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Accelerated Partial-Breast Irradiation: Trial by Media or by Science?
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Editorial
Accelerated Partial-Breast Irradiation: Trial by Media or by Science? Laurie W. Cuttino, M.D.,* Julia R. White, M.D.,y Rachel Rabinovitch, M.D.,z David A. Gewirtz, Ph.D.,* Mitchell S. Anscher, M.D.,* David E. Wazer, M.D.,x,k Frank A. Vicini, M.D.,{ Thomas B. Julian, M.D.,# and Douglas W. Arthur, M.D.* *Virginia Commonwealth University, Richmond, Virginia; yOhio State University, Columbus, Ohio; zUniversity of Colorado, Denver, Colorado; xTufts University, Boston, Massachusetts; kBrown University, Providence, Rhode Island; {Michigan Healthcare Professionals/21st Century Oncology, Royal Oak, Michigan; and #Drexel University College of Medicine/ Allegheny General Hospital, Pittsburgh, Pennsylvania Received Feb 21, 2012, and in revised form Feb 21, 2012. Accepted for publication Feb 29, 2012 On December 7, 2011, investigators from The University of Texas MD Anderson Cancer Center (MDACC) presented an abstract, “Partial Breast Brachytherapy Is Associated with Inferior Effectiveness and Increased Toxicity Compared with Whole Breast Radiation in Older Patients,” at the San Antonio Breast Symposium. This retrospective analysis is based on the Surveillance, Epidemiology, and End Results (SEER)-Medicare combined database. The authors reported a small but statistically significant increase of 1.8% in the rate of mastectomies as well as increased toxicity after treatment with breast brachytherapy (BB) for accelerated partial-breast irradiation (APBI) compared with whole-breast irradiation (WBI). On the basis of these findings and despite being presented only in abstract form, the authors concluded that BB “was associated with inferior effectiveness as well as increased acute and late toxicities compared with WBI in this cohort of older breast cancer patients.” The conclusions of this abstract generated tremendous attention in the lay press and have raised concern about APBI in both clinicians and patients. In response, we will compare and contrast the results of this abstract with representative publications on APBI and review the evidence-based patient selection guidelines that have been generated by the American Society for Radiation Oncology (ASTRO). The MDACC abstract describes a retrospective analysis of 130,535 women aged 67 years with invasive breast cancer diagnosed during the period 2000-2007 and treated with lumpectomy followed by either WBI or BB. A total of 123,244 patients (94%) were treated with WBI, and 7291 patients (6%) were
treated with BB. Patients treated with BB were less likely to have axillary lymph node involvement or to have received chemotherapy and were more likely to be older, white, and have comorbid illness. Median follow-up was 3.84 years. Cumulative incidence of subsequent mastectomy was compared between the 2 treatment groups using the log-rank test. Adjusted risk of subsequent mastectomy was determined using a multivariate Cox proportional hazards model including demographic, socioeconomic, and clinical covariates. A total of 2335 billing codes for mastectomy were recorded after treatment with WBI, and 177 were recorded after BB. This is a 5-year cumulative incidence of mastectomy of 2.2% in patients treated with WBI and 4% in patients treated with BB (P<.001), an absolute difference of 1.8%. On multivariate analysis, there was a 2-fold increased risk for subsequent mastectomy in patients treated with BB (hazard ratio 2.22; 95% confidence interval [CI] 1.89-2.61; P<.001). Risks of acute complications as defined by hospitalization or infection within 120 days of radiation were compared using the c2 test. Breast brachytherapy was associated with a higher risk of hospitalization (9.6% vs 5.7%; P<.001) (adjusted odds ratio 1.71; 95% CI 1.58-1.86) and infection (8.1% vs 4.5%; P<.001) (adjusted odds ratio 1.85; 95% CI 1.69-2.02; P<.001) compared with WBI. Breast brachytherapy was also associated with a significantly higher 5-year cumulative incidence of rib fracture (4.2% vs 3.6%), fat necrosis (9.1% vs 3.7%), and breast pain (14.9% vs 11.7%) but a lower incidence of pneumonitis (0.1% vs 0.8%) compared with WBI.
Reprint requests to: Laurie W. Cuttino, MD, Virginia Commonwealth University Health System, Department of Radiation Oncology, 401
College St, P.O. Box 980058, Richmond, Virginia 23298. Tel: (804) 2874340; Fax: (804) 287-4314; E-mail: [email protected] Conflict of interest: D.E.W. is a consultant for ART, Inc.
Int J Radiation Oncol Biol Phys, Vol. 83, No. 4, pp. 1075e1077, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2012.02.059
1076 Cuttino et al.
International Journal of Radiation Oncology Biology Physics
We believe there are a number of significant limitations inherent in large observational database methodology that challenge the validity of the conclusions made regarding treatment efficacy for BB APBI. Examples of just some of these limitations include the use of surrogate metrics, treatment era bias, the retrospective nature of the analysis, selection bias, and incomplete treatment data. In the absence of outcome data, the authors have used billing codes as a surrogate for clinical events. The use of mastectomy as a surrogate indicator for in-breast cancer recurrence adds a significant degree of uncertainty owing to its unknown accuracy as a reliable measure. As an example of the inherent problem, we can look further at events other than in-breast recurrence that can be labeled by the same mastectomy codes. Patients may be coded as mastectomy after a contralateral breast cancer, the diagnosis of a BRCA mutation, elective mastectomy, or other indications unrelated to treatment failure. We also must appreciate that the patients included in this study were treated between 2002 and 2007. The initial singlelumen balloon breast brachytherapy system for APBI was first approved by the US Food and Drug Administration in 2002. Therefore, patients in this SEER-Medicare data-based study likely reflect the outcome from early adopters of the technology. At that time patient selection criteria had not been clearly established, and dosimetric planning was largely 2-dimensional. Three-dimensional computed tomography-based treatmentplanning systems were only in the early stages of introduction into common use. In fact, it was not until the opening of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B39/Radiation Therapy Oncology Group (RTOG) 0413 phase III clinical trial comparing APBI with WBI in 2005 that clear and comprehensive dosimetric goals and guidelines were established. In the SEER-Medicare database, no information regarding proper dose delivery is available. Thus, it is impossible to judge the quality of BB represented, which can have crucial implications for efficacy and toxicity. A critical piece of missing information in the MDACC abstract is patient selection criteria. As a retrospective analysis, it is subject to the selection bias inherent to any study of this design. Other investigators have demonstrated the pitfalls of using large observational databases to evaluate efficacy of cancer therapy, given the subjectivity of selection criteria that can significantly affect analysis (1). In this abstract, the impact of selection bias is further complicated by incomplete treatment data. Patient selection criteria for APBI have been the subject of a long and continued debate. To address this, ASTRO formed an expert panel to generate evidence-based patient selection guidelines for APBI in 2009. Recommendations were based on the results of a systematic literature review and were supplemented by expert opinion (2). In the process of development, 4 published randomized clinical trials and 38 prospective single-arm studies were reviewed. The ASTRO guidelines divided selection criteria for APBI outside a clinical trial into 3 groups: suitable, cautionary, and unsuitable. Selection criteria that fell into the cautionary or unsuitable groups had less frequently been studied and as a result had limited outcome data in the existing literature. It was recommended that cases with cautionary and unsuitable selection criteria be treated with APBI on a clinical trial. Because all the patients in the SEER-Medicare abstract were treated before the generation of these guidelines, it is not possible to judge whether the reported increased rate of mastectomy is a result of inappropriate patient selection for APBI during the period
investigated or rather the result of APBI in general, as suggested by the authors. We believe it should be emphasized to reassure patients and physicians that BB APBI has nearly 2 decades of evidence in the literature supporting its use in appropriately selected and treated patients. For example, results from multi-institution cooperative group trials have been published by RTOG (95-17) and GermanAustrian groups, demonstrating 5-year local recurrence rates of 3% and 2%, respectively, with the use of multicatheter BB for APBI (3, 4). The American Society of Breast Surgeons (ASBS) Mammosite Registry is an observational database of 1440 earlystage breast cancer patients from 97 institutions treated with single-lumen balloon brachytherapy during the period 2002-2004, an era contemporary to the MDACC abstract. With a median follow-up of 54 months, there have been 37 cases (2.6%) of in-breast recurrence (5). The abstract’s focus on the potential toxicity of BB APBI is commended because it is an important concern with the integration of newer technology. The incidence of breast infection in the ASBS Mammosite registry is 9.6%, compared with the 8.5% reported in the SEER-Medicare abstract. An analysis of 483 patients treated with single-lumen BB at 9 institutions similarly reported a 9% incidence of infection overall. With improvements in technique, the risk of infection with BB has been reduced over time. When balloon devices are placed after the time of lumpectomy, as is now the standard of care, the incidence of infection is 4.8% (6). The MDACC abstract reported a rate of fat necrosis of 7.3%, compared with only 2.6% of patients in the ASBS Mammosite registry trial (7). Most importantly, the Data Safety and Monitoring Board for NSABP B-39/RTOG 0413 has yet to encounter any notable toxicity associated with APBI as compared with WBI (personal communication, T. Julian, protocol officer for NSABP B-39/RTOG 0413, Feb 16, 2012). In closing, the efficacy of APBI in comparison with WBI is best answered by randomized phase III clinical trials. The NSABP B39/RT0G 0413 trial is nearing its accrual goal but needs the support of physicians and patients to reach completion. We encourage enrollment on available clinical trials to solidify and expand our understanding of APBI, or treatment selection based on the ASTRO evidence-based guidelines for APBI for offprotocol application. We caution against the use of large observational databases for assessment of BB APBI treatment efficacy in which the majority of essential patient, treatment, and outcome parameters are unknown. This abstract provides little meaningful information, in contrast to the results of many carefully performed prospective clinical trials of APBI accumulated over 20 years. In particular, we believe this abstract should be interpreted in the proper context of the entire APBI experience, to avoid undermining trial accrual and to avoid an unnecessary and improper reaction from the lay press and from the radiation oncology community.
References 1. Giordano SH, Kuo YF, Duan Z, et al. Limits of observational data in determining outcomes from cancer therapy. Cancer 2008;112:2456-2466. 2. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009;74: 987-1001.
Volume 83 Number 4 2012 3. Arthur DW, Winter K, Kuske RR, et al. A Phase II trial of brachytherapy alone after lumpectomy for select breast cancer: tumor control and survival outcomes of RTOG 95-17. Int J Radiat Oncol Biol Phys 2008;72:467-473. 4. Strnad V, Hildebrandt G, Potter R, et al. Accelerated partial breast irradiation: 5-year results of the German-Austrian multicenter phase II trial using interstitial multicatheter brachytherapy alone after breastconserving surgery. Int J Radiat Oncol Biol Phys 2011;80:17-24. 5. Vicini F, Beitsch P, Quiet C, et al. Five-year analysis of treatment efficacy and cosmesis by the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry Trial in patients treated
Editorial response to MDACC APBI abstract 1077 with accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2011;79:808-817. 6. Cuttino LW, Keisch M, Jenrette JM, et al. Multi-institutional experience using the MammoSite radiation therapy system in the treatment of early-stage breast cancer: 2-year results. Int J Radiat Oncol Biol Phys 2008;71:107-114. 7. Khan A, Arthur D, Vicini F, et al. Six-year analysis of treatment-related toxicities in patients treated with accelerated partial breast irradiation on the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry Trial. Ann Surg Oncol. 2011 Nov 23. [Epub ahead of print].
Radiation Oncology biology
physics
www.redjournal.org
Editorial
Accelerated Partial-Breast Irradiation: Trial by Media or by Science? Laurie W. Cuttino, M.D.,* Julia R. White, M.D.,y Rachel Rabinovitch, M.D.,z David A. Gewirtz, Ph.D.,* Mitchell S. Anscher, M.D.,* David E. Wazer, M.D.,x,k Frank A. Vicini, M.D.,{ Thomas B. Julian, M.D.,# and Douglas W. Arthur, M.D.* *Virginia Commonwealth University, Richmond, Virginia; yOhio State University, Columbus, Ohio; zUniversity of Colorado, Denver, Colorado; xTufts University, Boston, Massachusetts; kBrown University, Providence, Rhode Island; {Michigan Healthcare Professionals/21st Century Oncology, Royal Oak, Michigan; and #Drexel University College of Medicine/ Allegheny General Hospital, Pittsburgh, Pennsylvania Received Feb 21, 2012, and in revised form Feb 21, 2012. Accepted for publication Feb 29, 2012 On December 7, 2011, investigators from The University of Texas MD Anderson Cancer Center (MDACC) presented an abstract, “Partial Breast Brachytherapy Is Associated with Inferior Effectiveness and Increased Toxicity Compared with Whole Breast Radiation in Older Patients,” at the San Antonio Breast Symposium. This retrospective analysis is based on the Surveillance, Epidemiology, and End Results (SEER)-Medicare combined database. The authors reported a small but statistically significant increase of 1.8% in the rate of mastectomies as well as increased toxicity after treatment with breast brachytherapy (BB) for accelerated partial-breast irradiation (APBI) compared with whole-breast irradiation (WBI). On the basis of these findings and despite being presented only in abstract form, the authors concluded that BB “was associated with inferior effectiveness as well as increased acute and late toxicities compared with WBI in this cohort of older breast cancer patients.” The conclusions of this abstract generated tremendous attention in the lay press and have raised concern about APBI in both clinicians and patients. In response, we will compare and contrast the results of this abstract with representative publications on APBI and review the evidence-based patient selection guidelines that have been generated by the American Society for Radiation Oncology (ASTRO). The MDACC abstract describes a retrospective analysis of 130,535 women aged 67 years with invasive breast cancer diagnosed during the period 2000-2007 and treated with lumpectomy followed by either WBI or BB. A total of 123,244 patients (94%) were treated with WBI, and 7291 patients (6%) were
treated with BB. Patients treated with BB were less likely to have axillary lymph node involvement or to have received chemotherapy and were more likely to be older, white, and have comorbid illness. Median follow-up was 3.84 years. Cumulative incidence of subsequent mastectomy was compared between the 2 treatment groups using the log-rank test. Adjusted risk of subsequent mastectomy was determined using a multivariate Cox proportional hazards model including demographic, socioeconomic, and clinical covariates. A total of 2335 billing codes for mastectomy were recorded after treatment with WBI, and 177 were recorded after BB. This is a 5-year cumulative incidence of mastectomy of 2.2% in patients treated with WBI and 4% in patients treated with BB (P<.001), an absolute difference of 1.8%. On multivariate analysis, there was a 2-fold increased risk for subsequent mastectomy in patients treated with BB (hazard ratio 2.22; 95% confidence interval [CI] 1.89-2.61; P<.001). Risks of acute complications as defined by hospitalization or infection within 120 days of radiation were compared using the c2 test. Breast brachytherapy was associated with a higher risk of hospitalization (9.6% vs 5.7%; P<.001) (adjusted odds ratio 1.71; 95% CI 1.58-1.86) and infection (8.1% vs 4.5%; P<.001) (adjusted odds ratio 1.85; 95% CI 1.69-2.02; P<.001) compared with WBI. Breast brachytherapy was also associated with a significantly higher 5-year cumulative incidence of rib fracture (4.2% vs 3.6%), fat necrosis (9.1% vs 3.7%), and breast pain (14.9% vs 11.7%) but a lower incidence of pneumonitis (0.1% vs 0.8%) compared with WBI.
Reprint requests to: Laurie W. Cuttino, MD, Virginia Commonwealth University Health System, Department of Radiation Oncology, 401
College St, P.O. Box 980058, Richmond, Virginia 23298. Tel: (804) 2874340; Fax: (804) 287-4314; E-mail: [email protected] Conflict of interest: D.E.W. is a consultant for ART, Inc.
Int J Radiation Oncol Biol Phys, Vol. 83, No. 4, pp. 1075e1077, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2012.02.059
1076 Cuttino et al.
International Journal of Radiation Oncology Biology Physics
We believe there are a number of significant limitations inherent in large observational database methodology that challenge the validity of the conclusions made regarding treatment efficacy for BB APBI. Examples of just some of these limitations include the use of surrogate metrics, treatment era bias, the retrospective nature of the analysis, selection bias, and incomplete treatment data. In the absence of outcome data, the authors have used billing codes as a surrogate for clinical events. The use of mastectomy as a surrogate indicator for in-breast cancer recurrence adds a significant degree of uncertainty owing to its unknown accuracy as a reliable measure. As an example of the inherent problem, we can look further at events other than in-breast recurrence that can be labeled by the same mastectomy codes. Patients may be coded as mastectomy after a contralateral breast cancer, the diagnosis of a BRCA mutation, elective mastectomy, or other indications unrelated to treatment failure. We also must appreciate that the patients included in this study were treated between 2002 and 2007. The initial singlelumen balloon breast brachytherapy system for APBI was first approved by the US Food and Drug Administration in 2002. Therefore, patients in this SEER-Medicare data-based study likely reflect the outcome from early adopters of the technology. At that time patient selection criteria had not been clearly established, and dosimetric planning was largely 2-dimensional. Three-dimensional computed tomography-based treatmentplanning systems were only in the early stages of introduction into common use. In fact, it was not until the opening of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B39/Radiation Therapy Oncology Group (RTOG) 0413 phase III clinical trial comparing APBI with WBI in 2005 that clear and comprehensive dosimetric goals and guidelines were established. In the SEER-Medicare database, no information regarding proper dose delivery is available. Thus, it is impossible to judge the quality of BB represented, which can have crucial implications for efficacy and toxicity. A critical piece of missing information in the MDACC abstract is patient selection criteria. As a retrospective analysis, it is subject to the selection bias inherent to any study of this design. Other investigators have demonstrated the pitfalls of using large observational databases to evaluate efficacy of cancer therapy, given the subjectivity of selection criteria that can significantly affect analysis (1). In this abstract, the impact of selection bias is further complicated by incomplete treatment data. Patient selection criteria for APBI have been the subject of a long and continued debate. To address this, ASTRO formed an expert panel to generate evidence-based patient selection guidelines for APBI in 2009. Recommendations were based on the results of a systematic literature review and were supplemented by expert opinion (2). In the process of development, 4 published randomized clinical trials and 38 prospective single-arm studies were reviewed. The ASTRO guidelines divided selection criteria for APBI outside a clinical trial into 3 groups: suitable, cautionary, and unsuitable. Selection criteria that fell into the cautionary or unsuitable groups had less frequently been studied and as a result had limited outcome data in the existing literature. It was recommended that cases with cautionary and unsuitable selection criteria be treated with APBI on a clinical trial. Because all the patients in the SEER-Medicare abstract were treated before the generation of these guidelines, it is not possible to judge whether the reported increased rate of mastectomy is a result of inappropriate patient selection for APBI during the period
investigated or rather the result of APBI in general, as suggested by the authors. We believe it should be emphasized to reassure patients and physicians that BB APBI has nearly 2 decades of evidence in the literature supporting its use in appropriately selected and treated patients. For example, results from multi-institution cooperative group trials have been published by RTOG (95-17) and GermanAustrian groups, demonstrating 5-year local recurrence rates of 3% and 2%, respectively, with the use of multicatheter BB for APBI (3, 4). The American Society of Breast Surgeons (ASBS) Mammosite Registry is an observational database of 1440 earlystage breast cancer patients from 97 institutions treated with single-lumen balloon brachytherapy during the period 2002-2004, an era contemporary to the MDACC abstract. With a median follow-up of 54 months, there have been 37 cases (2.6%) of in-breast recurrence (5). The abstract’s focus on the potential toxicity of BB APBI is commended because it is an important concern with the integration of newer technology. The incidence of breast infection in the ASBS Mammosite registry is 9.6%, compared with the 8.5% reported in the SEER-Medicare abstract. An analysis of 483 patients treated with single-lumen BB at 9 institutions similarly reported a 9% incidence of infection overall. With improvements in technique, the risk of infection with BB has been reduced over time. When balloon devices are placed after the time of lumpectomy, as is now the standard of care, the incidence of infection is 4.8% (6). The MDACC abstract reported a rate of fat necrosis of 7.3%, compared with only 2.6% of patients in the ASBS Mammosite registry trial (7). Most importantly, the Data Safety and Monitoring Board for NSABP B-39/RTOG 0413 has yet to encounter any notable toxicity associated with APBI as compared with WBI (personal communication, T. Julian, protocol officer for NSABP B-39/RTOG 0413, Feb 16, 2012). In closing, the efficacy of APBI in comparison with WBI is best answered by randomized phase III clinical trials. The NSABP B39/RT0G 0413 trial is nearing its accrual goal but needs the support of physicians and patients to reach completion. We encourage enrollment on available clinical trials to solidify and expand our understanding of APBI, or treatment selection based on the ASTRO evidence-based guidelines for APBI for offprotocol application. We caution against the use of large observational databases for assessment of BB APBI treatment efficacy in which the majority of essential patient, treatment, and outcome parameters are unknown. This abstract provides little meaningful information, in contrast to the results of many carefully performed prospective clinical trials of APBI accumulated over 20 years. In particular, we believe this abstract should be interpreted in the proper context of the entire APBI experience, to avoid undermining trial accrual and to avoid an unnecessary and improper reaction from the lay press and from the radiation oncology community.
References 1. Giordano SH, Kuo YF, Duan Z, et al. Limits of observational data in determining outcomes from cancer therapy. Cancer 2008;112:2456-2466. 2. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009;74: 987-1001.
Volume 83 Number 4 2012 3. Arthur DW, Winter K, Kuske RR, et al. A Phase II trial of brachytherapy alone after lumpectomy for select breast cancer: tumor control and survival outcomes of RTOG 95-17. Int J Radiat Oncol Biol Phys 2008;72:467-473. 4. Strnad V, Hildebrandt G, Potter R, et al. Accelerated partial breast irradiation: 5-year results of the German-Austrian multicenter phase II trial using interstitial multicatheter brachytherapy alone after breastconserving surgery. Int J Radiat Oncol Biol Phys 2011;80:17-24. 5. Vicini F, Beitsch P, Quiet C, et al. Five-year analysis of treatment efficacy and cosmesis by the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry Trial in patients treated
Editorial response to MDACC APBI abstract 1077 with accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2011;79:808-817. 6. Cuttino LW, Keisch M, Jenrette JM, et al. Multi-institutional experience using the MammoSite radiation therapy system in the treatment of early-stage breast cancer: 2-year results. Int J Radiat Oncol Biol Phys 2008;71:107-114. 7. Khan A, Arthur D, Vicini F, et al. Six-year analysis of treatment-related toxicities in patients treated with accelerated partial breast irradiation on the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry Trial. Ann Surg Oncol. 2011 Nov 23. [Epub ahead of print].