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.

Summary Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p<0·0001). 10-year breast cancer mortality was similarly reduced (18·9% vs 21·3%; RR 0·87, 95% CI 0·83–0·92; p<0·0001), as was all-cause mortality (22·1% vs 24·8%; RR 0·87, 95% CI 0·83–0·91; p<0·0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4·1% vs 4·6%; RR 0·88, 95% CI 0·78–0·99; p=0·034). Recurrence reductions were similar in the seven trials (n=10 004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24·0% vs 28·3%; RR 0·83, 95% CI 0·76–0·91; p<0·0001), in the six trials (n=11 028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28·1% vs 31·3%; RR 0·87, 95% CI 0·80–0·94; p=0·0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30·4% vs 35·0%; RR 0·82, 95% CI 0·74–0·90; p<0·0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0·0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics. Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrentl...

The Medical Research Council (MRC) United Kingdom trial for childhood acute lymphoblastic leukaemia (UKALL X) randomised patients aged 0-14 years inclusive with an initial white blood count of less than 100 × 10 9 /l to receive an early intensification block, a late intensification block, both, or neither. The next trial, UKALL XI, for children aged 1-14 years, randomised between different central nervous system (CNS) directed therapies. At the beginning of the trial, all patients were also randomised between late intensification alone and both early plus late blocks. The effects of both the early and the late block in UKALL X alone have been reported previously. This paper examines the effect of the addition of the early intensification block to treatment which included late intensification, combining the data from UKALL X and the first part of UKALL XI. Early intensification was associated with fewer bone marrow relapses and a reduction in the odds of death of 0.63 (95% confidence interval: 0.46-0.87). Survival was significantly improved with an increase at 5 years of 8%, from 79 to 87%. Following this demonstration that early intensification improves survival, the effect of a third intensification block is under investigation.

SummaryWe report on the outcome of children with Philadelphia positive acute lymphoblastic leukaemia (Ph+ ALL) treated on the UK Medical Research Council (MRC) trial for childhood ALL, MRC ALL 97, between January 1997 and June 2002. Forty-two (2AE3%) patients were Ph+. Nineteen (45%) had <25% blasts in bone marrow (BM) within the first 2 weeks of treatment and were defined as a good response group (GRG), the others as a poor response group (PRG). Thirty-six (86%) achieved first complete remission (CR1) at the end of induction, of which 28 underwent BM transplantation (BMT). The median follow-up was 42 months (range, 21-84). The 3-year event-free survival (EFS; 52%, 95% CI, 36-66%) was a considerable improvement on the previous MRC UKALL XI trial (27%). EFS for the GRG and PRG were 68% (43-84%) and 39% (18-59%), respectively (P ¼ 0AE03); presenting white cell count <50 · 10 9 /l (P ¼ 0AE02) was predictive for overall survival. Changes in the MRC ALL97 trial within the study period resulted in some Ph+ ALL receiving daunorubicin and either prednisolone or dexamethasone during induction. Though the use of daunorubicin during induction was not a prospective study question, EFS was significantly better for those whose induction included this drug (P ¼ 0AE02). Steroid randomization was not stratified for Ph+ ALL patients and was not predictive for EFS. BMT in CR1 appeared to reduce the risk of a subsequent BM relapse. These results show significant improvement on previous MRC trials; future therapeutic strategies should include early intensive therapy and BMT in CR1.

BackgroundThe average age at which people start smoking has been decreasing in many countries, but insufficient evidence exists on the adult hazards of having started smoking in childhood and, especially, in early childhood. We aimed to investigate the association between smoking habits (focusing on the age when smokers started) and causespecific premature mortality in a cohort of adults in Cuba.Methods For this prospective study, adults were recruited from five provinces in Cuba. Participants were interviewed (data collected included socioeconomic status, medical history, alcohol consumption, and smoking habits) and had their height, weight, and blood pressure measured. Participants were followed up until Jan 1, 2017 for cause-specific mortality; a subset was resurveyed in 2006-08. We used Cox regression to calculate adjusted rate ratios (RRs) for mortality at ages 30-69 years, comparing never-smokers with current smokers by age they started smoking and number of cigarettes smoked per day and with ex-smokers by the age at which they had quit.