TITLE:

Stereotactic Body Therapy Radiation for the Treatment of Early Stage Non Small Cell Lung Cancer Judith Walsh, MD, MPH Professor of Medicine Division of General Internal Medicine Department of Medicine University of California San Francisco California Technology Assessment Forum

AUTHOR:

PUBLISHER:

DATE OF PUBLICATION:

June 29, 2011

PLACE OF PUBLICATION:

San Francisco, CA

STEREOTACTIC BODY RADIATION THERAPY FOR THE TREATMENT OF EARLY STAGE NON SMALL CELL LUNG CANCER
A Technology Assessment INTRODUCTION The California Technology Assessment Forum (CTAF) was requested to review the scientific evidence for the use of Stereotactic Body Radiation Therapy (SBRT) for the treatment of early stage non small cell lung cancer (NSCLC) in medically inoperable patients. Given that the major treatment goal for non small cell lung cancer is to obtain local control, is SBRT a viable therapeutic option for patients who are medically inoperable? Secondarily, given its potentially less invasive approach, is it a viable option for patients who are potentially operable as an alternative to surgery? CTAF evaluated this topic in June, 2008, but has been asked to readdress the topic in light of additional published evidence. Most of the available evidence focuses on the use of radiosurgery for treatment of medically inoperable patients who have few treatment options. However, SBRT is also being evaluated for patients who have operable cancers and its use in this patient population will be addressed as well.

BACKGROUND Lung cancer is the number one cause of cancer mortality in both men and women. In the U.S. in 2010, there will be an estimated 222,520 new cases of lung cancer and an estimated 157,300 deaths from lung cancer1. The therapeutic approach to lung cancer depends on whether it is small cell or non small cell lung cancer and on the extent of disease. Staging is based on whether or not there is involvement of nodes and/or evidence of metastatic disease. For non small cell lung cancer, the TNM (tumor, lymph nodes, metastasis) staging criteria is used. Stage 1 disease is local disease without regional lymph node or metastatic involvement. Stage 1 disease is divided into Stage 1A and Stage 1B, based on the size of the primary tumor. Stage T1A is defined as a tumor of 2 cm or less in diameter, and Stage T1B (includes tumors >2 cm but 3 cm in diameter. T2 tumors are >3 cm in diameter and tumors of any size that are growing into the mainstem bronchus and or involving the pleura or causing atelectasis or 2

obstructive pneumonia that involves less than an entire lung. Recent changes in the staging definitions make some of the more recent study results more difficult to compare with historical controls. The primary treatment for patients with early non small cell lung cancer is surgery. Lobectomy and pneumonectomy are associated with three to five year survival rates of 60% to 80%. Lesser surgical therapies such as wedge resection are options, but result in less local control 2. Many patients are medically inoperable, with severe medical diseases and early stage tumors (e.g. T 1 and T 2 tumors) and are not operative candidates. Medical inoperability is defined as the presence of comorbid illnesses that render the patient at higher than acceptable risk of surgical morbidity and mortality3. There is no standard approach for these individuals. The usual treatment option is conventional fractionated radiotherapy (XRT), which is typically given in small doses over many sessions. Historically, conventional radiotherapy has been associated with a three year survival of 15% to 45%4-6, which is much lower than that seen with surgery in better risk groups. A large systematic review of over 2,000 medically inoperable patients with NSCLC receiving radiotherapy alone showed complete responses ranging from 33% to 61% and local failure rates between 6% and 70%7. However, comparison of the patients who receive XRT with those who undergo surgery is difficult. Radiotherapy treated patients are more likely to have many co-existing medical problems, such as heart disease, chronic obstructive pulmonary disease (COPD), diabetes and vascular disease, that make them less likely to survive. Since survival in NSCLC is highly correlated with local control, local control is often used as a surrogate measure for survival. There are three ways to improve local control with XRT- 1) increase the total dose; 2) increase the radiosensitivity of the tumor; and 3) increase the dose per fraction. Any of these strategies typically include some type of image guidance to target the tumor cells, while minimizing toxicity to healthy tissue. To date, strategies that involve increasing the total dose of XRT have not resulted in improved local control. Improving radiosensitivity with chemotherapy is used in Stage III tumors, although this may be associated with more damage to normal tissues, such as the esophagus. Increasing the dose per fraction appears to potentially be the most promising approach. Radiosurgery is the application of very high doses of ionizing radiation in larger than traditional fractionation to much smaller than traditional radiotherapy fields, often with the integration of advanced modalities for tumor imaging and devices for tumor immobilization. The concept of radiosurgery was developed by Dr. Lars Laskell in the 1950s and was initially used in the brain and spine for brain tumors and metastatic disease.

With the hypofractionated approach, more radiotherapy is given less often. For hypofractionated but non-stereotactic regimens, a daily dose of 2.5-3.4 GY is given which compares to 1.8-2.0 Gy for conventional radiotherapy. The current indications for stereotactic body radiotherapy are a tumor <5 CM N0M0. Since the goal is to target tumor and avoid normal tissue, body and respiratory movements must be minimized. Body fixation is obtained by placing the patient in an immobilization device such as a special stereotactic body frame to minimize body movement. The patient must be able to stay in the full body frame for at least 30 minutes. Minimizing the motion associated with respiration is also important. Respiratory motion control is achieved in three ways: 1) Tracking: a tumor motion surrogate is correlated with all phases of the respiratory cycle. This surrogate, such as a point on the chest wall or a breathing flow detector, drives the position of the respiration beam; 2) Respiratory gating is also important to ensure that radiation is delivered only at certain phases of the respiratory cycle (typically end expiration which is longer and more stable) and special software is typically required; and 3) Respiratory inhibition: the tumor is targeted and as much normal tissue as possible is spared. Methods to achieve this include forced breath hold and external abdominal compression that limits diaphragmatic breathing.

TECHNOLOGY ASSESSMENT (TA) TA Criterion 1: The technology must have final approval from the appropriate government regulatory bodies. The device used for SBRT is a linear accelerator. There are many manufacturers who have received FDA 510(k) clearance for their devices. Those devices with FDA clearance to treat extracranial lesions are: CyberKnife (Accuray, Inc, Sunnyvale, CA), XKnife-4 (Radionics, Burlington, MA), Synergy (Elekta, Stockholm, Sweden), Hi-ART System (TomoTherapy, Madison, WI), Novalis (BrainLAB AG, Germany), Trilogy System with RapidArc (Varian, Palo Alto, CA,), and Primatom (Siemens Medical Systems, Concord, CA). Many of these devices have additional planning capabilities such as the Primatom from Seimens Medical Systems which includes the Primus linear accelerator and a Somatom CT scanner. TA Criterion 1 is met. TA Criterion 2: The scientific evidence must permit conclusions concerning the effectiveness of the technology regarding health outcomes. Search Methods:

For this review, we updated our prior search for the CTAF evaluation performed in 2008. We searched Medline, the Cochrane clinical trials database, Cochrane reviews database, and the Database of Abstracts of Reviews of Effects (DARE) using the search terms of radiosurgery or stereotactic or radiation therapy cross referenced with lung cancer or non small cell lung carcinoma or non small cell lung cancer.. In addition, we searched the bibliographies of the identified articles and other reviews to identify primary data sources and search strategies to ensure a complete review of the relevant literature. The abstracts of citations were reviewed for relevance and all potentially relevant articles were reviewed in full. Studies were included if they included medically inoperable patients or operable patients being treated for early stage NSCLC. Studies were excluded if they only focused on metastatic lung lesions. Additional studies were excluded if they only involved treatment with a single dose of radiotherapy. Our search identified 274 articles. We reviewed the titles and excluded those that were not clearly related to the research question. We then reviewed 41 abstracts. After combining these results with our prior 2008 search and updating some of the studies that subsequently reported longer term follow-up, we identified 21 retrospective studies and 11 completed prospective studies. The retrospective studies are described in Table 1. The remainder were prospective studies; two were reviews of prospective databases; three were Phase I studies, four were Phase II studies, and was a combined phase I, phase II study8-11. The outcomes evaluated included survival, cause specific survival, percentage achieving local control, percent with local failure and toxicity. Most publications measured more than one outcome. Although two retrospective studies compared SBRT to an alternative treatment, we did not find any completed trials comparing SBRT to an alternative treatment. There are eight ongoing Phase II or Phase III studies- three in the U.S. are sponsored by Radiation Therapy Oncology Group (RTOG) and are multi-institutional, two others are not RTOG sponsored and are taking place in the U.S. and the remaining others are taking place in Japan, Scandinavia, and Australia . The ongoing studies are assessing the role of SBRT in operative patients (RTOG, 0618; STARS, L), two are comparing SBRT to conventional radiation therapy (CHISEL, SPACE) and four are determining the optimal dose of SBRT to maximize benefit (RTOG, 0813, RTOG 0915JCOG, 0403, Washington University).

TABLE 1: Stereotactic Body Radiation Therapy for Early Non Small Cell Lung Cancer: Results of Retrospective Studies STUDY Onishi, 200712 STUDY SITE Multi-institutional in Japan N 257 (158 medically inoperable) INTERVENTION 18-75 Gy in 1-2 fractions INCLUSION Stage 1 T1N0M0 DURATION OF FOLLOW UP 38 months OUTCOMES FOR THOSE WITH NSCLC 5 year overall survival 56%; 3 year overall survival for medically operable 70.8% with BED >100 and 30.2% with BED <100 24 month median overall survival 50% probability of 2 year overall survival (44% for primary lung cancer) 3 year survival 66%; 88% cause specific survival 86% in medically operable 94% local control 52% 1 year and 32% 2 year survival 39% showing complete response; 43% showed partial response; primary and metastatic disease not reported separately

Pennathur, 200913

University of Pittsburgh

100 (19 had metastatic disease)

20 Gy single fraction increased to 60 Gy in 3 fractions

Uematsu, 200114

National Defense Medical College, Japan

50

50-60 Gy 5-10 FX

Primary, recurrent or metastatic lung cancer; all stages; medically inoperable, failure of prior therapies or refusal to have surgery T1-2N0M0 Medically inoperable or refused surgery

20 months

36 months

Wulf, 200415 Lee, 200316

U of Wuerzburg, Germany University of Ulsan, South Korea

20 28 (9 primary lung cancers)

3 x 10 G or 3 x 1212.5 Gy 3-4 x 10 Gy

T1-T3N0M0 Medically inoperable Primary lung cancer

11 months 18 months

Ricardi, 201017

University of Turin

62)

15 Gy x 3

Stage 1 NSCLC Medically inoperable T1-2, N0M0 Stage iA or 1 B Stage 1 Stage 1

28 months

Scorsetti, 2007 Italy18 Brown, 200719 Baumann, 200620 Zimmerman, 200521 Onimaru, 200322 Hara, 200623

Instituto Clinico Humanitas, Italy CyberKnife Center in Miami Karolinska Hospital, Sweden Technical University, Germany Hokkaido University Japan International Medical Center of Japan

43 59 138 30

30.5 Gy in 1-4 fractions 15-67.5 Gy in 1-5 fractions 30-48 Gy in 2-4 fractions 24-37.5 Gy in 3-5 doses 48-60 GY in 8 doses 20-34 Gy single dose

14 months 1-33 months Median not reported 33 months 18 months

Local control at 3 years 87.8% Overall survival 57.1% 53% 2 year survival 86% alive at 1-33 month follow up 3 year survival 52% 5 year survival 26% 80% 12 month survival 75% 24 month survival 47% 2 year survival 60% 2 year cause specific survival 76.5% 1 year survival 41% 2 year survival Primary lung cancer not analyzed separately 1 year survival 83% 3 year survival 53% No difference in regional recurrence, distant mets or freedom from any failure Local control 100% for those receiving 50 GY 3/7 had local

46 (26 with primary lung cancer) 59 (11 with primary lung cancer)

Stage 1 Stage 1

17 months 12 months

Fritz, 200624 Grills, 201025

Germany Michigan

58 (33 primary lung cancer) 124

30 Gy single dose 48=60 Gy in 4-5 fractions or surgery

Stage 1 Stage 1 Borderline surgical candidates Stage 1

18 months 2.5 years

Chang, 200826

University of Texas

27

40 or 50 Gy in 4 doses

17 months

Videtic27

Cleveland Clinic

26

10 Gy x 5 days

Sage I

40.9 months

Parashar, 201028

Cornell Medical Center, New york

55

SBRT or surgical resection with seed implantation SBRT 45 or 60 Gy in 3 fractions 100 GY Median 18 Gy in 3 fractions 9 gy in 5 fractions 10 Gy in 5 fractions 6-12.5 Gy in 3-8 fx or 26 gy x 1

Malignant solitary lung nodule

17.5 months

recurrences with 40 Gy 3 year local control 94.4% 3 year overall survival 52% No significant differences in local control, distant mets, survival or toxicity 65% 1 year survival 44% 2 year survival 62.2% two year survival Reduced local control in those who received 9 Gyx 5 885 local control at 24 months

Van Zyp, 201029 Oshiro, 201030 Olsen, 201131 Guckenberger, 200732

Netherlands Japan Missouri Europe

38 21 19 70 (38 primary lung cancer)

Age 80 or over Stage I Centrally located tumors Single primary lung lesion Inoperable early stage NSCLC or metastatic disease

23 months 20 months 11-16 months 24 months

Gy N0M0 BED Met SBRT

Gray No nodes and no metastatic disease Biologically Effective Dose metastases Stereotactic Body Radiotherapy

NSCLC Non small cell lung cancer

Table 2: Prospective Studies of Stereotactic Body Radiation Therapy for Early Stage Non Small Cell Lung Cancer

STUDY COMPLETED Timmerman, 201011

TYPE Phase II

LOCATION U.S. Multiinstitutional 55

INTERVENTION 3 fractions 20 Gy each=60 Gy

INCLUSION Medically inoperable T1-3 tumors <5 cm ; no lymph nodes, peripheral (excludes tumors of proximal bronchial tree Stage 1 Medically inoperable T1-2, N0Mo Stage 1 A or 1B lung cancer Stage 1 T1 or T2 N0M0 T1-3N0M0 Stage I Medically inoperable Stage I or 2 81% medically inoperable Medically inoperable or refused surgery Medically

OUTCOMES Local control and toxicity

Fakiris, 20098 Koto, 20079 Nagata, 200510 Le, 200633 Timmerman, 200334 Bral, 201035 Bauman, 200936 Lagerwaard, 200837 Bradley, 201038 Stauder, 201139

Phase II Phase II Phase I/II Phase I Dose Escalation Phase I Dose Escalation Phase II Phase II Review of prospective database Review of prospective database Review of

University of Indiana, US Japan Japan Stanford, CA U of Indiana, US Belgium Sweden, Norway and Denmark Netherlands Washington University, St. Louis U.S.

70 31 45 32 (21 with NSCLC) 37 40 57 206 91 84 pts with

60-66 Gy in 3 fractions 45 Gy in 3 fractions 48 Gy in 4 fractions 60-66 Gy in 20-22 Gy fracs 15-30 Gy single 24-60 Gy in 3 fractions 60 Gy in 3 fractions 45-66 Gy Range: 20 Gy x 3 to 7.5 Gy x 8 Median 54 Gy in 3 fractions 32-60 Gy in 3-5

Survival Local Control Survival Survival Local Control Survival Local Control Local Control and survival Progression free survival Overall survival and disease free survival Local control Pulmonary

prospective database ONGOING RTOG 0618 RTOG 0813

88 lesions (64 primary or recurrent U.S. Multiinstitutional U.S. Multiinstitutional U.s. multiinstitutional Japan 33 Accrual complete 48 of 94 as of 5/6/11 94 accrual complete Accrual plans 100 inoperable and 65 operable patients

fractions

inoperable NSCLC or metastatic lung lesions

toxicity

U.S. Phase II multiinstitutional Phase I/II

20 Gy x 3 vs. surgery;

RTOG 0915

Phase II

JCOG 0403 Recently completed results reported in abstract form

Single arm Phase II

Tumor <5 Cm ; operable disease Goal to determine MTD Medically Anticipated 11.5 Gy/FX inoperable centaly located tumors 48 gy in 4 fx vs 34 Gy Medically in 1 fx inoperable peripheral tumors 48 Gy in 4 fractions Operable over 4-8 days patients with clinical stage 1A

Local control and toxicity Rate of tumor control Toxicity

3 year survival

10

Washington University SPACE

Phase I/II Phase II two arms

U.S. Scandinavia

Goal =75 100

MTD to be determined9range 9 GY x5 to 12 GY x 5) 66 GY in 3 fractions vs. Conventional treatment 70 Gy with 2 Gy per fraction in 35 fractions

Stage I or II Central tumors Stage 1 medically inoperable Peripheral tumors Stage 1 medically inoperable Peripheral

Treatment related toxicity Local control rate 3 year survival

CHISEL

Phase III

STARS

Phase III

Gy MTD

Gray Maximum tolerated dose

Hypofractionated SBRT (total dose of 60-66 Gy vs conventional radiotherapy U.S. multi-center Goal of ecyberKnife Stage 1 1030 stereotactic Non small cell radiotherapy with Operable surgical resection SPACE Stereotactic Precision And Conventional Radiotherapy Evaluation RTOG Radiation Therapy Oncology Group N0M0 No nodes and no metastatic disease

Australia

Goal of 100

Time to local failure

3 year survival

NSCLC Non small cell lung cancer JCOG Japan Clinical Oncology Group

11

Table 3: Results of Phase I and II Studies of Stereotactic Body Radiation Therapy for Early Stage Non Small Cell Lung Cancer STUDY Timmerman, 201011 Fakiris, 20098 TYPE Phase II LOCATION U.S. multi-center N 55 INTERVENTION 54 GY in 3 fractions INCLUSION Stage 1 Medically inoperable Peripheral tumors Stage 1 Medically inoperable T1-2, N0M0 DURATIO N OF FOLLOW UP 34.4 months OUTCOMES 90.6% 3 year local control 55.8% 3 year survival 3 year survival 42.7% 88.1% 3 year local control 3 year survival 71.7% 3 year cause specific survival 88.5% 98% local control survival for Stage 1 A:92%% 1 year and 83% 3 year Survival for Stage 1B:1 year 82% and 3 year 72% 91% survival>20Gy 54% survival <20 Gy 6/37 local failure 92% local control at 3 years

Phase II

U of Indiana, US

70

60-66 Gy in 3 fractions

50.2 months

Koto, 20079

Phase II

Japan

31

45 Gy in 3 fractions

32 months

Nagata, 200510

Phase I/II

Japan

45

48 Gy in 4 fractions

Stage 1 A or 1B lung cancer

30 months

Le, 200633

Phase I Dose Escalation Phase I Dose Escalation Phase II

Stanford, CA

32 (21 with NSCLC) 37 57

60-66 Gy in 20-22 Gy fractions 15-30 Gy single 24-60 Gy in 3 fractions 45-66 Gy in 3 fractions

Stage 1

12 months

Timmerman, 200334 Bauman, 200936

U of Indiana, US Sweden, Norway and Denmark

T1 or T2 N0M0 T1N0M0 and T2N0N0

15.2 months 35 months

12

Bral, 201035

Phase II

Belbium

40

60 Gy in 3 fractions

T1-3N0M0

2 years

75 local relapse 5% regional relapse 16% with distant mets 975 progression free survival at one year 84% progression free survival at two years

Gy N0M0 Met

Gray No nodes and no metastatic disease metastases

Level of Evidence: 4, 5 TA Criterion 2 is met.

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TA Criterion 3: The technology must improve net health outcomes. Retrospective Studies: The ideal therapy for early NSCLC is surgery, which typically results in three to five year survival rates of 60% to 80%. Lesser surgical therapies are typically associated with lower survival rates. For patients who are medically inoperable, standard radiation therapy results in much lower three to five year survival, on the order of 15% to 45%. A total of 21 retrospective studies of hypofractionated SBRT in the treatment of NSCLC have been reported (Table 1). Each study included between 20 and 257 patients. The majority of participants were either medically inoperable or refused surgical intervention. Five of these studies were conducted in Japan. The remaining studies were conducted in the U.S., Europe and Korea. The total radiation dose received ranged from 15-75 Gy and was given in 1-8 doses. Median length of follow up ranged from 11 to 40.9 months. Among those retrospective studies reporting one year survival, 52% to 86% were alive at one year. Among those retrospective studies reporting three year survival, 52% to 88% of individuals were alive at three years. The largest retrospective study was a multi-institutional study from Japan12,40. This study included 257 patients from 13 institutions, 158 of whom were medically inoperable. All had tumors that were Stage 1- T1, N0M0. Median length of follow up was 38 months. Five year survival overall was 56% . The cause specific three and five year survival rates were both 78%. In the medically operable patients, the three year overall survival was much higher- it was 70.8% with a BED of >100 Gy and 30.2% with a BED of <100 Gy. The results of these studies suggest that SBRT is associated with improved survival compared with what has historically been seen in other studies with conventional radiotherapy. In addition, the very high survival seen in medically operable patients seems particularly promising. Local control appears to be dramatically better with SBRT compared with that typically achieved with conventional radiotherapy. However, since none of the retrospective studies compared individuals treated with SBRT to individuals treated with conventional radiotherapy, direct comparisons cannot be made. A total of 361 patients were included in two studies that were reviews of existing SBRT databases where the data were collected prospectively37,38. Both of these studies included medically inoperable patients or patients who refused surgery. In general, these studies showed high rates of local control and SBRT was reasonably well tolerated.

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Completed Phase I and II Studies in Medically Inoperable Patients: To date eight Phase I and II studies of SBRT for the treatment of NSCLC have been completed. The Phase I studies focused on local control and toxicity. The Phase II studies included a total of 213 patients and assessed survival and local control in medically inoperable patients. In the U.S., Fakiris and colleagues conducted a Phase II study at the University of Indiana8. A total of 70 patients with stage 1, medically inoperable lung cancers were treated with 60-66 GY in three fractions. Mean followup was 50.2 months. Local control rate was 88.1% at 3 years; three year survival was 42.7%8,41. Two other Phase II studies were conducted in Japan and included 76 patients with Stage 1 lung cancer9,10. All received 45-48 Gy in 3-4 fractions and were followed from 30-32 months. Three year survival ranged from 71.7% to 83% 9,10. A final phase II study was conducted in the Netherlands and included 57 patients. They were followed for 35 months and there was a 92% rate of local control at 3 years, 5% had regional relapse and 16% had distant metastatic disease36. Important toxicities were seen in the University of Indiana study. Patients who were treated for tumors in the regions around the proximal bronchial tree or chest were more likely to have Grade 3 or 4 toxicities (including pneumonia, pleural effusions, apnea, decline in pulmonary function tests) than those with peripheral tumors 8,41. Because of the high toxicity seen in patients in the University of Indiana study with central lesions who received 6066 Gy, the recently published multicenter Radiation Therapy Oncology Group trial, RTOG 0236, includes only individuals with peripheral tumors. This was the first cooperative group, multicenter to study the use of SBRT. In this study, 59 patients with early stage but medically inoperable lung cancer received SBRT (8 Gy per fraction for 3 fractions) over 1 to 2 weeks. The primary end point was two year tumor control (defined as absence of primary tumor failure) and the secondary endpoints were disease free survival, treatment related toxicity and overall survival. Fifty-five patients were followed for an average of 34.4 months. The three year tumor control rate was 97.6% (95% C.I. 84.3-99.7). Median overall survival was 48.1 months; there was a 22.1% rate of disseminated failure. The three year survival rate was 55.8%. Although seven patients had treatment related grade 3 adverse events, and two patients had treatment related grade 4 adverse events, there were no grade 5 adverse events. Thus there were high rates of local tumor control with moderate treatment related morbidity although a significant incidence of disseminated failure. Finally, in this study, to ensure the technical quality of the radiation treatment, there was an extensive credentialing process, which probably contributed to the outcomes. Ongoing Phase II and III Studies: There are eight ongoing Phase II or Phase III studies - three in the U.S. are sponsored by Radiation Therapy Oncology Group (RTOG) and are multi-institutional, two others are not RTOG sponsored and are taking place in the U.S. and the remaining others are taking place in Japan, Scandinavia, and Australia . The ongoing studies are assessing the role of SBRT in operative patients (RTOG, 0618; STARS, L) - two are comparing SBRT to conventional radiation therapy (CHISEL, SPACE) and four are determining the optimal dose

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of SBRT to maximize benefit (RTOG, 0813, RTOG 0915JCOG, 0403, Washington University). All studies will evaluate local control, toxicity and survival. One of the RTOG studies includes patients with more centrally situated medically inoperable tumors and because of the toxicity seen at higher doses will use a gentler fractionation approach. The Japanese study (JCOG) has recently completed enrollment, but the results are not yet available. At this time, it is unlikely that a phase II trial comparing SBRT to conventional radiotherapy will be performed in the U.S. When the idea was considered at the National Institutes of Health, it was deemed unethical to randomize patients to conventional radiotherapy. Therefore, any additional evidence for the efficacy of SBRT in the treatment of medically inoperable NSCLC will come from the completion and follow up of the ongoing Phase II trials. However, two ongoing Phase II studies in other countries (Scandinavia and Australia) are comparing SBRT to conventional radiotherapy in medically inoperable patients. Potential Benefits: Potential benefits include that SBRT is a non-invasive outpatient treatment; it is more convenient than conventional radiotherapy, there is no surgical pain or risk of nosocomial infection, there is the potential to save inpatient and ICU costs, less lost time from work, less chronic pain and loss of respiratory capacity. It appears to lead to improved local control compared with historical controls and may lead to improved survival compared with conventional XRT, especially in medically inoperable patients. Potential Negative Effects: Potential negative effects with SBRT include increased toxicity that has been seen when more centrally located tumors are treated. Complications include pulmonary complications, radiation pneumonitis and esophageal problems. The increased dose to the tumor can also lead to an increased dose to the lungs. Toxic late effects include devascularization, fibrosis and ulceration. Nerves and blood vessels are particularly prone to the toxic effects41. Recent evidence from RTOG 0236 showed that SBRT appears to be relatively safe in patient with peripheral lesions. Ongoing studies are assessing safety and efficacy and determination of optimal dose in those with central lesions. While the University of Indiana study defined a dose that was too high to safely treat central lesions, the optimal dose is currently not known. Summary: Multiple case series and several Phase I and II studies suggest that SBRT is beneficial for the treatment of NSCLC in medically inoperable patients. However, none of these studies directly compared SBRT to an alternative treatment, although comparison with the historical outcomes for patients treated with conventional radiotherapy suggest a significant benefit for medically inoperable patients treated with SBRT. There are potential toxicities, especially for centrally located tumors, although the treatment of peripheral tumors appears to be safe. Local control appears to be improved with SBRT compared with conventional radiotherapy. In addition, a trial comparing SBRT with conventional radiotherapy for medically inoperable patients is unlikely to be done in the U.S.

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Thus, for medically inoperable patients with peripheral lesions, SBRT is safe and improves health outcomes compared with conventional radiotherapy. For medically inoperable patients with central lesions, there are important toxicities at high SBRT doses, and the optimal dose of SBRT to achieve efficacy and avoid toxicity is not known. Finally, in medically operable patients, there is currently no prospective evidence that SBRT improves health outcomes. TA Criterion 3 is met for medically inoperable patients with peripheral lesions who have few alternative treatment options. TA Criterion 3 is not met for medically inoperable patients with central lesions or for medically operable patients. TA Criterion 4: The technology must be as beneficial as any established alternatives.

Medically inoperable patients: There are few treatment options for medically inoperable NSCLC. The usual treatment approach is conventional radiotherapy. Three year survival with conventional XRT is approximately 15% to 45%.4-6 Among the retrospective studies of SBRT reporting three year survival, survival rates ranged from 52% to 66%14,18,20,40. One study showed an overall five year survival of 56%12. Among the Phase I and II studies of SBRT reporting three year survival, survival rates ranged from 42.7% to 83%9,10. The recent results of the RTOG 0236 study of medically inoperable patients with peripheral lesions showed a three year tumor control rate of 97.6% (95% C.I. 84.3-99.7). Median overall survival was 48.1 months; there was a 22.1% rate of disseminated failure. The three year survival rate was 55.8%. There is the potential for significant toxicity with SBRT, especially with centrally located tumors, although treatment of peripheral lesions appears to be safer. In the recent multi-center cooperative RTOG 0236 study, there was only moderate toxicity (9 grade 3 and grade 4 events in 59 patients and no grade 5 events). Because of the concern about increased toxicity with the treatment of central lesions, ongoing studies are evaluating the optimal dose of SBRT for the treatment of centrally located tumors. None of the completed Phase II studies directly compared SBRT to conventional radiotherapy or an alternative treatment. Although it is difficult to compare the survival in the retrospective studies or Phase I/II trials with the historical survival of patients treated with conventional radiotherapy in other studies, it is not likely that a prospective study comparing SBRT with conventional radiotherapy will be done in the U.S., as it has been deemed unethical.

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Medically operable patients: For medically operable patients, there is no evidence that SBRT improves outcomes. To date, no published trials have compared SBRT with surgery in medically operable patients. There are ongoing studies comparing these two treatment options, but the results will not be available for several years. In conclusion, for medically inoperable patients who have few treatment options, SBRT for the treatment of peripheral lesions leads to improved outcomes compared with historical outcomes with conventional radiotherapy. Although there are no completed trials comparing the two modalities, it is unlikely that any trials will be done as it has been deemed unethical. For medically inoperable patients with centrally located tumors, SBRT has been associated with significant toxicities. Ongoing studies are evaluating the optimal dose of SBRT to maximize benefit and minimize toxicity. For patients who are medically operable, there is currently no evidence that SBRT improves health outcomes compared with surgery. Evidence from ongoing Phase II trials should provide additional information. TA Criterion 4 is met for medically inoperable patients with peripheral lesions who have few alternative treatment options. TA Criterion 4 is not met for medically inoperable patients with central lesions or for medically operable patients. TA Criterion 5: The improvement must be attainable outside of the investigational setting.

The major multi-site study that has evaluated the use of SBRT is the RTOG 0236 study. Although this study was done in multiple sites to ensure the technical quality of the radiation treatment, there was an extensive credentialing process, which probably contributed to the positive outcomes seen in the study. This makes the studys results potentially less generalizable to the community setting. Evidence from the Amersham Cancer Registry did show that survival was improved in patients with lung cancer after SBRT was introduced in 2002 and increased even more after there was full access to SBRT after 200542. In addition, many of the results of the reported retrospective studies, which were performed in many large clinical settings, would suggest that the results would be attainable outside of investigational institutions. Because SBRT has not yet been established in clinical trials as improving net health outcomes for medically inoperable individuals with early stage NSCLC and central lesions or for medically operable patients, we cannot evaluate whether any improvement is attainable outside investigational settings.

TA Criterion 5 is met for medically inoperable patients with peripheral lesions who have few alternative treatment options.

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TA Criterion 5 is not met for medically inoperable patients with central lesions or for medically operable patients. CONCLUSION In summary, SBRT for the treatment of medically inoperable NSCLC is a promising new technology. These patients have few treatment options and conventional radiotherapy is associated with limited survival. Retrospective mostly single center studies have showed promise, but have not directly compared SBRT with conventional radiotherapy. Early phase I and II trials also suggest improved survival, but have not included a comparison group. In addition, an increase in Grade 3 toxicity has been seen when treating centrally located tumors at high SBRT doses However, recent analysis of the toxicity profile in RTOG 0236, a trial of SBRT in medically inoperable patients with peripheral lesions showed very low rates of toxicity at 12 month follow-up, suggesting that treatment of peripheral lesions is safe. Ongoing trials will help to define the optimal dose of SBRT for central tumors and will provide additional information about survival and longer term toxicity and some studies will also compare SBRT with other treatment options. The evidence is insufficient at this time to recommend SBRT as a treatment for medically operable early stage NSCLC. Additional follow- up of the ongoing Phase II trials will provide additional important information about long term toxicity and survival. RECOMMENDATION It is recommended that stereotactic body radiation therapy for the treatment of early stage non small cell lung cancer in medically inoperable patients with peripheral lesions meets CTAF criteria 2-5 for safety, effectiveness and improvement in outcomes. It is recommended that stereotactic body radiation therapy for the treatment of early stage non small cell lung cancer in medically inoperable patients with central lesions and medically operable patients does not meet CTAF TA criteria 2-5, for safety, effectiveness, and improvement in outcomes. The California Technology Assessment Forum panel voted unanimously in favor of the recommendation as written June, 29, 2011 (This is the second review of this topic by CTAF)

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RECOMMENDATIONS OF OTHERS Blue Cross Blue Shield Association (BCBSA) .No technology assessment on SBRT was found on the BCBSA Technology Assessment Center web site. Centers for Medicare and Medicaid Services (CMS) No CMS National Coverage Determination (NCD) was found for SBRT for non small cell lung cancer. California Radiological Society (CRS) The CRS was invited to attend the meeting and to provide an opinion regarding SBRT for non small cell lung cancer. The CRS did not provide an opinion on this technology nor did a representative attend the meeting. American Society of Therapeutic and Radiation Oncology (ASTRO) ASTRO provided an opinion on this technology. Two ASTRO representatives provided testimony at the meeting. California Thoracic Society (CTS) The CTS was invited to attend the meeting and to provide an opinion regarding SBRT for non small cell lung cancer. CTS did not provide an opinion on this technology nor did a representative attend the meeting. . American College of Chest Physicians (ACCP) The ACCP was invited to attend the meeting and to provide an opinion regarding SBRT for non small cell lung cancer. The ACCP did not provide an opinion on this technology nor did a representative attend the meeting. Association of Northern California Oncologists (ANCO) ANCO was invited to attend the meeting and provide an opinion regarding SBRT for non small cell lung cancer. ANCO provided an opinion on this technology; no representative attended the meeting. Medical Oncology Association of Southern California (MOASC) MOASC was invited to attend the meeting and provide an opinion regarding SBRT for non small cell lung cancer. MOASC did not provide an opinion on this technology nor did a representative attend the meeting. National Comprehensive Cancer Network (NCCN) The NCCN Clinical Practice Guideline in Oncology version 3.2011 notes that SBRT is an established treatment for inoperable stage 1 with node negative peripheral lesions.

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ABBREVIATIONS USED IN THIS REVIEW CTAF SBRT NSCLC TNM XRT COPD Gy N0M0 BED DARE RTOG JCOG SPACE PFTs California Technology Assessment Forum Stereotactic Body Radiotherapy Non small cell lung cancer Tumor, lymph nodes, metastasis External Radiation Therapy Chronic obstructive pulmonary disorder Gray No nodes and no metastatic disease Biologically Effective Dose Database of Abstracts of Reviews of Effects Radiation Therapy Oncology Group Japan Clinical Oncology Group Stereotactic Precision And Conventional Radiotherapy Evaluation Pulmonary function tests

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REFERENCES

1. 2. 3.

4. 5.

6. 7. 8.

9. 10.

11. 12. 13.

Cancer Facts & Figures 2010. 2011; http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/docum ent/acspc-026238.pdf, 2011. Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. The Annals of thoracic surgery. Sep 1995;60(3):615-622; discussion 622-613. Colice GL, Shafazand S, Griffin JP, Keenan R, Bolliger CT. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidencedbased clinical practice guidelines (2nd edition). Chest. Sep 2007;132(3 Suppl):161S177S. Armstrong JG, Minsky BD. Radiation therapy for medically inoperable stage I and II non-small cell lung cancer. Cancer treatment reviews. Dec 1989;16(4):247-255. Dosoretz DE, Galmarini D, Rubenstein JH, et al. Local control in medically inoperable lung cancer: an analysis of its importance in outcome and factors determining the probability of tumor eradication. International journal of radiation oncology, biology, physics. Oct 20 1993;27(3):507-516. Dosoretz DE, Katin MJ, Blitzer PH, et al. Medically Inoperable Lung Carcinoma: The Role of Radiation Therapy. Seminars in radiation oncology. Apr 1996;6(2):98-104. Rowell NP, Williams CJ. Radical radiotherapy for stage I/II non-small cell lung cancer in patients not sufficiently fit for or declining surgery (medically inoperable). Cochrane Database Syst Rev. 2001(2):CD002935. Fakiris AJ, McGarry RC, Yiannoutsos CT, et al. Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. International journal of radiation oncology, biology, physics. Nov 1 2009;75(3):677-682. Koto M, Takai Y, Ogawa Y, et al. A phase II study on stereotactic body radiotherapy for stage I non-small cell lung cancer. Radiother Oncol. Dec 2007;85(3):429-434. Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. International journal of radiation oncology, biology, physics. Dec 1 2005;63(5):1427-1431. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. Mar 17 2010;303(11):1070-1076. Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol. Jul 2007;2(7 Suppl 3):S94-100. Pennathur A, Luketich JD, Heron DE, et al. Stereotactic radiosurgery for the treatment of lung neoplasm: experience in 100 consecutive patients. The Annals of thoracic surgery. Nov 2009;88(5):1594-1600; discussion 1600.

22

14. 15.

16. 17. 18. 19. 20.

21. 22. 23. 24. 25. 26. 27.

28.

Uematsu M, Shioda A, Suda A, et al. Computed tomography-guided frameless stereotactic radiotherapy for stage I non-small cell lung cancer: a 5-year experience. International journal of radiation oncology, biology, physics. Nov 1 2001;51(3):666-670. Wulf J, Haedinger U, Oppitz U, Thiele W, Mueller G, Flentje M. Stereotactic radiotherapy for primary lung cancer and pulmonary metastases: a noninvasive treatment approach in medically inoperable patients. International journal of radiation oncology, biology, physics. Sep 1 2004;60(1):186-196. Lee SW, Choi EK, Park HJ, et al. Stereotactic body frame based fractionated radiosurgery on consecutive days for primary or metastatic tumors in the lung. Lung cancer (Amsterdam, Netherlands). Jun 2003;40(3):309-315. Ricardi U, Filippi AR, Guarneri A, et al. Stereotactic body radiation therapy for early stage non-small cell lung cancer: results of a prospective trial. Lung cancer (Amsterdam, Netherlands). Apr 2010;68(1):72-77. Scorsetti M, Navarria P, Facoetti A, et al. Effectiveness of stereotactic body radiotherapy in the treatment of inoperable early-stage lung cancer. Anticancer research. Sep-Oct 2007;27(5B):3615-3619. Brown WT, Wu X, Fayad F, et al. CyberKnife radiosurgery for stage I lung cancer: results at 36 months. Clinical lung cancer. Sep 2007;8(8):488-492. Baumann P, Nyman J, Lax I, et al. Factors important for efficacy of stereotactic body radiotherapy of medically inoperable stage I lung cancer. A retrospective analysis of patients treated in the Nordic countries. Acta oncologica (Stockholm, Sweden). 2006;45(7):787-795. Zimmermann FB, Geinitz H, Schill S, et al. Stereotactic hypofractionated radiation therapy for stage I non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands). Apr 2005;48(1):107-114. Onimaru R, Shirato H, Shimizu S, et al. Tolerance of organs at risk in small-volume, hypofractionated, image-guided radiotherapy for primary and metastatic lung cancers. International journal of radiation oncology, biology, physics. May 1 2003;56(1):126-135. Hara R, Itami J, Kondo T, et al. Clinical outcomes of single-fraction stereotactic radiation therapy of lung tumors. Cancer. Mar 15 2006;106(6):1347-1352. Fritz P, Kraus HJ, Muhlnickel W, et al. Stereotactic, single-dose irradiation of stage I non-small cell lung cancer and lung metastases. Radiation oncology (London, England). 2006;1:30. Grills IS, Mangona VS, Welsh R, et al. Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small-cell lung cancer. J Clin Oncol. Feb 20 2010;28(6):928-935. Chang JY, Balter PA, Dong L, et al. Stereotactic body radiation therapy in centrally and superiorly located stage I or isolated recurrent non-small-cell lung cancer. International journal of radiation oncology, biology, physics. Nov 15 2008;72(4):967-971. Videtic GM, Stephans K, Reddy C, et al. Intensity-modulated radiotherapy-based stereotactic body radiotherapy for medically inoperable early-stage lung cancer: excellent local control. International journal of radiation oncology, biology, physics. Jun 1 2010;77(2):344-349. Parashar B, Patel P, Monni S, et al. Limited resection followed by intraoperative seed implantation is comparable to stereotactic body radiotherapy for solitary lung cancer. Cancer. Nov 1 2010;116(21):5047-5053.

23

29.

30. 31. 32. 33. 34. 35. 36. 37. 38.

39. 40. 41. 42.

van der Voort van Zyp NC, van der Holt B, van Klaveren RJ, Pattynama P, Maat A, Nuyttens JJ. Stereotactic body radiotherapy using real-time tumor tracking in octogenarians with non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands). Sep 2010;69(3):296-301. Oshiro Y, Aruga T, Tsuboi K, et al. Stereotactic body radiotherapy for lung tumors at the pulmonary hilum. Strahlenther Onkol. May 2010;186(5):274-279. Olsen JR, Robinson CG, El Naqa I, et al. Dose-Response for Stereotactic Body Radiotherapy in Early-Stage Non-Small-Cell Lung Cancer. International journal of radiation oncology, biology, physics. Apr 6 2011. Guckenberger M, Heilman K, Wulf J, Mueller G, Beckmann G, Flentje M. Pulmonary injury and tumor response after stereotactic body radiotherapy (SBRT): results of a serial follow-up CT study. Radiother Oncol. Dec 2007;85(3):435-442. Le QT, Loo BW, Ho A, et al. Results of a phase I dose-escalation study using singlefraction stereotactic radiotherapy for lung tumors. J Thorac Oncol. Oct 2006;1(8):802809. Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest. Nov 2003;124(5):1946-1955. Bral S, Gevaert T, Linthout N, et al. Prospective, Risk-Adapted Strategy of Stereotactic Body Radiotherapy for Early-Stage Non-Small-Cell Lung Cancer: Results of a Phase II Trial. International journal of radiation oncology, biology, physics. Aug 12 2010. Baumann P, Nyman J, Hoyer M, et al. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol. Jul 10 2009;27(20):3290-3296. Lagerwaard FJ, Haasbeek CJ, Smit EF, Slotman BJ, Senan S. Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. International journal of radiation oncology, biology, physics. Mar 1 2008;70(3):685-692. Bradley JD, El Naqa I, Drzymala RE, Trovo M, Jones G, Denning MD. Stereotactic body radiation therapy for early-stage non-small-cell lung cancer: the pattern of failure is distant. International journal of radiation oncology, biology, physics. Jul 15 2010;77(4):1146-1150. Stauder MC, Macdonald OK, Olivier KR, et al. Early pulmonary toxicity following lung stereotactic body radiation therapy delivered in consecutive daily fractions. Radiother Oncol. May 2011;99(2):166-171. Onishi H, Araki T, Shirato H, et al. Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multiinstitutional study. Cancer. Oct 1 2004;101(7):1623-1631. Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol. Oct 20 2006;24(30):4833-4839. Palma D, Visser O, Lagerwaard FJ, Belderbos J, Slotman BJ, Senan S. Impact of Introducing Stereotactic Lung Radiotherapy for Elderly Patients With Stage I Non-SmallCell Lung Cancer: A Population-Based Time-Trend Analysis. Journal of Clinical Oncology. 2010;28(35):5153-5159.

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