No abstract

The long-term results of this trial of adjuvant combination chemotherapy confirm our preliminary observations of the effectiveness of the treatment in women with node-positive breast cancer.

SummaryBackgroundNeoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials.MethodsWe obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality).FindingsPatients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5–14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4–8·6]; rate ratio 1·37 [95% CI 1·17–1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92–1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95–1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94–1·15]; p=0·45).InterpretationTumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered—eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy.FundingCancer Research UK, British Heart Foundation, UK Medical Research Council, and UK Department of Health.

Prolonged cyclic combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil was evaluated as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. After 27 months of study, treatment occurred in 24 per cent of 179 control patients and in 5.3 per cent of 207 women given combination chemotherapy (P less than 10(-6)), the advantage appearing statistically significant in all subgroups of patients. Patients with four or more positive axillary nodes had a higher per cent of relapses than those with fewer nodes. The initial new clinical manifestations occurred in distant sites in 81.5 per cent of relapsed patients. Long-term chemotherapy produced an acceptable toxicity, thus allowing the administration of a high percentage of drug dosage. These results should be considered with caution, since, at present, the effect of this therapy on survival and possible long-term side effects remain unknown.

Current findings indicate that primary chemotherapy can be safely administered in women with large tumors (>5.0 cm) and can allow breast-sparing surgery in a high fraction of patients (62%). However, to assess effectively the worthiness of this approach on long-term results, properlyconceived large randomized studies with newer and more effective drug regimens are warranted.