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Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006–007018–39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. UK National Institute for Health Research, Health Technology Assessment Programme.

The role of postmastectomy chest-wall irradiation in patients with breast cancer classified as pN1 (with involvement of one to three axillary nodes) or pN0 (pathologically node negative) with additional risk factors is uncertain. In this international, phase 3, randomized trial, we evaluated the omission of chest-wall irradiation in women with \"intermediate-risk\" breast cancer - defined as cancer that was stage pT1N1, pT2N1, or pT3N0 or stage pT2N0 with a histologic grade of 3, lymphovascular invasion, or both (tumor size: T1, ≤2 cm; T2, >2 cm to 5 cm; or T3, >5 cm) - that was treated with mastectomy, an axillary procedure, and systemic therapy. Patients were assigned to undergo chest-wall irradiation (40 to 50 Gy; the irradiation group) or not to undergo chest-wall irradiation (the no-irradiation group). The primary end point was overall survival, with 10 years of follow-up. Chest-wall recurrence, regional recurrence, disease-free survival, distant metastasis-free survival, causes of death, and radiation-related adverse events were also assessed. The intention-to-treat population included 808 patients in the irradiation group and 799 in the no-irradiation group. The median follow up was 9.6 years. Overall survival was 81.4% with chest-wall irradiation and 81.9% with no chest-wall irradiation according to 10-year Kaplan-Meier estimates (hazard ratio for death, 1.04; 95% confidence interval [CI], 0.82 to 1.30; P = 0.80). A total of 29 patients had a chest-wall recurrence - 9 (1.1%) in the irradiation group and 20 (2.5%) in the no-irradiation group (between-group difference, <2 percentage points; hazard ratio, 0.45; 95% CI, 0.20 to 0.99). Disease-free survival was 76.2% in the irradiation group and 75.5% in the no-irradiation group (hazard ratio for recurrence or death, 0.97; 95% CI, 0.79 to 1.18), and distant metastasis-free survival was 78.2% and 79.2%, respectively (hazard ratio for distant metastasis or death, 1.06; 95% CI, 0.86 to 1.31). In this trial, chest-wall irradiation did not result in higher overall survival than no chest-wall irradiation among patients with intermediate-risk, early breast cancer treated with mastectomy and contemporary adjuvant systemic therapy. (Funded by the Medical Research Council and others; SUPREMO ISRCTN Clinical Study Registry number, 61145589.).