Concomitant Radio-chemotherapy (CT-RT) versus Sequential CT-RT In Locally Advanced Non-Small-Cell Lung Cancer (NSCLC): A Meta-Analysis Using Individual Patient Data (IPD) From Randomised Clinical Trials (RCTs)

Purpose/Objective(s) 

The previous IPD meta-analyses of CT in locally advanced NSCLC indicated that adding sequential CT or concomitant CT to radiotherapy improved survival (BMJ 1995;311:899, Ann Oncol 2006;17:473). The NSCLC Collaborative Group performed a meta-analysis of RCTs that compared concomitant CT-RT versus sequential CT-RT.

Materials/Methods 

Systematic searches for RCTs were followed by the central collection, checking and re-analysis of updated IPD. Results from individual trials were combined using the stratified (by trial) log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival, secondary outcomes were progression-free survival (PFS), cumulative incidences of loco-regional and distant progression, and acute toxicity.

Results 

Seven trials which randomized 1,307 patients were eligible for the meta-analysis. IPD was received from 1,205 patients from 6 RCTs (92% of patients). The survival and PFS analyses were based on these trials and loco-regional and distant progression analyses were based on 5 trials. Median follow-up was 5 years. Two trials used same drugs and doses for concomitant and sequential CT. For sequential CT, all trials used at least cisplatin, induction CT was used in 5 trials and consolidation CT in one. For concomitant CT, cisplatin was used in 5 trials, and carboplatin in one trial. One trial used consolidation CT after concomitant CT.

Concomitant CT-RT increased the rate of severe acute oesophageal toxicity (grade 3–4) from 4% to 18% with a relative risk of 4.9 (95% CI = [3.1–7.8], p < 0.0001). There was no significant difference between concomitant and sequential CT-RT for pulmonary acute toxicity. Haematological toxicity rates were highly variable among trials and the data were not pooled.

There was a significant benefit of concomitant CT-RT as compared to sequential CT-RT on survival (HR = 0.85, 95% CI = [0.75–0.95], p = 0.0066), with an absolute benefit of 5.9% (from 18.1% with sequential CT-RT to 24% with concomitant CT-RT) at 3 years. For progression-free survival, the HR was 0.90 (95% CI = [0.80–1.02], p = 0.0866). Concomitant CT decreased loco-regional progression (HR = 0.76, 95% CI = [0.62–0.94], p = 0.011), but its effect was not different from that of sequential CT on distant progression (HR = 1.04, 95% CI = [0.86–1.25], p = 0.669). There was no clear evidence of a difference in effect by type of CT, nor by patient characteristics (age, sex, performance status, histology or stage).

Conclusions 

Concomitant CT-RT, as compared to sequential CT-RT, improved survival of patients with locally advanced NSCLC, mainly due to the decrease of loco-regional progression, at the cost of increased acute oesophageal toxicity.

Unrestricted grants from French PHRC, LNCC and Sanofi-Aventis.