Brachytherapy 13 (2014) 178e186

Perioperative image-adapted brachytherapy for the treatment of paranasal

sinus and nasal cavity malignancies
Ingo U. Teudt1,*,6, Jens E. Meyer2,6, Matthias Ritter3, Barbara Wollenberg3, Torsten Kolb2,
Steffen Maune4, Gy
orgy Kovacs5,6
1
Department of Otolaryngology, Head and Neck Surgery, Asklepios Klinik Altona, Hamburg, Germany
Department of Otolaryngology, Head, Neck and Plastic Surgery, Asklepios Klinik St. Georg, Hamburg, Germany
3
Department of Otolaryngology, Head and Neck Surgery, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
4
Department of Otolaryngology, Head and Neck Surgery, City Hospital Cologne-Holweide, Cologne, Germany
5
Interdisciplinary Brachytherapy Unit, University of Luebeck, Luebeck, Germany
2

ABSTRACT

PURPOSE: Sinonasal malignancies are a rare group of cancers often associated with late presentation and poor prognosis. In the past, there was little progress regarding survival rate, and often,
multimodal treatment regimens are required. The aim of this study was to evaluate the clinical
outcome of perioperative image-adapted brachytherapy (IABT) as part of a multidisciplinary treatment regimen for the therapy of sinonasal cancer.
METHODS AND MATERIALS: Since 2006, patients with sinonasal cancer at the University
Hospital of Schleswig-Holstein Campus Luebeck, Germany, were offered a multimodal treatment
concept including head and neck surgery, perioperative IABT with or without external beam radiation therapy, and chemotherapy. In a retrospective study, such patients were analyzed for survival
rate, tumor control, and toxicity of the interdisciplinary treatment.
RESULTS: Thirty-five consecutive patients were analyzed. The majority of patients (63%) were
treated for a primary tumor and 62% presented with tumor Stages IIIeIV. The mean follow-up time
with IABT was 28 months. Overall survival estimate was 72% after 3 years. Disease-specific survival, disease-free survival, and local control rates were 83%, 63%, and 67%, respectively. On univariate analysis, a significant better disease-free survival rate was found in patients treated for
primary, but not recurrent, sinonasal cancer ( p 5 0.006). The overall treatment toxicities were
mainly classified Grade I.
CONCLUSIONS: Interdisciplinary perioperative IABT is associated with excellent locoregional
control and survival rates. IABT is well tolerated and shows low toxicity. Furthermore, visual acuity
can be preserved in advanced cases. The implementation of perioperative IABT into multimodal
treatment regimens improves the oncologic outcome. 2014 American Brachytherapy Society.
Published by Elsevier Inc. All rights reserved.

Keywords:

Paranasal sinus cancer; Nasal cavity cancer; Brachytherapy; Brachytherapy tube; Multimodal treatment; Survival; Toxicity

Introduction
Malignancies of the paranasal sinuses and nasal cavity
are a rare group of cancer often associated with late

Received 23 May 2013; received in revised form 4 October 2013;

accepted 16 October 2013.
* Corresponding author. Department of Otolaryngology, Head and
Neck Surgery, Asklepios Klinik Altona, Paul-Ehrlich-Strasse 1, 22763
Hamburg, Germany. Tel.: 49-40-1818818490; fax: 49-40-1818814705.
E-mail address: I.Teudt@asklepios.com (I.U. Teudt).
6
These authors delivered equal contribution to the article.

presentation and poor prognosis. In the past, there was little

progress regarding survival rate, and often, multimodal
treatment regimens are required (1, 2). The paranasal sinuses consist of four paired air-filled spaces that surround
the nasal cavity. They are named after the bone they are
located in (maxillary sinuses, frontal sinuses, ethmoidal sinuses, and sphenoidal sinuses). All sinuses are connected to
the nasal cavity via small openings in the bone and mucosa.
The nasal cavity itself starts anteriorly at each nostril and
ends posteriorly in the nasopharynx. It is divided by the
nasal septum. In larger tumor volumes, the origin of the tumor, nasal cavity, or paranasal sinuses is often not possible

1538-4721/$ - see front matter 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.brachy.2013.10.009

I.U. Teudt et al. / Brachytherapy 13 (2014) 178e186

to be distinguished. Because of its localization, asymptomatic growth is common, and patients often present with
advanced disease at the time of their histologic diagnosis.
Nasal congestion, bloody discharge, and double vision
because of orbital displacement or tumor invasion are some
of the typical symptoms for which the patient seeks medical
care. Sinonasal malignancies approximately account for 3%
of all head and neck cancers only (3). Depending on the tumor entity, standard treatment regimen for the previously
mentioned malignancies usually consists of radical surgery
combined with radiation therapy. Even with recent progress
in surgical techniques, such as endoscopic-guided power
tools, a complete tumor removal can be limited by its proximity to the optical system or central structures. Furthermore, radical surgical treatment can result in loss of
visual acuity. However, external surgical approaches via
lateral rhinotomy, medial maxillectomy, or craniofacial
resection, combined with midfacial degloving, are still
reasonable for the need of better visualization and complete
tumor removal.
Because of the previously mentioned limitations,
postoperative external beam radiation therapy (EBRT) is
often indicated and improves local tumor control (2, 4).
Still, structures such as the orbital system, brainstem,
or cranial nerves can be harmed by EBRT, leading to visual
and nerve toxicity. In the past, nonmaximal radiation of the
target volume often had to be tolerated to spare severe
treatment-related toxicity. By the use of three-dimensional
conformal radiotherapy or intensity-modulated radiation
therapy (IMRT), both acute and late toxicities of radiation
were reduced, and no radiotherapy-induced blindness or
normal tissue necrosis was seen (5e7). The use of protons/heavy ions in EBRT is reserved to a few special institutions worldwide. Conformal proton radiation lowers the
treatment toxicity on the surrounding normal tissues and
allows local dose-escalation protocols (8). Because of the
physical properties, proton therapy is more suitable for
deeper tumor lesions, whereas electron therapy is more
applicable for superficial tumors. Furthermore, electrons
deliver higher dose to the skin than other beam qualities,
and conformation of the beams to the given anatomy is
not accurate. Photon therapy in form of IMRT lies in between (9, 10).
Recently, perioperative image-adapted brachytherapy
(IABT) gained more attention for the treatment of sinonasal
cancer. IABT allows the application of high local radiation
doses to the target region while avoiding severe adverse
events in the surrounding healthy tissues. This is possible
by postoperative and fractionated positioning the radiation
source (mostly 192Ir) guided through previously intraoperative implanted plastic tubes directly into the target area (tumor bed). Even in patients already treated with EBRT,
additional dose escalation within the region of recurrence
is possible because of the very conformal dose delivery.
By combination of perioperative IABT and function preservation (partly debulking) surgery in first- and second-line

179

treatment strategies, an improvement of prognosis and

quality of life was anticipated for the patients.
The aim of the present study was to evaluate the clinical
outcome of perioperative IABT after less aggressive surgery as part of a multidisciplinary treatment regimen for
the therapy of sinonasal cancer.

Methods and materials

At the University Hospital Schleswig-Holstein Campus
Luebeck, Germany, 184 patients suffering from head and
neck cancer were treated between January 2006 and January
2013 by a multidisciplinary approach including surgery and
IABT with or without EBRT and chemotherapy. The aim of
the multidisciplinary treatment was to achieve increased tumor control, better survival rates, and less radiation toxicity
by the addition of IABT.
In a retrospective study of this cohort, 35 patients treated
for paranasal and nasal cavity malignancies, hereafter
referred to as sinonasal cancer, could be identified. All
patients were staged, and the tumor stages were classified using the actual tumor-nodes-metastasis and Union for International Cancer Control (UICC) classification (11). Patients
with recurrent disease treated elsewhere by primary EBRT
or surgery were also included in the study. All patient characteristics are presented in Table 1.
The cohort was analyzed for overall survival (OS),
disease-specific survival (DSS), and disease-free survival
(DFS) rates. Data for local control (LC), regional control
(RC), and distant control (DC) rates were collected. All
treatment regimens were reviewed for acute and late toxicities of IABT. The intention to treat was curative. The retrospective study was approved by the ethics committee of the
University of Luebek, Germany (11-065A).
Pretreatment and treatment planning
For all patients, complete medical history, physical examination, and routine blood counts including liver and
renal function tests were taken. The clinical tumor stage
was defined by CT and/or MRI of the head and neck regions, CT or X-ray of the chest, and CT or ultrasound scan
of the upper abdomen. Biopsy of the tumor was performed
either with local anesthesia as an outpatient procedure or
via microscopic/endoscopic sinus surgery under general
anesthesia.
All patient data were presented to an interdisciplinary
tumor board consisting of a radiotherapist, brachytherapy
expert, oncologist, and head and neck surgeon for further
treatment planning. Before therapy was started, preoperative
interdisciplinary treatment planning was performed on CT
and/or MRI examinations. The aim was the maximal tumor
resection with function preservation of surrounding structures at risk (e.g., eyes, optic nerve) and optimal intraoperative placement of brachytherapy tubes for postoperative
IABT.

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I.U. Teudt et al. / Brachytherapy 13 (2014) 178e186

Table 1
Patient and tumor characteristics
Characteristics
Age (yr)
!59
$60
Gender
Male
Female
Tumor site
Nasal cavity
Paranasal sinuses
Histopathology
Squamous cell carcinoma
Adenocarcinoma
Melanoma
Transitional cell carcinoma
Adenoid cystic carcinoma
Hemangiopericytoma
Unspecified
Tumor grade
Grade 1
Grade 2
Grade 3
No grade available
Classification
UICC I
UICC II
UICC III
UICC IV
Tumor onset
Primary disease
Recurrent disease
Margin of resection
R0
R1
R2
Not defined
Tumor susceptibility
Single cancer disease
Multiple types of cancer

Number
of patients

60 (median)
16
19

46
54

26
9

74
26

16
19

46
54

22
7
2
1
1
1
1

63
20
6
3
3
3
3

3
13
17
2

9
37
49
6

6
7
4
18

17
20
11
51

22
13

63
47

19
11
1
4

54
31
3
11

29
6

83
17

UICC 5 Union for International Cancer Control.

Tumor resection and intraoperative brachytherapy

plastic tube applicator placement
Surgery was performed by the head and neck surgeon under surveillance of the brachytherapy expert to achieve the
optimal brachytherapy plastic tube applicator (PT) placement. In most cases, tumor-free margins (R0) were achieved.
In cases of microscopically positive resection margins (R1),
the attendance of a brachytherapy expert optimized the
placement of PTs. During surgery, an adequate number of
applicators were implanted into the tumor bed and sutured
to the negative or positive margins of the resection. All
applicators were manually implanted as either loops or
blind-ended PTs. Fixation of the applicators was achieved
by rooting the tubes through drilled channels in the maxillary bone or through screw holes of individualized and
implanted osteosynthesis plates. Additional fixation was
achieved with absorbable sutures. Plating systems not only

serve as a framework for suturing the PTs into place but also
restore midface contour after bony resection (Fig. 1a). After
wound closure, all applicators were fixed with sutured radiopaque buttons to the skin (Fig. 1b). After PT implantation,
intravenous antibiotics were started to prevent wound infection and continued as oral therapy during the brachytherapy
period.
The geometry and anatomic places of the PTs were
chosen interdisciplinary to gain an optimized radiation dose
distribution and reliable surgical procedures: Tube distances (in the range of 5e12 mm) were enlarged in regions
requiring higher radiation doses and decreased if the
surrounding sensitive structures such as the optical nerve
necessitates a lower radiation dose.
Postoperative IABT
The total radiation dose of IABT was chosen as complementary to previous or subsequent EBRT or as adjuvant
radiation after surgery. Evaluation of proper PT placement
was performed by cranial helical CT imaging (2-mm slice
thickness) and documented also as orthogonal radiographs
(Fig. 2a). Treatment planning was conducted via cranial CT
imaging with or without MRI slice matching simulation data
in a three-dimensional virtual reconstruction setting (BrachyVision; Varian, USA and Oncentra Brachy; Elekta, Sweden).
With the use of cross-section imaging data, applicators positions were digitized on each image manually, whereas regions of interest (eye or optic nerve) were contoured in a
manual, semiautomatic, or automatic mode (Fig. 2b).
A fraction dose of 2.5 Gy covering the target was prescribed. The application was twice daily (no radiation on
weekend and public holidays) with minimum 6 hours apart.
The total IABT radiation dose never exceeded 35 Gy
(range, 10e35 Gy; average, 23 Gy; median, 20 Gy). The
reference isodose was prescribed within maximum
10 mm distance lateral from a tube and the maximum allowed plastic tube surface dose was 4 the reference
isodose value (12). Regarding the biologically effective
dose of the applied total dose, we underline that the correct
calculation is difficult (13). For example, 10e12 fractions
of 2.5 Gy in 5e8 days (no radiation on weekend) result
in approximately 45e55 Gy normal tissue dose; however,
because of the steep dose falloff in brachytherapy, several
areas of the irradiated volume will be covered by the
150e200% isodose, especially in anatomic regions where
frozen histology stated the R1 resection. Because of this,
the biologically effective dose will be much higher in this
small volume. This fact represents the main advantage of
the use of brachytherapy versus any external beam technology, in which doses are much more homogenous within the
target volume. Because of the technical potential of a stepping source and individual treatment planning, dose distribution within a target volume was adapted to the anatomic
situation. IABT was started 2e14 days after surgery
(average, 7.3; median, 7 days). IABT 2 days after surgery

I.U. Teudt et al. / Brachytherapy 13 (2014) 178e186

181

Fig. 1. (a) Intraoperative view of brachytherapy tubes in place. Note the guidance and fixation of tubes via titanium reconstruction plates. Surgical approach
was a lateral rhinotomy for the resection of a maxillary carcinoma. (b) Same patient after surgery with button secured brachytherapy tubes ready for IABT.
IABT 5 image-adapted brachytherapy.

was uncommon and was conducted in 1 patient only

because of a very confined T1N0M0 squamous cell carcinoma (SCC) of the nasal cavity with good wound healing.
Because of higher tumor stadiums, preirradiation and
fastidious surgery some cases exceeded the standard 5 days
gap between surgery and the start of IABT. The reported
maximum of 14 days delay occurred in 1 patient because
of wound healing complications with the need of revision
surgery. The total IABT radiation treatment time ranged
from 2 to 7 days (average, 4.6; median, 4 days). No treatments were done on Saturdays and Sundays and on public
holidays.

treated with EBRT elsewhere are also summarized within

the 21 patients.
In the actual treatment regimen at our hospital, the majority of patients (43%) underwent surgery combined with
IABT alone. Additional treatment modalities and their order are summarized in Table 2. From all patients, 63%
had no prior treatment of their malignancy. First-line treatment modalities of the remaining 37% of patients are also
depicted in Table 2.
In 11 patients (31%), chemotherapy was combined with
EBRT consisting of cisplatin (9 patients), taxane (3 patients), and etoposide (1 patient). Chemotherapy was
confined to patients with SCC.

Tube removal
After completion of IABT, all applicators were removed
under general anesthesia by an ear, nose, and throat surgeon
to cover possible complications like extensive bleeding
(Fig. 2c).
Multimodal treatment regimens
All patients received IABT. Depending on the dose of
previous or subsequent EBRT, the brachytherapy dose
ranged from 10 to 35 Gy (average, 23 Gy; median,
20 Gy). Subsequent or sequential EBRT was performed in
21 patients (60%), with radiation dosages ranging from
40 to 63 Gy (average, 54 Gy; median, 50.4 Gy). Patients

Follow-up
Patients who lived in the neighborhood of the institution
were regularly followed up, starting 1 month after initial
treatment, followed by 3-month intervals within the first
2 years, and 6-months intervals for the remaining 3 years.
Follow-up data were extracted from the patient charts for
this study. Patients living in a far distance from the institution were followed up by local Head and neck Departments
and their local physicians. In all cases, follow-up data were
recently updated. Questionnaires regarding survival and
health condition were sent to the responsible physician of
each patient.

Fig. 2. (a) CT scan after surgery and brachytherapy tube (BT) insertion of the same patient depicted in Fig. 1. Note that the BTs are placed in loops through
the right maxillary sinus to provide good stabilization in the target area. (b) Planning and image-adapted visualization of the calculated isodoses for brachytherapy. (c) Good facial cosmesis after IABT. The picture shows the patient 2 days after BT removal. IABT 5 image-adapted brachytherapy.

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I.U. Teudt et al. / Brachytherapy 13 (2014) 178e186

Table 2
Actual and previous treatment modalities summarized for all patients
Modalities
Actual treatment
Surgery IABT
Surgery IABT EBRT
Surgery IABT Chemo
Surgery IABT EBRT Chemo
Surgery EBRT IABT
Surgery EBRT Chemo IABT
EBRT Surgery IABT
EBRT Surgery IABT Chemo
RCT Surgery IABT
Previous treatment
Surgery
Surgery EBRT
Surgery EBRT Chemo
EBRT
RCT

Number
of patients

15
3
1
3
2
1
5
1
4

42
9
3
9
6
3
14
3
11

9
1
1
1
1

26
3
3
3
3

IABT 5 image-adapted brachytherapy; EBRT 5 external beam radiation therapy; Chemo 5 chemotherapy; RCT 5 radiochemotherapy.

Adverse events
Acute and late toxicities due to the treatment regimen
with IABT were identified using the Common Terminology
Criteria for Adverse Events (14). Early adverse events were
collected from notes in the chart of the patient during treatment and from the first control examination 2 months later.
Late toxicities of the patients were collected via the previously mentioned questionnaire sent out to the primary
physician or by personal phone interview.
Statistics
Follow-up time was defined as the beginning of IABT
until the last patient contact or event. LC rate was based
on the number of months between the IABT start and the
day of local progression. For censored patients, the last date
of contact or death was used in the survival estimates. The
survival time was calculated from the beginning of IABT to

last contact or death. All estimated survival rates were

calculated by the KaplaneMeier method using SPSS statistics 21 (IBM, USA) (15). Survival functions were
compared using the log-rank test. A p-value of !0.05
was considered statistically significant.
Results
From January 2006 to February 2013, 35 patients with
a histologically confirmed sinonasal cancer were treated
with IABT at the University Hospital Schleswig-Holstein
Campus Luebeck, Germany. Mean follow-up for all patients was 28 months (range, 1e69 months; median, 28
months).
Disease control
Of the 35 patients, 28% developed a local failure during
follow-up with a mean time to local recurrence of 3 months
(range, 0e30 months). The KaplaneMeier estimate of
LC was 67% after 3 years. Univariate analysis revealed a
highly significant correlation of LC with tumor onset (primary vs. recurrent disease p 5 0.002) and a trend toward
significance ( p 5 0.052) with UICC classification lower
than Stage IV. The LC after 3 years for patients treated
for primary disease was 91% vs. 30% for patients treated
for recurrent disease. Statistically significant differences
were not found with respect to patient subgrouped by
age, gender, localization, histology, tumor grade, resection
margins, and tumor susceptibility.
Regional lymph node failure occurred in only 1 patient
(3%) 24 months after IABT. This patient was primarily
staged with N0 neck. From the 4 patients (11%) initially
staged positive for neck lymph nodes, no patient experienced regional recurrence. Positive necks were treated with
neck dissection in all four cases. RC was calculated with
97% after 3 years.
Only 1 patient was diagnosed with distant metastasis
localized in the cervical spine. The distant metastasis was

Fig. 3. Overall survival, disease-specific survival, and disease-free survival for all patients included in this study.

I.U. Teudt et al. / Brachytherapy 13 (2014) 178e186

183

detected together with a local recurrence of the primarily

treated melanoma 5 months after treatment with IABT.
Thus, DC was calculated with 97% after 3 years.

Table 3
Adverse events reported after surgery and IABT categorized following the
Common Terminology Criteria for Adverse Events version 4.0

Survival analysis

Adverse events after IABT

The OS rate at the end of this study was 77%. According

to the KaplaneMeier method, the 3-year survival estimate
was calculated with 72% (Fig. 3). On univariate analysis,
no statistically significant differences were seen for age,
gender, localization, histology, tumor grade, tumor onset
(primary or recurrent), and tumor susceptibility. A significant better OS could be found for UICC lower than Stage
IV ( p 5 0.007). There was a trend toward significance with
the presence of clear surgical margins ( p 5 0.06).
From the 8 patients who died during the follow-up, 5 patients died as a result of intercurrent disease. The KaplaneMeier method revealed a 3-year DSS of 83% (Fig. 3).
On univariate analysis, DSS was only significantly correlated with UICC lower than Stage IV ( p 5 0.032) and with
the presence of clear surgical margins ( p 5 0.023).
Among the 27 patients alive, 24 were free of cancer at
the time of the last follow-up. The DFS at the end of the
study was 69%. According to the KaplaneMeier method,
the 3-year DFS was calculated with 63% (Fig. 3). On univariate analysis, no statistically significant correlation could
be found to the previously mentioned variables except to
the tumor onset (primary vs. recurrent). The DFS estimate
after 3 years was 83% for patients treated for primary tumor
disease vs. 34% for patients treated for recurrent disease
( p 5 0.006).
Acute and late toxicities
The overall complication rate was 57%. For 11 patients
(31%) acute toxicity was documented and mainly presented
as sinus disorder with mucosal crusting (11%; 2 patients
Grade I and 2 patients Grade II) and as periorbital edema
(9%; 3 patients Grade I). Another 3 patients (9%) needed
surgical and medical procedures because of wound healing
complications (Grades IeIII). All acute toxicities are summarized in Table 3.
Late toxicity occurred in 18 patients (51%). Again, sinus
disorder with mucosal crusting in 6 patients was the leading
adverse event (17%; 2 patients Grade I and 4 patients Grade
II). Five patients (14%) needed surgical and medical procedures because of wound healing complications (4 patients
Grade I and 1 patient Grade II), and 5 (14%) patients reported dysgeusia Grade I due to hyposmia. Table 3 summarizes all late toxicities categorized using the Common
Terminology Criteria for Adverse Events.
Complications after IABT were found not to be statistically significantly correlated to patients subgrouped by age,
gender, UICC stage, brachytherapy dose, EBRT dose, previous treatment, actual treatment, histology, tumor site,
onset, and susceptibility.

Acute toxicities
Sinus disorder
(mucosal crusting)
Periorbital edema
Surgical and medial
procedures
Flushing
Pain of skin
Watering eyes
Dysesthesia
Alopecia
Fatigue
Late toxicities
Sinus disorder
(mucosal crusting)
Surgical and medial
procedures
Dysgeusia due to
hyposmia
Watering eyes
Pain of skin
Periorbital edema
Eustachian tube
dysfunction

No. of
patients

Grade
I

Grade
II

Grade
III

11

3
3

9
9

3
1

d
1

d
1

2
2
1
1
1
1

6
6
3
3
3
3

2
1
1
1
1
1

d
1
d
d
d
d

d
d
d
d
d
d

17

14

14

2
2
2
1

6
6
6
3

2
1
d
1

d
1
2
d

d
d
d
d

IABT 5 image-adapted brachytherapy.

Discussion
Because of the low incidence of sinonasal cancer, large
prospective treatment trials are missing, and treatment guidelines are mostly based on small retrospective studies. The
treatment of sinonasal cancer remains a challenge to the surgeon and radiotherapist involved. Because of its localization
with high proximity to delicate structures such as orbit and
brain, clear margins are sometimes hard to achieve, and en
bloc resections with large security margins are often impossible. These anatomic difficulties can also impede aggressive
pre- or postoperative EBRT. Despite more endoscopic surgical tools, the principles of sinonasal tumor resection have
not much changed over the past decades and still require an
experienced surgeon. However, the ways of delivering radiation dose have changed. New radiation techniques such as
three-dimensional conformal radiotherapy and IMRT are
available to lower toxicity of adjacent structures. In contrast
to these new techniques, brachytherapy yields an old
approach to deliver high radiation dosages in a confined
target volume and has been used for the treatment of prostatic
and uterine cancer for many decades. Today, brachytherapy
has gained actuality in the treatment of head and neck cancers
(16e20) and here especially for the local dose escalation and
reirradiation of sinonasal cancer (17, 21, 22). In the 2009
published GEC-ESTRO (Groupe Europeen de Curietherapie
and European Society for Radiotherapy & Oncology) recommendations of brachytherapy for head and neck SCCs, one

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I.U. Teudt et al. / Brachytherapy 13 (2014) 178e186

Table 4
Recent studies analyzing the clinical outcome of patients treated for sinonasal cancer
Study group

Ref.

Katz et al., 2002

Hojo et al. 2012
Koivunen et al., 2012
Pickhard et al., 2012
Turner and Reh, 2012
Wiegner et al., 2012
Dirix et al., 2007
Hoppe et al., 2007
Dirix et al., 2007
Chen et al., 2007
Jansen et al., 2000
Grau et al., 2001
Dulguerov et al., 2001
Pommier et al., 2000
Teudt et al. (current
study)

(37)
(39)
(36)
(32)
(1)
(7)
(6)
(40)
(5)
(41)
(4)
(42)
(2)
(43)

Patients
(n)

Tumor site

Treatment

OS (%)

DFS
(%)

DSS
(%)

LC
(%)

Benchmark
(yr)

Median
follow-up (mo)

78
75
244
45
6739
52
127
85
25
127
73
315
220
40
35

Sinonasal
Sinonasal
Sinonasal
Sinonasal
Sinonasal
Sinonasal
Sinonasal
Sinonasal
Sinonasal
Sinonasal
Sinonasal
Sinonasal
Sinonasal
Sinonasal
Sinonasal

Surg, EBRT, and both

EBRT with or without surg
Surg, EBRT, and both
Surg with or without EBRT
Surg, EBRT, and both
EBRT with or without surg
Surg EBRT
Surg EBRT
Surg EBRT
EBRT with or without surg
EBRT with or without surg
EBRT with or without surg
Surg, EBRT, and both
EBRT with or without surg
Surg D IABT with or
without EBRT

50
72.1
38
31
49.7e56.4
66
54
67
88
52
46.2
35
40
65.9
72

X
X
X
X
X
X
37
55
77
54
39.3
X
X
X
63

56
X
57
X
X
X
X
X
X
X
X
40
54.5
X
83

60
48.7
63
78
X
64
53
62
81
62
62.5
41
59
73.1
67

5
3
5
5
5
2
5
5
2
5
5
5
5
2
3

X
51.6
47.1
31
X
26.6
66
60
27
49
66
X
72
19
28

Ref. 5 reference; OS 5 overall survival; DSS 5 disease-specific survival; DFS 5 disease-free survival; LC 5 local control; Surg 5 surgery;
EBRT 5 external beam radiation therapy; IABT 5 image-adapted brachytherapy.

chapter was dedicated to the paranasal sinus system (23).

Interstitial brachytherapy of sinonasal cancer is not novel.
Early interstitial brachytherapy of nasal vestibule carcinoma
dates back to the seventies and eighties using radium and
iridium pins (24e26). During the nineties, afterloading machines became available with the use of brachytherapy tubes
in individualized molds leading to high-dose-rate brachytherapy (HDR) as we use it today (27). In a recently published
feasibility trial, an intraoral mold for HDR brachytherapy
of tumors arising in the maxillary antrum was tested (28).
In the present study, all patients were treated with intraoperatively placed single sutured plastic tubes and brachytherapy in an afterloading setting. Further details regarding
this technique have been published elsewhere extensively
(22, 29e31). In sinonasal cancer, treatment of the entire
orbit can be required for tumors involving the roof of the
sphenoid sinus or invading the orbit and skull base. The
functional loss and mutilation after aggressive surgery or
radiotherapy can be large. In this case, IABT combined surgery and EBRT offer the chance of organ and function preservation in Stages I, II, and in some Stage III tumors with
orbital invasion (23).
Tumor characteristics of our study were similar to the results of a large analysis with more than 6000 sinonasal cancers collected by the National Cancer Institute (SEER
database) (1). The occurrence of sinonasal cancer is usually
around 60 years of age and has a male predominance. SCC
is the leading type of histology with more than 50% followed by adenocarcinoma and melanoma (1). Because of
inconspicuous growth in the pneumatized sinus system,
many patients present with locally advanced sinonasal cancer Stages T3eT4 or UICC Stages IIIeIV. In the literature,
rates from 21% to 98% are reported (5, 7, 32). Furthermore,
surgeons find less advanced diseases in their patient cohort
than radiotherapists do for primary radiotherapy. In our

study, 63% of the patients were treated for sinonasal cancer

in UICC Stages IIIeIV.
Because brachytherapy in the treatment of sinonasal
cancer is not widely used, the comparison of disease control and survival analysis with other studies is difficult.
Thus, our results will also be matched to studies without
brachytherapy using EBRT for the treatment of sinonasal
cancer.
Nag et al. analyzed 34 patients with locally advanced tumors of the paranasal sinus receiving HDR brachytherapy
after surgery with or without EBRT. The actuarial OS rate
after 5 years was 44%, LC 65%, RC 94%, and DC 56%.
The DFS was calculated with 42% after 5 years (33). In
our study, the 3- and 5-year LC and RC were estimated
with 67% and 97%, respectively, being nearly identical to
the reported values from Nag et al. However, large differences occurred in OS, DFS, and DC rates. The much better
rates in our analysis, with 72%, 63%, and 97%, respectively, can be explained with 37% of our patients having
early-stage tumors and with 46% having their primary cancer site in the nasal vestibule, which is reported to have a
better prognosis (1, 34). In addition, the mean follow-up
time of our study was 28 months only vs. 60 months in
the group by Nag.
In Table 4, some of the recently published treatment regimens using EBRT with or without surgery and in few cases
chemotherapy are compared with our study regarding survival and LC rates (Table 4). It has to be emphasized that
all cited studies show differences in potentially important
prognostic variables related to tumor extent and treatment
modality. However, the close relation between the survival
and the LC rates in most of the cited studies underscores
the fact that the prognosis for patients with nasal and paranasal sinus carcinoma is related directly to the LC of the
disease (2).

I.U. Teudt et al. / Brachytherapy 13 (2014) 178e186

185

In conclusion, the good survival and tumor control rates

in our study are encouraging. It is noteworthy that the
3-year DFS increased up to 83% in patients treated for primary sinonasal cancer versus 34% when treated for recurrent disease ( p 5 0.006, log rank). Consequently,
brachytherapy with its acceptable toxicity, as shown below,
should be implemented early into treatment regimens of sinonasal cancer and not only used for second-line treatment.
In our data, 11% of patients presented with a neck
metastasis, and only 1 patient (3%) developed a neck
metastasis for regional failure. Dulguerov et al. reported
corresponding rates of 12% and 13%, respectively (2). In
a recent meta-analysis, Scurry et al. considered elective
therapy of the clinically negative neck of patients with
intranasal SCC (35). SCC was only present in 63% of our
cohort, but the conclusion by Scurrys cannot be supported
by our data and is therefore in line with other authors.
Recurrent disease is mainly caused by local failure (33%
in our study) and not by local or distant recurrence. However, these findings can vary with the extent of the tumors
and their locations weighted in the respective study. The
low incidence of regional recurrence and its missing statistic influence on survival rates in our study supports the
finding of other authors that elective treatment of clinically
negative neck patients with sinonasal cancer is not mandatory (32, 36, 37).

heterogenous use of chemotherapy and the fact that some

patients were already treated at another institution make
the interpretation of the results difficult. Furthermore, the
median follow-up time of 28 months is short, leading to
an estimated, and not observed, survival analysis at a 3-year
follow-up. As mentioned previously, because of the low
incidence of sinonasal cancers, it is nearly impossible to
set up a randomized prospective study design to compare
different treatment arms. Only large multicenter studies
could help to validate the performance of different treatment options, including IABT, in terms of local tumor control and survival analysis.

Adverse events

References

A common complication after IABT is reported to be a

soft tissue necrosis. Bone necrosis became rare because bony structures such as mandible or maxilla were systematically protected by lead gutters used during IABT. Most
necroses can be managed using antibiotics, analgesics,
and mouthwashes. Hyperbaric oxygen therapy remains
for severe cases (23). In our study, 68% of adverse events
were Grade I only. From the 29% of Grade II toxicities, half
of the patients suffered from nasal crusting requiring intensive sinonasal care up to 2 years after the treatment. Similar
observations were made in a study examining tumor control
and cosmesis of early-stage nasal vestibule cancer treated
by HDR brachytherapy (38). Only 1 patient experienced
Grade III toxicity with wound healing complications and
the need of surgical revision. However, the higher amount
of wound healing complications reported in our study has
to be evaluated critically because skin penetration by
plating systems or undesirable scarring with skin retractions can also be seen after surgery without radiation. No
adverse effect was observed with visual acuity after IABT.
Nearly all patients reported the time having applicators implanted as not painful and well tolerable.

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Conclusion
IABT in combination with surgery of sinonasal cancers
with or without EBRT is associated with excellent locoregional control and survival. There is a low risk of highgrade radiation toxicity, and IABT improves the oncologic
outcome, such as DFS in early stages of sinonasal cancer.
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treatment in this anatomic region.

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