California Technology Assessment Forum

TITLE: AUTHOR: 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 PUBLISHER: California Technology Assessment Forum DATE OF PUBLICATION: June 29, 2011 PLACE OF PUBLICATION: San Francisco, CA 1

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 cancer 1. 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 mortality 3. 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. 3

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: 4

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 study 8-11. 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). 5

TABLE 1: Stereotactic Body Radiation Therapy for Early Non Small Cell Lung Cancer: Results of Retrospective Studies STUDY STUDY SITE N INTERVENTION INCLUSION DURATION OF FOLLOW UP Onishi, 2007 12 Pennathur, 2009 13 Uematsu, 2001 14 Wulf, 2004 15 Lee, 2003 16 Multi-institutional in Japan University of Pittsburgh National Defense Medical College, Japan U of Wuerzburg, Germany University of Ulsan, South Korea 257 (158 medically inoperable) 100 (19 had metastatic disease) 18-75 Gy in 1-2 fractions 20 Gy single fraction increased to 60 Gy in 3 fractions OUTCOMES FOR THOSE WITH NSCLC Stage 1 T1N0M0 38 months 5 year overall survival 56%; 3 year overall survival for medically operable 70.8% with BED >100 and 30.2% with BED <100 Primary, recurrent or metastatic lung cancer; all stages; medically inoperable, failure of prior therapies or refusal to have surgery 50 50-60 Gy 5-10 FX T1-2N0M0 Medically inoperable or refused surgery 20 3 x 10 G or 3 x 12-12.5 Gy 28 (9 primary lung cancers) 20 months 24 month median overall survival 50% probability of 2 year overall survival (44% for primary lung cancer) 36 months 3 year survival 66%; 88% cause specific survival 86% in medically operable 94% local control 11 months 52% 1 year and 32% T1-T3N0M0 Medically inoperable 2 year survival 3-4 x 10 Gy Primary lung cancer 18 months 39% showing complete response; 43% showed partial response; primary and metastatic disease not reported separately 6

Ricardi, 2010 17 University of Turin 62) 15 Gy x 3 Stage 1 NSCLC Medically inoperable Scorsetti, 2007 Italy 18 Brown, 2007 19 Baumann, 2006 20 Zimmerman, 2005 21 Onimaru, 2003 22 Hara, 2006 23 Instituto Clinico Humanitas, Italy CyberKnife Center in Miami Karolinska Hospital, Sweden Technical University, Germany Hokkaido University Japan International Medical Center of Japan 43 30.5 Gy in 1-4 fractions 59 15-67.5 Gy in 1-5 fractions 138 30-48 Gy in 2-4 fractions 30 24-37.5 Gy in 3-5 doses 46 (26 with primary lung cancer) 59 (11 with primary lung cancer) Fritz, 2006 24 Germany 58 (33 primary lung cancer) Grills, 2010 25 Michigan 124 48=60 Gy in 4-5 fractions or surgery Chang, 2008 26 University of Texas 28 months Local control at 3 years 87.8% Overall survival 57.1% T1-2, N0M0 14 months 53% 2 year survival Stage ia or 1 B 1-33 months Median not reported 86% alive at 1-33 month follow up Stage 1 33 months 3 year survival 52% 5 year survival 26% Stage 1 18 months 80% 12 month survival 75% 24 month survival 48-60 GY in 8 doses Stage 1 17 months 47% 2 year survival 60% 2 year cause specific survival 20-34 Gy single dose Stage 1 12 months 76.5% 1 year survival 41% 2 year survival Primary lung cancer not analyzed separately 30 Gy single dose Stage 1 18 months 1 year survival 83% 3 year survival 53% 27 40 or 50 Gy in 4 doses Stage 1 Borderline surgical candidates 2.5 years No difference in regional recurrence, distant mets or freedom from any failure Stage 1 17 months Local control 100% for those receiving 50 GY 3/7 had local 7

recurrences with 40 Gy Videtic 27 Cleveland Clinic 26 10 Gy x 5 days Sage I 40.9 months 3 year local control 94.4% 3 year overall survival 52% Parashar, 2010 28 Cornell Medical Center, New york 55 SBRT or surgical resection with seed implantation Malignant solitary lung nodule Van Zyp, 2010 29 Netherlands 38 SBRT 45 or 60 Gy in 3 fractions Age 80 or over Stage I Oshiro, 2010 30 Japan 21 100 GY Median Centrally located tumors Olsen, 2011 31 Missouri 19 18 Gy in 3 fractions Single primary lung 9 gy in 5 fractions lesion 10 Gy in 5 fractions Guckenberger, 2007 32 Gy N0M0 BED Gray Europe 70 (38 primary lung cancer) No nodes and no metastatic disease Biologically Effective Dose NSCLC Non small cell lung cancer Met SBRT metastases Stereotactic Body Radiotherapy 6-12.5 Gy in 3-8 fx or 26 gy x 1 Inoperable early stage NSCLC or metastatic disease 17.5 months No significant differences in local control, distant mets, survival or toxicity 23 months 65% 1 year survival 44% 2 year survival 20 months 62.2% two year survival 11-16 months Reduced local control in those who received 9 Gyx 5 24 months 885 local control at 24 months Table 2: Prospective Studies of Stereotactic Body Radiation Therapy for Early Stage Non Small Cell Lung Cancer 8

STUDY TYPE LOCATION N INTERVENTION INCLUSION OUTCOMES COMPLETED Timmerman, 2010 11 Phase II U.S. Multiinstitutional Fakiris, 2009 8 Phase II University of Indiana, US 55 3 fractions 20 Gy each=60 Gy Medically inoperable T1-3 tumors <5 cm ; no lymph nodes, peripheral (excludes tumors of proximal bronchial tree 70 60-66 Gy in 3 fractions Stage 1 Medically inoperable Local control and toxicity Survival Local Control Koto, 2007 9 Phase II Japan 31 45 Gy in 3 fractions T1-2, N0Mo Survival Nagata, 2005 10 Phase I/II Japan 45 48 Gy in 4 fractions Stage 1 A or 1B lung cancer Survival Local Control Le, 2006 33 Phase I Dose Escalation Stanford, CA 32 (21 with NSCLC) 60-66 Gy in 20-22 Gy fracs Stage 1 Survival 15-30 Gy single Timmerman, Phase I U of Indiana, US 37 24-60 Gy in 3 fractions T1 or T2 N0M0 Local Control 2003 34 Dose Escalation Bral, 2010 35 Phase II Belgium 40 60 Gy in 3 fractions T1-3N0M0 Local Control and survival Bauman, 2009 36 Phase II Sweden, Norway 57 45-66 Gy Stage I Progression free and Denmark Medically survival Lagerwaard, 2008 37 Bradley, 2010 38 Review of prospective database Review of prospective database Netherlands 206 Range: 20 Gy x 3 to 7.5 Gy x 8 Washington University, St. Louis 91 Median 54 Gy in 3 fractions inoperable Stage I or 2 81% medically inoperable Medically inoperable or refused surgery Overall survival and disease free survival Local control Stauder, 2011 39 Review of U.S. 84 pts with 32-60 Gy in 3-5 Medically Pulmonary 9

ONGOING RTOG 0618 prospective database U.S. Phase II multiinstitutional U.S. Multiinstitutional RTOG 0813 Phase I/II U.S. Multiinstitutional RTOG 0915 Phase II U.s. multiinstitutional JCOG 0403 Recently completed results reported in abstract form 88 lesions (64 primary or recurrent 33 Accrual complete 48 of 94 as of 5/6/11 94 accrual complete Single arm Phase II Japan Accrual plans 100 inoperable and 65 operable patients fractions inoperable NSCLC or metastatic lung lesions 20 Gy x 3 vs. surgery; Tumor <5 Cm ; operable disease Goal to determine MTD Anticipated 11.5 Gy/FX 48 gy in 4 fx vs 34 Gy in 1 fx 48 Gy in 4 fractions over 4-8 days Medically inoperable centaly located tumors Medically inoperable peripheral tumors Operable patients with clinical stage 1A toxicity Local control and toxicity Rate of tumor control Toxicity 3 year survival 10

Washington University Phase I/II U.S. Goal =75 MTD to be determined9range 9 GY x5 to 12 GY x 5) SPACE Phase II two arms Scandinavia 100 66 GY in 3 fractions vs. Conventional treatment 70 Gy with 2 Gy per fraction in 35 fractions CHISEL Phase III Australia Goal of 100 Hypofractionated SBRT (total dose of 60-66 Gy vs conventional radiotherapy STARS Phase III U.S. multi-center Goal of 1030 ecyberknife stereotactic radiotherapy with surgical resection Stage I or II Central tumors Stage 1 medically inoperable Peripheral tumors Stage 1 medically inoperable Peripheral Stage 1 Non small cell Operable Gy Gray SPACE Stereotactic Precision And Conventional Radiotherapy Evaluation NSCLC Non small cell lung cancer JCOG Japan Clinical Oncology Group RTOG Radiation Therapy Oncology Group MTD Maximum tolerated dose N0M0 No nodes and no metastatic disease Treatment related toxicity Local control rate 3 year survival Time to local failure 3 year survival 11

Table 3: Results of Phase I and II Studies of Stereotactic Body Radiation Therapy for Early Stage Non Small Cell Lung Cancer STUDY TYPE LOCATION N INTERVENTION INCLUSION DURATIO N OF FOLLOW UP Phase II U.S. multi-center 55 54 GY in 3 fractions Stage 1 Medically inoperable Peripheral tumors Timmerman, 2010 11 Fakiris, 2009 8 Phase II U of Indiana, US 70 60-66 Gy in 3 fractions Stage 1 Medically inoperable OUTCOMES 34.4 months 90.6% 3 year local control 55.8% 3 year survival 50.2 months 3 year survival 42.7% 88.1% 3 year local control Koto, 2007 9 Phase II Japan 31 45 Gy in 3 fractions T1-2, N0M0 32 months 3 year survival 71.7% 3 year cause specific survival 88.5% Nagata, 2005 10 Phase I/II Japan 45 48 Gy in 4 fractions Stage 1 A or 1B lung cancer Le, 2006 33 Timmerman, 2003 34 Phase I Dose Escalation Phase I Dose Escalation Stanford, CA 32 (21 with NSCLC) Bauman, 2009 36 Phase II Sweden, Norway and Denmark 60-66 Gy in 20-22 Gy fractions 15-30 Gy single 30 months 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% Stage 1 12 months 91% survival>20gy 54% survival <20 Gy U of Indiana, US 37 24-60 Gy in 3 fractions T1 or T2 N0M0 15.2 months 6/37 local failure 57 45-66 Gy in 3 fractions T1N0M0 and T2N0N0 35 months 92% local control at 3 years 12

75 local relapse 5% regional relapse 16% with distant mets Bral, 2010 35 Phase II Belbium 40 60 Gy in 3 fractions T1-3N0M0 2 years 975 progression free survival at one year 84% progression free survival at two years Gy Gray N0M0 Met No nodes and no metastatic disease metastases Level of Evidence: 4, 5 TA Criterion 2 is met. 13

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 Japan 12,40. 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 prospectively 37,38. 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. 14

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 Indiana 8. 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 cancer 9,10. 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 disease 36. 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 60-66 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 ½ 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 15

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 effects 41. 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. 16

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. 17

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 study s 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 2005 42. 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. 18

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) 19

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. 20

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 21

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