Accelerated Radiotherapy After Breast-Conserving Surgery for Early Stage Breast Cancer

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1 Technology Evaluation Center Accelerated Radiotherapy After Breast-Conserving Surgery for Early Stage Breast Cancer Assessment Program Volume 24, No. 9 June 2010 Executive Summary Background Radiation therapy is the standard care for patients undergoing breast-conserving surgery, as an individual-level meta-analysis based on multiple randomized, controlled trials shows that such therapy reduces recurrences and lengthens survival. The conventional radiation therapy regimen consists of about 25 treatments of 2 Gray (Gy; a measure of absorbed radiation dose) each delivered over 5 to 6 weeks. Not all patients undergo radiation therapy following breast-conserving surgery. The duration and logistics of treatment may be barriers to some women. Therefore, several accelerated radiotherapy approaches have been proposed to make the regimen less burdensome. n Accelerated (also called hypofractionated ) whole-breast irradiation, which reduces the number of fractions and the duration of treatment to about 3 weeks. This approach has been commonly used in Canada and Europe. n Accelerated partial-breast irradiation (APBI), which irradiates a limited part of the breast in and close to the tumor cavity. By reducing the area irradiated, fewer treatments are needed and the total treatment takes about 1 week. Several approaches can be used to deliver APBI, including interstitial brachytherapy, balloon brachytherapy, external beam, or intraoperative (which occurs on only 1 day). Objective To evaluate the outcomes, particularly local recurrence, of 2 accelerated alternatives to conventional whole-breast radiotherapy after breast-conserving surgery: 1) accelerated, hypofractionated, wholebreast irradiation therapy; 2) accelerated, partial-breast irradiation (APBI) therapy. Search Strategy For accelerated whole-breast irradiation, papers from the 2007 TEC Assessment were supplemented by those identified in the recent California Technology Assessment Forum report on this technology, as well as reference lists and review articles. For accelerated partial-breast irradiation, a MEDLINE search was performed in September 2009, using the same terms listed in the literature search cited in the consensus statement of the American Society of Radiation Oncology (ASTRO). Abbreviated searches to update the literature were performed in February BlueCross BlueShield Association An Association of Independent Blue Cross and Blue Shield Plans Selection Criteria All comparative English-language articles in peer-reviewed journals on accelerated radiotherapy following breast-conserving surgery were included. Uncontrolled (i.e., single-arm) studies were excluded, because indirect comparisons in this setting are not reliable. Initial patient differences may account for perceived differences in treatment outcomes; they cannot be controlled for adequately to ensure the validity of the conclusions. Abstracts were excluded, unless copies of the slide presentation used at a national professional meeting could be obtained or the abstracts provided follow-up data for a previously published comparative article that described the study in detail. NOTICE OF PURPOSE: TEC Assessments are scientific opinions, provided solely for informational purposes. TEC Assessments should not be construed to suggest that the Blue Cross Blue Shield Association, Kaiser Permanente Medical Care Program or the TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any particular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 1

2 Technology Evaluation Center Main Results Accelerated Whole-Breast Irradiation. Four randomized, controlled trials compared accelerated whole-breast radiotherapy to 5-week whole-breast radiotherapy, as well as a fifth, older, nonrandomized study. Three of the 4 trials are rated good quality using the modified U.S. Preventive Services Task Force criteria; the fourth trial was rated fair, and the nonrandomized study, poor. Two of the studies are particularly useful, as they directly compared a 5-week to a 3-week regimen. They are both prospectively designed, noninferiority trials. Both trials accepted a maximum loss of efficacy of 5 percentage points in local or locoregional recurrence in the accelerated group at 5 or 10 years (one-sided α = or 0.05). Although the studies differ in the specific fractionation schedules and patient characteristics, they report no difference in local recurrence rates (i.e., recurrence of the cancer in the same breast) across treatment arms. One study from the U.K. includes women with grade 1 3 tumors. About 75% of the women had negative lymph nodes, and about 42% had a radiation boost to the tumor bed. Randomization was stratified for hospital, type of surgery (about 15% had a mastectomy), and plans for tumor bed boost. Systemic therapy, primarily tamoxifen, was used by some patients and appeared to be fairly evenly distributed across treatment groups. The treatment arms compared a total dose of 40 Gy in 15 fractions over 3 weeks to 50 Gy in 25 fractions over 5 weeks. The hazard ratios for 40 Gy accelerated whole-breast radiotherapy versus conventional whole-breast radiotherapy were not statistically significant (using the log-rank test) for local or locoregional relapse. The absolute difference in locoregional relapse rates after 5 years was 0.7% (95% CI: 1.7%, 0.9%). There were statistically significant differences in the 2 treatment regimens for distant relapse and overall survival, with relapse more frequent and survival longer for the 40 Gy accelerated whole-breast irradiation. This unexpected difference between treatment arms began to appear at about 1 year. The authors speculate that it could be due to chance and might change with longer follow-up. The 6-year follow-up period on this trial is too short to reach firm conclusions; follow-up continues. The second randomized, controlled trial from Canada compared accelerated whole-breast irradiation versus whole-breast irradiation. Of 2,429 eligible patients, 51% agreed to participate in the trial. Intention-to-treat analysis was used. The 10-year local recurrence was 6.2% for the 42.5-Gy arm accelerated whole-breast irradiation arm and 6.7% for the conventional 50-Gy whole-breast irradiation (absolute difference: 0.5%; 95% CI: 2.5%, 3.5%). Local recurrence rates with accelerated whole-breast radiotherapy were not worse than conventional whole-breast irradiation, when applying a noninferiority margin of 5%. In exploratory subgroup analyses, treatment effects were similar by age, tumor size, estrogen-receptor status, and chemotherapy use (48% had no systemic therapy). However, local recurrence at 10 years for patients with high-grade tumors was 4.7% for the conventional whole-breast irradiation arm and 15.6% for the 42.5-Gy accelerated whole-breast irradiation arm. The absolute difference equals 10.9 percentage points (95% CI: 19.1, 2.8, test for interaction, p=0.01). The patients in this trial all had invasive carcinoma of the breast with negative lymph nodes and surgical margins and they did not have a radiotherapy boost to the tumor site. Exclusion criteria for the trial included invasive disease or ductal carcinoma in situ involving the margins of excision, tumors that were larger than 5 cm in diameter, and a breast width of more than 25 cm at the posterior border of the medial and lateral tangential beams, which could increase the heterogeneity of the radiation dose to the breast. In the trial, lymph node status was determined by axillary dissection, but recent reports suggest that sentinel lymph node biopsy is likely to be as effective. The overall body of evidence on accelerated whole-breast irradiation compared to conventional whole-breast irradiation suggests local recurrence rates with accelerated whole-breast radiotherapy were not worse than conventional whole-breast irradiation in patients meeting the criteria of the Canadian trial, when applying a noninferiority margin of 5%. Longer follow-up is needed for the U.K. trial. Accelerated Partial-Breast Irradiation. There are 2 randomized, controlled trials on interstitial or external-beam, accelerated, partial-breast irradiation (APBI) compared to conventional wholebreast irradiation, as well as 7 nonrandomized, comparative studies. All of these studies evaluated interstitial or external brachytherapy; no published comparative studies were found that assessed balloon brachytherapy or intraoperative APBI. Quality of both trials was rated as poor. For the first, accrual was stopped before reaching the goal specified to evaluate differences in local recurrence, Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.

3 Accelerated Radiotherapy After Breast-Conserving Surgery for Early Stage Breast Cancer to allow patients to participate in another trial. The randomization process was unclear; patients deemed technically unsuitable for interstitial brachytherapy were given external-beam APBI, and the patient characteristics and outcomes for each type of APBI were not reported separately. Finally, the sample size of 126 was relatively small, and longest follow-up reported was 66 months. Similar local and regional failure rates were found in the treatment arms. The other randomized, controlled trial on APBI was reported in 1990 and 1993, and many changes in the care of breast cancer have occurred since then. The study was rated as poor because the initial groups were potentially unbalanced and nodal status was based on clinical exam, among other factors. Recurrence was higher for the limited field treatment arm (analogous to partialbreast irradiation) than for the wide field arm (analogous to whole-breast irradiation), but some of the excess recurrences in the limited field arm were axillary. This may be accounted for by the fact that the axillary area was included in the wide field radiotherapy, but not in the limited field, and the initial work-up for nodal involvement was limited. The follow-up was 65 months, and the sample size 708. The other 7 nonrandomized, comparative studies were all rated as poor, due to potential baseline differences in treatment groups, lack of multivariable analyses to account for them, inclusion of patients who did not meet eligibility criteria, variations in treatment within arms, and generally small sample sizes and insufficient follow-up. Overall, the body of evidence on interstitial APBI compared to conventional whole-breast irradiation is weak, and it is extremely weak (i.e., no comparative studies) for balloon brachytherapy, intraoperative APBI, and external-beam APBI. Authors Conclusions and Comments Accelerated Whole-Breast Irradiation. The evidence suggests that accelerated whole-breast irradiation provides a reasonable, shorter alternative to conventional whole-breast irradiation among women who had breast-conserving surgery and are at low risk of recurrence. In a Canadian trial, the 10-year local recurrence was 6.2% for the 42.5-Gy accelerated whole-breast irradiation arm and 6.7% for the conventional whole-breast irradiation arm (absolute difference: 0.5%; 95% CI: 2.5%, 3.5%). Accelerated whole-breast irradiation cuts the radiotherapy treatment time by about 40% without any apparent negative consequences after 10 years of follow-up. The results should be interpreted in the context of a noninferiority design with a margin of 5%. In exploratory subgroup analyses, treatment effects were similar by age, tumor size, estrogenreceptor status, and chemotherapy use. However, local recurrence at 10 years for patients with high-grade tumors was 4.7% for the conventional whole-breast irradiation arm and 15.6% for the 42.5-Gy accelerated whole-breast irradiation arm. The absolute difference equals 10.9 percentage points (95% CI: 19.1, 2.8; test for interaction: p=0.01). Patient selection is key and at this point, only patients similar to those in the Canadian trial should be considered for this therapy. Outcomes could vary in women with other disease characteristics. The patients in this trial all had invasive carcinoma of the breast with negative lymph nodes and surgical margins, and they did not have a radiotherapy boost to the tumor site. Exclusion criteria for the trial included invasive disease or ductal carcinoma in situ involving the margins of excision, tumors that were larger than 5 cm in diameter, and a breast width of more than 25 cm at the posterior border of the medial and lateral tangential beams, which could increase the heterogeneity of the radiation dose to the breast. In the trial, lymph node status was determined by axillary dissection, but recent reports suggest that sentinel lymph node biopsy is likely to be as effective. Forty-one percent of the women received tamoxifen, despite the fact that 71% had disease that was shown to be estrogen-receptor positive. Patients selecting this accelerated whole-breast radiotherapy should be told that while the current evidence on this radiotherapy regimen is solid, it is not as strong as that for conventional wholebreast irradiation. Additional randomized, controlled trials or longer follow-up of the existing trials could uncover additional concerns. Some potential adverse events, such as cardiac ischemia, may take longer to become evident. This regimen has been widely used outside the U.S. without substantial reports of major adverse events. Potential patients should be carefully selected and given full information, while the results of longer follow-up for the START B trial are awaited Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 3

4 Technology Evaluation Center Accelerated Partial-Breast Irradiation. The data on APBI compared to whole-breast irradiation are insufficient to draw any conclusions about the relative effectiveness of these modalities. Furthermore, it is becoming increasingly clear that each type of APBI should be judged on its own merits, and studies comparing different APBI techniques to each other as well as to whole-breast irradiation are needed. Fortunately, a number of large randomized, controlled trials are underway. Given the current level of evidence, it is important for patients to be aware of the uncertainty regarding the outcomes of this approach. This information should include failure rates for the specific devices (e.g., explantation for MammoSite, incomplete expansion of the catheters for some of the hybrid devices), as well as the uncertainty regarding their comparative effectiveness. The intermediate alternative provided by accelerated whole-breast irradiation should also be presented to women who meet the criteria for the Canadian trial, as well as the critical importance of completing radiotherapy for the majority of patients undergoing breast-conserving surgery. In a review of the APBI trials currently underway, Mannino and Yarnold (note Yarnold is a lead author on the START A and B trials) raise several concerns regarding variations across the trials. The extent of the initial breast-conserving surgery can vary substantially across studies, as well as the definition of the targeted tumor cavity. A larger margin is usually drawn around the tumor cavity for 3D-CRT, for example, because of the need to allow for variations in set-up and respiration motion. Studies of APBI usually distinguish between same site relapse, i.e., close to the irradiated area and elsewhere relapse, yet it is unclear whether what constitutes the same site varies across studies. The percentage of relapses occurring elsewhere in the ipsilateral breast in studies of whole-breast radiotherapy following breast-conserving surgery range from 18% to 42% (these studies may include some patients at higher risk of recurrence). Proponents of APBI have sometimes asserted that elsewhere tumors are rare, that they are mostly new primary tumors (rather than a recurrence), or that earlier studies have shown that radiotherapy is not effective on these tumors in any case. Mannino and Yarnold challenge each of these points in turn, although they also conclude that the results of the trials currently underway will provide level 1 evidence for or against APBI. Summary of Application of the Technology Evaluation Criteria Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether accelerated radiotherapy meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria to decrease recurrence and reduce treatment sequelae after breast-conserving surgery for early stage breast cancer. 1. The technology must have final approval from the appropriate governmental regulatory bodies. The various radiotherapy modalities presented in this Assessment have been approved or cleared for marketing by the U.S. Food and Drug Administration (FDA). The brachytherapy devices, however, contain a black box warning required by the FDA indicating that The safety and effectiveness of the [brachytherapy device] as a replacement for whole-breast irradiation in the treatment of breast cancer has not been established. 2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes. Accelerated Whole-Breast Irradiation. Two randomized, controlled trials rated as good quality with over 3,000 participants compared accelerated and conventional whole-breast irradiation. Local recurrence rates with accelerated whole-breast radiotherapy were not worse than conventional whole breast irradiation, when applying a noninferiority margin of 5%. Follow-up for one study was 6 years, which is insufficient; results of longer follow-up are being collected. The follow-up period for the other study, however, was 12 years, with 10-year recurrence rates reported. This time period is sufficient to gauge the relative outcomes of these two treatment approaches. However, these results only apply to women similar to those in the Canadian trial, who had invasive carcinoma of the breast with negative lymph nodes and surgical margins, and they did not have a radiotherapy boost to the tumor site. Exclusion criteria for the trial included invasive disease or ductal carcinoma in situ involving the margins of excision, tumors that were larger than 5 cm in diameter, and a breast width of more than 25 cm at the posterior border of the medial and lateral tangential beams, which could increase the heterogeneity of the radiation dose to the breast. In the trial, Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.

5 Accelerated Radiotherapy After Breast-Conserving Surgery for Early Stage Breast Cancer lymph node status was determined by axillary dissection, but recent reports suggest that sentinel lymph node biopsy is likely to be as effective. Accelerated Partial-Breast Irradiation. Two poor quality randomized, controlled trials and 7 poor quality nonrandomized, comparative studies on interstitial APBI compared to conventional whole-breast radiotherapy were found. They are insufficient to permit conclusions concerning the effect of interstitial brachytherapy on health outcomes. No comparative studies were found on balloon brachytherapy, external-beam APBI, or intraoperative APBI, and thus the evidence on these modalities are insufficient, as well. 3. The technology must improve the net health outcome. Accelerated Whole-Breast Irradiation. Indirect evidence is available on the impact of accelerated whole-breast irradiation on the net health outcome. A number of trials and individual-level metaanalyses have demonstrated that the use of radiation therapy after breast-conserving therapy reduces recurrence and improves survival. In the Canadian trial, local recurrence rates with accelerated whole-breast radiotherapy were not worse than conventional whole-breast irradiation, when applying a noninferiority margin of 5%. Therefore, the available evidence suggests that accelerated whole-breast irradiation also improves the net health outcome compared to no radiotherapy for women meet the criteria for Canadian clinical trial (i.e., invasive carcinoma of the breast with negative lymph nodes and surgical margins, and no radiotherapy boost to the tumor site). Accelerated Partial-Breast Irradiation. Since available evidence is insufficient to permit conclusions regarding the equivalence of APBI and conventional whole-breast irradiation and since APBI has not and cannot ethically be compared to using no radiation therapy after breast-conserving surgery, it cannot be determined whether accelerated radiotherapy improves the net health outcome. 4. The technology must be as beneficial as any established alternatives. Accelerated Whole-Breast Irradiation. Evidence is available that accelerated whole-breast irradiation is not worse than the longer whole-breast regimen, when applying a noninferiority margin of 5%. With treatment duration of 3 weeks rather than 5 weeks, it is more convenient and less taxing for patients and may improve adherence with the standard of care that women undergo radiation therapy following breast-conserving surgery. Accelerated Partial-Breast Irradiation. Since available evidence is insufficient to permit conclusions, it cannot be determined whether accelerated partial-breast irradiation is as beneficial as wholebreast, standard radiotherapy after breast-conserving surgery for early stage breast cancer. Longer follow-up ideally in randomized, controlled trials, several of which are underway for APBI is needed to ascertain whether accelerated radiotherapy is as beneficial as the current standard of care up to approximately 10 years after treatment. 5. The improvement must be attainable outside the investigational settings. Accelerated Whole-Breast Irradiation. The 2 major studies on accelerated whole-breast irradiation were large, multicenter trials conducted at 10 sites in Canada and 23 sites in the U.K. These results should be attainable outside investigational settings. Accelerated Partial-Breast Irradiation. Whether accelerated partial breast radiotherapy improves health outcomes after breast-conserving surgery for early stage breast cancer has not been demonstrated in the investigational setting. Based on the above, accelerated whole-breast radiotherapy after breast-conserving surgery for early stage breast cancer meets the TEC criteria for women who meet the entry criteria for the Canadian trial (i.e., invasive carcinoma of the breast with negative lymph nodes and surgical margins, and no radiotherapy boost to the tumor site; exclusion criteria for the trial included invasive disease or ductal carcinoma in situ involving the margins of excision, tumors that were larger than 5 cm in diameter, and a breast width of more than 25 cm at the posterior border of the medial and lateral tangential beams, which could increase the heterogeneity of the radiation dose to the breast ). Accelerated partial-breast radiotherapy after breast-conserving surgery for early stage breast cancer does not meet the TEC criteria Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 5

6 Technology Evaluation Center Contents Assessment Objective 7 Background 7 Methods 10 Part I: Accelerated Whole-Breast Irradiation Formulation of the Assessment 12 Review of Evidence 12 Discussion and Conclusions 35 Summary of Application of 36 the Technology Evaluation Criteria References 39 Appendix 41 Part II: Accelerated Partial-Breast Irradiation Formulation of the Assessment 25 Review of Evidence 26 Published in cooperation with Kaiser Foundation Health Plan and Southern California Permanente Medical Group. TEC Staff Contributors Lead Author Barbara Mauger Rothenberg, Ph.D.; Co-Author David J. Samson, M.S.; TEC Executive Director Naomi Aronson, Ph.D.; Director, Clinical Science Services Kathleen M. Ziegler, Pharm.D.; Research/Editorial Staff Claudia J. Bonnell, B.S.N., M.L.S.; Maxine A. Gere, M.S. Blue Cross and Blue Shield Association Medical Advisory Panel Allan M. Korn, M.D., F.A.C.P. Chairman, Senior Vice President, Clinical Affairs/Medical Director, Blue Cross and Blue Shield Association; Alan M. Garber, M.D., Ph.D. Scientific Advisor, Staff Physician, U.S. Department of Veterans Affairs; Henry J. Kaiser, Jr., Professor, and Professor of Medicine, Economics, and Health Research and Policy, Stanford University; Steven N. Goodman, M.D., M.H.S., Ph.D. Scientific Advisor, Professor, Johns Hopkins School of Medicine, Department of Oncology, Division of Biostatistics (joint appointments in Epidemiology, Biostatistics, and Pediatrics). Panel Members Peter C. Albertsen, M.D., Professor, Chief of Urology, and Residency Program Director, University of Connecticut Health Center; Sarah T. Corley, M.D., F.A.C.P., Chief Medical Officer, NexGen Healthcare Information Systems, Inc. American College of Physicians Appointee; Helen Darling, M.A. President, National Business Group on Health; Josef E. Fischer, M.D., F.A.C.S., William V. McDermott Professor of Surgery, Harvard Medical School American College of Surgeons Appointee; I. Craig Henderson, M.D., Adjunct Professor of Medicine, University of California, San Francisco; Mark A. Hlatky, M.D., Professor of Health Research and Policy and of Medicine (Cardiovascular Medicine), Stanford University School of Medicine; Saira A. Jan, M.S., Pharm.D., Associate Clinical Professor, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Residency Director and Director of Clinical Programs Pharmacy Management, Horizon Blue Cross and Blue Shield of New Jersey; Leslie Levin, M.B., M.D., F.R.C.P.(Lon), F.R.C.P.C., Head, Medical Advisory Secretariat and Senior Medical, Scientific and Health Technology Advisor, Ministry of Health and Long-Term Care, Ontario, Canada; Bernard Lo, M.D., Professor of Medicine and Director, Program in Medical Ethics, University of California, San Francisco; Barbara J. McNeil, M.D., Ph.D., Ridley Watts Professor and Head of Health Care Policy, Harvard Medical School, Professor of Radiology, Brigham and Women s Hospital; William R. Phillips, M.D., M.P.H., Clinical Professor of Family Medicine, University of Washington American Academy of Family Physicians Appointee; Alan B. Rosenberg, M.D., Vice President, Medical Policy, Technology Assessment and Credentialing Programs, WellPoint, Inc.; Maren T. Scheuner, M.D., M.P.H., F.A.C.M.G., Director, Genomics Strategic Program Area, VA HSR&D Center of Excellence for the Study of Healthcare Provider Behavior, VA Greater Los Angeles Healthcare System; Natural Scientist, RAND Corporation; Adjunct Associate Professor, Department of Health Services, UCLA School of Public Health; J. Sanford Schwartz, M.D., F.A.C.P., Leon Hess Professor of Medicine and Health Management & Economics, School of Medicine and The Wharton School, University of Pennsylvania; Earl P. Steinberg, M.D., M.P.P., President and CEO, Resolution Health, Inc.; Robert T. Wanovich, Pharm.D., Vice-President, Pharmacy Affairs, Highmark, Inc.; A. Eugene Washington, M.D., M.Sc., Executive Vice Chancellor and Provost, University of California, San Francisco; Jed Weissberg, M.D., Senior Vice President, Quality and Care Delivery Excellence, The Permanente Federation. CONFIDENTIAL: This document contains proprietary information that is intended solely for Blue Cross and Blue Shield Plans and other subscribers to the TEC Program. The contents of this document are not to be provided in any manner to any other parties without the express written consent of the Blue Cross and Blue Shield Association Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.

7 Accelerated Radiotherapy After Breast-Conserving Surgery for Early Stage Breast Cancer Assessment Objective This Assessment evaluates the outcomes of 2 accelerated alternatives to conventional whole-breast radiotherapy after breast-conserving surgery: 1) accelerated, hypofractionated whole-breast irradiation therapy and 2) accelerated partial-breast irradiation (APBI) therapy. Background Breast Conservation Therapy Survival after breast-conservation therapy is equivalent to survival after mastectomy for patients diagnosed with tumors categorized as stage I or II. Breast-conservation therapy is a multimodality treatment that consists of breastconserving surgery to excise the tumor with adequate margins, followed by whole-breast external-beam radiation therapy administered as 5 daily fractions per week over 5 to 6 weeks. Local boost irradiation to the tumor bed often is added to whole-breast irradiation to provide a higher dose of radiation at the site where recurrence most frequently occurs. For some patients, breast-conservation therapy also includes axillary lymph node dissection, sentinel lymph node biopsy, or irradiation of the axilla. A number of randomized, controlled trials have demonstrated that the addition of radiotherapy after breast-conserving surgery reduces recurrences and mortality. In an individual-level meta-analysis, the Early Breast Cancer Trialists Collaborative Group (EBCTCG 2005) reported 5-year risk of local recurrence of 7.3% among patients who received breast-conserving surgery and who were allocated to radiotherapy versus 25.9% among those not (2p< ; n=51,958 woman-years), for an absolute difference of 19 percentage points. Among women with node-negative disease, the 5-year risk for those not assigned to radiotherapy was 22.9% versus 6.7% for those receiving it (n=6,097 women). The corresponding percentages for node-positive disease are 41.1% versus 11.0% (n=1,214 women), respectively, for those without or with radiotherapy. While initial results did not find any effect of whole-breast irradiation on survival, longer follow-up has shown that postsurgical radiotherapy increases survival, as well as reducing the risk of local recurrence. The Early Breast Cancer Trialists Collaborative Group (2005) found that whole-breast irradiation reduced the 15-year breast cancer mortality risk from 35.9% to 30.5% (breast cancer death rate ratio: 0.83; SE: 0.05; 95% CI: 0.75, 0.91; 2p=0.0002; n=7,311 women); there was a similar reduction in mortality from all causes (5.3%, SE: 1.8; 2p=0.005). For women with node-negative disease, the 15-year mortality rate for those assigned to radiotherapy was 26.1% versus 31.2% for those not assigned to radiotherapy (logrank 2p=0.006); the corresponding numbers for patients with node-positive disease was 47.9% versus 55.0% (logrank 2p=0.01). Consequently, radiation therapy is generally recommended following breast-conserving surgery. A potential exception is for older women at low risk of recurrence. For example, the National Comprehensive Cancer Network (NCCN) guidelines (2010) state that women aged 70 years or older may omit radiotherapy if they have estrogen-receptor positive, T1 tumors. clinically negative lymph nodes, and plan to take adjuvant endocrine therapy. An article on use of lumpectomy and tamoxifen with or without whole-breast radiotherapy in this same population found that the addition of radiation had no impact on rates of mastectomy for local recurrence, distant metastases, or 5-year rates of overall survival (Hughes et al. 2004). However, the rate of local or regional recurrence at 5 years was 1% in the group receiving tamoxifen and radiation and 4% in the group taking tamoxifen alone (p<0.001). The authors concluded that Lumpectomy plus adjuvant therapy with tamoxifen alone is a realistic choice for the treatment of women 70 years of age or older who have early, estrogen-receptor-positive breast cancer. The primary outcome tracked in this Assessment, and in many of the studies of post-breast-conserving-surgery radiotherapy, is ipsilateral breast recurrence (IBR). Although other outcomes, such as survival and adverse events, are also important, IBR is an informative and pragmatic measure for the effectiveness of therapy. This outcome is also important to the patient, because recurrence leads to further treatment, often mastectomy, and predicts an increased risk of mortality. In addition, the duration of follow-up needed to measure ipsilateral breast recurrenceis substantially shorter than for mortality. The EBCTCG individual-level meta-analysis provides data on the pattern of recurrences among patients undergoing breast-conserving surgery with and without radiotherapy for over 10 years. In web figure 6a at ox.ac.uk/~ebctcg/local2000/annex.pdf, data on the percentage of patients per year with isolated 2010 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 7

8 Technology Evaluation Center local recurrence is 2.7% and 9.0% for those with and without whole-breast irradiation, respectively, in year 0; 1.5% and 4.8% in years 1 2; 1.1% and 3.7% in years 3 4; 0.8% and 1.9% in years 5 9; and 0.2% for both groups in years 10 and higher (trend χ² 1 =4.3, 2p=0.04). While the recurrence rate falls over time, it persists for more than 10 years. In the Owen et al. (2006) study described below, local recurrence was highest between years 3 to 5 of follow-up, and 67% of events took place in the first 5 years. However, that means that 33% of events took place after 5 years. For APBI, recurrence away from the tumor site is of greatest interest. Unfortunately, few articles report ipsilateral breast recurrence by year of follow-up and location near or away from the tumor site. One study (Recht et al. 1988) reported frequencies separately for ipsilateral breast recurrences classified as true relapses or marginal misses (TR/MM), and those that occurred elsewhere in the same breast that permit comparison for recurrences up to 5 years with those after 5 years. While elsewhere recurrences were relatively infrequent (total of 4%), three-fourths of these occurred after 5 years. Additional data on patterns of recurrences, by year of follow-up and location in the breast, can be found in the prior TEC Assessment on APBI (2007; Vol. 22, No. 4). The data presented in this Assessment and the prior Assessment indicate that 8 10 years of follow-up is needed to assess the impact of whole-breast versus alternative radiotherapy regimens on local recurrence after breast-conserving surgery. Most patients diagnosed with stage I or II breast cancer now are offered a choice of breastconserving therapy or modified radical mastectomy, but breast-conserving therapy is selected less often than expected. Studies have shown that those living furthest from treatment facilities are least likely to select breast-conserving therapy instead of mastectomy and most likely to forgo radiation therapy after breast-conserving surgery (Farrow et al. 1992; Athas et al. 2000; Nattinger et al. 2001). A study using data from the National Cancer Institute s Surveillance, Epidemiology, and End Results (SEER) tumor registries from 1992 to 2002 examined how many women with early stage (I or II) breast cancer received radiotherapy within 4 months following breast-conserving surgery (Du and Gor 2007). After adjusting for age, they found that in 2002, 30.8% of Caucasian women and 44.7% of African-American women had not received radiotherapy. Furthermore, these rates had increased from 24.7% for Caucasians and 34.0% for African Americans in Given that duration and logistics appear to be barriers to completion of treatment, there has been interest in developing shorter radiotherapy regimens. Two approaches have been explored. The first method is to provide the same dose to the whole breast in a shorter time by increasing the dose provided per treatment (hypofractionation). This approach was initially avoided out of concern that increasing doses to target the tumor more effectively might induce more severe adverse events from radiation exposure, thus, tipping the balance between benefits and harms. More recent research, some of which is highlighted below, has allayed some of these concerns. Accelerated whole-breast irradiation has been used especially in Canada and Europe. The second approach to reducing radiotherapy treatment time is accelerated partial-breast irradiation. It differs from conventional wholebreast irradiation in several ways. First, the radiation targets only the segment of the breast surrounding the area where the tumor was removed, rather than the entire breast. Second, the duration of treatment is 4 to 5 days rather than 5 to 6 weeks, because the radiation is delivered in fewer fractions at larger doses per fraction to the tumor bed. Third, the radiation dose is intrinsically less uniform within the target volume when APBI uses brachytherapy (i.e., the implantation of radioactive material directly in the breast tissue). The major types of radiotherapy used after breast-conserving surgery are outlined in Table 1. They differ in their techniques, instrumentation, dose delivery, and possibly in their outcomes. To appreciate the differences among radiotherapy techniques, it is useful to understand attributes of radiation delivery. The goals of cancer radiotherapy are usually to provide the tumor or tumor bed with a high dose of homogeneous radiation (e.g., all parts of the tumor cavity receive close to the targeted dose). Areas adjacent to the tumor may be treated with a lower dose of radiation (e.g., with whole-breast irradiation, to treat any unobserved cancerous lesions). Radiation outside the treatment area should be minimal or nonexistent. The goal is Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.

9 2010 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 9 Table 1. Major Types of Radiation Therapy Following Breast-Conserving Surgery Radiation Therapy Type Accelerated? Whole (W) or Partial (P) Breast External-beam (E) or Brachytherapy (B)? Approximate Duration of Treatment Published RCTs (length of follow-up in years) Conventional whole-breast irradiation N W E 5 6 weeks Multiple; >15 yrs Accelerated whole-breast irradiation Y W E 3 weeks 4; 10 yrs Interstitial APBI* Y P B 1 week 2; 5.4 years Balloon APBI** Y P B 1 week 0 External-beam APBI*** Y P E 1 week 0 Intraoperative APBI**** Y P Not applicable 1 day 0 * Interstitial brachytherapy entails placement of multiple hollow needles and catheters to guide placement of the radioactive material by a remote afterloading device. It is more difficult to perform than other types of brachytherapy and has a steep learning curve. ** Balloon brachytherapy, e.g., MammoSite, entails inserting a balloon into the tumor bed, inflating the balloon, confirming its position radiographically, and then using a remote afterloader to irradiate the targeted area. Some brachytherapy systems combine aspects of interstitial and balloon brachytherapy. *** External-beam APBI is delivered in the same way as conventional or accelerated whole-breast radiotherapy but to a smaller area. All 3 external-beam regimens can use three-dimensional, conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT). ****Intraoperative APBI is performed during breast-conserving surgery, when a single dose of radiation is delivered to the exposed tumor bed. Accelerated Radiotherapy After Breast-Conserving Surgery for Early Stage Breast Cancer

10 Technology Evaluation Center to target the tumor or adjacent areas at risk of harboring unseen cancer with an optimum dose, while avoiding healthy tissues. Relevant considerations in selecting a radiotherapy regimen for breast cancer following breastconserving surgery are as follows: 1. Is an optimal dose delivered to all of the tumor bed? Doses that are too low may elevate the risk of recurrence, while doses that are too high can increase toxic effects. 2. Should the rest of the breast, which may harbor unseen cancers, be treated? Not treating these cancers with radiotherapy may increase the number of recurrences, while not irradiating healthy tissue reduces toxic effects, improves cosmesis, and may even reduce the risk of subsequent cancers from the radiation itself. 3. How can the healthy tissues adjacent to the cancer best be protected, especially critical organs such as the lungs and heart (particularly for left-breast tumors)? Exposing these areas to higher levels of radiation may increase the risk of long-term complications. Guidelines and Recommendations According to the NCCN guidelines (2010), partial-breast irradiation should be performed only as part of a prospective trial and can be performed using brachytherapy or external-beam therapy (including three-dimensional, conformal radiation therapy [3D-CRT] or intensity-modulated radiation therapy [IMRT]). For patients not eligible for inclusion in a trial, partial-breast irradiation should only be performed for those with a low risk of recurrence. Intraoperative radiotherapy with a single dose can be performed at those institutions with the expertise and experience. For whole-breast radiotherapy, NCCN recommends either a conventional whole-breast irradiation regimen or a total dose of 42.5 Gy with 2.66 Gy per fraction, which equals 16 fractions. Although the NCCN guidelines do not specify the duration of treatment, the latter is presumably an accelerated whole-breast irradiation regimen. A boost to the tumor bed is recommended for higher risk whole-breast radiotherapy patients, i.e., those who are younger than 50 years old and have positive axillary nodes, lymphovascular invasion, or close margins. The American Society of Breast Surgeons and the American Society for Radiation Oncology (ASTRO) have issued guidelines for the selection of patients for APBI, which are summarized in Table 2. FDA Status The newer radiotherapy modalities presented in this Assessment have been approved or cleared for marketing by the U.S. Food and Drug Administration (FDA; see Appendix Table A). All brachytherapy devices have been approved through the 510(k) process and are either balloon brachytherapy or hybrid balloon-interstitial brachytherapy devices. The FDA has required a black box warning on each stating that The safety and effectiveness of the [brachytherapy device] as a replacement for whole breast irradiation in the treatment of breast cancer has not been established. In 2009, two malfunctions and 1 injury related to the SAVI was reported to the MAUDE (Manufacturer and User Facility Device Experience; scripts/cdrh/cfdocs/cfmaude/search.cfm) adverse event list; and 4 malfunctions and 3 injuries for MammoSite. None was found for the other devices. Methods Search Methods For accelerated whole-breast irradiation, papers had been identified in the previous Assessment (2007) and were supplemented by those identified in the recent California Technology Assessment Forum report on this technology (Tice 2009), as well as reference lists and review articles. For accelerated partial-breast irradiation, a MEDLINE search was performed using the same terms listed in the literature search cited in the consensus statement of the American Society of Radiation Oncology (Smith et al. 2009). Abbreviated searches to update the literature were performed in February Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.

11 2010 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 11 Table 2. Professional Medical Society Criteria for Performing APBI Categories Factor ASTRO Criteria: Suitable ASTRO Criteria: Cautionary ASTRO Criteria: Unsuitable Patient factors Age 60 years years <50 years 45 years BRCA1/2 mutation Not present Present Pathologic factors Tumor size 2 cm cm >3 cm 3 cm T stage T1 T0 or T2 T3-4 Criteria for APBI from American Society of Breast Surgeons Margins Negative 2 mm Close (<2 mm) Positive Microscopically negative Grade Any LVSI No Limited/focal Extensive ER status Positive Negative* Multicentricity Unicentric Present Multifocality Histology Clinically unifocal, total size 2.0 cm Invasive ductal or other favorable subtypes Clinically unifocal, total size= cm Invasive lobular Clinically multifocal or microscopically multifocal, total size 3 cm Pure DCIS Not allowed 3 cm >3 cm 3 cm EIC Not allowed 3 cm >3 cm Associated LCIS Allowed Nodal factors N stage pn0 (i, i + ) pn1, pn2, pn3 SN pn0 Nodal surgery SN Bx, ALND None performed Treatment factors Neoadjuvant therapy Not allowed If used Gray shading=not reported *Strongly encouraged to enroll in NSABP B-39/RTOG trial. Abbreviations DCIS: ductal carcinoma in situ; EIC: extensive intraductal component; ER status: estrogen receptor status; LCIS: lobular carcinoma in situ; LVSI: lymphovascular space invasion; N stage: nodal stage; T stage: tumor stage Sources: Smith et al [ASTRO criteria; see also Prosnitz et al. 2009]; American Society of Breast Surgeons Invasive ductal carcinoma or DCIS Accelerated Radiotherapy After Breast-Conserving Surgery for Early Stage Breast Cancer

12 Technology Evaluation Center Selection Criteria All comparative English-language articles in peer-reviewed journals on accelerated radiotherapy following breast-conserving surgery were included. Uncontrolled (i.e., single arm) studies were excluded, because indirect comparisons in this setting are not reliable. Initial patient differences may account for any perceived differences in treatments and cannot be controlled for adequately to ensure the validity of the conclusions. Abstracts were excluded, unless copies of the slide presentation used at a national professional meeting could be obtained or they provided follow-up data for a previously published comparative article that described the study in detail. Medical Advisory Panel Review This Assessment was reviewed by the Blue Cross and Blue Shield Association Medical Advisory Panel (MAP) on December 17, To maintain the timeliness of the Assessment s scientific information, literature search updates were performed subsequent to the Panel s review (see Search Methods ). If the search updates identified any additional studies that met the criteria for detailed review, the results of these studies were included in the tables and text where appropriate. Part I: Accelerated Whole-Breast Irradiation Formulation of the Assessment Patient Indications Relevant patients are those who select breastconserving surgery and radiation therapy for initial treatment of stage I or II breast cancer and are at low risk of local and regional recurrence. Technologies to be Compared Conventional whole-breast external-beam radiotherapy following breast-conserving surgery: It can be delivered in the form of photons (megavoltage X-rays or γ rays from a cobalt-60 source) or high-energy electrons (6 15 MeV) from a linear accelerator. It is usually given in fractions of Gy per day, 5 days weekly, with a total whole-breast irradiation dose of Gy and a boost dose of Gy when included. Accelerated, hypofractionated whole-breast external-beam radiotherapy following breastconserving therapy: The precise specifications vary, but it is generally given in fractions of Gy over the course of 3 weeks with a total whole-breast irradiation dose of Gy and a boost dose of Gy when included. Health Outcomes Benefits. The potential health benefits of accelerated whole-breast irradiation compared to whole-breast irradiation include a reduced number of treatments and a shorter duration of total treatment. These advantages may encourage adherence with the standard of care that women undergo radiation therapy following breast-conserving surgery, Harms. The potential harms associated with accelerated whole-breast irradiation compared to whole-breast irradiation are primarily increased toxicity from the higher doses of radiotherapy per treatment and a possibility of greater recurrence. In terms of duration of treatment, it is an intermediate option between whole-breast irradiation and APBI. Specific Assessment Question For women undergoing breast-conserving therapy, does accelerated whole-breast irradiation improve the net health outcome by at least as much as conventional whole-breast irradiation? Review of Evidence One means of accelerating radiotherapy following breast-conserving surgery is to increase the dose per treatment and reduce the total number of treatments. This option has been explored primarily in Canada and Europe. The challenge has been to identify the radiation dose per fraction that balances the impact of radiation on tumor control versus the rate of late adverse events (see, for example, Yarnold et al. 2005; START 2008a). The initial concern with breast radiotherapy was that treating a patient with more than 2 Gy per fraction (i.e., treatment episode) would lead to a steeper rise in late adverse events than in tumor control, thereby worsening outcomes. Some cancers, such as squamous cell carcinomas of the head and neck, are subject to this constraint, while higher doses per fraction may be tolerated for other cancers. The studies evaluating accelerated whole-breast radiotherapy have focused both on identifying the optimal dose per fraction and on comparing an accelerated whole-breast regimen to the traditional regimen. As a result, some studies have Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.

13 Accelerated Radiotherapy After Breast-Conserving Surgery for Early Stage Breast Cancer compared the use of fewer, higher dose fractions to the traditional regimen while keeping the duration of treatment constant, e.g., twenty-five 2-Gy fractions over 5 weeks versus thirteen 3-Gy fractions over 5 weeks. These studies demonstrate the impact of a larger fraction, while controlling for the duration of treatment. Others also reduce the duration of treatment for the accelerated regimen while increasing the dose per treatment, i.e., fifteen 2.67-Gy fractions over 3 weeks. While both types of studies are important, the latter are more directly applicable to assessing the use of an accelerated whole-breast regimen in clinical practice. Four randomized trials of accelerated whole-breast radiotherapy versus whole-breast irradiation have been published. Patients and health care providers were not blinded to treatment allocation, unless otherwise indicated. Two articles report on one trial (Yarnold et al. 2005; Owen et al. 2006). Two other trials (START 2008a, b) were part of the same larger effort in the U.K., and their design was based in part of the preliminary results of the first trial. Also, the tumor control data from the Yarnold et al. (2005) and Owen et al. (2006) study were incorporated into parts of the START A trial. The fourth trial was conducted in Canada (Whelan et al. 2002, 2010). The Canadian study and one of the British studies (START B) are particularly useful, as they directly compare a 5-week to a 3-week regimen. They are both prospectively designed noninferiority trials. Both trials were planned to accept a maximum loss of efficacy of 5 percentage points in the accelerated group (one-sided α = or 0.05). The key features and summary results of all of these studies, as well as a quasi-experimental comparative study conducted in 1999 (Yamada et al. 1999), are reported in Tables 3 and 4. Whelan et al. (2002, 2010) conducted a randomized trial of accelerated whole-breast irradiation versus whole-breast irradiation. Of 2,429 eligible patients, 51% agreed to participate in the trial. During the study, 20 of 1,234 patients did not complete the assigned treatment, but intention-to-treat analysis was used. The 5-year local recurrence rates were 2.8% (calculated by subtracting local-recurrence-free survival reported in paper from 100%) in the 42.5-Gy accelerated whole-breast irradiation arm versus 3.2% in the conventional wholebreast irradiation arm (difference: 0.4%; 95% CI: -1.5%, 2.4%). Local recurrence rates with 42.5-Gy accelerated whole-breast radiotherapy were not worse than conventional whole-breast irradiation, when applying a noninferiority margin of 5%. Data are presented on 5-year local recurrence by age, tumor size, and adjuvant systemic therapy. Results were reported by treatment group according to stratification factors. The largest absolute difference in recurrence between treatment arms was 3.6% (95% CI: -1.7 to 9.0) for patients younger than 50 years old (accelerated whole-breast irradiation, 3.6%; whole-breast irradiation, 7.2%). No statistically significant differences between treatment arms (using 2-sided log rank test) were found for disease-free survival (p=0.37) or overall survival (p=0.78). No statistically significant differences in cosmetic outcomes or adverse events are reported. An update of this study was published in 2010 (Whelan et al. 2010). The results reported on a median 144 months of follow-up. The 10-year local recurrence was 6.2% for the 42.5-Gy accelerated whole-breast irradiation arm and 6.7% for the conventional whole-breast irradiation arm (absolute difference: 0.5%; 95% CI: 2.5%, 3.5%). The percentage of patients with a good or excellent cosmetic outcome was 70% for accelerated whole-breast irradiation and 71% for whole-breast irradiation (absolute difference: 1.5%, 95% CI: 6.9%, 9.8%). At 10 years, 8.9% of accelerated whole-breast irradiation and 7.7% of whole-breast irradiation patients had Grade 2 or 3 late skin toxicity; 11.9% and 10.4%, respectively, had Grade 2 or 3 late subcutaneous tissue toxicity, although the sample size declined from 1,220 at baseline to 451 at 10 years. In exploratory subgroup analyses, treatment effects were similar by age, tumor size, estrogen-receptor status, and chemotherapy use. However, local recurrence at 10 years for patients with high-grade tumors was 4.7% for the conventional whole-breast irradiation arm and 15.6% for the 42.5-Gy accelerated wholebreast irradiation arm. The absolute difference equals 10.9 percentage points (95% CI: 19.1, 2.8, test for interaction, p=0.01). Strong points of the study design include randomization; histopathologic confirmation of local recurrence and, if possible, first recurrence at other sites; use of standardized instruments (European Organisation for Research and Treatment of Cancer [EORTC] Cosmetic Rating System and Radiation Therapy Oncology Group [RTOG]/EORTC late radiation morbidity scale); description of sample size calculations; small loss to follow-up (<5%); and intention-to-treat 2010 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 13