New Insights Into the Effect of Adjuvant Cisplatin-Based Chemotherapy on the Type of Failure in Non-Small-Cell Lung Cancer. a Competing-Risk and Multistate Approach

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ABSTRACT Aim: During the last decade, adjuvant cisplatin-based chemotherapy has become the standard therapy against resected non-small cell lung cancer (NSCLC) following two meta-analyses of randomised trials that showed a survival benefit of about 5% at five years with chemotherapy. Individual trials however, have shown variable results on the treatment effect on disease relapse and on non-cancer mortality after five years. Methods: The International Adjuvant Lung Cancer Trial accrued 1867 patients randomised between an adjuvant cisplatin-based chemotherapy arm and a control arm, who were followed up for a median of 7.5 years. Of these, 1687 patients were enrolled from 132 centres that initially accepted to report the times to cancer-related events. In this latter population, we used competing risks and multistate models to estimate the effects of adjuvant chemotherapy on the risks of local relapse, distant metastasis, and death. Results: Adjuvant chemotherapy proved to be highly effective against local relapses (hazard ratio HR = 0.73; 95%CI: 0.60–0.90; p = 0.003) and non-brain metastases (HR = 0.79; 95%CI: 0.66–0.94; p = 0.008) but not against brain metastases (HR = 1.10; 95%CI: 0.82–1.40; p = 0.61). The effect on non-cancer mortality was non-significant during the first five years (HR = 1.10; 95%CI: 0.81–1.50; p = 0.29), whereas the risk of non-cancer mortality was subsequently higher in the treatment arm (HR = 3.6; 95%CI: 2.20–5.90; p Conclusions: Adjuvant cisplatin-based chemotherapy has reduced the risk of local relapse and of non-brain metastasis in NSCLC patients, thereby improving survival. This treatment exerted no residual effect on mortality during the first five years, but a higher risk of non-cancer mortality was found thereafter. Even if this late effect concerned a small number of patients, detailed long-term follow-up should be strongly recommended for all patients in randomised trials evaluating adjuvant treatments in NSCLC. Disclosure: All authors have declared no conflicts of interest.