TY - JOUR
T1 - Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer
T2 - a randomised, phase 3, equivalence trial
AU - Vicini, Frank A.
AU - Cecchini, Reena S.
AU - White, Julia R.
AU - Arthur, Douglas W.
AU - Julian, Thomas B.
AU - Rabinovitch, Rachel A.
AU - Kuske, Robert R.
AU - Ganz, Patricia A.
AU - Parda, David S.
AU - Scheier, Michael F.
AU - Winter, Kathryn A.
AU - Paik, Soonmyung
AU - Kuerer, Henry M.
AU - Vallow, Laura A.
AU - Pierce, Lori J.
AU - Mamounas, Eleftherios P.
AU - McCormick, Beryl
AU - Costantino, Joseph P.
AU - Bear, Harry D.
AU - Germain, Isabelle
AU - Gustafson, Gregory
AU - Grossheim, Linda
AU - Petersen, Ivy A.
AU - Hudes, Richard S.
AU - Curran, Walter J.
AU - Bryant, John L.
AU - Wolmark, Norman
N1 - Funding Information:
This trial was funded by the NCI, Department of Health and Human Services, Public Health Service Grants U10-CA-180868, U10-CA-180822, UG1-CA-189867, and U24-CA-19067.
Funding Information:
FAV reports consultancy fees from ImpediMed, outside the submitted work, and is an employee of the MHP Radiation Oncology Institute. JRW reports a grant to her institution from IntraOp Medical, which supports a separate clinical trial (OSU 16106), and support for travel from IBA and Qfix, outside the submitted work. RRK reports an unrestricted educational and research grant from Elekta for an interstitial brachytherapy collaborative clinical research study (PROMIS), and minor stock options with Cianna Medical. PAG reports grants from the US National Cancer Institute (NCI), outside the submitted work. KAW reports grants from NCI for NRG Oncology/Radiation Therapy Oncology Group, in support of the submitted work. SP reports consultancy fees from MedPacto to his institution, patents related to Oncotype Dx (all rights transferred to NSABP Foundation), and stock options with ImmuneOncia Therapeutics and Novomics. HMK serves on the advisory boards of Genomic Health, Cardinal Health, and Targeted Medical Education, and has received consultancy fees and grants to his institution from Genomic Health. He is an employee of the New England Journal of Medicine group, and has received an honorarium from Physicians' Education Resources, and editorial royalties from McGraw-Hill Professional and UpToDate. LJP reports a patent pending with PFS Genomics. JPC reports grants from NCI, during the conduct of the study. EPM serves on the advisory boards of Genomic Health, Genentech, Roche, Biotheranostics, and Daiichi Sankyo, is a consultant for Merck, and is a member of the Speaker's Bureau with Genentech, Roche, and Genomic Health. HDB sits on the Breast Advisory Board of Merck, is a consultant and lectures with the Speakers' Bureau of Genomic Health, and has stock with AbbVie and Pfizer, outside the submitted work; and reports grants from the US National Institutes of Health, including support for travel, during the conduct of the study. WJC Jr is a consultant with Bristol-Myers Squibb and is a member of data monitoring committees with AstraZeneca. All other authors declare no competing interests.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/12/14
Y1 - 2019/12/14
N2 - Background: Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation. Methods: We did this randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413) in 154 clinical centres in the USA, Canada, Ireland, and Israel. Adult women (>18 years) with early-stage (0, I, or II; no evidence of distant metastases, but up to three axillary nodes could be positive) breast cancer (tumour size ≤3 cm; including all histologies and multifocal breast cancers), who had had lumpectomy with negative (ie, no detectable cancer cells) surgical margins, were randomly assigned (1:1) using a biased-coin-based minimisation algorithm to receive either whole-breast irradiation (whole-breast irradiation group) or APBI (APBI group). Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumour bed, and APBI was delivered as 34 Gy of brachytherapy or 38·5 Gy of external bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period. Randomisation was stratified by disease stage, menopausal status, hormone-receptor status, and intention to receive chemotherapy. Patients, investigators, and statisticians could not be masked to treatment allocation. The primary outcome of invasive and non-invasive IBTR as a first recurrence was analysed in the intention-to-treat population, excluding those patients who were lost to follow-up, with an equivalency test on the basis of a 50% margin increase in the hazard ratio (90% CI for the observed HR between 0·667 and 1·5 for equivalence) and a Cox proportional hazard model. Survival was assessed by intention to treat, and sensitivity analyses were done in the per-protocol population. This trial is registered with ClinicalTrials.gov, NCT00103181. Findings: Between March 21, 2005, and April 16, 2013, 4216 women were enrolled. 2109 were assigned to the whole-breast irradiation group and 2107 were assigned to the APBI group. 70 patients from the whole-breast irradiation group and 14 from the APBI group withdrew consent or were lost to follow-up at this stage, so 2039 and 2093 patients respectively were available for survival analysis. Further, three and four patients respectively were lost to clinical follow-up (ie, survival status was assessed by phone but no physical examination was done), leaving 2036 patients in the whole-breast irradiation group and 2089 in the APBI group evaluable for the primary outcome. At a median follow-up of 10·2 years (IQR 7·5–11·5), 90 (4%) of 2089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2036 women in the whole-breast irradiation group had an IBTR (HR 1·22, 90% CI 0·94–1·58). The 10-year cumulative incidence of IBTR was 4·6% (95% CI 3·7–5·7) in the APBI group versus 3·9% (3·1–5·0) in the whole-breast irradiation group. 44 (2%) of 2039 patients in the whole-breast irradiation group and 49 (2%) of 2093 patients in the APBI group died from recurring breast cancer. There were no treatment-related deaths. Second cancers and treatment-related toxicities were similar between the two groups. 2020 patients in the whole-breast irradiation group and 2089 in APBI group had available data on adverse events. The highest toxicity grade reported was: grade 1 in 845 (40%), grade 2 in 921 (44%), and grade 3 in 201 (10%) patients in the APBI group, compared with grade 1 in 626 (31%), grade 2 in 1193 (59%), and grade 3 in 143 (7%) in the whole-breast irradiation group. Interpretation: APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR for breast-conserving therapy. Our trial had broad eligibility criteria, leading to a large, heterogeneous pool of patients and sufficient power to detect treatment equivalence, but was not designed to test equivalence in patient subgroups or outcomes from different APBI techniques. For patients with early-stage breast cancer, our findings support whole-breast irradiation following lumpectomy; however, with an absolute difference of less than 1% in the 10-year cumulative incidence of IBTR, APBI might be an acceptable alternative for some women. Funding: National Cancer Institute, US Department of Health and Human Services.
AB - Background: Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation. Methods: We did this randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413) in 154 clinical centres in the USA, Canada, Ireland, and Israel. Adult women (>18 years) with early-stage (0, I, or II; no evidence of distant metastases, but up to three axillary nodes could be positive) breast cancer (tumour size ≤3 cm; including all histologies and multifocal breast cancers), who had had lumpectomy with negative (ie, no detectable cancer cells) surgical margins, were randomly assigned (1:1) using a biased-coin-based minimisation algorithm to receive either whole-breast irradiation (whole-breast irradiation group) or APBI (APBI group). Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumour bed, and APBI was delivered as 34 Gy of brachytherapy or 38·5 Gy of external bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period. Randomisation was stratified by disease stage, menopausal status, hormone-receptor status, and intention to receive chemotherapy. Patients, investigators, and statisticians could not be masked to treatment allocation. The primary outcome of invasive and non-invasive IBTR as a first recurrence was analysed in the intention-to-treat population, excluding those patients who were lost to follow-up, with an equivalency test on the basis of a 50% margin increase in the hazard ratio (90% CI for the observed HR between 0·667 and 1·5 for equivalence) and a Cox proportional hazard model. Survival was assessed by intention to treat, and sensitivity analyses were done in the per-protocol population. This trial is registered with ClinicalTrials.gov, NCT00103181. Findings: Between March 21, 2005, and April 16, 2013, 4216 women were enrolled. 2109 were assigned to the whole-breast irradiation group and 2107 were assigned to the APBI group. 70 patients from the whole-breast irradiation group and 14 from the APBI group withdrew consent or were lost to follow-up at this stage, so 2039 and 2093 patients respectively were available for survival analysis. Further, three and four patients respectively were lost to clinical follow-up (ie, survival status was assessed by phone but no physical examination was done), leaving 2036 patients in the whole-breast irradiation group and 2089 in the APBI group evaluable for the primary outcome. At a median follow-up of 10·2 years (IQR 7·5–11·5), 90 (4%) of 2089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2036 women in the whole-breast irradiation group had an IBTR (HR 1·22, 90% CI 0·94–1·58). The 10-year cumulative incidence of IBTR was 4·6% (95% CI 3·7–5·7) in the APBI group versus 3·9% (3·1–5·0) in the whole-breast irradiation group. 44 (2%) of 2039 patients in the whole-breast irradiation group and 49 (2%) of 2093 patients in the APBI group died from recurring breast cancer. There were no treatment-related deaths. Second cancers and treatment-related toxicities were similar between the two groups. 2020 patients in the whole-breast irradiation group and 2089 in APBI group had available data on adverse events. The highest toxicity grade reported was: grade 1 in 845 (40%), grade 2 in 921 (44%), and grade 3 in 201 (10%) patients in the APBI group, compared with grade 1 in 626 (31%), grade 2 in 1193 (59%), and grade 3 in 143 (7%) in the whole-breast irradiation group. Interpretation: APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR for breast-conserving therapy. Our trial had broad eligibility criteria, leading to a large, heterogeneous pool of patients and sufficient power to detect treatment equivalence, but was not designed to test equivalence in patient subgroups or outcomes from different APBI techniques. For patients with early-stage breast cancer, our findings support whole-breast irradiation following lumpectomy; however, with an absolute difference of less than 1% in the 10-year cumulative incidence of IBTR, APBI might be an acceptable alternative for some women. Funding: National Cancer Institute, US Department of Health and Human Services.
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U2 - 10.1016/S0140-6736(19)32514-0
DO - 10.1016/S0140-6736(19)32514-0
M3 - Article
C2 - 31813636
AN - SCOPUS:85076132594
SN - 0140-6736
VL - 394
SP - 2155
EP - 2164
JO - The Lancet
JF - The Lancet
IS - 10215
ER -