Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data

Abstract

Background: Individual participant data meta-analyses of postoperative chemotherapy have shown improved survival for patients with non-small-cell lung cancer (NSCLC). We aimed to do a systematic review and individual participant data meta-analysis to establish the effect of preoperative chemotherapy for patients with resectable NSCLC.

Methods: We systematically searched for trials that started after January, 1965. Updated individual participant data were centrally collected, checked, and analysed. Results from individual randomised controlled trials (both published and unpublished) were combined using a two-stage fixed-effect model. Our primary outcome, overall survival, was defined as the time from randomisation until death (any cause), with living patients censored on the date of last follow-up. Secondary outcomes were recurrence-free survival, time to locoregional and distant recurrence, cause-specific survival, complete and overall resection rates, and postoperative mortality. Prespecified analyses explored any variation in effect by trial and patient characteristics. All analyses were by intention to treat.

Findings: Analyses of 15 randomised controlled trials (2385 patients) showed a significant benefit of preoperative chemotherapy on survival (hazard ratio [HR] 0·87, 95% CI 0·78-0·96, p=0·007), a 13% reduction in the relative risk of death (no evidence of a difference between trials; p=0·18, I(2)=25%). This finding represents an absolute survival improvement of 5% at 5 years, from 40% to 45%. There was no clear evidence of a difference in the effect on survival by chemotherapy regimen or scheduling, number of drugs, platinum agent used, or whether postoperative radiotherapy was given. There was no clear evidence that particular types of patient defined by age, sex, performance status, histology, or clinical stage benefited more or less from preoperative chemotherapy. Recurrence-free survival (HR 0·85, 95% CI 0·76-0·94, p=0·002) and time to distant recurrence (0·69, 0·58-0·82, p<0·0001) results were both significantly in favour of preoperative chemotherapy although most patients included were stage IB-IIIA. Results for time to locoregional recurrence (0·88, 0·73-1·07, p=0·20), although in favour of preoperative chemotherapy, were not statistically significant.

Interpretation: Findings, which are based on 92% of all patients who were randomised, and mainly stage IB-IIIA, show preoperative chemotherapy significantly improves overall survival, time to distant recurrence, and recurrence-free survival in resectable NSCLC. The findings suggest this is a valid treatment option for most of these patients. Toxic effects could not be assessed.

Funding: Medical Research Council UK.

Figure 1

Effect of preoperative chemotherapy on survival Each square denotes the HR for that trial comparison with the horizontal lines showing the 95% and 99% CIs. The size of the square is directly proportional to the amount of information contributed by the trial. The black diamond gives the pooled HR from the fixed effect model; the centre of this diamond denotes the HR and the extremities the 95% CI. O–E=observed minus expected. HR=hazard ratio. MIP=mitomycin, ifosphamide, cisplatin. SWOG=South West Oncology Group. JCOG=Japanese Cancer Oncology Group. MRC=Medical Research Council. BLT=Big Lung Trial. ChEST=Chemotherapy for Early Stages Trial. NATCH=Neoadjuvant/Adjuvant Trial of Chemotherapy. df=degrees of freedom. *Number of events/number entered.

Figure 2

Kaplan-Meier curves (non-stratified) of the effect of preoperative chemotherapy on time to survival

Figure 3

Forest plot of the interactions between the effect of preoperative chemotherapy on survival and covariates The circles represent (fixed effect) meta-analyses of the HRs representing the interactions between the effect of chemotherapy and patient characteristics; the horizontal line shows the 95% CI. HR=hazard ratio.

Figure 4

Kaplan-Meier curves (non-stratified) of the effect of preoperative chemotherapy on time to distant and locoregional recurrence and recurrence-free survival Analyses of recurrence outcomes were calculated from a landmark time of 6 months from the date of randomisation; for this reason time on the x-axis starts at 6 months.