Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2155-2164 |
| Number of pages | 10 |
| Journal | The Lancet |
| Volume | 394 |
| Issue number | 10215 |
| DOIs | |
| State | Published - Dec 14 2019 |
ASJC Scopus subject areas
- Medicine(all)
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Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer : a randomised, phase 3, equivalence trial. / Vicini, Frank A.; Cecchini, Reena S.; White, Julia R.; Arthur, Douglas W.; Julian, Thomas B.; Rabinovitch, Rachel A.; Kuske, Robert R.; Ganz, Patricia A.; Parda, David S.; Scheier, Michael F.; Winter, Kathryn A.; Paik, Soonmyung; Kuerer, Henry M.; Vallow, Laura A.; Pierce, Lori J.; Mamounas, Eleftherios P.; McCormick, Beryl; Costantino, Joseph P.; Bear, Harry D.; Germain, Isabelle; Gustafson, Gregory; Grossheim, Linda; Petersen, Ivy A.; Hudes, Richard S.; Curran, Walter J.; Bryant, John L.; Wolmark, Norman.
In: The Lancet, Vol. 394, No. 10215, 14.12.2019, p. 2155-2164.Research output: Contribution to journal › Article › peer-review
}
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: In this trial, we investigated whether a several-day course of radiotherapy (APBI) to the surgical cavity region was equivalent to several weeks of radiotherapy to the entire breast (whole-breast irradiation) in preventing IBTR after lumpectomy for patients with early-stage breast cancer. APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR on the basis of the upper limit of the hazard ratio's CI. However, the absolute difference in the 10-year cumulative incidence of IBTR was less than 1%. The risk of a recurrence-free interval event was significantly higher for APBI than whole-breast irradiation but the absolute difference between 10-year recurrence-free estimates was also small (<1·6%). Distant disease-free interval, overall survival, and disease-free survival were not different for APBI versus whole-breast irradiation. In the three decades since the 1991 National Cancer Institute Consensus Statement supporting breast conservation for patients with early-stage disease, 16 numerous clinical trials and meta-analyses have confirmed the importance of adjuvant radiotherapy for tumour control in the treated breast. 12,17 These data reflect outcomes from adjuvant whole-breast irradiation. Because more than 50% of patients with breast cancer each year are diagnosed with early-stage disease, 18 approximately 100 000 women annually would have to consider radiotherapy for breast conservation in the USA alone. It is important that women know whether new radiotherapy approaches that might be more convenient are equally effective as whole-breast irradiation. The primary endpoint of the NSABP B-39/RTOG 0413 trial was, therefore, to ensure that the outcomes with short-course APBI would be equivalent to those with whole-breast irradiation for women who want breast-conserving therapy. To that end, the trial was designed to include a representative population of patients with early-stage breast cancer undergoing breast conservation and was powered to detect whether APBI could become an equivalent standard approach for all patients. Our finding that APBI was not equivalent to whole-breast irradiation for in-breast tumour control contrasts with results from other randomised trials that enrolled more narrowly selected patient populations. The Ontario Clinical Oncology Group RAPID trial, 19 for example, sought to show whether APBI was non-inferior to whole-breast irradiation, enrolling 2135 patients who had received lumpectomy and had node-negative breast cancers smaller than 3 cm. They excluded women who were younger than 40 years or who had lobular or multifocal breast cancer. With 84% of these patients having hormone-sensitive breast cancers and their median age being 61 years, the IBTR at 8 years from APBI was 3% versus 2·8% from whole-breast irradiation, thus APBI was non-inferior. Two other randomised trials 20,21 with similar non-inferiority designs in comparable populations (mostly patients with node-negative breast cancer, at least 95% of whom had hormone-sensitive disease, and with median age >60 years), also showed that APBI was non-inferior to whole-breast irradiation when measuring IBTR incidence at 5 years post-lumpectomy. Likewise, the UK IMPORT LOW trial 22 found that protracted APBI (delivered over 15 treatments daily for 3 weeks) was also non-inferior to whole-breast irradiation with the same delivery schedule when the outcome was IBTR. The trial recruited patients with invasive, mostly node-negative (97%) breast cancer, a median age of 62 years, and tumours that were 90% grade I–II and 95% hormone-sensitive. By comparison, the large population enrolled in our study had a median age of 54 years and included subgroups known to have both worse and better incidence of IBTR that is more broadly representative of all patients with breast cancer who undergo breast radiotherapy after lumpectomy. However, our exploratory post-hoc analysis showed no difference in the treatment effect in any of the risk categories or stratification factors, except for invasive pathological tumours 10 mm in diameter or smaller, for which APBI was favourable. This interaction with treatment was not significant in any of the other subgroups. Our findings, therefore, support whole-breast irradiation post-lumpectomy for all patients who have breast conservation. When we designed our trial, the influence of breast cancer subtype on IBTR after breast-conserving therapy was unknown. One of the limitations of our trial is the absence of human epidermal growth factor receptor 2 (HER2) information for the enrolled patients with invasive breast cancer. Furthermore, our study was not designed to assess whether whole-breast irradiation and APBI following breast-conserving surgery are equivalent in different subgroups of patients, or to test for differences in outcomes from the various APBI techniques. Therefore, even the predefined subgroups included in the exploratory analyses were not adequately powered to draw definitive conclusions regarding the treatment effect. Differences in outcomes among the various forms of APBI, as well as quality of life (including patient-reported outcomes and cosmetic results), and quality assurance analyses are reported in separate works. 19,23 The protracted time required to deliver whole-breast irradiation has been associated with greater use of mastectomy or underuse of radiotherapy after lumpectomy. 5,6 Hypofractionated whole-breast irradiation has reduced treatment duration to 3–4 weeks but still requires daily commuting, days off work, childcare, or other arrangements, so patients would prefer an even shorter radiation course. 7,8 APBI was developed as an alternative to potentially improve access to effective breast conservation therapy by reducing treatment duration to several days to further lessen burden of care. Although equivalence to whole-breast irradiation was not shown in our study, the small difference in 10-year IBTR and recurrence-free interval without a significant difference in distant disease-free interval, disease-free survival, and overall survival might be acceptable to small breast cancer populations similar to those enrolled in other trials. 19,20 The safety of APBI might consequently become an important factor for selecting radiotherapy methods. The RAPID trial 19 reported worse grade 2 acute toxicity with whole-breast irradiation and worse grade 2–3 late toxicity from APBI. A similar pattern was not seen in our trial. Other trials evaluating different partial breast irradiation methods have reported similar toxicity to that of whole-breast irradiation. 20,23 To our knowledge, our study represents the largest and most comprehensive trial investigating the efficacy of APBI compared with whole-breast irradiation after lumpectomy in a broad population of patients with breast cancer. Our findings support whole-breast irradiation but the absolute outcome difference compared with APBI is small, so partial breast irradiation might also be an acceptable treatment for some patients. Contributors All authors contributed to: the conception or design of the work, or the acquisition, analysis, or interpretation of data; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any parts are appropriately investigated and resolved. FAV was responsible for the literature search and figures. JRW oversaw the trial and performed the radiation quality assurance review. WJC Jr contributed to protocol review and securing funding. JLB participated in form review. TBJ contributed to daily trial monitoring. BMcC contributed to pilot studies of accelerated partial breast irradiation. Declaration of interests 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. Funding Information: The study protocol and informed consent form will be made available. Individual participant data that underlie the results reported in this Article, after de-identification, will be available within 1 year after publication and will be accessible through the NCTN Data Archive. Acknowledgments 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. 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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UR - http://www.scopus.com/inward/citedby.url?scp=85076132594&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(19)32514-0
DO - 10.1016/S0140-6736(19)32514-0
M3 - Article
C2 - 31813636
AN - SCOPUS:85076132594
VL - 394
SP - 2155
EP - 2164
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10215
ER -