Oncology · Medical Literature
Postmastectomy chest wall radiotherapy for breast cancer (SUPREMO): 5-year quality-of-life results from a randomised, controlled, phase 3 trial.
Abstract
The SUPREMO trial reported adjuvant chest wall radiotherapy had no effect on 10-year overall survival (primary endpoint) in patients with intermediate-risk breast cancer after mastectomy. The quality of life (QOL) substudy of SUPREMO (UK patients only) examines the effects of chest wall radiotherapy in patients with intermediate-risk breast cancer 1 year, 2 years, 5 years, and 10 years after treatment. Here, we report 5-year QOL results (a secondary endpoint), including prespecified subgroup analyses. SUPREMO is an international, parallel-group, randomised, controlled, phase 3 trial. Women aged 18 years or older with intermediate-risk breast cancer (defined as pT1-2N1 or pT3N0 or pT2N0 with histological grade 3, or lymphovascular invasion, or both) who had undergone mastectomy (and axillary surgery) were randomly assigned (1:1) to receive chest wall radiotherapy (40-50 Gy in 15-25 fractions) or no radiotherapy. Randomisation was in permuted blocks with varying block length, stratified by centre, without masking of patients or investigators. All UK patients were invited to the QOL substudy. Consenting patients completed validated questionnaires (European Organisation for Research and Treatment of Cancer Quality of Life Core 30-item questionnaire; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Breast Cancer Module, 23 items; Body Image Scale; and Hospital Anxiety and Depression Scale) before randomisation and at 1 year, 2 years, 5 years, and 10 years. Here, we report the prespecified primary QOL outcomes of global QOL, fatigue, physical function, chest wall symptoms, shoulder and arm symptoms, body image, anxiety, and depression in the intention to treat population, using repeated measures mixed-effects models. This trial is registered with the ISRCTN registry, ISRCTN61145589 and is now completed. Between Aug 4, 2006, and April 29, 2013, SUPREMO recruited 1691 patients internationally, of whom 1679 were randomly assigned to receive chest wall radiotherapy (n=845) or not (n=834). Of 1233 patients from UK centres (619 in the chest wall radiotherapy group and 614 in the no chest wall radiotherapy group), 989 (80%) consented to the QOL substudy: 947 (96%) of 989 returned baseline questionnaires and 620 (75%) of 832 patients returned the expected year-5 questionnaires. Chest wall symptoms were worse with chest wall radiotherapy (effect estimate 1·99 [95% CI 0·36-3·62]; p=0·017) with an improvement between years 1, 2, and 5. Chemotherapy was associated with less improvement over time (effect estimate 2·97 [95% CI 0·24-5·71]; p=0·033) but without interaction with chest wall radiotherapy. No statistically significant differences were observed in other QOL domains (arm symptoms, body image, fatigue, pain, overall QOL, physical functioning, or anxiety and depression). In the subgroup analyses, patients who had a sentinel lymph node biopsy followed up by an axillary lymph node clearance with chest wall radiotherapy had worse chest wall symptoms than those having a single axillary operation (difference chest wall radiotherapy vs no chest wall radiotherapy -5·29 [95%CI -8·53 to -2·05]; p=0·0015). The 5-year QOL findings showed worse chest wall toxicity and no effect on other QOL domains. The subgroup analyses suggested a potential negative effect of chemotherapy and axillary clearance after sentinel node biopsy. UK Medical Research Council, National Institute for Health and Care Research, European Organisation for Research and Treatment of Cancer, Edinburgh Trustees of Breast Cancer Institute in Edinburgh and the Edinburgh Cancer Centre NHS Endowment funds, The Dutch Cancer Society, Trustees of the Hong Kong and Shanghai Banking Corporation.
Clinical relevance
The SUPREMO trial addresses a longstanding clinical dilemma regarding the benefit-versus-harm of adjuvant postmastectomy chest wall radiotherapy (CWRT) in intermediate-risk breast cancer (pT1-2N1, pT3N0, or pT2N0 with grade 3 histology and/or lymphovascular invasion) — a population for whom radiotherapy guidelines have historically been inconsistent. Having already demonstrated no improvement in 10-year overall survival, this 5-year quality-of-life (QOL) substudy now provides prospective, patient-reported evidence on the toxicity burden of CWRT in this setting. These findings are directly relevant to shared decision-making conversations with the large subset of breast cancer patients who fall into intermediate-risk categories after mastectomy.
Key findings
1. Chest wall symptoms were statistically significantly worse in patients who received CWRT compared to controls at 5 years (effect estimate 1.99 [95% CI 0.36–3.62]; p=0.017), though an improvement trajectory was observed between years 1, 2, and 5. 2. No statistically significant differences between treatment arms were identified in any other prespecified QOL domains, including arm symptoms, body image, fatigue, pain, global QOL, physical functioning, anxiety, or depression at 5 years. 3. Receipt of chemotherapy was independently associated with less improvement in chest wall symptoms over time (effect estimate 2.97 [95% CI 0.24–5.71]; p=0.033), without a statistically significant interaction with CWRT assignment. 4. In a prespecified subgroup analysis, patients who underwent sentinel lymph node biopsy (SLNB) followed by axillary lymph node clearance (ALNC) and received CWRT had significantly worse chest wall symptoms than those who had a single axillary operation (difference CWRT vs. no CWRT: −5.29 [95% CI −8.53 to −2.05]; p=0.0015). 5. Of 989 UK patients who consented to the QOL substudy (80% of eligible UK participants), 96% returned baseline questionnaires and 75% returned expected year-5 questionnaires, supporting adequate follow-up for a secondary endpoint analysis. 6. These 5-year QOL data complement the previously reported primary endpoint showing no 10-year overall survival benefit from adjuvant CWRT in this intermediate-risk population.
Practice implications
Given the absence of survival benefit and the demonstrated chest wall toxicity burden — particularly in patients receiving both chemotherapy and a two-stage axillary procedure (SLNB followed by ALNC) — clinicians should exercise heightened caution when recommending routine adjuvant CWRT to intermediate-risk mastectomy patients, and should incorporate these QOL data explicitly into multidisciplinary tumor board discussions and patient counseling. Patients who have undergone SLNB followed by ALNC represent a subgroup at elevated risk for CWRT-related chest wall morbidity and warrant individualized risk-benefit assessment before radiotherapy is prescribed. Pending the 10-year QOL results, current evidence does not support routine postmastectomy CWRT for intermediate-risk breast cancer outside of a shared decision-making framework that accounts for cumulative axillary surgical burden and systemic therapy exposure.