ependymoma, 11 nonpineal ST-PNET, 8
pineoblastoma, 2 ATRT. Received Arm B only (8-in-1), RT omitted in most cases
• Conclusion: OS is poor, a subset remained disease-free with chemo only
• Comment: Results inferior compared to Baby POG, probably due to less intensive chemo, but ~20%
long-term survivors with chemo only
• Baby POG I (1986-90)
• Response rate: best in medulloblastoma, glioma, ependymoma. Poor/no response in brain-stem gliomas and
embryonal tumors
• Conclusion: Chemo effective in infancy. If GTF, chemo alone provided excellent control. No clinically
important neurotoxicity. However, cannot recommend for embryonal tumors
• 10-years, 1999 PMID 11554387 — "The treatment of malignant brain tumors in infants and very young
children: an update of the Pediatric Oncology Group experience." (Duffner PK et al. Neuro-oncol. 1999
Apr;1(2):152-61.)
• ST PNET (17 children): 5-year OS 27%. Failures early
• 3-year survival: GTR 100% vs. STR 11%
• Conclusion: Some children may have prolonged survival
Radiation Oncology/CNS/Pineal
Pineal Gland Tumors
Epidemiology
• 1% adult CNS tumors
• 5% pediatric CNS tumors
• Three separate tumor types:
• Pineal parenchyma tumors
• Glial parenchyma tumors
• Germ cell tumors
• Dramatic variation geographically in distribution (germinoma ~50% in Japan, <30% in Europe)
• Determined by the spatial anatomy and direction of growth
• Obstruction of aquaduct: hydrocephalus presenting as headaches, nausea, vomiting
• Compromise of superior colliculus: vertical gaze palsy, pupillary and oculomotor nerve paresis (Parinaud
syndrome)
• Progressive growth: cranial nerve neuropathies, hypothalamic dysfunction
• Metastatic disease rare, but leptomeningeal spread in ~20% pineoblastomas and ~10% germ cell tumors
Pineal Gland Histology

• Principle cell in the pineal gland is the pinocyte
• Specialized neuron related to retinal cones & rods
• Takes sympathetic input from retina via the suprachiasmatic nucleus
• Converts the stimulation into hormonal output by producing melatonin, which impacts LH and FSH
• Relationship between light-dark cycle, pineal gland, and circadian rhythm
• Stain for neuron specific enolase (NSE) and Synaptophysin
• Surrounding stroma is made of astrocytes
• Stain for GFAP, S-100, and Vimentin
• Germ cells are embryonal remnants, typically presenting in midline structures
Pathology
• Germ cell tumors
• Germinoma (30-40%)
• Non-seminomatous germ cell tumor (10-20%)
• Pineal parenchymal tumors (15-30%)
• Pineocytoma (WHO Grade II):
• Well-differentiated low grade tumor
• Characteristic pineocytomatous rosettes
• May have neuronal, astrocytic, or mixed (ganglioglioma) differentiation
• Pineal parenchymal tumour of intermediate differentiation (WHO Grade III)
• Intermediate grade tumor, between pineocytoma and pineoblastoma.
• Reasonably rare, constituting only 10% of pineal parenchyma tumors
• Pineoblastoma (WHO Grade IV):
• Primitive high grade tumor
• Believed to arise from an immature neural progenitor cells; may have pineal, neuronal, glial, or retinoblastic
differentiation
• May be part of bilateral retinoblastoma with pineoblastoma syndrome ("→ trilateral retinoblastoma
syndrome"), and may be associated with the Rb mutation
• Necrosis is common
• Histologically indistinguishable from → Supratentorial PNET and infratentorial PNET (medulloblastoma)
• Similarly has a significant propensity for leptomeningeal spread
• Papillary tumor of the pineal region (PTPR)
• Rare, recently described entity
• Histologically similar to ependymoma, and thought to arise from specialized ependymocytes
• Glial tumors
• Astrocytomas (10-30%)
• Benign lesions
• Pineal gland cysts, vascular malformations, vein of Galen aneurysms
Treatment Overview
• Work-up includes MRI, CSF, serum markers for bHCG and AFP
• Tissue diagnosis is critical, since management varies significantly based on pathology
• Stereotactic pineal gland biopsy
• Open surgery (typically not favored since only few tumors are amenable to complete resection, many are
chemo-RT sensitive, and there is a real risk of worsening visual deficits)
• CSF diversion may be necessary in patients symptomatic from obstructing hydrocephalus, although if open
surgery is done, may not be necessary
• Germ cell tumors are treated with definitive RT or chemo-RT as with other Germ cell tumors
• Pineoblastoma is treated with surgery followed by adjuvant chemotherapy and craniospinal irradiation like other
→ CNS PNETs). More detail below
• to be continued ...
Pineocytoma
Pineocytoma
• Most reports are small series; largest has 9 patients

• Age difference: Pediatric pineocytomas behave more aggresively, with high rate of recurrence; adult cases appear
more benign
• Barrow Neurological Institute:
• If symptomatic, attempt resection. Adjuvant GKS for subtotal resection
• If small and asymptomatic, stereotactic biopsy, and primary GKS
• Pittsburgh data suggests primary GKS as well
• Mayo data suggests adjuvant RT for subtotal resection to 50-55 Gy
• Barrow Neurological Institute; 2004 (Arizona)(1990-2003) PMID 15271241 -- "Diagnosis and management of
pineocytomas." (Deshmukh VR, Neurosurgery. 2004 Aug;55(2):349-55; discussion 355-7.)
• Retrospective. 9 patients. Mean age 44 years. Surgery: 3 GTR, 6 subtotal or bx. Adjuvant RT in 5/9 patients
(n=2 IMRT 54/30, n=3 GKS)
• Outcome: 4/9 local recurrences (3 clinical, 1 radiographic). Mean time to recurrence 3.5 years
• Radiosurgery: all stable or decreased at 3 years
• Treatment recommendations: If symptomatic, attempt resection. For subtotally resected, adjuvant GKS. For
small asymptomatic tumors, stereotactic biopsy and primary GKS. Need close follow-up
• Mayo; 1996 PMID 8952565 -- "Histologically confirmed pineal tumors and other germ cell tumors of the brain."
(Schild SE, Cancer. 1996 Dec 15;78(12):2564-71.)
• Retrospective. 135 patients with pineal tumors (pineoblastoma 15, intermediate/mixed PPT 6, pineocytoma 9).
• Outcome: 5-year OS pineocytoma 86%, intermediate/mixed PPT/pineoblastoma 49%
• Predictor of survival: RT >50 Gy
• Conclusion: Prognosis depends on tumor type; survival depends on dose of RT
• University of Pennsylvania; 1987 (1975-1985) PMID 3815306 -- "Pineocytomas of childhood. A reappraisal of
natural history and response to therapy." (D'Andrea AD, Cancer. 1987 Apr 1;59(7):1353-7.)
• Retrospective. 4 children (11% of all pineal region tumors). Surgery + CSI+boost (n=3) or local RT (n=2) or
chemo-RT (n=1).
• Outcome: 4/6 recurrences, median 2 years after diagnosis. 3 leptomeningeal dissemination
• Conclusion: Aggressive tumors in pediatric population; RT alone inadequate
Pineoblastoma
• Pathology as above; histologically similar to other CNS PNETs. Many older trials grouped pineoblastoma
together with → supratentorial PNETs
• Mainly occurs in young children (estimated 40-50% in age <1 year) . Children <3 years appear to have
particularly aggressive disease, with frequent advanced presentation
• Rare in adults (<10%), largest series is from Japan national Brain Tumor Registry spanning 30 years, with 34
patients
• Strong tendency to invade surrounding tissue and disseminate through CSF
• Typical approach is surgery, followed by chemotherapy and CSI
• Older children can have a reasonable survival
• Efforts to eliminate RT in young children have resulted in poor outcomes (POG, CCG, and German trials).
However, long-term CSI toxicity is severe, so efforts are under way for dose intensification with stem cell
transplant
Children
• German HIT-SKK87, HIT 91, and HIT-SKK92 (1987-1992, 1992-1997)
• Please see → Supratentorial PNET for more detailed protocol information
• Subset of 11 patients with PB. If <3 years, surgery + chemo with RT deferred until >3 years or progression
(n=5). If >3 years, surgery + chemo + CSI (35.2/22 + 20/10 boost) +/- maintenance chemo (n=6)
• 2007 PMID 16941074 -- "Childhood pineoblastoma: experiences from the prospective multicenter trials
HIT-SKK87, HIT-SKK92 and HIT91." (Hinkes BG, J Neurooncol. 2007 Jan;81(2):217-23.)
• Older children (>3): 5/6 alive with median OS/PFS 7.9 years after chemo and RT. All had M0 disease
• Younger children (<3): 0/5 alive with median OS 0.9 years and PFS 0.6 years. All had M1 disease and/or
postop residual disease. Response to chemo lower, only 1/5 received RT
• Role of RT: all older children received it, and benefited (PR->CR or stayed in CR). One younger child
received who, after progressing on chemo, and showed PR to it
• Conclusion: Combined chemo and RT feasible and effective if >3 years. More intensified regimens
necessary for <3 years
• Subsequent HIT trial for young children with supratentorial PNET investigates short dose-intense induction,
followed by high-dose chemo and CSI
• CCG 921 (1986-1992)

• Please see → Supratentorial PNET for more detailed protocol information
• Older children (>1.5 years) treated with surgery + CSI + chemo; infants (<1.5 years) treated with surgery +
chemo (8-in-1) only
• Pineal only; 1995 PMID 7751882 -- "Survival and prognostic factors following radiation and/or
chemotherapy for primitive neuroectodermal tumors of the pineal region in infants and children: a report of the
Childrens Cancer Group." (Jakacki RI, J Clin Oncol. 1995 Jun;13(6):1377-83.)
• Pineoblastoma subset of 25 patients, 17 age >1.5, 8 infants
• Infants: all infants developed progressive disease, median PFS 4 months
• Older children: 3-year PFS 61% (better than ST-PNET, SS). After RT, 70% had residual pineal region
mass, which persisted as long as 5 years before resolving
• Conclusion: Chemo alone (8-in-1) ineffective for infants. CSI + chemo effective for older children
• All ST-PNETs; 1995 PMID 7602359 -- "Prognostic factors and treatment results for supratentorial primitive
neuroectodermal tumors in children using radiation and chemotherapy: a Childrens Cancer Group randomized
trial." (Cohen BH, J Clin Oncol. 1995 Jul;13(7):1687-96.)
• ST-PNET subset of 55 patients, age >1.5 years.
• Outcome: 3-year OS 57%, PFS 45%; pineal PNET better at 73% and 61% (SS); stage M0 PFS 50% vs. M+
0%. No difference between chemo arms
• Toxicity: 8-in-1 arm worse
• Conclusion: No difference between chemo arms; M0 and pineal site better outcome
• Baby POG I (1986-90)
• 1995 PMID 7753001 -- "Lack of efficacy of postoperative chemotherapy and delayed radiation in very young
children with pineoblastoma. Pediatric Oncology Group." (Duffner PK, Med Pediatr Oncol. 1995
Jul;25(1):38-44.)
• Subset of PB infants (age <3 years, but 8/11 <1 year). 11 patients. Partial surgical resection
• Outcome: All children failed chemo, 9/11 in primary site, 8/11 had leptomeningeal progression at time of
failure. All children died, survival 4-13 months
• Conclusion: Chemo alone not effective
Adults
• Japan; 2005 (1969-1998) PMID 15782004 -- "Management and survival of pineoblastoma: an analysis of 34
adults from the brain tumor registry of Japan." (Lee JY, Neurol Med Chir (Tokyo). 2005 Mar;45(3):132-41;
discussion 141-2.)
• Registry study. All patients registered in national Brain Tumor Registry of Japan reviewed. 34 adults, 22 male.
Median age 35 years (16-66). Gross total resection 5/34. CSI 29/34 with median dose 50 Gy (30-70 Gy).
• Outcome: median OS 2.2 years.
• Predictors: CSI >40 Gy and GTR improved survival
• Conclusion: Poor prognosis in adults

• UCSF; 1995 (1975-1992) PMID 7501100 -- "Pineoblastoma in adults." (Chang SM, Neurosurgery. 1995
Sep;37(3):383-90; discussion 390-1.)
• Retrospective. 11 patients. Median age 36 years (17-59). All with symptomatic hydrocephalus. Gross total
resection 1/11. CSI 10/11 (CSI 24-45 Gy with tumor boost to 54-59.4 Gy). 7/11 chemo
• Outcome: M+ (5/10) median PFS 10 months, median OS 2.5 years; M0 (5/10) all alive at 2.2 years follow-up
• Conclusion: M0 patients can do well after surgery + CSI, benefit of chemo unclear
SRS
• Marseille; 2006 (France) PMID 16172830 -- "The role of Gamma Knife radiosurgery in the treatment of pineal
parenchymal tumours." (Reyns N, Acta Neurochir (Wien). 2006 Jan;148(1):5-11; discussion 11.)
• Retrospective. 13 patients (8 pineocytomas, 5 pineoblastomas). SRS alone in 6 cases, after surgery 3 cases,
with chemo 3 cases, s/p EBRT 1 case. Mean marginal dose 15 Gy (11-20 Gy). Mean F/U 2.8 years
• Outcome: pineocytoma 8/8 alive, pineoblastoma 2/5 alive
• Toxicity: none major
• Conclusion: SRS effective and safe for pineocytoma, should have a role in multimodality treatment for
pineoblastoma
• Pittsburgh; 2002 PMID 12234394 -- "The role of radiosurgery for the treatment of pineal parenchymal tumors."
(Hasegawa T, Neurosurgery. 2002 Oct;51(4):880-9.)
• Retrospective. 16 patients treated with SRS as primary or adjuvant. Pineocytoma (n=10), mixed tumor (n=2),
pineoblastoma (n=4). Mean margin dose 15 Gy. Mean F/U 4.3 years
• Outcome: 2-year OS 75%, 5-year OS 67%; LC rate 100%; 5/16 died, 4 secondary to leptomeningeal or
extracranial spread
• Conclusion: SRS valuable modality for pineocytomas; can be used as boost for malignant pineal tumors
• Komaki; 2001 (Japan) PMID 11767295 -- "Stereotactic gamma radiosurgery for pineal and related tumors."
(Kobayashi T, J Neurooncol. 2001 Sep;54(3):301-9.)
• Retrospective. 30 patients with pineal (64%) and nearby tumors. Pineocytoma (n=3), pineoblastoma (n=2).
Pineal RT mean marginal dose 15.7 Gy
• Outcome: pineocytoma 2/3 CR, 1/3 PR, no progression at 22 months; pineoblastoma 1/2 PR, 1/2 PG
• Conclusion: GKS is expected to be effective approach
Brachytherapy
Iodine-125
• Budapest; 2006 PMID 17163340 -- "Review of radiosurgery of pineal parenchymal tumors. Long survival
following 125-iodine brachytherapy of pineoblastomas in 2 cases." (Julow J, Minim Invasive Neurosurg. 2006
Oct;49(5):276-81.)
• Case report. 2 patients. Follow-up 5.1 and 4.8 years
• Outcome: shrinkage 73% and 77%, both negative on PET
• Conclusion: Two successful treatments reported
Germ Cell Tumors

• Please see the Germ cell page for further discussion
Papillary Tumor of the Pineal Region (PTPR)

• Rare; 41 cases reported as of 2007
• Mean age at presentation 31 years, with slight female predominance
• Most common presenting symptom headache, secondary to obstructing hydrocephalus
• Usually well-circumscribed, large lesions, sometimes with cystic component
• Main histological feature is papillary architecture
• Frequent local recurrences, but spinal dissemination rare (WHO Grade II or III)
• WHO; 2007 PMID 17598824 -- "Papillary tumor of the pineal region and spindle cell oncocytoma of the
pituitary: new tumor entities in the 2007 WHO Classification." (Roncaroli F, Brain Pathol. 2007 Jul;17(3):314-8.)
[http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1750-3639.2007.00081.x Free Full Text]]
• WHO Pathology codification
• INSERM; 2006 PMID 17021405 -- "Prognosis and histopathologic features in papillary tumors of the pineal
region: a retrospective multicenter study of 31 cases." (Fevre-Montange M, J Neuropathol Exp Neurol. 2006
Oct;65(10):1004-11.)
• Retrospective. 31 patients. Median age 29 years. Gross total resection 21/31 patients. RT 15 patients.
• Outcome: 5-year OS 73%, PFS 27%
• Conclusion: Frequent local recurrences
• Lyon; 2003 PMID 12657936 -- "Papillary tumor of the pineal region." (Jouvet A, Am J Surg Pathol. 2003
Apr;27(4):505-12.)
• Initial pathology report. 6 cases
Radiation Oncology/Peds/ATRT 77
Radiation Oncology/Peds/ATRT
Epidemiology
• Estimated 2-3% of primary CNS tumors in <18 population.
• Majority of patients present at age <3 yrs.
• A workshop on ATRT (PMID 12142780) reported that pathologic review of a recent CCG study suggests ATRT
may represent a significant proportion of brain tumors in children <3 yrs old.
Diagnosis
• Major diagnostic dilemma is distinguishing from medulloblastoma.
• IHC necessary for diagnosis (vimentin, EPA, and SMA found in rhabdoid tumors but not medulloblastoma)
• IN11 gene mutated in ~85% of ATRT.
Treatment
• Treatment strategy includes maximum surgical debulking, chemotherapy and radiation therapy.
Radiation Therapy
• Neurological Institute, Taipei, 2006 (1990-2003) - PMID 16406394 -- "Impact of radiotherapy for pediatric
CNS atypical teratoid/rhabdoid tumor (single institute experience)." Chen YW et al. Int J Radiat Oncol Biol Phys.
2006 Mar 15;64(4):1038-43.
• 17 pts w/ ATRT who received radiotherapy as part of their treatment regimen.
• Time interval b/w surgery and RT initiation was important prognostic factor on multi-variate analysis for
overall survival.
• St. Jude's, 2005 (1984-2003) - PMID 15735125 -- "Atypical teratoid/rhabdoid tumors (ATRT): improved
survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy."
J Clin Oncol. 2005 Mar 1;23(7):1491-9.
• 37 pts w/ ATRT (22 pts 3 yrs or younger)
• Majority of pts >3 yrs received CSI.
• 2yr OS was significantly better for pts >3 yrs old.
• The only survivors who were <3 y/o received RT as part of their tx.
• Boston Regimen - PMID 15803379 -- "Continuous remission of newly diagnosed and relapsed central nervous
system atypical teratoid/rhabdoid tumor."
• Early pilot data
Reviews
• Brown; 2007 - PMID 16855864 — "Atypical teratoid/rhabdoid tumor: the controversy behind radiation therapy."
(Squire SE, J Neurooncol. 2007 Jan;81(1):97-111.)
Radiation Oncology/Retinoblastoma
Epidemiology
• Most common primary ocular malignancy of childhood; ~4% of
pediatric malignancies
• Incidence 1/20,000
• ~250 cases per year in USA
• Higher rates in developing countries
• Bilateral disease 20-30%
• 10% patients have family history; 90% are sporadic (of these
20-30% are bilateral, and therefore heritable)
• Overall 40% have hereditary retinoblastoma, 60% have sporadic type
• Average age at diagnosis 1 year for bilateral; 2 years for unilateral
• Uncommonly, patients with bilateral retinoblastoma can also develop a midline neuroblastic tumor. The
syndrome is called "trilateral retinoblastoma" (75% of the third tumors are → pineoblastoma)
• Heritable form transmitted in autosomal dominant fashion
• Clinical presentation
• Leukocoria (white reflection in the pupil): initially inconstant, visible at certain angles/light conditions, may be
seen on flash photography
• Strabismus
• Also iris rubeosis, hypopyon, hyphema, orbital cellulitis, and exophthalmia
• Some children may have no symptoms
Diagnosis
• Awake examination with attention to visual acuity, extraocular
movement, pupillary examination, slit-lamp examination, and
indirect ophthalmoscopy
• Ocular fundus examination under general anesthesia: white tumor
with angiomatous dilation of the vessels
• Unilateral or bilateral nature of the lesions
• Number of tumors
• Location in the retina (posterior pole, anterior retina), and
anatomica relations with optic disc and macula
• Tumor size (diameter, thickness) Fundoscopic examination
• Subretinal fluid and tumor seeds
• Vitreous seeding (localized vs diffuse)
• Ocular ultrasound: On A-mode shows very intense reflections from calcium deposits. On B-mode shows a
heterogenous acoustic solidity with highly reflective intrinsic echoes within the tumor and attenuation of orbital
pattern
• Differential diagnosis includes Coats' disease, retinal

detachment, retinopathy of prematurity, persistent hyperplastic
primary vitreous
• MRI: assessment of local extension to optic nerve, anterior
chamber, and orbital fat. Slightly hyperintense on T1, hypointense
on T2. Also to rule out trilateral retinoblastoma
• CT: intraocular mass with a higher density than the vitreous body,
calcified in 90% of cases and moderately enhanced after iodine
contrast agent injection. However, should be minimized due to Sagital MRI
ionizing exposure, particularly in heritable cases

• If patients needs enucleation, consider systemic staging with CSF cytology, bone marrow cytology, and spinal
axis MRI
• Genetic testing should be considered
Pathology
• First disease for which genetic etiology was demonstrated
(Knudson, 1971 - two hit hypothesis)
• Rb gene located on 13q14 is part of G1/S checkpoint. It is also
required for appropriate exit from the cell cycle of retinal progenitor
cells and for rod development
• >900 mutations of Rb gene have been reported, many in areas of
binding domain with E2F
• However, other molecular events are also necessary for
tumorigenesis; n-myc is amplified in ~10%
• Given higher prevalence in developing countries, HPV (Human
Papilloma Virus, via E7) may play a role
• Neuroepithelial origin
• Tumor cells form Flexner-Wintersteiner rosettes
Staging
Flexner-Wintersteiner rosettes
• Historically, retinoblastoma was separated into intraocular and
extraocular disease
• Intraocular retinoblastoma was classified using the Reese-Ellsworth staging, which was based on the likelihood of
preserving the eye after EBRT. However, it does not have good predictive power in strategies involving initial
chemotherapy
• International Classification System was developed in 2003 to predict outcomes in response to chemotherapy and
focal consolidative therapy, and is used in COG protocols
Reese Ellsworth Staging
• Stage Ia - solitary, <4 disc diameters, at or behind equator
• Stage Ib - multiple, <4 disc diameters, at or behind equator
• Stage IIa - solitary, 4-10 disc diameters, at or behind equator
• Stage IIb - multiple, 4-10 disc diameters, at or behind equator
• Stage IIIa - anterior to equator
• Stage IIIb - solitary tumor >10 disc diameters, behind equator
• Stage IVa - multiple tumors, some >10 disc diameters
• Stage IVb - anterior to ora serrata (serrated jct. between retina & ciliary body)
• Stage Va - massive tumor, > 50% retina
• Stage Vb - vitreos seeding
International Classification System
Group Characteristics
Group A <= 3mm height, >= 3mm from fovea, >= 1.5 mm from optic nerve
(Small)
Group B >3mm height, clear subretinal fluid <= 3mm from tumor margin
(Medium)
Group C Localized vitreous seeding (C1), subretinal seeding <= 3mm from tumor margin (C2), or both (C3)
(Confined
Medium)
Group D Diffuse vitreous (D1) or subretinal seeding >3mm from tumor margin (D2), or both (D3). Subretinal fluid >3mm from tumor
(Diffuse margin
Large)
Group E No visual potential, or presence of >=1 of the following: tumor in anterior segment, tumor in ciliary body, neovascular glaucoma,
(Advanced) vitreous hemorrhage, phthisical eye, orbital cellulitis-like presentation, involvement of optic nerve, extraocular disease on
neuroimaging
Treatment
• For small localized tumors, enucleation or EBRT were used historically. EBRT use declined recently due to
significant late toxicity and risk of second tumors. There is now increasing use chemotherapy and focal therapies
such as thermotherapy, photocoagulation, cryotherapy, and plaque brachytherapy
• For extensive unilateral lesions, enucleation or definitive radiation are the main approaches
• Indications for adjuvant treatment after enucleation are somewhat controversial, but may include optic nerve
involvement posterior to the lamina cribrosa as an independent finding; posterior uveal invasion (includes
choroidal invasion); any degree of concomitant choroid and optic nerve involvement; tumor involving the
optic nerve posterior to the lamina cribrosa (passage through sclera) as an independent finding; scleral
invasion; anterior chamber seeding; ciliary body infiltration; iris infiltration
• COG has an ongoing study of adjuvant carboplatin, etoposide, and vincristine x 6 cycles in patients considered
at "high risk" after enucleation (ARET0332) for the following high-risk criteria:
• Massive choroid replacement defined as posterior uveal invasion grades IIC and IID
• Any posterior uveal involvement with any optic nerve involvement (optic nerve head, prelamina and post
lamina cribrosa (Note: both posterior uveal involvement AND optic nerve involvement are required)
• For bilateral disease, conservative approaches have been suggested, but depend on size, number, and location of
lesions
• Chemoreduction, with enucleation of the "worse" eye and focal therapy of the "better" eye can be considered
• Patients with extraocular retinoblastoma have a poor prognosis, although high-dose chemo with stem cell rescue
is being explored by COG
• Treatment Guideline based on UCSF Protocol (PMID 19477707, 2009)
• Group A: Focal therapy only (laser, cryotherapy, hyperhtermia, brachytherapy)
• Group B: Vincristine + carboplatin up to 6 cycles; focal therapy with 2-6 cycles
• Group C: Vincristine + carboplatin + etoposide up to 6 cycles; focal therapy
• Group D: Same as C. EBRT
• Group E: Enucleation. Prophylactic 3-agent chemotherapy
External Beam Radiation Therapy

• Historically used as a treatment alternative to avoid enucleation in select patients
• Target was entire retina, up to ora serrata anteriorly
• Initially, "D-shaped" field was used
• Alternatively, a wedge pair with anterior and lateral fields could be used
• To obtain better sparing of lens, anterior lens block could be added
• Local control rates were >75% for early lesions
• However, long-term toxicity was significant. In particular, stunted growth of orbital bone and poor long term
cosmetic outcome became a problem
• Orbital bone growth centers are located along the sutures, frontozygomatic in lateral wall, frontomaxillary in
the medial wall, and zygomatic-maxillary in the orbital floor
• Also, for patients with hereditary retinoblastoma, risk of second malignancy has been reported as high as 51% at
50 years
• Efforts are now under way to avoid EBRT in the primary treatment setting, and use it for salvage only
• Two dosimetric studies have shown that proton therapy may be dosimetrically superior to photon EBRT in
settings where focal therapies are not appropriate
• MSKCC, 1996 (1979-84) - PMID 8641925 -- "External beam radiation therapy and retinoblastoma: long-term
results in the comparison of two techniques." Int J Radiat Oncol Biol Phys. 1996; 35(1):45-51
• 123 pts, 1979-91, tx'd w/ primary EBRT (larger fx size, 2.5 Gy, used b/f 1984), range of xrt 38-50 Gy
• Series compared a modified lateral beam technique to an anterior lens sparing technique; local control for
Group I-III tumors appeared to be improved w/ modified lateral beam (84% vs 38% at 5 yrs)
• Hahnemann, 1996 (1980-1991) - PMID 8641908 -- "External beam radiation for retinoblastoma: results, patterns
of failure, and a proposal for treatment guidelines." Int J Radiat Oncol, Biol, Phys. 1996; 35(1):125-32
• 27 pts, 34 eyes, RE Groups I-V tx'd w/ definitive EBRT (median 45 Gy)
• Local control 78.5% in RE Groups I-II, 20% in RE III-V; EBRT did NOT appear to prevent new tumors in
clinically uninvolved retina.
• St. Jude's, 1969 PMID 5822720 Cassady, Ellsworth et al. "Radiation therapy in retinoblastoma. An analysis of
230 cases." Radiology. 1969; 93(2):405-9
• 230 pts, largest US series of retinoblastoma pts treated w/ EBRT. 3.3-4.0 Gy delivered 3x per week.
• Local control 73% in RE Groups I-II, 20% in RE III-V.
• No significant difference in local tumor control when doses of 32.5-35 Gy compared to 40-45 Gy.
Plaque Brachytherapy
• Plaque brachytherapy introduced in 1931 with radon seeds
• I-125 used commonly in the U.S., Ru-106 in Europe
• For Ru-106 plaques, tumors should be <5 mm deep due to steeper dose fall-off
Iodine-125
• Thomas Jefferson
• Salvage; 2006 (1994-2005) PMID 16949158 -- "Iodine 125 plaque radiotherapy as salvage treatment for
retinoblastoma recurrence after chemoreduction in 84 tumors." (Shields CL, Ophthalmology. 2006
Nov;113(11):2087-92. Epub 2006 Sep 1.)
• Retrospective. 84 tumors in 71 eyes in 64 patients, solid recurrences after chemoreduction (vincristine,
etoposide, carboplatin x6 cycles + thermotherapy or cryotherapy). I-125 plaque, dose 40 Gy to tumor
surface + 2 mm margin. Mean thickness 4 mm. Mean foveola dose 45 Gy, optic disc 22 Gy. Prior EBRT in
30%. Median F/U 4 years
• Outcome: Local control after chemoreduction 95%, after chemoreduction + EBRT 100%
• Toxicity: Proliferative retinopathy 17%, maculopathy 24%, cataract chemoreduction 19% vs
chemoreduction + EBRT 42%, iris neovascularization 8%
• Conclusion: I-125 plaque BT offers excellent tumor control; complications should be anticipated
• 2001 (1976-1999) PMID 11713089 -- "Plaque radiotherapy for retinoblastoma: long-term tumor control and
treatment complications in 208 tumors." Ophthalmology. 2001; 108(11):2116-21.
• Retrospective. 141 children managed w/ plaque brachy; 71% received prior therapy (chemo, EBRT,
cryotherapy, photocoagulation, etc); 35% s/p prior tx failure
• Outcome: 5-year local control 79%, if primary therapy 88%
• Toxicity: 27% non-proliferative retinopathy, 15% proliferative retinopathy, 31% cataracts, 0% scleral
necrosis at 5 yrs
• Conclusion: Good tumor control, particularly for those that fail prior therapy
• University of Cape Town; 2002 PMID 12459368. "Postenucleation orbits in retinoblastoma: treatment with 125I
brachytherapy." Int J Radiat Oncol Biol Phys 2002; 54(5):1446-54
• 57 cases b/w 1983-2000, treated w/ post enucleation brachy; 34 Gy (w/ 30 cases also receiving chemo); 21
cases w/ +margins, extrascleral tumor or mets
Ruthenium-106
• Lausanne, Switzerland; 2008 (1992-2006) PMID 18207660 -- "(106)Ruthenium brachytherapy for
retinoblastoma." (Abouzeid H, Int J Radiat Oncol Biol Phys. 2008 Jul 1;71(3):821-8. Epub 2008 Jan 22.)
• Retrospective. 39 children, 41 eyes, 63 tumors. First line treatment 5%, second-line 21%, salvage 74%. Plaque
diameter >= 2 mm than tumor diameter, margin 1 mm to tumor height for sclera. Prescription dose target 50
Gy at apex. Minimum F/U 1 year
• Outcome: 1-year tumor control 73%. Recurrence 12% if 1st/2nd line, and 32% if salvage. Eye retention 76%
(though 3/10 removed eyes for different tumor than the one treated)
• Toxicity: Retinal detachments 17%, proliferative retinopathy 2%, cataract 10%
• Conclusion: Ru-106 brachytherapy effective
Proton Therapy
• Paul Scherrer Institut; 2008 PMID 18290958 -- "New developments in external beam radiotherapy for
retinoblastoma: from lens to normal tissue-sparing techniques." (Munier FL, Clin Experiment Ophthalmol. 2008
Jan-Feb;36(1):78-89.)
• Case report of 6 patients, and literature review
• MD Anderson; 2005 PMID 16168831 -- "Treatment planning with protons for pediatric retinoblastoma,
medulloblastoma, and pelvic sarcoma: how do protons compare with other conformal techniques?" (Lee CT, Int J
Radiat Oncol Biol Phys. 2005 Oct 1;63(2):362-72.)
• Treatment planning. 8 patients (3 Rb, 2 MB, 3 pelvic sarcoma), retrospective DVH comparison of 3D-CRT,
electrons, IMRT, protons
• Retinoblastoma: Protons best coverage combined with most orbital bone sparing (>5 Gy protons 10%,
electrons 25%, 3D lateral beam 41%, 3D anterolateral beam with lens block 51%, 3D anterolateral beam
without lens block 65%, IMRT 69%). Single appositional electron field next best technique. 3D-CRT
techniques significantly inferior
• Medulloblastoma: Protons least dose to cochlea, hypothalamus/pituitary. IMRT second best for posterior fossa.
For craniospinal, 3D electrons better than 3D photons
• Pelvic sarcoma: Protons superior for ovary dose
• Conclusion: Protons superior, both for target coverage and for normal structure sparing
• Harvard
• 2006 Abstract Link [1] -- "The Use of Gantry Decreases Normal Tissue Exposure in Proton Beam
Radiotherapy of Intraocular Retinoblastoma" (Ciralsky JB, Invest Ophthalmol Vis Sci 2006;47: E-Abstract
2815.)
• Case report. Historically treated 35 patients using lateral beam. First 2 patients treated with gantry using
anterolateral oblique beam.
• 2005 PMID 15667981 -- "Proton radiation therapy for retinoblastoma: comparison of various intraocular
tumor locations and beam arrangements." (Krengli M, Int J Radiat Oncol Biol Phys. 2005 Feb 1;61(2):583-93.)
• Treatment planning. Different retinoblastoma tumor locations (posterior-central, nasal, temporal), different
eye positions (straight, intrarotated, extrarotated), different beam arrangements (lateral, anterolateral
oblique, anteromedial oblique)
• Conclusion: Homogenous target coverage, true lens sparing. Doses to orbit structures minimized depending
on tumor location
Secondary Malignancies after RT

• New York Hospital PMID 9544627 "Second nonocular tumors in survivors of bilateral retinoblastoma: a
possible age effect on radiation-related risk." Ophthalmology. 1998;105(4):573-9
• Retrospective review of 816 pts w/ bilateral retinoblastoma in NY area.
• 2nd malignancies more common if pts tx'd w/ EBRT before age 12 mo's.
• NCI Analysis; 1997 (1914-1984) PMID 9333268 "Cancer incidence after retinoblastoma. Radiation dose and
sarcoma risk." (Wong FL, JAMA. 1997 Oct 15;278(15):1262-7.)
• Cohort study, NY and MA hospitals. 1604 cases of retinoblastoma, survived >1 year. 961 hereditary
• 2nd cancer incidence at 50 years: if germline mutation 51% (RR 30), if sporadic 5% (not elevated)
• Sarcoma risk: related to dose; threshold 5 Gy, 11x increase at 60+ Gy
• Conclusion: Genetic predisposition substantial impact on risk of subsequent cancers
Trilateral Retinoblastoma
• Sao Paulo; 2007 (Brazil)(1986-2003) PMID 16572402 -- "Trilateral retinoblastoma." (Antoneli CB, Pediatr
Blood Cancer. 2007 Mar;48(3):306-10.)
• Retrospective. 470 children with Rb, 4 with pineoblastoma (2/4 with family history). 3 had bilateral disease
• Outcome: All died within 12 months
• Conclusion: New therapeutic approaches needed
Review
• UCSF; 2009 PMID 19477707 -- "Frontiers in the Management of Retinoblastoma." (Lin P, Am J Ophthalmol.
2009 May 23.)
References
[1] http:/ / abstracts. iovs. org/ cgi/ content/ abstract/ 47/ 5/ 2815?maxtoshow=& HITS=10& hits=10& RESULTFORMAT=1&
andorexacttitle=and& andorexacttitleabs=and& andorexactfulltext=and& searchid=1& FIRSTINDEX=0& sortspec=relevance& volume=47&
firstpage=2815& resourcetype=HWCIT,HWELTR
Radiation Oncology/CNS/Acoustic neuroma

Epidemiology
The overall incidence of symptomatic acoustic neuromas is 1/100,000 persons, however, autopsy results have shown
that subclinical acoustic neuromas are present in up to 1% of people. Acoustic neuromas account for ~8% of
intracranial tumors and 80-90% of CPA tumors. Most people with symptomatic acoustic neuromas will present
between the ages of 30 and 50. They are almost always unilateral; bilateral acoustic neuromas are limited to patients
with NF-2.
Risk Factors
• Acoustic trauma: OR of 2.2 if 10 years exposure to extremely loud noise, OR of 13.1 if 20 or more years of
exposure.
• Parathyroid adenoma: OR of 3.4 for actousic neuromas.
• NF-2: Accounts for 10% of patients with acoustic neuroma, typically bilateral. Recall that NF2 gene is a tumor
suppressor gene on chromosome 22 that encodes a membrane cytoskeletal protein called merlin or schwannomin
that appears to be involved in actin-cytoskeleton organization. NF2 associated with bilateral ANs, gliomas,
meningiomas, cataracts, and neurofibromas.
Pathology
Acoustic neuromas arise from the Schwann cell perineural elements of the affected nerve and occur with equal
frequency on the superior and inferior branches of the vestibular nerve (rarely affect the cochlear portion of CN
VIII). They arise at the junction of the central myelin produced by glial cells and peripheral myelin produced by
Schwann cells (Obersteiner-Redlich zone). On light microscopy one will see zones of alternately dense and sparse
cellularity called Antoni A and B areas, respectively. Acoustic neuromas will also stain positive for the S100 protein.
Natural History
The natural history of acoustic neuromas is variable. The average growth rate is 1.9mm/year. 40% of tumors overall
(higher for smaller tumors) will show no growth or even shrinkage on serial images. However, there is no predictive
relation between growth rate and size of tumor at presentation.
The symptoms involved with acoustic neuroma are due to cranial nerve involvement and tumor progression.
• Acoustic nerve: Symptomatic involvement in 95% of patients, major symptoms being hearing loss and tinnitus.
Hearing loss present in 95%, but only about 66% were actually aware of this deficit. The hearing loss is usually
chronic (over years). Tinnitus is present in 63% of patients.
• Vestibular nerve: Involved in 61% of patients and manifests as mild to moderate unsteadiness while walking.
True spinning vertigo is uncommon due to the slow growing nature of these tumors.
• Trigeminal nerve: Disturbance occurs in 17% of patients with symptoms such as facial numbness, hypesthesia,
and pain. These symptoms usually occur after hearing loss is present for more than two years, and vestibular
symptoms for more than one year.
• Facial nerve: Involved in 6% of patients. Seen as facial paresis and taste disturbances.
• Posterior fossa: Compression on the cerebellum or brainstem results in ataxia. May also see serious complications
such as brainstem compression, cerebellar tonsillar herniation, hydrocephalus, and death.
Work-up
• Physical Exam:
• Confirm sensorineural hearing loss with Rinne test (tuning fork
on mastoid bone, AC>BC) and Weber test (vibratory sound
louder on the “good” side)
• Also check for other CN deficits (absent corneal reflex, facial
twitching, hypesthesia)
• Audiometry:
• The best initial screening test
• Typically shows asymmetric SHL, usually more prominent in the
higher frequencies. Functional hearing typically described as <50
dB and >50% speech discrimination
• Hearing loss does not necessarily correlate with tumor size.
• Brainstem auditory evoked potentials: Delay in conduction time on
the affected side.
• Imaging: MRI with gadolinium can detect tumors as small as 1-2mm. Seen as an enhancing lesion “ice cream
cone” in the region of internal acoustic canal or a “dumbbell” extending into the foramen magnum.
Treatment
The three treatment options for acoustic neuroma are surgery, radiation therapy, and observation.
Surgery
Typically performed by an otologist and a neurosurgeon. The learning curve is very steep, on the order of 20-60
cases. There are three surgical approaches used in the removal of acoustic neuromas.
• Retromastoid suboccipital: An incision is made behind the ear and the mastoid bone and some inner ear structures
are removed. Advantages to this approach include decreased risk of facial nerve damage and ability to attempt
hearing preservation. A disadvantage is that using this approach, if the tumor extends distally into the IAC,
complete removal may not be possible.
• Middle fossa: This approach involves an incision just anterior to the ear with removal of the underlying bone to
expose the area of interest. Hearing preservation is attempted with this approach, but depending on location of the
tumor complete removal may not be feasible.
• Translabyrinthine: This approach goes directly through the inner ear and invariably sacrifices hearing.
Results: Anatomic preservation of the facial nerve is achieved in 93% of patients and of the cochlear nerve in 68%.
Hearing preservation rate for surgery is 47%. Complications of surgery: Death (1%), hemiparesis (1%), CN palsey
(5%), hematomas (2.2%), CSF fistulas (9.2%), hydrocephalus (2.3%), bacterial meningitis (1.2%), wound revisions
(1.1%). (Samii, Neurosurgery 1997 Jan;40(1):11-21)
Radiosurgery
GKS--Patient’s head is fixed in MRI compatible Leksell stereotactic frame and 1-1.5mm slice MRI is obtained.
Prescribe dose of 12.5-13.0 Gy to the 50% isodose line. TV defined as macroscopic tumor seen on MRI/CT.
Evaluate dose fall-off to cochlea and brain stem. Tumor control rate (97%), Normal facial function (>99%),
Trigeminal function (97%), Hearing preservation (up to 77%). (Lunsford, J Neurosurg 2005 Jan;102 Suppl:195-9)
Proton Beam Radiosurgery--Now only used for pts with non-serviceable hearing and tumors <2.0cm. Use 3 fiducial
markers in the outer table of the cranium, as well as placement of head in a stereotactic frame. A 3D CT based
planning system is used. 160 MeV proton beam is used to administer 3 converging beams to a max dose of 13 cobalt
Gray equivalents to TV. Evaluate dose fall-off to brainstem and cochlea. Excellent tumor control (95%) and
preservation of CNs V (89%) and VII (91%) Hearing preservation: 33%. (Weber, Neurosurgery 2003
Sep;53(3):577-86)
Fractionated stereotactic radiotherapy--Patient’s head is immobilized in a mask and linear accelerator is used to apply
the radiation. Dose: 50-55 Gy in 25-30 fractions to the 80% isodose line. The data for FSR has shown excellent
tumor control, preservation of hearing/CN function, and reduced treatment related toxicity. (Combs, IJROBP 2005
Sep 1; 63 (1):75-81)
Observation
In certain cases it may be feasible to observe the patient and his/her VS with MRI scans every 6-12 months.
Problems with this approach include ongoing hearing loss, and possible mass effects with large tumors.
External Beam RT
• Thomas Jefferson; 2009 PMID 19042095 -- "Toward dose optimization for fractionated stereotactic
radiotherapy for acoustic neuromas: comparison of two dose cohorts." (Andrews DW, Int J Radiat Oncol Biol
Phys. 2009 Jun 1;74(2):419-26. Epub 2008 Nov 29.)
• Retrospective. 89 patients. Two dose levels: 50.4 Gy vs 46.8 Gy. Median F/U 4.4 and 5.4 years
• Outcome: Tumor control 100% both groups.
• Toxicity: Raw 3-year hearing preservation 46.8 Gy 79% vs. 50.4 Gy 68% (SS). Pure tone hearing better in
low-dose cohort 46.8 Gy 33db vs. 50.4 Gy 40 db (SS). Actuarial hearing preservation rate significantly longer
for low-dose group 3.2 years vs. 1.5 years (SS). Predictors for hearing dose cohort and pretreatment hearing
class
• Conclusion: Lower dose of 46.8 Gy had 100% local control with better hearing preservation rate
• Harvard; 2005 (1992-2001) PMID 15987541 -- "Stereotactic radiotherapy for vestibular schwannomas:
favorable outcome with minimal toxicity." (Chan AW, Neurosurgery. 2005 Jul;57(1):60-70; discussion 60-70.)
• Retrospective. 70 patients (new 47%, progressive after observation 31%, postop 3%, recurrent 19%), NF2 in
11 patients. Treated with linac SRT. Median dose 54/30 to 95% isodose. Median tumor volume 2.4 cm3.
• Outcome: 3-year LC 100%, 5-year LC 98%. Freedom from resection 98% and 92%. Initial tumor volume
predictive of resection: 5-year FFR if <8 cm3 97% vs. >8 cm3 47%. No difference due to NF2 status
• Toxicity: 3-year facial nerve 99%, trigeminal nerve 96%. Prior surgery predictive of TN toxicity (86% vs.
98%)
• Conclusion: Conventionally fractionated SRT results in very favorable outcome
Comparison of radiosurgery and surgery

• France, (Regis, J Neurosurgery. 2002 Nov;97(5):1091-100). Non-randomized prospective series using pre- and
post-operative questionnaires to evaluate functional outcomes after GKS or microsurgery. The minimum
follow-up was 3 years, the GKS group had 97 patients and the microsurgery group had 110 patients. Outcomes in
table below:
Facial motor CN V Preserved Overall functional Hospital Stay Mean days missed from
disturbance disturbance Hearing disturbance (Days) work
Surgery 37% 29% 37.5% 39% 23 130
GKS 0% 4% 70% 9% 3 7
• Baylor, 2002 (1993-2000) - PMID 12459364 — "Treatment of acoustic neuroma: stereotactic radiosurgery vs.
microsurgery." Karpinos M et al. Int J Radiat Oncol Biol Phys. 2002 Dec 1;54(5):1410-21.
• Retrospective. 75 pts with Gamma Knife, 25 with microsurgery.
• No difference in tumor control. RS more effective in: preservation of measurable hearing (57% vs 14%).
Microsurgery had higher rate of: facial neuropathy (35%/6%) and trigeminal neuropathy (22%/12%). Also no
difference in: serviceable hearing, tinnitus, imbalance, dysarthria, dysphagia, and headache. Longer hospital
stay and more perioperative complications (47% vs 4%) for microsurgery.
Comparison of SRS and FSRT

• Amsterdam; 2003 (Meijer, IJROBP 2003 Aug; 56 (5):1390-1396). 129 patients with ANs from 1992-1999 were
prospectively selected for SRS or FSRT based on whether or not they had teeth. All treatments were linac based.
The dentate patients received FSRT (20Gy/5fx and 25Gy/5fx) and the edentate patients received SRS (10Gy and
12.5Gy). Mean follow-up was 33 months. Results in table below.
Tumor CN V preservation CN VII Perservation Hearing Preservation

Control
SRS 100% 92% 93% 75%
FSRT 94% 98% 97% 61%
• Conclusion: Comparable rate of tumor control and preservation of hearing, CN V, and CN VII.
• Thomas Jefferson; 2001 (1994-2000) PMID 11483338 -- "Stereotactic radiosurgery and fractionated stereotactic
radiotherapy for the treatment of acoustic schwannomas: comparative observations of 125 patients treated at one
institution." (Andrews, IJROBP. 2001 Aug 1;50(5):1265-78).
• Retrospective. 122 patients (GKS 69, fractionated 52). GKS dose 12 Gy, fractionated dose 50/25. Mean F/U
2.3 years
• Outcome: tumor control SRS 98% vs. FSRT 97% (NS)
• Toxicity: CN V preservation 95% vs. 93% (NS), CN VII preservation 98% vs. 98% (NS); functional hearing
33% vs. 81% (SS)
• Conclusions: Comparable rates of tumor control and CN preservation, improvement in servicable hearing
Proton Therapy
• Harvard; 2003 (1992-2000) PMID 12943574 -- "Proton beam radiosurgery for vestibular schwannoma: tumor
control and cranial nerve toxicity." (Weber DC, Neurosurgery. 2003 Sep;53(3):577-86; discussion 586-8.)
• Retrospective. 88 patients, proton SRS. Median volume 1.4 cm3. Prior surgery 17%. Facial nerve function
normal 90%, good/excellent hearing 9%, servicable hearing 15%. Median dose 12 CGE (10-18 CGE)
prescribed to median 70% isodose line. Median F/U 3.2 years
• Outcome: 5-year LC 94%, radiological reduction in 95%
• Toxicity: In GR Grade 1-2, 33% retained servicable (GR Grade 2) hearing. 5-year normal facial nerve 91%
and trigeminal nerve 89%. Facial neuropathy predicted by prescribed dose, maximum dose, and
inhomogeneity
• Conclusion: Proton beam SRS effective treatment, reduced prescribed dose associated with decrease in facial
neuropathy
• Loma Linda; 2002 (1991-1999) PMID 11844261 -- "Fractionated proton beam radiotherapy for acoustic
neuroma." (Bush DA, Neurosurgery. 2002 Feb;50(2):270-3; discussion 273-5.)
• Retrospective. 31 ANs in 30 patients. Mean tumor volume 4.3 cm3. If useful hearing, 54 CGE, if no hearing 60
CGE. Mean F/U 2.8 years
• Outcome: 0% progression, 38% regression
• Toxicity: 31% maintained useful hearing. No CNV or CNVII dysfunction
• Outcome: Fractionated PT excellent LC
Toxicity
• Please see Inner Ear NTCP for more information
Bevacizumab
• Harvard; 2009 PMID 19587327 -- "Hearing improvement after bevacizumab in patients with neurofibromatosis
type 2." (Plotkin SR, N Engl J Med. 2009 Jul 23;361(4):358-67. Epub 2009 Jul 8.)
• Retrospective. 10 patients, NF-2 and progressive vestibular schwannoma, not candidates for surgery/RT.
Treated with bevacizumab 5 mg/kg, median duration of therapy 12 months
• Outcome: tumor shrinkage in 9/10; best volumetric reduction 26%. Hearing response 4/7, stabel 2/7,
progressive hearing loss 1/7
• Conclusion: VEGF blockade improved hearing in some patients, and was associated with volume reduction
Radiation Oncology/CNS/Pituitary adenoma

Pituitary Adenoma
Overview
• Comprise ~10% of intracranial tumors
• Benign histologically
• Can cause significant morbidity due to 1) hormonal imbalances and 2) local compression of critical structures
(optic chiasm and hypothalamus)
• Treatment overview:
• Microadenoma, not secreting prolactin: surgery
• Microadenoma, secreting prolactin: bromocriptine
• Macroadenoma: multimodality approach, typically surgery, adjuvant RT and if secretory hormone suppression
Proton Therapy
• Loma Linda; 2006 (1991-2001) PMID 16257131 -- "Fractionated proton beam irradiation of pituitary
adenomas." (Ronson BB, Int J Radiat Oncol Biol Phys. 2006 Feb 1;64(2):425-34. Epub 2005 Oct 27.)
• Retrospective. 47 patients with pituitary adenomas. 42 prior resection, 5 primary RT. Functional 49% (n=23).
Median dose 54 CGE in 30 fractions, mean target volume 8 cm3
• Outcome: Stabilization in 100% with visible tumor, resolution 24%, regression 29%, stabilization 46%. If
functional, biochemical control 86%, normalization 38%. OS 89%, due to disease progression 2 patients
(Cushings)
• Toxicity: Temporal lobe necrosis with headaches 1 patient (2%), new visual deficits 3 patients (23%),
hypopituitarism 11 patients (30%), panhypopituarism 2 patients (5%)
• Conclusion: Fractionated proton RT achieved effective radiologic, endocrinological, and symptomatic control;
significant morbidity uncommon
• Lawrence Berkeley Laboratory
• 1991 PMID 1808652 -- "Heavy-charged-particle radiosurgery of the pituitary gland: clinical results of 840
patients." (Levy RP, Stereotact Funct Neurosurg. 1991;57(1-2):22-35.)
• Retrospective. 840 patients, 30 treated with protones, and 810 with helium ion. Pituitary tumors n=475
(59%), systemic disease treatment by inducing hypopituitarism n=365 (41%).
• Outcome: Great majority marked and sustained biochemical and clinical improvement
• Toxicity: Hypopituitarism in ~30%, focal temporal lobe necrosis ~1%
• 1980 (1957-1978) PMID 7415170 Full paper [1] -- "Treatment of acromegaly, Cushing disease and Nelson
syndrome." (Lawrence JH, West J Med. 1980 Sep;133(3):197-202.)
• Retrospective. 429 patients (acromegaly 72%, Cushing's disease 13%, chromophobe adenoma 8%,
prolactin-secreting adenoma 4%, Nelson's syndrome 4%). Treated with alpha particles or protons. Dose ~60
Gy
• Outcomes reported
• Harvard, 1968 (1963-1967) PMID 4966299 -- "Proton-beam therapy in acromegaly." (Kjellberg RN, N Engl J
Med. 1968 Mar 28;278(13):689-95.)
• Retrospective. 14/22 patients with acromegaly. Median time from onset to treatment 11.8 years. 5 prior RT
therapy (36-40 rads). Proton dose typically 100-120 Gy (60-140 Gy), given 12 portals.
• Outcome: 7/12 improved clinically, 3/12 unchanged, 2/12 worse.
• Complications: Transient diplopia, H/A, anterior pituitary insufficiency
References
[1] http:/ / www. pubmedcentral. nih. gov. ezproxy. library. tufts. edu/ picrender. fcgi?artid=1272259& blobtype=pdf
Radiation Oncology/CNS/Trigeminal neuralgia/

Overview
Trigeminal Neuralgia
Epidemiology
• 15,000 new cases in US per year; incidence 4/100,000 - 5/100,000
• Majority of idiopathic TN after age 50
Definition
• International Headache Society
• Classical TN (also called Idiopathic, or tic douloureux)
• A) Paroxysmal attack lasting from fraction of a second to 2 minutes, affecting one or more of the trigeminal
nerve divisions
• B) One of the two following: 1) intense, sharp, superficial, stabbing or 2) precipitated from trigger areas or
by a trigger factor
• C) Stereotyped in the individual patient
• D) No other neurological deficits
• E) Not attributed to another disorder
• Symptomatic TN (also called Secondary)
• Symptoms indistinguishable from Classical TN but caused by a demonstrable structural lesion (e.g.
neuroma, vascular compression)
Signs and symptoms

• Idiopathic has five classical features:
• Paroxysmal
• Provokable
• Unilateral
• Confined to the trigeminal nerve distribution
• Unassociated with gross trigeminal motor or sensory loss.
• Atypical TN is any pain that lacks the 5 classical features.
• Multiple sclerosis-associated TN similar pain as idiopathic, but in the setting of MS
• Typically does not wake patient up at night
• Unilateral in most cases, if bilateral then not simultaneously
• Trigger zones in distribution of CN V, include light touch, chewing, talking, brushing teeth, cold air,
smiling/grimacing
Pain Scales
Barrow Neurological Institute (BNI)
Grade I no pain, no medication
Grade II occasional pain, no medication
Grade IIIa no pain, medication
Grade IIIb pain, medication controlled
Grade IV pain, not well controlled
Grade V no pain relief
Marseille scale
Class I no pain, no medication
Class II no pain, medication
Grade III >90% pain frequency

reduction
Grade >50% pain frequency

IV reduction
Grade V no significant pain relief
Grade pain worsening

VI
Etiology
• Idiopathic TN
• Compression of trigeminal nerve by aberrant artery or vein suspected in 80-90% of cases
• Resulting demyelination somehow triggers TN (possibly via ephaptic cross-talk between fibers mediating light
touch and pain)
• Also evidence for central pain mechanisms (refractory period after episode, trans of pain after single stimulus,
latency from stimulus to onset)
• Secondary TN
• Caused by other structural compressions (e.g. vestibular schwannoma, meningioma, epidermoid cyst,
aneurysm, AVM)
• Oregon, 2004 PMID 15540931 -- "Pathophysiology of trigeminal neuralgia: new evidence from a trigeminal
ganglion intraoperative microneurographic recording. Case report. (Burchiel KJ, J Neurosurg. 2004
Nov;101(5):872-3.)
• Intraop recordings suggest TN pain generated by an abnormal discharge within peripheral NS, both in
trigeminal ganglion neurons and/or the nerve itself
Anatomy
• Trigeminal nerve (CN V) supplies sensory to the face, and sensory and motor to muscles of mastication
• V1 - Ophthalmic
• V2 - Maxillary
• V3 - Mandibular
• Nerve exits at midlateral surface of the pons
• Meckel's cave - gasserian ganglion (sensory ganglion), located 2 cm anterior to trigeminal root entry zone.
Imaging
• Thin slice (1mm) MRI/MRA to rule out structural lesions. Sensitivity and specificity for identifying vascular
compression 89% and 50%
• Tufts
• 2006 PMID 16436823 -- "Nerve atrophy in severe trigeminal neuralgia: noninvasive confirmation at MR
imaging--initial experience." (Erbay SH, Radiology. 2006 Feb;238(2):689-92.)
• 31 patient MRIs reviewed. Mean diameter on symptomatic side 2.11 mm vs. 2.62 mm (SS). Mean
cross-sectional area 4.50 mm2 vs. 6.28 mm2 (SS)
• 2005 PMID 15662790 -- "Targeting the cranial nerve: microradiosurgery for trigeminal neuralgia with CISS
and 3D-flash MR imaging sequences." (Zerris VA, J Neurosurg. 2005 Jan;102 Suppl:107-10.)
• Multiple imaging sequences evaluated. CISS/3D-Flash preferred method
• MC Wisconsin PMID 16029818 -- "Effect of image uncertainty on the dosimetry of trigeminal neuralgia
irradiation." (Jursinic PA, Int J Radiat Oncol Biol Phys. 2005 Aug 1;62(5):1559-67.)
• Conclusion: uncertainty of target by MRI >2x than by CT. 4&8 mm collimator higher isodose line than 4mm
collimator
• UCLA PMID 15730595 -- "Three-dimensional fast imaging employing steady-state acquisition magnetic
resonance imaging for stereotactic radiosurgery of trigeminal neuralgia." (Chavez GD, Neurosurgery. 2005
Mar;56(3):E628; discussion E628.)
• Evaluation of 3-D-FIESTA sequence in 15 patients. 3-D-FIESTA sequence successfully demonstrated the

trigeminal complex (root entry zone, trigeminal ganglion, rootlets, and vasculature) in 14 patients (93.33%).
The 3-D-FIESTA sequence also allowed visualization of the branches of the trigeminal nerve inside Meckel's
cavity.
• Conclusion: SRS targeting of specific trigeminal branches may be feasible
• Rosewell Park PMID 11733329 -- "Focal enhancement of cranial nerve V after radiosurgery with the Leksell
gamma knife: experience in 15 patients with medically refractory trigeminal neuralgia." (Alberico RA, AJNR Am
J Neuroradiol. 2001 Nov-Dec;22(10):1944-8.)
• Retrospective. 15 patient MRIs. RT dose 35-45 Gy at 50% isodose line. Mean time to follow-up imaging 61
days
• Target enhancement in 10/15; remaining 5 had RT dose 35 Gy
Treatment
• Please see the → treatment and → retreatment pages
Cost-Effectiveness
• Mayo
• 1999-2001 PMID 15951649 -- "A prospective cost-effectiveness study of trigeminal neuralgia surgery."
(Pollock BE, Clin J Pain. 2005 Jul-Aug;21(4):317-22.)
• Prospective, nonrandomized. 126 patients (MVD 33, GR 51, SRS 69)
• Outcomes (6 months, 24 months): MVD (85%, 78%) vs. GR (61%, 55%) vs. SRS (60%, 52%). MVD > GR
= SRS
• Cost per quality adjusted pain-free year: MVD $8174 vs. GR $6342 vs. SRS $8269
• PMID 14677455 -- "CSNS Resident Award: the economics of trigeminal neuralgia surgery." (Ecker RD, Clin
Neurosurg. 2003;50:387-95.)
• No abstract

Treatment
Trigeminal Neuralgia Treatment
Treatment Overview
• Medical (carbamazepine, phenytoin, gabapentin, baclofen) first, until failure
• Surgical
• Destructive: radiofrequency rhizotomy, glycerol rhizotomy, balloon compression, peripheral neurectomy
• Non-destructive: microvascular decompression
• Radiosurgery
• Gamma Knife
• Linac-based
Medical treatment
• Meta-analysis (1960-2005) PMID 17174762 -- "Drug treatment of trigeminal neuralgia: a systematic review of
the literature." (Chole R, J Oral Maxillofac Surg. 2007 Jan;65(1):40-5.)
• 21 publications with high level of evidence (6 randomized, 15 controlled clinical trials), 348 patients
• Conclusion: Anticonvulsants effective, but difficult to compare/combine data in a scientifically meaningful
manner
Surgery
• Pittsburg
• 1972-1991 -- "The Long-term Outcome of Microvascular Decompression for Trigeminal Neuralgia." (Barker
et al. NEJM. 1996, 334:17, 1077-1083)
• Retrospective study of 1185 patients who underwent microvascular decompression.
• Immediate pain relief in 82%, partial 16%, and none in 2%. 75% had complete relief at 1 year, 9 % partial.
64% had complete relief at 10 years, 4 had partial (first surgery).
• 11% had re-operation for recurrent or refractory symptoms-total 80% had complete relief at 1 year and 8%
partial, 70% had complete relief at 10 years, 4 had partial.
Decision Analysis
• Queen Mary; 2007 PMID 17451880 -- "Decision analysis of medical and surgical treatments for trigeminal
neuralgia: how patient evaluations of benefits and risks affect the utility of treatment decisions." (Spatz AL, Pain.
2007 Oct;131(3):302-10. Epub 2007 Apr 23.)
• 156 patients evaluated with time-trade-off utility measurement questionnnaire
• Outcome: MVD highest maximum expected utility (16.08), followed by balloon compression (15.97), glycerol
rhizolysis (15.61), and RFA (14.93). Meds alone worst at 14.61. Difference between highest and lowest
treatments 7%, and sensitive to utility values
• Conclusion: Patients should consider surgery over meds, but treatment utility differences minimal
SRS vs. Surgery

• Columbia; 2007 PMID 17167238 -- "Microvascular decompression vs. gamma knife radiosurgery for typical
trigeminal neuralgia: preliminary findings." (Brisman R, Stereotact Funct Neurosurg. 2007;85(2-3):94-8.)
• Prospective protocol. 85 patients (GKS 61, MVD 24). GKS 75 Gy max.
• Outcome: CR (no pain, no meds): 1 year GKS 58% vs. MVD 68%; 2 years 24% vs. 68% (p=0.09)
• Toxicity: no permanent complications
• Conclusion: MVD more likely than GKS to result in complete pain relief
• UCSF
• 2005 PMID 16419978 -- "Management of medically refractory trigeminal neuralgia in patients with multiple
sclerosis." (Cheng JS, Neurosurg Focus. 2005 May 15;18(5):e13.)
• Retrospective. 11 patients with TN-MS. Mean f/u 40 months
• Conclusion: Complete pain relief in TN-MS significantly more difficult than other TN, including highly
refractory TN. SRS effective procedure, resulting in fewer retreatments, longer pain-free intervals compared
with MVD or RF ablation
• 2005 PMID 16419977 1997-2004 -- "Recurrent or refractory trigeminal neuralgia after microvascular
decompression, radiofrequency ablation, or radiosurgery." (Sanchez-Mejia RO, Neurosurg Focus. 2005 May
15;18(5):e12.)
• Retrospective. 32/209 patients treated with SRS, MVD or RFA required retreatment.
• Outcome: 19/93 MVD retreated (20%). 5/12 RFA retreated (42%), 8/108 (7.7%) SRS retreated, 2 with SRS.
• Conclusion: lowest re-treatment rates with SRS. SRS also more likely to be final treatment for recurrence,
regardless of initial treatment
• Cooper University; 2005 1994-2002 PMID 16111575 -- "Glycerol rhizotomy versus gamma knife radiosurgery
for the treatment of trigeminal neuralgia: an analysis of patients treated at one institution." (Henson CF, Int J
Radiat Oncol Biol Phys. 2005 Sep 1;63(1):82-90.)
• Retrospective. 36/79 patients (GR) and 63/109 (GK) evaluated. RT 70-90 Gy to 100% isodose.
• Initial success: (Barrow I-III) 86% GR vs. 92% GK. Median time to relief <24hr GR vs. 3 weeks GK.
• Failure or pain recurrence: 53% GR vs. 42% GK (NS). Median time to failure 5mo GR vs. 8 mo GK (NS). End
of treatment 39% GR vs. 24% GK failed
• Side effects: facial numbness 54% GR vs. 30% GK, bothersome 33% GR vs. 11% GK. GK lower pain score
(OR 4.3)
• Conclusion: GR for acute pain relief, GK otherwise
• Mayo
• 2005 PMID 15951649 1999-2001 -- "A prospective cost-effectiveness study of trigeminal neuralgia surgery."
(Pollock BE, Clin J Pain. 2005 Jul-Aug;21(4):317-22.)
• Prospective, nonrandomized. 126 patients (MVD 33, GR 51, SRS 69)
• Outcomes (6 months, 24 months): MVD (85%, 78%) vs. GR (61%, 55%) vs. SRS (60%, 52%). MVD > GR
= SRS
• Cost per quality adjusted pain-free year: MVD $8174 vs. GR $6342 vs. SRS $8269
• 2005 PMID 15913282 1999-2004 -- "Comparison of posterior fossa exploration and stereotactic radiosurgery
in patients with previously nonsurgically treated idiopathic trigeminal neuralgia." (Pollock BE, Neurosurg
Focus. 2005 May 15;18(5):E6.)
• Retrospective. 55 patients PFE (MVD 89%, partial nerve section 11%), 28 patients SRS as initial treatment.
RT mean dose 89.1 Gy. Mean f/u 25.5 months
• Outcome: Pain free at 1 year: 75% vs. 59% (SS). Additional surgery in 18% after PFE vs. 29% after SRS
(NS)
• Side effects: facial numbness/dysesthesias: PFE 15% vs. SRS 43%

• Conclusion: PFE more effective as primary therapy
Gamma Knife
• There is only one prospective trial published, from Marseille. At 1 year, 83% were pain free, with 58% off
medications as well
• There are a number of retrospective, single institution studies published
• Target: ipsilateral trigeminal nerve adjacent to the pons with single shot 4mm collimator
• Dose: Typically 70-90 Gy
Prospective
• Marseille, 2006 (France) PMID 16776335 -- "Prospective controlled trial of gamma knife surgery for essential
trigeminal neuralgia." (Regis J, J Neurosurg. 2006 Jun;104(6):913-24.)
• Phase I. 100 patients, 42 prior surgical treatment. RT: median dose 85 Gy (70 - 90 Gy). Minimum F/U 12
months, median ?
• Pain relief: 83/100 patients pain free at 12 months, 58/100 patients pain free and off meds. 17 patients
underwent additional procedures
• Probability of worse outcome (SS and trend): <60 year old, isocenter-nerve emergence distance >8mm, large
cistern surface, lower minimal nerve dose, prior procedure
• Side effects: Mild facial paresthesia 6%, hypesthesia 4%
Retrospective
Please see the Literature Review
GKS Technique
• Brussels (Belgium)
• 2007 PMID 17689881 -- "Clinical Evaluation of Targeting Accuracy of Gamma Knife Radiosurgery in
Trigeminal Neuralgia." (Massager N, Int J Radiat Oncol Biol Phys. 2007 Aug 7; [Epub ahead of print])
• Retrospective. 78 patients treated with 90 Gy. 68 (83%) had follow-up MRI with focal nerve enhancement.
F/U MRI fused with treatment MRI and correlated
• Outcome: Median deviation between pre and post MRI 0.91 mm. RT dose within contrast enhancement on
post MRI median 77 Gy, range 49-85 Gy
• Conclusion: Median deviation low
• 2007 PMID 17415205 -- "Influence of nerve radiation dose in the incidence of trigeminal dysfunction after
trigeminal neuralgia radiosurgery" (Massager N, Neurosurgery. 2007 Apr;60(4):681-7; discussion 687-8.)
• Comparative. 358 patients (109 Brussels, 259 Marseilles). Three dosimetry groups: Group I <90 Gy no
blocking, Group II 90 Gy no blocking, Group III 90 Gy blocking
• Toxicity: mild Group I 15% vs. Group II 21% vs. Group III 49%; bothersome 1.4% vs. 2.4% vs. 10%
• Pain control: excellent 66% vs. 77% vs. 84%; good 81% vs. 85% vs. 90%
• Conclusion: Incidence of TN dysfunction and pain relief vary according to energy deposited to
retrogasserian nerve root. Effect may be related to energy to nerve root rather than maximal dose delivered
• 2006 PMID 16682146 -- "Effect of beam channel plugging on the outcome of gamma knife radiosurgery for
trigeminal neuralgia." (Massager N, Int J Radiat Oncol Biol Phys. 2006 Jul 15;65(4):1200-5.)
• Retrospective. 109 patients, 49 had channel blocking to brainstem. RT 90 Gy
• Blocking increased lenght of trigeminal nerve exposure, and thus mean dose.
• Outcome: better pain outcome (84% vs. 62% nonblocked), but worse trigeminal dysfunction (47% vs. 32%)
• 2004 PMID 15070111 -- "Gamma knife surgery for idiopathic trigeminal neuralgia performed using a
far-anterior cisternal target and a high dose of radiation." (Massager N, J Neurosurg. 2004
Apr;100(4):597-605.)
• Retrospective. 47 patients. Mean f/u 16 months
• Pain relief: 68% excellent, 89% fair (>50%). Prognostic factors: higher dose, shorter distance to brainstem,
development of facial sensory disturbance
• Side effects: Mild facial numbness 38%, bothersome 4%
• Conclusion: target nerve 5-8 mm from brainstem
• Wake Forest; 2006 PMID 17121135 -- "Does dose rate affect efficacy? The outcomes of 256 gamma knife
surgery procedures for trigeminal neuralgia and other types of facial pain as they relate to the half-life of cobalt."
(Balamucki CJ, J Neurosurg. 2006 Nov;105(5):730-5.)
• Retrospective. 239/326 patients. 80% experienced >50% pain relief, 56% complete relief
• Neither dose rate nor treatment time were significantly associated with control rate or degree of pain relief
• Conclusion: Consistent treatment any time during first half-life of Co source
• Columbia
• 2005 PMID 15850900 -- "Where to locate the isocenter? The treatment strategy for repeat trigeminal neuralgia
radiosurgery." (Zhang P, Int J Radiat Oncol Biol Phys. 2005 May 1;62(1):38-43.)
• Retrospective. 40 patients with repeat GK. RT max 75 Gy initially, 40 Gy retreatment. Median f/u 28
months
• Pain relief: complete 27%, nearly complete 18%, partial 20%, minimal/none 35%
• Isocenter distance: mean 2.86 mm (complete/nearly complete relief) vs. 1.93 (partial/none relief). Farther
distance with trend to better pain relief
• Side effects: 7% moderate dysesthesia (4/10), 3% severe dysesthesia (7/10) after retreatment. Not related to
isocenter distance
• 2002 PMID 12015844 -- "Trigeminal Nerve-Blood Vessel Relationship as Revealed by High-resolution
Magnetic Resonance Imaging and Its Effect on Pain Relief after Gamma Knife Radiosurgery for Trigeminal
Neuralgia." (Brisman R, Neurosurgery. 2002 Jun;50(6):1261-6, discussion 1266-7.)
• Blood vessel - CNV contact evaluated. Group I (none) 24%, Group II (close) 17%, Group III (contact) 59%.
Contact more often in men (SS), more often with unilateral TN.
• If no prior surgery, BV-CNV contact may be prognostic factor
• 2000 PMID 11143235 -- "Gamma knife radiosurgery for trigeminal neuralgia: dose-volume histograms of the
brainstem and trigeminal nerve." (Brisman R, J Neurosurg. 2000 Dec;93 Suppl 3:155-8.)
• Volume of brainstem that receives >20% of Dmax (VB20), and volume of trigeminal nerve that receives
>50% of Dmax (VT50) assessed
• VB20 excellent pain control: 6 months <20mm3 32% vs. >20mm3 56% (SS), 12 months <20mm3 27% vs.
>20mm3 50% (SS)
• VB20 is lower in TN-MS. VB20 is inversely related to VT50
• Conclusion: isocenter proximity to brainstem (reflected by higher VB20) is better
• Upstate 2005 1998-2003 PMID 15662807 -- "Gamma knife surgery for trigeminal neuralgia: improved initial
response with two isocenters and increasing dose." (Alpert TE, J Neurosurg. 2005 Jan;102 Suppl:185-8.)
• Retrospective. 63 patients, 1 shot in 27 vs 2 shots in 36 patients. Dose 20 patients <=80 Gy, 21 patients 85 Gy,
22 patients >=90 Gy. Pain evaluated using BNI scale
• Pain relief: Initial 90%, overall 27%. Facial numbness 8%
• Number of shots: "2" 2.83 BNI improvement vs. "1" 1.72 BNI improvement (SS)
• Dose: SS improvement with each higher dose group

• Maryland
• 2005 ASTRO Abstract 2336 -- "Evaluating the Influence of Dose-Rate on Outcome with Gamma-Knife
Stereotactic Radiosurgery in the Treatment of Trigeminal Neuralgia" (Patel S)
• Retrospective. 61 patients. 31 prior to source change, 30 after source change. RT dose 75 Gy (70-80 Gy).
Median f/u 30 months
• Dose rate: 161.6 cGy/min (151-179) vs. 342.9 cGy/min (321-366)
• Pain control: 61% vs. 83% (SS). Recommend dose escalation below dose rate 179.4 cGy/min
• Side effects: 16% vs. 10% (NS)
• 2004 PMID 15380590 1996-2001 -- "Gamma knife surgery for trigeminal neuralgia: outcome, imaging, and
brainstem correlates." (Cheuk AV, Int J Radiat Oncol Biol Phys. 2004 Oct 1;60(2):537-41.)
• Retrospective. 96/112 patients. RT 75 Gy (60-80Gy)
• Imaging: 58% good, 31% fair, 10% poor. No correlation to outcome
• Dose to brain stem: 44% received 10% of Dmax, 56% received 20% of Dmax. No correlation to outcome
• Nerve compression: 11% by MRI. No correlation to outcome
• 2004 PMID 15379025 -- "Selective source blocking for Gamma Knife radiosurgery of trigeminal neuralgia
based on analytical dose modelling." (Li K, Phys Med Biol. 2004 Aug 7;49(15):3455-63.)
• Algorithm to selectively block sources to minimize dose to brainstem.
• Moderate number of plugs (30-50) significantly lowers (40%) dose to brainstem. No mention of dose to
trigeminal nerve in abstract
• 2003 PMID 12870587 -- "A technique to sharpen the beam penumbra for Gamma Knife radiosurgery."
(Guerrero M, Phys Med Biol. 2003 Jun 21;48(12):1843-53.)
• Physical penumbra (defined as distance 90% to 50% isodose) typically 1-2 mm. Technique to insert a conic
filter into individual plug collimator to flatten beam profile
• Able to reduce single penumbra width by 30-60%, at cost of reduced beam intensity by 20-50%
• 2005 Northwest Hospital (Seattle) ASTRO Abstract -- "Dose-Response and Dose-Complication Relationships in
Stereotactic Radiosurgery for Trigeminal Neuralgia" (Meier R, Abstract 2353)
• Retrospective. 252 patients, typical or atypical TN. RT to 76 Gy (58 patients), 87 Gy (101 patients), or 98 Gy
(93 patients) using 0.87 output factor. Mean f/u 3.9 years, 2.0 years, 1.7 years
• Pain control: favorable 74%, 75%, 76% (NS)
• Side effects: sensory deficit 9%, 22%, 39% (SS)
• Conclusion: dose escalation doesn't improve pain control, but has more complications
• Cleveland Clinic 2004 PMID 15007220 -- "Gamma knife radiosurgery for trigeminal neuralgia: comparing the
use of a 4-mm versus concentric 4- and 8-mm collimators." (Kanner AA, Stereotact Funct Neurosurg.
2004;82(1):49-57.)
• 101 patient evaluated, 54 treated with 4-mm helmet, and 47 with 4/8-mm helmet. RT 75 Gy to 100% isodose
line
• No difference in outcome
• Royal Hallamshire 2002 (UK) PMID 12507100 -- "The clinical application of plugging patterns for the Leksell
gamma knife." (Vaughan P, J Neurosurg. 2002 Dec;97(5 Suppl):579-81.)
• Plugging singnificantly improved conformity and reduced brain stem exposure, without altering length of TN
treated
• Mayo 2001 PMID 11440460 1997-1999 -- "High-dose trigeminal neuralgia radiosurgery associated with
increased risk of trigeminal nerve dysfunction." (Pollock BE, Neurosurgery. 2001 Jul;49(1):58-62; discussion
62-4.)
• Retrospective. 68 patients. 40% 70 Gy, 60% 90 Gy. Mean f/u 14.4 months
• Pain control: 70 Gy 41% pain free vs. 90 Gy 61% (NS)
• Side effects: 70 Gy 15% TN dysfunction vs. 90 Gy 54% (SS). Bothersome in 4% vs. 32%. Corneal numbness
in 3/41 (8%). Pain control better in those with TN dysfunction
• Conclusion: recommend dose <90 Gy
• Comment in PMID 12051192 "High-dose trigeminal neuralgia radiosurgery associated with increased risk of
trigeminal nerve dysfunction." (Regis J, Neurosurgery. 2002 Jun;50(6):1401-2; author reply 1402-3.)
• Pittsburgh 2001 PMID 11567820 -- "Does increased nerve length within the treatment volume improve
trigeminal neuralgia radiosurgery? A prospective double-blind, randomized study." (Flickinger JC, Int J Radiat
Oncol Biol Phys. 2001 Oct 1;51(2):449-54.)
• Randomized. 87 patients. RT 75 Gy to 1 or 2 isocenters. Median f/u 26 months
• Pain relief: excellent 52%, good (low dose meds) 14%, partial 17%, failed 17%. Identical for 1 or 2 isocenters.
Relapse in 42% of responding patients
• Side effects: 14% of 2 isocenters vs. 7% of 1 isocenter (NS). Complications correlated (SS) to nerve length
irradiated
Linac
Linac Outcomes
• Wisconsin 2005 PMID 16331167 -- "Linear accelerator radiosurgery for trigeminal neuralgia." (Richards GM,
Neurosurgery. 2005 Dec;57(6):1193-200; discussion 1193-200.)
• Retrospective. 28 patients. RT 80 Gy with 4-mm collimator and 7-arc technique. Median f/u 12 months
• Outcome: 57% complete pain relief, 75% 3 point pain reduction (10 point scale). Median time to pain relief 1
month. Mean time to pain recurrence 14 months. Women longer mean time to pain recurrence (16 vs. 7
months)
• Side effects: 3 patients mild facial numbness; 1 neurotrophic keratopathy
• Stanford
• 2005 PMID 15913285 2002-2004 -- "CyberKnife radiosurgery for idiopathic trigeminal neuralgia." (Lim M,
Neurosurg Focus. 2005 May 15;18(5):E9.)
• Retrospective. 41 patients with typical TN. Mean follow-up 11 months
• Pain control: Initial 93% at median 7 days. Pain control 88% excellent, 5% moderate, 7% no change.
Recurrence 16%, median time to recurrence 6 months. Long term response (@ 11 months) 78%
• Higher prescribed doses not associated with pain relief or recurrence rate. Hypesthsia rate related to length
of trigeminal nerve treated
• 2003 PMID 14742972 -- "Cyberknife radiosurgery for trigeminal neuralgia." (Romanelli P, Stereotact Funct
Neurosurg. 2003;81(1-4):105-9.)
• Preliminary report. CT cisternography for localization. 10 patients, 7 achieved pain relief.
• Minnesota 2004 PMID 15637446 -- "Long-term follow-up of trigeminal neuralgia treatment using a linear
accelerator." (Kubicek GJ, Stereotact Funct Neurosurg. 2004;82(5-6):244-9.)
• Retrospective. 20 patients. RT 82.3 - 100 Gy. Median f/u 56.5 months
• Pain control: 35% complete, 78% >50% improvement. Recurrence 63%, mean interval 21.5 months
• Kaiser Permanente 2004 2002-2003 PMID 15537188 -- "Treatment of trigeminal neuralgia with linear
accelerator radiosurgery: initial results." (Chen JC, J Neurosurg. 2004 Nov;101 Suppl 3:346-50.)
• Retrospective. Novalis. 32 patients treated. RT 85-90 Gy in 5- or 7- noncoplanar arcs with 4-mm collimator.
For GKS retreatment, 60 Gy dose
• Pain relief: BNI I-III in 78% patients, median time to relief 6 weeks.
• UCLA
• 2004 PMID 14981193 -- "Noninvasive linear accelerator radiosurgery as the primary treatment for trigeminal
neuralgia." (Frighetto L, Neurology. 2004 Feb 24;62(4):660-2.)
• Retrospective. 22 patients treated on dedicated Linac
• Pain control: 95.5% significant pain relief
• 2003 PMID 14519214 1999-2001 -- "Linear accelerator radiosurgery using 90 gray for essential trigeminal
neuralgia: results and dose volume histogram analysis." (Goss BW, Neurosurgery. 2003 Oct;53(4):823-8;
discussion 828-30.)
• Retrospective. 25 patients. RT 90 Gy with 5-mm collimator. Median f/u 18 months
• Pain relief: 76% excellent, 100% >50% relief
• Side effects: 32% facial numbness, none painful. No correlation with brainstem volume
• 2003 PMID 12959439 1995-2001 -- "Dedicated linear accelerator radiosurgery for the treatment of trigeminal
neuralgia." (Smith ZA, J Neurosurg. 2003 Sep;99(3):511-6.)
• Retrospective. 60 patients, 68% essential TN, 20% secondary, 11% atypical. RT mean 83 Gy (70-90 Gy).
5-mm collimator in 75% patients, 7.5-mm collimator in 25% patients. Mean f/u 23 months
• Pain relief: essential TN 56% excellent, 88% good+excellent; secondary pain 58% significant; atypical pain
"worse results". Relief experienced at mean 2.7 months
• Side effects: 25% new numbness
• 2002 ASTRO Abstract 1995-2001 -- "Linear Accelerator Radiosurgery Comparing 90Gy and Less Than 90 Gy
for Essential Trigeminal Neuralgia" (Goss B, Abstract 247, 2002)
• Retrospective. 41 patients treated. RT dose 70-85 Gy (16 patients), 90 Gy (25 patients). Median f/u 13
months
• Pain control: 70-85Gy - 37% excellent, 31% good. Relapse 50%. 90Gy - 76% excellent, 24% good. Relapse
32%. Lenght of pain relief, good&excellent response better in 90Gy
• Side effects: 70-85Gy - 31% numbness, none bothersome. 90Gy - 32% numbness, none bothersome
Linac technique
• Maryland PMID 16264249 -- "Comparative analyses of linac and Gamma Knife radiosurgery for trigeminal
neuralgia treatments." (Ma L, Phys Med Biol. 2005 Nov 21;50(22):5217-27.)
• Dose fall-off and set-up error tolerance of linac vs. Gamma Knife
• Equivalent dose fall-off with high number of arcs. However, increased treatment time and icocenter accuracies
a concern
• Minnesota PMID 15753942 -- "Linac-based stereotactic radiosurgery for treatment of trigeminal neuralgia."
(Gerbi BJ, J Appl Clin Med Phys. 2004 Summer;5(3):80-92.)
• Accuracy comparable to Gamma Knife, dose distributions equivalent. Disadvantage time involved.
Outcome Evaluation
• ESI-55 PMID 1556879 -- "A health-related quality of life instrument for patients evaluated for epilepsy surgery."
(Vickerey BG, Med Care. 1992 Apr;30(4):299-319.)
• 55 item scale to measure health-related quality of life in epilepsy patients
• Reliable, valid, sensitive to differences in seizure status
• Used by Marseille group in the prospective TN trial to evaluate QOL
Serious SRS side effects

• Semmelweist; 2007 (Hungary) PMID 17317993 -- "Pathological findings following trigeminal neuralgia
radiosurgery." (Szeifert GT, Prog Neurol Surg. 2007;20:244-8.)
• Case report. Retreatment, initial dose 90 Gy distally, followed by 70 Gy proximally. Hemorrhagic stroke 26
days after 2nd treatment
• Autopsy: neurovascular conflict close to 2nd shot, with acute and chronic radiation-induced lesions in
trigeminal nerve
• Amakusa; 2005 (Japan) PMID 16167795 -- "[A case of delayed facial palsy following gamma knife radiosurgery
for intractable trigeminal neuralgia]" [Article in Japanese] (Itai K, Masui. 2005 Sep;54(9):1018-20.)
• Case report. 77 y/o F. SRS RT 77 Gy.
• After 20 months developed left facial palsy with hydropsia, left xerophthalmia, left facial hypesthesia.
Resolved over several months on oral prednisolone
• Mayo
• 2004 PMID 15317722 -- "Vision loss as a complication of gamma knife radiosurgery for trigeminal neuralgia."
(Naseri A, Br J Ophthalmol. 2004 Sep;88(9):1225-6.)
• Case report. RT 40 Gy to the 50% isodose line. Presented 15 months later
• Initial exam showed vision 20/25, fine punctate epitheliopathy, no corneal sensation. 10 weeks later vision
20/200, severe epithelial keratopathy. Punctal plug placed, artificial tears, vision returned to 20/60 over 6
weeks
• 2000 PMID 11077103 -- "Radiation induced vascular injury after stereotactic radiosurgery for trigeminal
neuralgia: case report." (Maher CO, Surg Neurol. 2000 Aug;54(2):189-93.)
• Case report. SRS failed, patient underwent MVD. At operation, two adjacent veins and the superior
cerebellar artery noted to have focal changes consistent with atheromatous disease.
• Chiba; 2002 (Japan) PMID 12507089 -- "Gamma knife radiosurgery for trigeminal neuralgia: the dry-eye
complication." (Matsuda S, J Neurosurg. 2002 Dec;97(5 Suppl):525-8.)
• Retrospective. 33/41 patients treated with GKS to 80 Gy, 4-mm collimator, single isocenter. Mean f/u 13
months
• 3 patients reported "dry eye", with diminution/absence of corneal reflex. No other abnormalities. Hypesthesia
of V1 developed prior to "dry eye". Brain stem irradiated volume significantly correlated with complication
• UCLA; 1997 PMID 9018707 -- "Leksell Gamma Knife treatment of tic douloureux." (Rand RW, Neurosurg Clin
N Am. 1997 Jan;8(1):75-8.)
• Retrospective. 12 patients. F/u 3-4 years. Pain control: 8/12 improvement or complete relief.
• Side effects: 1 radionecrosis in medial temporal lobe
Radiobiology
• Maryland PMID 11674826 -- "An investigation of eye lens dose for gamma knife treatments of trigeminal
neuralgia." (Ma L, J Appl Clin Med Phys. 2000 Autumn;1(4):116-9.)
• Phantom studies and in vivo dosimetry for 6 patients. Average dose to ipsilateral lens 7.7 cGy (+/- 0.6 cGy).
Calculated cataract probability 0.1%
• Pittsburgh PMID 10764273 -- "Histological effects of trigeminal nerve radiosurgery in a primate model:
implications for trigeminal neuralgia radiosurgery." (Kondziolka D, Neurosurgery. 2000 Apr;46(4):971-6;
discussion 976-7.)
• 2 adult baboons SRS to 80 and 100 Gy (4 nerves total). Target proximal trigeminal nerve just anterior to pons.
Nonirradiated baboon brains as controls. 6 months after MRI and pathology
• MRI: 4 mm area of contrast enhancement
• Pathology: axonal degeneration, mild edema, with remnants of myelinated axons. Large and small myelinated
and unmyelinated fibers affected. No inflammation. Nerve necrosis at 100 Gy treatment. Trigeminal ganglion
normal.
• NCI PMID 7607923 -- "Clinical toxicity of peripheral nerve to intraoperative radiotherapy in a canine model."
(Johnstone PA, Int J Radiat Oncol Biol Phys. 1995 Jul 15;32(4):1031-4.)
• 40 animals, laparotomy with IORT 0-75 Gy to lumbosacral plexus. Then periodically sacrificed to monitor
peripheral nerve. F/u 5 years
• Dose >= 25 Gy resulted in ipsilateral neuropathy. Inverse relationship between dose and time-to-neuropathy,
ED50 for paralysis 17.2 Gy. One animal treated with 15 Gy IORT developed paralysis after much longer
latency. Consider 15 Gy threshold for paralysis.
Historical Note
• PMID 9309292 -- First use of RT for trigeminal neuralgia in 1897
• PMID 15397004 -- "Roentgenotherapy in trigeminal neuralgia." (Trostler IS, Miss Valley Med J. 1949
Nov;71(6):204.)

Retreatment
Trigeminal Neuralgia Retreatment
Gamma Knife Retreatment
Re-treatments
Institution Patients F/U First GKS Dose Second GKS Success Side Effect
(mo) Dose
SD Gamma Knife Center 26 ? 97 Gy 97 Gy 85% ?
Columbia 40 18 75 Gy 40 Gy 45% 7% moderate, 3% severe
Prague 19 ? 70-80 Gy 70-80 Gy 89% 32% hypesthesia
Mayo Clinic 19 24 87 Gy 76.1 Gy 61% 58% dysfunction, 16% bothersome
Maryland 28 14 75 Gy 70 Gy 82% 43% numbness, 14% bothersome
Kentucky 35 19 90 Gy 90 Gy 84% 33% dysfunction, 3% bothersome
Barrow Neurological Institute 19 14 78.2 Gy 46.6 Gy 73% 42% numbness, 0% bothersome
Pittsburgh 27 20 75.6 Gy 64.4 Gy 48% 13% dysfunction
Tianjin 12 18 75.6 Gy 74.2 Gy 92% 11% numbness
Northwest Hospital 51 ? 76-98 Gy ? 80% 16% numbness
• San Diego Gamma Knife Center 2006 NSA Abstract -- "Dose response of Gamma Knife surgery for trigeminal
neuralgia and high-dose salvage of failed Gamma Knife surgery" (Ott K, Neurosurgical Society of America
Abstract, 2006)
• Retrospective. 263 patients treated, 26 retreated. RT dose range 26-140 Gy. Average f/u 32 months
• Pain control: Typical TN 85% excellent/good, Atypical TN 46% excellent/good. Dose response present, now
use 97 Gy for both treatment and retreatment.
• Side effects: >50% facial numbness, usually transient. Better pain control results
• Retreatment: Same benefit. Comparable facial numbness, better response. Some with fair/poor/no response
initially had excellent response on retreatment
• Columbia
• 2005 PMID 15850900 -- "Where to locate the isocenter? The treatment strategy for repeat trigeminal neuralgia
radiosurgery." (Zhang P, Int J Radiat Oncol Biol Phys. 2005 May 1;62(1):38-43.)
• Retrospective. 40 patients with repeat GK. RT max 75 Gy initially, 40 Gy retreatment. Median f/u 28
months
• Pain relief: complete 27%, nearly complete 18%, partial 20%, minimal/none 35%
• Isocenter distance: mean 2.86 mm (complete/nearly complete relief) vs. 1.93 (partial/none relief). Farther
distance with trend to better pain relief
• Side effects: 7% moderate dysesthesia (4+/10), 3% severe dysesthesia (7+/10) after retreatment. Not related
to isocenter distance
• 2003 PMID 14742963 1998-2003 -- "Repeat gamma knife radiosurgery for trigeminal neuralgia." (Brisman R,
Stereotact Funct Neurosurg. 2003;81(1-4):43-9.)
• Retrospective. 335 patients treated to 75 Gy, 45 patients retreated with 40 Gy. Mean 15 months f/u
• Final pain relief: >50% in 62%. If no prior neurosurgical procedure, more likely to have better pain relief
• Side effects: significant dysesthesias (>5/10) in 2 patients (4%)
• Prague (Czech)
• 2005 PMID 15662776 -- "Treatment of essential trigeminal neuralgia with gamma knife surgery." (Urgosik D,
J Neurosurg. 2005 Jan;102 Suppl:29-33.)
• Retrospective. 107 patients, retreat in 19 patients, same dose. RT 70-80 Gy.
• Pain relief: Initial 96% (complete 80%). Median time to improvement 3 months (1 day, 13 months).
Recurrence 25%, median interval 36 months (6, 94).
• Retreatment: 19 patients (17%), initial pain relief 89% (complete 58%). Relapse 1 patient thus far
• Side effects: Hypesthesia 20% after first GK, 32% after second GK. Median interval 35 months (3, 94) after
first GK, 21 months (1, 72) after second
• Mayo
• 2005 PMID 15629611 1997-2002 -- "Repeat radiosurgery for idiopathic trigeminal neuralgia." (Pollock BE,
• Retrospective. 19 patients retreated. Median interval 16 months. Median dose 76.1 Gy (median additive
dose 163.1 Gy). Median f/u 24 months
• Pain relief: 74% excellent, 95% >50% pain reduction. 61% excellent outcome at 2 years. 2 patients recurred
at 7, 22 months.
• Side effects: 58% facial parathesia, numbness or dyesthesia, 16% bothersome. 2 patients (11%) corneal
numbness. Recommend reducing dose
• 2000 PMID 11143237 1997-1999 -- "Results of repeated gamma knife radiosurgery for medically
unresponsive trigeminal neuralgia." (Pollock BE, J Neurosurg. 2000 Dec;93 Suppl 3:162-4.)
• Retrospective. 10 patients retreated. Median interval 13 months. All initially significant reduction, none
with facial numbness
• Pain relief: 80% excellent outcome at 1 year. All developed minor dysfunction
• Maryland
• 2005 ASTRO Abstract 1996-2004 -- "Comparison of Repeat GK-SRS for Refractory or Recurrent Trigeminal
Neuralgia: Does Dose Matter" (Dutta PR, Abstract 2118)
• Retrospective. 63/69 patients (Maryland 28, Kentucky 35).
• Maryland:
• First GKS RT median 75 Gy (70-80 Gy), second GKS 70 Gy (45-75 Gy). Median retreatment in 13
months. Median f/u 14 months
• Pain control: Initially 43% excellent, 43% good. Retreatment 39% excellent, 43% good. All 3 with
initially poor response did not respond to retreatment
• Side effects: 25% new after 2nd GKS, total 43% numbness; 14% bothersome but had complete relief
• Kentucky
• First GKS median 90 Gy (80-90 Gy), second GKS 90 Gy (70-90 Gy). Median f/u 19 months
• Pain control: initially 33% excellent, 22% good. Retreatment 64% excellent, 20% good. Of 8 with poor
response, 50% excellent result after retreatment
• Side effects: 25% new after 2nd GKS, total 33% numbness or dysesthesia. 3% bothersome
• Conclusion: Cumulative dose 150 Gy vs. 180 Gy. Similar pain control, but 180 Gy more likely to have
excellent outcome. Minimal bothersome effects.
• 2004 1996-2001 PMID 15093906 -- "Repeat gamma knife radiosurgery for refractory or recurrent trigeminal
neuralgia: treatment outcomes and quality-of-life assessment." (Herman JM, Int J Radiat Oncol Biol Phys.
2004 May 1;59(1):112-6.)
• Retrospective. 112 treated, 18 underwent repeat GKS. Median 8 months (3-42 months). Median RT 75 Gy
first GKS, 70 Gy second GKS. Median f/u 37 months after first GKS, 24 months after second GKS
• Pain control: Excellent 50%, good 28%, fair 6%, poor 16%. None of initial failures responded to repeat
GKS
• Side effects: 2 patients (11%) facial numbness, 1 bothersome
• 2003 ASTRO Abstract -- "Repeat Gamma Knife Radiosurgery for Refractory or Recurrent Trigeminal
Neuralgia" (Petit H, Abstract 22, 2003). Full paper Herman 2004 above
• Barrow Neurological Institute; 2002 1997-2002 PMID 12507092 -- "Gamma knife radiosurgery for recurrent
trigeminal neuralgia." (Shetter AG, J Neurosurg. 2002 Dec;97(5 Suppl):536-8.)
• Retrospective. 19/29 patients. Questionnaires. Initial RT dose mean 78.2 Gy (70-90). RT retreatment mean
dose 46.6 Gy (35-80). Mean f/u 13.5 months
• Pain control: 53% excellent, 21% pain free but on reduced meds
• Side effects: Facial numbness 42%, none bothersome. Those with facial numbness greater likelihood of being
pain free
• Pittsburgh 2002 PMID 11841716 -- "Repeat radiosurgery for refractory trigeminal neuralgia." (Hasegawa T,
Neurosurgery. 2002 Mar;50(3):494-500; discussion 500-2.)
• Retrospective. 27/31 patients assessed. Median dose 75.6 Gy (60-80 Gy), retreatment 64 Gy (50-80 Gy).
Median f/u 43 months after 1st GKS, 20 months after 2nd GKS.
• Pain control: 18% excellent, 30% good, 37% fair, 15% poor. Overall 48% complete pain relief (with or
without meds)
• Dose-response: low dose (120-135 Gy) vs. high dose (140-160 Gy): NS, although slightly fewer excellent and
slightly more good outcomes with low dose. Now deliver 50-60 Gy)
• Side effects: 13% dysfunction
• Tianjin 2001 (China) 1996-1999 PMID 12007276 -- "Stereotactic radiosurgery for primary trigeminal neuralgia
using the Leksell Gamma unit." (Zheng LG, Stereotact Funct Neurosurg. 2001;76(1):29-35.)
• Retrospective. 80 patients. RT dose mean 75.6 Gy (70-90 Gy). Follow-up 24 months
• Pain control: excellent 52%, good 31%, fair 10%, fail 6%. Mean time to improvement 22 days (1-120 days).
Recurrence 10% in 5-26 months later
• Retreatment: 12 patients (7 recurrent, 5 failures). RT dose mean 74.2 Gy (70-80 Gy). Mean f/u 18 months,
9/12 excellent result, 2/12 good result, 1 failed. Mean time to improvement 15 days (1-120)
• Side effects: 11% facial numbness
• Norhtwest Hospital 2000 Abstract 1991-1999 -- "Gamma Knife radiosurgery for treatment of trigeminal
neuralgia: long term results" (Young RF, 3rd TN Conference, 2000)
• Retrospective. 435 patients. RT 76-98 Gy. Median f/u 51 months. 51 patients retreated. Joint with Good
Samaritan data??
• Pain control: 6 months - 60% excellent, 30% good (some meds). Last f/u - 78% excellent/good. Including
retreatment, 65% excellent, 20% good
• Retreatment: success 80%
• Side effect: 16% facial numbness
Radiation Oncology/CNS/Sphenopalatine neuralgia 106
Radiation Oncology/CNS/Sphenopalatine
neuralgia
Sphenopalatine Neuralgia
• Rare craniofacial pain syndrome, also known as Sluder's Neuralgia
• Characterized by unilateral pain in the orbit, mouth, nose, and posterior mastoid process.
• Also associated increased autonomic activity resulting in ipsilateral nasal drainage, eye irritation, and lacrimation
• May be caused by irritation of the pterygopalatine ganglion, possibly secondary to infection
• Typically female 2:1 male predominance
• Pittsburgh; 1997 PMID 9285614 -- "Stereotactic radiosurgical treatment of sphenopalatine neuralgia. Case
report." (Pollock BE, J Neurosurg. 1997 Sep;87(3):450-3.)
• Case report. SRS 45 Gy to 50% isodose line. Pain free x8 months
• Recurrence 50% pain at 17 months, retreated with 40 Gy to 50% isodose line, and pain-free at 7 month
follow-up
Radiation Oncology/CNS/Cluster Headaches

Chronic Cluster Headaches

• Sudden onset of unilateral pain, typically originating around the eyes, temple, cheek, and forehead. Typically
along the V1 division of the trigeminal nerve
• Frequently with concurrent ipsilateral autonomic activity, resulting in ptosis, miosis, lacrimation, conjunctival
injection, rhinorrhea, and nasal congestion
• Epidemiology
• Prevalence of cluster headaches is estimated at 0.2%; incidence at 2-10/100,000
• ~10% develop chronic cluster headaches (remissions <30 days or duration >1 year)
• ~20& of CCH patients are highly refractory to medical treatment
• Male 6:1 female predominance
• Mean age of onset 30 years
• Seasonal predilection for spring and fall
• Increased incidence in monozygotic twins; 14x risk in first-degree relative and 2x risk in second-degree
relative suggests role for genetic factors
• Pathophysiology is not clear, but clinical presentation and functional imaging suggests central origin, with
posterior hypothalamic hyperactivity. However, the pterygopalatine ganglion may also be involved, due to
confluence of multiple nerve fibers passing through
• Multiple surgical modalities (e.g. surgical sectioning of various nerves, MVD, deep brain stimulation, etc) have
been explored, but all involved potential complications from surgery
• Deep brain stimulation has proven to effective in both reducing pain and increasing efficacy of pain medications
• Gamma Knife treatment targeting trigeminal nerve has not been successful, and has had much higher rate of side
effects than same protocol used safely for trigeminal neuralgia. It is not clear whether the trigeminal nerve is more
Radiation Oncology/CNS/Cluster Headaches 107
sensitive to RT in cluster headaches or more resistant to RT in trigeminal neuralgia

• A single case report from Stanford suggest targeting the pterygopalatine ganglion at a lower dose might be
efficacious
• Stanford; 2007 PMID 17327771 -- "Cyberknife targeting the pterygopalatine ganglion for the treatment of
chronic cluster headaches." (Lad SP, Neurosurgery. 2007 Mar;60(3):E580-1; discussioin E581.)
• Case report. SRS targert to pterygopalatine ganglion; 45.5 Gy to 78% isodose line (Dmax 65 Gy)
• Outcome: Good pain control
• Minnesota; 2006 (1997-2001) PMID 17277688 -- "Long-term results of radiosurgery for refractory cluster
headache." (McClelland S, Neurosurgery. 2006 Dec;59(6):1258-62; discussion 1262-3.)
• Retrospective. 10 patients with refractory CH. GKS 75 Gy at 100% isodose to most proximal part of trigeminal
nerve, with 50% isodose line outside brain stem. Median F/U 3.3 years
• Outcome: pain relief fair in 1/10 and poor in 9/10 patients.
• Toxicity: 50% facial numbness
• Conclusion: no sustained pain relief when targetting TN
• Marseille
• Prospective trial. 10 patients. GKS target cisternal segment of trigeminal nerve. Dmax 80-85 Gy. Brainstem
dose 4-11.1 Gy.
• 2006 PMID 17277687 -- "Trigeminal nerve radiosurgical treatment in intractable chronic cluster headache:
unexpected high toxicity." (Donnet A, Neurosurgery. 2006 Dec;59(6):1252-7; discussion 1257.) Median F/U 3
years
• Outcome: 2/10 CR, 1/10 good result, 7/10 no improvement.
• Toxicity: 90% disturbances (3/10 paresthesia, 6 hypoesthesia including 2 deafferentation pain)
• Conclusion: High rate of toxicity and failure, despite same methodology ast TN. Do not recommend for
intractable CCH
• 2005 PMID 15654036 -- "Gamma knife treatment for refractory cluster headache: prospective open trial."
(Donnet A, J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):218-21.) Mean F/U 1 year
• Outcome: 3/10 patients no pain, 3/10 patients few attacks, 4/10 no improvement
• Toxicity: 50% injury (3/10 paresthesia, 1/10 hypoaesthesia, 1/10 deafferentation pain)
• Conclusion: Rate and severity of nerve injury unexpectedly high; procedure less attractive
• Ford Headache Clinic; 1998 (Alabama) PMID 9504996 -- "Gamma knife treatment of refractory cluster
headache." (Ford RG, Headache. 1998 Jan;38(1):3-9.)
• Case report. 6 patients. Dmax 70 Gy to CNV entry zone. Follow up 8-14 months
• Outcome: 4/6 excellent relief, 1/6 good relief, 1/6 fair relief
• Toxicity: none
• Conclusion: GKS affords great promise with negligible risk
Radiation Oncology/CNS/Arteriovenous
malformation
Overview
• Originally described by Luschka and Virchow in the mid 1800s, AVMs are abnormal communications between
arteries and veins without the normal capillary flow.
• The incidence in the US population is 0.14% (140 cases per 100,000 persons or 1 case per 700 persons). This is
approximately one fifth to one seventh the incidence of intracranial aneurysms.
• Abnormal communication between artery and vein, with disproportionate and unbalanced hydrodynamic stress
across them. The direct connection between the arterial and venous systems exposes the venous system to
abnormally high pressures and results in the formation of enlarged feeding vessles and enlarged draining venous
structures.
• Point of abnormal communication is known as the nidus
• Annual risk of hemorrhage 2-6%, with associated fatality rate 10-20%
• Primary treatment approach is typically surgical resection
• Risk evaluated by Spetzler-Martin score (PMID 3760956) (size, location, pattern of venous drainage), which
estimates post-op morbidity and mortality
• SRS typically used if surgery is considered too risky: surgical inaccessibility, expected high morbidity due to
eloquent location or large size, medically inoperable
• Goal of SRS treatment is to eliminate risk of catastrophic intracranial hemorrhage
• Probability of obliteration ("cure") is ~80% for smaller lesions, and depends on dose
• There is a definite associated between AVM and aneurysm with about 8% of AVM patients developing a cerebral
aneurysm and about 1% of patients with an aneurysm found to have an AVM. Aneurysms are most commonly
found on arteries feeding the AVM.
• AVMs are congenital lesions that result from the failure of the embryonic vascular plexus to fully differentiate
and develop a mature capillary bed. While the structure may change or grow postnatally, they are thought to only
be seen in the presence of a prenatally lesion. Tissues adjacent to the AVM may be mildly hypoxic due to
“stealing” blood from adjacent healthy tissue. This may lead to expression of pro-angiogenic factors such as
VEGF and bFGF.
• Hemorrhage is the most common reason for presentation (~50%). It is often associated with the acute onset of a
severe headache that may be described as “the worst headache of my life”. Depending on the location, it may also
be associated with a new neurologic deficit. Seizure can be seen in about 45% of patients, headache in 33%,
neurologic deficit in 20%.
• Pediatric patients can present with heart failure, macrocephaly, and/or prominent scalp veins.
Management
• Surgery - Cure is immediate and permanent after complete
resection. Is generally recommended for grade 1, 2, and
(sometimes) 3 lesions. One of the primary risks is that of
hemorrhage into healthy parts of the brain.
• Endovascular neurosurgery -- Involves the obliteration of vessels
with glues or particles delivered via arterial catheter. Its main use is
“neoadjuvantly” prior to crainiotomy to decrease intraoperative
bleeding. It can also be used prior to SRS to decrease the size of an
AVM. Embolization can be curative for lesions <1cm that are fed by a SINGLE artery. The main risk involves
occluding a vessel that also supplies normal brain. The pathologic vessels usually recanalize over time, so this is
rarely used by itself.
• Stereotactic radiosurgery -- Can be used if surgery is considered too risky: inaccessible location, expected high
morbidity due to location, large size, medically inoperable. The goal of SRS is to eliminate the risk of
catastrophic intracranial hemorrhage. Some groups have used staged or fractionated SRS to treat larger lesions. It
can take 2 or more years for a full destructive effect and the risk for hemorrhage is not reduced during this time.
Cure rates for lesions <3cm are 80-90%.
• Ondra 1990 J Neurosurgery PMID 2384776 -- Retrospective series on 160 patients with untreated
symptomatic AVMS with a mean follow-up of 23.7 years (seen between 1942 and 1975 at Helsinki
University). The rate of major rebleeding was 4% per year and the mortality rate was 1% per year. Nearly 25%
of patients were dead from AVM hemorrhage. There was no significant difference based on whether a patient
presented with hemorrhage, seizure, or other.
• Friedman 1995 J Neurosurgery PMID 7815144 -- Report of 158 patients at UF treated between 1988 and 1993.
Mean dose of 1560 cGy to the periphery with mean volume of 9 mls. Mean f/u of 33 months during which
patients were followed with MRI until findings suggested complete thrombosis at which time an arteriogram
was performed to verify occlusion. If a persistent nidus was found at 36 months, patients were re-treated. The
goal was to relate size to outcome. Only 56 patients had “definitive endpoints” (death related to hemorrhage,
retreatment, angiographic cure) so this data may be quite biased. Due to the significant selection of whom they
reported on, the more interesting data may be their complications. Seizure within 48 hrs of SRS was seen in
4.6% of patients (all of these initially presented with seizure). Hemorrhage was seen in 4% of patients between
2 and 11 months after treatment. Transient delayed complications (HA, dysphasia) was seen in 2% of patients
with resolution after steroids.
• Flickinger 1996 IJROBP PMID 8960516 -- Retrospective review of 216 patients (1987-1992) with
gammaknife radiosurgery for AVM at U Pitt. Of these, 197 had angiographic followup with a median treated
volume of 4.1 ml. Complete obliteration was seen in 72% of patients. On multivariate analysis, a correlation
with minimum dose was seen, but not with volume or maximum dose. Very few patients were treated with <15
Gy or >25 Gy. Very nice figures in the paper.
• Flickinger 2000 IJROBP PMID 10725624 -- Review from 85 AVM patients who developed symptomatic
complications and 337 control patients without complications to develop a method to better predict permanent
complications from AVM radiosurgery. Essentially, the risk of developing complications is related to the
location and volume receiving 12 Gy. History of prior hemorrhage and marginal dose did not significantly
predict injury.
• Maruyama 2005 NEJM PMID 15647577 -- Retrospective analysis of 500 patients treated with gammaknife RS
to assess the effects of RS on rates of hemorrhage. RS dose was 20 Gy with use of the 50% isodose line.
RESULTS: 42/500 patients had a hemorrhage before radiosurgery. 23/458 patients had a hemorrhage during
the latency period (the interval between RS and angiographic obliteration). 6/250 patients had hemorrhages
after obliteration. The annual rate of repeated hemorrhage prior to radiosurgery was about 6% among those
patients who presented with hemorrhage.
• Controversies-- Given the increased use of cranial imaging estimates are that 50-60% of newly diagnosed AVMs
are detected incidentally. Although the traditional stated risk of hemorrhage is 2-3% per year, this is typically
calculated from the time of diagnosis. More recent estimates place the risk of hemorrhage at closer to 1%.
Predictors of AVM hemorrhage include increasing age, deep brain location, associated aneurysms, and deep
venous drainage. This has led to: ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous
Malformations), an ongoing multicenter randomized trial enrolling 800 patients, that is comparing treatment
(sugery, radiation, or both, physician decision) of unruptured lesions with conservative management.
Review
• 2007 PMID 17596605 -- "Clinical practice. Arteriovenous malformations of the brain." (Friedlander RM, N Engl
J Med. 2007 Jun 28;356(26):2704-12.)
Proton Therapy
Toxicity
• Harvard; 2003 (1965-1993) PMID 12924697 -- "Dose-volume prediction of radiation-related complications after
proton beam radiosurgery for cerebral arteriovenous malformations." (Barker FG 2nd, J Neurosurg. 2003
Aug;99(2):254-63.)
• Retrospective. 1,250 patients. DVH information reviewed. Median size 33.7 cm3, 23% <10 cm3, largest 927
cm3. Median dose 10.5 Gy. Median F/U 6.5 years
• Toxicity: permanent late toxicity 4% (hemiparesis 2%, visual field defects 1%, other <1%: cognitive
dysfunction, ataxia, speech deficits, hemisensory deficits, hearing loss). Median time-to-complication 1.1 years
(0.2 - 6.8 years)
• Predictors: Median dose complications 17 Gy vs no complications 10 Gy. If dose <12 Gy, complication rate
0.5% but a complication also occurred at 5 Gy. Complication rate related to dose, volume, thalamic/brainstem
location, and age (median age 31). Significantly more complications than predicted by Kjellberg's model (e.g
expected 2-2.5% complication bin had 34% actual complications)
• Conclusion: Estimate of risks after proton SRS for AVM; dose-volume model developed
Radiation Oncology/CNS/Cavernous malformation 111
Radiation Oncology/CNS/Cavernous
malformation
Overview
• A cavernous malformation is a vascular malformation composed of sinusoidal vessels without a large feeding
artery.
• The primary difference between a cavernous malformation and an → AVM is the lower pressure gradient.
• Represent 8-15% of intracranial malformations
• 70-80% are supratentorial.
• 0.25% to 6% annual risk of hemorrhage.
Treatment
Stereotactic radiosurgery
• Pittsburgh, 2002 (1987-2000) - PMID 12015835 -- "Long-term results after stereotactic radiosurgery for patients
with cavernous malformations." Hasegawa T et al. Neurosurgery. 2002 Jun;50(6):1190-7.
Radiation Oncology/Paraganglioma
Overview
• Paragangliomas are still sometimes called glomus tumors (not to be confused with glomus tumors of the skin)
and chemodectomas, but paraganglioma is the currently accepted and preferred term
• A rare neoplasm that can be found in the abdomen (85%), thorax (12%), and in the head and neck region (3%)
• Incidence estimated at 1:1,000,000
• Categorized as a neuroendocrine tumor
• Usually considered benign and complete surgical removal results in cure. However, in about 3-5% of cases they
are malignant and have the ability to metastasize.
• Most occur as single tumors. When they occur in multiple sites they are usually found as a part of a heritable
syndrome such as MEN types II-A and II-B and Carney syndrome.
Inheritance
• Familial paragangliomas account for ~25% of cases, are often multiple and bilateral, and occur at an earlier age.
• Mutations of the genes SDHD (previously known as PGL1), PGL2, and SDHC (previously PGL3) have been
identified as causing familial head and neck paragangliomas.
• Mutations of SDHB play an important role in familial adrenal pheochromocytoma and extra-adrenal
paraganglioma (of abdomen and thorax), although there is considerable overlap in the types of tumors associated
with SDHB and SDHD gene mutations.
Pathology
• Arise from the glomus cells, which are special chemoreceptors located along blood vessels that have a role in
regulating blood pressure and blood flow.
• The glomus cells are a part of the paraganglion system, composed of the extra-adrenal paraganglia of the
autonomic nervous system, derived from the embryonic neural crest. Thus, paragangliomas are a type of
neuroendocrine tumor, and are closely related to pheochromocytomas. Although all paragangliomas contain
neurosecretory granules, only about 1-3% have clinical evidence of oversecretion.
• According to the WHO classification of neuroendocrine tumors, paragangliomas are classified as having a neural
cell line of origin. In the categorization proposed by Wick, the paragangliomas belong to Group II.
• The main concentration of glomus cells are found are in the carotid body and the aortic bodies
• Individual tumor cells are polygonal to oval and are arranged in distinctive cell balls, called Zellballen. These cell
balls are separated by fibrovascular stroma and surrounded by sustenacular cells.
• The paragangliomas appear grossly as sharply circumscribed polypoid masses and they have a firm to rubbery
consistency. They are highly vascular tumors and may have a deep red color.
• With IHC, the chief cells located in the cell balls are positive for chromogranin, synaptophysin, NSE, serotonin
and neurofilamen; they are S-100 negative. The sustenacular cells are S-100 positive and focally positive for
GFAP. By histochemistry, the paraganglioma cells are argyrophilic, PAS negative, mucicarmine negative, and
argentaffin negative.
Clinical characteristics
Paragangiomas are described by their site of origin and are often given special names:
• Carotid paraganglioma (carotid body tumor): Is the most common of the head and neck paragangliomas. It
usually presents as a painless neck mass, but larger tumors may cause cranial nerve palsies, usually of the vagus
nerve and hypoglossal nerve.
• Glomus tympanicum and Glomus jugulare: Both commonly present as a middle ear mass resulting in tinnitus
(in 80%) and hearing loss (in 60%). The cranial nerves of the jugular foramen may be compressed, resulting
swallowing difficulty.
• Vagal paragangliomas: These are the least common of the head and neck paragangliomas. They usually present
as a painless neck mass, but may result in dysphagia and hoarseness.
• Other sites: Rare sites of involvement are the larynx, nasal cavity, paranasal sinuses, thyroid gland, and the
thoracic inlet.
Treatment
• The main treatment modalities are surgery, embolization and radiotherapy.
• When radiation is given, doses are in the range of 45-50 Gy.
• For stereotactic radiosurgery, median margin dose (50% isodose) used is ~16 Gy
Glomus Jugulare
Overview
• Typically considered slow-growing (estimated doubling time 4.2
years) benign tumors, <5% malignant potential
• However, they are locally agressive neoplastic lesions, involving
bony erosion and destruction of neurovascular structures
• Commonly arise from the paraganglia of the jugular bulb
• Typically invade the tympanic cavity and jugular foramen
• Can extensively invade petroclival region
• Can invade cavernous sinus above
• Can invade hypoglossal canal below
• Clinical presentation typically with tinnitus or hearing loss, but may
also impact jugular foramen CNs
• Glasscock-Jackson Classification:
G-J Class Description
I Small tumor involing jugular bulb, middle ear, and mastoid
II Tumor extending under internal auditory canal; may have intracranial canal extension
III Tumor extending into petrous apex; may have intracranial canal extension
C1 Tumor extending beyond petrous apex; into clivus or infratemporal fossa
• Fisch Classification:
Fisch Description
Class
A Tumor limited to the middle ear cleft
B Tumor limited to the tympanomastoid area, with no infralabyrinthine involvement
C Tumor invading infralabyrinthine compartment and petrous apex
C1 Tumor with limited involvement of the vertical carotid canal
C2 Tumor invading the vertical carotid canal
C3 Tumor invading the horizontal carotid canal
D1 Tumor with intracranial extension <2cm
D2 Tumor with intracranial extension >2cm
• Optimal treatment strategy is not clear, with multiple options:

• Surgery: primary option if brainstem compression, or in young patients with functional CN loss. Surgical
morbidity not insignificant
• Fractionated RT: typical doses 45-55 Gy, mechanism of action likely related to fibrosis of feeding vessels and
not direct glomus cell destruction. Complication rate low
• SRS: No long-term experience yet, but appears a good option due to high conformality. RT dose typically ~16
Gy at 50% margin isodose. Typically ~1/3 have volume shrinkage, and ~2/3 no change, <10% further growth.
Clinically ~50% may experience improvement
• Embolization: typically considered an adjunctive treatment to surgery or RT. Not adequate alone due to poor
tumor coverage and frequent re-vascularization
Stereotactic Radiosurgery
• Verona, 2006 (Italy)(1996-2005) PMID 16955038 -- "Glomus jugulare tumors: the option of gamma knife
radiosurgery." (Gerosa M, Neurosurgery. 2006 Sep;59(3):561-9; discussion 561-9.)
• Retrospective. 20 patients (3 primary GKS, 8 recurrence post surgery, 11 recurrence after embolization).
Average volume 7 cm3, mean marginal dose 17.3 Gy (13-24). Estimated doubling 4.2 years. Mean F/U 4.2
years
• Outcome: Improved volume 40%, no change 55%
• Toxicity: Improved CN function 25%, no neuro change 65%, hearing loss 10%
• Conclusion: GKS effective, negligible side effects
• Virginia, 2005 PMID 15662818 -- "Gamma knife surgery for glomus jugulare tumors: an intermediate report on
efficacy and safety." (Sheehan J, J Neurosurg. 2005 Jan;102 Suppl:241-6.)
• Retrospective. 8 patients. Median margin dose 15 Gy (12-18). Median F/U 2.7 years
• Outcome: clinically 100% stability or improvement; radiographically 4/7 decreased, 3/7 stable
• Toxicity: None
• Conclusion: Effective local control and preservation of neurologic function
• Mayo Clinic, 2004 PMID 15329025 -- "Stereotactic radiosurgery in patients with glomus jugulare tumors."
(Pollock BE, Neurosurg Focus. 2004 Aug 15;17(2):E10.)
• Retrospective. 42 patients treated with GKS. Mean volume 13.2 cm3. Mean margin dose 14.9 Gy. Mean F/U
3.7 years
• Outcome: 31% decreased, 67% unchanged, 2% grew. PFS at 7 years 100%, at 10 years 75%
• Toxicity: 15% new deficit (hearing loss, facial numbness, vocal cord paralysis, vertigo). Hearing preservation
81% at 4 years
• Conclusion: GKS good tumor control, safe
• Stanford, 2004 PMID 15329026 -- "Efficacy and safety of stereotactic radiosurgery for glomus jugulare tumors."
(Lim M, Neurosurg Focus. 2004 Aug 15;17(2):E11.)
• Retrospective. 13 patients with 16 tumors. Treated with LINAC/Cyberknife to 14-27 Gy. Median F/U 3.4
years
• Outcome: clinically 100% stable; radiographically 100% decreased or stable
• Toxicity: one transient ipsilateral vocal cord paralysis (however, patient also had prior EBRT)
• Conclusion: RS effective and safe
• Vienna, 2001 (Austria)(1993-1999) PMID 11696882 -- "Efficiency of gamma knife radiosurgery in the treatment
of glomus jugulare tumors." (Saringer W, Minim Invasive Neurosurg. 2001 Sep;44(3):141-6.)
• Retrospective. 12 patients. All Fisch Class D. Mean F/U 4.2 years
• Outcome: clincally 50% improved, 50% no change; radiographically decreased 25%, stable 75%
• Toxicity: transient cranial neuropathy in 17%.
• Conclusion: GKS attractive treatment option
• European Multicenter, 1999 (1992-1998) PMID 10592113 -- "Gamma Knife radiosurgery of the glomus
jugulare tumour - early multicentre experience." (Liscak R, Acta Neurochir (Wien). 1999;141(11):1141-6.)
• Retrospective. 6 sites, 52/66 patients. Median margin dose 16.5 Gy (10-30). Median F/U 2 years
• Outcome: clinically 29% improved, 65% stable; radiographically decreased 40%, stable 60%
• Conclusion: safe, with no acute morbidity; need longer follow-up
• Graz, 1999 (Austria)(1992-1998) PMID 10536716 -- "Gamma knife radiosurgery for glomus jugulare tumours."
(Eustacchio S, Acta Neurochir (Wien). 1999;141(8):811-8.)
• Retrospective. 10/13 patients with imaging followup. Median marginal dose 13.5 Gy to 50% isodose line.
• Outcome: 40% decreased volume, 60% unchanged. Improved clinical status in 50%, stable in 50%
• Toxicity: none
• Conclusion: effective treatment option
• Prague, 1998 (Czech Republic)(1993-1997) PMID 9782246 -- "Leksell gamma knife radiosurgery of the tumor
glomus jugulare and tympanicum." (Liscak R, Stereotact Funct Neurosurg. 1998 Oct;70 Suppl 1:152-60.)
• Retrospective. 14 patients. Mean maximum dose 37.4 Gy (20-44); mean margin dose 19.4 Gy (10-25). Mean
F/U 1.7 years
• Outcome: radiographically 30% improved, 70% stable; clinically 36% improved
• Toxicity: worsening hearing in 21%
• Conclusion: GKS safe treatment; will need long follow-up
Surgery vs. SRS

• Meta-analysis, 2004 (1994-2004) PMID 15329019 -- "Comparison of radiosurgery and conventional surgery for
the treatment of glomus jugulare tumors." (Gottfried ON, Neurosurg Focus. 2004 Aug 15;17(2):E4.)
• 7 surgical series 374 patients, 8 GKS series 142 patients. Mean F/U surgery 4.1 years, GKS 3.3 years
• Outcome: local control surgery 92%, recurrence 3%; GKS decrease 36%, stable 61%, recurrence 2%
• Toxicity: surgery CSF leak 8%, mortality 1.3%; GKS morbidity 8%, no mortality
• Conclusion: Both treatments safe and efficacious; surgery higher morbidity but long term GKS outcomes
unknown
References
• Pellitteri PK et al. Paragangliomas of the head and neck. Oral Oncology 2004 Jul;40(6):563-75. (PMID 15063383
[1]
)
• Sukhamay Lahiri, "Aortic body", in AccessScience@McGraw-Hill [2]
• John T. Hansen, "Carotid body", in AccessScience@McGraw-Hill [3]
• Wick MR. Neuroendocrine neoplasia. Current concepts. Am J Clin Pathol. 2000 Mar;113(3):331-5. (PMID
10705811 [4])
• The Otology Group [5]
References
[1] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=pubmed& dopt=Abstract& list_uids=15063383
[2] http:/ / www. accessscience. com/ server-java/ Arknoid/ science/ AS/ Encyclopedia/ 0/ 04/ Est_042400_frameset. html
[3] http:/ / www. accessscience. com/ server-java/ Arknoid/ science/ AS/ Encyclopedia/ 1/ 11/ Est_110700_frameset. html
[4] http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Retrieve& db=pubmed& dopt=Abstract& list_uids=10705811
[5] http:/ / www. theotologygroup. com/ skullbased/ s1. html
Radiation Oncology/CNS/Cancer pain

• St. Petersburg; 2006 (Russia) PMID 16715713 -- "[Proton irradiation of the pituitary gland for alleviating pain
in patients with disseminated prostate cancer] -- [Article in Russian]" (Kondrate'ev BV, Vopr Onkol.
2006;52(1):92-4.)
• Retrospective. 80 prostate cancer patients with pain from bony mets. Stereotactic ablation of frontal lob of
pituitary. Narrow beams of 1,000 MeV protons.
• Outcome: 70% suspended pain meds, remainder decreased
• Toxicity: No untoward side-effects
Radiation Oncology/Chordoma
Epidemiology
• Arise from embryonic notochordal remnants along neuraxis, which in adults are primarily located at skull base
and in sacrum
• Rare tumor; US incidence 0.08/100,00
• Represents 6% of skull base tumors; but 2-4% of primary bone neoplasms
• Median age is 60 (though in blacks age 27)
• More common in males (incidence 0.10/100,000) than females (0.06/100,000)
• Predominately in whites (91%), rare in blacks (2%)
• Characterized by slow growth, with local destruction of bone and extension into adjacent soft tissues. Typically
have an indolent course with multiple local recurrences
• As many as 30-40% may metastasize, but typically toward the end of disease course
• NCI/SEER; 2001 PMID 11227920 -- "Chordoma: incidence and survival patterns in the United States,
1973-1995." (McMaster ML, Cancer Causes Control. 2001 Jan;12(1):1-11.)
• SEER database. 400 cases, microscopically confirmed chordoma.
• Epidemiology: Incidence 0.08/100,000; more common in males (0.10) than females (0.06); more common in
whites (91%). Youngest age quartile cranial presentation (54%) vs. oldest age quartile sacral presentation
(41%)
• Treatment: Surgery alone 48%, surgery + EBRT 38%, RT only 14%. Sacral lesions more likely RT alone
(32% vs. 11%)
• Outcome: median OS 6.3 years; 5-year OS 68%, 10-year OS 40%
Anatomy
• In adults, remnants of notochord are present as the nucleus pulposus
of the intravertebral discs, and distribution of tumors matches
distribution of the remnants
• ~35% in sphenooccipital region (almost always involving clivus)
• 15-30% in vertebral column
• 30-50% in sacrococcygeal region
• NCI/SEER; 2001 (1973-1995) PMID 11227920 -- "Chordoma:
incidence and survival patterns in the United States, 1973-1995."
(McMaster ML, Cancer Causes Control. 2001 Jan;12(1):1-11.)
• SEER database. 400 cases, microscopically confirmed.
• Outcome: Cranial 32%, spinal 33%, sacral 29%
• Mayo Clinic; 1973 (1910-1971) PMID 4722921 -- "Chordomas
and cartilaginous tumors at the skull base." (Heffelfinger MJ,
Cancer. 1973 Aug;32(2):410-20.)
• Retrospective. 155 chordomas. 49% sacro-coccygeal, 36%
spheno-occipital, 15% vertebral column. Presentation, pathology,
and outcomes reviewed
Presenting Symptoms
• Location-dependent
• Combination of pain, weakness, sensory abnormalities, motor
abnormalities and bowel/bladder dysfunction
• Pain onset typically insidious; median duration 14 months (4-24 months) in one study
• Sacral:
• Tumors can grow to a large size
• Primary presenting complaint is lower back / sciatic pain, and constipation
• Mobile spine:
• Neurologic deficit more common than in sacrum, approaching 50%
• Airway obstruction or dysphagia in cervical spine
• Skull base:
• May be intracranial or extracranial, with mass effect symptoms depending on location
• Headaches and/or facial pain are common
• Pituitary insufficiency, hemianopsia/diplopia, cranial nerve deficits, nasal stuffiness.
Histologic Subtypes
• Conventional
• Chondroid
• Better prognosis
• Subtype with predilection for skull base location
• Dedifferentiated
• Memorial Sloan Kettering; 2008 PMID 18641983 -- "Chordoma
and chondrosarcoma gene profile: implications for
immunotherapy." (Schwab JH, Cancer Immunol Immunother. 2008
Jul 19. [Epub ahead of print])
• Affymetrix gene expression profiles, 6 chordoma and 14
chondrosarcoma. Validation by qPCR and IHC
• Outcome: Both show overexpression of extracellular matrix genes compared to other sarcoma types.
Chordoma selective expression of T Brachyury and CD24; chondrosarcoma Type IX and XI collagen.
HMW-MAA expressed in chordoma 62%, chondrosarcoma 48%
• Conclusion: Similar gene profile of upgregulated ECE matrix genes
Treatment Overview
• Maximal resection followed by proton beam irradiation.
• Overall survival is dependent upon local control of disease. Prognostic factor for local control of disease is
amount of residual tumor after original surgery (<25cc residual tumor is better).
• Clear margins are achieved in <50% of skull base chordomas.
• Doses of 70 CGE necessary for control of residual disease.
Surgery
• Most important prognostic factor is en bloc resection with negative surgical margins
• Technically, this may be achieved in ~50% of patients, and leads to 70% long-term control rate
• Extensive infiltrating disease at presentation
• Nearby critical structures, resulting in severe morbidity from radical approaches
• Primary operation is critical, as reoperation has significantly lower rates of technical success
• Subtotal resection results in ~70% recurrence rate
Skull Base
• Hannover; 2007 (Germany) PMID 17695386 -- "Chordomas of the skull base: surgical management and
outcome." (Samii A, J Neurosurg. 2007 Aug;107(2):319-24.)
• Retrospective. 49 patients. Transethmoidal approach 36%, pterional 23%, retrosigmoid 23%.
• Outcome: GTR 49%, subtotal resection 51%. Initial surgery GTR 78%. 5-year OS 65%, 10-year OS 39%
• Toxicity: New neurological deficit 12%
• Conclusion: Chordoma cannot be regarded as surgically curable tumors, given the 5- and 10-year OS
• University of Washington; 2006 (1988-2004) PMID 16883163 -- "Patient outcome at long-term follow-up after
aggressive microsurgical resection of cranial base chordomas." (Tzortzidis F, Neurosurgery. 2006
Aug;59(2):230-7; discussion 230-7.)
• Retrospective. 74 patients, aggressive microsurgical resection of cranial base chordomas, 121 procedures.
Primary operation 63%, re-operation 37%. Mean F/U 8 years
• Outcome: Gross total resection 72%, subtotal resection 28%. During F/U, NED 32%, alive with disease 50%,
died of disease 15%, died of complications 3%. 10-year RFS 31% (primary surgery 42% vs reoperation 26%,
SS)
• Conclusion: Aggressive microsurgical resection can be followed by long-term tumor free survival, with good
functional outcome
Mobile Spine Chordoma

• Bologna; 2006 PMID 16481964 -- "Chordoma of the mobile spine: fifty years of experience." (Boriani S, Spine.
2006 Feb 15;31(4):493-503.)
• Retrospective. 52 chordomas of mobile spine, 37 cases 1991-2002.
• Outcome: Post-op mortality 8%. If en bloc resection, 67% (12/18) without relapse at median F/U 8 years,
100% of relapses (6/6) had prior inadequate resections. All others (RT alone, surgery with SM+, or surgery
with SM+ and adjuvant RT) had recurrences <2 years. Intralesional excsion + RT high rate of recurrence 75%
• Conclusion: The only protocol associated with continuously disease-free survival is margin-free en bloc
resection
Sacral Chordoma
• Mayo Clinic; 2005 (1980-2001) PMID 16203885 -- "Operative management of sacral chordoma." (Fuchs B, J
Bone Joint Surg Am. 2005 Oct;87(10):2211-6.)
• Retrospective. 52 patients with sacro-coccygeal chordoma. Posterior approach 42%, combined anteroposterior
approach 58%. Wide surgical margin 40%. Median F/U 7.8 years
• Outcome: LR 44%; RFS 5-years 59%, 10-years 46%. OS 5-years 74%, 10-years 52%, 15-years 47%. Wide
surgical margin most important predictor for survival (100%)
• Conclusion: Wide surgical margin most important predictor of survival and local recurrence
• Goteborg; 2000 (Sweden)(1968-1998) PMID 10813725 -- "Prognostic factors in chordoma of the sacrum and
mobile spine: a study of 39 patients." (Bergh P, Cancer. 2000 May 1;88(9):2122-34.)
• Retrospective. 39 patients with chordoma, 30 sacral and 9 vertebral. Modern surgical techniques. Mean F/U
8.1 years
• Outcome: wide SM 59%. LR 44%, DM 28%. 5-year OS 84%, 10-year OS 64%
• Conclusion: Improved local control and survival with new surgical techniques
• MD Anderson; 1999 (1954-1994) PMID 9894966 -- "Sacral chordoma: 40-year experience at a major cancer
center." (York JE, Neurosurgery. 1999 Jan;44(1):74-9; discussion 79-80.)
• Retrospective. 27 patients with sacral chordoma. 26/27 pain, 17/27 autonomic dysfunction. Single operation
44%, two surgeries 33%, multiple surgeries 22%. RT used in 19% of operations
• Outcome: median OS 7.4 years. Recurrence in 70% of surgeries. Median DFS radical surgery 2.3 years vs.
subtotal surgery 8 months (SS). If subtotal resection, adjuvant RT 2.1 years vs. no RT 8 months (SS)
• Conclusion: Frequent recurrences. Radical resection leads to improved DFS; adjuvant RT after subtotal
resection also leads to improved DFS
Photon Therapy
Conventional
• Princess Margaret; 1996 (1958-1992) PMID 8961370 -- "Chordoma: long-term follow-up after radical photon
irradiation." (Catton C, Radiother Oncol. 1996 Oct;41(1):67-72.)
• Retrospective. 48 patients with chordoma (sacrum 48%, 42%, mobile spine 10%) referred for consideration, 44
post-op with gross residual disease, 4 microscopic residual disease. RT 26 patients 50/25, 8 patients
hyperfractionated 40/44 @ 1 Gy/fx TID, 3 referred for charged particles. 67% patient symptomatic
(neurological or pain)
• Outcome: median OS 5.2 years, median TTP 2.9 years. 5-year PFS 23%, 10-year PFS 15%. 1/23 complete
response, but good palliation in 85%. No difference between median dose 40 Gy and 60 Gy groups. Median
OS after re-treatment 1.5 years. Dead of disease 78%, alive with disease 17%, NED 5%
• Conclusion: Overt residual chordoma rarely cured with conventional EBRT, but treatment does provide useful
and prolonged palliation. Suitable patients should be referred for stereotactic photon or particle beam therapy
Proton Beam Therapy

• Orsay; 2008 (France)(1996-2006) PMID 18440726 -- "Proton therapy in pediatric skull base and cervical canal
low-grade bone malignancies." (Habrand JL, Int J Radiat Oncol Biol Phys. 2008 Jul 1;71(3):672-5. Epub 2008
Apr 25.)
• Retrospective. 30 children with chordoma (n=26), chondrosarcoma (n=3), and chondroma (n=1). Location in
skull base (n=13), skull base with extension to cervical canal (n=12), or cervical canal (n=1). Median age 13.5
years. Surgery followed by photon/proton therapy. Mean total dose 68.4 CGE (54.6-71); mean photon dose
37.4 Gy (30.6-45), mean proton dose 32.1 CGE (20-70.2). F/U 2.2 years
• Outcome: Local control chordoma 21/26 (81%), chondrosarcoma 3/3 (100%), chondroma 1/1 (100%). 5-year
PFS chordoma 77%, chondrosarcoma 100%
• Toxicity: Grade 3 auditory toxicty 1 patient, Grade 2 pituitary failure 7 patients
• Conclusion: Well tolerated, excellent local control
• Institut Curie; 2005 (1992-2002) PMID 16227160 -- "Chordomas of the base of the skull and upper cervical
spine. One hundred patients irradiated by a 3D conformal technique combining photon and proton beams." Noel
G et al. Acta Oncol. 2005;44(7):700-8.
• Retrospective. 100 patients w/ skull base or upper cervical spine chordoma tx'd w/ proton/photon therapy.
Median total dose to tumor 67 CGE.
• 2 yr local control rate 86.3%, 4 yr local control rate 53.8%.
• Multivariate analysis showed minimal dose to tumor <56 CGE and failure to encompass 95% tumor w/ 95%
isodose line were independent factors for local control.
• Harvard/Loma Linda; 2002 (1992-1999) PMID 11958897 -- "Proton radiotherapy in management of pediatric
base of skull tumors." (Hug EB, Int J Radiat Oncol Biol Phys. 2002 Mar 15;52(4):1017-24.)
• Retrospective. 29 patients. Chordoma (n=10), chondrosarcoma (n=3), rhabdomyosarcoma (n=4), other
sarcomas (n=3), giant cell tumors (n=6), angiofibromas (n=2), chondroblastoma (n=1). Dose 45 - 78.6 CGE in
standard fractions. Mean F/U 3.3 years
• Outcome: Malignant tumors - LC 75% (chordoma 60%, chondrosarcoma 100%, rhabdo 100%, other sarcomas
66%), 5-year OS 56%. Benign tumors - LC 8/9, 5-year OS 100%
• Toxicity: Severe late in 7% (motor weakness, sensory deficits)
• Conclusion: Proton RT after major skull base surgery can offer considerable tumor control and survival
• Loma Linda; 1999 (1992-98) - PMID 10470818 -- "Proton radiation therapy for chordomas and
chondrosarcomas of the skull base." Hug EB et al. J Neurosurg. 1999 Sep;91(3):432-9.
• Retrospective. 33 chordoma pts (and 25 chondrosarcomas) tx'd w/ proton beam irradiation after maximal
surgery. Dose range of 64.8-79.2 CGE.
• 5yr OS for chondrosarcoma was 79%. 5yr local control for chondrosarcoma was 76%.
• Control rates were influenced by brainstem involvement and tumor volume.
• Chordoma with worse outcomes than chondrosarcoma.
• MGH; 1995 (1975-93) - PMID 7558946 -- "Radiation therapy for chordomas of the base of skull and cervical
spine: patterns of failure and outcome after relapse." Fagundes MA et al. Int J Radiat Oncol Biol Phys. 1995 Oct
15;33(3):579-84.
• 63 pts w/ treatment failure who were tx'd at MGH w/ surgery + combined photon/proton RT to median dose of
70 CGE (66.6-77.4).
• 95% of these pts had local failure as element of their disease failure; 78% had local failure as site of first
failure.
Carbon Ion Radiotherapy

• Heidelberg, Germany, 2007 (1998-2005) - PMID 17363188 -- "Effectiveness of carbon ion radiotherapy in the
treatment of skull-base chordomas." Schulz-Ertner D et al. Int J Radiat Oncol Biol Phys. 2007 Jun
1;68(2):449-57.
• 96 pts w/ skull base chordoma tx'd w/ carbon ion radiotherapy. All pts had gross residual tumor. Median total
dose of 60 CGE (range 60-70). 20 fx over 3 wks.
• 80.6% local control at 3 yrs, 70% local control at 5 yrs.
• 91.8% OS at 3 yrs, 88.5% OS at 5 yrs.
Treatment Toxicity
Temporal Lobe Damage

• MGH, 1998 (1984-93) - PMID 9588918 -- "Temporal lobe (TL) damage following surgery and high-dose photon
and proton irradiation in 96 patients affected by chordomas and chondrosarcomas of the base of the skull."
Santoni R et al. Int J Radiat Oncol Biol Phys. 1998 Apr 1;41(1):59-68.
• 99 pts w/ chordoma or chondrosarcoma of skull base tx'd w/ photon/proton radiotherapy.
• 10 pts developed temporal lobe damage w/ 8 pts having moderate to severe symptoms.
• Actuarial temporal lobe damage rate was 7.6% at 2 yrs, 13.2% at 5 yrs.
Visual Complications
• Liverpool; 2003 (UK) PMID 12724692 -- "Visual complications of proton beam therapy for clival chordoma."
(Bowyer J, Eye. 2003 Apr;17(3):318-23.)
• Case report. 4 patients referred for post-op proton therapy.
• Outcome: Bilateral visual loss in 2/4 (50%) patients at 1 and 2 years post proton therapy
• Conclusion: Proton beam therapy not innocuous
Review
• Milan; 2006 (Italy) PMID 17545801 -- "Chordoma." (Casali PG, Curr Opin Oncol. 2007 Jul;19(4):367-70.)
Foundations of Education and Instructional Assessment/Edition 4/Foundations Table of Contents/Chapter
9/9.4.3/Read more about the benefits of school/community partnerships from teachers and administration at QLMS!
Radiation Oncology/Head & Neck/General

add: hypopharynx - randomized surgery vs chemo/rt

For IMRT, see → Head & Neck IMRT
Lymphatic Risk
• MD Anderson; 1972 (1948-1965) PMID 5031238 -- "Distribution of cervical lymph node metastases from
squamous cell carcinoma of the upper respiratory and digestive tracts." (Lindberg R, Cancer. 1972
Jun;29(6):1446-9.)
• Retrospective. 2044 patients, previously untreated. Incidence and topographic distribution of neck LNs
Incidence of clinical nodal metastases

Site Overall T1 T2 T3 T4
N0 N+ N0 N+ N0 N+ N0 N+ N0 N+
Oral tongue 65 35 86 14 70 30 52 48 23 77
Floor of mouth 70 30 89 11 71 29 56 44 46 54
Retromolar 55 45 88 12 62 38 46 54 32 78
Trigone
Soft Palate 56 44 92 8 63 37 35 65 33 67
Tonsil 24 76 29 71 32 68 30 70 10 90
Base of tongue 22 78 30 70 29 71 25 75 15 85
Nasopharynx 13 87 7 93 15 85 11 89 17 83
Pharyngeal wall 41 59 75 25 70 30 33 67 24 76
Supraglottic larynx 45 55 61 39 58 42 35 65 41 59
Hypopharynx 25 75 37 63 30 70 21 79 26 74
• University of Florida; 1995 PMID 7782203 -- "Retropharyngeal adenopathy as a predictor of outcome in

squamous cell carcinoma of the head and neck." (McLaughlin MP, Head Neck. 1995 May-Jun;17(3):190-8.)
• Retrospective. 619 patients. Review of pretreatment CT and/or MRI to determine presence of retropharyngeal
LNs
• Outcome: Highest incidence in NPC (74%) and pharyngeal wall (19%). Neck relapse and DM significantly
higher, RFS and OS significantly worse if present
• Conclusion: Retropharyngeal adenopathy predictor of poor outcome
Incidence of CT/MRI retropharyngeal nodal metastases

Site Clinical Neck
Overall cN0 cN+
Nasopharynx 74 40 86
Pharyngeal wall 19 16 21
Soft palate 13 5 19
Tonsil 9 4 12
Pyriform sinus 5 0 9
Base of tongue 4 0 6
Supraglottic larynx 2 0 4
• Washington University; 2002 (1997-2000) PMID 12128118 -- "Determination and delineation of nodal target
volumes for head-and-neck cancer based on patterns of failure in patients receiving definitive and postoperative
IMRT." (Chao KS, Int J Radiat Oncol Biol Phys. 2002 Aug 1;53(5):1174-84.)
• Retrospective. 126 patients treated with IMRT. System for nodal target volumes used. Median F/U 2.2 years.
Patterns of failure analyzed.
• Outcome: persistent/recurrent nodal disease in 12% of definitive IMRT patients and 9% of postop IMRT
patients
• Conclusion: Development of guidelines for nodal target volumes
Incidence of pathologic nodal metastases

Site Level I Level II Level Level IV Level V Retropharngeal*
III
N- N+ N- N+ N- N+ N- N+ N- N+ N- N+
Nasopharynx - 40 86
Oral tongue 14 39 19 73 16 27 3 11 0 0 - -
FOM 16 72 12 51 7 29 2 11 0 5 - -
Alveolar ridge 25 38 19 84 6 25 5 10 1 4 - -
RMT
Base of tongue 4 19 30 89 22 22 7 10 0 18 0 6
Tonsil 0 8 19 74 14 31 9 14 5 12 4 12
Pharyngeal wall 0 11 9 84 18 72 0 40 0 20 16 21
Pyriform sinus 0 2 15 77 8 57 0 23 0 22 0 9
Supraglottic larynx 6 2 18 70 18 48 9 17 2 16 0 4
Glottic larynx 0 9 21 42 29 71 7 24 7 2 - -
*Radiologically enlarged retropharyngeal nodes.
Table adapted from Chao 2002 (PMID 12128118)
Incidence of contralateral and bilateral lymph nodes:

• >30% cN+ bilateral - pharyngeal wall (50%), pyriform sinus (49%), supraglottis (39%)
• cN- but pN+ bilateral - pyriform sinus (59%), BOT (55%), phar. wall (37%), oral tongue (33%), supraglottis
(26%), FOM (21%), glottic larynx (15%)
Adopted from Chao 2002 (PMID 12128118)
Effect of surgery to radiotherapy interval (SRI)
Higher dose may "make up for" prolonged treatment time

• MSKCC, 1990 - PMID 2325418 — "Impact of the time interval between surgery and postoperative radiation
therapy on locoregional control in advanced head and neck cancer." Schiff PB et al. J Surg Oncol. 1990
Apr;43(4):203-8.
• Patients receiving < 60 Gy had locoregional recurrence rate of 7% when SRI < 6 weeks vs 27% when greater
than 6 weeks. However when doses > 60 Gy were given, failure rates were 15% and 12%, respectively.
Recursive Partitioning Analysis

• RTOG RPA, 1996 - PMID 8646692 — "Recursive partitioning analysis of 2105 patients treated in Radiation
Therapy Oncology Group studies of head and neck cancer." Cooper JS et al. Cancer. 1996 May 1;77(9):1905-11.
• 2105 pts. For survival, most predictive factor was T stage. For T1-T2, next most important was tumor location,
whereas for T3-T4, it was KPS. For LRC, N stage was most important; for N0, T stage was next most
important, whereas for N+ number of treatment fractions was.
• Survival: Group 1) T2 or less, glottic, age < 75; 2) Group 1 but age >= 75; 3) T2 or less, not glottic, N0-2,
KPS >= 80, age < 75; or T3-4 N0-2 site:NP,OP,SGL,sinus KPS 90-100; 4) T2 or less, not glottic, N3, KPS
>=80; or T3-4, N0-2, KPS 90-100, oral cavity, hypopharynx, or glottis; or T3-4 N3 or Nx KPS < 90; 5) T2 or
less, not glottic, KPS <80; or N3, T3-4, KPS 90-100, N3; or T3-4, N1-3, KPS < 90.
• Local control:
• PMID 11443750 - "Validation of the RTOG recursive partitioning classification for head and neck tumors."
Cooper et al. - Tested validity using a separate database from RTOG 85-27.
• PMID 15672358, 2005 - "Comparison of the Radiation Therapy Oncology Group recursive partitioning
classification and Union Internationale Contre le Cancer TNM classification for patients with head and neck
carcinoma."
• 2166 pts classified both by RPA and TNM stage and compared overall survival and loco-regional DFS. No
differences between the systems in terms of survival, but for locoregional control, RPA system depended on
treatment and was not generalizable.
Altered Fractionation
• Chandigarh, India (1998-2004) -- Standard QD vs. Concomitant Boost
• 2008 PMID 18343310 -- "Concomitant Boost Radiotherapy Compared with Conventional Radiotherapy in
Squamous Cell Carcinoma of the Head and Neck - a Phase III Trial from a Single Institution in India."
(Ghoshal S, Clin Oncol (R Coll Radiol). 2008 Apr;20(3):212-20.)
• Randomized. SCCHN, Stage III-IV oropharynx, hypopharynx, larynx. Arm 1) 66/33 vs. Arm 2) concomitant
boost 45/25 + 22.5/15 over 5 weeks, >6 hours apart. Compliance >95%
• Outcome: 2-year DFS standard 52% vs. concomitant 72% (SS), LRC 55% vs. 74% (SS).
• Toxicity: Grade 3 mucositis standard 19% vs. concomitant 35% (SS). No difference in days missed
• Conclusion: Concomitant boost superior in advanced H&N cancers
• RTOG 90-03 (1991-1997) -- SF vs HF vs Split course AFX vs AFX-CB
• Randomized, 4 arms. 1073 patients. Stage III-IV (oral cavity, oropharynx, or supraglottic larynx) or Stage
II-IV (base of tongue, hypopharynx). Arm 1) SF standard fractionation 70/35 @ 2 Gy/fx vs. Arm 2) HF
hyperfractionated 81.6/68 @ 1.2 Gy BID vs. Arm 3) AFX-S split course accelerated fractionation 67.2/42 @
1.6 Gy BID with 2 week break after 38.4 Gy vs. Arm 4) AFX-CB concomitant boost 72 Gy given 54/30 @ 1.8
Gy + 18/12 @ 1.5 Gy concurrent BID boost
• 2-years; 2000 PMID 10924966 -- "A Radiation Therapy Oncology Group (RTOG) phase III randomized study
to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation
radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003." (Fu KK, Int J Radiat
Oncol Biol Phys. 2000 Aug 1;48(1):7-16.). Median F/U 2 years, 3.4 for alive patients
• Outcome: 2-year LRC SF 46% vs. HF 54% (SS) vs. AFX-S 47% (NS) vs. AFX-CB 54% (SS); DFS 32%
vs. 38% (NS) vs. 33% (NS) vs. 39% (NS); OS 46% vs. 54% (NS) vs. 46% (NS) vs. 51% (NS)
• Sites of failure: LF 44% vs. 38% vs. 43% vs. 375; RF 32% vs. 27% vs. 31% vs. 33%
• Toxicity: Increased acute effects but no increase in late effects
• Conclusion: HF or CB improve LRC compared to SF, no impact on DFS and OS. Split course comparable
to SF
• Education; 2003 PMID 14508838 -- "Effect of education level on outcome of patients treated on Radiation
Therapy Oncology Group Protocol 90-03." (Konski A, Cancer. 2003 Oct 1;98(7):1497-503.)
• Post hoc analysis. More patients in SF had higher education level
• Outcome: patients attending college significantly better LRC and OS; significant predictor of outcome on
multivariate analysis
• Conclusion: Better education predicts for better outcome
• Nutrition; 2006 PMID 16287132 -- "Impact of nutrition support on treatment outcome in patients with locally
advanced head and neck squamous cell cancer treated with definitive radiotherapy: a secondary analysis of
RTOG trial 90-03." (Rabinovitch R, Head Neck. 2006 Apr;28(4):287-96.)
• Post hoc analysis. Prospective data on nutritional support (NS) before treatment (BNS), during treatment
(TNS), or after treatment (NoNS). BNS patients had higher Stage, poorer KPS
• Outcome: Patients with BNS had significantly less weight loss and Grade 3+ mucositis. However, they had
worse 5-year LRC: BNS 29% vs. TNS 55% vs. NoNS 57% (SS), and OS 16% vs. 36% vs. 49% (SS). On
multivariate analysis, BNS independent prognostic factor for LRF and OS
• Conclusion: Nutritional support before RT associated with inferior treatment outcome
• Emotional; 2007 PMID 17955501 -- "Emotional well-being does not predict survival in head and neck cancer
patients: a Radiation Therapy Oncology Group study." (Coyne JC, Cancer. 2007 Dec 1;110(11):2568-75.)
• Post-hoc analysis. RTOG 9003 and RTOG 9111. Prospective analysis of FACT-G questionnaire
• Outcome: No impact of well-being on any outcomes
• Conclusion: Emotional functioning not independent predictor of survival
• TWiST Analysis; 2008 PMID 19107946 -- "Quality-adjusted survival analysis of Radiation Therapy
Oncology Group (RTOG) 90-03: Phase III randomized study comparing altered fractionation to standard
fractionation radiotherapy for locally advanced head and neck squamous cell carcinoma." (Konski AA, Head
Neck. 2008 Dec 23. [Epub ahead of print])
• Quality-adjusted survival analysis using Q-TWiST methodology (quality-adjusted time without toxicity or
relapse); utilities obtained by threshold analysis
• Outcome: Quality-adjusted survival (relapse utility = 0.5, toxicity utility = 0.8): SFX 13 mo vs. HFX 14.3
mo (0.06) vs. split-AFX 13.5 (NS) vs. AFX-CB 13.6 (NS)
• Conclusion: Quality adjusted survival better only for hyperfractionated fractionation, not for accelerated.
Q-TWiST analysis can identify patient groups that would benefit from more aggressive therapy based on
their utilities
• RTOG 88-09 (1989-90) -- Split course AFX vs. AFX-CB
• Phase I/II, randomized. 70 patients, Stage III-IV HNSCC. Arm 1) split-course accelerated hyperfractionation
AFX-S 1.6 Gy/fx BID to 67.2 Gy/6 weeks, 2-week break after 38.4 Gy vs. Arm 2)concomitant boost AFX-C
1.8 Gy/fx QD to 54 Gy and 1.5 Gy/fx to a boost field during the last 11 treatment days for a total dose of 70.5
Gy/6 weeks.
• 1995 PMID 7790243 — "Randomized phase I/II trial of two variants of accelerated fractionated radiotherapy
regimens for advanced head and neck cancer: results of RTOG 88-09." (Fu KK et al. Int J Radiat Oncol Biol
Phys. 1995 Jun 15;32(3):589-97.) Median F/U 2 years
• Outcome: No difference in LRC, DFS, or OS
• Toxicity: Acute mucositis increased in both arms, no difference in late toxicity (Grade 4 6% vs. 17%)
• Conclusion: Regimens can be given; no difference between the two schemes. Resulted in RTOG 90-03
• M.D.Anderson (1985-88) -- CB
• PMID 2262355 — "Concomitant boost radiotherapy schedules in the treatment of carcinoma of the
oropharynx and nasopharynx." Ang KK et al. Int J Radiat Oncol Biol Phys. 1990 Dec;19(6):1339-45.
• 79 pts, mostly oropharynx. Treated with 1 of 3 regimens of concomitant boost. 69-72 Gy in 6 weeks with the
boost consisting of 10-12 fractions.
• Trend toward better primary tumor control (p=0.11) if boost given during last the last 10-12 fractions versus
the first 10-12 fractions or twice a week throughout the treatment.
• RTOG 83-13 (1983-1987) -- HF Dose Escalation
• Phase I/II, randomized. 451 patients. Advanced H&N cancer. Dose escalation with hyperfractionation. 1.2 Gy
BID, 4 hrs apart, to 67.2 (n=59) -> 72.0 (n=119) -> 76.8 (n=98) -> 81.6 Gy (n=123). Daily interfraction
interval >4 hours in 32%, 50%, 43%, and 71%
• 2-years; 1990 PMID 2180866 -- "Dose-response for local control with hyperfractionated radiation therapy in
advanced carcinomas of the upper aerodigestive tracts: preliminary report of radiation therapy oncology group
protocol 83-13." (Cox JD, Int J Radiat Oncol Biol Phys. 1990 Mar;18(3):515-21.)
• Outcome: 2-year LC 25% vs. 37% vs. 42% (p=0.08) No survival difference.
• Toxicity: 2-year Grade 4 necrosis 10% vs. 5% vs. 14%, no info yet for 81.6 Gy group
• Conclusion: Trend to improved LC with higher doses
• Late effects; 1995 PMID 7790242 -- "Late effects of hyperfractionated radiotherapy for advanced head and
neck cancer: long-term follow-up results of RTOG 83-13." (Fu KK, Int J Radiat Oncol Biol Phys. 1995 Jun
15;32(3):577-88.) Median F/U 1.7 year, if alive 6.1 years
• Late toxicity: No difference between groups. Grade 4 7% vs. 3% vs. 7% vs. 5%; Grade 3 17% vs. 14% vs.
20% vs. 13%
• Interfraction interval: Constant 2% if >4.5 hours; if <4.5 hours then increasing 2-years 6.3%, 3-years 7.5%,
4 years 8.0%, 5-years 8.6%
• Conclusion: No apparent dose-response relationship for lat effects; daily interfraction interval needs to be
>4.5 hours
• EORTC 22811, 1986 - multiple fractions per day +/- misonidazole vs standard RT
• 523 pts. TID regimen: 1.6 Gy TID x 10 days (48 Gy), 3 week rest, then boost to 67.2 Gy (4 more days). Total
6 weeks. Standard: 1.7-2 Gy/fx to 70 Gy in 7 weeks.
• Early results (1986): PMID 3516953
• No difference in survival or local control.
• EORTC 22791 (1980-87)
• PMID 1480768 — "Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final
analysis of a randomized trial of the EORTC cooperative group of radiotherapy." Horiot JC et al. Radiother
Oncol. 1992 Dec;25(4):231-41.
• 356 pts. T2-3 N0-1 oropharynx excluding base of tongue, size < 3 cm. Randomized to 70 Gy in 7-8 weeks vs
80.5 Gy pure hyperfractionation in 70 fx in 7 weeks (1.15 Gy BID)
• 59% (HF) local disease-free vs 40% (CF). Superiority of HF over CF in T3 tumors but not T2 tumors. Trend in
improvement in overall survival (p=0.08). No difference in late effects.
• RTOG 79-13 (1979-83) - 1.2 Gy BID vs. 1.8-2 Gy daily
• Randomized. 187 patients. Stage III-IV, or T2N0 base of tongue, nasopharynx, and maxillary sinus.
Conventional RT (66-73.8 Gy in 1.8-2 Gy/fx QD) vs hyperfractionated (60 Gy in 1.2 Gy BID, 3-6 hrs apart)
• 1987 PMID 3542916 — "Hyperfractionated photon radiation therapy in the treatment of advanced squamous
cell carcinoma of the oral cavity, pharynx, larynx, and sinuses, using radiation therapy as the only planned
modality: (preliminary report) by the Radiation Therapy Oncology Group (RTOG)." Marcial VA et al. Int J
Radiat Oncol Biol Phys. 1987 Jan;13(1):41-7.
• Outcome: 2-year LRC conventional 29% vs. hyperfractionated 30% (NS)
• Toxicity: Worse acute toxicity but similar rate of late reactions. More severe acute reactions if interfraction
interval <4.5 hours
• Conclusion: No outcome difference, worse acute toxicity
• U.Florida; 1993 (1978-89) - PMID 8440619 — "Twice-a-day radiotherapy for squamous cell carcinoma of the
head and neck: the University of Florida experience." Parsons JT et al. Head Neck. 1993 Mar-Apr;15(2):87-96.
• 419 patients, locally advanced. 1.2 Gy BID to 74.4-79.2 Gy.
• LC was improved or the same as historical controls (with qd RT) for each stage, T2-T4.
• RTOG 77-03; 1978 - No PMID. "Hyperfractionation where we stand - a preliminary RTOG report." (Marks R, In
J Radiat Oncol Biol Phys 1978 2:139-140.
• Hyperfractionation pilot study.
• Outcome: 1.25 Gy BID to 66 Gy gave adequate tumor control, with acceptable acute and late toxicity. But 1.5
Gy BID was too toxic, and required treatement break
• Results led to RTOG 79-13
Neutrons
• Initial results from Hammersmith Hospital appeared promising
• However, results from a randomized RTOG trial with mixed neutrons/photons did not show a benefit in local
control or overall survival
• A follow up randomized international study with pure neutrons compared with photons again did not show a
benefit, with significantly worse long-term toxicity
• Neutron trials in general head & neck cancers have for now been abandoned. There may be a role for neutrons in
salivary glands
• NTCWG 85-22 (1986-1991)
• Randomized. 5 institutions in US and UK. 169 patients, Stage III-IV (T1N3, T2N+, or T3-4) SCC of H&N.
Arm 1) neutrons 20.4/12 over 4 weeks vs. Arm 2) photons 70/35
• 3-years; 1995 PMID 7790244 -- "Fast-neutron therapy in advanced head and neck cancer: a collaborative
international randomized trial." (Maor MH, Int J Radiat Oncol Biol Phys. 1995 Jun 15;32(3):599-604.)
• 3-year outcome: CR neutrons 70% vs. photons 52% (SS); LRF 63% vs. 68% (NS); OS 27% both arms (NS)
• Toxicity: acute comparable, late Grade 3-5 neutrons 40% vs. photons 18% (SS)
• Conclusion: Long term outcomes comparable, but toxicity worse with neutrons
• US Neutron Cooperative (1977-1982)
• Randomized. 327 patients, inoperable SCC of H&N (oral cavity, oropharynx, supraglottic larynx,
hypopharynx), T2-4 any N. Arm 1) neutron/photon beams (photons 40-44 Gy + neutrons 7.5-10 Gy) vs. 2)
photon/electron beams 66-74 Gy
• 1989 PMID 2681103 -- "Mixed neutron/photon irradiation of unresectable squamous cell carcinomas of the
head and neck: the final report of a randomized cooperative trial." (Griffin TW, Int J Radiat Oncol Biol Phys.
1989 Nov;17(5):959-65.). Minimum F/U 6 years
• Outcome: no difference in LRC or OS; LRC subgroup N+ mixed 30% vs. photons 18% (p=0.05), N0 mixed
33% vs. photons 64% (SS); control of disease in LN 45% vs. 26% (SS)
• Conclusion: No difference between neutron/photon vs. photon/electron beam
Surgery + RT vs. Chemo-RT

• Singapore (1996-2000)
• Randomized. Stopped early due to slow accrual. 199 patients, resectable Stage III/IV SCHNC excluding NPC
and salivary glands (larynx 32% (supraglottis 23%), oral cavity 27%, oropharynx 21%, hypopharynx 12%). T4
56%. Arm 1) surgery + adjuvant RT 60/30 vs. Arm 2) RT 66/33 + concurrent cisplatin 20 mg/m2 + 5-FU 1000
mg/m2 x2 cycles. 90% received at least 1 cycle of chemo
• 2005 PMID 16012523 -- "Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV
nonmetastatic squamous cell head and neck cancer: a randomised comparison." (Soo KC, Br J Cancer. 2005
Aug 8;93(3):279-86.) Median F/U 6 years
• Outcome: 3-year DFS: S+RT 50% vs. chemo-RT 40% (NS). Organ preservation (larynx/hypopharynx 68%,
oropharynx 55%, oral cavity 21%). Chemo-RT group had poor surgical salvage of 47%, with no long-term
survivors (possibly due to larger proportion of T4 and oral cavity cancers)
• Conclusion: Chemo-RT not superior to surgery+RT, but can be attempted for organ preservation in larynx,
hypopharynx, and oropharynx. Poor organ preservation (and salvage) in oral cavity
Chemotherapy and radiation
Chemo benefit RT equivalent

• Duke; 2007 PMID 17674979 -- "How much radiation is the chemotherapy worth in advanced head and neck
cancer?" (Kasibhatla M, Int J Radiat Oncol Biol Phys. 2007 Aug 1;68(5):1491-5.)
• Modeling. Data from RTOG 90-03.
• Outcome: 1% increase in BED yields 1.1% in LRC. Mean BED for standard fractionated RT 60.2 Gy, for
altered fractionated RT 66 Gy, for standard fractionated chemo-RT 71 Gy, and for altered fractionated
chemo-RT 76 Gy
• Conclusion: Chemo increases BED by ~10 Gy, equivalent to 12 Gy in 2 Gy/fx
• Comment (Fowler JF, PMID 18474309): correction of several elementary radiobiologic errors. Average gain is
8.8 Gy(10) not 10.6 Gy (10). Concomitant chemotherapy is equivalent to additional 3.6 fractions of 2 Gy/fx
Concurrent
3 randomized trials showed the superiority of RT with concurrent chemotherapy over RT alone: 1) Intergroup
Nasopharynx trial, 2) RTOG 91-11, and 3) Head & Neck Intergroup trial. The regimen was piloted by RTOG 81-17.
• GORTEC (France) - PMID 10601378 — "Randomized trial of radiation therapy versus concomitant
chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma." Calais G et al. J Natl Cancer Inst.
1999 Dec 15;91(24):2081-6.
• 226 pts. Randomized to RT alone vs RT + 5-FU and carboplatin x 3 cycles.
• 3-year OS 51% (chemo/RT) vs 31% (RT); DFS 42% vs 20%
• ASTRO 2002: 5-yr OS 23% vs 16% (p=0.05), 5-yr LRC 48% vs 25% (SS), no diff in DM.
• RTOG 91-11; 2003
• See details in the Larynx chapter
• Head and Neck Intergroup (1992-1999) -- RT vs. chemo-RT vs. split-course chemo-RT
• Randomized, 3 arms. Stopped prematurely for poor accrual. 295/462 patients with strictly unresectable
HNSCC, excluding nasopharynx, paranasal sinus, salivary glands, or unknown primary. Arm 1) RT alone
70/35 vs. Arm 2) RT 70/35 + concurrent cisplatin 100 mg/m2 Q3W (based on RTOG 81-17) vs. Arm 3) Split
course RT 30/15 + concurrent cisplatin 75 mg/m2 and 5-FU 1000 mg/m2, followed by surgery (if resectable,
16%), otherwise additional RT 30-40 Gy
• 2003 PMID 12506176 — "An intergroup phase III comparison of standard radiation therapy and two
schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer."
(Adelstein DJ, J Clin Oncol. 2003 Jan 1;21(1):92-8.) Median F/U 3.4 years
• Outcome: 3-year OS RT 23% vs. chemo-RT 37% (SS) vs. Split-course chemo-RT 27% (NS); 3-year DSS
33% vs. 51% (SS) vs. 41% (NS). No difference in site of failure, DM rate ~20%
• Toxicity: Grade 3+ RT 52% vs. chemo-RT 89% vs. split-course chemo-RT 77%
• Conclusion: Addition of concurrent high dose cisplatin to conventional radiation improves surival
• RTOG 97-03 (1997-99) Protocol [1]
• Purpose: tolerability of these regimens
• Phase II. 241 pts. Advanced Stage III-IV (T3-4,N1-3,M0) of OC, OP, or HP. Randomized to 1) 70 Gy / 7
weeks with daily cisplatin and 5-FU during the last 10 days of RT (XCF); 2) 70 Gy / 13 weeks every other
week with concurrent daily hydroxyurea and 5-FU (FHX); 3) 70 Gy / 7 weeks with weekly cisplatin and
paclitaxel (XCT). Arm 1 is intended to give the maximum intensity of treatment during the period of
accelerated repopulation.
• ASCO 2001 Abstract [2] — "Preliminary Results of RTOG 9703 - a Phase II Randomized Trial of Concurrent
Radiation (RT) and Chemotherapy for Advanced Squamous Cell Carcinomas (SCC) of the Head and Neck."
Garden AS et al. Abstract #891. Proc Am Soc Clin Oncol 2001;20:223a.
• Median f/u 1.6 yrs. 1-yr and 2-yr OS 72% and 60% (XCF), 87% and 65% (FHX), and 80% and 67%
(XCT). Compared to historic controls from RTOG database treated with RT alone or with RT + cisplatin on
RTOG 8117, large reductions in death rates for pts treated on all 3 arms.
• PMID 15254053, 2004 — "Preliminary results of Radiation Therapy Oncology Group 97-03: a randomized
phase II trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head
and neck." Garden AS et al. J Clin Oncol. 2004 Jul 15;22(14):2856-64.
• 2-yr DFS and OS 38.2% and 57.4% for XCF, 48.6% and 69.4% for FHX, and 51.3% and 66.6% for XCT.
• Long-term results, 2007: No PMID. Abstract [3] — "Results of Radiation Therapy Oncology Group 97-03 - A
randomized phase II trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of
the head and neck: long-term results and late toxicities." Garden AS et al. Int J Radiat Oncol Biol Phys
2007;69(2):S140 (Abstract #10)
• No significant difference in OS, LRF, or toxicities. 10% of patients had grade 4 late toxicity; 20% required
long-term feeding tube.
• Conclusion: All arms were tolerable with acceptable toxicity.
• Hellenic COG (Greece)(1995-1999) -- concurrent cisplatin or concurrent carboplatin
• Randomized, 3 arms. 124 patients, locally advanced HNC (no NPC). Arm 1) RT alone 70/35 vs. Arm 2) RT
with concurrent cisplatin 100 mg/m2 vs. Arm 3) RT with concurrent carboplatin 7 AUC.
• 3-years; 2004 PMID 15299181 -- "Concomitant radiochemotherapy vs radiotherapy alone in patients with
head and neck cancer: a Hellenic Cooperative Oncology Group Phase III Study." (Fountzilas G, Med Oncol.
2004;21(2):95-107.)
• Outcome: Median time-to-progression RT 6 months vs. RT + cisplatin 45 months vs. RT + carboplatin 18
months (SS); median OS 1 year vs. 4 years vs. 2 years (SS); 3-year OS 17% vs. 52% vs. 42% (SS)
• Toxicity: more severe N/V in RT + cisplatin
• Conclusion: Platinum-based concurrent chemo-RT improves survival compared to RT alone; cisplatin
better than carboplatin
• Slovenia (1991-1993) -- concurrent mitomycin C and bleomycin
• Randomized. Closed prematurely due to superior result of concurrent treatment. 64 patients (oropharynx 41),
inoperable H&N. Arm 1) RT alone 66-70 Gy in 2 Gy/fx vs. Arm 2) Same RT with concurrent mitomycin C
and bleomycin (and nicotinamide, chlorpromazine, dicoumarol)
• 1998 PMID 9719123 -- "Concomitant radiotherapy with mitomycin C and bleomycin compared with
radiotherapy alone in inoperable head and neck cancer: final report." (Zakotnik B, Int J Radiat Oncol Biol
Phys. 1998 Jul 15;41(5):1121-7.). Median F/U 3.5 years
• Outcome: DFS RT 8% vs. chemo-RT 37% (SS); OS 7% vs. 26% (p=0.08). Oropharynx subgroup OS 10%
vs. 38% (SS)
• Conclusion: Concurrent chemo significantly improves CR, DFS and OS in inoperable oropharyngeal cancer
• 5-years; 2005 PMID 15800716 -- "Inoperable oropharyngeal carcinoma treated with concomitant irradiation,
mitomycin C and bleomycin - long term results." (Budihna M, Neoplasma. 2005;52(2):165-74.) Median F/U
7.1 years
• Oropharyngeal subset. 95 patients. RT 60-73 Gy, concurrent mitomycin C + bleomycin
• Outcome: 5-year LRC 55%, DFS 51%, OS 32%. Probability of new malignancy 23%. Gamma-value of
dose-response curve 2.86
• Conclusion: Outcome directly proportional to intensity of RT and chemo. MiC increased
radioresponsiveness by effect on hypoxic fraction
• Head & Neck Intergroup / RTOG 84-06 (ECOG 1982-1987, RTOG 1984-1987) -- concurrent cisplatin 20
mg/m2
• Randomized. 319 patients. All sites, Stage III-IV unresectable. Arm 1) RT alone conventional 68-78 Gy vs.
Arm 2) same RT + low dose cisplatin 20 mg/m2/week
• 1990 No PMID - "Radiation alone vs. radiation with weekly low dose cisplatinum in unresectable cancer of the
head and neck" (Haselow RE, in Head and Neck Cancer Vol II. Fee WE (ed), Toronto: B. C. Decker:
1990:279-281)
• Outcome: No difference in LRC or OS
• Conclusion: No benefit for concurrent low-dose weekly cisplatin
• RTOG 81-17 (1981-1984)
• Phase I/II. 124 patients, locally advanced inoperable H&N cancer (oropharynx 39%, nasopharynx 22%, oral
cavity 18%, hypopharynx 7%, larynx 7%, sinuses 7%). Stage III 18%, Stage IV 82%. Concurrent RT 66-73.8
Gy with cisplatin 100 mg/m2 q3 weeks. 60% completed planned treatment
• 1987 PMID 3802013 -- "Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous
cell carcinoma of the head and neck. An RTOG Study." (Al-Sarraf M, Cancer. 1987 Jan 15;59(2):259-65.)
• Severe toxicity: stomatitis 31%, leukopenia 11%, anemia 8%, N/V 6%
• Outcome: 1-year DFS 51%, OS 66%. Nasopharynx CR 82%, OP/larynx/sinuses 75%, oral cavity 56%,
hypopharynx 37%
• Conclusion: Concurrent cisplatin effective and safe in advanced H&N
• 1990 PMID 2224782 — "Concomitant cisplatin chemotherapy and radiotherapy in advanced mucosal
squamous cell carcinoma of the head and neck. Long-term results of the Radiation Therapy Oncology Group
study 81-17." (Marcial VA et al. Cancer. 1990 Nov 1;66(9):1861-8.)
• Outcome: 4-year LRC 43%, OS 34%. LRC and OS better in non-keratinizing SCC. High CR rate in
nasopharynx.
• Toxicity: renal 1 Grade 5 and 2 Grade 4
• Conclusion: Results justify a randomized trial of chemo-RT vs. RT alone
• Wisconsin (1961-1973)
• Randomized. Subset report of 136 patients oral cavity, oropharynx. Advanced SCCHN. Arm 1) RT alone vs.
Arm 2) RT + concurrent 5-FU 5 mg/kg. RT 50-60 Gy using orthovoltage/Cobolt/4MV sources
• 1976 PMID 175693 -- "Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma
of the oral cavity and oropharynx: a randomized study." (Lo TC, AJR Am J Roentgenol. 1976
Feb;126(2):229-35.)
• Outcome: LC and OS better in chemo-RT, but only oral cavity significant (2-year LC 18% vs. 55%)
• Toxicity: Both acute and late complications more severe in concurrent group
• Conclusion: Concurrent 5-FU appears effective, but complications
Altered fractionation with chemotherapy

• RTOG 0129 (2002-2005) -- Concurrent SFX vs. concurrent AFX with cisplatin
• Randomized. 723 patients, selected Stage III-IV (T2N2-3M0, T3-4 Any N M0, no T1-2N1 or T1N2-3) oral
cavity, oropharynx, hypopharynx, or larynx. Arm 1) Conventional chemo-RT 70/35 in 7 weeks vs Arm 2)
Concomitant boost chemo-RT 72/42 in 6 weeks. Cisplatin 100 mg/m2 Q3W
• 2007 ASTRO Abstract - "A phase III trial to compare standard versus accelerated fractionation in combination
with concurrent cisplatin for head and neck carcinomas (RTOG 0129): report of compliance and toxicity."
(Ang K,Int J Radiat Oncol Biol Phys 69 (3 Suppl): A-21, S12-13, 2007) Median F/U 2.0 years, living 2.4 years
• Outcome: Feeding tube before therapy SFX 25% vs. 22%, EOT 68% vs. 67%, 1-year 30% vs. 27%. No
difference in any toxicity endpoint
• Conclusion: Compliance high, no higher acute toxicity in C-AFX compared with C-SFX arm
• Spanish trial, 1990 — "Single fraction per day versus two fractions per day versus radiochemotherapy in the
treatment of head and neck cancer." Sanchiz F et al. IJROBP 1990; 19(6):1347-50.
• Brizel (Duke), 1998 - PMID 9632446 — "Hyperfractionated irradiation with or without concurrent chemotherapy
for locally advanced head and neck cancer." Brizel DM et al. N Engl J Med. 1998 Jun 18;338(25):1798-804.
• Improved LRC 26% and OS 21%, absolute at 3 yrs.
• Jeremic, 2000 - PMID 10735893 — "Hyperfractionated radiation therapy with or without concurrent low-dose
daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized
trial." Jeremic B et al. J Clin Oncol. 2000 Apr;18(7):1458-64.
• German trial, 2001 - PMID 11483325 — "Intensified hyperfractionated accelerated radiotherapy limits the
additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced
head-and-neck cancer." Staar S et al. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1161-71.
• Difference in LRC and OS (increase of 6% and 9%) N.S.

• Swiss trial, 2004 (1994-2000) - PMID 15534360 — "Concomitant cisplatin significantly improves locoregional
control in advanced head and neck cancers treated with hyperfractionated radiotherapy." Huguenin P et al. J Clin
Oncol. 2004 Dec 1;22(23):4665-73.
• Randomized to HF-RT (1.2 Gy BID to 74.4 Gy) +/- concomitant cisplatin (2 cycles of 20 mg/m2 on days 1-5
of weeks 1 and 5)
• Improved LRC and distant DFS but no difference in OS.
Pending trials:
• RTOG 99-14 (closed Nov 2000) - Ang. Phase II, concomitant boost with cisplatin. Concomitant boost 72 Gy in 6
weeks. Large field 32.4 Gy (1.8 Gy/fx). Boost field 1.5 Gy/fx x 12 fx = 18 Gy, >6 hrs after first daily fraction
with additional 21.6 Gy (1.8 Gy/fx) to large field. Total dose to large field is 54 Gy. Offcord at 45 Gy. Cisplatin
100 mg/m2 on days 1 and 22.
• Enrolled Stage III-IV OC, OP, HP, and larynx.
Induction Chemo + Concurrent ChemoRT vs Concurrent ChemoRT Alone

• Spain (2002-2007) -- Induction chemo + chemo-RT vs chemo-RT alone
• Randomized. 439 patients, locally advanced unresectable H&N (oropharynx/oral cavity 63%, T4 75%, N2-N3
61%). Arm 1) Induction PF x3 cycles followed by chemo-RT cisplatin 100 mg/m2 Q3W + RT 70 Gy vs. Arm
2) Induction TPF x3 cycles followed by chemo-RT vs. Arm e) Chemo-RT alone
• 2009 ASCO Abstract [4] -- "Final results of a randomized phase III trial comparing induction chemotherapy
with cisplatin/5-FU or docetaxel/cisplatin/5-FU follow by chemoradiotherapy (CRT) versus CRT alone as
first-line treatment of unresectable locally advanced head and neck cancer (LAHNC). (Hitt R, J Clin Oncol
27:15s, 2009 (suppl; abstr 6009))
• Outcome: Time-to-progression induction 12 months vs chemo-RT 4.9 months (HR 0.5, SS). LRC induction
61% vs. chemo-RT 44% (OR 0.5, SS)
• Toxicity: G3+ mucositis induction 83% vs chemo-RT 69%
• Conclusion: Combination of induction chemo followed by chemo-RT increases loco-regional control and
prolongs time-to-progression compared with chemo-RT alone
Induction chemotherapy
• EORTC 24971 / TAX 323 -- PF vs TPF
• Randomized. 358 patients with unresectable Stage III/IV disease and no mets (Oropharynx 46%, hypopharynx
29%, oral cavity 18%, larynx 7%) Induction PF (cisplatin 100mg/m2, 5-FU 1000mg/m2) vs. TPF (docetaxel
75mg/m2, cisplatin 75mg/m2, 5-FU 750 mg/m2) x4 cycles. If no progression, RT start within 4-7 weeks after
completing chemo. RT standard (66-70 Gy) or accelerated (max 70 Gy) or hyperfractionated (max 74 Gy). No
concurrent chemo (?)
• Protocol compliance: PF 66% completed induction vs. TPF 76%. Progressive disease PF 7% vs. TPF 8%;
adverse events PF 12% vs. TPF 6%; death PF 7% vs. TPF 3%
• 2007 PMID 17960012 -- "Cisplatin, Fluorouracil, and Docetaxel in Unresectable Head and Neck Cancer"
(Vermorken JB, N Engl J Med 2007 Oct 25; 357(17):1695-704). Median F/U 2.7 years
• Outcome: median PFS TPF 11 months vs. PF 8.2 months (SS); median OS 14 months vs. 19 months (SS),
risk of death decreased by 27%
• Toxicity: TPF leukopenia and neutropenia vs. PF thrombocytopenia, N/V, stomatitis, hearing loss
• Conclusion: Induction with TPF superior over induction with PF
• TAX 324 -- PF vs TPF

• Randomized. 501 patients with Stage III/IV disease (resectable and unresectable) and no mets. Induction with
PF (cisplatin 100mg/m2, 5-FU 1000mg/m2) vs. TPF (docetaxel 75mg/m2, cisplatin 100mg/m2, 5-FU
1000mg/m2) x3 cycles. If response (>25% tumor reduction), chemo-RT start within 3-8 weeks. RT 70-74 Gy
in 2 Gy/fx, involved LNs 60-74 Gy, uninvolved LNs >=50 Gy. Concurrent carboplatin AUC 1.5. Surgery 6-12
weeks after RT if N2 and PR, if N3, or if residual disease
• Protocol compliance: 98% completed induction, completion per protocol TPF 73% vs. PF 68%
• 2007 PMID 17960013 -- "Cisplatin and Fluorouracil Alone or with Docetaxel in Head and Neck Cancer"
(Posner MR, N Engl J Med 2007 Oct 25; 357(17):1705-15). Minimum F/U 2 years
• Outcome: median OS TPF 5.9 years vs. PF 2.5 years (SS); 3-year OS 62% vs. 48% (SS). Locoregional
control 70% vs. 62% (SS), no difference in DM
• Toxicity: TPF neutropenia vs. PF hematologic adverse events
• Conclusion: Induction with TPF superior over induction with PF
Trials:
• Wayne State, 1985 - PMID 4038469 — "Improved complete response rate and survival in advanced head and
neck cancer after three-course induction therapy with 120-hour 5-FU infusion and cisplatin." Rooney M et al.
Cancer. 1985 Mar 1;55(5):1123-8.
• Pilot study. Pts received one of several regimens of induction chemotherapy: 2 courses cisplatin + vincristine +
bleomycin (COB), 2 courses cisplatin + 96-hr 5-FU infusion, or 3 courses cisplatin + 120-hr 5-FU infusion. Pts
went on to surgery or RT.
• High overall response rate in all 3 arms. CR rate higher in 120-hr 5-FU/Cisplatin regimen, 54% vs 29% (COB)
and 19% (96-hr). Also higher survival for that regimen. Responders to initial chemo have higher survival vs
non-responders.
• Conclusion: multimodality treatment is feasible.
• 1985 - PMID 3889230 — "A randomized trial of adjuvant chemotherapy in head and neck cancer." Taylor SG et
al. J Clin Oncol. 1985 May;3(5):672-9.
• Randomized. 95 pts. two-week course of induction chemo prior to regional therapy, then adjuvant chemo
q3months for one year. Initially received methotrexate / leucovorin, but was changed to Adriamycin + cisplatin
because of toxicity concerns.
• No difference in disease control or survival.
• VA Larynx Trial, 1991 - PMID 2034244
• Randomized. Pts with Stage III or IV laryngeal carcinoma randomized to induction chemo + XRT or surgery +
XRT.
• See details at Larynx.
• RTOG 91-11, 2003 - PMID 14645636
• Larynx. 3 arms: induction chemo + RT, concurrent chemo/RT, XRT alone.
• See details at Larynx.
• RTOG 68-01 -- Methotrexate
• Randomized. 638 patients, Stage III-IV oral cavity (23%), oropharynx (55%), supraglottic larynx (12%),
hypopharynx (10%). Arm 1) RT alone vs. Arm 2) IV MTX 25 mg q3d x5 followed by RT. RT 55-80 Gy
• 1980 PMID 7410127 -- "Adjuvant intravenous methotrexate or definitive radiotherapy alone for advanced
squamous cancers of the oral cavity, oropharynx, supraglottic larynx or hypopharynx." (Fazekas JT, Int J
Radiat Oncol Biol Phys. 1980 May;6(5):533-41.)
• Outcome: median OS RT vs. MTX-RT: oral cavity 11.8 mo vs. 12.4 mo, oropharynx 13.6 mo vs. 13.1 mo,
SGL 17.2 mo vs. 19.2 mo, hypopharynx 9.7 mo vs. 13.4 mo
• Conclusion: Minimal gain, induction methotrexate should not be used
Intraarterial chemotherapy
• RTOG 96-15 - RADPLAT
• PMID 15735120, 2005 — "Supradose intra-arterial cisplatin and concurrent radiation therapy for the treatment
of stage IV head and neck squamous cell carcinoma is feasible and efficacious in a multi-institutional setting:
results of Radiation Therapy Oncology Group Trial 9615." Robbins KT et al. J Clin Oncol. 2005 Mar
1;23(7):1447-54.
Other biologic agents

Cetuximab (Erbitux), C-225 - monoclonal anti-EGFR antibody
• Phase I PMID 11432891, 2001 (1997-98) — "Phase I study of anti--epidermal growth factor receptor antibody
cetuximab in combination with radiation therapy in patients with advanced head and neck cancer." Robert F et al.
J Clin Oncol. 2001 Jul 1;19(13):3234-43.
• 16 pts. Dose finding study. RT to 70 Gy, 3 pts with hyperfractionated RT to 76.8 Gy. Cetuximab given with
loading dose of 400-500 mg/m2 then weekly infusions of 100-250 mg/m2.
• Phase III (1999-2002)
• Randomized. 424 pts. Stage III-IV, scca of oropharynx, hypopharynx, or layrnx. 56-63% had tumors of the
oropharynx. Randomized to RT +/- cetuximab. Given as 400 mg/m2 loading dose IV one week before RT,
followed by weekly infusions of 250 mg/m2 during RT.
• One of three radiotherapy regimens (70 Gy at 2 Gy/fx qd, 72-76.8 Gy at 1.2 Gy BID, or 72 Gy in 42 fractions
concomitant boost 1.8+1.5 Gy). 56% used concomitant boost, 26% once daily, and 18% twice daily.
• 2004 ASCO Abstract 5507 [5] — "Cetuximab prolongs survival in patients with locoregionally advanced
squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without
cetuximab." Bonner JA et al. Proc Am Soc Clin Oncol 23:488, 2004 (abstr 5507)
• 2005 ASCO Abstract 5533 [6] — "Improved Preservation of Larynx with the Addition of Cetuximab to
Radiation for Cancers of the Larynx and Hypopharynx" Bonner JA et al.
• Subset analysis, including 171 pts with tumors of the hypopharynx or larynx. Hazard ratio for larynx
preservation was 0.62 (confidence interval included 1). Underpowered study for this endpoint.
• 3-years, 2006 PMID 16467544, 2006 — "Radiotherapy plus cetuximab for squamous-cell carcinoma of the
head and neck." Bonner JA et al. N Engl J Med 2006; 354: 567-78. Median F/U 4.5 years.
• Locoregional control: Median duration Cetuximab + RT 24.4 months vs RT alone 14.9 mo (SS); 3-year
LRC: 47% vs. 34%. Cetuximab 32% reduction in LR progression
• Progression-free survival: Median 17.1 months vs. 12.4 months; 3-year PFS 42% vs. 31%; Risk of DM
similar
• Survival: Median 4.1 years vs 2.4 years (SS); 3-yr OS 55% vs 45%. Cetuximab 26% reduction in the risk of
death.
• Toxicity: Comparable, except 9 patients rash. Second primary cancer in 8% vs 5%.
• Conclusion: improved survival (10% absolute at 3-yrs) and locoregional control.
• QoL, 2007 PMID 17538164 -- "Quality of life in head and neck cancer patients after treatment with high-dose
radiotherapy alone or in combination with cetuximab." (Curran D, J Clin Oncol. 2007 Jun 1;25(16):2191-7.)
• Quality of Life assessment (QLQ-C30) at baseline, week 4, month 4, month 8, one year.
• Outcome: No significant differences
• Conclusion: Cetuximab improves locoregional control and survival without adversely impacting QoL
• Editorial PMID 16467552: RT alone in the control arm is suboptimal therapy; current standard of care is RT +
cisplatin, which has shown greater benefit than cetuximab. Also, cetuximab appeared only effective in the
hyperfractionated arms. No survival benefit for hypopharynx and larynx subgroups. Standard of care should
still be RT + cisplatin, but if not tolerated, then cetuximab a good option
• RTOG 02-34 (ongoing) - A phase II randomized trial of surgery followed by chemoradiotherapy plus C225
(cetuximab) for advanced squamous cell carcinoma of the head and neck.
• RTOG 05-22 (ongoing) - A phase III trial of concurrent accelerated radiation and cisplatin versus concurrent
accelerated radiation, cisplatin, and cetuximab (C225) followed by surgery for residual disease for stage III and
IV head and neck carcinomas.
Cetuximab + RT Toxicity
• Dusseldorf, 2007 PMID 17671265 -- "Severe cutaneous reaction during radiation therapy with concurrent
cetuximab." (Budach W, N Engl J Med. 2007 Aug 2;357(5):514-5.)
• 2 cases reported. Grade 4 toxicity. Images.
Hypoxia
• Anemia is associated with significantly worse locoregional control and survival, as shown in secondary analysis
of RTOG 85-27
• However, both a European randomized trial and randomized RTOG 99-03 showed worse outcomes in patients
given erythropoietin support
• Hypoxic cell sensitizers (misonidazole and etanidazole) did not show a clinical benefit
• Carbogen breathing was also not shown to have any benefit
Erythropoietin:
• RTOG 99-03 (2000-2003) - study closed early
• Randomized. Closed early due to other data suggesting worse locoregional control. 141 patients (40% of goal)
with SCCHN, Stage I-IV. Hemoglobin men <13.5 g/DL and women <12.5 g/dL. RT +/- erythropoietin 40K
units weeily. If Stage III-IV, concurrent chemo-RT and/or accelerated RT.
• 2007 PMID 17716826 -- "Radiotherapy With or Without Erythropoietin for Anemic Patients With Head and
Neck Cancer: A Randomized Trial of the Radiation Therapy Oncology Group (RTOG 99-03)." (Machtay M,
Int J Radiat Oncol Biol Phys. 2007 Nov 15;69(4):1008-17. Epub 2007 Aug 23.). Median F/U 2.5 years
• Hemoglobin: at 4 weeks control -0.2 g/dL vs. Epo +1.7 g/dL
• Outcome: 3-year LRF control 36% vs. Epo 44% (NS). No difference in OS (52% vs. 47%) or toxicity
• Conclusion: Addition of Epo did not improve outcomes
• European Multinational (1997-2001)
• Randomized. 351 patients with oral cavity, oropharynx, hypopharynx, larynx. Hemoglobin <13.0 g/dL men,
<12.0 g/dL women. RT 60-70 Gy +/- Epo 300 U/kg 3x weekly
• 2003 PMID 14575968 -- "Erythropoietin to treat head and neck cancer patients with anaemia undergoing
radiotherapy: randomised, double-blind, placebo-controlled trial" (Henke M, Lancet. 2003 Oct
18;362(9392):1255-60.)
• Hemoglobin: 82% given Epo reached >14.0 (men) or >15 (women) compared with 15% control
• Outcome: LR failure placebo 54% vs. Epo 64% (SS), median PFS 2.0 years vs. 1.1 years (SS); OS 48% vs.
39% (same 34% mortality from cancer but worse cardiac/general mortality for Epo)
• Conclusion: Significantly worse LR control and survival with Epo
Etanidazole: hypoxic cell sensitizer
• RTOG 85-27 (1988-1991)

• Randomized. 521 pts. Stage III-IV. Randomized to RT 66-74 Gy alone or RT + etanidazole (ETA) 3x/week.
• 1995 PMID 7790241 -- "Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus
etanidazole with radiotherapy alone for locally advanced head and neck carcinomas." (Lee DJ, Int J Radiat
Oncol Biol Phys. 1995 Jun 15;32(3):567-76.)
• Outcome: 2-year LRC control 40% vs etanidazole 40% (NS); OS 41% vs 43%. For N0-1 patients,
advantage for ETA for LRC 55% vs 37% (SS).
• Conclusion: No benefit for etanidazole overall, subset benefit in N0-1 disease
• 1998 PMID 9869231 -- "Anemia is associated with decreased survival and increased locoregional failure in
patients with locally advanced head and neck carcinoma: a secondary analysis of RTOG 85-27." (Lee WR, Int
J Radiat Oncol Biol Phys. 1998 Dec 1;42(5):1069-75.)
• Subset of 451 patients. 46% normal Hgb (men >14.5, women >13), 64% anemic
• Outcome: 5-year OS normal Hgb 36% vs. anemic 22% (SS); LRFR 52% vs. 68% (SS)
• Toxicity: Grade 3+ normal Hgb 20% vs. 13% (NS)
• Conclusion: Low Hgb levels result in worse survival and LR failure
Misonidazole - hypoxic cell sensitizer
• RTOG 79-15 (1979-1983)
• Randomized. 206 patients, 42% oropharynx, 78% T3-T4, 84% N+. Arm 1) RT + placebo vs. Arm 2) RT +
misonidazole 2.0 gm/m2 weekly (on day of misonidazole, RT given BID)
• 1987 PMID 3301758 -- "Failure of misonidazole-sensitized radiotherapy to impact upon outcome among stage
III-IV squamous cancers of the head and neck." (Fazekas J, Int J Radiat Oncol Biol Phys. 1987
Aug;13(8):1155-60.)
• Outcome: 2-year LR rate placebo 26% vs. misonidazole 22% (NS); 3-year OS 22% in both groups
• Conclusion: No benefit
• 1989 PMID 2689395 -- "The role of hemoglobin concentration in the outcome of misonidazole-sensitized
radiotherapy of head and neck cancers: based on RTOG trial #79-15." (Fazekas JT, Int J Radiat Oncol Biol
Phys. 1989 Dec;17(6):1177-81.)
• Outcome: No difference
• RTOG 79-04 (1979-1983)
• Randomized. 40 patients, unresectable Stage III-IV oral cavity, oropharynx, hypopharynx. Arm 1) RT 44-52
Gy in 4 Gy/fx vs. Arm 2) same RT + misonidazole 1.5 gm/m2 3x per week
• 1989 PMID 2646255 -- "A phase I/II study of the hypoxic cell sensitizer misonidazole as an adjunct to high
fractional dose radiotherapy in patients with unresectable squamous cell carcinoma of the head and neck: a
RTOG randomized study (#79-04)." (Lee DJ, Int J Radiat Oncol Biol Phys. 1989 Feb;16(2):465-70.)
• Outcome: 2-year LRC: RT alone 10% vs. RT + MISO 17% (NS)
• Toxicity: No difference
• Conclusion: No benefit for misonidazole; high fractional dose RT tolerable
Carbogen - (95% oxygen, 5% C02)
• RTOG 70-02 (1972-1976)
• Randomized. 254 patients. T2-4N0-3, Oral cavity, oropharynx, nasopharynx, hypopharynx, larynx; also
esophageal cancers (24%). Arm 1) RT + concurrent carbogen breathing vs. Arm 2) RT + air. RT 60-70 Gy
(oral cavity max 80 Gy)
• 1979 PMID 120869 - "Carbogen breathing during radiation therapy-the Radiation Therapy Oncology Group
Study." (Rubin P, Int J Radiat Oncol Biol Phys. 1979 Nov-Dec;5(11-12):1963-70.)
• Outcome: 2-year LC carbogen 51% vs. air 51% (NS); no SS difference by site. Median OS carbogen 1.5
years vs. air 1.5 years (NS)
• Toxicity: No significant difference
• Conclusion: No difference
Hyperbaric Oxygen
• Yale (1974-1975) -- RT in air vs RT in HBO
• Randomized. 48 patients, locally advanced unresectable SCCHN. Arm 1) RT in air 25.3/2 vs. Arm 2) RT in
HBO-4 23/2. HBO given under general anesthesia, 4 atmospheres
• 1999 PMID 10606475 -- "Radiation therapy with hyperbaric oxygen at 4 atmospheres pressure in the
management of squamous cell carcinoma of the head and neck: results of a randomized clinical trial." (Haffty
BG, Cancer J Sci Am. 1999 Nov-Dec;5(6):341-7.)
• Outcome: CR air 52% vs. HBO 84%, 5-year LC 16% vs. 29%. No difference in OS, DM or second primary
tumors
• Severe toxicity: air 28% vs. HBO 52%
• Conclusion: Substantial improvement in response rate with HBO. Hypofractionation scheme suboptimal
Treatment technique
Risk of extracapsular extension:
• <1 cm - 17-43%, 1-3 cm - 65-83%, >3 cm - 67-95%.
• PMID 7316852 (1981, Johnson), PMID 7105450 (1982, Snow), PMID 4027895 (1985, Snyderman), PMID
3583851 (1987, Carter), PMID 2030629 (1991, Hirabayashi)
Margin around lymph nodes:
• PMID 16243444, 2006 — MDACC: "Determining optimal clinical target volume margins in head-and-neck
cancer based on microscopic extracapsular extension of metastatic neck nodes." Apisarnthanarax S et al. Int J
Radiat Oncol Biol Phys. 2006 Mar 1;64(3):678-83.
• 96 lymph nodes up to 3 cm with extracapsular extension were examined. Mean and median ECE extent was
2.2 and 1.6 mm. Was <5mm in 96% of nodes. No correlation with size of lymph node and distance of ECE.
• Recommend 1 cm CTV margins to cover microscopic nodal extension.
Time-to-treatment:
• Please see the Time-to-treatment section
Daily time of treatment
• NCIC HN3 -- morning RT vs. afternoon RT
• Randomized, proof of principle. 205/216 patients, receiving primary or postop RT. Arm 1) morning (8-10 AM)
RT vs. Arm 2) afternoon (4-6 PM) RT; no chemo. Primary outcome mucositis
• 2008 PMID 18805649 -- "Comparison of Toxicity Associated with Early Morning Versus Late Afternoon
Radiotherapy in Patients with Head-and-Neck Cancer: A Prospective Randomized Trial of the National Cancer
Institute of Canada Clinical Trials Group (HN3)." (Bjarnason GA, Int J Radiat Oncol Biol Phys. 2008 Sep 19.
[Epub ahead of print])
• Outcome: Grade 3+ mucositis AM RT 53% vs. PM RT 62% (p=0.2). In patients with RT dose 66-70 Gy,
45% vs. 67% (SS). Also longer time-to-mucositis >7.9 weeks vs. 5.6 weeks (SS). Significant benefit in
patients who continued to smoke 43% vs. 76% (SS)
• Conclusion: Morning RT associated with significantly less weight loss, and reduction in oral mucositis in
patients getting >=66 Gy
LN response by size
• Brisbane (Australia); 2008 (1997-2003) PMID 19032396 -- "Predicting regional control based on pretreatment
nodal size in squamous cell carcinoma of the head and neck treated with chemoradiotherapy: a clinician's guide."
(Porceddu SV, J Med Imaging Radiat Oncol. 2008 Oct;52(5):491-6.)
• Retrospective. 117 patients, HNSCC, N+, treated with concurrent chemo-RT. Median RT dose 70 Gy.
Stratified into pretreatment LN <=3 cm vs. 3-6 cm vs. >6 cm
• Outcome: Regional control if LN <=3 cm 88% vs. 3-6cm 72% vs. >6 cm 50% (SS)
• Conclusion: Quantitative guide for regional control based on pre-rx nodal size
Larynx/Hypopharynx RT
• West Florida; 1992 PMID 1616592 -- "A technique for postoperative irradiation of carcinomas of the larynx and
hypopharynx." (Amos EH, Med Dosim. 1992;17(2):65-7.)
• Postop RT technique. 15 degree lateral kick-out of table and 15 degree gantry rotation for each of 2 lateral
fields. Benefit lower dose to shoulder and avoid hotspot near cord
• Univ North Carolina; 1991 PMID 1869469 -- "A comparison of postoperative techniques for carcinomas of the
larynx and hypopharynx using 3-D dose distributions." (Sailer SL, Int J Radiat Oncol Biol Phys. 1991
Aug;21(3):767-77.)
• Postop RT techcnique for larynx/hypopharynx. Comparison of minimantle technique (MGH), 3F technique
(University of Florida), 3F technique (standard), and kicked out lateral technique
• Conclusion: Favor kicked-out lateral technique for better coverage and homogeneity
Reviews
• PMID 3278390, 1988 - "Radiation Therapy Oncology Group (RTOG) studies in head and neck cancer."
Prediction of Response
• MSKCC, 2007 PMID 17416856 -- "Identification of angiogenesis/metastases genes predicting
chemoradiotherapy response in patients with laryngopharyngeal carcinoma." (Ganly I, J Clin Oncol. 2007 Apr
10;25(11):1369-76.)
• Gene arrays. Correlation of 277 genes (angiogenesis and/or mets) to locoregional control
• MDM2 and erbB2 are predictors of locoregional failure in patients treated with chemo-RT
Patterns of failure
• M.D.Anderson, Hong, 1985 - PMID 4027864 — "Patterns of relapse in locally advanced head and neck cancer
patients who achieved complete remission after combined modality therapy." Hong WK et al. Cancer. 1985 Sep
15;56(6):1242-5.
• 103 pts treated with induction chemotherapy followed by surgery and/or RT. 71 pts were free of disease.
5-year recurrence rate was 51% (39% local and 26% distant failure). Relapse patterns were affected by: site
(oral cavity more likely to fail locally, hypopharnx more likely to have DM); type of treatment (surgery + RT
had lower local failure); TN stage (T3-4N3 had higher risk of local and distant failure); oropharynx (higher
local + distant failure).
Planned Neck Dissection

• General consensus suggests that adjuvant neck dissection is not necessary for patients with N1 neck and CR after
chemo-RT
• Historically, ipsilateral neck recurrence was lower for N2/N3 disease after primary RT + adjuvant neck dissection
than either modality alone
• The necessity of adjuvant neck dissection after chemo-RT is controversial
• ~25% of patients with clinical/radiographic CR who undergo neck dissection have residual disease
• 30-40% of patients with clinical/radiographic detectable disease who undergo neck dissection have no residual
disease
• Thus, overall accuracy of neck response by clinical/radiographic evaluation is ~60%
• PET shows promise, and appears more accurate than clinical, CT, or MRI neck evaluation
• It may be reasonable to observe patients with clinical/radiographic CR, and negative PET 12 weeks after
completing chemo-RT
• It is not clear what negative PET means in setting of clinical/radiographic detectable disease
• TROG 98.02 subset analysis suggests that after chemo-RT, ipsilateral failure is low in patients with
clinical/radiographic CR
• TROG 98.02
• Subset analysis. TROG 98.02 is Phase II randomized trial of RT 70/35 with Arm 1) concurrent
cisplatin/tirapazamine vs. Arm 2) concurrent cisplatin/5-FU. Subset patients with initial N2-3 disease, who
achieved complete clinical/radiological CR at 12 weeks (N2 63%, N3 40%) and no planned neck dissection
was performed
• 2008 PMID 18286488 -- "N2-N3 neck nodal control without planned neck dissection for clinical/radiologic
complete responders-Results of Trans Tasman Radiation Oncology Group Study 98.02." (Corry J, Head Neck.
2008 Feb 19 [Epub ahead of print]). Median F/U 4.3 years
• Outcome: First failure: local 4%, locoregional 2%, distant 28%, locoregional + distant 6%. No patients with
neck-only failure
• Conclusion: Patients with CR do not need planned neck disection
Radiation Injury
Please see Radiation Oncology/Toxicity/Head & Neck
References
[1] http:/ / www. rtog. org/ members/ protocols/ 97-03/ 97-03. pdf
[3] http:/ / www. redjournal. org/ article/ PIIS036030160701019X/ fulltext
[4] http:/ / www. asco. org/ ASCOv2/ Meetings/ Abstracts?& vmview=abst_detail_view& confID=65& abstractID=31776
[5] http:/ / www. asco. org/ ac/ 1,1003,_12-002636-00_18-0026-00_19-002132,00. asp
[6] http:/ / www. asco. org/ ac/ 1,1003,_12-002643-00_18-0034-00_19-0032608,00. asp
Radiation Oncology/Head & Neck/Post-op

Postoperative RT
Surgical Technique
• No universally accepted definition of "resectable" vs "unresectable" tumor
• Lymph node dissection classification (PMID 12117328)
• Radical neck dissection: all ipsilateral cervical LN groups from inferior border of mandible superiorly to
clavicly inferiorly and from lateral border of sternohyoid muscle/hyoid bone/contralateral anterior belly of
digastric muscle anteriorly to anterior border of trapezius posteriorly. All lymph nodes from Level I - V. Spinal
accessory nerve, internal jugular vein, and sternocleidomastoid muscles are removed. No removal of
suboccipital, periparotid, buccal, retropharyngeal, and paratracheal lymph nodesModified radical neck
• Modified radical neck dissection: excision of all lymph nodes routinely removed by radical neck dissection
with preservation of one or more nonlymphatic structures, ie, spinal accessory nerve, internal jugular vein,
and/or sternocleidomastoid muscle.
• Selective neck dissection (SND): cervical lymphadenectomy with preservation of 1 or more of the lymph node
groups that are routinely removed in the radical neck dissection. The lymph node groups removed are based on
the patterns of metastases, which are predictable relative to the primary site of disease
• Supraomohyoid neck dissection: SND I-III. Oral cavity cancers. In case of oral tongue, some recommend
SND I-IV. For cancers involving midline, bilateral SND I-III
• Lateral neck dissection: SND II-IV. Oropharyngeal, hypopharyngeal, and laryngeal cancers. If
retropharyngeal LNs, they can be dissected as well
• Posterolateral neck dissection: SND II-V. Cutaneous melanoma
• Anterior neck dissection: SND VI. Thyroid, larynx, hypopharynx
• Extended neck dissection: removal of 1 or more additional lymph node groups or nonlymphatic structures, or
both, not encompassed by the radical neck dissection. Examples of lymph node groups include the
parapharyngeal (retropharyngeal), superior mediastinal, perifacial (buccinator), and paratracheal lymph nodes.
Examples of nonlymphatic structures include the carotid artery, hypoglossal nerve, vagus nerve, and paraspinal
muscles.
Selective neck dissection

• Goettingen, Germany, 2001 (1986-1997) PMID 11226954 -- "Efficacy of selective neck dissection: a review of
503 cases of elective and therapeutic treatment of the neck in squamous cell carcinoma of the upper aerodigestive
tract." (Ambrosch P, Otolaryngol Head Neck Surg. 2001 Feb;124(2):180-7.)
• Retrospective. 503 patients, selective neck dissection. pN0 49% vs pN+ 51%. Postop RT pN0 14% vs. pN+
62%. Median F/U 3.4 years
• Outcome: 3-year RR pN0 5% vs. pN1 5% vs. pN2 12%. RT marginal benefit for pN1 and significant benefit
for pN2 or ECE
• Conclusion: Results achieved with selective neck dissection compare favorably with reported modified radical
neck dissection
Criopharyngeal myotomy
• RTOG 85-30 (1989-1994)
• Randomized. 125 patients. Arm 1) standard surgery vs. Arm 2) surgery + cricopharyngeal myotomy
• 1999 PMID 10488976 -- "Failure of cricopharyngeal myotomy to improve dysphagia following head and neck
cancer surgery." (Jacobs JR, Arch Otolaryngol Head Neck Surg. 1999 Sep;125(9):942-6.)
• Outcome: No difference in oropharyngeal swallowing efficiency at 6 months
• Conclusion: No benefit for cricopharyngeal myotomy
Surgery + Post-op RT vs Primary RT

• RTOG; 1993 (1985-1990) PMID 8262821 — "Is a surgical resection leaving positive margins of benefit to the
patient with locally advanced squamous cell carcinoma of the head and neck: a comparative study using the
intergroup study 0034 and the Radiation Therapy Oncology Group head and neck database." Laramore GE et al.
Int J Radiat Oncol Biol Phys. 1993 Dec 1;27(5):1011-6.
• Compared pts treated on a prospective Intergroup study (surgical group) with pts from a historical database
who received RT alone, matched for similar characteristics. 109 pts in the surgical group had positive margins
and most received post-op RT.
• 4-yr LRC 44% (positive margins) vs 24% (RT). No difference in MS or 4-yr OS.
• Conclusion: incomplete surgery (+adjuvant RT) affords improved local control compared to RT alone
Surgery + RT vs. Primary Chemo-RT

• Singapore (1996-2000)
oropharynx 55%, oral cavity 21%, paranasal sinus 0%). Chemo-RT group had poor surgical salvage of
47%, with no long-term survivors
hypopharynx, and oropharynx
Pre-op RT vs Post-op RT
• Historically, pre-op RT was favored since it facilitated regression of tumor, and improved LRC over surgery
alone
• However, morbidity of this approach lead to greater emphasis on post-op RT in 1960's and 1970's (see Fletcher
PMID 13403033 (1957), PMID 4190460(1970))
• Randomized trial RTOG 73-03 demonstrated significantly better LRC for post-op RT
• Please see discussion tab for more trials
• RTOG 73-03 (1973-1979)
• Randomized. 320 patients. Operable stage T2-T4 any N (but not fixed); oral cavity, oropharynx, supraglottic
larynx, hypopharynx, or maxillary sinus. Arm 1) Pre-op RT 50 Gy vs. Arm 2) Post-op RT 60 Gy. In addition,
OC and OP lesions may be randomized Arm 3) definitive RT 65-70 Gy, with surgery reserved for salvage
(n=43).
• 5-years; 1987 PMID 3449477 — "Combined radiation therapy and surgery in the management of advanced
head and neck cancer: final report of study 73-03 of the Radiation Therapy Oncology Group." (Kramer S et al.
Head Neck Surg. 1987 Sep-Oct;10(1):19-30.) Median F/U 5 years
• Outcome: LRC post-op 65% vs pre-op 48% (SS). Higher rate of persistent disease and recurrence in pre-op.
Trend toward improved survival, 38% vs 33% (p=0.1).
• Toxicity: Complication rate similar.
• Definitive RT arm: For OC and OP lesions (three-arm randomization), 4-yr OS pre-op 30% vs post-op 36%
vs definitive 33% (NS), and LRC 43% vs 52% vs 38% (NS); however total number of patients was small
• Conclusion: Post-op RT superior to pre-op RT
• 10-years; 1999 PMID 1993628 — "Randomized study of preoperative versus postoperative radiation therapy
in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03." (Tupchong L et al. Int J
Radiat Oncol Biol Phys. 1991 Jan;20(1):21-8.)
• Only pre-op vs. post-op subset (n=277). Oral cavity (14%), oropharynx (17%), hypopharynx (43%),
supraglottic larynx (26%)
• Outcome: LRC pre-op 58% vs. post-op 70% (SS), <2 years no difference (failures 59% vs. 58%), but
marked >2 years (failures 27% vs 8%); OS no difference due to late (>2 years) deaths from DM and from
second primaries
• Supraglottic larynx: LRC pre-op 53% vs. post-op 77% (SS); 78% failures <2 years
• Toxicity: no difference
• Conclusion: Post-op RT better for LRC (especially in SGL), but no impact on OS due to distant failure and
second primaries
• Comment: some argument for definitive chemoRT instead of surgery and post-op RT since after 2 yrs, distant
mets are primary cause of failure resulting in similar 10 OS in this trial. LRC still better for post-op vs
definitive RT alone. Also, different doses used, at the time believed equivalent given the setting
• Univ. Florida; 1989 (1964-84) - PMID 2912947 — "Postoperative irradiation for squamous cell carcinoma of the
head and neck: an analysis of treatment results and complications." (Amdur RJ, Int J Radiat Oncol Biol Phys.
1989 Jan;16(1):25-36.)
• Retrospective. 134 patients, 96% Stage III-IV.
• Outcome: 5-year OS 33%. SM- 37% vs. SM+ 17% (SS); LRC SM- 81% vs. SM+ 53% (SS)
Induction Chemotherapy
• SWOG 8006 (1980-1985) -- Induction chemo vs. standard surgery + RT
• Randomized. 158 patients. Stage III-IV, resectable HNSCC (oral cavity, oropharynx, hypopharynx, larynx).
Arm 1) Surgery + post-op RT vs. Arm 2) Induction cisplatin 50 mg/m2 + MTX + vincristine + bleomycin
• 1988 PMID 3054373 -- "Preoperative chemotherapy in advanced resectable head and neck cancer: final report
of the Southwest Oncology Group." (Schuller DE, Laryngoscope. 1988 Nov;98(11):1205-11.) Median F/U 5
years
• Outcome: median OS induction chemo 1.5 years vs. control 2.5 years (NS)
• Conclusion: No benefit for induction chemo
Surgery alone vs Postop RT

• For patients with locally advanced disease, surgery + postop RT has been widely practiced since Maccomb and
Fletcher publication in 1957
• Two small randomized trials suggested improvement in LRC for postop RT over surgery alone. Similarly, several
single institution retrospective series showed benefit for improved LRC
• SEER analysis suggests that postop RT in patients with LN+ results in 5-year CSS/OS increase by 10%. Surgery
alone cures a third of patients, adjuvant RT adds 10% survival benefit, although this varies dramatically by site
and nodal stage
• Current indications include pT3-T4, pN2-N3 disease, nodal disease in Levels IV-V, PNI+, or LVI+
• Mt. Sinai/SEER analysis (1988-2001)
• Overall; 2008 PMID 18076014 -- "Adjuvant radiotherapy improves overall survival for patients with lymph
node-positive head and neck squamous cell carcinoma." (Lavaf A, Cancer. 2008 Feb 1;112(3):535-43.)
• Population based SEER analysis. 8795 patients, HNSCC, treated with surgery, pN+. excluded nasopharynx.
Use of chemo not tracked, but trials showing benefit not published until 2004. Median F/U 4.7 years
• Outcome: Adjuvant RT used in 84% (preop 7%, postop 89%). 5-year OS surgery alone 33% vs. surgery +
RT 43% (SS); 5-year CSS 42% vs. 51% (SS)
• Conclusion: Adjuvant RT improved 5-year CSS and OS by 10%
• By site; 2008 PMID 18164833 -- "Adjuvant radiotherapy and survival for patients with node-positive head and
neck cancer: an analysis by primary site and nodal stage." (Kao J, Int J Radiat Oncol Biol Phys. 2008 Jun
1;71(2):362-70. Epub 2007 Dec 31.)
• Population based SEER analysis. 5297 patients, HNSCC, treated with surgery, pN+
• Outcome: Adjuvant RT 81%. 5-year OS surgery 35% vs. surgery + RT 46% (SS)
• By nodal stage: 5-year OS N1 44% vs. 52% (SS); N2a 28% vs. 44% (SS); N2b 18% vs. 42% (SS);
N2c-N3 22% vs. 34% (SS)
• By primary site: 5-year OS oral cavity 30% vs. 34% (NS); oropharynx 53% vs. 62% (SS); larynx 31%
vs. 43% (SS); hypopharynx 24% vs. 39% (SS)
• Multivariate predictors: adjuvant RT, age, primary site, nodal stage, tumor stage, marital status
• Conclusion: Adjuvant RT significantly improves overall survival; all stages including N1 appear to benefit
• Mayo Clinic; 1998 (1974-1990) PMID 9486600 -- "Combined neck dissection and postoperative radiation
therapy in the management of the high-risk neck: a matched-pair analysis." (Lundahl RE, Int J Radiat Oncol Biol
Phys. 1998 Feb 1;40(3):529-34.)
• Retrospective, matched pair. 95 patients with pN+ who underwent postop RT (N1 17%, N2 80%, N3 3%).
Median RT dose 55 Gy. Compared with previously published 284 patients treated with neck dissection alone,
as matched pairs. Median F/U 5.3 years
• Outcome: Relative risk for dissected neck recurrence 5.8, any neck recurrence 4.7, cancer related death 2.2,
and any death 1.7.
• Conclusion: Postop RT for high-risk neck can reduce negative outcomes
• Orissa, India -- surgery +/- postop RT
• 1996 PMID 8903493 -- "Post-operative radiotherapy in carcinoma of buccal mucosa, a prospective
randomized trial." (Mishra RC, Eur J Surg Oncol. 1996 Oct;22(5):502-4.)
• Randomized. Locally advanced SCC of buccal mucosa. Arm 1) surgery only vs. Arm 2) postoperative RT
• Outcome: DFS surgery alone 38% vs. postop RT 68% (SS)
• Conclusion: Postop RT improves DFS in SCC of buccal mucosa
• City of Hope (1981-1984) -- surgery +/- postop RT
• Randomized. Stopped early due to lack of benefit at interim analysis. 51 patients, stage III-IV SCC of oral
cavity, pharynx, or larynx. Arm 1) surgery alone vs. Arm 2) surgery + postop RT
• 1988 PMID 3288812 -- "Postoperative radiation as adjuvant treatment for carcinoma of the oral cavity, larynx,
and pharynx: preliminary report of a prospective randomized trial." (Kokal WA, J Surg Oncol. 1988
Jun;38(2):71-6.) Median F/U 2.5 years
• Outcome: Recurrence rate surgery alone 56% vs. postop RT 37% (NS); trend due to higher recurrence rate
in contralateral nonoperated neck (5% vs. 15%). No difference in DFS or OS
• Conclusion: Adjuvant postop RT doesn't improve DFS or OS; trend toward better control
• Comment: Lack of benefit ascribed to low dose of RT prescribed (see PMID 9486600 for discussion)
• MD Anderson; 1957 PMID 13403033 -- "Planned combination of surgery and radiation in treatment of advanced
primary head and neck cancers." (Maccomb WS, Am J Roentgenol Radium Ther Nucl Med. 1957
Mar;77(3):397-414.)
Post-op Chemotherapy + Radiation

• Historically, resectable locally advanced HNSCC were treated with surgery + adjuvant RT. Unfortunately,
recurrence rates were ~30%, DM rates ~25%, and 5-year OS was ~30%. Majority of recurrences were
loco-regional. Patients with SM+ did particularly poorly
• RTOG 85-03 evaluated sequential post-op cisplatin/5-FU followed by RT. There was no benefit in loco-regional
control or overall survival
• Meanwhile, early randomized data from Yale (1993) showed an LRC and DFS benefit for concurrent mitomycin
C. The LRC and DFS benefit, though without impact on OS, was confirmed in a study from Slovenia evaluating
adjuvant mitomycin C and bleomycin
• An early randomized French trial (Bachaud, 1996) demonstrated a survival benefit with concurrent cisplatin
• Concurrent cisplatin with RT was subsequently evaluated in two large randomized trials in US (RTOG 95-01) and
Europe (EORTC 22931). The EORTC trial showed significantly better LRC, DFS and OS; the RTOG trial
showed significantly better LRC and DFS without impact on OS. Patients had "high-risk" features, which
variously included SM+, LN+, ECE, PNI+, LVI+, and T3-4 disease. Joint analysis showed significant benefit for
ECE+ or SM+ disease
• Current NCCN recommendations (v2.2008) specify ECE+ or SM+ for concurrent chemo-RT; patients with
pT3-T4, pN2-N3, nodal disease in levels IV-V, PNI+ or LVI+ may be treated with RT alone or considered
individually for chemo-RT
• However, concurrent cisplatin may be reasonably toxic and a concurrent carboplatin was evaluated. Two trials
were closed early due to slow accrual; analysis of the smaller data sets revealed no impact on DFS or OS
• to be continued ...
Post-op Sequential Chemo + RT

• RTOG 85-03 / Intergroup 0034 (1984-1989) -- cisplatin/5-FU
• Randomized. 442 patients. Completely resected tumors of oral cavity, oropharynx, hypopharynx, or larynx. R2
excision not allowed. Arm 1) Post-op RT alone vs Arm 2) Post-op chemotherapy (cisplatin/5-FU x 3 courses
q3wk) followed by RT. RT dose 50-54 Gy; boost to 60 Gy for close margins (<5mm) or ECE.
• 1992 PMID 1618662 — "Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and
neck: report on Intergroup Study 0034." (Laramore GE, Int J Radiat Oncol Biol Phys. 1992;23(4):705-13.)
• Outcome: 4-year OS RT 44% vs. chemo-RT 48% (NS); DFS 38% vs. 46% (NS); LRC 70% vs. 74% (NS);
reduced first failure in neck 10% vs. 5% (SS), DM 23% vs. 15% (SS)
• Subgroup analysis of high-risk group (margins < 5mm, CIS at margin, ECE) showed a trend to
improvement in LC with chemo. So it may be important to select high-risk group to see a benefit from
chemo.
• Conclusion: No benefit for adjuvant sequential chemo-RT over RT alone
• RTOG 81-16 -- cisplatin/5-FU
• Phase I/II. Sequential chemotherapy. Two studies (A&B): A) Induction cisplatin/5-FU + surgery + RT (42
patients); B) surgery + sequential cisplatin/5-FU x3 cycles + RT (29 patients)
• 1989 PMID 2499175 — "Chemotherapy following surgery for head and neck cancer. A Radiation Therapy
Oncology Group Study." (Jacobs JR, Am J Clin Oncol. 1989 Jun;12(3):185-9.)
• Conclusion: Sequential post-op chemo-RT is feasible
• 1991 PMID 1998567 -- "5-year results of cisplatin and fluorouracil infusion in head and neck cancer." (Jacobs
JR, Arch Otolaryngol Head Neck Surg. 1991 Mar;117(3):288-91.)
• Outcome: median OS induction group 1.7 years, adjuvant group 2.6 years. 65% of induction chemo group
didn't undergo surgery as planned. 5-year OS no difference 27% vs. 23%
• Loma Linda (1979-1983) -- induction/sequential adjuvant MTX
• Randomized. 55 patients. Potentially resectable SCCHN. Arm 1) Surgery + RT vs. Arm 2) Induction MTX x4
doses then surgery then MTX x4 doses then RT then MTX x8 doses. RT 60 Gy or 65 Gy with close SM
• 1987 PMID 3806169 -- "Adjuvant methotrexate escalated to toxicity for resectable stage III and IV squamous
head and neck carcinomas--a prospective, randomized study." (Rentschler RE, J Clin Oncol. 1987
Feb;5(2):278-85.)
• Outcome: No difference in DFS or OS (numbers not given); no difference in sites of recurrence
• Conclusion: No benefit for sequential MTX
Post-op Concurrent Chemo-RT

• Slovenia (1997-2001) -- mitomycin C and bleomycin
• Randomized. 114 patients, Stage III-IV SCCHN (oral cavity, oropharynx, hypopharynx, larynx). Primary
curative surgery. Arm 1) Post-op RT (56 Gy if R0, 66-70 Gy if R1-2) vs. Arm 2) Same RT + concurrent
mitomycin C and bleomycin. Stratified in regular risk and high risk (ECE, PNI, LVI, R1-2)
• 2-years; 2003 PMID 12829141 -- "Postoperative concomitant irradiation and chemotherapy with mitomycin C
and bleomycin for advanced head-and-neck carcinoma." (Smid L, Int J Radiat Oncol Biol Phys. 2003 Jul
15;56(4):1055-62.) Median F/U 2.7 years
• Outcome: 2-year LRC chemo-RT 86% vs. RT alone 69% (SS); DFS 76% vs. 60% (NS); OS 74% vs. 64%
(SS). Benefit in high risk patients
• Conclusion: Concomitant chemo-RT with mitomycin C and bleomycin improves LRC and OS
• 5-years; 2007 PMID 17197122 -- "Patterns of failure in patients with locally advanced head and neck cancer
treated postoperatively with irradiation or concomitant irradiation with Mitomycin C and Bleomycin."
(Zakotnik B, Int J Radiat Oncol Biol Phys. 2007 Mar 1;67(3):685-90. Epub 2006 Dec 29.)
• Outcome: 5-year LRC chemo-RT 88% vs. RT alone 65% (SS), DFS 53% vs. 33% (SS), OS 55% vs. 37%
(NS). No difference in DM rate (20% vs. 22%, NS). Second malignancy chemo-RT 8% vs. RT 34% (SS)
• Toxicity: Grade 3+ chemo-RT 26% vs. RT 19% (NS), thyroid dysfunction 56% vs. 36% (NS)
• Conclusion: Concomitant chemo-RT improves LRC and DFS; second primaries less frequent
• Multi-Institutional -- Carboplatin
• Randomized. (Pittsburgh, Michigan, Cinncinati). Closed early due to slow accrual. 72 patients.
Macroscopically resected, Stage III/IV SCCHN, high risk features (SM+, >= 3 LN+, ECE, PNI, LVI). Arm 1)
post-op RT alone vs. Arm 2) post-op RT + concurrent carboplatin 100 mg/m2 QW. RT 59.4/33. Median F/U
5.3years
• 2007 PMID 18091334 -- "Long-Term Results of a Phase III Randomized Trial of Postoperative Radiotherapy
With or Without Carboplatin in Patients With High-Risk Head and Neck Cancer." (Argiris A, Laryngoscope.
2007 Dec 12 [Epub ahead of print])
• Outcome: 5-year DFS RT alone 53% vs. RT + carboplatin 41% (NS); OS 47% vs. 41% (NS)
• Toxicity: Infrequent in both arms
• Conclusion: No benefit with addition of carboplatin, possibly due to small sample size. Well tolerated.
• ARO 96-3 (Germany)(1997-2004) -- cisplatin + 5-FU
• Randomized. 440 patients with high-risk SCCA (3+ LN, ECE, SM+). Arm 1) RT alone vs. Arm 2) RT with
concurrent cisplatin/5-FU. RT 66/33. Chemo cisplatin 20 mg/m2 and 5-FU 600 mg/m2 both day 1-5 and 29-33
• 5-years; 2006 ASCO Abstract [1] -- "Postoperative concurrent radiochemotherapy versus radiotherapy in
high-risk SCCA of the head and neck: Results of the German phase III trial ARO 96-3." (Fietkau R, Journal of
Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement),
2006: 5507)
• Outcome: 5-year LRC RT 72% vs. chemo-RT 89% (SS); PFS 50% vs. 62% (SS); OS 49% vs. 58% (NS)
• Toxicity: Grade 3+ mucositis RT 13% vs. 21% (SS)
• Conclusion: Post-op concurrent chemo-RT improves LRC and PFS
• RTOG 95-01 / Intergroup (1995-2000) -- cisplatin
• Randomized. 416 patients. Oral cavity, oropharynx, larynx, hypopharynx. Macroscopically complete resection.
High risk (2 or more: LN+, ECE, or SM+). Arm 1) RT alone vs RT with concurrent cisplatin (100 mg/m2
Q3W x 3 cycles). RT 60/30 plus optional boost to 66/33 high-risk areas. High risk groups: 81% with 2+ LN;
19% with positive margins. Primary endpoint LRC.
• 2-years; 2002 Abstract #903, ASCO 2002 - Cooper et al. Video webcast [2] Video webcast: Discussion [3]
• Outcome: 2-year LRC chemo-RT 79% vs. RT 74% (NS); DFS 63% vs. 442% (SS), OS 63% vs. 57% (NS)
• Toxicity: 2% treatment-related deaths from chemo/RT.
• 2-years; 2004 PMID 15128893 — "Postoperative concurrent radiotherapy and chemotherapy for high-risk
squamous-cell carcinoma of the head and neck." (Cooper JS et al. N Engl J Med. 2004 May
6;350(19):1937-44.). Median F/U 3.7 years
• Outcome: 2 year LRC chemo-RT 82% vs. RT 72% (SS), DFS significantly increased with a HR of 0.78
(2-year estimates not reported), but OS not significantly different.
• Toxicity: acute Grade 3+ chemo-RT 77% vs. RT 34% (SS); late effects 21% vs. 17% (NS); 2%
treatment-related death, all in chemo-RT group
• Conclusion: In high risk patients, postop concurrent chemo-RT improves LRC and DFS. Toxicity is
substantially higher
• Comment: Higher percentage of patients with oropharynx primaries than EORTC trial, which may explain
why radiation alone arm did better compared to EORTC.
• EORTC 22931 (1994-2000) -- cisplatin
• Randomized. 334 patients. Oral cavity, oropharynx, hypopharynx, or larynx. T3-4 any N with negative
margins (except T3N0 of larynx); T1-2 N2-3; T1-2 N0-1 with high-risk features (ECE, SM+, PNI, LVI); or
oral cavity/oropharynx with LN+ at levels IV or V. Arm 1) RT alone vs. Arm 2) RT + concurrent cisplatin 100
mg/m2 Q3W. RT dose 54/27 + boost to 66 Gy high risk areas. High risk groups: 56% with 2+ LN; 26% with
positive margins; 53% with extracapsular extension. Primary end-point PFS.
• 5-years; 2004 PMID 15128894 - "Postoperative irradiation with or without concomitant chemotherapy for
locally advanced head and neck cancer." (Bernier J, N Engl J Med. 2004 May 6;350(19):1945-52.) Median
F/U 5 years
• Outcome: 5-year PFS chemo-RT 47% vs RT 36% (SS); OS 53% vs 40% (SS); LRC 82% vs 69% (SS). No
difference in DM rate (21% vs. 25%, NS).
• Toxicity: No difference between groups
• Conclusion: Post-op concurrent cisplatin with RT is more efficacious in locally advanced H&N, without
significantly more complications
• Comment: Patients selected on basis of both pathologic factors (surgical margin, extracapsular extension) and
clinical factors (T-stage and N-stage). Very high risk patients (T3-T4 with SM+) were excluded.
• France (1994-2002) -- carboplatin
• Randomized. Stopped early after publication of a French trial (Bachaud). 144 patients, oropharynx (49%),
hypopharynx (29%), larynx (22%), T1-4N0-3, macroscopic resection. Surgery + neck dissection. Arm 1) RT
vs. Arm 2) RT + concurrent carboplatin 50mg/m2 BIW. RT 54 Gy if R0, 72 Gy if R1, bilateral neck 54 Gy,
ECE boost 9 Gy.
• 2008 PMID 18222010 -- "Randomized clinical trial of post-operative radiotherapy versus concomitant
carboplatin and radiotherapy for head and neck cancers with lymph node involvement." (Racadot S, Radiother
Oncol. 2008 Jan 24 [Epub ahead of print]). Median F/U 8.8 years
• Outcome: 2-year LRC RT alone 68% vs. chemo-RT 73% (NS), worse for oropharynx vs. larynx; OS 55%
vs. 58% (NS)
• Conclusion: Concurrent carboplatin BIW showed no benefit
• RTOG 88-24 (1989-1990) -- cisplatin
• Phase II. 51 patients. Resectable, Stage III-IV HNSCC (oral cavity, oropharynx, hypopharynx, larynx). Stage
IV 84%, SM+ 53%. RT 60/30 with concurrent cisplatin 100 mg/m2 q3weeks.
• Compared results with historic data of sequential chemo/RT (INT 0034). No significant difference in survival
compared with INT 0034.
• 1997 PMID 9128951 -- "Postoperative radiotherapy with concurrent cisplatin appears to improve locoregional
control of advanced, resectable head and neck cancers: RTOG 88-24." (Al-Sarraf M, Int J Radiat Oncol Biol
Phys. 1997 Mar 1;37(4):777-82.)
• Outcome: 3-year OS 48%, LRC 81%, DM-free 57%
• Toxicity: Grade 3 20%, Grade 4 12%
• Conclusion: Post-op concurrent cisplatin with RT may improve LRC
• France (1984-88) -- cisplatin
• Randomized. Closed early due to slow accrual due to increasing use of neoadjuvant chemotherapy. 83
patients. Stage III-IV oral cavity, oropharynx, hypopharynx, larynx, or unknown primary, LN+ with ECE. Arm
1) RT alone vs. Arm 2) RT + cisplatin 50 mg/m2 QW. RT 65-70 Gy (1.7 Gy/fx), neck 54 Gy
• 1996 PMID 8985019 — "Combined postoperative radiotherapy and weekly cisplatin infusion for locally
advanced head and neck carcinoma: final report of a randomized trial." (Bachaud JM et al. Int J Radiat Oncol
Biol Phys. 1996 Dec 1;36(5):999-1004.)
• Outcome: LRF RT alone 41% vs. chemo-RT 23% (p=0.08), similar DM rate, 2-year OS 46% vs. 72% (SS),
5-year OS 13% vs. 36% (SS)
• Severe late toxicity: RT alone 15% vs. chemo-RT 20%
• Conclusion: Improved survival with concurrent cisplatin
• Yale (1980-92) -- Mitomycin C
• Randomized. 2 consecutive randomized trials. 113 patients, treated with surgery. Arm 1) RT vs. Arm 2) RT
with concurrent Mitomycin C 15 mg/m2 x 1-2 doses. Second trial: Arm 1) RT vs. Arm 2) RT + Mitomycin C
with dicoumarol.
• 5-years; 1993 PMID 7691784 -- "Mitomycin C as an adjunct to postoperative radiation therapy in squamous
cell carcinoma of the head and neck: results from two randomized clinical trials." (Haffty BG, Int J Radiat
Oncol Biol Phys. 1993 Sep 30;27(2):241-50.) Median F/U 7.7 years
• Outcome: LRC mitomycin C 87% vs. control 67% (SS), DFS 67% vs. 44%, OS 56% vs. 41% (NS). No
local failures in Mitomycin C arm vs. 12 in RT alone
• Conclusion: Concurrent Mitomycin C with RT results in improved DFS, and LRC benefit
Pending
• RTOG 02-34 (ongoing) - A phase II randomized trial of surgery followed by chemoradiotherapy plus C225
(cetuximab) for advanced squamous cell carcinoma of the head and neck.
• RTOG H-0024 (Closed) - early chemo followed by chemo/RT
• Taxol (80 mg/m2) within postop day 7-14. RT on week 4 to 60 Gy over 6 weeks. During last 3 weeks,
cisplatin (20 mg/m2) + taxol (30 mg/m2) weekly.
Pathologic N1 Disease
• Louvain, Belgium; 2009 (1990-2002) PMID 18648835 -- "Results of selective neck dissection in the primary
management of head and neck squamous cell carcinoma." (Schmitz S, Eur Arch Otorhinolaryngol. 2009
Mar;266(3):437-43. Epub 2008 Jul 22.)
• Retrospective. 146 patients, unilateral/bilateral selective neck dissection in 249 necks. Median F/U 3.1 years
• Outcome: 25% cN0 patients were pN+. Regional recurrence 3% overall, dissected 2% and undissected 1%.
pN0 failure rate 1%. pN1 failure rate without PORT 9% vs with PORT 5%. ECE in 16%, almost all treated
with PORT, but failure rate still 22%
• Conclusion: Selective node dissection reliable to stage cN0 neck, and as definitive operation for pN0, most
pN1 and pN2b necks. PORT not justified for pN1 but justified for pN2b and ECE
• Gottingen, Germany; 2008 (1986-2002) PMID 18302275 -- "Value of postoperative radiotherapy in patients
with pathologic N1 neck disease." (Jackel MC, Head Neck. 2008 Jul;30(7):875-82.)
• Retrospective. 118 patients, H&N cancer, curative surgery, pN1 disease with ECE. Majority had selective neck
dissection (Level II-III 63%, Level I-III 19%, Level II-IV 15%). Postop RT in 20%, postop chemo-RT 19%;
less postop therapy since 1995.
• Outcome: Regional control: Isolated nodal failure 7% (surgery 10% vs. postop RT 2%), all nodal failures 16%
(21% vs. 9%). 3-year neck reccurence rate surgery alone 11% vs. postop RT 3% (NS)
• Conclusion: Data suggest a trend to improved regional control for pN1 with postop RT
Radiation technique
High-risk groups
• Historical risk factors: Primary disease site (PMID 5014916), surgical margins (PMID 755803), perineural
invasion (PMID 476992), number and location of positive nodes (PMID 1015542), extracapsular extension
(PMID 7316852)
• Peters: Risk factors included oral cavity, close or positive margins, nerve invasion, 2 or more positive nodes,
largest node > 3 cm, extracapsular extension, Zubrod score 2 or more, delay in starting radiotherapy of more than
6 weeks.
• Intermediate risk - 1 risk factor, excluding ECE
• High risk - 2 or more factors, or ECE
• Joint RTOG 85-03 and 88-24 analysis:
• Intermediate risk - extracapsular extension or 2+ involved lymph nodes
• High risk - positive surgical margin
• Joint EORTC/RTOG analysis:
• High risk - Extracapsular extension or positive surgical margin
• Current treatment recommendations (NCCN v2.2008)
• Postoperative RT: pT3-pT4, N2-N3 nodal disease, nodal disease in Levels IV or V, perineural invasion,
lymphovascular invasion
• Postoperative chemo-RT (cisplatin 100 mg/m2 Q3W): extracapsular extension, positive surgical margins, also
consider based on clinical data for patients as above for postop RT
• EORTC / RTOG Joint Analysis; 2005 PMID 16161069 — "Defining risk levels in locally advanced head and
neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the
EORTC (#22931) and RTOG (# 9501)." (Bernier J, Head Neck. 2005 Oct;27(10):843-50.)
• Retrospective subgroup analysis of combined data from postop chemo-RT trials EORTC 229131 and RTOG
9501. Both trials concomitant cisplatin 100 mg/m2 Q3W and RT 60-66 Gy. Difference in "high-risk": EORTC
SM+ , ECE, clinical involvement of Level IV-V from oral cavity/oropharynx primary, perineural disease, or
vascular embolism vs. RTOG SM+, ECE, 2+ LN. Difference in endpoints: EORTC PFS vs RTOG LRC.
Difference in dose: EORTC 66 Gy in 91% vs RTOG 66 Gy in 13%.
• Risk factors: ECE or SM+ had negative impact on OS. No other factors (2+ lymph nodes, PNI+, LVI+, Stage
III-IV disease) showed benefit
• LRC: Pooled risk reduction 42% (SS). If SM+/ECE+, risk reduction 48%. If other factors, reduction not
significant (EORTC 58%, p=0.1; RTOG 18%, p=0.5)
• DFS: Poled risk reduction 23% (SS). If SM+/ECE+, risk reduction 30%. If other factors, reduction not
significant (EORTC 25%, p=0.3; RTOG 8%, p=0.7)
• OS: Pooled risk reduction 28% (SS). If SM+/ECE+, risk reduction 26% (SS). If other factors, reduction not
significant (EORTC 25%, p=0.06; RTOG 6%, p=.07)
• Conclusion: Significant benefit for chemo-RT over RT in patients with extracapsular extension or SM+, but
benefit not significant for 2+ lymph nodes, PNI+, LVI+ or Stage III-IV disease
• RTOG 8503/8824 Joint Analysis - PMID 9744457 — "Precisely defining high-risk operable head and neck
tumors based on RTOG #85-03 and #88-24: targets for postoperative radiochemotherapy?" (Cooper JS, Head
Neck. 1998 Oct;20(7):588-94.)
• Retrospective. Data collected from RTOG 85-03 (INT 0034) and RTOG 88-24, which were sequential and
concurrent chemo-radiotherapy trials for post-op H&N cancers
• New risk factors grouping: Group 1: no risk features; Group 2: 2+ lymph nodes or ECE; Groups 3: SM+
• Outcome: 5-year LRR 17% vs. 27% vs 61%; Median OS 5.6 years vs. 2.6 years vs. 1.5 years
• Conclusion: Suggested benefit for concurrent chemo-radiotherapy with a 50% decrease in local-regional
recurrence, but only a small increase in survival (18% reduction in death rate).
Radiotherapy dose
• Fletcher: 60 Gy
• Peters, 1993: 63 Gy for ECE+, otherwise 57.6 Gy
• RTOG 9501: 60 Gy +/- 6 Gy boost (given in 13%)
• EORTC 22931: 66 Gy to high risk region, 54 Gy to large field
• Recommendations (NCCN v2.2008):
• Primary: >= 60 Gy in 2 Gy/fx
• Involved nodal stations: >= 60 Gy in 2 Gy/fx
• Uninvolved nodal stations: >= 50 Gy in 2 Gy/fx
• Fletcher recommended 50 Gy in 25 fractions to control microscopic disease in an undissected neck. But Fletcher
recommended 60 Gy in 30 fractions for a post-operative neck because of hypoxia due to disturbed vascular
supply (in the Textbook of Radiotherapy, 2nd edition).
• Peters (M.D. Anderson), 1993 (1983-91) - PMID 8482629 — "Evaluation of the dose for postoperative radiation
therapy of head and neck cancer: first report of a prospective randomized trial." Peters LJ et al. Int J Radiat Oncol
Biol Phys. 1993 Apr 30;26(1):3-11.
• Purpose: 1) define groups with high and low risk for recurrence, 2) determine the optimal radiotherapy dose, 3)
study the dose-response relationship for normal tissue injury
• Randomized. 302 pts. (report based on 240 pts). Eligible pts: oral cavity, oropharynx, hypopharynx, larynx, or
unknown primary. Used a points system to assign pts to low or high risk. Low-risk pts randomized between
57.6 Gy and 63 Gy. (originally randomized to 52.2-54 Gy as well, but this arm was dropped.) High-risk pts
randomized between 63 Gy and 68.4 Gy. All gross tumor had to be removed but + margins allowed. 54 Gy
was given to surgically undisturbed sites with subclinical disease (i.e. contralateral neck) or putative sites of
unknown primary. 57.6 Gy to dissected but pathologically negative neck. The randomized dose was given to
the pathologically involved neck and primary — separate randomized doses to neck and primary, but when the
primary site was randomized to a higher dose, it took precedence; if neck was to receive higher dose than the
primary, then neck boosted with electrons to the higher dose.
• Disease control by dose: 2-year loco-regional recurrence rate of 26%. Disease-specific survival continued to
decline up to about 5 years due to metastatic disease or second primary tumor. Low risk pts receiving <= 54
Gy had a higher primary failure rate than those with >= 57.6 Gy; no increase in control with doses above 57.6
Gy. Also, the point system they used did not accurately predict for recurrence since high and low risk pts
receiving the same dose had the same LF rate.
• Analysis of prognostic factors: analyzed a subset of 199 pts who received at least 57.6 Gy. Only independent
risk factor was extracapsular extension; more than 1 positive LN was of borderline significance. Also a cluster
of 2 or more risk factors was associated with worse prognosis. Crude recurrence rate was 20-30% if ECE+ but
only 5-13% if ECE- and fewer than 4 other risk factors. With 4 or risk factors other than ECE, did just as bad
as with ECE.
• Dose response for high risk group: for pts with ECE, 2-yr control rate was 52% for 57.6 Gy vs 74% for 63 Gy.
No added benefit for 68.4 Gy.
• Conclusions: 57.6 Gy is adequate dose for post-op RT without extracapsular extension; 63 Gy for pts with
ECE.
• See list of risk factors used in this paper (separate section above).
Alternative Fractionation
• Evidence for intensifying RT through accelerated fractionation/hyperfractionation after surgery is not strong
• Some benefit might be seen in patients who delay start of RT >7 weeks, but this is on subset analysis
• Balanced against this is the fact that toxicity typically tends to be significantly higher
• Sklodowska-Curie Cancer Center, Poland (2001-2004) -- conventional RT 5-days/week vs. accelerated RT
7-days/week
• Randomized. 279 patients, high-risk SCC larynx (57%) vs. oral cavity/oropharynx (43%). High risk
determined by score using tumor site, SM status, SM width, LVI, grade, number of LN+, ECE, and LN grade.
Surgery + lymph node dissection. Arm 1) Conventional RT 63/35 over 7 weeks vs. Arm 2) Accelerated RT
63/35 over 5 weeks
• 2008 PMID 18342964 -- "Randomized clinical trial on 7-days-a-week postoperative radiotherapy for high-risk
squamous cell head and neck cancer." (Suwinski R, Radiother Oncol. 2008 May;87(2):155-63. Epub 2008 Mar
14.)
• Outcome: 3-year LRC CF 64% vs. CAIR 70% (NS). Planned subset analysis oropharynx/oral cavity 53%
vs. 74% (SS), larynx 72% vs. 67% (NS). LC 73% vs. 81% (NS); neck control 81% vs. 83% (NS). 3-year
OS 52% vs. 55% (NS)
• Toxicity: Confluent mucositis CF 33% vs. CAIR 60%, but considered acceptable. Late toxicity Grade 3-4
CF 6% vs. 13%
• Conclusion: Improvement in LRC restricted to patients with oropharynx/oral cavity; no benefit in patients
with larynx
• Italy Multi-Institutional (1994-2001) -- conventional 60/30 vs. accelerated concomitant boost 64/35
• Randomized. 226 patients, locally advanced oral cavity, oropharynx, larynx, or hypopharynx, with high-risk
features (pT4, SM+, N2-3, PNI+, LVI+, ECE+, subglottic extension) after surgery. Arm 1) conventional RT
60/30 vs. Arm 2) accelerated RT "biphasic concomitant boost" during first/last week to deliver 64 Gy over 5
weeks. Primary endpoint LRC
• 2005 PMID 15708255 -- "Accelerated versus conventional fractionated postoperative radiotherapy for
advanced head and neck cancer: results of a multicenter Phase III study." (Sanguineti G, Int J Radiat Oncol
Biol Phys. 2005 Mar 1;61(3):762-71.) Median F/U 2.5 years
• Outcome: 2-year LRC CF 80% vs. AF 78% (NS), trend to benefit for patients with RT delay >7 weeks.
2-year OS 67% vs. 64% (NS)
• Toxicity: Confluent mucositis CF 27% vs. AF 50% (SS), duration same. Late toxicity 18% vs. 27% (NS),
though data preliminary
• Conclusion: Accelerated fractionation not beneficial overall, might be option for patients who delay starting
RT
• MDACC/Mayo/Moffitt (1991-1995) -- risk adapted; conventional 63/35 in 7 weeks vs. accelerated 63/35 in 5
weeks
• Risk adapted, part randomized. 213 patients, oral cavity, oropharynx, larynx, hypopharynx. Risk factors ECE,
>1 nodal group, >=2 LN+, >3-cm LN, oral cavity, SM+, PNI+ (Peters 1993)
• Low risk (no risk factors): no RT
• Intermediate risk (1 risk factor, excluding ECE): conventional RT 57.6/32
• High risk (ECE or 2+ risk factors): randomized Arm 1) conventional RT 63/35 in 7 weeks vs. accelerated
RT 63/35 in 5 weeks concomitant boost. Undissected neck received 54 Gy and dissected but negative neck
57.6 Gy.
• 2001 PMID 11597795 — "Randomized trial addressing risk features and time factors of surgery plus
radiotherapy in advanced head-and-neck cancer." (Ang KK, Int J Radiat Oncol Biol Phys. 2001 Nov
1;51(3):571-8.) Median F/U 4.9 years

• Outcome: 5-year LRC low risk patients 90% vs. intermediate risk patients 94% vs. high risk patients 68%
(SS). High risk CF ~60% vs. AF ~75% (NS). 5-year OS low risk 83% vs. intermediate risk 66% vs. high
risk 42%, CF ~35% vs. AF ~50% (NS)
• Treatment time: 5-year LRC <11 weeks 76% vs. >11 weeks 62% vs >13 weeks 38% (SS); 5-year OS 48%
vs. 27% v. 25% (SS). Surgery-RT interval >6 weeks detrimental
• Conclusion: Risk stratification appropriate. Accelerated fractionation better for patients with delay >6
weeks of starting RT, combined treatment time should be <11 weeks
• Cairo, Egypt -- conventional RT 60/30 vs. accelerated RT 46.2/33 TID in 2 weeks
• Randomized. 70 patients, T2N1-2 or T3-4 any N, s/p radical surgery. Arm 1) conventional RT 60/30 vs. Arm
2) accelerated RT 46.2/33 TID over 2 weeks
• 2002 PMID 11870530 -- "Accelerated hyperfractionation (AHF) compared to conventional fractionation (CF)
in the postoperative radiotherapy of locally advanced head and neck cancer: influence of proliferation."
(Awwad HK, Br J Cancer. 2002 Feb 12;86(4):517-23.)
• Outcome: 3-year LRC AHF 88% vs. CF 57% (SS), 3-year OS 60% vs. 46% (NS). No benefit for T(pot)
evaluation on multivariate analysis, though rapid tumors higher risk of DM. Surgery-RT gap shouldn't
exceed 6 weeks
• Toxicity: acute mucositis more severe in AHF, fibrosis and late edema also worse in AHF
• Conclusion: Accelerated hyperfractionation improved local control, but without survival impact
• Cairo, Egypt -- conventional RT 50/25 vs. accelerated RT 42/30 TID in 11 days
• Randomized. 56 patients, locally advanced HNSCC, s/p radical surgery. Arm 1) conventional RT 50/25 vs.
Arm 2) accelerated RT 42/30 TID over 11 days
• 1992 PMID 1480771 -- "Accelerated versus conventional fractionation in the postoperative irradiation of
locally advanced head and neck cancer: influence of tumour proliferation." (Awwad HK, Radiother Oncol.
1992 Dec;25(4):261-6.)
• Outcome: 3-year DFS 46%, no difference between arms. AHF better survival in fast growing tumors
(thymidine labeling index >10.4%)
• Toxicity: Acute toxicity higher in AF arm, but 3-year late toxicity CF 87% vs. AF 64% (SS)
• Conclusion: No survival benefit for AF overall, but benefit in faster growing tumors
Overall treatment time

• Based, in part, on the fact that overall treatment time for intact head & neck cancers influences outcome and the
theory of accelerated repopulation. (Withers' data - Radiobiology).
• Overall treatment time should be less than 100 days.
• RT should begin within 6 weeks of surgery
• University of Pennsylvania; 2002 (1992-97) - PMID 11891941 — "Importance of the treatment package time in
surgery and postoperative radiation therapy for squamous carcinoma of the head and neck." Rosenthal DI et al.
Head Neck. 2002 Feb;24(2):115-26.
• Retrospective. 208 pts.
• Overall package time (>= vs < 100 days) was significant on multivariate analysis.
• Rouen, France; 2001(1981-92) - PMID 11163507 — "Influence of the delay of adjuvant postoperative radiation
therapy on relapse and survival in oropharyngeal and hypopharyngeal cancers." Bastit L et al. Int J Radiat Oncol
Biol Phys. 2001 Jan 1;49(1):139-46.
• Retospective. 420 pts.
• Surgery to radiotherapy interval was not a significant predictor for failure.
• Florida; 1997 (1964-94) - PMID 9300748 — "An analysis of factors influencing the outcome of postoperative
irradiation for squamous cell carcinoma of the oral cavity." Parsons JT et al. Int J Radiat Oncol Biol Phys. 1997
Aug 1;39(1):137-48.
• Oral cavity.
• Improved local control for the unfavorable group if overall "package time" (i.e. from surgery to end of
radiotherapy) was within 100 days. For surgery to XRT interval (cutoff: 45-50 days), there was a
nonsignificant trend. Also a trend for shorter duration of RT.
• Memorial Sloan Kettering; 1990 (1975-80) - PMID 2325418 — "Impact of the time interval between surgery
and postoperative radiation therapy on locoregional control in advanced head and neck cancer." Schiff PB et al. J
Surg Oncol. 1990 Apr;43(4):203-8.
• Retrospective. 111 pts. Examined time from surgery to start of RT (S-R interval).
• Of 50 pts with S-R interval of 6 weeks or more, 11 (22%) had a local recurrence. 8 of these 11 had RT dose <
56 Gy. Of 17 pts with a delay of 6 weeks who had at least 60 Gy, only 2 (12%) had LR. For those who started
RT within 6 weeks and had at least 60 Gy, 3/20 (15%) had a LR. The effect of delay was significant only in
those who had < 60 Gy.
• Conclusion: prolonged delay in starting RT does not by itself have a negative impact if doses of 60 Gy or more
are given.
Reviews
• 2003 PMID 12560449 - "Does delay in starting treatment affect the outcomes of radiotherapy? A systematic
review." Huang J et al. J Clin Oncol. 2003 Feb 1;21(3):555-63.
• Increased LRR for starting RT > 6 wks after surgery (OR = 2.89).
• 1998 PMID 9676534 Full text (PDF) [4], 1998 — "Adjuvant therapy in head and neck cancer." Vikram B et al.
CA Cancer J Clin. 1998 Jul-Aug;48(4):199-209.
References
[2] http:/ / play. rbn. com/ play. ram?url=irbs/ RBNCRM/ ASTRO/ g2demand/ plenary/ play91. smil& mode=compact& proto=rtsp
[4] http:/ / caonline. amcancersoc. org/ cgi/ reprint/ 48/ 4/ 199
Radiation Oncology/Head & Neck/Nasopharynx/

Staging
Nasopharynx Cancer Staging
Staging
AJCC 6th edition:
Tumor
• T1 - confined to nasopharynx
• T2 - extends to soft tissues
• T2a - extends to oropharynx and/or nasal cavity without parapharyngeal extension
• T2b - any tumor with parapharyngeal extension (i.e. beyond the pharyngobasilar fascia)
• T3 - involves bony structures and/or paranasal sinuses
• T4 - intracranial extension and/or involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit, or
masticator space
Nodes
• N1 - unilateral nodes, 6 cm or less, above the supraclavicular fossa
• N2 - bilateral nodes, 6 cm or less, above the supraclav fossa
• N3a - lymph node greater than 6 cm
• N3b - extension to the supraclav fossa (defined as the triangular region described by Ho, bounded by the superior
margin of the sternal head of the clavicle, the superior margin of the lateral end of the clavicle, and the point
where the neck meets the shoulder. This includes some of level IV as well as V.)
Overall stage
• I - T1 N0
• IIA - T2a N0
• IIB - T1-T2 N1, T2b N0 (i.e. T2b or N1)
• III - T3 N0-2, or T1-3 N2 (i.e. T3 or N2)
• IVA - T4 N0-2
• IVB - N3
• IVC - M1
Notes
• Division of Stage II into A and B compared to other H&N sites
• Shift of more advanced N-stages into lower stage groupings — N1 is stage II instead of III, N2 is III instead of IV
• Retropharyngeal nodes staging has been controversial, since CT is often unable to differentiate them from
parapharyngeal involvement of primary tumor. However, MRI appears more sensitive, and patients who are N0
but with positive RLN by MRI have prognosis similar to patients with N1 disase as should probably be classified
as such
Older staging systems
AJCC 5th edition (1997)

• same as 6th edition
AJCC 4th edition (1988):

• T1 - tumor confined to one wall of the nasopharynx
• T2 - two walls or more
• T3 - extension to oropharynx and nasal cavity
• T4 - invades skull base or cranial nerve
• N1 - single ipsilateral node <= 3 cm
• N2a - single ipsilateral node 3-6 cm
• N2b - multiple ipsilateral nodes < 6 cm
• N2c - contralateral or bilateral nodes < 6 cm
• N3 - nodes > 6 cm
Overall stage:
• I - T1 N0
• II - T2 N0
• III - T3 or N1
• IV - T4 or N2-3 or M1
(similar to other H&N sites in newest staging system)
• Note: downstaging of disease in AJCC 4th edition — N1 was moved to Stage II and N2 was moved to Stage III.
This is an important difference to note when comparing older trials to newer treatment modalities since the
definition of "advanced stage" has changed.
Chinese Staging (1992)

• T1 - nasopharynx only
• T2 - nasal cavity, oropharynx, soft palate, anterior cervical vertebrae soft tissue, proximal parapharyngeal space
• T3 - distal parapharyngeal space, CN involvement, base of skull, pterygoprocss zone, pterygopalatine fossa
• T4 - multiple CN involvement, paranasal sinus, cavernous sinus, orbit, infratemporal fossa, or C1-C2 vertebra
• N0 - no nodes
• N1 - upper cervical LN <4cm
• N2 - lower cervical LN, or 4-7 cm
• N3 - SCV, or >7cm, or fixed, or skin infiltration
Staging:
• I - T1N0
• II - T2 or N1
• III - T3 or N2
• IVA - T4 or N3
• IVB - M1
Ho's Staging (1978)

• T1 - nasopharynx only
• T2 - extension to nasal fossa, oropharynx, or parapharyngeal region
• T3 - bony involvement, skull base, cranial nerve palsy, orbits, laryngopharynx, or infratemporal fossa
• N0 - no nodes
• N1 - above laryngeal cartilage
• N2 - below laryngeal cartilage but above SCV fossa
• N3 - SCV lymph nodes

Overview
Nasopharyngeal Cancer Overview
Epidemiology
• Markedly different geographical prevalence
• Rare in the US: 0.2-0.5 cases per 100,000 people
• Common in China, Hong Kong and Taiwan: 25-50 per 100,000. Accounts for ~5% of all cancers and ~50% of
H&N cancers in Taiwan
• Also common in North Africa, the Middle East, and in Inuits
• Association with salted fish, Ebstein-Barr virus
• Smoking and alcohol don't have a clear association with the disease
• In general, affects a younger population
• Up to 90% present with N+ disease, and ~50% have bilateral N+ disease
Anatomy
• Includes vault, lateral walls, and posterior wall
• Anterior border begins at the end of the nasal cavity, at the posterior choana (where nasal septum disappears).
Radiographically this can be seen as the posterior wall of the maxillary sinus. It extends along plane of the airway
to the level of free border of the soft palate posteriorly
• Lateral walls consist of the torus tubarius (Eustachian tube opening), pharyngeal recess (Fossa of Rosenmuller)
posterior to torus tubarius, and behind these are the superior pharyngeal constrictor muscles, and behind this is the
medial pterygoid plate.
• Superior border is the cribriform plate and sphenoid sinus. Clivus consists of part of the sphenoid bone (behind
the sinus, the tail end of the sella turcica) and part of the occipital bone and forms the posterior border of the
nasopharynx. Hard and soft palates (the inferior border) sits about C2.
• Eustachean tube passes through base of skull between foramen ovale and lacerum to reach nasopharynx
• Inferior border (floor) is the superior surface of the soft palate
• Cranial nerves are important since NPC may commonly extend along them intracranially:
• Cavernous sinus - III, IV, V1 + V2 (not V3), VI - (all pass through superior orbital fissure except V2 is
through foramen rotundum)
• Foramen rotundum - V2
• Foramen ovale - V3 - anterolateral to clivus
• Foramen lacerum - lateral to front part of clivus - plugged with cartilage in vivo
• Jugular foramen - IX, X, XI - lateral to foramen magnum
• Hypoglossal canal - XII - lateral to foramen magnum
• Nearby is the tensor veli palatini, levator veli palatini
• Pharyngeal recess (Fossa of Rosenmuller)
• Postulated to be the origin of most NPC cancers
• Posterior to torus tubaris (posterior lip of the medial end of the cartilagenous eustachean tube)
• Herniation of nasopharyngeal mucosa through deficiency between skull base and superior-most fibers of
pharyngeal constrictors
• PMID 1876886 (Full text for pictures [1]): >50% are deeper than 1 cm (range 2mm - 19mm), and 90% are
narrower than 5 mm. It points lateraly ~45% from sagittal plane
Pathology
WHO classification:
• Type 1: squamous cell carcinoma (often referred to as keratinizing) - 20%
• Type 2a: non-keratinizing carcinoma (NKC). The differentiated form is sometimes called transitional cell
carcinoma. - 30-40%
• Type 2b: undifferentiated carcinoma (lymphoepithelioma is a subtype) - 40-50%
Spread
• Spreads along walls of nasopharynx with local invasion
• Can spread to cavernous sinus through foramen lacerum (and involve CN III-VI [except V3]).
• Commonly has involvement of jugular foramen and hypoglossal canal (CN IX-XII).
• 65-90% have lymph node involvement at presentation
• About 50% have bilateral lymph node involvement
• Cervical Level IIb seem to be the first echelon nodes in NPC, closely followed by lateral retropharyngeal LNs
• Retropharyngeal LN involvement is common, but difficult to detect on CT. In CT based studies, RLN were
positive in 30-50%, while in MRI based studies this number may be as high as 80%
• Distant mets are less common at initial presentation but in recurrent disease are more common than in other H&N
cancers.
• Mets correlate more with nodal status than T stage.
• Distant Mets by N stage: N1=10-20%, N2=30-40%, N3=40-70%.
• Spreads to bones > lungs, liver, and brain.
Retropharyngeal lymph nodes

• It is not clear whether these are staged as N0 or N1, with differences among institutions
• Prognosis for RLN+ N0 appears comparable to N1
• RLNs atrophy with age, and are usually obliterated by adulthood. Normal axial diameterin patients >40 year is ~3
mm. Therefore, some studies use minimal axial diameter >=5 mm on MRI as a size crietrion for RLN mets
• Most RLN+ are located at C1 level, and incidence decreases steadily from C1 to C3
• It appears that afferent lymphatic vessels of lateral RLN in NPC begin in the parapharyngeal space (T2 tumors);
lymphatic drainage of nasal cavity, oropharynx, and pharyngeal wall (and thus lymphatic drainage of T3 and T4
tumors) may be primarily to cervical lymph nodes
• Singapore; 2009 (1992-1994) PMID 19189339 -- "Retropharyngeal nodal metastasis related to higher rate of
distant metastasis in patients with N(0) and N(1) nasopharyngeal cancer." (Tham IW, Head Neck. 2009 Feb 2.
• Retrospective. 667 patients, NPC, Stage T2-4 N0-1. RLN+ in 47% by CT. Median F/U 8.3 years
• Outcome: Patients with N0 and RLN+ had similar hazard for DM as patients with N1, and worse than patients
with N0 and RLN-
• Conclusion: Patients with N0 disease and RLN lymph nodes share similar prognosis as patients with N1
disease
• Fudan, China; 2009 PMID 18538502 -- "Patterns of retropharyngeal node metastasis in nasopharyngeal
carcinoma." (Wang XS, Int J Radiat Oncol Biol Phys. 2009 Jan 1;73(1):194-201. Epub 2008 Jun 4.)
• Retrospective. 618 NPC patients. MRI staging. LN+ in 88%; RLN+ alone 6%, cervical LN+ alone 28%, both
RLN and cervical LN 66%. Incidence of RLN lower 72% than cervical LN 93%
• Location of RLN: occipital bone 6%, C1 76%, C2 17%, C3 0.5%. Incidence significantly higher with
parapharyngeal involvement
• Conclusion: Level IIb LNs seems first-echelon nodes in NPC; incidence of RLN mets decreases steadily in
level
• Sun Yat-sen, China; 2007 PMID 17332287 -- "Retropharyngeal lymph node metastasis in nasopharyngeal
carcinoma: prognostic value and staging categories." (Ma J, Clin Cancer Res. 2007 Mar 1;13(5):1445-52.)
• Retrospective. 749 patients, NPC. RLN+ in 51% by CT
• Outcome: On multivariate analysis, in N0 patients, RLN+ independent predictor for OS, LRFS and DMFS. No
difference in unilateral vs bilateral RLN+. Survival if N0 and RLN+ similar to survival if N+
• Conclusion: RLN mets affect prognosis in N0 patients, and should be classified as N1
Response to treatment
Despite rapid response to initial treatment, high incidence of local failure.
Treatment Overview
• Surgery plays only a minimal role due to significant potential morbidity
• Historically, RT alone was used, and resulted in 5-year OS 35-50%
• Early-stage (I-II) outcomes were good, with 5-year RFS 75-95% and OS 70-80%
• However, advanced-stage (III-IV) 5-year RFS was ~50%, and OS only 10-40%
• Early stage disease (Stage I-II) typically continues to be managed with RT alone
• Advanced stage disease (Stage III-IV) is managed with concurrent chemo-RT; it is not clear whether there is any
benefit to further adjuvant chemotherapy
Surgery
• Due to deep location of nasopharynx, and anatomic proximity to critical structures, radical surgery is typically not
used
• Role of surgery is initially for biopsy for histological confirmation
• It may also be used for management of the neck for persistently enlarged lymph nodes
• Finally, there may be role in persistent or recurrent disease
References
[1] http:/ / smj. sma. org. sg/ 3203/ 3203a9. pdf

Early Stage
Nasopharyngeal Cancer - Early Stage
Overview
• Early-stage (I-II) outcomes are good with radiation alone
• 5-year RFS is 75-95% and OS is 70-80%
• Most historical series use 2D radiation, but several reports with a short follow up show good outcomes with
IMRT
• IMRT in particular has significantly better sparing of the objective (stimulated/unstimulated flow) parotid
function in a randomized setting
• Dose tends to be 66-72 Gy in 2 Gy/fraction; elective sites receive 50-60 Gy using dose painting
Radiotherapy alone
• Taiwan; 2005 (1983-1998) PMID 15936544 -- "Treatment outcomes and late complications of 849 patients with
nasopharyngeal carcinoma treated with radiotherapy alone." (Yeh SA, Int J Radiat Oncol Biol Phys. 2005)
• Retrospective. 849 consecutive NPC patients (Stage I 6%, Stage IIA 3%, Stage IIB 35%, Stage III 32%, Stage
IVA 19%, Stage IVB 5% by AJCC-5), WHO type I 1%, II 62%, type III 37%. RT median 70 Gy, if BT boost
median 74 Gy
• Outcome: 5-year OS 59%, DFS 52%; OS by Stage: I 82%, II 72%, III 55%, IVA 42%, IVB 39%
• Toxicity: xerostomia 90%, hearing impairment 54%, tinnitus 52%, Lhermitte's sign 21%, trismus 12%,
temporal necrosis 6%
• RTOG (Marcial et al) - PMID 6993442 (no abstract) — complete response to local tumor, 96% for T1, 88% for
T2, 81% for T3, and 74% for T4. For N+ neck, ranged from 93% to 71%. 5-year survival overall was 40%.
Altered fractionation
• RTOG 71-03 (1971-1979)
• Randomized. 121 patients. All Stages. Arm 1) split course RT (30/10, 3 week rest, 30/10) vs. Arm 2) 66/33 or
66/30
• 1980 PMID 6993442 -- "Split-course radiation therapy of carcinoma of the nasopharynx: results of a national
collaborative clinical trial of the Radiation Therapy Oncology Group." (Marcial VA, Int J Radiat Oncol Biol
Phys. 1980 Apr;6(4):409-14.)
• 5-year outcome: LC 86% vs. 80% (NS), LRC 86% vs. 78% (NS), DFS 40% vs. 30% (NS)
• Late toxicity: comparable, except edema worse with continuous RT (42% vs. 24%)
• Conclusion: No difference between fractionation schedules, less social impact with split course
• Wang et al. - PMID 2720596 — Not randomized. Accelerated hyperfractionation (twice a day). Compared to
similar stage patients treated with once a day XRT, and 5-year local control for T1-2 was 89% (hyperfract) vs
55%, and 77% vs 45% for T3-4.
Treatment Technique
Use of IMRT
• UCSF experience
• 2000 PMID 11020568 — "Three-dimensional intensity-modulated radiotherapy in the treatment of
nasopharyngeal carcinoma: the University of California-San Francisco experience." Sultanem K et al. Int J
Radiat Oncol Biol Phys. 2000 Oct 1;48(3):711-22.
• 65-70 Gy to GTV (including + LN), 60 Gy to CTV, 50-60 Gy to the negative neck. Treated at 1.8 Gy per
day to CTV and neck and 2.12-2.25 Gy/day to GTV. CTV consisted of entire nasopharynx, posterior 1/3 of
nasal cavity and maxillary sinuses, retropharyngeal LN region, clivus, skull base, pterygoid fossae,
parapharyngeal space, inferior sphenoid sinus.
• 4-year local PFS was 97%, local-regional PFS 98%, and DM-free rate 66%. 4-year OS 88%
• 2002 PMID 12007936 — "Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an
update of the UCSF experience." Lee N et al. Int J Radiat Oncol Biol Phys. 2002 May 1;53(1):12-22.
• 2004 Dose constraints PMID 15183492
• First group of pts treated with IMRT for the primary tumor and conventional fields for the lymph nodes.
This group retrospectively reviewed to determine dose endpoints to critical normal structures. Second group
of pts treated with IMRT to both primary and nodes. Based on dose endpoints defined, new plans were
developed for the second group of pts and compared to the original plans.
• Prescription dose 70 Gy at 2.12 Gy/fx (33 fx) to GTV, 59.4 Gy at 1.8 to PTV.
UCSF IMRT Dose Constraints

Organ Max T1-T2 T3-T4 Organ Limit T1-T2 T3-T4
Serial Organs
Chiasm max 27.5 42.7 Chiasm 5% 21.5 36.4
Spinal cord max 38.3 42.2 Spinal cord 1mL 30.6 33.0
Brainstem max 50.9 55.3 Brainstem 5% 40.4 43.1
Optic nerve 23.7 41.6 Optic nerve 5% 22.2 34.4
Eye 25.0 32.8 Eye 5% 13.5 21.9
Parallel Organs
Parotid mean 26.8 27.8 Parotid 50% 25.1 24.6
TMJ mean 33.8 38.0 TMJ 50% 30.5 36.7
Ear mean 41.4 49.6 Ear 50% 38.3 49.8
Side Effect Trials

IMRT salivary function
• Prince of Wales Hospital; 2007 (Hong Kong)(2001-2003) PMID 17971582 -- "Prospective randomized study of
intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients."
(Kam MK, J Clin Oncol. 2007 Nov 1;25(31):4873-9.)
• Randomized. 60 patients with T1-2bN0-1 nasopharynx. Arm 1) IMRT 66 Gy (CTV=GTV + 1cm; at-risk
anatomic sites; LN Levels IB-II, LN upper Level V, LN retropharyngeal; PTV=CTV+3mm), lower neck LN+
66 Gy anterior field, LN- 54-60 Gy + intracavitary BT boostvs. Arm 2) 66 Gy 2D + intracavitary BT boost
• Outcome: observer-rated severe xerostomia IMRT 39% vs. 2D-RT 82% (SS), stimulated parotid flow (SS),
unstimulated parotid flow (SS), but no difference in patient-reported feeling of xerostomia
• Conclusion: IMRT superior in preserving objective parotid function, but no difference in patient-reported
benefit
• Editorial (PMID 17971579): Observer-rated scoring underestimates patient reports and has low agreement
among various observers. Suspect sparing of parotid alone not sufficient. Parotid gland produces saliva without
mucins (lubricants, bind water, and provide selective permeability barrier). Mucin-secreting glands (e.g. minor
salivary glands, submandibular glands) produce <10% saliva but >50% mucins. May need to spare these
glands as well for subjective feeling of benefit
• Queen Mary Hospital; 2006 (Hong Kong)(2000-2004) PMID 17145528 -- "Xerostomia and quality of life after
intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial
report on a randomized controlled clinical trial." (Pow EH, Int J Radiat Oncol Biol Phys. 2006 Nov
15;66(4):981-91.)
• Randomized. 51 patients, Stage II (T2N0-1, AJCC 1997). Arm 1) conventional RT 68 Gy, neck 66 Gy vs. Arm
2) IMRT, GTV dose 68-72 Gy, PTV 66-68 Gy. Stimulated whole (SWS) and parotid (SPS) saliva flow
evaluated, QoL SF-36, EORTC Core, EORTC QLQ-H&N35 questionnaires. Minimum F/U 1 years
• 1-year outcome: 25% whole flow (SWS) IMRT 50% vs. 2D 5% (SS), 25% parotid flow (SPS) 83% vs. 9%
(SS). At 2 months, both group had xerostomia, but IMRT group improved significantly better over time. Also
improvements in QoL
• Conclusion: IMRT significantly better than conventional RT for salivary function and QoL
Middle ear ventilation tube
• Hong Kong; 2002 PMID 12512893 -- "Randomized evaluation of the audiologic outcome of ventilation tube
insertion for middle ear effusion in patients with nasopharyngeal carcinoma." (Ho WK, J Otolaryngol. 2002
Oct;31(5):287-93.)
• Randomized. ? patients. NPC and middle ear effusion. Arm 1) pre-RT ventilation tube insertion vs. Arm 2)
observation. Audiologic assessment throughout. F/U 4 years
• Outcome: No difference in hearing changes up to 4 years
• Conclusion: Ventilation tube insertion before RT did not offer hearing benefit
Pointers
• Pre-treatment
• Nutrition consult, with consideration for G-tube
• Dental evaluation
• Set-up
• Supine, head extended
• Thermoplast mask to shoulders

Advanced Stage
Nasopharyngeal Cancer - Advanced Stage
Chemotherapy with radiation

• Because Stage III-IV NPC has a fairly poor prognosis with RT alone, multiple efforts were made to add
chemotherapy to the regimen
• Induction chemotherapy was evaluated in 5 randomized trials; two showed small benefit for disease-free survival,
but none showed an overall survival benefit. As a result, induction chemotherapy is currently not indicated
• Adjuvant chemotherapy was evaluated in 3 randomized trials; there was no benefit
• Phase II RTOG 81-17 demonstrated the feasibility of concurrent cisplatin with RT in advanced H&N cancers; it
included 22% NPC. Subsequent Intergroup trial 0099 showed a survival benefit for concurrent cisplatin with RT,
followed by adjuvant chemotherapy. This was the first trial to do so; however, the RT only arm had an
unexpectedly low survival, compared with results from RT alone in Asian (endemic) studies
• Concurrent chemo-RT benefits were confirmed by a randomized trial from Taiwan in an endemic population,
which used concurrent cisplatin + 5-FU. However, a re-analysis of the data suggests that concurrent chemo-RT is
only beneficial for "low-risk" advanced stage patients. "High-risk" advanced stage patients did not gain any
benefit from that chemo regimen, and may require more intense, neoadjuvant, or further adjuvant chemotherapy
• A Singaporean trial used the INT 0099 regimen, and again demonstrated a survival benefit
• Concurrent chemo-RT is now considered a standard of care in Stage III-IV NPC; given previously different
staging, some IIB patients were included in the trials and may benefit from concurrent chemotherapy as well. The
INT 0099 regimen is the best characterized; unfortunately, compliance with the regimen is only 60-70%
• Because concurrent chemo-RT results in reasonable local control, but adjuvant chemo has not resulted in good
systemic control, efforts are underway to try induction -> concurrent chemo-RT. Several Phase II trials have
reported encouraging results in patients with significant N disease
• Meta-analysis; 2006 PMID 16377415 -- "Chemotherapy in locally advanced nasopharyngeal carcinoma: an

individual patient data meta-analysis of eight randomized trials and 1753 patients." (Baujat B, Int J Radiat Oncol
Biol Phys. 2006 Jan 1;64(1):47-56.)
• 8 trials, 1753 patients (concurrent: INT 0099, PWH-QEH Hong Kong, QMH Hong Kong, induction: PWH
Hong Kong, AOCOA, VUMCA, Hokkaido, adjuvant: Taiwan). Individual updated patient data. Median F/U 6
years
• Outcome: Addition of chemo absolute survival benefit of 6% at 5 years (56% to 62%), absolute EFS benefit of
10% (42% to 52%)
• Significant interaction between timing of chemo and OS; highest benefit from concurrent chemo
• Conclusion: Chemotherapy has small but significant benefit for OS and EFS, seen when administered
concomitantly
• Meta-analysis; 2002 - PMID 12040275 — "Combined chemoradiation versus radiation therapy alone in locally
advanced nasopharyngeal carcinoma: results of a meta-analysis of 1,528 patients from six randomized trials."
(Huncharek M et al. Am J Clin Oncol. 2002 Jun;25(3):219-23.)
• 6 trials, 1528 patients (concurrent: INT 0099; induction: Hong Kong, Guangzhou, AOCOA, VUMCA;
adjuvant: Italian). Chemoradiation vs radiation alone in locally advanced patients, either adjuvantly,
neoadjuvantly, or concurrently.
• Outcome: DFS/PFS improved 2 years 37%, 3 years 40%, 4 years 34%. OS improved 2 years 20% (NS), 3
years 19% (NS), 4 years 21% (SS)
• Conclusion: Addition of chemotherapy improves DFS/PFS and OS
Concurrent chemo-RT
• Hong Kong NPC-9902 (T-disease) (1999-2004)
• Randomized, 2x2 design. Closed early due to slow accrual. 189 patients, WHO grade II-III, Stage T3-4N0-1
(AJCC-5)(key problem locoregional failure; see companion trial NPC-9901). Arm 1) conventional RT alone
vs. Arm 2) accelerated RT vs. Arm 3) conventional RT + concurrent chemo vs. Arm 4) accelerated RT +
concurrent chemo. Conventional RT >=66 in 2 Gy/fx, 5 days/week. Accelerated same regimen but 6
days/week. Technique 2D or 3D-CRT or IMRT boost. Concurrent chemo cisplatin 100 mg/m2 q3 weeks,
adjuvant chemo cisplatin 80 mg/m2 + 5-FU 1000 mg/m2
• 3-years; 2006 PMID 16904519 -- "Preliminary results of a randomized study (NPC-9902 Trial) on therapeutic
gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal
carcinoma." (Lee AW, Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):142-51.). Median F/U 2.9 years
• Outcome: 3-year FFS RT 70%, AFRT 63%, chemo-RT 74%, chemo-AFRT 94% (SS). On multivariate
analysis, concurrent chemo significant, accelerated RT not significant. OS 83%, 73%, 87%, 88% (NS)
• Toxicity Grade 3-5: Acute: RT 55%, AFRT 70%, chemo-RT 83%, chemo-AFRT 86% (concurrent chemo
SS worse). Late: 17%, 21%, 27%, 32% (chemo-AFRT borderline p=0.05 worse). Most late toxicity
otologic.
• Conclusion: Preliminary, concurrent chemo with accelerated fractionation could significantly improve local
tumor control
• Hong Kong NPC-9901 (N-disease) (1999-2004)
• Randomized. 348 patients, WHO grade II-III, T1-4N2-N3 (AJCC-5)(key problem distant failure; see
companion trial NPC-9902). Arm 1) RT alone vs. Arm 2) RT + concurrent cisplatin 100 mg/m2 q3 weeks. RT
>= 66 Gy (2D, 3D-CRT or IMRT)
• 3-years; 2005 PMID 16192584 -- "Preliminary results of a randomized study on therapeutic gain by
concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong
Kong Nasopharyngeal Cancer Study Group." (Lee AW, J Clin Oncol. 2005 Oct 1;23(28):6966-75.) Median
F/U 2.3 years

• Outcome: DFS chemo-RT 72% vs. RT alone 62% (SS), LRC 92% vs. 82% (SS), DM 76% vs. 73% (NS),
OS 78% vs. 78% (NS)
• Toxicity: acute chemo-RT 84% vs. RT alone 53% (SS); late 28% vs. 13% (SS), most late toxicity otologic
• Conclusion: Preliminary, significant benefit for tumor control at the cost of higher toxicity. No early OS
benefit
• Singapore SQNP01 (1997-2003)
• Randomized. 221 patients, WHO II-III, T3-4 or N2-3 (AJCC-5). Arm 1) RT alone vs. Arm 2) RT + concurrent
cisplatin 100 mg/m2 q3 weeks + adjuvant cisplatin 80 mg/m2 + 5-FU 1000 mg/m2 x3 cycles. RT technique 70
Gy primary, 60 Gy neck + 10 Gy electron boost to lymph nodes. 71% patients received all 3 cycles of
concurrent chemo
• 3-years; 2005 PMID 16170180 -- "Randomized trial of radiotherapy versus concurrent chemoradiotherapy
followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union
against cancer stage III and IV nasopharyngeal cancer of the endemic variety." (Wee J, J Clin Oncol. 2005 Sep
20;23(27):6730-8.) Median F/U 3.2 years
• Outcome: 3-year DFS chemo-RT 72% vs. RT 53% (SS); OS 80% vs. 65% (SS); 2-year DM chemo-RT
13% vs. RT alone 30% (SS)
• Toxicity: Grade 3-5 in 48%, mucositis chemo-RT 48% vs. RT 32% (SS), anorexia 22% vs. 4% (SS), emesis
5% vs. 0% (SS). Also significant hematologic toxicity
• Conclusion: Confirmation of INT 0099 results; also applicable in endemic NPC
• Queen Mary Hospital, Hong Kong (1995-2001)
• Randomized, 2x2 design (concurrent chemo vs. none, adjuvant chemo vs. none). Ho's Stage T3 or N2-3 or LN
>=4 cm (AJCC 6th II-IV). Arm 1) RT alone vs. Arm 2) concurrent chemo-RT vs. Arm 3) RT + adjuvant
chemo vs. Arm 4) concurrent chemo-RT + adjuvant RT. Concurrent chemo was FU prodrug uracil/tegafur,
adjuvant chemo was cisplatin/5-FU and vincristine/bleomycin/MTX x3+3 cycles. RT 1995-1997 62.5/25 split
course with 1 week break; 1997-2001 68/34 primary and 66/33 neck. If parapharyngeal extension or residual
disease, 10 Gy boost
• 3-years; 2004 PMID 15226332 -- "Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a
factorial study." (Kwong DL, J Clin Oncol. 2004 Jul 1;22(13):2643-53.)
• Outcome: 3-year concurrent CRT vs. RT alone FFS 69% vs. 58% (NS), OS 86% vs. 77% (p=0.06), LRC
80% vs. 72% (NS), DM 15% vs. 29% (SS). 3-year adjuvant chemo vs. none FFS 62% vs. 65% (NS), OS
80% vs. 83% (NS), no difference on LRC or DM.
• Conclusion: Trend to improvement with concurrent chemo-RT over RT alone (p=0.06), no benefit to
adjuvant chemo
• Prince of Wales Hospital / Queen Elizabeth Hospital, Hong Kong (1994-1999)
• Randomized. 350 patients, Ho's Stage N2-3 or N1 with LN >=4 cm (AJCC-6 Stage II-IVB). Arm 1) RT with
concurrent cisplatin 40 mg/m2 q week vs. Arm 2) RT alone. RT 66 Gy, parapharyngeal boost 10-20 Gy
allowed. Primary end point PFS
• 2-years; 2002 PMID 11956263 -- "Concurrent chemotherapy-radiotherapy compared with radiotherapy alone
in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III
randomized trial." (Chan AT, J Clin Oncol. 2002 Apr 15;20(8):2038-44.) Median F/U 2.7 years
• Outcome: 2-year PFS chemo-RT 76% vs. RT alone 69% (NS). Subgroup analysis benefit for Ho's T3
• Conclusion: Concurrent chemo-RT well tolerated, but no benefit
• 5-years; 2005 PMID 15812080 -- "Overall survival after concurrent cisplatin-radiotherapy compared with
radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma." (Chan AT, J Natl Cancer Inst.
2005 Apr 6;97(7):536-9.) Median F/U 5.5 years

• Outcome: 5-year OS chemo-RT 70% vs. RT 59% (p=0.07). Subgroup analysis no benefit for T1-2, but
benefit for T3-4 (HR 0.51)
• Conclusion: Trend for survival benefit; promising treatment strategy
• Taiwan (1993-1999)
• Randomized. 284 patients, NPC Stage III-IV M0, histology WHO I (3%), WHO II (73%), WHO III (24%).
Arm 1) RT 70-74 Gy alone vs. Arm 2) concurrent cisplatin 20 mg/m2 + 5-FU 400 mg/m2 during week 1 and
5. RT: CTV = GTV+2cm, included entire base of skull, sphenoid sinus, 2cm beyond mastoid process, posterior
half of maxillary sinus/nasal cavity. Dose 70-74 Gy primary tumor and LN+, 50-60 Gy N0 neck. Chemo
completed by 94% patients
• 5-years; 2003 PMID 12586799 -- "Phase III study of concurrent chemoradiotherapy versus radiotherapy alone
for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival." (Lin JC, J
Clin Oncol. 2003 Feb 15;21(4):631-7.). Median F/U 5.4 years
• 5-year outcome: PFS RT alone 53% vs. chemo-RT 72% (SS); OS 54% vs. 72% (SS)
• Toxicity Grade 3-4: mucositis 35% vs. 45%, skin 26% vs. 35%
• Conclusion: Concurrent chemo-RT superior to RT alone for advanced NPC
• Re-analysis; 2004 PMID 15337551 -- "Another way to estimate outcome of advanced nasopharyngeal
carcinoma--is concurrent chemoradiotherapy adequate?" (Lin JC, Int J Radiat Oncol Biol Phys. 2004 Sep
1;60(1):156-64.)
• Original (AJCC 1992) stage: Stage III 20%, Stage IV 80%. Restaged (AJCC 1997): Stage II/III 71%, Stage
IV 29%. New risk definition: high-risk (LN >6cm or SCV LN or AJCC 1992 T4N2 or multiple LN mets
with 1 LN >4cm) 42% vs. low-risk 58%
• Low-risk group (chemo-RT vs. RT): LC 95% vs. 77% (SS), neck control 100% vs. 96% (NS), DM 90% vs.
78% (SS), PFS 87% vs. 61% (SS), OS 83% vs. 60% (SS). Chemo-RT significantly better
• High-risk group (chemo-RT vs. RT): LC 75% vs. 68% (NS), neck control 92% vs. 87% (NS), DM 60% vs.
60% (NS), PFS 44% vs. 43% (NS), OS 56% vs. 46% (NS). No difference with concurrent chemo
• Conclusion: Concurrent chemo-RT superior for low-risk patients, but inadequate for high-risk patients
• NYU; 2000 (1995-1997) - PMID 10863053 — "Improved outcome secondary to concurrent chemoradiotherapy
for advanced carcinoma of the nasopharynx: preliminary corroboration of the intergroup experience." (Cooper JS
et al. Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):861-6.)
• Retrospective single institution. Repeated regimen of Intergroup 0099. Stage III-IV.
• Outcome: 3-year OS was 93% and DFS was 65%; both substantially better than historical controls
• Conclusion: INT 0099 regimen should be standard of care
• Intergroup 0099 / RTOG 88-17 (1989-1995)
• Randomized. Trial stopped early due to significant survival benefit. 147 patients. NPC Stage III-IV (Stage IV
91%; but also included few N1 patients, which are IIB today), histology WHO I (25%), WHO II (35%), WHO
III (41%). Arm 1) RT 70 Gy alone vs RT 70 Gy with concurrent cisplatin 100 mg/m2 q3 weeks and adjuvant
cisplatin + 5-Fu . CT-based treatment planning. Fields: included 2 cm margin on gross disease and included
entire base of skull and sphenoid sinus, 2 cm posterior to mastoid process; anteriorly included posterior 1/3 of
maxillary sinus and nasal cavity. Dose: 70 Gy to primary. For neck to clavicle, 50 Gy for N0 disease, 66 Gy
for nodes <= 2 cm, and 70 Gy for nodes > 2 cm. Cisplatin given every 3 weeks at 100 mg/m2 x 3 cycles. Then
adjuvant chemo began 4 weeks after finishing RT: cisplatin 80 mg/m2 and 5-FU 1000 mg/m2/d by 96-hr
infusion q4w x 3 cycles. Partial or radical neck dissections for persistent neck disease. Chemo completed by
55%
• 1998 PMID 9552031 - "Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal
cancer: phase III randomized Intergroup study 0099." Al-Sarraf et al. J Clin Oncol. 1998 Apr;16(4):1310-7.
• 3-year outcome: PFS chemo-RT 69% vs. RT alone 24% (SS); OS 78% vs 47% (SS). Median OS not
reached for chemo-RT vs. 2.5 years for RT alone.
• Toxicity Grade 3-4: stomatitis 29% vs. 19%, nausea 14% vs. 5%, leukopenia 23% vs. 1%
• Conclusion: Concurrent chemo-RT superior to RT alone for advanced NPC
• Comment: First randomized trial to show a survival benefit for the use of concurrent chemo, unexpectedly low
RT alone outcome (several retrospective series showed >70% OS with RT alone in endemic patients), RT
technique considered less aggressive than that practiced in Asia (particularly lack of parapharyngeal and
intracavitary boost), not applicable to non-US patients
• RTOG 81-17 (1981-1984)
• Phase II. 124 patients, locally advanced inoperable H&N cancer (oropharynx 39%, nasopharynx 22%, oral
cavity 18%, hypopharynx 7%, larynx 7%, sinuses 7%). Stage III 18%, Stage IV 82%. Concurrent RT 66-73.8
Gy with cisplatin 100 mg/m2 q3 weeks. 60% completed planned treatment
• Overall; 1987 PMID 3802013 -- "Concurrent radiotherapy and chemotherapy with cisplatin in inoperable
squamous cell carcinoma of the head and neck. An RTOG Study." (Al-Sarraf M, Cancer. 1987 Jan
15;59(2):259-65.)
• Severe toxicity: stomatitis 31%, leukopenia 11%, anemia 8%, N/V 6%
• Outcome: 1-year DFS 51%, OS 66%. Nasopharynx CR 82%
• Conclusion: Concurrent cisplatin effective and safe in advanced H&N
• NPC Subset; 1990 PMID 2199621 -- "Chemo-radiotherapy in patients with locally advanced nasopharyngeal
carcinoma: a radiation therapy oncology group study." (Al-Sarraf M, J Clin Oncol. 1990 Aug;8(8):1342-51.)
• Subset analysis, 27 NPC patients, 96% Stage IV, 67% poorly differentiated. All patients received >64.5 Gy.
• Severe toxicity: stomatitis 41%, xerostomia 15%
• Outcome: 4-year DFS 45%, OS 55%
• Conclusion: Chemo-RT in NPC effective, should be evaluated in phase III
Concurrent RT with biologics

• Beijing Hospital, China (2001-2003) -- RT +/- recombinant adenovirus-p53
• Randomized. 82 patients with NPC. Arm 1) RT 70/35 alone vs. Arm 2) RT + recombinant adenovirus-p53
(rAd-p53) injected intratumorally QW x8
• 2008 PMID 19103729 -- "Effect of Recombinant Adenovirus-p53 Combined With Radiotherapy on
Long-Term Prognosis of Advanced Nasopharyngeal Carcinoma." (Pan JJ, J Clin Oncol. 2008 Dec 22. [Epub
ahead of print]) Median F/U 5.1 years
• Outcome: p53 mRNA detected in 94% postinjection biopsies, with upregulation of p21 and Bax. 5-year
LRF RT 28% vs RT + rAd-p53 3% (SS); 5-year DFS 57% vs. 67% (NS); 5-year OS 59% vs. 67% (NS)
• Toxicity: Transient fever after rAd-p53 administration
• Conclusion: rAd-p53 was safe and biologically active, and improves tumor control and survival rate
Induction chemo-RT vs. RT alone

• Pooled long-term AOCOA/Guangzhou data
• Pooled data from 2 similar PIII trials comparing induction chemo-RT vs. RT alone. 784 patients. Induction
cisplatin, bleomycin, 5-FU or cisplatin, epirubicin. RT 70 Gy. Median F/U 5.6 years
• 5-years; 2005 PMID 15657403 -- "Long-term survival after cisplatin-based induction chemotherapy and
radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of two phase III trials." (Chua DT, J Clin
Oncol. 2005 Feb 20;23(6):1118-24.)
• Outcome: 5-year DFS induction chemo 63% vs. RT 58% (SS), OS 62% vs. 58% (NS). LRF decreased by
18%, DM decreased by 13%, but no significant difference in failure patterns
• Conclusion: Induction chemo-RT modest decrease in DFS, but no impact on OS. Concurrent chemo-RT
should remain standard of care
• Early Stage NPC; 2006 PMID 16750333 -- "Improvement of survival after addition of induction
chemotherapy to radiotherapy in patients with early-stage nasopharyngeal carcinoma: Subgroup analysis of
two Phase III trials." (Chua DT, Int J Radiat Oncol Biol Phys. 2006 Aug 1;65(5):1300-6. Epub 2006 Jun 5.)
• Subset analysis. AJCC 1997 Staging. Group 1 (T1-2N0-1, was entirely IIB) vs. Group 2 (T1-2N2-3) vs.
Group 3 (T3-4N0-1) vs. Group 4 (T3-4N2-3).
• Outcome: no difference in LRC, DM, or OS for Groups 2-4. Group 1 5-year OS induction chemo 79% vs.
RT alone 67% (p=0.048), DM 86% vs. 74% (SS)
• Conclusion: Group 1 (T1-2N0-1; all IIB) relatively poor survival due to mets, improved with induction
chemo. No benefit for induction in Groups 2-4
• Guangzhou (1993-1994) - cisplatin, 5-FU, bleomycin
• Randomized. 456 patients. Chinese stage III-IV M0. Arm 1) RT alone vs. Arm 2) Neoadjuvant cisplatin 100
mg/m2, bleomycin 10 mg/m2, and 5-FU 800 mg/m2 x2-3 cycles, followed by RT within 2 weeks. RT 68-72
Gy primary tumor, involved neck 60-62 Gy, uninvolved neck 60 Gy. If residual tumor after RT, could boost
10-14 Gy EBRT or 20-24 Gy HDR in 4-5 fractions
• 5-years; 2001 PMID 11230478 -- "Results of a prospective randomized trial comparing neoadjuvant
chemotherapy plus radiotherapy with radiotherapy alone in patients with locoregionally advanced
nasopharyngeal carcinoma." (Ma J, J Clin Oncol. 2001 Mar 1;19(5):1350-7.)
• Outcome: 5-year OS induction chemo 63% vs. RT alone 56% (NS); RFS 59% vs. 49% (SS); LRC 82% vs.
74% (p=0.05); no difference on DM
• Conclusion: No survival benefit for induction chemotherapy
• Hokkaido RTOG (1991-1998) -- cisplatin, 5-FU
• Randomized. 80 patients. Stage I-IV M0. Arm 1) RT alone vs. Arm 2) Neoadjuvant cisplatin 80 mg/m2, 5-FU
800 mg/m2 q3 weeks x2 cycles. RT 66-68 Gy to primary tumor and LN+, 50 Gy to negative LNs
• 5-years; 2002 PMID 12001120 -- "A prospective, randomized trial comparing neoadjuvant chemotherapy with
radiotherapy alone in patients with advanced nasopharyngeal carcinoma." (Hareyama M, Cancer. 2002 Apr
15;94(8):2217-23.). Median F/U 4.1 years
• Outcome: 5-year OS induction chemo 60% vs. RT alone 48% (NS); DFS 55% vs. 43% (NS). No difference
in LRC; most patients experienced LR failure before DM failure
• Conclusion: Neoadjuvant chemo didn't improve DFS or OS
• Asian-Oceanic Clinical Oncology Association (AOCOA) (1989-1993) -- cisplatin, epirubicin
• Randomized. 286 patients. Ho's staging T3 or N2-N3 disease or LN+ >= 3cm. Arm 1) neoadjuvant cisplatin 60
mg/m2 + epirubicin 110 mg/m2 x2-3 cycles followed by RT vs. Arm 2) RT alone. RT dose 66-74 Gy (median
71 Gy) to primary tumor, 60-76 Gy (median 66 Gy) to neck.
• 3-years; 1998 PMID 9840526 -- "Preliminary report of the Asian-Oceanian Clinical Oncology Association
randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the
treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Asian-Oceanian Clinical
Oncology Association Nasopharynx Cancer Study Group." (Chua DT, Cancer. 1998 Dec 1;83(11):2270-83.).
• Outcome: 3-year RFS induction chemo 48% vs. RT 42% (NS); OS 78% vs. 71% (NS)
• Conclusion: No benefit for induction chemo
• International Nasopharynx Cancer Study Group: VUMCA I (1989-1993) -- cisplatin, epirubicin, bleomycin
• Randomized. 339 patients. Undifferentiated carcinoma (WHO 2 or 3), any T stage, N2-3, M0. Arm 1) RT 70
Gy alone vs. Arm 2) induction BEC (bleomycin, epirubicin, cisplatinum) q3 weeks x 3 cycles followed by RT.
• 1996 PMID 8655368 — "Preliminary results of a randomized trial comparing neoadjuvant chemotherapy
(cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV(> or = N2, M0)
undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival." (No Authors, Int J
Radiat Oncol Biol Phys. 1996 Jun 1;35(3):463-9.) Median F/U 4.1 years
• Toxicity: treatment-related deaths RT alone 1% vs chemo->RT 8%
• Outcome: 2-year DFS RT alone 40% vs. chemo->RT 60% (per graph), no difference in LRC. No difference
in OS.
• Conclusion: BEC chemotherapy improves DFS, no impact on OS
• Prince of Wales Hospital PWH-88, Hong Kong (1988-1991) -- cisplatin, 5-FU
• Randomized. 82 patients. Ho's classification N3 or LN+ >4 cm. Arm 1) Neoadjuvant cisplatin 100 mg/m2 +
5-FU 1000 mg/m2, 4 weeks later RT 66 Gy with lower neck to 58 Gy, then 4 cycles of adjuvant chemo vs.
Arm 2) RT alone. Could boost residual disease after RT to 18-24 Gy in 3 fractions with Ir-192 HDR
• 2-years; 1995 PMID 7558945 — "A prospective randomized study of chemotherapy adjunctive to definitive
radiotherapy in advanced nasopharyngeal carcinoma." (Chan AT, Int J Radiat Oncol Biol Phys. 1995 Oct
15;33(3):569-77.) Median F/U 2.4 years
• Outcome: 2-year DFS chemo-RT 68% vs. RT alone 72% (NS); OS 80% vs. 80% (NS); no difference in
LRC, DM, or time-to-relapse
• Conclusion: No benefit for sequential chemo-RT
Adjuvant chemo after RT

• Queen Mary Hospital (Hong Kong)(1995-2001)
• Randomized, 2x2 design (concurrent chemo vs. none, adjuvant chemo vs. none). Ho's Stage T3 or N2-3 or LN
>=4 cm (AJCC 6th II-IV). Arm 1) RT alone vs. Arm 2) concurrent chemo-RT vs. Arm 3) RT + adjuvant
chemo vs. Arm 4) concurrent chemo-RT + adjuvant RT. Concurrent chemo was FU prodrug uracil/tegafur,
adjuvant chemo was cisplatin/5-FU and vincristine/bleomycin/MTX x3+3 cycles. RT 1995-1997 62.5/25 split
course with 1 week break; 1997-2001 68/34 primary and 66/33 neck. If parapharyngeal extension or residual
disease, 10 Gy boost
• 3-years; 2004 PMID 15226332 -- "Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a
factorial study." (Kwong DL, J Clin Oncol. 2004 Jul 1;22(13):2643-53.)
• Outcome: 3-year concurrent CRT vs. RT alone FFS 69% vs. 58% (NS), OS 86% vs. 77% (p=0.06), LRC
80% vs. 72% (NS), DM 15% vs. 29% (SS). 3-year adjuvant chemo vs. none FFS 62% vs. 65% (NS), OS
80% vs. 83% (NS), no difference on LRC or DM.
• Conclusion: Trend to improvement with concurrent chemo-RT over RT alone (p=0.06), no benefit to
adjuvant chemo
• Taiwan COG (1994-1999) -- observation vs. cisplatin/5-FU/leucovorin
• Randomized. 154 patients. Stage IV M0 (AJCC 1992). Arm 1) RT 70-72 Gy vs. Arm 2) weekly cisplatin 20
mg/m2, 5-FU 2200 mg/m2, leucovorin 120 mg/m2 x9 weeks
• 5-years; 2002 PMID 11955734 -- "A phase III study of adjuvant chemotherapy in advanced nasopharyngeal
carcinoma patients." (Chi KH, Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1238-44.) Median F/U 4.1 years
• Outcome: 5-year OS RT alone 60% vs. adjuvant chemo 50% (NS), RFS 54% vs. 54% (NS)
• Toxicity: No Grade 3+ mucositis; Grade 3+ leukopenia 2%
• Conclusion: Adjuvant chemo after RT offers no benefit for OS or RFS
• Italian NRC (1979-83) -- observation vs. vincristine/cyclophosphamide/adriamycin
• Randomized. 229 NPC patients, T1N1-T4N3. Complete remission after RT , then Arm 1) observation vs. Arm
2) VCA (vincristine, cyclophosphamide, adriamycin) x 6 monthly cycles. RT 60-70 Gy to primary tumor, base
of skull, and involved nodes, negative LN 50 Gy (frequently split course over 8-10 weeks)
• 4-years; 1988 PMID 3047335 — "Adjuvant chemotherapy with vincristine, cyclophosphamide, and
doxorubicin after radiotherapy in local-regional nasopharyngeal cancer: results of a 4-year multicenter
randomized study." (Rossi A et al. J Clin Oncol. 1988 Sep;6(9):1401-10.)
• Outcome: 4-year RFS observation 56% vs. chemo 58% (NS), no difference in OS; Similar pattern of failure
with distant mets in about 50% who failed.
• Toxicity: mild to moderate in most patients
• Conclusion: No benefit for adjuvant VCA chemo
• Comment: more patients at low risk for distant failure; less active chemo combination
Dose Escalation
• Queen Mary Hospital; 2006 (Hong Kong)(2000-2004) PMID 16213105 -- "Preliminary results of radiation dose
escalation for locally advanced nasopharyngeal carcinoma." (Kwong DL, Int J Radiat Oncol Biol Phys. 2006 Feb
1;64(2):374-81. Epub 2005 Oct 5.)
• Retrospective. 50 patients, T3-T4 NPC (Stage III 28%, Stage IVA/B 72%). RT dose: GTV 76 Gy (whole NP,
tumor extending outside NP, skull-base erosions, intracranial disease), PTV 70 Gy, enlarged LNs 72 Gy, all
given in 35 fractions. 34 patients concurrent cisplatin (initial 11 were RT only to establish safety, subsequent
patients offered INT 0099 protocol). Median F/U 2.1 years
• Outcome: 2-year LRC 96%, DM-free 94%, DFS 93%, OS 92%. 4 recurrences: 2 LR and 2 DM. All patients
with recurrence did not have chemo.
• Toxicity: 1 treatment-related death from adjuvant chemo; 2 late carotid pseudoaneurysms with torrential
epistaxis
• Conclusion: Dose-escalation to 76 Gy combined with chemo is feasible in T3-T4 NPC
Brachytherapy boost
• Long Beach Memorial Hospital; 2000 (1978-97) PMID 10889385 -- "Brachytherapy for primary and recurrent
nasopharyngeal carcinoma: 20 years' experience at Long Beach Memorial." (Syed AM, Int J Radiat Oncol Biol
Phys. 2000 Jul 15;47(5):1311-21.)
• Retrospective. 56 patients (primary n=15, recurrent/persistent n=34, NPC with prior H&N RT n=7). A wide
variety of treatments described.
• Conclusion: Interstitial brachytherapy can be effective
Technique
• RTOG 0225 (2003-2005) Protocol [1] PMID 19564532 -- "Intensity-Modulated Radiation Therapy With or
Without Chemotherapy for Nasopharyngeal Carcinoma: Radiation Therapy Oncology Group Phase II Trial
0225." (Lee N, J Clin Oncol. 2009 Jun 29. [Epub ahead of print])
• Phase II. Multi-institutional IMRT use. 68 patients, Stage I-IVb NPC (94% WHO type 2-3). IMRT 70/33; if
T2b+ or N+ concurrent cisplatin, adjuvant cisplatin/5-FU.
• Outcome: Prescribed IMRT given to 84%; prescribed chemo 65%. 2-year LC 93%, LRC 89%, DMFR 85%.
2-year PFS 93%, OS 80%
• Toxicity: Acute Grade 4 mucositis 4%; Late Grade 3 dysphagia 5%, xerostomia 3%. Long-term
PEG-dependent 4%
• Conclusion: IMRT feasible in multi-institutional setting
Reirradiation
• Guangzhou; 2007 (China)(1999-2005) PMID 17601682 -- "Outcome of fractionated stereotactic radiotherapy for
90 patients with locally persistent and recurrent nasopharyngeal carcinoma." (Wu SX, Int J Radiat Oncol Biol
Phys. 2007 Nov 1;69(3):761-9.)
• Retrospective. 90 patients with persistent (n=34) or recurrent (n=56) treated with SRT. Median dose 18/3 or
48/6. Median F/U 1.7 years
• Outcome: 3-year PFS 55%, DSS 57%
• Toxicity: late complications 19%, 2 fatal hemorrhage
• Conclusion: SRT effective, lower risk than reported SRS
• Harvard; 1987 PMID 3597157 — "Re-irradiation of recurrent nasopharyngeal carcinoma--treatment techniques
and results." Wang CC et al. Int J Radiat Oncol Biol Phys. 1987 Jul;13(7):953-6.
Proton Therapy
• Orsay; 2002 PMID 12504770 -- "[Comparison with dose-volume histograms of two conformal irradiation
techniques used for the treatment of T4N0M0 nasopharyngeal cancer, one with association of photons and
protons and another with photons alone] - [Article in French]" (Noel G, Cancer Radiother. 2002
Dec;6(6):337-48.)
• Treatment planning. 5 patients with T4N0 NPC, treated with concurrent chemo-RT using combined
photon/proton beams. Photons to 44 or 54 Gy using 3D-CRT, proton boost 16 or 26 Gy in 1.8-2.0 Gy/fx
• Outcome: Conformality ratio for photon/proton plan 3.1 vs. photons only 5.7 for CTV1, no difference for
CTV2. Normal tissues favored photon/proton plan
• Conclusion: Combined photons/protons improve conformality over photons alone
• Loma Linda; 1999 (1991-1997) PMID 10551231 -- "Nasopharyngeal carcinoma: repeat treatment with
conformal proton therapy--dose-volume histogram analysis." (Lin R, Radiology. 1999 Nov;213(2):489-94.)
• Retrospective. 16 patients with NPC. Initial treatment 50-88 Gy (1 postop RT 50 Gy, 16 primary 65-88 Gy).
Retreatment mean dose 62.8 Gy (59.4-70.2 GGE). Mean F/U 2 years
• Outcome: 2-year LRFS 50%, OS 50%. By DVH coverage "optimal" 83% vs "suboptimal" 17% (SS)
• Toxicity: No CNS side effects
• Conclusion: Adequate tumor coverage important for LRC and survival
• Lawrence Berkely Laboratory; 1992 PMID 1618678 -- "Recurrent locally advanced nasopharyngeal carcinoma
treated with heavy charged particle irradiation." (Feehan PE, Int J Radiat Oncol Biol Phys. 1992;23(4):881-4.)
• Retrospective. 11 patients. Recurrent NPC, with base of skull invasion, CN deficit 64%. Heavy charged
particles. Initial treatment median 70.2 Gy (61-81 Gy). Median time to recurrence 1.5 years. Median
retreatment dose 50 GyE (32-62)
• Outcome: LC 45%. 5-year OS 31%
• Conclusion: Results appear superior to others using conventional photon therapy
• Harvard; 1989 PMID 2542199 -- "Proton therapy for carcinoma of the nasopharynx: a study in comparative
treatment planning." (Brown AP, Int J Radiat Oncol Biol Phys. 1989 Jun;16(6):1607-14.)
• Treatment planning. Proton vs photon comparison
• Outcome: Proton superior dose-distribution, increase 5 Gy in median tumor dose, substantial reduction in
normal tissue dose
• Conclusion: Superior dose distribution of protons should translate into improved control and reduced
morbidity
References
[1] http:/ / www. rtog. org/ members/ protocols/ 0225/ 0225. pdf
Radiation Oncology/Head & Neck/Larynx/

Staging
Laryngeal Cancer Staging
Tumor Stage
Supraglottis
• T1: Tumor limited to one subsite of supraglottis with normal vocal cord mobility
• Subsites: False cords, arytenoids, suprahyoid epiglottis, infrahyoid epiglottis, aryepiglotic folds
• T2: Tumor invades mucosa of more than one adjacent subsite* of supraglottis or glottis or region outside the
supraglottis (e.g., mucosa of base of tongue, vallecula, or medial wall of pyriform sinus) without fixation of the
larynx
• T3: Tumor limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid area,
pre-epiglottic tissues, paraglottic space, and/or minor thyroid cartilage erosion (e.g., inner cortex)
• T4a: Tumor invades through the thyroid cartilage, and/or invades tissues beyond the larynx (e.g., trachea, soft
tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus)
• T4b: Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures
Radiation Oncology/Head & Neck/Larynx/Staging 172
Glottis
• T1: Tumor limited to the vocal cord(s), which may involve anterior or posterior commissure, with normal
mobility
• T1a: Tumor limited to one vocal cord
• T1b: Tumor involves both vocal cords
• T2: Tumor extends to supraglottis and/or subglottis and/or with impaired vocal cord mobility
• T3: Tumor limited to the larynx with vocal cord fixation and/or invades paraglottic space, and/or minor thyroid
cartilage erosion (e.g., inner cortex)
• T4a: Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft
tissues of neck, including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus)
Subglottis
• T1: Tumor limited to the subglottis
• T2: Tumor extends to vocal cord(s) with normal or impaired mobility
• T3: Tumor limited to larynx with vocal cord fixation
• T4a: Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft
tissues of neck, including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus)
Lymph Node Stage

• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Metastasis in a single ipsilateral lymph node 3 cm or smaller in greatest dimension
• N2: Metastasis in a single ipsilateral lymph node larger than 3 cm but 6 cm or smaller in greatest dimension, or in
multiple ipsilateral lymph nodes 6 cm or smaller in greatest dimension, or in bilateral or contralateral lymph
nodes 6 cm or smaller in greatest dimension
• N2a: Metastasis in a single ipsilateral lymph node larger than 3 cm but 6 cm or smaller in greatest dimension
• N2b: Metastasis in multiple ipsilateral lymph nodes 6 cm or smaller in greatest dimension
• N2c: Metastasis in bilateral or contralateral lymph nodes 6 cm or smaller in greatest dimension
• N3: Metastasis in a lymph node larger than 6 cm in greatest dimension
Metastasis Stage
• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis
AJCC Overall Stage

• I - T1 N0
• II - T2 N0
• III - T3 N0, T1-3 N1
• IVA - T4a N0-2, T1-4a N2
• IVB - T4b any N, any T N3
• IVC - M1

Overview
Laryngeal Cancer Overview
Epidemiology
• ~10K cases/year in the U.S.
• ~2% of all cancers; most common upper aerodigestive tract cancer
• Risk factors: tobacco, extensive use of voice
• 40% locally advanced
Pathology
• 95% squamous cell CA; usually well-moderately well differentiated
• 1-2% verrucous CA; bulky, exophytic, heavily keratinized
Anatomy
• For clinical staging, larynx consists of three regions: supraglottis, glottis, and subglottis
• The external structure is formed by hyoid bone, thyroid cartilage and cricoid cartilage
• Internal structure is formed by the epiglottis and the arytenoid, corniculate, and cuneiform cartilages
• The epiglottis is joined superiorly to the hyoid bone by the hyoepiglottic ligament and inferiorly to the thyroid
cartilage by the thyroepiglottic ligament (just below the thyroid notch and above the anterior commissure)
• The vocal ligaments and muscles attach to the vocal process of the arytenoid posteriorly and the thyroid
cartilage anteriorly. Beneath the epithelium of the free edge of the vocal cord is the lamina propria
• The intrinsic muscles of the larynx control the movement of the cords; the extrinsic muscles control primarily
swallowing. The intrinsic muscles are innervated by the recurrent laryngeal nerve, except for cricothyroid
muscle, which is innervated by the superior laryngeal nerve
• Supraglottis:
• Sites: Suprahyoid epiglottis (suprahyoid and infrahyoid), aryepiglottic folds, arytenoids, false cords
• Inferior border: horizontal plane passing through lateral margin of the ventricle
• Lymphatics: Rich network, pass through thyrohyoid membrane into subdigastric, midjugular, and lower
jugular nodes
• Glottis
•
Sites: true vocal cords, anterior and posterior commissures
•
Vocal cords are 3-5 mm thick
•
Inferior border: 5 mm below free margin of vocal cords
•
Horizontal plane 1 cm in thickness
•
Lymphatics: True vocal cords don't have any; lymphatic spread via tumor extension to supraglottis or
subglottis
• Subglottis
• Anatomy: 5mm below the free margin of true vocal cords to inferior margin of cricoid cartilage
• Lymphatics:
• Larynx is formed from two embryologically defined regions, separate at laryngeal ventricle, with different
lymphatic patterns
• Supraglottis forms from primitive buccopharyngeal anlage and as such as rich lymphatics that drain to upper
internal jugular LNs. Supraglottic tumors have therefore much higher incidence of nodal mets at presentation
• Glottis and subglottis form from tracheobronchial buds and as such have sparse lymphatics that drain to
internal jugular and paratracheal LNs. Channels unite to form one anterior and two posterolateral pedicles.
Anterior drains through cricothyroid membrane into mid- and lower jugular nodes, or via prelaryngeal node
into pretracheal and supraclavicular LNS. Posterior drain through cricotracheal membrane into paratracheal
nodes
Treatment Overview
• Supraglottis
• LN+ 55% (commonly subdigastric and midjugular), 16% bilateral
• Supraglottis Page
• Glottis
• Glottis Page
• Most common laryngeal cancer in USA. Majority occur in anterior 2/3 of vocal cords
• Symptoms - persistent hoarseness, later dyspnea, chronic cough, hemoptysis, stridor
• LN+ <2% in T1, 5% in T2, 15-20% in T3, 20-30% in T4
• Treatment:
• No randomized trials comparing surgery to RT to laser resection
• For T1-T2: local control, laryngeal preservation, and survival comparable after laser resection, RT, and
partial laryngectomy. Voice quality comparable with laser resection and RT in smaller lesions, worse in
larger lesions after partial laryngectomy. Therefore recommendation for T1 and T2 with normal cord
mobility treated with RT or laser resection for superior voice preservation. Bulky T2 and impaired cord
mobility treated with RT or partial laryngectomy
• Neck dissection in T1-T2 is controversial
• RT fields:
• T1 and early T2 - two small opposing lateral fields centering on vocal cords, parallel to trachea. From upper
thyroid notch to lower border of the cricoid (at C6). Anterior border 1 cm anterior to the skin surface at the
level of vocal cords. Posterior border to include anterior portion of posterior pharyngeal wall. 5 x 5 cm2
field usually good.
• Subglottis
• Subglottis Page
• Primary lesions are rare (<3%); usually extension from glottis. 50-70% are SCC
• Symptoms - usually asymptomatic, but can present with horseness, dyspnea, stridor
• Disease often advanced at presentation; thorcacic cavity involved in T3-T4(~50%)
• LN+ in 20-50%
• Treatment - no consensus due to small numbers, but Toronto reports good experience with primary RT
• Stage I-II: RT (include lower neck and mediastinum)
• Stage III-IV: surgery (include larynx, thyroid, parastomal LNs), post-op RT if LN+ (include lower neck and
mediastinum)
• RT fields - lateral opposed fields inferiorly 2cm below primary tumor, superiorly encompassing upper jugular
nodes. Also an anterior low neck and upper mediastinum T-field
Surgery, or post-op RT
• Overall survival for advanced (Stage III-IV) cancer treated with laryngectomy or laryngectomy + post-op RT was
0-50% at 5-years.
• Results in functional morbidity: loss of voice, swallowing, permanent tracheostomy.
• Partial laryngectomy that spares the voice for selected T3N0 pts
Organ preservation
• Historically, total laryngectomy was the standard of care for advanced cancers of the larynx and hypopharynx
• A landmark VA Larynx Trial showed that induction chemotherapy + RT had equivalent larynx preservation and
survival rate as total laryngectomy + postop RT. This concept was confirmed in hypopharynx by EORTC 24891,
though a small GETTEC trial that closed early showed survival benefit for laryngectomy + postop RT
• Concurrent chemo-RT was shown to be superior to induction chemotherapy + RT or RT alone in RTOG 91-11
• T4 larynx management continues to be based on VA larynx trial. Odds ratio of responding to induction
chemotherapy was 5.6 for T1-3 vs T4 (p=0.01), and in the subset of patients who then underwent RT, salvage
laryngectomy was required in 56% vs. in 28% of T3 tumors. However, the absolute number of these patients was
very small. In clinical practice, patients with T4 larynx are not typically considered candidates for larynx
preservation
Prognostic factors
Size:
• University of Florida, 1997 (1966-94) - PMID 9196155 — "Definitive radiotherapy for T3 squamous cell
carcinoma of the glottic larynx." Mendenhall WM et al. J Clin Oncol. 1997 Jun;15(6):2394-402.
• Volume measured by CT scan correlated with LC. 87% LC for < 3.5 cm3 vs 29% for > 3.5 cm3.
Radiation alone
• In selected patients (T3N0) results in 40-70% larynx preservation rate and survival similar to that with surgery
• In advanced cases, radiation alone (with surgical salvage) results in worse survival
Laryngectomy + postop RT vs. Chemo-RT

• Singapore (1996-2000) -- Surgery + postop RT vs. concurrent chemo-RT
hypopharynx, and oropharynx
• GETTEC (1986-1989) -- total laryngectomy + postop RT vs induction chemo + RT
• Randomized. Trial stopped prematurely because patients refused laryngectomy. 68 patients. Larynx,
T3N0-N2b. Supraglottic larynx or resectable disease not eligible. Arm 1) Total laryngectomy, if N0 then
modified neck dissection, if N+ then radical neck dissection followed by post-op RT. Postop RT 50 Gy if SM-
and LN-; else 65-70 Gy vs. Arm 2) Induction chemo cisplatin 100 mg/m2 + 5-FU 1000 mg/m2 Q3W x3
cycles, followed by RT 65-70 Gy (36%). If tumor progression on chemo, received total laryngectomy (55%)
• 1998 PMID 9692058 -- "Randomized trial of induction chemotherapy in larynx carcinoma." (Richard JM, Oral
Oncol. 1998 May;34(3):224-8.) Median F/U 8.3 years
• Outcome: Induction 55% progressed and required laryngectomy. 2-year OS induction 69% vs.
laryngectomy 84% (SS)
• Conclusion: Larynx preservation cannot be considered a standard treatment at the present time
• VA Larynx Trial (1985-1989) - Total laryngectomy + postop RT vs. induction chemo + RT
• Randomized. 332 patients. Stage III or IV (excluding T1N1) cancer of the glottic or supraglottic larynx (63%
supraglottic). Arm 1) Classic wide-field total laryngectomy, regional LND + postop RT vs. Arm 2) Induction
chemo (cisplatin 100 mg/m2 + 5-FU 1000 mg/m2 Q3W x3 cycles) + radical RT. If not at least a PR to chemo
after 2nd cycle, underwent surgery and post-op RT. Primary RT 66-76 Gy and neck 50-75 Gy depending on
nodal size. Assessed 12 weeks after RT and had salvage laryngectomy if residual disease in larynx or neck
dissection for residual nodal disease. Postop RT 50 Gy to microscopic disease, 60 Gy to high risk areas, and
65-74 Gy to residual disease.
• 2-years; 1991 PMID 2034244 — "Induction chemotherapy plus radiation compared with surgery plus
radiation in patients with advanced laryngeal cancer." (The Department of Veterans Affairs Laryngeal Cancer
Study Group. N Engl J Med. 1991 Jun 13;324(24):1685-90.) Median F/U 2.7 years
• Outcome: 2-year OS chemo-RT 68% vs surgery+RT 68% (NS); DFS (NS) but but pattern of recurrence
differed, with more recurrence at the primary site (12% vs 2%) in chemo/RT group vs more distant mets in
surgery group (17% vs 11%).
• Larynx preservation: Overall 64%. Laryngectomy 18% after induction alone, 11% after induction + RT for
persistent tumor, 7% for recurrent tumor (majority within 1st year). Salvage laryngectomy T3 29% vs. T4
56% (SS), Stage III 29% vs. Stage IV 44% (SS)
• Conclusion: Induction chemotherapy and radiation can be effective in preserving larynx, without
compromising survival
• 3-years; 1993 PMID 8221647 -- "Recent advances in head and neck cancer--larynx preservation and cancer
chemoprevention: the Seventeenth Annual Richard and Hinda Rosenthal Foundation Award Lecture." (Hong
WK, Cancer Res. 1993 Nov 1;53(21):5113-20.)
• Nice overview of larynx preservation history. 3-year outcome induction chemo 56% vs. surgery-RT 53%
(NS). Survival for patients who failed induction chemo and underwent laryngectomy (18%) comparable.
Larynx preservation 62%, improved swallowing.
• No difference in survival at 10 years of follow-up. (later paper)
Chemo-RT vs. RT Alone

• EORTC 24954 (1996-2004) -- Sequential chemo-RT vs. alternating chemo-RT
• Randomized. 450 patients. Larynx T2-T4 N0-N2 (21% by AJCC staging) or Hypopharynx T2-T4 N0-N2 (79%
by AJCC staging), surgical candidates for total laryngectomy not requiring flap closure. Excluded if candidates
for partial laryngectomy. Arm 1) Sequential chemo->RT. Induction cisplatin 100 mg/m2 + 5-FU 1000 mg/m2
x4 cycles followed by RT 70 Gy; if stable/progression on chemo, total laryngectomy vs Arm 2) Alternating
chemo->RT. Cisplatin 20 mg/m2 + 5-FU 200 mg/m2 x1 week -> RT 20 Gy -> cisplatin/5-FU x1 week -> RT
20 Gy -> cisplatin/5-FU x1 week (based on prior Italian randomized data)
• 6-years; 2009 PMID 19176454 -- "Phase 3 Randomized Trial on Larynx Preservation Comparing Sequential
vs Alternating Chemotherapy and Radiotherapy." (Lefebvre JL, J Natl Cancer Inst. 2009 Jan 27. [Epub ahead
of print]) Median F/U 6.5 years
• Outcome: Larynx preservation sequential 1.6 years vs. 2.3 years (NS); 5-year larynx preservation 30% vs.
36% (NS). Median OS sequential 4.4 years vs. alternating 5.1 years (NS); median PFS 3.0 vs 3.1 years
(NS). DSS ~50%. Salvage surgery sequential 30% vs. alternating 22%. No difference in patterns of relapse
• Toxicity: Grade 3-4 mucositis sequential 32% vs. alternating 21%; late fibrosis 16% vs. 11%
• Conclusion: Both strategies valid for larynx preservation
• Editorial (PMID 19176460): larynx preservation defined as survival with larynx without tumor,
tracheotomy or use of feeding tube, which gives these states equal utility as death; other issues with
endpoints used for larynx preservation. Need a common standardized endpoint
• RTOG 91-11 / Intergroup (1992-2000) -- Sequential chemo -> RT vs. concurrent chemo-RT vs. RT alone
• Randomized, 3 arms. 518/547 patients. Stage III or IV cancers of the glottic or supraglottic larynx, which
would require total laryngectomy. Excluded T1 and large volume T4 (penetrating through cartilage or >1cm
into BOT). Arm 1) Induction cisplatin 100 mg/m2 + 5-FU C.I. 1000 mg/m2 Q3W x3 cycles, followed by RT
for CR or followed by laryngectomy for PR (this Arm based on results of the VA Larynx trial) vs. Arm 2)
Concurrent cisplatin 100 mg/m2 Q3W + RT vs. Arm 3) RT alone. RT dose was 70/35, elective neck and SCV
50/25. Patient in the first arm who had salvage surgery for poor response to chemo received adjuvant RT to
50-70 Gy depending on surgical margin status. Planned lymph node dissection was performed for LN > 3cm or
multiple lymph nodes at original staging. In induction group, 83% continued to RT and most of others received
more chemotherapy or RT but not surgery. End point was preservation of larynx
• ASTRO; 2002 Webcast: Moshe Maor [1] Discussion: Louis Harrison [2]
• 4-years; 2003 - PMID 14645636 — "Concurrent chemotherapy and radiotherapy for organ preservation in
advanced laryngeal cancer." (Forastiere AA et al. N Engl J Med. 2003 Nov 27;349(22):2091-8.) Median F/U
3.8 years
• Larynx preservation: induction 72% (SS) vs. concurrent 84% vs. RT alone 67% (SS). No benefit to
induction chemo over RT alone. Laryngectomy-free survival at 2-years and 5-years was 59%/43%
(induction), 66%/45% (concurrent), and 53%/38% (RT alone), with no S.S. difference between the two
chemo groups but a S.S. difference between concurrent and RT alone. There was no difference in LFS
between the two chemo arms due to an increase in intercurrent deaths for the concomitant group.
• Speech & swallow: 2-year moderate+ impediment induction 3% vs. concurrent 6% vs. RT alone 8% (NS)
• Outcome: 2-year OS induction 76% vs. concurrent 74% vs. RT alone 75% (NS). 5-year OS 55% vs. 54%
vs. 56% (NS). LC 64% (SS) vs. 80% vs. 56% (SS), no benefit for induction over RT alone. DM induction
9% vs. chemo-RT 8% vs. RT alone 16% (SS)
• Toxicity: Grade 3-4 induction chemo 24% vs. concurrent chemo 30% vs. RT alone 36% (NS);
treatment-related deaths 3% vs. 5% vs. 3%
• Conclusion: Larynx preservation best with concurrent chemo; distant mets reduced by chemotherapy.
• Salvage Laryngectomy; 2003 PMID 12525193 — "Outcome of salvage total laryngectomy following organ
preservation therapy: the Radiation Therapy Oncology Group trial 91-11." (Weber et al. Arch Otolaryngol
Head Neck Surg. 2003 Jan;129(1):44-9.)
• Outcome: Total laryngectomy induction 28% vs. concurrent 16% vs. RT alone 31% (SS). Complication rate
52-59% (NS), pharyngocutaneous fistula 15-30%. LRC 74% vs. 74% vs. 90%. 2-year OS 69% vs. 71% vs.
76% (NS)
• Conclusion: Laryngectomy following organ preservation treatment has acceptable morbidity. Survival not
influenced by initial organ preservation strategy
• 5-years; 2006 ASCO Abstract [3] -- "Long-term results of Intergroup RTOG 91-11: A phase III trial to
preserve the larynx--Induction cisplatin/5-FU and radiation therapy versus concurrent cisplatin and radiation
therapy versus radiation therapy." (Forastiere AA, Journal of Clinical Oncology, 2006 ASCO Annual Meeting
Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 5517)
• Outcome: 5-year laryngectomy-free survival I+RT 45% vs CRT 47% vs. RT 34% (SS). Laryngeal
preservation 70% vs. 84% vs 66% (SS). LRC 55% vs 69% vs 51% (SS). CRT significantly better than I+RT
or R. DM low 14% vs. 13% vs 22% (NS). OS 59% vs. 55% vs. 53% (NS)
• Conclusion: Concurrent chemo-RT superior treatment in terms of larynx preservation and locoregional
control, but no difference in 5-year overall survival
Practice Guidelines
• ASCO; 2006 PMID 16832122 -- "American Society of Clinical Oncology clinical practice guideline for the use
of larynx-preservation strategies in the treatment of laryngeal cancer." (ASCO, J Clin Oncol. 2006 Aug
1;24(22):3693-704.)
References
[3] http:/ / www. asco. org/ ASCO/ Abstracts+ %26+ Virtual+ Meeting/ Abstracts?& vmview=abst_detail_view& confID=40&
abstractID=30895

Supraglottis
Anatomy
• Subsites of the supraglottic larynx: epiglottis, arytenoid cartilages, false cords, aryepiglottic folds
• Major lymphatic drainage of supraglottic larynx are levels II, III, IV.
• 55% clinically positive nodes at diagnosis, 16% bilateral
• Anatomic Landmarks
• Hyoid bone - C3
• Superior border of thyroid cartilage - C4
• Cricoid cartilage - C6
Staging
AJCC Staging System
• Tumor
• T1 - limited to one subsite, normal vocal cord mobility
• T2 - more than one adjacent subsite, but no fixation of vocal cords
• T3 - vocal cord fixation, or invasion of the following: postcricoid area, pre-epiglottic tissues, paraglottic space,
or minor thyroid cartilage erosion (inner cortex)
• T4a - invades through thyroid cartilage or invades tissues beyond the larynx (trachea, soft tissue of neck,
extrinsic muscles of the tongue, strap muscles, thyroid, esophagus)
• T4b - invades prevertebral space, carotid, or mediastinum
• Nodes (same as for most H&N sites)
• N0 - no nodes
• N1 - single ipsilateral lymph node, 3 cm or less
• N2a - single ipsilateral LN, > 3 cm but <= 6 cm
• N2b - multiple ipsilateral LN, none > 6 cm
• N2c - bilateral or contralateral LN, none > 6 cm
• N3 - LN > 6 cm
• Metastasis
• M0 - none
• M1 - yes
Stage Grouping
• Stage I - T1N0
• Stage II - T2N0
• Stage III - T3N0, T1-3N1
• Stage IVA - T4a or N2
• Stage IVB - T4b or N3
• Stage IVC - M1
Treatment
• T1 and favorable T2N0 can be treated w/ definitive xrt or larynx conserving surgery.
• Unfavorable T2N0 can be treated w/ definitive chemoxrt or larynx conserving surgery.
• Indications for postoperative xrt include: close/positive margins, LVI, PNI
• Locally advanced disease should be treated with definitive chemoxrt
Pre-op RT vs. Post-op RT

• RTOG 73-03 (1973-1979)
(n=43).
second primaries
second primaries
Definitive RT
• Varese, Italy, 1997 (1983-92) PMID 9282245 -- Spriano G et al. "Conservative management of T1-T2N0
supraglottic cancer: a retrospective study." Am J Otolaryngol. 1997 Sep-Oct;18(5):299-305.
• 166 pts w/ SGL CA tx'd w/ larynx conserving surgery or definitive xrt
• DFS 88% (surg) vs 76% (xrt)
• Ultimate local control for xrt was 92% if salvage surgery was taken into account.
• Likely of salvage rescuing a local failure was ~50%.
• Larynx preservation rate was 95% (surg) vs 72% (xrt)
• Rotterdam, 1990 (1965-79) PMID 2298616 -- Hoekstra CJ et al. "Squamous cell carcinoma of the supraglottic
larynx without clinically detectable lymph node metastases: problem of local relapse and influence of overall
treatment time." Int J Radiat Oncol Biol Phys. 1990 Jan;18(1):13-21.
• 203 pts w/ SCC of SGL tx'd curatively. 193 tx'd w/ primary xrt reserving surgery for salvage; re-evaulation
occured at 40 Gy and definitive course to 60-70 Gy was given if pts had response at re-eval. 33 pts required
surgery.
• 53% RFS for T2, 39% RFS for T4
Hyperfractionation
• MDACC, 1989 (1984-87) PMID 2808039 -- Wendt CD et al. "Hyperfractionated radiotherapy in the treatment of
squamous cell carcinomas of the supraglottic larynx." Int J Radiat Oncol Biol Phys. 1989 Nov;17(5):1057-62.
• 41 pts w/ SCC of SGL tx'd w/ 1.2 Gy BID to 72-79 Gy (76.8 median).
• Local control rates improved w/ hyperfractionation over historical MDACC controls (96% vs 82% at 1 yr,
87% vs 76% at 2 yrs).
• MGH, 1986 (1979-84) PMID 3943989 -- Wang CC et al. "Twice-a-day radiation therapy for supraglottic
carcinoma." Int J Radiat Oncol Biol Phys. 1986 Jan;12(1):3-7.
• 106 pts tx'd w/ 1.6 Gy BID to 64 Gy in split course compared to 79 pts tx'd w/ conventional fractionation to 65
Gy
• 3yr local control was 76% (hyperfractionated) vs 50% (conventional)
• 3yr local control for T1/T2 was 88% vs 63%
• 3yr local control for T3/T4 was 66% vs 33%
Induction Chemo-RT vs. Primary RT alone

• RTOG 68-01 -- methotrexate
Salvage Surgery
• Gainesville, 1995 (1964-91) PMID 7790245 -- Parsons JT et al. "Salvage surgery following radiation failure in
squamous cell carcinoma of the supraglottic larynx." Int J Radiat Oncol Biol Phys. 1995 Jun 15;32(3):605-9.
• 206 pts tx'd curatively w/ xrt. 46 pts had local failure (22%). Deemed successful surgical salvage if NED at 2
yrs.
• 26 pts had total laryngectomy, 4 had voice sparing salvage procedure.
• Most failures after salvage were b/c of inability to control local dz.
• Rate of post-surgical complications 37%
• 1/2 to 2/3 of pts w/ local failure undergo salvage surgery. 25-30% long term DFS in this population.

Glottis
Glottic Larynx
Overview
• Anatomy - true vocal cords, anterior and posterior commissures down to 5 mm below free margin of vocal cords
• Most common laryngeal cancer in USA. Majority occur in anterior 2/3 of vocal cords
• Symptoms - persistent hoarseness, later dyspnea, chronic cough, hemoptysis, stridor
• Staging
• T1 - limited to vocal cords, with normal mobility
• T1a - limited to one vocal cord
• T1b - involves both vocal cords
• T2 - extends to supraglottis or subglottis, and/or with impaired vocal cord mobility
• T3 - vocal cord fixation or invades paraglottic space or minor thyroid cartilage erosion
• T4 - invades through other tissues (thyroid cartilage, thyroid, trachea, pharynx, etc)
• T4a - invades through thyroid cartilage or tissues beyond the larynx
• T4b - invades prevertebral space, carotid, mediastinum
• Lymphatics - true vocal cords don't have any; lymphatic spread via tumor extension to supraglottis or subglottis
• LN+ <2% in T1, 5% in T2, 15-20% in T3, 20-30% in T4
• Treatment:
• No randomized trials comparing surgery to RT to laser resection
• For T1-T2: local control, laryngeal preservation, and survival comparable after laser resection, RT, and partial
laryngectomy. Voice quality comparable with laser resection and RT in smaller lesions, worse in larger lesions
after partial laryngectomy. Therefore recommendation for T1 and T2 with normal cord mobility treated with
RT or laser resection for superior voice preservation. Bulky T2 and impaired cord mobility treated with RT or
partial laryngectomy
• Neck dissection in T1-T2 is controversial
• RT fields:
• T1 and early T2 - two small opposing lateral fields centering on vocal cords, parallel to trachea. From upper
thyroid notch to lower border of the cricoid (at C6). Anterior border 1 cm anterior to the skin surface at the
level of vocal cords. Posterior border to include anterior portion of posterior pharyngeal wall. 5 x 5 cm2 field
usually good.
Outcomes
• Florence; 2005 (1970-1999) PMID 16095847 -- "Radical radiotherapy for early glottic cancer: Results in a series
of 1087 patients from two Italian radiation oncology centers. I. The case of T1N0 disease." (Cellai E, Int J Radiat
Oncol Biol Phys. 2005 Dec 1;63(5):1378-86.)
• Retrospective. 831 T1 glottic patients in 2 institutions. RT: two lateral parallel opposed or slightly angled
photon beams with or without wedges or a direct anterior electron field.
• Outcome: 5-year OS (10-year OS): 77% (57%); local control 84% (83%), salvage 95% (93%)
• Predictors of local control: gender, tumor extent, anterior commissure involvement, beam type, dose >65 Gy
• 20-year second tumor probability: 23% (second tumor deaths > laryngeal tumor deaths)
• Conclusion: Use doses >65 Gy and field size 36-49 cm2
• Florence; 2005 (1970-1999) PMID 16115737 -- "Radical radiotherapy for early glottic cancer: Results in a series
of 1087 patients from two Italian radiation oncology centers. II. The case of T2N0 disease." (Frata P, Int J Radiat
Oncol Biol Phys. 2005 Dec 1;63(5):1387-94.)
• Retrospective. 256 T2 glottic patients in 2 institutions. RT: two lateral parallel opposed or slightly angled
photon beams with or without wedges or a direct anterior electron field.
• Outcome: 5-year OS (10-year OS): 59% (37%); local control 73% (70%), salvage 86% (85%)
• Predictors of local control: bulky tumor, impaired cord mobility
• 20-year second tumor probability: 23% (laryngeal tumor deaths > second tumor deaths)
• Conclusion: Consider RT a standard treatment for T2. Late damage infrequent
• Aviano; 2003 PMID 12910521 -- "Radiotherapy for patients with early-stage glottic carcinoma: univariate and
multivariate analyses in a group of consecutive, unselected patients." (Franchin G, Cancer. 2003 Aug
15;98(4):765-72.)
• Retrospective. 410 patients with T1-T2 SCC treated 1986-2001
• 10-year OS (5-year): 64% (83%); median time to recurrence 7 months
• Predictors of local control: persistent dysphonia, year of RT
• 22% rate of 2nd primary malignancy -> major cause of death; only 2 died of laryngeal CA
• U Florida; 2001 PMID 11600604 -- "T1-T2N0 squamous cell carcinoma of the glottic larynx treated with
radiation therapy." (Mendenhall WM, J Clin Oncol. 2001 Oct 15;19(20):4029-36.)
• Retrospective. 519 patients with T1-T2
• 5-year local control: T1 93-94%, T2 72-80%; low complications
• Predictors of local control: overall treatment time, T-stage, grade
Fractionation
Randomized
• Osaka (Japan)(1993-2001) -- RT 2 Gy/fx (60-66 Gy) vs. RT 2.25 Gy/fx (56.25-63 Gy)
• Randomized. 180 patients with glottic T1N0. Arm 1) RT 60/30 (small tumors) or 66/33 (large tumors) @ 2
Gy/fx over ~46 days vs. Arm 2) RT 56.25/25 (small tumors) or 63/28 (large tumors) @ 2.25 Gy/fx over ~39
days. Parallel opposed fields with individualized wedge-filtered technique, majority 5x5 cm
• 5-years; 2006 PMID 16169681 -- "Radiotherapy for early glottic carcinoma (T1N0M0): results of prospective
randomized study of radiation fraction size and overall treatment time." (Yamazaki H, Int J Radiat Oncol Biol
Phys. 2006 Jan 1;64(1):77-82. Epub 2005 Sep 19.)
• Outcome: 5-year LC 2 Gy/fx 77% vs. 2.25 Gy/fx 92% (SS); CSS 97% vs. 100% (NS)
• Late Toxicity: no severe late toxicity, no difference in early/minor late toxicity
• Conclusion: Use of 2.25 Gy/fx with shorter overall treatment time showed superior local control compared
to conventional 2 Gy/fx, without worse toxicity
• RTOG 95-12 / EORTC 22992 -- 70/30 vs. 79.2/66 @ 1.2 Gy BID
• Randomized. 250 patients. T2a-bN0 vocal cord. Modified AJCC staging: T2a - tumor extends to supraglottic
and/or subglottic structures without impaired mobility; T2b - tumor causes impaired mobility. Randomized
SFX 70 Gy (2 Gy/fx) vs HFX 79.2 Gy (1.2 Gy BID). Boost after 50 Gy (std fx) or 60 Gy (BID). Primary
fields: (minimum) 6x6 cm field, centered over mid-thyroid cartilage. Upper border 0.5-1 cm above thyroid
notch, posterior border 1 cm behind thyroid cartilage, inferior border at the bottom of the cricoid cartilage, and
1 cm fall off anteriorly. Larger field sizes may be needed to obtain 2 cm margins around the primary. No
elective nodal irradiation. Boost includes tumor plus 1 cm margin. Boost may reduce posteriorly off the
arytenoids if the posterior 1/3 of the cord is not involved by tumor. Bolus (2-5mm) may be used over the
anterior larynx for anterior tumors.
• 2006 ASTRO Abstract "A Randomized Trial of Hyperfractionation vs. Standard Fractionation In T2
Squamous Cell Carcinoma of the Vocal Cord" (Trotti A, IJRBOP Volume 66, Issue 3, Supplement 1, 1
November 2006, Page S15)
• 5-year outcome: LC HFX 79% vs. SFX 70% (NS); DFS 51% vs. 37% (NS); OS 73% vs. 62% (NS)
• Toxicity: HFX modestly higher acute skin, mucosal, and laryngeal toxicity; high grade late effects
uncommon
• Conclusion: Local control modestly higher, but with only 58 failures, don't have sufficient power
• Comment: SFX relatively low
Retrospective
• New Zealand; 2006 (1986-1998) PMID 16635034 -- "TN/TN glottic carcinoma: a comparison of two
fractionation schedules." (Short S, Australas Radiol. 2006 Apr;50(2):152-7.)
• Retrospective. 145 patients with T1-T2 glottis. RT 6MeV beams, standard fractionation (SFX) 60-66 Gy in
30-33 fx (2 Gy/fx) over 6-6.5 weeks (1986-1992) vs. accelerated/hypofractionated regimen (AHFX) 52.5-55
Gy in 20 fx (2.75 Gy/fx) over 4 weeks. Median F/U 4.9 years
• 5-year OS: 78%, toxicity comparable
• T1N0: loco-regional control AHFX 95% vs. SFX 75% (SS), 5-year laryngectomy-free survival AHFX 95% vs.
SFX 75% (SS)
• T2N0: loco-regional control AHFX 81% vs. SFX 80% (NS), 5-year laryngectomy-free survival AHFX 92%
vs. SFX 80% (NS)
• Conclusion: Accelerated hyperfractionation better for T1, same for T2. Comparable toxicity.
• MD Anderson; 2003 PMID 12527044 -- "Results of radiotherapy for T2N0 glottic carcinoma: does the "2" stand
for twice-daily treatment?" (Garden AS, Int J Radiat Oncol Biol Phys. 2003 Feb 1;55(2):322-8.)
• Retrospective. 230 patients with T2, treated 197-1998. Median f/u 82 months
• RT: 180 patients treated with parallel-opposed fields. 89 patients treated with 2 Gy/fx to 32-75 Gy, 57 patients
treated with 2-2.2 Gy to 66-70 Gy, and 81 patients treated with BID fxs to 74-80 Gy
• 5-year local control: 72% (91% after salvage); BID fxs 79% vs. QD fxs 67% (p=0.06)
• Predictors of local control: subglottic extension, daily dose <=2 Gy/fx
• Conclusion: BID to 77 Gy better than QD to 70 in 2 Gy/fx in T2N0
• Poland; 1999 PMID 9989520 -- "Clinical radiobiology of glottic T1 squamous cell carcinoma." (Skladowski K,
• Retrospective. 235 patients with T1N0 treated by RT alone. RT conventional 5-day schedule, dose 51-70 Gy,
dose/fx 1.5-3.0 Gy/fx, on-treatment time 24-79 days. Median f/u 4 years
• Outcome: 5-year LC 84%
• Predictors of control: worse if dose <61 Gy, increase in treatment time 45 to 55 days decreased TCP by 13%.
Potential doubling time: 5.5 days. Hemoglobin: drop in 1g/dl resulted in TCP decrease by 6%
• Conclusion: The significant correlation between the total dose, overall treatment time, hemoglobin
concentration, and tumor control probability has been found for T1 glottic cancer
• UCSF; 1997 (1956-1995) PMID 9300746 -- "Influence of fraction size, total dose, and overall time on local
control of T1-T2 glottic carcinoma." (Le QT, Int J Radiat Oncol Biol Phys. 1997 Aug 1;39(1):115-26.)
• Retrospective. 398 patients with T1-T2 glottic cancer, daily RT. Tumor dose 46.6 - 77.6 Gy (median 63 Gy).
• Outcome: 5-year LC T1 85%, T2 70%.
• T1 subset: No impact of size/schedule. Anterior commisure involvement 80% vs. none 88%. If treated in
1981-1995, 91%
• T2 subset: Treatment time <=43 days 100% vs. >43 days 84%; Fraction size <1.8 Gy 44% vs. >=2.25 Gy
100%; Total dose <=65 Gy 60% vs. >65 Gy 78%; normal cord mobility 79% vs. impaired cord mobility 45%;
subglottic extension 58% vs. no subglottic extension 77%
• Toxicity: severe 1.8%
• Conclusion: Risk factors evaluated for T1 and T2 glottic cancers
Field Size
• Osaka (Japan)(1982-1992) -- RT 5x5 cm vs. RT 6x6 cm
• Randomized. 273 patients with T1N0 glottic cancer, treated with RT 4 MV bilateral portals. Arm 1) field size
5x5 cm vs. Arm 2) field size 6x6 cm. Dose 60/30
• 5-years; 1996 PMID 8721266 -- "Radiation therapy for early glottic carcinoma (T1N0M0). The final results of
prospective randomized study concerning radiation field." (Chatani M, Strahlenther Onkol. 1996
Mar;172(3):169-72.)
• Outcome: 5-year RFS 5x5 88% vs 6x6 88% (NS)
• Toxicity: acute toxicity same (NS); late toxicity 5x5 17% vs. 6x6 23% (SS)
• Conclusion: Small field (5x5 cm) is recommended
Specific Situations
Anterior commissure extension
• 2004 Lausanne PMID 14762660 -- Decreased local control following radiation therapy alone in early-stage
glottic carcinoma with anterior commissure extension. (Zouhair A, Strahlenther Onkol. 2004 Feb;180(2):84-90.)
• Retrospective. 122 patients with T1-T2N0 treated 1983-2000; median f/u 85 months
• RT: 3D-CRT in 40%, median dose 70 Gy in 2Gy/fx over 46 days
• 5-year OS: 80%, DFS 70%; median time to recurrence 13 months. Only 6 died of laryngeal CA
• Poor predictors of local control: anterior commissure extension, arytenoid protection, male gender
Subglottic extension
• 1997 Louisiana State PMID 9192435 -- Glottic cancer with subglottic extension. (Ampil FL, Radiat Med. 1997
Mar-Apr;15(2):103-7.)
• Retrospective. 27 patients over 13 years. Surgery + RT (60%), RT alone (40%)
• Locoregional failure: 18% in surgery + RT, 40% in RT alone (NS)
• 2-year OS: 53% surgery + RT, 42% RT alone (NS)
• Recommend: surgery + RT
Quality-of-life
• PMID 15936548 -- A screening questionnaire for voice problems after treatment of early glottic cancer. (van
Gogh CD, Int J Radiat Oncol Biol Phys. 2005)
• Conclusion: "The questionnaire proved to be a reliable, valid, and feasible method to detect voice impairment
in daily life. The questionnaire is easy to fill in, and interpretation is straightforward. It is useful for both
radiation oncologists and otorhinolaryngologists in their follow-up of patients treated for early glottic cancer."
Set-Up
• T1 larynx is typically a clinical verification set up, unless OBI available
• Isocenter should line up 1cm below and 1cm posterior to the thyroid notch on visual field inspection
Review
• 2004 PMID 15112257 -- Management of T1-T2 glottic carcinomas. (Mendenhall WM, Cancer. 2004 May
1;100(9):1786-92.)
Keywords: radiation, radiotherapy
Radiation Oncology/Head & Neck/Hypopharynx

Hypopharynx Cancer
Epidemiology
• 2,500-3,000 annual cases in US
• Pyriform sinus most common (65-75%), posterior pharyngeal wall 10-20%, postcricoid region 5-15%
• Majority (>80%) present with Stage III-IV disease
• Highly associated with tobacco use; EtOH impact not as clear (per Perez, 5th ed). Also occupational exposure to
dust, iron compounds, fumes
• HPV associated in 20-25%, clinical implications not yet clear
• May arise in the setting of Plummer-Vinson syndrome, characterized by iron deficiency anemia, hypopharyngeal
webs, weight loss, and dysphagia
Anatomy
• Extent
• Superior extent - level of superior border of hyoid bone / floor of valecula
• Inferior extent - level of lower border of cricoid cartilage
• Anterior extent - connection of the two pyriform sinuses at post cricoid region.
• Posterior extent - posterior pharyngeal wall
• Subsites
• Bilateral pyriform sinuses
• Extends from pharyngoepiglottic fold to upper end of esophagus, at the lower border of cricoid cartilages
• Superiorly are surrounded by thyrohyoid membrane, through which passes the internal branch of superior
laryngeal nerves. Tumor involvement can result in referred otalgia
• Postcricoid region
• Mucosa overlying cricoid cartilage. Arytenoids and AE folds form the superior border. Esophageal mucosa
forms the inferior border
• Posterior pharyngeal wall
• Squamous mucosa covering middle/inferior pharyngeal constrictor muscles, typically <1 cm thinck
Nodal Drainage
• Rich lymphatic network draining through thyrohyoid membrane into JD LNs; there may also be direct drainage to
spinal accessory LNs
• Typical primary drainage for posterior pharyngeal wall: Level II and III, typically below jugulodigastric LN
• Surgical reports show direct drainage to lateral retropharyngeal LNs, bypassing JD LNs
• Case report from Dana Farber shows involvement of retropharyngeal LNs at base of skull
• >50% present with clinically positive LNs
• Dana Farber, 2007 PMID 17290070 -- "Retropharyngeal nodes in hypopharynx cancer on positron emission
tomography." (Allen AM, J Clin Oncol. 2007 Feb 10;25(5):599-601.)
• Case report. Hypopharynx T2N1 (2.5cm right jugulodigastric LN)
• PET/CT: Additionally bilateral lateral retropharyngeal nodes (nodes of Rouviere) positive. Patient upstaged to
Stage IV (T2N2c)
• Conclusion: recommend including lateral retropharyngeal LNs to base of skull in IMRT volumes
Staging
Primary Tumor
• T1 - one subsite of hypopharynx and <= 2 cm
AJCC Subsites: left/right pyriform sinus, left/right lateral hypopharyngeal wall, posterior hypopharyngeal
wall, postcricoid region
• T2 - more than one subsite of hypopharynx or adjacent site, or >2 but <=4 cm
• T3 - >4 cm, or fixation of hemilarynx
• T4a - invades thyroid or cricoid cartilage, hyoid, thyroid gland, esophagus, central compartment soft tissue (e.g,
strap muscles, subcutaneous fat)
• T4b - invades prevertebral fascia, encases carotid, involves mediastinum
Note: T4a and T4b are the same as for larynx (glottic, subglottic, and supraglottic)
Regional Lymph Nodes
• NX - Cannot be assessed
• N0 - No regional lymph nodes metastasis
• N1 - Single ipsilateral lymph node, <= 3cm in greatest dimension
• N2
• N2a - Single ipsilateral lymph node, 3-6 cm in greatest dimension
• N2b - Multiple ipsilateral lymph nodes, <= 6cm in greatest dimension
• N2c - Bilateral or contralateral lymph nodes, <= 6cm in greatest dimension
• N3 - Lymph node(s) >6 cm in greatest dimension
Distant Metastasis
• MX - Cannot be assessed
• M0 - No distant metastasis
• M1 - Distant metastsis
Clinical Stage
• Stage 0 - Tis N0 M0
• Stage I - T1 N0
• Stage II - T2 N0
• Stage III - T3 or N1
• Stage IVC - M1
Treatment
• Memorial Sloan Kettering; 2007 PMID 17493769 -- "Concurrent chemotherapy and intensity-modulated
radiotherapy for locoregionally advanced laryngeal and hypopharyngeal cancers." (Lee NY, Int J Radiat Oncol
Biol Phys. 2007 Oct 1;69(2):459-68. Epub 2007 May 9.)
• Retrospective. 20 larynx and 11 hypopharynx patients, treated with IMRT and concurrent platinum-based
chemo. Most Stage IV disease. RT dose painting GTV 70 Gy (@2.12 Gy/fx), high-risk CTV 59.4 Gy (@1.8
Gy/fx, typically Levels II-IV; Levels I or V not routinely contoured unless judged high risk eg positive Level
II), low-risk CTV 54 Gy (@1.64 Gy/fx, uninvolved contralateral neck and base of skull). Chemo cisplatin 100
mg/m2 Q3W or carbo 60-70 mg/m2 + 5-FU 600 mg/m2. Median F/U 2.2 years
• Outcome: 2-year LC 86%, RC 94%, laryngectomy-free 89%, DM-free 92%, OS 63%.
• Toxicity: No late G2+ xerostomia. PEG-dependent hypopharynx 31% vs. larynx 15%
• Conclusion: IMRT + chemo encouraging LR control in advanced larynx/hypopharynx. However, high rate of
PEG dependency
• Kyushu, 2005 (Japan) PMID 15936545 -- "Chemoradiation therapy with or without salvage surgery for early
squamous cell carcinoma of the hypopharynx." (Nakamura K, Int J Radiat Oncol Biol Phys. 2005)
• 43 patients with Stage I/II: 30-40 Gy +/- chemo, if complete response (75%), RT to 61.2 Gy
• 5-year OS 70.4%, DSS 89.5%
• Conclusion: Majority of patients with early hypopharyngeal cancer was curable. However, second
malignancies influenced the overall outcome of patients with early hypopharyngeal cancer.

• RTOG 73-03 (1973-1979)
(n=43).
second primaries
second primaries

• RTOG 68-01
Laryngectomy + RT vs. Chemo-RT

• EORTC 24891 (1990-1993) - Surgery + post-op RT vs Induction cisplatin/5-FU + RT
• Randomized. 194/202 patients. Operable SCC of the pyriform sinus or AE fold, Stage T2-T4 N0-N2b, N3
(N2c initially allowed, stopped in 1992). Arm 1) Immediate surgery + post-op RT 50-70 Gy vs. Arm 2)
Induction cisplatin 100 mg/m2 + 5-FU 1000 mg/m2 x2 cycles. If CR, then RT 70 Gy. If PR, then
cisplatin/5-FU x another cycle. If CR, then RT 70 Gy. If PR, or PD anytime, then surgery. RT given 50 Gy
bilateral neck + 20 Gy boost to tumor/palpable LNs. Surgery was total laryngectomy with partial
pharyngectomy to allow primary closure
• 4-years; 1996 PMID 8656441 — "Larynx preservation in pyriform sinus cancer: preliminary results of a
European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer
Cooperative Group." Lefebvre JL et al. J Natl Cancer Inst. 1996 Jul 3;88(13):890-9.) Median F/U 4.25 years
• Outcome: median OS surgery 2.1 years vs. chemo-RT 3.7 years (equivalent). Larynx preservation 3-years
42%, 5-years 35%. LF 12% vs. 17%, RF 19% vs. 23%
• Conclusion: Larynx-preserving strategy is feasible, induction chemo followed by RT is new standard
treatment for EORTC.
• 10-years; 2004 ASCO Abstract [1] -- "Is laryngeal preservation (LP) with induction chemotherapy (ICT) safe
in the treatment of hypopharyngeal SCC? Final results of the phase III EORTC 24891 trial." (Lefebvre JL,
Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No
14S (July 15 Supplement), 2004: 5531) Median F/U 10 years
• Outcome: 5-year OS surgery 33% vs. chemo-RT 38%; 10-year OS 14% vs. 13%. 5-year PFS 26% vs. 32%.
Larynx preservation 5-years 22% (58% survivors), 10-years 9% (69% survivors)
Primary Chemo-RT Timing Strategies

• France (2001-2005) -- Induction chemo-RT vs. concurrent chemo-RT
• Randomized. 75 patients, T3 pyriform sinus (N0-N3). 4 centers. Arm 1) concurrent chemo-RT. Chemo
cisplatin 100 mg/m2 Q3W, RT 70 Gy vs. Arm 2) induction chemo cisplatin 100 mg/m2 + 5-FU 100 mg/m2 x2
courses. If CR/PR >80%, RT 70 Gy, else total laryngectomy
• 2009 PMID 19449227 -- "Randomized phase III trial comparing induction chemotherapy followed by
radiotherapy to concomitant chemoradiotherapy for laryngeal preservation in T3M0 pyriform sinus
carcinoma." (Prades JM, Acta Otolaryngol. 2009 May 15:1-6.) Median F/U 2 years
• Outcome: 2-year laryngeal preservation concurrent 92% vs induction 68% (SS). Local control 81% vs.
62%. Distant mets 19% vs 38%. EFS 36% vs. 41% (NS). 2-year OS 47% vs. 51% (NS)
• Toxicity: any toxicity 76% vs 71%
• Conclusion: Concurrent chemo-RT superior to sequential chemo-RT

• EORTC 24954 (1996-2004) -- Sequential chemo-RT vs. alternating chemo-RT
• Randomized. 450 patients. Larynx T2-T4 N0-N2 (21% by AJCC staging) or Hypopharynx T2-T4 N0-N2 (79%
by AJCC staging), surgical candidates for total laryngectomy not requiring flap closure. Excluded if candidates
for partial laryngectomy. Arm 1) Sequential chemo->RT. Induction cisplatin 100 mg/m2 + 5-FU 1000 mg/m2
x4 cycles followed by RT 70 Gy; if stable/progression on chemo, total laryngectomy vs Arm 2) Alternating
chemo->RT. Cisplatin 20 mg/m2 + 5-FU 200 mg/m2 x1 week -> RT 20 Gy -> cisplatin/5-FU x1 week -> RT
20 Gy -> cisplatin/5-FU x1 week (based on prior Italian randomized data)
• 6-years; 2009 PMID 19176454 -- "Phase 3 Randomized Trial on Larynx Preservation Comparing Sequential
vs Alternating Chemotherapy and Radiotherapy." (Lefebvre JL, J Natl Cancer Inst. 2009 Jan 27. [Epub ahead
of print]) Median F/U 6.5 years
• Outcome: Larynx preservation sequential 1.6 years vs. 2.3 years (NS); 5-year larynx preservation 30% vs.
36% (NS). Median OS sequential 4.4 years vs. alternating 5.1 years (NS); median PFS 3.0 vs 3.1 years
(NS). DSS ~50%. Salvage surgery sequential 30% vs. alternating 22%. No difference in patterns of relapse
• Toxicity: Grade 3-4 mucositis sequential 32% vs. alternating 21%; late fibrosis 16% vs. 11%
• Conclusion: Both strategies valid for larynx preservation
• Editorial (PMID 19176460): larynx preservation defined as survival with larynx without tumor,
tracheotomy or use of feeding tube, which gives these states equal utility as death; other issues with
endpoints used for larynx preservation. Need a common standardized endpoint
• Conclusion: Similar survival curves with larynx preservation as with conventional total laryngectomy, with
2/3 survivors retaining their larynx
References
[1] http:/ / www. asco. org/ ASCO/ Abstracts+ & + Virtual+ Meeting/ Abstracts?& vmview=abst_detail_view& confID=26& abstractID=3215
Radiation Oncology/Head & Neck/Oral cavity

Includes lip and oral cavity.
Anatomy
Divided into specific areas:
• Mucosal lip - vermillion surface only
• Buccal mucosa - membrane lining inner surface of the lip and cheeks to the attachment of mucosa to alveolar
ridges and pterygomandibular raphe
• Lower alveolar ridge - mucosa overlying the alveolar ridge of the mandible. Extends from lower buccal gutter to
free mucosa of the floor of the mouth. Posteriorly goes to ascending ramus of the mandible
• Upper alveolar ridge - mucosa overlying the alveolar ridge of the maxilla. Extends from upper buccal gutter to
junction of hard palate. Posteriorly goes to upper end of pterygopalatine arch
• Retromolar trigone - mucosa overlying ascending ramus of mandible from posterior surface of last molar tooth to
apex, adjacent to tuberosity of maxilla
• Floor of mouth - semilunar space over mylohyoid and hyoglossus muscles. Extends from inner surface of lower
alveolar ridge to undersurface of tongue, and posteriorly to base of anterior pillar of the tonsil. Contains ostia of
submaxillary and sublingual salivary glands
• Hard palate - semilunar area between upper alveolar ridge and mucous membrane covering the palatine process of
maxillary palatine bones. Extends from inner surface of superior alveolar ridge to posterior edge of the palatine
bone
• Oral tongue - extends anteriorly from circumvallate papillae to undersurface of the tongue at the junction of the
floor of mouth. It consists of tip, lateral borders, dorsum, and undersurface
Staging
• Tumor:
• T1 - 2 cm or less
• T2 - > 2 cm but <= 4 cm
• T3 - >4 cm
• T4 (Lip) - Invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face (i.e. chin or
nose)
• T4a (Oral cavity) - Invades through cortical bone, into deep (extrinsic) muscle of tongue, maxillary sinus, or
skin of face
• T4b - Involves masticator space, pterygoid plates, or skull base, or encases internal carotid artery
• Node:
• N0 - no nodes
• N3 - LN > 6 cm
• Metastasis:
• M0 - none
• M1 - yes
• Stage grouping:
• I - T1 N0
• II - T2 N0
• III - T3 N0, T1-3 N1
• IVA - T4a, N2
• IVB - T4b, N3
• IVC - M1

• RTOG 73-03 (1973-1979)
(n=43).
second primaries
second primaries

• Singapore (1996-2000)
hypopharynx, and oropharynx. Poor organ preservation in oral cavity
Induction chemo-RT vs. Primary RT alone

• RTOG 68-01
Oral Tongue
• Osaka University, Japan Randomized Trial, 1996 (1992-93) - PMID 8985043 -- "Phase III trial of high and
low dose rate interstitial radiotherapy for early oral tongue cancer." Inoue T et al. Int J Radiat Oncol Biol Phys
1996 Dec 1;36(5):1201-4.
• Inclusion criteria: T1-2N0 that could be tx'd w/ single plane implant, localized at lateral tongue border, <1cm,
absence of severe concurrent dz
• Pts randomized to LDR (70 Gy over 4-9 days) vs HDR 60 Gy in 10 fx over 6 days; 15 pts in LDR arm, 14 in
HDR arm
• 86% local control at 2yrs for LDR, 100% for HDR
• UPDATE PMID 11516867 -- 51 pts evaluable in update. 5yr local control 77% (LDR) and 76% (HDR)
• Kobe University, Japan, 2005 PMID 15921890 -- "A comparison of brachytherapy and surgery for the treatment
of stage I-II squamous cell carcinoma of the tongue." Umeda M et al. Int J Oral Maxillofac Surg. 2005
Oct;34(7):739-44.
• 180 pts w/ stage I-II oral tongue CA tx'd w/ LDR (78), HDR (26), or surgery (71)
• Local recurrence seen in 17% LDR, 35% HDR, and 6% surgery groups
• After salvage, local control was 91% in LDR, 85% in HDR and 100% in surgery groups
• 5yr OS 84% in LDR, 73% in HDR, and 95.4% in surgery groups for stage I, 72%, 51.5% and 93.8% in stage II
• MDACC, 1990 (1963-79) - PMID 2370178 -- "Primary radiotherapy in the treatment of stage I and II oral tongue
cancers: importance of the proportion of therapy delivered with interstitial therapy." Wendt CD et al. Int J Radiat
Oncol Biol Phys 1990 Jun;18(6):1287-92.
• 103 pts w/ T1-2N0 SCC of oral tongue (18 T1, 85 T2). Tx regimens included interstital brachy alone,
hypofractionated EBRT + interstitial brachy, conventional fractionation EBRT + interstitial brachy, EBRT
alone.
• 5/8 pts w/ EBRT alone failed locally. 6/18 w/ interstitial alone failed locally.
• 2 yr local control 92% if EBRT doses <40 Gy w/ hi proportion of RT given by interstitial brachy. 2yr local
control 65% if EBRT >40 Gy w/ lower brachy doses.
• 44% neck recurrences if no therapy to neck.
• 13% severe complication rate
Buccal Mucosa
• Orissa, India Randomized Trial, 1996 - PMID 8903493 -- "Post-operative radiotherapy in carcinoma of buccal
mucosa, a prospective randomized trial." Mishra RC et al. Eur J Surg Oncol. 1996 Oct;22(5):502-4.
• Pts w/ stage III and IV SCC of buccal mucosa. Randomized to surgery alone vs surg + postop RT.
• DFS 38% (surgery alone) vs 68% (postop RT)
• Centre Alexis Vautrin, France, 1995 (1973-91) - PMID 7673032 -- "An original technique of brachytherapy in
the treatment of epidermoid carcinomas of the buccal mucosa." Lapeyre M et al. Int J Radiat Oncol Biol Phys.
1995 Sep 30;33(2):447-54.
• 42 pts (36 T1, 35 N0) SCC of buccal mucosa tx'd w/ brachytherapy.
• Either parallel wires technique or loop technique used. 23 pts w/o elective nodal tx, 8 w/ EBRT, 4 w/ neck
dissection
• 63% OS at 2 yrs, 47.5% OS at 5 yrs; >80% recurrences w/i 1 yr
• 91% local control w/ loop technique, 58% local control w/ parallel wire technique.
• Elective nodal tx appeared to be necessary if lesion >1cm
Floor of mouth
• Gustave-Roussy Institute, France, 2002 (1970-85) - PMID 11955737 -- "Brachytherapy for T1-T2
floor-of-the-mouth cancers: the Gustave-Roussy Institute experience." Marsiglia H et al. Int J Radiat Oncol Biol
Phys. 2002 Apr 1;52(5):1257-63.
• 160 pts with carcinoma of FOM tx'd definitively with interstitial brachy. (49% had T1, 51% had T2, 21% had
N1).
• 89% actuarial survival at 2 yrs, 75% actuarial survival at 5 yrs.
• <10% rate of severe necrosis. 18% rate of bone necrosis in total.
• Roswell Park, 1997 (1971-91) - PMID 9243267 -- "Squamous cell carcinoma of the floor of mouth: a 20-year
review." Hicks WL Jr et al. Head Neck. 1997 Aug;19(5):400-5.
• 99 pts with carcinoma of FOM (43 w/ stage I or II).
• 21% likelihood of occult nodal metastatic disease in T1 pts.
• Local control for surgery alone for 81% and regional control was 71%
• RT improved regional control rate for stage IV.
• Conclusion: Elective treatment of regional lymphatics is warranted in carcinoma of FOM.
• Centre Alexis Vautrin, France, 1995 (1976-1992) - PMID 7480819 -- "Epidermoid carcinomas of the floor of
mouth treated by exclusive irradiation: statistical study of a series of 207 cases." Pernot M et al. Radiother Oncol.
1995 Jun;35(3):177-85.
• 207 pts w/ carcinoma of the FOM tx'd w/ definitive RT. 105 received EBRT + brachy, 102 received brachy
alone. 83% pts were N0.
• Local control at 5 yrs was 97% for T1, 72% for T2, 51% for T3.
• Exclusive brachy for T1-2 appeared to be preferable to a combination of EBRT + brachy in T1-2N0 pts.
• Gainesville, 1993 (1964-87) - PMID 8416850 — "Management of squamous cell carcinoma of the floor of
mouth." Rodgers LW Jr et al. Head Neck. 1993 Jan-Feb;15(1):16-9.
• 194 pts. Similar LC for RT alone or surgery alone. Recommend combination therapy for advanced lesions
because of poor local control for a single modality.
Retromolar Trigone
• Gainesville, 2005 (1966-2003) - PMID 15825160 -- "Retromolar trigone squamous cell carcinoma treated with
radiotherapy alone or combined with surgery." Mendenhall WM et al. Cancer. 2005 Jun 1;103(11):2320-5.
• 99 pts w/ SCC of RMT tx'd w/ RT alone (35) or RT + surg (64).
• 5yr locoregional control for RT alone for stage I-III was 51%, for RT + surg was 87%; 5yr LR control for
stage IV was 42% for RT alone, 62% for RT + surg
• Multi-variate analysis suggested surgery + RT was better modality than RT alone.
• Mallinckrodt, 2001 (1971-94) - PMID 11505486 -- "Cancer of retromolar trigone: long-term radiation therapy
outcome." Huang CJ et al. Head Neck. 2001 Sep;23(9):758-63.
• 65 pts w/ SCC of RMT tx'd w/ RT (10 pts preop, 39 pts postop, 15 tx'd w/ RT alone).
• 5yr DFS 76% w/ T1, 50% w/ T2, 72% w/ T3, 54% w/ T4
• MDACC, 1987 (1966-81) - PMID 3597160 -- "Results of irradiation in the squamous cell carcinomas of the
anterior faucial pillar-retromolar trigone." Lo K et al. Int J Radiat Oncol Biol Phys 1987 Jul;13(7):969-74.
• 159 pts w/ SCC of ant faucial pillar or RMT tx'd w/ definitive RT.
• Doses ranged from 60 to 75 Gy. If N0, only ipsi JD nodes treated.
• 92% of recurrences occured within 2 yrs.
• Local failure rates were 29% for T1, 30% for T2, 24% for T3, 40% for T4. After salvage surgery, ultimate
failure rate was 0% for T1, 6% for T2, 8% for T3, 20% for T4. 10% experienced neck failure.
• 30% developed some degree of bone exposure, 5.6% requiring segmental mandibular resection.
Radiation Oncology/Head & Neck/Oropharynx

Anatomy
• Superior edge - plane of superior surface of the soft palate
• Inferior edge - superior surface of hyoid bone / floor of the valecula
• Includes base of tongue, inferior (anterior) surface of the soft palate, uvula, anterior and posterior tonsillar pillars,
glossotonsillar sulci, pharyngeal tonsils, and lateral and posterior pharyngeal walls
Risk Factors
• Smoking
• Alcohol
• HPV 16
• chronic irritation
HPV infection as a risk factor

• Johns Hopkins, 2007 PMID 17494927 -- "Case-control study of human papillomavirus and oropharyngeal
cancer." D'Souza G et al. N Engl J Med. 2007; 356(19):1944-56
• Case control study of 100 pts w/ newly diagnosed oropharyngeal CA and 200 control pts.
• Oropharyngeal CA significantly associated w/ HPV type 16 and high lifetime number of oral sex partners (>6)
and high lifetime number of vaginal sex partners (>26).
• Smoking/alcohol w/ increased association with oropharyngeal CA among subjects w/o HPV-16 exposure.
Staging
AJCC Staging System
• Tumor
• T1 - <= 2 cm
• T2 - >2 and <=4 cm
• T3 - >4 cm
• T4a - invades larynx, deep/extrinsic muscles of the tongue, medial pterygoid, hard palate, or mandible
• T4b - invades lateral pterygoid, pterygoid plates, lateral nasopharynx, skull base, or encases carotid
• N0 - no nodes
• N3 - LN > 6 cm
• Metastasis
• M0 - none
• M1 - yes
Stage Grouping
• Stage I - T1N0
• Stage II - T2N0
• Stage IVC - M1
Risk of LN Involvement
• Johns Hopkins; 2009 (1998-2007) PMID 19131181 -- "Defining the risk of involvement for each neck nodal
level in patients with early T-stage node-positive oropharyngeal carcinoma." (Sanguineti G, Int J Radiat Oncol
Biol Phys. 2009 Aug 1;74(5):1356-64. Epub 2009 Jan 7.)
• Retrospective. 103 patients with T1-T2 clinically N+ oropharyngeal CA, who underwent neck dissection
(radical LND 15%, modified radical LND 71%, selective LND 14%).
• Outcome: Positive Level IB 9%, Level II 91%, Level III 41%, Level IV 18%, and Level V 3%. If CT (-), then
positive Level IB 3%, Level II 76%, Level III 17%, Level IV 6%, and Level V 1%. Can contour Level IB only
posterior half
• Conclusion: Levels II and III should be included in high risk volumes regardless of imaging, Level IV should
be low risk; Levels IB and V at very low risk and could be excluded from RT
Early Stage
• RTOG 00-22 (2001-2005) Protocol (PDF) [1]
• Prospective. 69 patients. Stage I-III (T1-2 N0-1) oropharynx (tonsil, base of tongue, or palate). Neck staging is
based on palpation, not CT, but patients who are "upstaged" by CT are eligible. RT 66 Gy / 30 fractions (2.2
Gy/fx) to primary target PTV and 54-60 Gy / 30 fractions (1.8-2.0 Gy/fx) to secondary target PTV. Objectives:
1) assess feasibility of target coverage and parotid sparing. 2) Determine patterns of failure. 3) Acute and late
effects. Median F/U 2.8 years.
• 2009 PMID 19540060 -- "Multi-Institutional Trial of Accelerated Hypofractionated Intensity-Modulated
Radiation Therapy for Early-Stage Oropharyngeal Cancer (RTOG 00-22)." (Eisbruch A, Int J Radiat Oncol
Biol Phys. 2009 Jun 17.)
• Outcome: 2-year LRF 9% (if major deviations 50%, else 6%, SS)
• Toxicity: Grade 2+ skin 12%, mucosa 24%, salivary 67%, esophagus 19%, ORN 6%. Xerostomia 6 months
55%, 1 years 25%, 2 years 16%; salivary output didn't recover over time
• Conclusion: Moderately AHFX IMRT alone feasible

• RTOG 73-03 (1973-1979)
(n=43).
second primaries
second primaries

• Singapore (1996-2000)

hypopharynx, and oropharynx; organ preservation in oral cavity poor

• RTOG 68-01 -- methotrexate
Altered Fractionation
• RTOG 90-03 (1991-1997) -- SF vs HF vs Split course AFX vs AFX-CB
• Randomized, 4 arms. 1073 patients. Stage III-IV (oral cavity, oropharynx, or supraglottic larynx) or Stage
II-IV (base of tongue, hypopharynx). Arm 1) SF standard fractionation 70/35 @ 2 Gy/fx vs. Arm 2) HF
hyperfractionated 81.6/68 @ 1.2 Gy BID vs. Arm 3) AFX-S split course accelerated fractionation 67.2/42 @
1.6 Gy BID with 2 week break after 38.4 Gy vs. Arm 4) AFX-CB concomitant boost 72 Gy given 54/30 @ 1.8
Gy + 18/12 @ 1.5 Gy concurrent BID boost
• 2-years; 2000 PMID 10924966 -- "A Radiation Therapy Oncology Group (RTOG) phase III randomized study
to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation
radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003." (Fu KK, Int J Radiat
Oncol Biol Phys. 2000 Aug 1;48(1):7-16.). Median F/U 2 years, 3.4 for alive patients
• Outcome: 2-year LRC SF 46% vs. HF 54% (SS) vs. AFX-S 47% (NS) vs. AFX-CB 54% (SS); DFS 32%
vs. 38% (NS) vs. 33% (NS) vs. 39% (NS); OS 46% vs. 54% (NS) vs. 46% (NS) vs. 51% (NS)
• Sites of failure: LF 44% vs. 38% vs. 43% vs. 375; RF 32% vs. 27% vs. 31% vs. 33%
• Toxicity: Increased acute effects but no increase in late effects
• Conclusion: HF or CB improve LRC compared to SF, no impact on DFS and OS. Split course comparable
to SF
• RTOG 71-01 (1971-1976) -- continuous vs. split-course
• 1993 PMID 8213620 -- ""Compensated" split-course versus continuous radiation therapy of carcinoma of the
tonsillar fossa. Final results of a prospective randomized clinical trial of the Radiation Therapy Oncology
Group." (Marcial VA, Am J Clin Oncol. 1993 Oct;16(5):389-96.)
• Randomized. 137 patients. All stages, no adenoCA. Arm 1) split course RT 30/10 + 30/10 vs. Arm 2)
continuous RT 60/30-66/33
• Outcome: 5-year LRC split course 25% vs. continuous 28% (NS); 5-year OS 19% vs. 29% (NS)
• Late toxicity: split course 17% vs. continuous 24% (NS)
• Conclusion: No difference
• EORTC 22791
• See Radiation Oncology:H&N
• Improved LC for T3 but not T2 tumors. Trend to improved OS.
Base of Tongue
• Clinical presentation
• Mild sore throat
• Many clinically silent locally, and present with neck mass
• With further enlargement, difficulty swallowing, nasal or "hot potato" voice quality, and ear pain
• Spread
• BOT proper: tend to stay confined to tongue for long time. Advanced lesions spread toward larynx, oral
tongue, and parapharyngeal space
• Valecula: spread along mucosal surface to epiglottis and lateral pharyngeal wall. Can penetrate hyoepiglottic
ligament into pre-epiglottic space
• Lateral BOT: spread into glossotonsillar sulcus, and then into neck
• LN drainage
• LN+ in 50-80%
• Bilateral LN+ in 35-55%
• If clinical ipsilateral N0, pN+ 20-30%
• Treatment overview
• Surgery and RT produce comparable outcomes; however, BOT excision generally causes greater disability
• Surgical approaches
• Small volume T1-T2 can consider transoral laser excision with neck dissection
• Approaches through the mandible can be via midline split or via horizontal split
• Suprahyoid, transhyoid, and infrahyoid approaches can also be used
• Removal of large tumors may require laryngectomy
• If N0, consider treating bilateral neck to Levels II-IV. If N+, consider treating bilateral neck to Levels I-V
• Outcome: local control for RT varies with stage, from >95% for T1 to ~50% for T4 (see PMID 16462500)
Definitive RT
• University of Florida; 2006 (1964-2003) PMID 16462500 -- "Definitive radiotherapy for squamous cell
carcinoma of the base of tongue." (Mendenhall WM, Am J Clin Oncol. 2006 Feb;29(1):32-9.)
• Retrospective. 333 patients with BOT, treated with definitive RT. Daily (25%, median dose 70 Gy) or twice
daily (75%, median dose 76.8 Gy or concomitant boost 72 Gy) fractionation. IMRT for last 3 year in N0 or
ipsilateral N+. Adjuvant chemo (more recently) in 18%. Median F/U 6.6 years
• Outcome: 5-year LC T1 98%, T2 92%, T3 82%, T4 53%. 5-year LRC Stage I-II 100%, III 82%, IVa 87%, IVb
58%. 5-year CSS by Stage 91%, 77%, 84%, 45%. 5-year OS by Stage 67%, 66%, 67%, 33%
• Toxicity: Severe complications 16%
• Conclusion: LRC and survival after RT comparable to surgery; morbidity less
Concurrent Chemotherapy
• MD Anderson; 2004 - PMID 15022283 (1975-98) — "Is concurrent chemoradiation the treatment of choice for
all patients with Stage III or IV head and neck carcinoma?" Garden AS et al. Cancer. 2004 Mar 15;100(6):1171-8.
• Retrospective. 299 pts with small tumors (T1-T2) of oropharynx that are Stage III-IV based on N-stage.
Treated with RT alone.
• Median f/u 82 mo. 5-yr LRF, DM, OS were 15%, 19%, and 64%. LRC was 95% for T1 vs 79% for T2.
• Conclusion: Excellent local control for small T-stage tumors of the oropharynx. Chemoradiotherapy would not
significantly benefit these pts.
Interstitial Brachytherapy
• Mass General Hospital, 2005 - PMID 15726587 (1983-00) -- "Definitive radiotherapy with interstitial implant
boost for squamous cell carcinoma of the tongue base." Karakoyun-Celik O et al. Head Neck. 2005
May;27(5):353-61.
• 40 pts w/ primary or recurrent SCC of BOT who received interstitial brachy as part of initial management.
54% had T3/T4 dz.
• Oropharynx, b/l necks, SC comprehensively irradiated w/ BOT receiving median of 61 Gy via EBRT. Median
implant dose 17.4 Gy (adjusted to reach dose to tumor of 80 Gy).
• 5 yr OS 62%, 10 yr OS 27%.
• Local control 78% at 5 yrs, 70% at 10 yrs. 78% organ preservation rate.
• 2 pts w/ grade 3 osteonecrosis (5%)
• William Beaumont, 1996 - PMID 8780531 (1986-1995) -- "Excellent functional outcome in patients with
squamous cell carcinoma of the base of tongue treated with external irradiation and interstitial iodine 125 boost."
Horwitz EM et al. Cancer. 1996 Sep 1;78(5):948-57.
• 20 pts w/ carcinoma of BOT w/ I-125 seed brachytherapy as component of tx.
• Pts received 50-66.6 Gy via EBRT followed by interstitial implant 2-3 wks later. Median implant dose of 27
Gy. Implant volume included tumor, glossotonsillar sulcus, and pharyngeal wall/tonsil in select cases.
• 5 yr actuarial local control rate of 88%. After salvage, overall 5 yr actuarial local control was 93%
• Speech and swallow preserved in 18/20 patients.
• Gainesville, 1990 - PMID 2370179 (1964-1986) -- "Is interstitial implantation essential for successful
radiotherapeutic treatment of base of tongue carcinoma?" Foote RL et al. Int J Radiat Oncol Biol Phys 1990
Jun;18(6):1293-8.
• 84 pts w/ SCC of BOT tx'd w/o interstitial implantation. (qD in 59 pts, BID in 25 pts)
• Local control rate for T2 (88%), T3 (77%), T4 (36%). Improved local control seen for T4 pts if BID
fractionation.
• Incidence of bone exposure 6%, soft tissue necrosis 19%
Management of Neck
• MSKCC, 1997 - PMID 9276364 (1981-1996) -- "Long-term regional control after radiation therapy and neck
dissection for base of tongue carcinoma." Lee HJ et al. Int J Radiat Oncol Biol Phys. 1997 Jul 15;38(5):995-1000.
• 68 pts w/ SCC of BOT tx'd w/ primary RT.
• 54 Gy to tumor via EBRT + 20-30 Gy interstitial implant. 50 Gy to neck (boosted to 60 Gy for if clinically
positive. Neck dissection done if clinically palpable neck nodes (even if complete response to RT)
• Actuarial 5 yr neck control 95%, 10 yr neck control 86%
• No cases of grade 3 fibrosis.
• Neck dissection suggested at time of implant for BOT SCC.
Tonsil
• RT alone: >80% LC for stages I-III; surgery can be reserved for salvage
• Concurrent chemotherapy used for advanced stage; planned neck dissection can be considered for bulky disease.
Conversely, primary surgery with adjuvant RT may be used
• Contralateral neck treatment: Overall failure rate <5% in select patients (mostly T1-2N0-1; see below). Consider
contralateral RT for CTV crossing midline, infiltration of base of tongue or glossopalatine sulcus, or N2c/N3
disease (Perez 5th)
Primary Outcomes
• University of Florida
• 2006 (1964-2003) PMID 16755183 -- "Definitive radiotherapy for tonsillar squamous cell carcinoma."
(Mendenhall WM, Am J Clin Oncol. 2006 Jun;29(3):290-7.)
• Retrospective. 503 patients; 198 planned neck dissection, 57 chemo. Minimum 2-year F/U
• 5-year outcome: LC: T1 88%, T2 84%, T3 78%, T4 61%. Neck control: N0 95%, N1 93%, N2a 89%, N2b
84%, N2c 77%, N3 66%. LRC: Stage I 92%, II 88%, III 88%, IVA 84%, IVB 66%. High failure rates for
anterior pillar lesions compared with fossa/posterior pillar
• Contralateral neck: 2/58 (3%) patients treated with ipsilateral primary & neck RT developed recurrence in
contralateral neck
• Severe late toxicity: 9%
• Conclusion: Definitive RT provides comparable cure rates as surgery, with lower complications
• 2000 PMID 10829041, 2000 (1964-1997) — "Radiation therapy for squamous cell carcinoma of the tonsillar
region: a preferred alternative to surgery?" Mendenhall WM et al. J Clin Oncol. 2000 Jun;18(11):2219-25.
• Retrospective. 400 pts. with T1-T4, N0-N3, tonsil cancers. Treated with radiation therapy alone. Minimum
2 year follow-up.
• Outcome: 5-yr LC by stage: T1, 83%; T2, 81%; T3, 74%; and T4, 60%.
• Recurrence: 83 patients had LR, 36 underwent a salvage procedure, and 17 pts were successfully salvaged.
(About 1/2 of LR can be successfully salvaged)
• Toxicity: No patients had severe acute complications from RT.
• Conclusion: Local-regional control similar after surgery or RT for tonsillar cancer, with the risks of a severe
or fatal complication higher for those patients treated surgically.
Contralateral Neck
• University of Florida; 2006 (1964-2003) PMID 16755183 -- "Definitive radiotherapy for tonsillar squamous cell
carcinoma." (Mendenhall WM, Am J Clin Oncol. 2006 Jun;29(3):290-7.)
• See full study above. Retrospective, 503 patients
• Contralateral neck: 2/58 (3%) patients treated with ipsilateral primary & neck RT developed recurrence in
contralateral neck
• Conclusion: Ipsilateral fields can be used for patients with well-lateralized tumors
• Erasmus Medical Center; 2004 (1986-2001) PMID 15183475 -- "Brachytherapy versus surgery in carcinoma of
tonsillar fossa and/or soft palate: late adverse sequelae and performance status: can we be more selective and
obtain better tissue sparing?" (Levendag P, Int J Radiat Oncol Biol Phys. 2004 Jul 1;59(3):713-24.)
• Retrospective. 190 patients with T1-3N0-3. For full details, please see PMID abstract
• Contralateral neck: 0/29 patients T1-3N0 disease and no contralateral treatment had recurrence. 6/149 (4%)
patients T1-3 ipsilateral N0/+ contralateral N0, with electively treated contralateral necks developed
recurrence. Substantial relapse (>10%) if base of tongue infiltration
• Conclusion: One can be more selective in treating contralateral neck; don't need to treat unless the tumor
extends beyond the midline of the soft palate (uvula) or beyond the lateral one-third of the ipsilateral base of
the tongue.
• Princess Margaret; 2001 (1970-91) - PMID 11567806 — "The benefits and pitfalls of ipsilateral radiotherapy in
carcinoma of the tonsillar region." O'Sullivan B et al. Int J Radiat Oncol Biol Phys. 2001 Oct 1;51(2):332-43.
• Retrospective. 228 pts were treated with ipsilateral nodal irradiation. 84% had T1-2, 58% N0 tumors. Median
F/U 5.7 years
• Contralateral failure: Crude rate 3.5%. T1 0%, T2 1.5%, T3 10%, T4 0%. N0 0%, N1 9%, N2/3 0%. All T1 or
N0 patients had no contralateral failures. Significant risk (>10%) if involving medial one third of palate, base
of tongue
• Conclusion: Selected cases of tonsilar carcinoma show low risk of contralateral neck failure with ipsilateral
technique.
• Hokkaido; 2000 (1989-1996) PMID 10699473 -- "Ipsilateral irradiation for carcinomas of tonsillar region and
soft palate based on computed tomographic simulation." (Kagei K, Radiother Oncol. 2000 Feb;54(2):117-21.)
• Retrospective. 32 patients, tonsil/soft palate. Tumor didn't cross midline, no contralateral LNs. Ipsilateral
technique 65/26 +/- 5-15 Gy boost. Median F/U 3.7 years
• Contralateral failure: 0%
• Conclusion: Ipsilateral technique for tumors that don't cross midline and have no contralateral LNs
• British Columbia; 1999 (1975-1993) PMID 10435802 -- "Cancer of the tonsil: the results of ipsilateral radiation
treatment." (Jackson SM, Radiother Oncol. 1999 May;51(2):123-8.)
• Retrospective. 178 patients ipsilateral RT, compared with 72 bilateral RT. Dose 60/25. T1-2 66%, T3 29%; N0
57%, N1 30%; Stage III-IV 63%
• Contralateral failure: crude rate 2.6%. Stage I 0%, II 2%, III 4%, IV 0%; N0 0%, N1 4%, N2-3 0% (but 52%
ipsilateral failure, ? first)
• Conclusion: Ipsilateral RT only has results comparable to bilateral RT, with fewer side effects, and low risk of
contralateral failure. Vast majority of failures inside original fields
Proton Therapy
• Loma Linda; 2005 (1991-2002) PMID 15890592 -- "Proton radiation for treatment of cancer of the oropharynx:
early experience at Loma Linda University Medical Center using a concomitant boost technique." (Slater JD, Int J
Radiat Oncol Biol Phys. 2005 Jun 1;62(2):494-500.)
• Prospective. 29 patients, localized Stage II-IV oropharyngeal cancer. Accelerated mixed photon and proton RT
75.9 GyE in 45 fractions to primary disease, involved LNs and subclinical areas. Photons lateral opposed beam
and anterior field for lower to 50.4/28. PT used as concomitant boost 25.5 GyE/17 starting Day 12, typically
single posterior oblique field. No chemotherapy mentioned
• Outcome: 5-year LC 88%, LN control 96%, LRC 84%; 2-year DFS 81%, 5-year DFS 65%
• Toxicity: Late Grade 3 in 10%
• Conclusion: Preliminary results reveal increased LRC without increased toxicity
Neoadjuvant Chemo
• ECOG E2399 PMID 17761982 -- "Phase II trial of chemoradiation for organ preservation in resectable stage III
or IV squamous cell carcinomas of the larynx or oropharynx: results of Eastern Cooperative Oncology Group
Study E2399." (Cmelak AJ, J Clin Oncol. 2007 Sep 1;25(25):3971-7.)
• Phase II. 105 patients. Resectable T2N+ or T3-4N0-3, larynx (34%) or oropharynx (66%) squamous cell.
Induction paclitaxel 175 mg/m2 and carboplatin AUC 6 x2 cycles, then concurrent paclitaxel 30 mg/m2 + RT
70 Gy. Primary endpoint organ preservation. 94% full dose RT. Median F/U 3 years
• Outcome: No progression on chemo. Organ preservation larynx 74%, OP 84%. Primary site salvage surgery
larynx 19%, OP 9%. 2-year OS larynx 63%, OP 83%
• Conclusion: High organ preservation in oropharynx but not larynx
References
[1] http:/ / www. rtog. org/ members/ protocols/ h0022/ h0022. pdf
Radiation Oncology/Head & Neck/Sinonasal/

Staging
Nasal Cavity and Paranasal Sinuses Staging
Maxillary Sinus
AJCC Staging System, 6th edition
Tumor
• T1 - Tumor limited to the maxillary sinus with no erosion or destruction of bone
• T2 - Tumor causing bony erosion or destruction including extension into the hard palate, middle nasal meatus,
except extension into posterior wall of maxillary sinus and pterygiod plates
• T3 - Tumor invades any of the following: bone of posterior wall of maxillary sinus, subcutaneous tissues, floor or
medial wall of orbit, pterygoid fossa, ethmoid sinuses
• T4a - Tumor invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribiform
plate, sphenoid or frontal sinuses
• T4b - Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other
than CN V2, nasopharynx, or clivus
Nodes
• N0 - no nodes
• N3 - LN > 6 cm
Metastasis
• M0 - none
• M1 - yes
Radiation Oncology/Head & Neck/Sinonasal/Staging 204
Stage Grouping
• Stage I - T1N0
• Stage II - T2N0
• Stage IVC - M1
Nasal Cavity and Ethmoid Sinus

• The nasal cavity and ethmoid sinuses share a common staging system
• Four subsites: septum, floor, lateral wall, and vestible
AJCC Staging System, 6th edition
Tumor
• T1 - Restricted to any one subsite, with or without bony invasion
• T2 - Invading two subsites in a single region or extending to involve an adjacent region within the nasoethmoidal
complex, with or without bony invasion
• T3 - Invades the medial wall or floor of the orbit, maxillary sinus, palate, or cribriform plate
• T4a - Invades any of the following: anterior orbital contents, skin of nose or cheek, minimal extension to anterior
cranial fossa, pterygoid plates, sphenoid or frontal sinuses
• T4b - Invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than V2,
nasopharynx, or clivus
Nodes (same as for most H&N sites)
• N0 - no nodes
• N3 - LN > 6 cm
Metastasis
• M0 - none
• M1 - yes
Stage Grouping
• Stage I - T1N0
• Stage II - T2N0
• Stage IVC - M1
Wang Classification (for carcinoma of the nasal vestibule)
• T1 - Tumor confined to skin
• T2 - Invades subcutaneous tissue and cartilage
• T3 - Invades bone

Overview
Nasal Cavity and Paranasal Sinuses

• For now please see individual subpages
Epidemiology
• Tumors of the nasal vestibule are frequently considered separately from nasal cavity and paranasal sinus tumors,
because they are essentially skin cancers and as such have a different natural history
• Primary tumors of the nasal cavity and paranasal sinuses are usually grouped together, because they are
frequently advanced at presentation and it's not clear from which site they originated
• Annual incidence ~1/100,000
• Occur more often in men, and age >40 (except salivary gland tumors and esthesioneuroblastoma which are seen
earlier)
Anatomy
• Sites
• Nasal vestibule
• Nasal cavity
• Maxillary sinuses
• Frontal sinuses
• Ethmoid sinuses
• Sphenoid sinus
• Lymphatic drainage
• Nasal vestibule: submandibular LNs, usually ipsilateral but may be bilateral
• Nasal cavity: olofactory group and respiratory group with different drainage patterns
• Olofactory group drains to lateral retropharyngeal LNs, but can also communicate with subarachnoid space
and CSF
• Respiratory group drain lower, in lateral retropharyngeal LNs or in Level II LNs
• Paranasal sinuses have minimal drainage
Pathology
• Benign: inverting papilloma can be associated with carcinoma in 5-15% of cases
• Squamous cell carcinoma most common
• Minor salivary glands account for 10-15% cases
• Lymphoma accounts for ~5%, and includes NK/T cell variant, which is locally very destructive
• → Mucosal melanoma accounts for ~1%
• Esthesioneuroblastoma
Treatment Overview
• Combination of radical surgery and postop radiation is a frequently used approach
• Surgical approaches depend on location, and include lateral rhinotomy, medial maxillectomy, total maxillectomy,
or craniofacial resection
• Extent of surgery correlates with DFS and OS, but not local control if RT is used
• Higher radiation doses are associated with improved local control, but visual toxicity is common
• Conversely, using conformal RT reduced toxicity while keeping survival comparable to conventional RT
• Poor overall survival ~50% at 5 years
Outcomes
• Ghent, Belgium
• 2005 (1998-2003) PMID 15915466 -- "Postoperative intensity-modulated radiotherapy in sinonasal carcinoma:
clinical results in 39 patients." (Duthoy W, Cancer. 2005 Jul 1;104(1):71-82.)
• Retrospective. 39 patients, surgery + postop RT. AdenoCA 79%, SCC 21%. Cribriform plate invasion 28%,
orbital invasion 36%. Median IMRT 70 Gy. Median F/U 2.6 years
• Outcome: 4-year LC 68%, 4-year OS 59%
• Toxicity: decreased vision 6%, no blindness
• Conclusion: Postop IMRT good LC, with low acute toxicity
• 2009 (1998-2006) PMID 18755554 -- "Intensity-modulated radiotherapy for sinonasal tumors: ghent
university hospital update." (Madani I, Int J Radiat Oncol Biol Phys. 2009 Feb 1;73(2):424-32. Epub 2008 Aug
26.)
• Retrospective. 84 patients. Postop IMRT in 89%, primary 11%. Median F/U 3.3 years
• Outcome: 5-year LC 71%, DFS 60%, DMFS 82%, DSS 67%, OS 58%. Invasion of cribriform plate
negative predictor
• Toxicity: No radiation blindness, 1 patient radiation retinopathy, 1 patient lacrimal duct stenosis, 3 patients
brain necrosis
• Conclusion: IMRT low rate of toxicity, with high local control and survival
• Turin, Italy; 2008 (2000-2005) PMID 18705398 -- "Stage III-IV sinonasal and nasal cavity carcinoma treated
with three-dimensional conformal radiotherapy." (Gabriele AM, Tumori. 2008 May-Jun;94(3):320-6.)
• Retrospective. 31 patients, locally advanced paranasal sinus and nasal cavity tumors. 3D-CRT. Postop (68%)
dose 60 Gy or radical dose 68 Gy (32%). Some use of chemotherapy. Median F/U 3.5 years
• Outcome: Postop: 5-year LC 74%, 5-year OS 72%. Radical RT 20% and 25%. Local recurrence most common
site of failure
• Toxicity: No radiation-induced blindness; 4 patients enucleation as part of radical surgery
• Conclusion: Local control remains low; 3D-CRT reduces risk of optical pathways but doesn't modify survival
• UCSF
• IMRT; 2007 (1998-2004) PMID 17189068 -- "Intensity-modulated radiation therapy for malignancies of the
nasal cavity and paranasal sinuses." (Daly ME, Int J Radiat Oncol Biol Phys. 2007 Jan 1;67(1):151-7.)
• Retrospective. 36 patients with PNS cancers, 32 after gross total resection. Sites: 13 ethmoid, 10 maxillary,
7 nasal cavity, 6 other. IMRT 70 Gy to GTV, and 60 Gy to CTV. Median F/U 51 months
• 5-year outcomes: LC 58%; DFS 55%; OS 45%
• Toxicity: minimal, no decreased vision, 1 xerophalmia, 1 lacrimal stenosis, 1 cataract
• Conclusion: IMRT no benefit on disease control, but low incidence of complications
• Historical; 2007 (1960-2005) PMID 17459609 -- "Carcinomas of the paranasal sinuses and nasal cavity
treated with radiotherapy at a single institution over five decades: are we making improvement?" (Chen AM,
Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):141-7. Epub 2007 Apr 24.)
• Retrospective. 127 patients, sinonasal carcinoma. Conventional 46%, 3D-CRT 39%, IMRT 18%
• Outcome: 5-year OS: 1960's 46%, 1970's 56%, 1980's 51%, 1990's 53%, 2000's 49%
• Toxicity: Grade 3-4 late: 53%, 45%, 39%, 28%, 16% (SS)
• Conclusion: No improvement in disease control or survival, but decreased incidence of complications
• MSKCC; 2006 (1987-2005) PMID 17161557 -- "Treatment of nasal cavity and paranasal sinus cancer with
modern radiotherapy techniques in the postoperative setting-the MSKCC experience." (Hoppe BS, Int J Radiat
Oncol Biol Phys. 2006 Dec 7)
• Retrospective. 85 patients with PNS, treated with post-op RT. Median RT 63 Gy. 62% treated with IMRT or
3D-CRT, rest with 2D. Median F/U 60 months
• 5-year outcomes: LC 62%, DM-free 82%, DFS 55%, OS 67%. Bad prognosis: squamous cell and cribriform
plate involvement
• Toxicity: 1 blindness (but no Grade 3-4 among patients treated with IMRT/3D-CRT)
• Conclusion: Local recurrence main problem. Modern RT safe.
Treatment Technique
• Utah; 1991 PMID 1764170 -- "Graduated block technique for the treatment of paranasal sinus tumors." (Tobler
M, Med Dosim. 1991 Dec;16(4):199-204.)
• 5-field graduated wedge technique. AP beam heavily weighted, prescribed just beyond lens. Lateral wedge
fields posteriorly fill-in dose as anterior contribution decreases
Proton Therapy
Clinical Outcomes
• Harvard
• 2008 (1991-2002) PMID 17902164 -- "Extent of surgery in the management of locally advanced sinonasal
malignancies." (Resto VA, Head Neck. 2008 Feb;30(2):222-9.)
• Retrospective. 102 patients, locally advanced, treated with proton therapy with or without surgery (R0 20%,
R1 49%, R2/biopsy 31%). Squamous cell 32%, neuroendocrine 29%, adenoid cystic 20%, sarcoma 13%,
adenocarcinoma 6%. Median RT dose if R0 resection 67.6 Gy, if R1/R2 resection 75.6 Gy usually given
BID. Median proton contribution 57%. Concurrent chemo 33% (typically for neuroendocrine). Median F/U
3.6 years, alive 5.1 years
• Outcome: 5-year LC R0 95% vs R1 82% vs R2 87% (NS, no difference by histology); 5-year DFMS 95%
vs. 69% vs 52% (no difference by histology). 5-year OS 90% vs 49% vs 39% (worst for squamous cell).
Regional failure rate 12%
• Conclusion: High dose proton RT excellent local control regardless of extent of surgery. However, DFS and
DMFS depended on extent of surgery. Can consider observation for regional neck
• 2006 (1991-2001) PMID 17050017 -- "Visual outcome of accelerated fractionated radiation for advanced
sinonasal malignancies employing photons/protons." (Weber DC, Radiother Oncol. 2006 Dec;81(3):243-9.
Epub 2006 Oct 16.)
• Retorspective. 36 patients, advanced stage nasal or paranasal malignant tumors. Treated with aggressive
surgery and post-op RT (78%) or radical RT (22%). Median dose 69.6 CGE, usually BID or concomitant
boost. Proton contribution 20-85% depending on beam availability. No concurrent chemo. Median F/U 4.4
years
• Outcome: 3-year OS 90%, 5-year OS 81%. 3-year DFS 77%, 5-year DFS 73%
• Toxicity: late visual/ocular toxicity Grade 2+ (retinopathy, optic neuropathy, cataract, dry-eye syndroma, or
nasolacrimal duct blockage) 22% in median 2.6 years after RT)
• Conclusion: AFRT enables delivery of 70 CGE with acceptable ophthalmologic complications
• 2002 (1992-1998) PMID 12173330 -- "Neuroendocrine tumors of the sinonasal tract. Results of a prospective
study incorporating chemotherapy, surgery, and combined proton-photon radiotherapy." (Fitzek MM, Cancer.
2002 May 15;94(10):2623-34.)
• Prospective. 19 patients with olofactory neuroblastoma or neuroendocrine carcinoma. Kadish Stage B 4/19,
Kadish Stage C 15/19. Induction cisplatin/etoposide x2 cycles, then proton/photon RT to 69.2 CGE
concomitant boost. If response, further 2 cycles of chemo. Median F/U 3.7 years
• Outcome: 5-year OS 74%; 5-year LC 88%
• Toxicity: 1 patient unilateral vision loss after induction chemo. 4 patients frontal/temporal lobe damage by
MRI. 2 patients soft tissue/bone necrosis. No radiation-induced visual loss
• Conclusion: This approach is successful, with radical surgery reserved for nonresponders
• Chiba; 2007 (1999-2005) PMID 17398027 -- "Proton-beam therapy for olfactory neuroblastoma." (Nishimura H,
Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):758-62. Epub 2007 Mar 29.)
• Retrospective. 14 patients (Kadish A 2/14, Kadish B 5/14, Kadish C 7/14). Dose 65 GyE in 2.5 Gy/fx. Median
F/U 3.3 years
• Outcome: 5-year LC 84%, 5-year RFS 71%, 5-year OS 93%
• Toxicity: Liquorrhea 1 patient, no other Grade 3+
• Conclusion: Excellent local control and survival outcome, without serious side effects
Treatment Planning
• PSI
• Paranasal; 2003 PMID 12559516 -- "Intensity modulation in radiotherapy: photons versus protons in the
paranasal sinus." (Lomax AJ, Radiother Oncol. 2003 Jan;66(1):11-8.)
• Treatment planning. Paranasal case, three dose levels 76 Gy, 66 Gy, and 54 Gy. IMRT vs IMPT comparison
• Outcome: Comparable target conformality and sparing of critical structures; low dose regions or target
homogeneity trade-off in IMRT plan
• Conclusion: Comparable target conformality and sparing of critical structures, low dose regions better with
IMPT
• Paraorbital; 2000 PMID 10863085 -- "Optimizing radiotherapy of orbital and paraorbital tumors:
intensity-modulated X-ray beams vs. intensity-modulated proton beams." (Miralbell R, Int J Radiat Oncol Biol
Phys. 2000 Jul 1;47(4):1111-9.)
• Treatment planning. 4 orbital/paraorbital tumors. IMRT vs IMPT.
• Outcome: PTV coverage comparable. DVHs for OAR better with IMPT, though predicted severe NTCP
equally low
• Conclusion: Both IMRT and IMPT optimally treated PTV and reduced severe late toxicity; IMPT better at
low/mid dose regions

Maxillary sinus
Epidemiology
• 3% of aerodigestive tract malignancies
• Peak incidence in age 50-59
• M:F 3:1
• 70-80% of tumors of the paranasal sinuses originate in maxillary sinus.
Risk Factors
• Medical/occupational exposure (thorotrast, nickel, chromium,hydrocarbons, nitrogen mustard)
• Woodworkers have 500 times greater risk than general population of having carcinoma of maxillary sinus
Anatomy
• The paranasal sinuses include the frontal, ethmoid, sphenoid, and maxillary sinuses.
Borders of Maxillary Sinus
• Medial border - nasal cavity
• Superior border - orbit
• Anterolateral border - facial bone
• Posteromedial border - infratemporal fossa
Ohngren's line is the oblique plane joining medial canthus of the eye with the angle of the mandible. It divides the
maxilla into the infrastructure and superstructure. This line was originally described in the 1930's by Dr. Ohngren to
delineate the limits of resectability of a tumor in the maxillary sinus. Tumors that extended into the superstructure
(superoposterior to Ohngren's line) were more likely to involve the orbit, ethmoids, and pterygopalatine fossa. This
line became the basis of original staging systems.
Nodal drainage of Paranasal sinuses
• Retropharyngeal nodes 1st echelon
• Periparotid nodes
• Submandibular nodes
Clinically involved nodes occur in approximately 15% of pts overall, but has been reported as >20% for SCC
histology.
Staging
2002 AJCC Staging (6th edition)
Tumor
• T1 - Tumor limited to the maxillary sinus with no erosion or destruction of bone
• T2 - Tumor causing bony erosion or destruction including extension into the hard palate, middle nasal meatus,
except extension into posterior wall of maxillary sinus and pterygiod plates
• T3 - Tumor invades any of the following: bone of posterior wall of maxillary sinus, subcutaneous tissues, floor or
medial wall of orbit, pterygoid fossa, ethmoid sinuses
• T4a - Tumor invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribiform
plate, sphenoid or frontal sinuses
• T4b - Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other
than CN V2, nasopharynx, or clivus
Nodes
• N0 - no nodes
• N3 - LN > 6 cm
Stage Grouping
• Stage I - T1N0
• Stage II - T2N0
• Stage IVC - M1
Treatment
• Radiation therapy alone can be used as a primary modality for T1-T2 N0 patients, inoperable patients.
• Indications for adjuvant radiation therapy include: T1N0 patients with positive margins, perineural invasion, T3
or T4; consider for T2N0. For any N+, radiation to the neck
• Contraindications of surgery include intracranial invasion, carotid involvement, bilateral cavernous sinus
involvement, and distant metastases
NCCN Radiation Therapy Guidelines:
• Definitive xrt for primary and gross adenopathy: >66 Gy
• Treatment of undissected neck: 50 Gy
• Adjuvant xrt for primary tumor bed: >60 Gy
• Adjuvant xrt to dissected neck (high risk nodal stations): >60 Gy
• Adjuvant xrt to dissected neck (low risk nodal stations): >50 Gy
Surgical Management
• Subtotal Maxillectomy - 2 walls of maxilla removed. Generally indicated only for early (T1-2 lesions) of
infrastructure.
• Radical Maxillectomy - The entire maxilla is removed. This is the standard operation for locally advanced
carcinoma of maxilla. Resection includes the maxilla, nasal bone, ethmoid sinus, and sometimes the pterygoid
plates. The surgery spares the zygoma, orbital periosteum, and palatal mucosa.
• Craniofacial Resection This surgery is indicated when tumor involves the roof of the ethmoid sinus. The
posterior line of resection is foramen ovale, foramen rotundum and internal carotid. The inferior line of resection
is similar to craniofacial frontoethmoidectomy and radical maxillectomy.
• Orbital Exenteration This surgery was practiced commonly in the 50's and 60's, but has fallen out of favor. It is
generally indicated when orbital fat invasion is seen or orbital contents grossly involved.
Adjuvant Radiation Therapy

• UT Southwestern, 2002 (1980-97) PMID 12439163 -- "Paranasal sinus malignancies: an 18-year single
institution experience." (Myers LL et al, Laryngoscope. 2002 Nov;112(11):1964-9.)
• 141 pts w/ paranasal sinus malignancy, 88% w/ locally advanced dz, 70% maxillary sinus, 26% ethmoid sinus
• 62% underwent surgery as part of multimodality tx approach.
• 5yr DSS 52%, 10yr DSS 35%
• Local recurrence rate 56%
• The Netherlands, 2000 (1977-1996) PMID 10924968 -- "Does the combination of radiotherapy and debulking
surgery favor survival in paranasal sinus carcinoma?" (Jansen EP et al, Int J Radiat Oncol Biol Phys. 2000 Aug
1;48(1):27-35.)
• 73 pts w/ paranasal sinus carcinoma tx'd w/ either combination therapy (surg + RT) or monotherapy (surg, RT
alone)
• 5yr local control 65% w/ combination surg + xrt, 47% w/ xrt alone
• Orbital invasion associated w/ poor local control.
• MDACC, 1991 (1969-85) PMID 1924855 -- "Maxillary sinus carcinomas: natural history and results of
postoperative radiotherapy." (Jiang GL et al, Radiother Oncol 1991 Jul;21(3):193-200.)
• 73 pts w/ maxillary sinus CA tx'd w/ surgery and postop xrt (dose of 50-60 Gy via wedged pair or 3-field
technique)
• 5yr local control was 78%
• 5yr relapse free survival was 51%
• Overall nodal recurrence rate w/o elective nodal irradiation was 38% for SCC or undifferentiated, 5% for
adenoid cystic.
Elective Nodal Irradiation

• Stanford, 2000 (1959-96) PMID 10701732 -- "Lymph node metastasis in maxillary sinus carcinoma." (Le QT,
Int J Radiat Oncol Biol Phys. 2000 Feb 1;46(3):541-9.)
• 97 pts w/ maxillary sinus carcinoma (61 receiving surgery + xrt, 36 pts xrt alone)
• 5yr actuarial survival 34%, 10 yr 31%
• Most common sites of nodal recurrence were levels I and II; 12% nodal relapse at 5yrs; 5yr actuarial risk of
nodal relapse was 20% w/o ENI, 0% w/ ENI.
• 5yr actuarial risk of distant relapse 29% w/ neck control, and 81% if neck failure.
Combined Modality Approach

• Tennessee, 2004 PMID 15313865 -- "Intra-arterial cisplatin and concomitant radiation therapy followed by
surgery for advanced paranasal sinus cancer." (Samant S, Arch Otolaryngol Head Neck Surg 2004
Aug;130(8):948-55.)
• 18 pts tx'd w/ preop high dose intra-arterial cisplatin + IV thiosulfate w/ concurrent xrt (50 Gy). 84% T4
lesions. Planned surgery 8 wks post xrt (organ sparing, if possible).
• 2 yr OS 68%, 5 yr OS 53%
Radiation Techniques and Treatment Planning

• Also please see H&N proton therapy
• Duke, 1999 PMID 10435816 -- "Conformal radiation therapy treatment planning reduces the dose to the optic
structures for patients with tumors of the paranasal sinuses." (Brizel, Radiother Oncol. 1999 Jun;51(3):215-8.)
• Comparison of 2D and 3D treatment plans, using Dmax, NTCP and V80
• Conformal plan better: ipsilateral optic nerve 13% NTCP reduction (SS), ipsilateral eye 3% (SS), optic chiasm
0.5% (SS) driven by decreased Dmax and V80

Ethmoid sinuses
Ethmoid cancer
Risk factors
• Occupational
• Sawdust, cement dust - ethmoid adenocarcinoma
• Exposure to thoratrast, nickel, cadmium, formaldehyde
• Pollution
• Smoking
• HPV (SCC)
• ?chronic sinusitis
Pathology
• SCC most common
• Mucoepidermoid
• Adenoid cystic
• Adenocarcinoma
• Rare:
• Olfactory neuroblastomas (esthesioneuroblastoma)
• Angiosarcoma
• Rhabdomyosarcoma
• Lymphoma
Natural history
• Usually well differentiated, slow growing
• Present due to local invasion beyond sinus although can sometimes present due to sinusitis or nasal obstruction
• Tumours commonly invade through bone - through cribriform plate to anterior cranial fossa, or lamina papyracea
to orbit
Route of spread
• Primarily through local invasion; nodal metastases are uncommon (< 20%, even lower for adenoid cystic)
• Nodal involvement is more common when there is extension into surrounding tissues
• Sinuses themselves are lymphatic poor
• First echelon lymph nodes are retropharyngeal
Presentation
• Facial or nasal pain
• Epistaxis
• Sinus obstruction
• Trismus (pterygoid involvement)
• Ocular symptoms: diplopia, visual disturbance, proptosis
• Neural involvement eg trigeminal neuralgia
Outcomes
• Local control 50-60%
• Overall survival 30-50% at 5 years
Management
• Most evidence is via retrospective single institution reports
• Options:
• Surgery (eg craniofacial resection, orbital exenteration)
• Often difficult as locally advanced by the time of presentation
• May include orbital exenteration if there is orbital invasion
• Radiotherapy
• Unclear whether preop or postop RT is better
• Preop chemoRT may improve resectability
• Adjuvant treatment does appear to increase local control although there exists no randomised data to
confirm this
• Radiotherapy as definitive management is most appropriate
• Difficult resection anatomically
• Dose 70Gy definitive, with chemotherapy for advanced lesions
• Comprehensive nodal irradiation (retropharyngeal nodes) only if node positive or extrasinus involvement
(skin, muscle)
• Dose limiting structures
• Eye, optic chiasm
• Brain
• Technique
• Ant and wedged laterals (posterior to eye)
• Treat neck nodes prophylactically if there is skin/muscle involvement otherwise target volume is
antrum alone
Radiation Oncology/Head & Neck/Protons

Proton Therapy in Head & Neck Cancers

• Nasopharynx
• Sinonasal tumors
• Adenoid cystic
• Oropharynx
General
• Tsukuba; 2004 (1983-2000) PMID 14762662 -- "Proton therapy for head and neck malignancies at Tsukuba."
(Tokuuye K, Strahlenther Onkol. 2004 Feb;180(2):96-101.)
• Retrospective. 33 patients with H&N malignancies, no surgery. Oral papilomatosis 12%, T1-2N0 21%, 67%
locally advanced. Treated with protons +/- photons (depending on beam availability). Median dose 76 Gy,
median proton dose 2.8 Gy/fraction.
• Outcome: 5-year LC 74%, 5-year OS 44%
• Toxicity: Grade 3+ acute 3%, late 18%
• Conclusion: High local control, with few toxicities compared with conventional RT. However, late toxicity if
prior significant RT
Treatment Planning
• Paul Scherrer Institute
• 2006 PMID 16916557 -- "Intensity modulated photon and proton therapy for the treatment of head and neck
tumors." (Steneker M, Radiother Oncol. 2006 Aug;80(2):263-7. Epub 2006 Aug 17.)
• Treatment planning. 5 patients, comparison of IMPT (3, 5, 9 fields and 2 spot sizes) and IMRT (5, 9 fields)
• Outcome: Critical organs best spared using 3-field IMPT. Little advantage to more fields, but advantage to
smaller spot size.
• Conclusion: IMPT better ability to spare organs at risk than IMRT for the same dose homogeneity
• 2001 PMID 11730999 -- "A treatment planning comparison of 3D conformal therapy, intensity modulated
photon therapy and proton therapy for treatment of advanced head and neck tumours." (Cozzi L, Radiother
Oncol. 2001 Dec;61(3):287-97.)
• Treatment planning. 5 patients, comparison of conventional photon/electron plan, 3D-CRT, IMRT, and
proton therapy. PTV 54 Gy.
• Outcome: PTV coverage for all techniques but conventional photon/electron plan; protons improved dose
homogeneity. For spinal cord and parotid, proton best sparing; IMRT plans superior to 3D-CRT and
conventional plans, but inferior to proton plans.
• Conclusion: IMRT and protons have potential to reduce toxicity over conventional RT
Radiation Oncology/Head & Neck/Protons 215
Review
• Harvard; 2008 PMID 18493920 -- "Proton radiation therapy for head and neck cancer." (Chan AW, J Surg
Oncol. 2008 Jun 15;97(8):697-700.)
• Review; 2006 PMID 16804876 -- "Particle beam radiotherapy for head and neck tumors: radiobiological basis
and clinical experience." (Jereczek-Fossa, Head Neck. 2006 Aug;28(8):750-60.)
Charged Particles
• Chiba
• 2008 PMID 18769999 -- "Comparative study of dose distribution between carbon ion radiotherapy and photon
radiotherapy for head and neck tumor." (Amirul Islam, Radiat Med. 2008 Aug;26(7):415-21. Epub 2008 Sep
4.)
• Treatment planning. 7 patients originally treated with carbon ion (sinonasal tumors). Carbon ion (CIRT) vs.
3D-CRT vs. IMRT.
• Outcome: Mean conformity index 3D-CRT 1.46, IMRT 1.43, CIRT 1.22. Photon plans greater volumes of
normal tissue at 10-95% isodose
• Conclusion: Carbon ion has potential to improve target dose conformity, inhomogeneity and OAR sparing
• 2004 (1994-1997) PMID 15380567 -- "Dose escalation study of carbon ion radiotherapy for locally advanced
head-and-neck cancer." (Mizoe JE, Int J Radiat Oncol Biol Phys. 2004 Oct 1;60(2):358-64.)
• Phase I/II. 36 patients, locally advanced H&N. Group A: 18 fractions (48.6/18 GyE to 70.2/18 GyE). Group
B: 16 fractions (52.8/16 to 64/16). Endpoint erythema and mucositis. Median F/U 7.5 years
• Outcome: MTD 70.2/18 (1/2 patients Grade 3 acute toxicity) and 64/16 (2/3 patients Grade 3 acute
toxicity). 5-year LC 75%, better with non-squamous tumors including adenoid cystic and melanoma
• Conclusoin: Carbon ion will deliver high local control without unacceptable toxicity
• Lawrence Berkeley Laboratory
• 1994 (1977-1992) PMID 8040010 -- "Experience in charged particle irradiation of tumors of the skull base:
1977-1992." (Castro JR, Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):647-55.)
• Retrospective. 233 patients treated with charged particles. Tumors arising/extending to skull base. Arising:
Chordoma 24%, chondrosarcoma 12%, meningioma 12%, other 9%; Extending: salivary glands 20%,
nasopharynx 14%, paranasal sinuses 10%. Mean dose 65 GyE. Median F/U 4.2 years
• Outcome: 5-year LC meningioma 85%, chondrosarcoma 78%, chordoma 63%
• Conclusion: Charged particle therapy effective in controlling skull base lesions
• 1988 PMID 3350726 -- "Charged particle radiotherapy of selected tumors in the head and neck." (Castro JR,
Int J Radiat Oncol Biol Phys. 1988 Apr;14(4):711-20.)
• Retrospective. 98 patients, H&N. Mean F/U 3 years
• Outcome: 2-year LC non-squamous 60%, squamous 35%
Radiation Oncology/Head & Neck/Salivary

gland
Tumors of the Salivary Glands
Epidemiology
• Median age for salivary gland malignancy is 55-65.
• Median age for benign salivary gland tumor is 10 yrs younger.
• Salivary gland malignancies represent 3-6% of head and neck cancers.
• Tumor distribution (Perez 5th edition):
• Parotid gland 70%
• Submandibular gland 8%
• Minor salivary glands 22%
Histology
• 75% of parotid masses are benign
• Low grade tumors of the parotid: acinic cell, low grade mucoepidermoid
• High grade tumors of the parotid: high grade mucoepidermoid, adenoid cystic, adenoCA, squamous cell
• Most common histology of malignant parotid gland tumor is mucoepidermoid (30%).
• Predominant histology of a malignant submandibular gland tumor is adenoid cystic.
• Histologic classification is often difficult, with significant interobserver variability and reclassification rate
Anatomy
Salivary Glands:
• Parotid - superficial to and behind ramus of the mandible. LN drainage to parotid nodes, and then to superficial
LNs along SCM muscle and to deep cervical chain
• Submandibular - in triangle between digastric muscle bellies and lower border of the mandible. LN drainage to
both submandibular LNs and directly to anterior subdigastic LNs
• Sublingual - medial to mandible, lateral to genioglossus muscle of the tongue, superior to mylohyoid muscle,
inferior to mucous membrane of the floor of the mouth. LN drainage to submandibular LNs or to deep internal
jugular chain
• Minor Salivary Glands - widely distributed throughout the upper aerodigestive tract (see below)
Parotid Gland
• Anatomical borders of parotid gland
• Superior - zygomatic arch
• Inferior - upper border of posterior belly of digastric
• Anterior - 2nd maxillary molar
• Posterior - tip of mastoid
• Lobes of parotid gland:
• Parotid gland divided into superficial and deep lobes.
• Lobes of parotid separated by relation to facial nerve (no fascial plane separating them).
Nodal drainage of Salivary Glands:

• Parotid:
• Periparotid and intraparotid nodes
• Level I, Level II, Level III
• Submandibular
• Level I, Level II, Level III
Staging
AJCC 6th edition:
• Tumor
• T1 - 2cm or less w/o extraparenchymal extension
• T2 - >2cm but not greater than 4cm; and w/o extraparenchymal extension
• T3 - >4cm or with extraparenchymal extension
• T4a - invades skin, mandible, ear canal or facial nerve
• T4b - invades skull base, pterygoid plates or encases carotid
• N0 - no nodes
• N3 - LN > 6 cm
Overall stage:
• I - T1 N0
• II - T2 N0
• III - T3 N0-1, or T1-3 N1 (i.e. T3 or N1)
• IVA - T4a N0-2, or T1-4a N2 (i.e. T4a or N2)
• IVB - T4b N0-3, or T1-4b N3 (i.e. T4b or N3)
• IVC - M1
Treatment
• Treatment of choice for malignancy of salivary glands is surgical resection.
• Superficial parotidectomy if possible for parotid malignancy
• Total parotidectomy indicated if tumor invades into or adjacent to deep lobe. Total parotidectomy still attempts
to spare CNVII.
• Facial nerve should be sacrificed if invasion of CNVII or facial palsy
• Indications for adjuvant RT typically includes positive margins, invasion outside of salivary gland, positive
nodes, high grade histology
• Treatment volume: No need for contralateral neck treatment even with positive ipsilateral neck nodes (see
Harrison, 1990). Treat parotid bed only for low grade cancers with indications for local irradiation but no
lymph node involvement. Treat parotid bed and ipsilateral neck for high grade cancers, recurrent cancers, or
LN metastases.
• Radiation dose: Tumor bed - 60 Gy at 2 Gy/fx or 63 Gy at 1.8 Gy/fx. Positive margins - 66-70 Gy. Neck
(undissected) - 50-54 Gy. Neck (dissected) - 60-63 Gy
• Neutrons are superior to photon RT based on a randomized RTOG-MRC trial; local control was dramatically
better but so was the rate of severe late effects. Neutron therapy is not routinely available, and not actively
pursued
Adjuvant Radiation
• Dutch Head and Neck Oncology Cooperative Group (NWHHT), 2005 PMID 15629600 -- Terhaard CHJ et al.
"The role of radiotherapy in the treatment of malignant salivary gland tumors," Int J Radiat Oncol Biol Phys.
2005 Jan 1;61(1):103-11.
• Largest series published for malignant salivary gland tumors.
• 498 pts w/ malignant primary salivary gland carcinoma. Of pts treated w/ surgery, 78% received adjuvant xrt
(median dose 62 Gy)
• Factors in which adjuvant radiation significantly improved local control included T3-T4, close margin,
incomplete resection, bony invasion, and PNI.
• Local control for surgery alone if T1-2 and clear margins was 95% at 5 yrs, and 90% at 10 yrs
• 5yr local control if definitive xrt was 50% if 66-70 Gy delivered.
• Memorial Sloan Kettering
• PMID 2166187, 1990 -- "Postoperative radiation therapy for major salivary gland malignancies." Harrison L et al.
J Surg Oncol. 1990 Sep;45(1):52-5.
• PMID 2306346, 1990 (1966-82) — "Malignant tumors of major salivary gland origin. A matched-pair analysis of
the role of combined surgery and postoperative radiotherapy." Armstrong JG et al. Arch Otolaryngol Head Neck
Surg. 1990 Mar;116(3):290-3.
• Matched pair analysis of patients with combined surgery + post-op RT and pts treated with surgery alone
(1939-65).
• 5-year survival for Stage I-II 81.9% (S+RT) vs 95.8% (S), and for Stage III-IV 51.3% vs 16.8%. For LN+
48.9% vs 18.7%.
• Conclusion: post-op RT improves survival for Stage III-IV and LN+.
• Johns Hopkins, 1990 (1975-87) PMID 2115032 -- North CA et al. "Carcinoma of the major salivary glands
treated by surgery or surgery plus postoperative radiotherapy," Int J Radiat Oncol Biol Phys 1990
Jun;18(6):1319-26.
• 87 pts w/ carcinoma of major salivary gland (70 parotid) tx'd w/ either surgery or surg + post-op RT (median
60 Gy).
• Factors associated w/ poor outcome included facial nerve paresis, undifferentiated histology, male sex, skin
invasion, and no RT.
• Patients w/ local recurrence had major advantage if RT was given as part of salvage.
Elective Nodal Irradiation

• UCSF; 2007 (1960-2004) PMID 17234357 -- "Patterns of nodal relapse after surgery and postoperative radiation
therapy for carcinomas of the major and minor salivary glands: what is the role of elective neck irradiation?"
(Chen AM, Int J Radiat Oncol Biol Phys. 2007 Mar 15;67(4):988-94.)
• Retrospective. 251 patients, N0 salivary gland malignancy (adenoid cystic 33%, mucoepidermoid 24%,
adenoCA 23%), gross total resection (R0 44%, R1 56%), no LND + RT. Median primary RT dose 63 Gy. 52%
had elective neck irradiation (ipsilateral neck 69%, bilateral 31%)
• 10-year outcome: Nodal failures in T1 7%, T2 5%, T3 12%, T4 16%.
• ENI reduced 10-yr nodal relapse from 26% to 0%, especially in squamous cell (67%), undifferentiated CA
(50%), adenoCA (34%). No nodal failures in adenoid cystic CA (0/84) or acinic cell (0/21), regardless of ENI.
• Conclusion: ENI effectively prevents nodal relapses

• Memorial Sloan Kettering, 1992 - PMID 1730113, (1939-82) Armstrong JG et al. "The indications for elective
treatment of the neck in cancer of the major salivary glands." Cancer. 1992 Feb 1;69(3):615-9.
• 474 pts. Clinically LN+ in 14%. Pathologically positive (occult) LN mets in 12% of those with clinically
negative neck.
• Size and grade were predictive of LN mets. Size: 20% (>4 cm) vs 4%; Grade: 49% (High grade) vs 7% (int or
low grade).
Definitive Radiation Therapy

• UCSF, 2006 (1960-2004) PMID 16965870 -- Chen AM et al. "Long-term outcome of patients treated by
radiation therapy alone for salivary gland carcinomas." Int J Radiat Oncol Biol Phys. 2006 Nov 15;66(4):1044-50.
• 45 pts w/ newly dx'd salivary gland carcinoma tx'd w/ definitive xrt to median dose of 66 Gy.
• 5 yr estimated local control was 70%, 10 yr 57%
• T3-4 disease and <66 Gy were predictors for local recurrence.
• Gainesville, 2005 (1964-2003) PMID 15880750 -- Mendenhall WM et al. "Radiotherapy alone or combined with
surgery for salivary gland carcinoma." Cancer. 2005 Jun 15;103(12):2544-50.
• Retrospective review of pts at U of FL tx'd w/ curative intent w/ RT alone (64) vs surg (160).
• T stage and use of surgery were predictors of local control.
• RT cured approximately 20% of advanced stage tumors if used alone.
Neutron Therapy
• RTOG-MRC Neutron Trial -- neutrons vs. photons/electrons
• Randomized. Stopped early due to neutron advantage. 32 patients, inoperable or recurrent major or minor
salivary gland tumors. Arm 1) Neutrons (17-22 nGy) vs. Arm 2) photon/electrons (55 Gy/4 weeks or 70
Gy/7.5 weeks)
• 2-years; 1988 PMID 2846479 -- "Neutron vs photon irradiation of inoperable salivary gland tumors: results of
an RTOG-MRC Cooperative Randomized Study." (Griffin TW, Int J Radiat Oncol Biol Phys. 1988
Nov;15(5):1085-90.) Minimum F/U 2 years
• Outcome: 2-year LRC neutrons 67% vs. photons/electrons 17% (SS); 2-year OS 62% vs. 25% (NS)
• Conclusion: Neutrons superior for local control, but no impact on survival
• Final; 1993 PMID 8407397 -- "Neutron versus photon irradiation for unresectable salivary gland tumors: final
report of an RTOG-MRC randomized clinical trial." (Laramore G, Int J Radiat Oncol Biol Phys. 1993 Sep
30;27(2):235-40)
• Outcome: 10-year LRC neutrons 56% vs. photons/electrons 17% (SS); OS 25% vs. 15% (NS). Median OS
3 years vs. 1.2 years
• Toxicity: Severe toxicity worse in neutron arm, but no difference in "life-threatening" complications
• Conclusion: Fast neutron RT appears to be the treatment of choice for patients with inoperable/recurrent
salivary gland tumors
• Comment: Remains as only randomized trial for malignant salivary gland tumors
• University of Washington, 2003 PMID 12975266 -- Douglas JG et al. "Treatment of salivary gland neoplasms
with fast neutron radiotherapy." Arch Otolaryngol Head Neck Surg 2003 Sep;129(9):944-8.
• 279 pts tx'd w/ curative intent using fast neutron therapy (263 had evidence of gross residual dz).
• Multivariate analysis showed improved CSS for pts w/ stage I-II dz, lack of skull base invasion, minor salivary
site.
Minor Salivary Glands

• Widely distributed throughout the upper aerodigestive tract: tumors present in 38% palate, 12% cheek/lips, 12%
antrum, 10% tongue, 10% nasal cavity, multiple other sites <10%
• Imaging depends on location, but should involve evaluation of bone involvement
• Definitive diagnosis should be via excisional biopsy
• Histology: 40% adenoid cystic, 16% mucoepidermoid, 16% adenoCA, 28% others
• Prognosis: worst for adenoid cystic
• General management (based on Perez 5th edition)
• Depending on site, attempt surgical resection (though not simple excision, as significant residual disease can
be left behind)
• Radiation may be used as adjuvant or primary, with techniques similar to squamous cell cancers in the same
location, except:
• Adenoid cystic involving a named branch of cranial nerve, in which case nerve path to skull base should be
treated. For focal perineural invasion, treatment to skull base should be based on anatomic location
• For paranasal sinuses or palate, base of skull should be treated due to proximity
• Fields may not need to electively include LNs, except if located in tongue, floor of mouth, pharynx, or
larnyx and neck was not dissected. However, UCSF data on elective nodal irradiation (ENI) above suggest
no benefit for adenoid cystic or acinic cell
• RT dose
• Negative margins: 60/30
• Microscopically positive margins: 66/33
• Grossly residual disease or primary treatment: 70/35
• Netherlands Cancer Institute; 2000 (Belgium)(1973-1994) PMID 11002213 -- "Stage as major long term
outcome predictor in minor salivary gland carcinoma." (Vander Poorten VL, Cancer. 2000 Sep
15;89(6):1195-204.)
• Retrospective. 55 patients with minor salivary gland cancer. Median F/U for alive patients 11.1 years
• Outcome: 5-year DSS 76%, 10-year DSS 74%
• Prognostic factors: younger age, lower AJCC stage, LN+, vascular invasion, nasopharynx/paranasal sinus
location
• Conclusion: comparable outcome to major salivary gland patients
Adenoid Cystic Carcinoma
Overview
• First described in 1853, named adenoid cystic in 1930
• Slow-growing epithelial tumor of salivary glands, thought to arise from intercalated mucous-secreting ducts. Can
arise anywhere within the upper respiratory tract
• Predominance in 5th-6th decade, and in females
• Estimated 5-10% of all salivary tumors, but common in minor salivary glands (30-40%). Parotid gland is the
single most common site, and accounts for ~25%. Manor salivary glands account for ~60% in total; most
common site is palate
• Histologically shows 3 patterns: glandular, tubular, and solid (worse prognosis)
• Characterized by persistent local recurrences, perineural spread, and distant metastases; lymphatic spread less
common
• Distant metastases may happen late, commonly affect lungs, are are frequently slow-growing and surgically
resectable
• Most important prognostic factor is Stage; more favorable outcome of major parotid glands compared with minor
is probably earlier diagnosis
• Overall, 5-year OS is exceptionally good but 10- and 20-year OS is exceptionally poor
• Most are treated surgically
• Role of adjuvant RT is controversial; some institutions use for all patients while others use for those with
unfavorable features. It is probably reasonable to offer adjuvant radiation for most patients, especially with
positive surgical margins or perineural invasion. RT dose should be >60 Gy
• Perineural invasion of small unnamed nerves may not be correlated with worse control if treated with adjuvant
RT; named branches of cranial nerves should probably be treated to skull base
• In patients with skull base extension (and likely R2 resection or unresectable), dose intensification with proton
therapy or carbon ion boost appears superior to IMRT alone
Photon Therapy
• MSKCC; 2007 (1990-2004) PMID 18029108 -- "Outcomes and Prognostic Variables in Adenoid Cystic
Carcinoma of the Head and Neck: A Recent Experience." (Gomez DR, Int J Radiat Oncol Biol Phys. 2007 Oct 27
• Retrospective. 59 patients (oral cavity 28%, paranasal sinuses 22%, parotid 14%, submandibular 14%) treated
with RT. Stage T1-T4. Base of skull treated in 90%. Median F/U of survivors 5.9 years
• Outcome: 5-year LC 91%, DM-free 81%, OS 87%; 10-year LC 81%, DM-free 49%, OS 65%
• Worse predictors: T4, gross/clinical nerve involvement, LN+
• Conclusion: RT combined with surgery offers excellent local control
• Heidelberg; 2006 PMID 16756669 -- "Inverse planned stereotactic intensity modulated radiotherapy (IMRT) in
the treatment of incompletely and completely resected adenoid cystic carcinomas of the head and neck: initial
clinical results and toxicity of treatment." (Munter MW, Radiat Oncol. 2006 Jun 6;1:17.)
• Retrospective. 25 patients, huge adenoid cystic tumors. Surgery R0 (16%), R1 (4%), R2 (80%). Treated with
IMRT, most using integrated boost. Median F/U 1.9 months
• Outcome: 3-year OS 72%. LF 12%, RF (adjacent LN) 12%
• Toxicity: Grade 3+ if small number of patients
• Conclusion: IMRT provides good control and low side effects
• UCSF; 2006 (1960-2004) PMID 16904520 -- "Adenoid cystic carcinoma of the head and neck treated by surgery
with or without postoperative radiation therapy: prognostic features of recurrence." (Chen AM, Int J Radiat Oncol
Biol Phys. 2006 Sep 1;66(1):152-9.)
• Retrospective. 140 patients treated with definitive surgery. T1 26%, T2 28%, T3 20%, T4 26%. SM+ 56%.
Post-op RT 64%, median dose 64 Gy (54-71 Gy). Base of skull treated routine for all patients with PNI.
Elective neck in 54%. Median F/U 5.5 years
• Outcome: LC 5-year 88%, 10-year 77%; 10-year OS 64%. Sites of failure: all LR were localize to original site
except for 2 base of skull recurrences in patients treated with suregery alone. No cervical LN failures. DM sites
were lung 71%, bone 14%, liver 9%, brain 6%
• Poor prognosis: T4, PNI, major nerve involvement, lack of post-op RT. Post-op RT beneficial in essentially all
subgroups except possibly if SM-. If received post-op RT, dose <60 Gy, T4, and major nerve involvement poor
prognosis
• Conclusion: Combined modality therapy with RT >60 Gy should be standard of care
• University of Florida; 2004 (1966-2001) PMID 14762884 -- "Radiotherapy alone or combined with surgery for
adenoid cystic carcinoma of the head and neck." (Mendenhall WM, Head Neck. 2004 Feb;26(2):154-62.)
• Retrospective. 101 patients, treated with RT alone or surgery + RT. Median F/U 6.6 years
• Outcome: LC 5-years RT 56% vs surgery + RT 94%, 10-years 43% vs. 91% (SS). OS 5-years 57% vs. 77%,
10-years 42% vs. 55%. Predictors for survival T-stage, clinical nerve invasion. DM 10-years 27%
• Conclusion: Optimal treatment for ACC is surgery + adjuvant RT
• Hanover; 2004 (Germany)(1981-2000) PMID 14690656 -- "Adenoid cystic carcinoma of the head and neck--a
20 years experience." (Kokemueller H, Int J Oral Maxillofac Surg. 2004 Jan;33(1):25-31.)
• Retrospective. 74 patients. Complete resection 45/74. Post-op RT 14 patients.
• Outcome: LC 5-years 64%, 10-years 56%, 15-years 52%; mean local control time 11.1 years; DM control
72%, 62%, 59%; mean distant control time 14.4 years; OS 71%, 54%, 37%; mean OS 4.7 years
• Poor prognosis: large size, PNI, SM+
• Conclusion: Insight into behavior of ACC
• UCLA; 2004 (1963-1997) PMID 15577803 -- "Adenoid cystic carcinoma of the submandibular gland: a 35-year
review." (Cohen AN, Otolaryngol Head Neck Surg. 2004 Dec;131(6):994-1000.)
• Retrospective. 22 patients, ACC of submandibular gland. Surgery in 21/22. Post-op RT if advanced size, PNI,
SM+, or LN+. Median F/U 5.6 years
• Outcome: DFS 3-years 66%, 5-years 57%, 10-years 41%; OS 76%, 70%, 37%
• Poor prognosis: large tumor, SM+, PNI, local recurrence
• Conclusion: High DFS rates; early Dx, wide surgery and post-op RT associated with favorable prognosis
• MD Anderson; 1995 (1962-1991) PMID 7790247 -- "The influence of positive margins and nerve invasion in
adenoid cystic carcinoma of the head and neck treated with surgery and radiation." (Garden AS, Int J Radiat
Oncol Biol Phys. 1995 Jun 15;32(3):619-26.)
• Retrospective. 198 patients, ACC treated with surgery, then post-op RT. Parotid 15%,
submandibular/sublingual 21%, minor salivary 62%, lacrimal 2%. Resection R1 42%, close 28%. PNI 69%,
major nerve PNI 28%. Median RT 60 Gy to tumor bed. Median F/U 7.8 years
• Outcome: LR 5-years 95%, 10-years 86%, 15-years 79%. LR by margin: positive 18%, close 9%, negative 5%
(SS). By PNI, PNI major nerve 18% vs. PNI minor nerve 9% (SS). Trend to better control with higher dose.
DM primary mode of recurrence (37%)
• Conclusion: Excellent local control using combined surgery + postop RT. PNI only adverse with major nerve
involvement. Recommend 60 Gy to tumor bed, 66 Gy if SM+
Proton Therapy
• Please also see the general H&N proton therapy page
• Harvard
• 2008 (1991-2002) PMID 17902164 -- "Extent of surgery in the management of locally advanced sinonasal
malignancies." (Resto VA, Head Neck. 2008 Feb;30(2):222-9.)
• Retrospective. 102 patients, locally advanced, treated with proton therapy with or without surgery (R0 20%,
R1 49%, R2/biopsy 31%). Squamous cell 32%, neuroendocrine 29%, adenoid cystic 20%, sarcoma 13%,
adenocarcinoma 6%. Median RT dose if R0 resection 67.6 Gy, if R1/R2 resection 75.6 Gy usually given
BID. Median proton contribution 57%. Concurrent chemo 33% (typically for neuroendocrine). Median F/U
3.6 years, alive 5.1 years
• Outcome: 5-year LC R0 95% vs R1 82% vs R2 87% (NS, no difference by histology); 5-year DFMS 95%
vs. 69% vs 52% (no difference by histology). 5-year OS 90% vs 49% vs 39% (worst for squamous cell).
Regional failure rate 12%
• Conclusion: High dose proton RT excellent local control regardless of extent of surgery. However, DFS and
DMFS depended on extent of surgery. Can consider observation for regional neck
• 2006 (1991-2002) PMID 17116822 -- "Proton beam radiation therapy for skull base adenoid cystic
carcinoma." (Pommier P, Arch Otolaryngol Head Neck Surg. 2006 Nov;132(11):1242-9.)
• Retrospective. 23 patients, adenoid cystic with skull base extension. Sinonasal 75%, nasopharynx 22%.
Surgery 52%. All patients definitive combined photon and proton RT (photons typically to elective LNs,
proton contribution 31-72%). Median dose 76 Gy BID or 73 Gy QD. Median F/U 5.2 years
• Outcome: 5-year LC 93%, DMFS 62%, DFS 56%, OS 77%. Prognostic factors vision change initially and
sphenoid sinus/clivus involvement
• Conclusion: Encouraging local control
Carbon Ion
• Heidelberg
• IMRT vs carbon; 2005 (1995-2003) PMID 15937907 -- "Therapy strategies for locally advanced adenoid
cystic carcinomas using modern radiation therapy techniques." (Schulz-Ertner D, Cancer. 2005 Jul
15;104(2):338-44.)
• Retrospective. 63 patients with ACC, 2 groups depending on carbon ion beam availability. Group A (n=29):
combined photons/carbon boost. Group B (n=34): photons only, delivered as stereotactic or IMRT. Carbon
ion allowed higher median GTV dose (72 GyE vs. 66 GyE). Median F/U Group A 1.3 years vs Group B 2
years
• Outcome: LRC 2-years photons/carbon 77% vs. IMRT 72%, 4-years 77% vs. 25% (p=0.08). 4-year DFS
53% vs. 23%, 4-year OS 76% vs. 78%
• Toxicity: Severe late toxicity <5% for both groups
• Conclusion: Combination of IMRT and carbon ion seemed advantageous over IMRT alone
• Overall; 2004 (1997-2002) PMID 14751537 -- "Results of carbon ion radiotherapy in 152 patients."
(Schulz-Ertner D, Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):631-40.)
• Retrospective. 152 patients treated with carbon ion RT, 21 unfavorable adenoid cystic with infiltration of
skull base and R2 resection enrolled (18 primary, 8 recurrent). Photons to 54 Gy (but 8/21 received lower
dose due to neighboring organ tolerances) followed by carbon ion boost 18 GyE. 14/21 patients planned
with IMRT. Median F/U 14 months
• Adenoid cystic outcome: LRF 4/21 (19%); 3-year LRC 62%, OS 75%
• Toxicity: acute Grade 3 in 9% (1 abscess, 1 mucositis)
• Conclusion: Carbon ion therapy is safe and offers high local control
• Feasibility; 2003 (1998-2002) PMID 12738314 -- "Feasibility and toxicity of combined photon and carbon ion
radiotherapy for locally advanced adenoid cystic carcinomas." (Schulz-Ertner D, Int J Radiat Oncol Biol Phys.
2003 Jun 1;56(2):391-8.)
• Phase I/II. 16 patients, ACC with R2 resection. Combined photon/carbon boost RT to 72 GyE. Photons
were stereotactic RT/IMRT. Median F/U 1 year
• Outcome: 1-year LC 65%, 3-year LC 65%; OS 100% and 83%
• Toxicity: No Grade 3+ acute toxicity
• Conclusion: Combined photon/carbon ion therapy is feasible and effective
Radiation Oncology/Thyroid/Workup
Front Page: Radiation Oncology | RTOG Trials [1]
Thyroid: Main Page | → Workup | → Papillary and follicular | → Medullary | → Hurthle cell | → Anaplastic
Staging
• papillary or follicular: (Under 45 years) I - II. (45 yrs+) I - II - III - IVA IVB IVC
• medullary: I - II - III - IVA IVB IVC
• anaplastic: IVA IVB IVC
Thyroid nodules
• 95% of palpable thyroid nodules in adults are benign.
• Prevalence is around 4% in the general population by palpation. Prevalence is 30-50% by ultrasound.
• FNA biopsy is the most reliable diagnostic test for a thyroid nodule. Can be positive for malignancy, negative, or
indeterminate.
If positive for malignancy, should proceed to definitive treatment.
If negative, serial follow-up is recommended.
Indeterminate biopsies can be:
• Suspicious for papillary carcinoma: patients with biopsy suspicious have a high likelihood (82%) of having
papillary carcinoma. Recommend total thyroidectomy.
• Suspicious for follicular or Hürthle cell carcinoma: Only 15-20% chance of invasive carcinoma. Usually proceed
to thyroidectomy with frozen section analysis.
Reviews:
• PMID 12588078, 2003 — "Thyroid nodules." Welker MJ et al. Am Fam Physician. 2003 Feb 1;67(3):559-66.
Guidelines:
• AACE/AME Guidelines (2006) - Website [2] PDF [3]
• PMID 16596732 — "American Association of Clinical Endocrinologists and Associazione Medici
Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules."
(Endocr Pract. 2006 Jan-Feb;12(1):63-102.)
Thyroid incidentalomas
Thyroid incidentalomas are thyroid nodules discovered incidentally by an imaging procedure (e.g. US or CT)
performed for an unrelated incidcation.
Prevalence:
• PMID 15009911, 2004 — "Prevalence, clinical and ultrasonographic characteristics of thyroid incidentalomas."
• PMID 15840794, 2005 — "Rates of malignancy in incidentally discovered thyroid nodules evaluated with
sonography and fine-needle aspiration."
Diagnosis:
• PMID 14678283, 2004 — "Ultrasonography-guided fine-needle aspiration of thyroid incidentaloma: correlation
with pathological findings."
Reviews:
• PMID 15145242, 2004 — "Management of thyroid incidentalomas."
Guidelines
Management/Treatment:
• AACE/AAES Guidelines (2001) - Website [2] PDF [4]
• PMID 11430305 — "AACE/AAES medical/surgical guidelines for clinical practice: management of thyroid
carcinoma. American Association of Clinical Endocrinologists. American College of Endocrinology." (Endocr
Pract. 2001 May-Jun;7(3):202-20.)
References
[1] http:/ / en. wikipedia. org/ wiki/ Radiation
[2] http:/ / www. aace. com/ pub/ guidelines/
[3] http:/ / www. aace. com/ pub/ pdf/ guidelines/ thyroid_nodules. pdf
[4] http:/ / www. aace. com/ pub/ pdf/ guidelines/ thyroid_carcinoma. pdf
Radiation Oncology/Thyroid/Papillary and

follicular
Clinical features
• Papillary
• most common (75%),
• palpable adenopathy in 33%; 35-50% chance of positive lymph nodes
• extrathyroidal extension 15%
• distant mets in 1-7% at diagnosis
• better 10-year survival (74-93%)
• Follicular
• less common (10%), 10% chance of lymph node involvement (may actually be 1% for pure follicular
carcinomas)
• 10-year survival somewhat lower (43-94%)
Risk of distant mets - about 1-2% (papillary) or 2-5% (follicular) at time of diagnosis
Pathology
• U Connecticut PMID 15944425 -- Independent clonal origins of distinct tumor foci in multifocal papillary
thyroid carcinoma. (2005 Shattuck TM, N Engl J Med. 2005 Jun 9;352(23):2406-12.)
• 10 patient samples analyzed, 5 independent clonal origin, 5 either shared or independent clonal origin
• Conclusion: "Individual tumor foci in patients with multifocal papillary thyroid cancer often arise as
independent tumors. This provides theoretical support for bilateral thyroidectomy and radioablation of
remaining tissue."
Prognostic indices
AMES (age, metastases, extent of primary cancer, tumor size) ^
• High risk features:
• Age: males > 41, females > 51
• Metastases: distant metastases
• Extent: papillary with extrathryoidal spread or follicular with major capsule invasion
• Size: >= 5 cm
• Risk groups:
• Low risk - not high risk
• High risk - 1) any patient with metastases, or 2) high risk age and either high risk extent or size
• Overall survival:
• Low risk 98% (95% DFS). High risk - 54% (45% DFS)
DAMES - modification of AMES with addition of DNA content measured by flow cytometry ^
• Risk groups:
• Low risk - Low risk AMES + euploid
• Intermediate risk - Low risk AMES + aneuploid
• High risk - High risk AMES + aneuploid
• Disease-free survival:
• Low risk - 92%. Intermediate 45%. High 0%.
AGES - age, tumor grade, tumor extent, tumor size (from Mayo clinic) ^
• Prognostic score = 0.05 x age in years (except in pts < 40, then y=0) +1 (grade 2) or +3 (grade 3 or 4) +1 (if
extrathyroidal) or +3 (distant mets) + 0.2 x tumor size in cm
• Risk categories - 0-3.99, 4-4.99, 5-5.99, >6 (median is 2.6)
• 20-year survival:
• <4 (99%), 4-5 (80%), 5-6 (33%), >6 (13%)
MACIS - metastasis, age, completeness of resection, invasion, size ^
• Prognostic score = 3.1 (age < 39 yrs) or 0.08 x age (if >40) + 0.3 x tumor size in cm + 1 (if incompletely resected)
+1 (if locally invasive) +3 (if distant mets)
• Risk categories - 0-5.99, 6-6.99, 7-7.99, >8
• 20-year survival:
• <6 (99%), 6-7 (89%), 7-8 (56%), >8 (24%)
Iodine-131
For papillary and follicular. Some Hurthle cell cancers may respond.
Total ablation achieved with either 30 mCi or 100 mCi dose in >80% of the pts who have a complete surgery. For
less complete surgery, 30 mCi dose is effective in only 66%. Dose required for total ablation is 300 Gy to the
residual thyroid. I-131 scan postoperatively: 1-5 mCi.
Role for post-operative I-131:
1. Ablate residual normal thyroid - increases sensitivity of subsequent I-131 whole body scans and allows
measurement of thyroglobulin levels to reflect recurrence disease
2. Destroy occult carcinoma - decrease recurrence rate
3. Allows post-treatment I-131 whole body scan to detect persistent disease
Procedure:
• Withhold Synthroid (T4; levothyroxine) for 4-6 weeks. Cytomel (T3; liothyronine) can be substituted for 3-4
weeks, but discontinued at least 2 weeks before radioiodine studies.
• TSH should be >25 to 30 at the time of the radioiodine study
• Administer I-131 tracer dose
• If high post-op uptake (>10%), should have completion surgery.
• Others can have treatment dose of I-131.
• Perform total body scan 4-7 days after treatment dose.
• Administer levothyroxine suppressive therapy
• Repeat total body scan in 6 months
Indications for Postoperative I-131

Strong indications for post-operative treatment:
• Distant metastases
• Incomplete resection
• High risk pts (papillary with MACIS 6+, Stage II-III follicular or Hurthle cell)
Probable indications:
• Papillary/follicular in children < 16 yrs
• Tall cell or columnar cell variant of papillary
Possible indications:
• Diffuse sclerosing variant of papillary
• Bulky bilateral LN mets
• Elevated thyroglobulin at 3 months post-op
No post-operative treatment needed for:
• Low risk pts: papillary with MACIS < 6, or Stage I follicular or Hurthle cell
Series showing I-131 Efficacy

• U.Michigan - PMID 6502251, 1984 — "An analysis of "ablation of thyroid remnants" with I-131 in 511 patients
from 1947-1984: experience at University of Michigan."
• Retrospective. Pts given treatment doses of I-131 after positive uptake postsurgically.
• No difference in rate of successful ablation between groups treated with 100-149 mCi, 150-174 mCi, 179-199
mCi, and 200 mCi or more.
• Conclusion: 100-149 mCi dose is appropriate adjuvant therapy.
• Ohio State - PMID 7977430, 1994 — "Long-term impact of initial surgical and medical therapy on papillary and
follicular thyroid cancer."
• Prospective, non-randomized. 1355 pts over 40 yrs.
• I-131 decreases recurrence rate by 33% compared to thyroid hormone therapy alone. No difference in
recurrence rate for low doses (29-50 mCi) vs high doses (51-200 mCi).
• Ohio State - PMID 9133698, 1997 — "Thyroid remnant 131I ablation for papillary and follicular thyroid
carcinoma." Mazzaferri EL et al. Thyroid. 1997 Apr;7(2):265-71.
• Retrospective. 1004 pts. Compared I131 ablation vs thyroid hormone alone or no further treatment.
• Decrease in recurrences by 75%, decreased rate of DM, and decreased cancer deaths after I131. Benefit
restricted to those with tumors >=1.5 cm (for recurrence and DM) and for age 40 or older with tumors >=1.5
cm (for cancer deaths). No difference between low and high dose therapy.
• I-131 treatment benefits pts with tumors >=1.5 cm.
• Review: Mazzaferri et al, 2001 — "Clinical review 128: Current approaches to primary therapy for papillary and
follicular thyroid cancer." Mazzaferri EL et al. J Clin Endocrinol Metab. 2001 Apr;86(4):1447-63.
External beam radiotherapy

Controversial. Early series show no benefit or even had patients who had received radiation doing worse. Modern
series appear to show benefit of a combination of RT + radioiodine in some patient populations (e.g. macroscopic
residual disease in the neck).
Post-operative Radiotherapy
• German MSDS Study (1999-2003) -- surgery + I-131 +/- adjuvant RT
• Originally randomized, converted to prospective cohort study. 279 patients met inclusion criteria, 45 consented
to randomization, 35 were randoimzed. T4 tumors (extending beyond capsule with/without LN involvement)
treated with surgery and I-131, then Arm 1) observation vs. Arm 2) adjuvant RT. If R0 resection used 59.4/33,
if R1 resection used 66.6/37. GTV1 = tumor region, ipsilateral or bilatera. GTV2 = thyroid bed, cervical LNs,
infra/supraclavicular LNs, uuper mediastinum.
• Acute Toxicity; 2003 PMID 14652672 -- "Acute toxicity of adjuvant radiotherapy in locally advanced
differentiated thyroid carcinoma. First results of the multicenter study differentiated thyroid carcinoma
(MSDS)." (Schuck A, Strahlenther Onkol. 2003 Dec;179(12):832-9.)
• Outcome: Grade 3+ in 9% (pharynx, larynx, and skin). Maximal late toxicity Grade 2 in 4 patients, no
Grade 3 toxicity
• Conclusion: Acute toxicity is tolerable
• Conversion; 2003 PMID 14668957 -- "Multicenter study differentiated thyroid carcinoma (MSDS).
Diminished acceptance of adjuvant external beam radiotherapy." (Biermann M, Nuklearmedizin. 2003
Dec;42(6):244-50.)
• Study converted to prospective cohort due to low acceptance of adjuvant RT (only 14% of trial cohort
actually assigned)
• Villejuif, France - PMID 3919920 "External radiotherapy in thyroid cancers." Tubiana et al. Cancer. 1985
• 97 pts treated w/ external beam xrt after incomplete resection; 76 pts treated with surgery alone. Low incidence
of local recurrence in pts tx'd with xrt (11% at 15 yrs vs 23% for pts treated w/ surgery alone; pts tx'd with xrt
had larger/more extensive tumors). Reasons for residual disease included laryngeal, tracheal, esophageal,
mediastinal or major vessel involvement.
• Conclusion: Radiotherapy effective means of controlling residual disease after surgery if doses >50 Gy
delivered.
• Princess Margaret Hospital, 1998 - PMID 9445196 — "The effects of surgery, radioiodine, and external
radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma." Tsang RW et al.
Cancer. 1998 Jan 15;82(2):375-88.
• 382 pts w/ stage I-IV papillary or follicular thyroid CA w/ median FU of 10.8 yrs. Factors predictive of local
relapse were age>60,poor differentiation,>4cm,macroscopic residual,lack of radioiodine. 10 yr OS was 93%
for papillary and 86% for follicular. Local control improved in cases of EBRT for microscopic residual disease
(93% vs 78% at 10yrs). If macroscopic residual disease, local control 62% at 5yrs if adjuvant EBRT.
• Conclusion: microscopically +margins and macroscopic residual disease both appear to benefit from adjuvant
external beam xrt.
• Essen, 1995 - PMID 8630926 "Impact of Adjuvant EBRT in pts with Perithyroidal Infiltration" Farahati et al.
Cancer. 1996
• 169 pts with T4 follicular or papillary thyroid and free of mets after 2nd radioiodine tx. Cohorts got either xrt
or no xrt; all got surgery, ablative I-131, levothyroxine. Xrt comprised of 50-60 Gy to neck. RFS benefit was
seen in pts >40 y/o w/ N+ disease.
• Conclusion: T4N+ should be considered for adjuvant xrt.
IMRT
• MSKCC, 2005 (2001-4) - PMID 16154712 — "Intensity-modulated radiation therapy for the treatment of
nonanaplastic thyroid cancer." Rosenbluth BD et al. Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1419-26.
• 20 pts with non-anaplastic thyroid cancer treated with IMRT. Treated microscopic disease to 54 Gy, higher
risk areas to 59.4-63 Gy, positive margins to 63-66 Gy, and gross disease to 63-70 Gy. Elective nodal volume
extended from the top of level II (sometimes retropharyngeal nodes were included) to below the thoracic inlet
to the level of the aortic arch. High risk area was the tumor bed and central neck lymphatics.
• Conclusion: IMRT is feasible for treatment of thyroid cancer
Recurrent disease
Excellent prognosis for patients with locoregional recurrences, with 70-90% long-term survivors. For patients who
develop distant metastasis, 50-90% die of their disease.
I-131 for ablation (if post-op scan reveals gross residual disease): 100 mCi.
I-131 for recurrent disease, post-op residual in the neck, nodal or distant metastases, or inoperable tumors: 150-250
mCi.
Re-imaging should be done 1-2 days after ablation or therapy.
Recommended maximum dose: 800-1000 mCi.
Estimation of absorbed dose is 0.1 Gy per microcurie per gram of thyroid cancer tissue.
References
• [1] - PMID 3194846
• [2] - PMID 1455318
• [3] - PMID 3686348
• [4] - PMID 8256208
• Larsen: Williams Textbook of Endocrinology, 10th ed., 2003 Saunders.
References
[1] http:/ / en. wikipedia. org/ wiki/ Radiation_oncology%2Fthyroid%2Fpapillary_and_follicular#endnote_AMES
[2] http:/ / en. wikipedia. org/ wiki/ Radiation_oncology%2Fthyroid%2Fpapillary_and_follicular#endnote_DAMES
[3] http:/ / en. wikipedia. org/ wiki/ Radiation_oncology%2Fthyroid%2Fpapillary_and_follicular#endnote_AGES
[4] http:/ / en. wikipedia. org/ wiki/ Radiation_oncology%2Fthyroid%2Fpapillary_and_follicular#endnote_MACIS
Radiation Oncology/Thyroid/Medullary
Epidemiology
• About 5% of thyroid cancers.
• Present in 5th decade.
• 80% are sporadic, but some can result from MEN 2 syndrome.
• There is also a Familial (non MEN 2-related) medullary thyroid cancer syndrome
Genetics
• Medullary thyroid CA associated w/ MEN 2 syndrome results from a mutation in RET gene.
• MEN 2 w/ ~70% penetrance
Pathophysiology
• Neuroendocrine tumor that derive from parafollicular C cells
• C cells secrete can secrete calcitonin (which can therefore be used as a tumour marker)
• Non iodine avid therefore no role for I-131 ablation after surgery
Radiation Oncology/Thyroid/Medullary 231
Staging
UICC/AJCC Staging
• Stage I - <2cm, confined to thyroid
• Stage II - 2-4cm, confined to thyroid
• Stage III - >4cm, N+ in level IV, or microscopic extrathyroid extension
• Stage IV - M+, N+ outside of level IV, gross soft tissue extension
Treatment
• Treatment includes total thyroidectomy with central neck lymph node dissection.
• Indications for adjuvant radiation: microscopic residual dz, extensive nodal involvement, extrathyroid extension.
Adjuvant Radiation
• University of Toronto, 1996 (1954-92) PMID 8875751 -- "Medullary thyroid cancer: analyses of survival and
prognostic factors and the role of radiation therapy in local control." Thyroid. 1996 Aug;6(4):305-10.
• 73 pts w/ medullary thyroid CA. 46 pts received xrt (median dose 40 Gy).
• On multi-variate analysis, factors that predicted for lower CSS were extraglandular invasion and postop gross
residual dz.
• Pts w/ high risk for locoregional relapse (microscopic residual dz, extraglandular invasion, N+) benefited from
RT.
• Conclusion: external beam RT recommended if high risk
• FFCI, 1992 (1971-89) PMID 1736326 -- "Results of postoperative radiation therapy in medullary carcinoma of
the thyroid: a retrospective study by the French Federation of Cancer Institutes--the Radiotherapy Cooperative
Group." Radiother Oncol. 1992 Jan;23(1):1-5.
• 59 pts w/ medullary thyroid CA receiving EBRT w/ curative intent. Total thyroidectomy in 55 pts. 11 pts w/
residual tumor, 44 pts w/ N+. Mean dose 54 Gy.
• 70% local control, with failures mostly occurring in RT field.
• MDACC, 1988 (1943-87) PMID 2807151 -- "Medullary thyroid carcinoma: prognosis of familial versus
nonfamilial disease and the role of radiotherapy." Samaan NA et al. Horm Metab Res Suppl. 1989;21:21-5.
• 202 pts w/ medullary thyroid CA
• Pts w/ MEN2 had longer survival rates than sporadic medullary thyroid CA
• When pts who were matched for age, extent of dz, and surgery were compared for effect of radiation therapy,
pts who had no radiotherapy were found to live significantly longer.
Radiation Oncology/Thyroid/Hurthle cell 232
Radiation Oncology/Thyroid/Hurthle cell

Variant of follicular carcinoma. Is relatively aggressive with prognosis worse than papillary carcinoma. Represent
about 3% of thyroid cancer.
Prognostic factors
• M.D.Anderson, 2003 (1944 - 1995) - PMID 12599224 — "Prognostic factors in patients with Hurthle cell
neoplasms of the thyroid." Lopez-Penabad L et al. Cancer. 2003 Mar 1;97(5):1186-94.
• 89 pts with Hurthle cell carcinoma, 38 with Hurthle cell adenoma.
Patterns of failure
Most recurrences are in the neck. Lung is most common site of distant mets. Recurrent disease in the neck can be
treated surgically.
Cause-specific mortality approximately 30%.
Treatment
Treatment should include total thyroidectomy and unilateral central compartment neck dissection. There is no known
role for adjuvant radiation therapy; however, the tumor is radiosensitive.
Only about 7% respond to I-131; however, one study (PMID 12599224; see M.D.Anderson study above) suggested a
survival benefit for thyroid ablation with radioactive iodine.
Adjuvant Radiation Therapy

• Mayo Clinic, 2003 - PMID 12829143 — "Is there a role for radiation therapy in the management of Hurthle cell
carcinoma?" Foote RL et al. Int J Radiat Oncol Biol Phys. 2003 Jul 15;56(4):1067-72.
Radiation Oncology/Thyroid/Anaplastic
Epidemiology
• 2% of thyroid cancers
• 13-39% thyroid cancer deaths
• F>M 3:1
• Mean age of diagnosis is 65
Pathophysiology
• Thought to be a de-differentiation of a previously differentiated thyroid cancer.
• 20% have history of differentiated thyroid CA
• 20-30% have concurrent papillary thyroid CA
• loss of p53 thought to be a major step in de-differentiation.
Histologic Subtypes
Histologic subtype has not been found to affect prognosis.
• Spindle Cell
• Giant Cell
• Squamoid
Staging
All anaplastic thyroid CA is considered stage IV.
AJCC 2002 6th Edition
• T4a - intrathyroid (resectable)
• T4b - extrathyroid (unresectable)
• N1a - level VI nodes
• N1b - unilateral, contralateral, bilateral cervical/superior mediastinal nodes
• Stage IVa - T4a (any N)
• Stage IVb - T4b (any N)
• Stage IVc - M1
Treatment
• Monotherapy (surgery, chemo, xrt) have not shown to benefit overall survival.
• Current treatment of choice is multi-modality. Upfront resection is preferred if tumor confined to thyroid.
• Hyperfractionated xrt with adriamycin treatment of choice for locally advanced non-metastatic. Consider
consolidative surgery if good response to chemoxrt.
• Dose of 60 Gy in 40 fx over 4 wks.
Treatment Prognostic Factors

• SEER Database Analysis, 2005 PMID 15739211 "Anaplastic thyroid carcinoma. Treatment outcome and
prognostic factors," (Kebebew E, Cancer. 2005; 103(7):1330-5.)
• 516 pts from SEER cancer registry tx'd for anaplastic thyroid CA from 1973-2000.
• Overall cause-specific mortality at 6 mo's was 68.4% and at 12 mo's was 80.7%.
• On multi-variate analysis age<60 and intrathyroid tumor (w/o mets) were independent predictors of lower
cause-specific mortality.
• Conclusion: given the majority of data for ATC derived from small single institution series which are subject
to selection bias, this analysis identifies prognostic factors that may be used to triage more aggressive
treatments to patients who may benefit.
Combined Modality Approach

• SEER Database Analysis, 2008 (1983-2002) PMID 18838882 — "Surgery and radiotherapy improves survival
in patients with anaplastic thyroid carcinoma: analysis of the surveillance, epidemiology, and end results
1983-2002." (Chen J, Am J Clin Oncol. 2008 Oct;31(5):460-4.)
• 261 pts who had surgery performed or recommended
• Median survival 4 months. On multivariate analysis, distant disease, tumor size > 7 cm, and treatment with
surgery (+/- RT) were significant related to survival. The addition of RT to surgery resulted in improved
survival for pts with disease extending into adjacent tissue but not for those with disease limited to the capsule
or with distant metastatic disease
• Conclusion: surgery and radiotherapy improves survival.
• Princess Margaret, 2001 PMID 11413523 "Completely resected anaplastic thyroid carcinoma combined with
adjuvant chemotherapy and irradiation is associated with prolonged survival," (Haigh PI, Cancer. 2001;
91(12):2335-42.)
• 33 pts w/ anaplastic thyroid cancer retrospectively reviewed to determine prognostic factors. 64% w/
metastatic dz. 92% received adjuvant therapy.
• Pts w/ curative resection w/ longer median survival.
• Conclusion: Complete resection or maximum tumor debulking followed by adjuvant chemo/xrt resulted in
some long term survivals.
• Mayo Clinic, 2001 PMID 11742333 "Anaplastic thyroid carcinoma: a 50-year experience at a single institution,"
(McIver B, Surgery. 2001; 130(6):1028-34.)
• 134 cases b/w 1949-99, mean age 67, 46% w/ mets at time of dx
• 72% underwent surgery, 30% w/ complete resection
• Neither surgery, chemo, nor radiation improved survival significantly. Combined modality approach was the
only approach that led to long-term survivors.
Altered Fractionation of Radiotherapy

• Princess Margaret, 2006 PMID 16967442 "Clinical outcome of anaplastic thyroid carcinoma treated with
radiotherapy of once- and twice-daily fractionation regimens," (Wang Y, Cancer. 2006; 107(8):1786-92)
• 47 pts w/ anaplastic thyroid CA tx'd b/w 1983-2004. Pts tx'd palliatively or w/ curative intent w/ goal to assess
local control, survival, toxicity of once vs twice daily regimens.
• 94% 6 mo local PFS if xrt w/ radical intent, 64% if palliative intent. Median OS 3.3 mo's longer if BID
fractionation (13.6 vs 10.3 mo's)
• Conclusion: twice daily fractionation appears to lead to better outcome.
• Royal Marsden Pure Accelerated XRT, 1999 PMID 10225555 "Phase II evaluation of high dose accelerated
radiotherapy for anaplastic thyroid carcinoma," (Mitchell G, Radiother Oncol. 1999; 50(1):33-8.)
• 17 pts w/ anaplastic thyroid CA tx'd w/ BID xrt to 60.8 Gy (1.8 Gy in AM, 2 Gy in PM)
• 3 pts w/ CR, 7 pts w/ partial response; toxicity from esophagitis/dysphagia high (40% grade 4
pharyngo-esophagitis, dysphagia)
• Conclusions of the authors were that toxicities of pure acceleration were unacceptably high in spite of
improved local control rate.
• Sweden, 1994 PMID 8055459 "Combined doxorubicin, hyperfractionated radiotherapy, and surgery in anaplastic
thyroid carcinoma. Report on two protocols. The Swedish Anaplastic Thyroid Cancer Group," (Tennvall J,
Cancer. 1994; 74(4):1348-54. )
• 33 pts w/ anaplastic thyroid CA tx'd w/ hyperfractionated xrt (30 Gy preop, 46 Gy postop), doxorubicin,
surgery
• 48% local control, 24% death from local failure, 4 pts survived 2 yrs
Radiation Oncology/Head & Neck/Recurrent

Recurrent H&N Cancer
Overview
Results of treatment:
• Chemotherapy alone: MS 7-9 months, 5-10% long-term survival
• RT alone (hyperfractionated): LRC 40%
• RT + 5-FU/hydroxyurea: 5-yr OS 14.6%
• RTOG 96-10: BID RT + 5-FU/hydroxyurea, MS 8 mos, OS 1 yr 41.7%, 2 yr 16.9%
• RTOG 99-11: BID RT + cisplatin/taxol, 2 yr OS 25.2%
See also: Radiation Oncology/Head & Neck/Nasopharynx/Advanced Stage#Reirradiation for reirradiation of
the nasopharnx
Surgery +/- Reirradiation

• GETTC/GORTEC (1999-2005) -- salvage surgery +/- reirradiation + chemotherapy
• Randomized. 130 patients, H&N cancer, either recurrence or second primary in a previously irradiated area, no
major sequelae. Treated with R0-R1 surgery. Arm 1) adjuvant salvage chemotherapy + re-irradiation vs. Arm
2) observation. RT given 60 Gy over 11 weeks with concurrent 5-FU and hydroxyurea
• 2008 PMID 18936479 -- "Randomized Trial of Postoperative Reirradiation Combined With Chemotherapy
After Salvage Surgery Compared With Salvage Surgery Alone in Head and Neck Carcinoma." (Janot F, J Clin
Oncol. 2008 Oct 20. [Epub ahead of print])
• Outcome: DFS improved (HR 1.68, SS), OS no difference
• Late toxicity: 2-years Grade 3-4 RT arm 39% vs. observation arm 10% (p=0.06)
• Conclusion: Full-dose reirradiation combined with chemo after salvage surgery significantly improved DFS
but not OS. Toxicity was higher
Reirradiation + chemo
• RTOG 99-11
• Phase II. 105 patients with recurrent SCCHN or second primary tumor (SPT, 23%) in prior RT field.
Oropharynx 40%, oral cavity 27%. Median prior RT dose 65 Gy. RT 1.5 Gy/fx BID x5 days, every 2 weeks,
x4. Concurrent cisplatin 15mg/m2 + paclitaxel 20mg/m2. GM-CSF on off weeks. (RT the same as RTOG
96-10).
• 2007 PMID 17947728 -- "Phase II study of low-dose paclitaxel and cisplatin in combination with split-course
concomitant twice-daily reirradiation in recurrent squamous cell carcinoma of the head and neck: results of
Radiation Therapy Oncology Group Protocol 9911." (Langer CJ, J Clin Oncol. 2007 Oct 20;25(30):4800-5.)
• Outcome: median OS 12 months; 2-year OS 26%
• Toxicity: Grade 4-5 in 28%, treatment-related death 8% (n=8)
• Conclusion: Despite high incidence of Grade 5 toxicity, results better than chemo alone
• U. Chicago; 2006 (1986-2001) PMID 16213104 — "Long-term outcome of concurrent chemotherapy and
reirradiation for recurrent and second primary head-and-neck squamous cell carcinoma." Salama JK et al. Int J
Radiat Oncol Biol Phys. 2006 Feb 1;64(2):382-91.
• 115 patients. Previously irradiated, recurrent or second primary. Treated on seven consecutive trials of
hydroxyurea and 5-FU with an optional 3rd agent (CDDP, Taxol, CPT-11) or 5-FU + Taxol + Gemcitabine.
Treated on 14 day cycles with chemo/RT given on days 1-5 followed by a 9 day break. Pts received 4 to 7
cycles. Most were treated at 2 Gy/day or 1.5 Gy BID. At least 70 Gy to gross disease. Included trials are:
PMID 2715806 (1989), PMID 1602911 (1992), PMID 7525886 (1994), PMID 9469365 (1998), PMID
10942062 (2000), PMID 15297392 (2004), PMID 15969989 (2005)
• RTOG 96-10
• 86 patients. Recurrent squamous cell cancer or a second primary in a previously irradiated field. RT finished >
6 months prior. RT 60 Gy at 1.5 Gy BID, with > 4 hrs between fractions, given on weeks 1, 3, 5, 7. Chemo
(5-FU/hydroxyurea) given prior to 2nd daily dose. Dose to spinal cord limited to 50 Gy (prior + current).
Fields include tumor with 2 cm margins. Treated with standard fields or 3D-CRT, no IMRT.
• 2001 PMID 11728690 — "RTOG 96-10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in
patients with squamous cell cancer of the head and neck." Spencer SA et al. Int J Radiat Oncol Biol Phys. 2001
Dec 1;51(5):1299-304.
• 2007 PMID 17764087 -- "Final report of RTOG 9610, a multi-institutional trial of reirradiation and
chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck." (Spencer SA, Head
Neck. 2007 Aug 31; [Epub ahead of print])
• Outcome: 2-year OS 15%, 5-year OS 4%; better survival if >1 year from prior RT. No dose-response
• Toxicity: Acute Grade 4 in 18%, Grade 5 in 8%. Late (>1-year) Grade 3-4 9%
• Conclusion: Feasible approach with acceptable acute and late effects
Ongoing:
• RTOG 04-21
• Randomized to re-irradiation + concurrent chemotherapy (cisplatin/taxol) vs chemo alone. Chemo is choice of
cisplatin/taxol, cisplatin/5-FU, or cisplatin/taxotere
Chemo Alone
• EXTREME (2004-2005) -- Chemotherapy (cisplatin or carbo/5-FU) +/- cetuximab
• Randomized. 442 patients with recurrent or metastatic SCC of H&N. Arm 1) chemotherapy (cisplatin 100
mg/m2 or carbo AUC 5 + 5F-FU 1000 mg/m2) x6 cycles vs. Arm 2) same chemotherapy + cetuximab 250
mg/m2 x6 cycles. If stable disease, cetuximab until disease progression or toxicity
• 2008 PMID 18784101 -- "Platinum-based chemotherapy plus cetuximab in head and neck cancer."
(Vermorken JB, N Engl J Med. 2008 Sep 11;359(11):1116-27.)
• Outcome: Median OS chemo 7 months vs. chemo+cetuximab 10 months (SS)
• Toxicity: Grade 4 comparable except sepsis worse in cetuximab arm
• Conclusion: Cetuximab + platinum chemotherapy improved overall survival compared with chemotherapy
alone
SBRT
• Catholic University of Korea; 2009 (2004-2006) PMID 19117695 -- "Fractionated stereotactic radiotherapy as
reirradiation for locally recurrent head and neck cancer." (Roh KW, Int J Radiat Oncol Biol Phys. 2009 Aug
1;74(5):1348-55. Epub 2008 Dec 29.)
• Retrospective. 36 patients, 44 sites, recurrent HNC. Median dose 30 Gy (18-40) in 3-5 fractions, prescribed to
65-85%. Prior RT median 70.2 Gy. Median GTV 23 cm3. Median F/U 1.5 years
• Outcome: CR 43%, PR 37%, SD 9%, progression 11%.
• Toxicity: Late Grade 3 in 8% (1 bone necrosis, 2 soft tissue necrosis)
• Conclusion: Effective salvage, with good short-term control; more experience needed
Pattern of Failure
• Michigan; 2009 PMID 19135312 -- "The pattern of failure after reirradiation of recurrent squamous cell head and
neck cancer: implications for defining the targets." (Popovtzer A, Int J Radiat Oncol Biol Phys. 2009 Aug
1;74(5):1342-7. Epub 2009 Jan 8.)
• Retrospective. 66 patients, curative-intent re-RT for unresectable recurrence. Target was rGTV + 0.5 cm
margin, no prophylactic LN or subclinical disease around rGTV. Median re-RT dose 68 Gy, concomitant
chemo 71%, AHFX 47%. Median F/U 3.5 years
• Outcome: 3rd recurrence or persistent disease in 77%. Majority (96%) of failures were within rGTV
• Toxicity: Late Grade 3+ toxicity 29%, mostly dysphagia
• Conclusion: Confine re-RT targets to rGTV to reduce reirradiated normal tissue
Radiation Oncology/Head & Neck/Palliation 238
Radiation Oncology/Head & Neck/Palliation

Head & Neck Palliation

• UCSD; 2008 (2001-2007) PMID 18798313 -- "Palliative radiation therapy for head and neck cancer: Toward an
optimal fractionation scheme." (Chen AM, Head Neck. 2008 Sep 16. [Epub ahead of print])
• Retrospective. 60 patients, primary H&N sites, typically painful recurrent disease. Used various regimens:
44.4/12 (RTOG 85-02 protocol @ 3.7 Gy/fx BIW at 2-3 week intervals), 70/35, 30/10, 37.5/15, 20/5
• Palliative response: 83%, 77%, 67%, 86%, 60% (NS)
• Toxicity: Grade 3+ 44.4/12 9% vs. other regimens 37% (SS)
• Conclusion: All schedules effective at palliation, RTOG 85-02 scheme less toxicity
Radiation Oncology/Head & Neck/Second

Primary
Second Primary Tumors in Head & Neck
Overview
• Second primary tumors are a major source of morbidity and mortality, particularly for patients who have been
effectively treated for early stage HNSCC
• The risk of developing a second primary is ~5%/year. Majority occur in H&N, esophagus, or lung; lung is the
most common site (31%), followed by oral cavity (17%)
• Continued smoking increases both risk of second primary tumor (HR 1.6) and death (HR 2.5) over that of former
smokers (HR 1.3 and 1.6) compared with non-smokers. This is a rationale to promote smoking cessation
• Concurrent treatment with chemotherapy doesn't appear to change risk of second cancers
• A high-dose isotretinoin given for 1 year decreased the risk of second primary in Stage I-IV patients in a
randomized trial; however, tolerance was poor with 70% patients requiring dose reduction
• A French trial, using a second generation retinanoic acid etretinate did not show any benefit. An Italian and
Austrial trial using isotertinoin also did show any benefit
• Finally, a tolerable low-dose isotretinoin given for 3 years to early stage patients in a large Intergroup trial did not
decrease risk of second primary tumors or death
• Memorial Sloan Kettering; 2005 (1986-1995) PMID 16265657, 2005 (1984-98) — "Second primary
malignancy of the aerodigestive tract in patients treated for cancer of the oral cavity and larynx." (Lin K et al.
Head Neck. 2005 Dec;27(12):1042-8. )
• Retospective. 1257 patients with oral cavity (n=595) and larynx (n=662). Endpoint development of second
primary (H&N, esophagus, or lung)
• Outcome: 5-year rate larynx 8%, oral cavity 10%. Larynx most common 2nd primary was lung, oral cavity
was another H&N.
• Predictors: Smokers 5x increased risk, EtOH 2x increased risk
• Conclusion: Rates comparable, patterns different. Smoking and EtOH independent risk factors
• SAKK 10/94; 2005 PMID 15936546 -- "Risk factors for developing a second upper aerodigestive cancer after
radiotherapy with or without chemotherapy in patients with head-and-neck cancers: An exploratory outcomes
analysis." (Taussky D, Int J Radiat Oncol Biol Phys. 2005)
• Analysis of Swiss SAKK 10/94 trial (RT +/- cisplatin). 521 patients. Median F/U 4.7 years
• Second primary tumors: No difference as a function of getting chemotherapy, age, PS, gender, T-stage, or
N-stage. Concomitant boost fewer SPTs
• Conclusion: Addition of chemotherapy doesn't influence incidence of second cancers
• RTOG Registry (76-19) (1977-1980)
• 1989 PMID 2674073 -- "Second malignancies in patients who have head and neck cancer: incidence, effect on
survival and implications based on the RTOG experience." (Cooper JS, Int J Radiat Oncol Biol Phys. 1989
Sep;17(3):449-56.)
• Prospective registry of H&N patients seen by RTOG. 928 HNSCC treated with RT only
• Second tumor risk: 3-years 10%, 5-years 15%, 8-years 23%; most occurred in patients with small primaries
due to their longer survival
• MD Anderson; 1989 PMID 2674081 -- "Second malignant tumors in head and neck squamous cell carcinoma:
the overshadowing threat for patients with early-stage disease." (Lippman SM, Int J Radiat Oncol Biol Phys. 1989
Sep;17(3):691-4.)
Prevention Trials
• Italian Head and Neck Chemoprevention Study Group 2004 (1992-1996) -- low-dose isotretinoin
• Randomized. 267 patients. Radically treated Stage III-IV HNSCC. Arm 1) placebo vs. Arm 2) isotretinoin 0.5
mg/kg vs. Arm 3) isotretinoin + Interferon alpha-2a (only 15 patients assigned due to financial problems) x1
year
• 2004 PMID 15138569 — "13-cis retinoic acid in head and neck cancer chemoprevention: results of a
randomized trial from the Italian Head and Neck Chemoprevention Study Group." (Toma S, Oncol Rep. 2004
Jun;11(6):1297-305.) Mean F/U 3.2 years
• Outcome: 5-year OS isotretinoin 59% vs. placebo 57% (NS); RFS 49% vs. 56% (NS)
• Toxicity: Grade III-IV in 4%, Grade I-II 69%
• Conclusion: Low-dose isotretinoin ineffective at chemoprevention
• Retinoid Head and Neck Second Primary Trial (INT/RTOG 91-15) (1991-1999) -- low dose isotretinoin
• Randomized. 1190 patients, treated, with Stage I-II HNSCC (oral cavity, larynx, pharynx), disease-free at least
4 months. Arm 1) low-dose isotretinoin (30 mg/day) vs. Arm 2) placebo x3 years
• Smoking; 2001 PMID 11489748 -- "The impact of smoking status, disease stage, and index tumor site on
second primary tumor incidence and tumor recurrence in the head and neck retinoid chemoprevention trial."
(Khuri FR, Cancer Epidemiol Biomarkers Prev. 2001 Aug;10(8):823-9.)
• Outcome: second primary tumor rate 5.1%/year; active smoker 5.7% vs. never smoker 3.5% (p=0.05);
Stage I 4.3% vs. Stage II 6.4% (SS)
• Conclusion: Significantly higher second primary tumor rate in active smokers, intermediate rate for former
smokers compared with never smokers
• 6-years; 2006 PMID 16595780 -- "Randomized phase III trial of low-dose isotretinoin for prevention of
second primary tumors in stage I and II head and neck cancer patients." (Khuri FR, J Natl Cancer Inst. 2006
Apr 5;98(7):441-50.) Median F/U 6 years
• Outcome: Second primary tumors rate 4.6%/year in both arms (NS); no difference in primary tumor–free
survival, RFS, smoking-associated DFS, and OS
• Predictors: second cancers 261 (22%); current smokers (HR 1.64, SS) more risk than former smokers (HR
1.32, SS) compared with non-smokers. Risk of death current smokers 2.51 vs. former smokers 1.60
• Sites of 2nd tumors: lung (31%), oral cavity (17%), larynx (8%), pharynx (5%)
• Conclusion: Low-dose isotretinoin not effective at reducing second primary tumors
• France -- etretinate
• Randomized. 316 patients, SCHNN T1-2N0-1 <=3 cm. Arm 1) etretinate 25 mg/day vs. Arm 2) placebo x2
years
• 5-years; 1994 PMID 7917535 -- "Prevention of second primary tumours with etretinate in squamous cell
carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomised study." (Bolla
M, Eur J Cancer. 1994;30A(6):767-72.) Median F/U 3.4 years
• Outcome: second primary tumor 18% (NS). No difference on LR or DM rate. 5-year OS and DFS no
difference
• Toxicity: discontinued in etretinate 33% vs. placebo 23% (SS)
• Conclusion: Etretinate does not prevent second primary tumors
• Queensland (Australia) -- high-dose or low-dose isotretinoin
• Randomized. Trial stopped early by sponsor after early analysis showed no benefit. 151 patients. T1-4N0-2
HNSCC. Arm 1) high-dose isotretinoin 1 mg/kg x1 year, then low-dose isotretinoin 0.5 mg/kg x2 years vs.
Arm 2) low-dose isotretinoin x3 years vs. Arm 3) placebo x3 years. 67% did not complete therapy (~1/3 in
high-dose due to side effects)
• 2005 PMID 15781758 -- "Chemoprevention of head and neck cancer with retinoids: a negative result." (Perry
CF, Arch Otolaryngol Head Neck Surg. 2005 Mar;131(3):198-203.)
• Outcome: Second primary cancer high-dose 9% vs. low-dose 17% vs. placebo 14% (NS); no difference in
DFS, RFS, or OS
• Toxicity: No difference between groups
• Conclusion: Use of isotretinoin not indicated for prophylaxis
• MD Anderson -- high-dose isotretinoin
• Randomized. 103 patients, treated Stage I-IV HNSCC. Arm 1) high dose isotretinoin 50-100 mg/m2 vs Arm 2)
placebo x1 year.
• 3-years; 1990 PMID 2202902 — "Prevention of second primary tumors with isotretinoin in squamous-cell
carcinoma of the head and neck." (Hong WK, N Engl J Med. 1990 Sep 20;323(12):795-801.) Median F/U 2.7
years
• Outcome: second primary tumors isotretinoin 4% vs. placebo 24% (SS). 93% tumors in H&N, esophagus,
or lung. No difference in local, distant, or regional recurrence of primary tumor.
• Conclusion: High dose isotretinoin effective in prevention of second primary
• 5-years; 1994 PMID 8271298 -- "Prevention of second primary tumors with isotretinoin in patients with
squamous cell carcinoma of the head and neck: long-term follow-up." (Benner SE, J Natl Cancer Inst. 1994
Jan 19;86(2):140-1.) Median F/U 4.5 years
• Outcome: second primary tumors isotretinoin 14% vs. placebo 31% (SS); but impact diminishes with time.
By 8 years, estimated rates of 19% vs. 44%. No patients developed second primary tumor while on drug
• Toxicity: 70% required dose reduction, 25% stopped
• No difference in OS. No impact on behavior of primary tumor.
Radiation Oncology/Melanoma/Mucosal
Mucosal Melanoma
Overview
• Rare, approximately 1% of all melanoma
• H&N sites ~50% of mucosal melanomas, anus/rectum ~25%, female genitalia ~20%
• No risk factors have been substantiated
• Staging
• No formal AJCC staging system
• Ballantyne staging (1970) for H&N locations
• Stage I: disease confined to the primary site (~75%)
• Stage II: regional lymph node metastasis (~18%)
• Stage III: distant metastasis (~7%)
• Surgery with negative margins should be primary approach
• Role of RT is unclear; there appears to be benefit in terms of local control, though impact on survival is unclear
• Survival is poor:
• 5-year OS nasal melanoma ~30%, oral melanoma ~10%, paranasal sinuses 0%
• 5-year OS LN- 30% vs. LN+ 20%
• Fractionation schedule is also not well established. Based on radiobiology, hypofractionated regimens may be
reasonable, but may be difficult to tolerate in H&N regions
General
• Princess Margaret; 1982 PMID 6181042 -- "Radiotherapy for mucosal melanomas." (Harwood AR, Int J Radiat
Oncol Biol Phys. 1982 Jul;8(7):1121-6.)
• Retrospective. 18 patients (H&N 12, anorectal 6). Literature review for combined 25 patients
• Outcome: local control 44%; if failed to respond to RT, rapid death. Local control >=4 Gy/fx 86% vs. <4
Gy/fx 28%
• Conclusion: For H&N, consider as primary treatment. For anorectal and vaginal, treatment palliative and
should be considered alternative to radical surgery
Head & Neck

• University of Florida; 2008 (1974-2005) PMID 18376227 -- "Mucosal melanoma of the head and neck."
(Wagner M, Am J Clin Oncol. 2008 Feb;31(1):43-8.)
• Retrospective. 17 patients with primary H&N mucosal melanoma treated with RT. 13 patients surgery + RT, 4
definitive RT.
• Outcome: LC surgery+RT 100% vs. definitive RT 25%. Regional control neck RT 89% vs. no RT 75% (NS);
all 3 patients with neck mets treated with surgery + neck dissection + RT and all died within 6 months.
1-year/5-year LC 79%/79%, RC 83%/83%, LRC 63%/63%, DMFS 29%/24%, OS 53%/28%
• Fractionation: no difference between QD and BID
• Conclusion: Locoregional control relative high, but most patients fail in distant sites. Approximately quarter
cured at 5 years
• Colorado; 2003 (1985-1998) PMID 12925346 -- "The role of postoperative adjuvant radiation therapy in the
treatment of mucosal melanomas of the head and neck region." (Owens JM, Arch Otolaryngol Head Neck Surg.
2003 Aug;129(8):864-8.)
• Retrospective. 48 patients, mucosal melanoma of H&N. Surgery alone 42%
• Outcome: LRC surgery alone 55%, surgery + RT 83%; DM 50% vs 46%; 5-year OS 45% vs 29%
• Conclusion: Addition of RT decreased rate of local failure, but didn't impact survival because of high rate of
distant mets
• Institut Gustave-Roussy; 2005 (France)(1979-1999) PMID 15578718 -- "Postoperative radiotherapy for primary
mucosal melanoma of the head and neck." (Temam S, Cancer. 2005 Jan 15;103(2):313-9.)
• Retrospective. 69 patients, primary H&N mucosal melanoma (67% sinonasal, 28% oral). Surgery alone 43%,
surgery + RT 57%
• Outcome: LR 54%, DM 68%. 2-year OS 47%, 5-year OS 20%
• Conclusion: Prognosis was poor; high rate of distant mets and low rate of local control. Post-op RT improved
local control even for small tumors
• UCLA
• 1995 PMID 7782202 -- "Mucosal melanoma of the nasal cavity and paranasal sinuses." (Kingdom TT, Head
Neck. 1995 May-Jun;17(3):184-9.)
• Retrospective. 13 patients, surgery alone 8 and surgery + RT 7.
• Outcome: 2-year OS 67%, 5-year OS 20%. LR 85%, DM 31%
• Conclusion: Those with postop RT appeared to do better with prolonged DFS and OS
• 1994 (1955-1991) PMID 8302112 -- "Mucosal melanoma of the head and neck: the impact of local control on
survival." (Lee SP, Laryngoscope. 1994 Feb;104(2):121-6.)
• Retrospective. 35 patients, mucosal melanoma H&N. Primary therapy radical surgery 43%, local resection
(31%), RT (17%), and systemic therapy (6%).
• Outcome: Local recurrence 80%. Local salvage in 24%. Patients with local control significantly longer
survival
• Conclusion: Aggressive local therapy should be initiated at presentation
• Yale; 1976 PMID 1000466 -- "Radiation therapy of malignant melanoma: experience with high individual
treatment doses." (Habermalz HJ, Cancer. 1976 Dec;38(6):2258-62.)
• Retrospective. 54 melanoma lesions, 3 mucosal melanoma. 1 patient treated with 42/7, with local recurrence at
1 months. 1 patient treated with 48/8, with CR for at least 18 months. 1 patient with 66/11, CR at 8 months
• Conclusion: Preliminary results, but RT may play a useful role
Review
• Multi-Institutional, Italy; 2008 PMID 17822915 -- "What is the role of radiotherapy in the treatment of mucosal
melanoma of the head and neck?" (Krengli M, Crit Rev Oncol Hematol. 2008 Feb;65(2):121-8. Epub 2007 Sep
5.)
• What is known: 1) Surgery continues to play a major role in the treatment strategy, 2) Radiotherapy might
improve local control after non-radical resection, 3) Radiotherapy is the most effective treatment modality for
unresectable disease
• What is unclear: 1) Indications for radiotherapy after complete resection, 2) Elective nodal irradiation, 3) Total
dose, 4) Fractionation, 5) Use of high LET radiation, 6) Use of chemotherapy and possibly new target therapy
in adjuvant setting
• UCSD; 1997 PMID 9338460 -- "Malignant mucosal melanoma of the head and neck: review of the literature and
report of 14 patients." (Manolidis S, Cancer. 1997 Oct 15;80(8):1373-86.)
• Review of 14 cases, and review of literature >1000 cases
• Moffitt Cancer Center; 1993 PMID 8516612 -- "Role of radiotherapy in the primary management of mucosal
melanoma of the head and neck." (Trotti A, Semin Surg Oncol. 1993 May-Jun;9(3):246-50.)
Carbon Ion
• Chiba; 2008 (1994-2004) PMID 19046826 -- "Mucosal Malignant Melanoma of the Head and Neck Treated by
Carbon Ion Radiotherapy." (Yanagi T, Int J Radiat Oncol Biol Phys. 2008 Nov 27. [Epub ahead of print])
• Prospective. 72 patients, mucosal melanoma of H&N. Dose 52.8 - 64 GyE in 16 fxs. Median F/U 4.1 years
• Outcome: 5-year LC 84%, DSS 40%, OS 27%. Tumor volume (>=100 ml) most significant prognostic
predictor
• Toxicity: No late Grade 3 toxicity
• Conclusion: Carbon ion RT safe and effective for mucosal melanoma. Overall survival comparable to surgery
Radiation Oncology/Head & Neck/IMRT

This page is for IMRT for head & neck.
Contouring targets
• See: Anatomy and contouring
Dose regimens
Simultaneous integrated boost:
• PTV 66 (primary), PTV 60 (high-risk nodal), PTV 54 (elective nodal) in 30 fractions. (2.2 Gy/fx, 2.0 Gy/fx, 1.8
Gy/fx). Equivalent (acute effects) to ~69-73 Gy to the primary at 1.8-2 Gy/fx.
Daily setup variations

• U. Wisconsin - PMID 15708257, 2005 — "The impact of daily setup variations on head-and-neck
intensity-modulated radiation therapy." Hong TS et al. Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):779-88.
• Study of 10 patients treated with conventional H&N radiotherapy techniques (not IMRT). Immobilization with
standard thermoplastic mask, room lasers, weekly portal imaging. Setup accuracy was assessed daily by
obtaining positioning errors (3 translations + 3 angular) using an optically guided positioning system. The
positional errors were applied to 10 H&N IMRT plans for analysis of the impact of positional errors on the
integrity of the IMRT plans over a 30 day course.
• Mean setup error in single dimension was 3.33 mm, composite vector of 6.97 mm. Tumor underdosing and
normal tissue overdosing were common.
• Conclusion: More rigorous immobilization and patient setup are needed for IMRT.
Radiation Oncology/Head & Neck/Brachytherapy 244
Radiation Oncology/Head & Neck/

Brachytherapy
Brachytherapy in H&N cancers

GEC-ESTRO Recommendations
• 2009 PMID 19329209 -- "GEC-ESTRO recommendations for brachytherapy for head and neck squamous cell
carcinomas." (Mazeron JJ, Radiother Oncol. 2009 May;91(2):150-6. Epub 2009 Mar 28.)
• Scant literature evidence. Recommendations for LDR, PDR, and HDR
• The recommendations cover in a general part (1) patient selection, the pre-treatment work up and patient care,
(2) treatment strategy, (3) target definition, (4) implant techniques, (5) dose and dose rate prescription, (6)
treatment planning and reporting, (7) treatment monitoring (8) catheter removal, and (9) post-treatment patient
care and follow-up.
Radiation Oncology/HN-supportive care

Xerostomia
Cevimeline (Exovac) - 30 mg TID. Can increase to 45 mg.
• 2 randomized studies comparing with placebo: PRT 003 and PRT 004.
• FDA approved for Sjogren's (but not XRT)
• PRT 003 and 004
• Randomized. 570 patients (284 in PRT 003, 286 in PRT 004). Cevimeline 30mg TID or placebo. Possible
dose-escalation to 45 mg TID at 6 weeks
• 2007 PMID 17379432 -- "Cevimeline for the treatment of postirradiation xerostomia in patients with head and
neck cancer." (Chambers MS, Int J Radiat Oncol Biol Phys. 2007 Jul 15;68(4):1102-9.)
• Outcome: PRT 003: improvement in dry mouth civemeline 47% vs. placebo 33% (SS); no difference in
PRT 004. Both studies significantly greater stimulated salivary flow
• Conclusion: well tolerated, improves unstimulated salivary flow
Caphosol (artificial saliva) Website [1] (Rx only)
• 1 box = 30 doses. use 4 to 10 doses / day.
• Supersatured solution of calcium and phosphate.
• Indicated for xerostomia and mucositis
Pilocarpine
• RTOG 97-09
Amifostine (Ethyol)
• Netherlands - PMID 16804929 — "Radiotherapy alone, versus radiotherapy with amifostine 3 times weekly,
versus radiotherapy with amifostine 5 times weekly: a prospective randomized study in squamous cell head and
neck cancer." Jellema AP et al. Cancer. 2006 Jun 27; [Epub ahead of print]
• Randomized. RT alone vs amifostine 5 days/wk vs amifostine 3 days/wk, both at 200 mg/m2. All received
bilateral neck RT. Assessed acute and late xerostomia and QOL at 6 weeks and every 6 months until 2 yrs.
• Difference in grade 2 or greater xerostomia at 6 months but not later. 28% of pts discontinued amifostine.
Moisturizing products:
• Biotene products (Website [2]) (OTC)
• Mouthwash, gum, gel, liquid (spray bottle). Also toothpaste.
• Numoisyn (Website [3]) (Rx)
• Lozenges (100 per bottle) - use PRN, up to 16/day
• Liquid (30 cc or 300 cc bottle) - use 2 cc (1/2 tsp) PRN, rinse in mouth
Accupuncture
• South Korea
• Randomized. 12 patients with H&N cancer and radiation-induced xerostomia. Arm 1) real acupuncture vs.
Arm 2) sham acupuncture BIW x 6 weeks. Measured whole stimulated and unstimulated salivary flow rate,
and questionnaire at 3 and 6 weeks after acupuncture
• 2008 PMID 18532895 -- "Manual Acupuncture Improved Quality of Life in Cancer Patients with
Radiation-Induced Xerostomia." (Cho JH, J Altern Complement Med. 2008 Jun 4. [Epub ahead of print])
• Outcome: Whole salivary flow rate: no difference. Unstimulated flow rate: acupuncture significantly better.
Subjective: acupuncture significantly less xerostomia
• Conclusion: Significantly improved amelioration of subjective xerostomia
Candidiasis
• Genoa (Italy) -- placebo vs. prophylactic fluconazole
• Randomized. 270 patients with H&N tumors, excluding glottic T1-2. Conventional RT fractionation. Arm 1)
fluconazole 100 mg QD vs. Arm 2) placebo. Starting 6th treatment until end of treatment. ~50% patients had
baseline yeast cultured. If patients developed candidiasis, they could stop protocol and be treated with
antimycotics at MD discretion
• 2008 PMID 18419630 -- "Effects of fluconazole in the prophylaxis of oropharyngeal candidiasis in patients
undergoing radiotherapy for head and neck tumour: results from a double-blind placebo-controlled trial."
(Corvo R, Eur J Cancer Care (Engl). 2008 May;17(3):270-7.)
• Outcome: candidiasis-free survival improved at 6 weeks fluconazole 81% vs. placebo 64% (SS) and 8
weeks 76% vs. 57% (SS); time-to-outbreak fluconazole 56 days vs. placebo 47 days; mean duration of RT
fluconazole 39.9 days vs. placebo 43.5 days (SS)
• All adverse events: fluconazole 70% vs. placebo 67% (NS) - most related to RT not fluconazole
• Conclusion: Prophylaxis with fluconazole significantly reduces rate and improves time to development of
oral candidiasis
Loramyc mucoadhesive buccal tablet (MBT)
• Nice (France) -- placebo vs. prophylactic miconazole
• Randomized. 282 patients, H&N cancer. Arm 1) single-dose 50mg MBT miconazole vs. Arm 2) 500 mg oral
gel (MOG) miconazole in 4 doses
• 2007 PMID 18044772 -- "Comparison of the efficacy and safety of miconazole 50-mg mucoadhesive buccal
tablets with miconazole 500-mg gel in the treatment of oropharyngeal candidiasis: a prospective, randomized,
single-blind, multicenter, comparative, phase III trial in patients treated with radiotherapy for head and neck
cancer." (Bensadoun RJ, Cancer. 2007 Nov 28 [Epub ahead of print])
• Outcome: Clinical success MBT 56% vs. MOG 49% (NS), superiority for MBT if multiple oral lesions
• Conclusion: MBT Loramyc well tolerated and not inferior; can be recommended as first-line treatment
Radiation dermatitis
Please see Skin care
Trismus
• Therabite - plastic device used to stretch the jaw
• Stack of tongue blades
Enteral Feeding
• Peter MacCallum Cancer Centre (Australia) -- NGT vs PEG tube
• Randomized. Closed early due to poor accrual. 33/150 patients, H&N cancer planned for curative RT,
'anticipated to require enteral feeding' (whole oral cavity RT, AHFX, CRT, >10% weight loss). Arm 1)
percutaneous endoscopic gastrostomy (PEG) tube vs. Arm 2) nasogastric (NGT) tube. Criteria for insertion:
intake <50% of calculated daily nutritional requirement and/or >5kg weight loss from start of treatment
• 2008 PMID 19032398 -- "Randomized study of percutaneous endoscopic gastrostomy versus nasogastric tubes
for enteral feeding in head and neck cancer patients treated with (chemo)radiation." (Corry J, J Med Imaging
Radiat Oncol. 2008 Oct;52(5):503-10.)
• Outcome: No difference in absolute weight, upper arm circumference at 6 weeks post treatment. No
difference in weight loss at 6 months. Median duration of use PEG 4.6 months vs. NGT 2.2 months (SS)
• Toxicity: No difference in G3 dysphagia. PEG site infections 27%, NGT dislodgement 61%. No difference
in chest infection. QoL overall no difference, but more pain with PEG (SS), more inconvenience with NGT
(SS), more altered body image with NGT (SS) during first week. No difference at removal.
• Cost: NGT $76 vs. PEG $736
• Patient selection: Off study, when patients allowed to choose, NGT = 73 patients and PEG = 32 patients
• Conclusion: No evidence to support routine use of PEG tubes over NGT
References
[1] http:/ / caphosol. com
[2] http:/ / www. biotene. com
[3] http:/ / alignpharma. com
Article Sources and Contributors

Radiation Oncology/ Epidemiology/ Worldwide Source: http://en.wikibooks.org/w/index.php?oldid=1606337 Contributors: Brim, Thenub314
Radiation Oncology/ Cancer epidemiology Source: http://en.wikibooks.org/w/index.php?oldid=1606051 Contributors: Brim, Jguk, Tdvorak, Thenub314
Radiation Oncology/ Epidemiology/ Most commons Source: http://en.wikibooks.org/w/index.php?oldid=1606037 Contributors: Brim, Thenub314
Radiation Oncology/ Epidemiology/ Survival Source: http://en.wikibooks.org/w/index.php?oldid=1606669 Contributors: Tdvorak
Radiation Oncology/ Staging Source: http://en.wikibooks.org/w/index.php?oldid=1606686 Contributors: Brim, Thenub314
Radiation Oncology/ CNS Source: http://en.wikibooks.org/w/index.php?oldid=1391563 Contributors: Brim, MDChanderson, Mattb112885, Tdvorak
Radiation Oncology/ Pilocytic Astrocytoma Source: http://en.wikibooks.org/w/index.php?oldid=1218566 Contributors: Brim, Tdvorak
Radiation Oncology/ Optic Pathway Glioma Source: http://en.wikibooks.org/w/index.php?oldid=1615724 Contributors: Bba, Brim, MDChanderson, Sack, Tdvorak
Radiation Oncology/ Brainstem Glioma Source: http://en.wikibooks.org/w/index.php?oldid=1574189 Contributors: MDChanderson, Tdvorak, Thenub314
Radiation Oncology/ CNS/ Low grade glioma Source: http://en.wikibooks.org/w/index.php?oldid=1605972 Contributors: Abhinambiar, BAW, Bba, Brim, Derbeth, Tdvorak, Thenub314, 1
anonymous edits
Radiation Oncology/ CNS/ Anaplastic glioma Source: http://en.wikibooks.org/w/index.php?oldid=1424393 Contributors: Tdvorak
Radiation Oncology/ CNS/ High grade glioma/ Overview Source: http://en.wikibooks.org/w/index.php?oldid=1427114 Contributors: Brim, Tdvorak
Radiation Oncology/ CNS/ High grade glioma/ Adjuvant therapy Source: http://en.wikibooks.org/w/index.php?oldid=1618785 Contributors: Brim, GG The Fly, Risaak, Tdvorak, 5
anonymous edits
Radiation Oncology/ CNS/ High grade glioma/ Recurrence Source: http://en.wikibooks.org/w/index.php?oldid=1267496 Contributors: Tdvorak
Radiation Oncology/ CNS/ Germinoma Source: http://en.wikibooks.org/w/index.php?oldid=1216463 Contributors: Tdvorak
Radiation Oncology/ CNS/ Ependymoma Source: http://en.wikibooks.org/w/index.php?oldid=1606688 Contributors: Brim, Neutron08, Tdvorak, Thenub314
Radiation Oncology/ CNS/ Choroid Plexus Source: http://en.wikibooks.org/w/index.php?oldid=1231817 Contributors: MDChanderson
Radiation Oncology/ Medulloblastoma/ Staging Source: http://en.wikibooks.org/w/index.php?oldid=1223128 Contributors: Tdvorak, 2 anonymous edits
Radiation Oncology/ Medulloblastoma/ Overview Source: http://en.wikibooks.org/w/index.php?oldid=1219836 Contributors: Tdvorak, 2 anonymous edits
Radiation Oncology/ Medulloblastoma/ Therapy Source: http://en.wikibooks.org/w/index.php?oldid=1460899 Contributors: Sack, Tdvorak
Radiation Oncology/ Medulloblastoma/ Protons Source: http://en.wikibooks.org/w/index.php?oldid=1392698 Contributors: Tdvorak
Radiation Oncology/ Peds/ CNS PNET Source: http://en.wikibooks.org/w/index.php?oldid=1606689 Contributors: Brim, Schwartzenator, Tdvorak, Thenub314
Radiation Oncology/ CNS/ Pineal Source: http://en.wikibooks.org/w/index.php?oldid=1006899 Contributors: MDChanderson, Tdvorak, 2 anonymous edits
Radiation Oncology/ Peds/ ATRT Source: http://en.wikibooks.org/w/index.php?oldid=1574186 Contributors: MDChanderson, Thenub314, 1 anonymous edits
Radiation Oncology/ Retinoblastoma Source: http://en.wikibooks.org/w/index.php?oldid=1642251 Contributors: MDChanderson, Neutron08, Tdvorak, Thenub314, 6 anonymous edits
Radiation Oncology/ CNS/ Acoustic neuroma Source: http://en.wikibooks.org/w/index.php?oldid=1644823 Contributors: Brim, Shogun0660, Tdvorak, Thenub314, 2 anonymous edits
Radiation Oncology/ CNS/ Pituitary adenoma Source: http://en.wikibooks.org/w/index.php?oldid=1216081 Contributors: Tdvorak
Radiation Oncology/ CNS/ Trigeminal neuralgia/ Overview Source: http://en.wikibooks.org/w/index.php?oldid=1397980 Contributors: Tdvorak, 1 anonymous edits
Radiation Oncology/ CNS/ Trigeminal neuralgia/ Treatment Source: http://en.wikibooks.org/w/index.php?oldid=1397979 Contributors: Tdvorak, 1 anonymous edits
Radiation Oncology/ CNS/ Trigeminal neuralgia/ Retreatment Source: http://en.wikibooks.org/w/index.php?oldid=1045829 Contributors: Tdvorak
Radiation Oncology/ CNS/ Sphenopalatine neuralgia Source: http://en.wikibooks.org/w/index.php?oldid=986138 Contributors: Tdvorak
Radiation Oncology/ CNS/ Cluster Headaches Source: http://en.wikibooks.org/w/index.php?oldid=986129 Contributors: Tdvorak
Radiation Oncology/ CNS/ Arteriovenous malformation Source: http://en.wikibooks.org/w/index.php?oldid=1462322 Contributors: Kimplera, MDChanderson, Tdvorak
Radiation Oncology/ CNS/ Cavernous malformation Source: http://en.wikibooks.org/w/index.php?oldid=1574188 Contributors: Brim, Thenub314, 6 anonymous edits
Radiation Oncology/ Paraganglioma Source: http://en.wikibooks.org/w/index.php?oldid=1628229 Contributors: CommonsDelinker, Tdvorak, Thenub314, 2 anonymous edits
Radiation Oncology/ CNS/ Cancer pain Source: http://en.wikibooks.org/w/index.php?oldid=1067575 Contributors: Tdvorak
Radiation Oncology/ Chordoma Source: http://en.wikibooks.org/w/index.php?oldid=1576737 Contributors: Adrignola, MDChanderson, Tdvorak, Thenub314, 1 anonymous edits
Radiation Oncology/ Head & Neck/ General Source: http://en.wikibooks.org/w/index.php?oldid=1605994 Contributors: Brim, Mike.lifeguard, Schwartzenator, Tdvorak, Thenub314, 6
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Radiation Oncology/ Head & Neck/ Post- op Source: http://en.wikibooks.org/w/index.php?oldid=1605978 Contributors: Brim, Dschro23, Panic2k4, Sack, Tdvorak, Thenub314, 2 anonymous
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Radiation Oncology/ Head & Neck/ Nasopharynx/ Staging Source: http://en.wikibooks.org/w/index.php?oldid=1405995 Contributors: Tdvorak
Radiation Oncology/ Head & Neck/ Nasopharynx/ Overview Source: http://en.wikibooks.org/w/index.php?oldid=1418993 Contributors: Sack, Tdvorak, 1 anonymous edits
Radiation Oncology/ Head & Neck/ Nasopharynx/ Early Stage Source: http://en.wikibooks.org/w/index.php?oldid=1103318 Contributors: Tdvorak
Radiation Oncology/ Head & Neck/ Nasopharynx/ Advanced Stage Source: http://en.wikibooks.org/w/index.php?oldid=1596562 Contributors: Tdvorak
Radiation Oncology/ Head & Neck/ Larynx/ Staging Source: http://en.wikibooks.org/w/index.php?oldid=1185534 Contributors: Tdvorak
Radiation Oncology/ Head & Neck/ Larynx/ Overview Source: http://en.wikibooks.org/w/index.php?oldid=1457341 Contributors: Tdvorak
Radiation Oncology/ Head & Neck/ Larynx/ Supraglottis Source: http://en.wikibooks.org/w/index.php?oldid=1105032 Contributors: MDChanderson, Tdvorak, 2 anonymous edits
Radiation Oncology/ Head & Neck/ Larynx/ Glottis Source: http://en.wikibooks.org/w/index.php?oldid=1607883 Contributors: Brim, Jguk, Tdvorak, Thenub314
Radiation Oncology/ Head & Neck/ Hypopharynx Source: http://en.wikibooks.org/w/index.php?oldid=1606050 Contributors: Brim, Sack, Tdvorak, Thenub314
Radiation Oncology/ Head & Neck/ Oral cavity Source: http://en.wikibooks.org/w/index.php?oldid=1606342 Contributors: Brim, MDChanderson, Schwartzenator, Tdvorak, Thenub314, 1
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Radiation Oncology/ Head & Neck/ Oropharynx Source: http://en.wikibooks.org/w/index.php?oldid=1606593 Contributors: Brim, MDChanderson, Schwartzenator, Tdvorak, Thenub314, 1
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Radiation Oncology/ Head & Neck/ Sinonasal/ Staging Source: http://en.wikibooks.org/w/index.php?oldid=1382730 Contributors: Tdvorak
Radiation Oncology/ Head & Neck/ Sinonasal/ Overview Source: http://en.wikibooks.org/w/index.php?oldid=1392710 Contributors: Tdvorak
Radiation Oncology/ Head & Neck/ Sinonasal/ Maxillary sinus Source: http://en.wikibooks.org/w/index.php?oldid=1606329 Contributors: Brim, MDChanderson, Tdvorak, Thenub314, 11
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Radiation Oncology/ Head & Neck/ Sinonasal/ Ethmoid sinuses Source: http://en.wikibooks.org/w/index.php?oldid=1628222 Contributors: Tdvorak, Thenub314, 1 anonymous edits
Radiation Oncology/ Head & Neck/ Protons Source: http://en.wikibooks.org/w/index.php?oldid=1388113 Contributors: Tdvorak
Radiation Oncology/ Head & Neck/ Salivary gland Source: http://en.wikibooks.org/w/index.php?oldid=1606334 Contributors: Abhinambiar, Brim, MDChanderson, Tdvorak, Thenub314, 1
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Radiation Oncology/ Thyroid/ Workup Source: http://en.wikibooks.org/w/index.php?oldid=1242991 Contributors: Brim, Jguk
Radiation Oncology/ Thyroid/ Papillary and follicular Source: http://en.wikibooks.org/w/index.php?oldid=1557956 Contributors: Brim, Fenerkanarya, Jguk, MDChanderson, Tdvorak, 1
anonymous edits
Radiation Oncology/ Thyroid/ Medullary Source: http://en.wikibooks.org/w/index.php?oldid=973235 Contributors: Brim, Jguk, MDChanderson, 5 anonymous edits
Radiation Oncology/ Thyroid/ Hurthle cell Source: http://en.wikibooks.org/w/index.php?oldid=940869 Contributors: Brim, Jguk, MDChanderson
Radiation Oncology/ Thyroid/ Anaplastic Source: http://en.wikibooks.org/w/index.php?oldid=1350663 Contributors: Brim, MDChanderson, Tdvorak
Radiation Oncology/ Head & Neck/ Recurrent Source: http://en.wikibooks.org/w/index.php?oldid=1618790 Contributors: Brim, Tdvorak
Radiation Oncology/ Head & Neck/ Palliation Source: http://en.wikibooks.org/w/index.php?oldid=1311254 Contributors: Tdvorak
Radiation Oncology/ Head & Neck/ Second Primary Source: http://en.wikibooks.org/w/index.php?oldid=1442161 Contributors: Tdvorak, Van der Hoorn
Radiation Oncology/ Melanoma/ Mucosal Source: http://en.wikibooks.org/w/index.php?oldid=1460061 Contributors: Tdvorak
Radiation Oncology/ Head & Neck/ IMRT Source: http://en.wikibooks.org/w/index.php?oldid=1606698 Contributors: Brim, Tdvorak, Thenub314
Radiation Oncology/ Head & Neck/ Brachytherapy Source: http://en.wikibooks.org/w/index.php?oldid=1606426 Contributors: Tdvorak, Thenub314
Radiation Oncology/ HN- supportive care Source: http://en.wikibooks.org/w/index.php?oldid=1605988 Contributors: Brim, Tdvorak, Thenub314, 2 anonymous edits
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RO/Head-neck

• Global cancer statistics: 2002 [1] 1999 [2]

Radiation Oncology/Cancer epidemiology

See also: Epidemiology in USA and → Worldwide epidemiology

Cancer Survival Data

Overall (SEER data) 6.3 years 68% 40%

→ Low Grade (WHO II)

RT alone (EORTC 22844) ~6 years 59%

RT alone (NCCTG) ~9 years 94% 72%

Observation (EORTC 22845) 7.4 years 66%

High Grade (WHO III)

RT alone (RTOG 9402) 4.7 years 46%

RT alone (EORTC 26951) 3.4 years 37%

High Grade (WHO IV)

Observation (BTCG 69-01) 3.2 months

RT alone (BTCG 69-01) 8.1 months

Surgery only (CONKO-001) 1.7 years 9%

Adjuvant 5FU/RT (GITSG 9173) 1.7 years 42%

Adjuvant 5FU/RT/Chemo (ESPAC-1) 1.7 years

Adjuvant GEM-RT/5-FU/GEM (RTOG 9704) 1.7 years

Adjuvant GEM (CONKO-001) 1.9 years 21%

Palliative bypass 6-7 months

RT/5-FU (FFCD-SFRO) 9 months 32%

RT/GEM (ECOG E4201) 11 months

GEM (FFCD-SFRO) 13 months 53%

RT/GEM (Taipei) 14 months 56% 15%

RT/TNFerade(PACT) 1.4 years 71%

Early Stage (cT1-T2)

Watchful waiting (SPCG-4) 86%

Surgery (SPCG-4) 91%

Early Stage Operable

Surgery (Stage I) composite 65%

Surgery (Stage I) Brazil 95%

Conventional RT (Stage I) composite 20%

SBRT (Stage I) Japan 83%

Surgery (Stage II) 45%

Spinal Cord Compression

RT Alone (Patchell) 3 months

Surgery + RT (Patchell) 4 months

See also: AJCC staging (discusses the various staging editions)

Head and Neck

for all: N(N1, N2a N2b N2c, N3)

• Extrahepatic bile ducts - IA IB - IIA IIB - III - IV

• Renal pelvis and ureter - I - II - III - IV

Central nervous system

2007 WHO Classification [1]

Radiation Oncology/Pilocytic Astrocytoma

Juvenile Pilocytic Astrocytoma

Adult Pilocytic Astrocytoma

Radiation Oncology/Optic Pathway Glioma

Optic Pathway Glioma

• Retrospective. 19 children with chiasmal/hypothalamic gliomas. 12 treated immediately for progressive

Radiation Oncology/Brainstem Glioma

Diffuse brainstem glioma

Focal brainstem glioma

Radiation Therapy for Diffuse Brainstem Glioma

Radiation Oncology/CNS/Low grade glioma

Adult low grade gliomas

Risk Factors Risk Score Median

Early vs Delayed Radiotherapy

Optic Pathway Glioma

Radiation Oncology/CNS/Anaplastic glioma