Gastric cancer: toward a cisplatin-free disease?

Historically, the cornerstone of treatment of advanced gastric cancer (GC) is 5-fluorouracil (5-FU)-based chemotherapy that increases median overall survival (OS) compared to best supportive care by some months. The addition of cisplatin (CDDP) to chemotherapy doublets showed a limited but significant benefit in term of OS according to a Cochrane meta-analysis. However, the recent individual patient-data GASTRIC meta-analysis, confirms this benefit in term of progression-free survival (PFS) but not OS, in randomized eight trials that include or not CDDP. The substitution of CDDP with a modern agent (oxaliplatin, irinotecan or taxanes) has been poorly evaluated in the literature. The REAL-2 phase III trial confirmed the equivalence of oxaliplatin and CDDP-based triplets, and a meta-analysis of three oxaliplatin-based randomized trials demonstrated that these combinations are better that CDDP-based doublets or triplets, improving both PFS (HR =0.88) and OS (HR =0.88). In particular, oxaliplatin-based chemotherapy was associated with less neutropenia and thromboembolic events, but with worse neurotoxicity. Given that the role of chemotherapy in advanced GC is palliative, CDDP-free regimens, and in particular oxaliplatin-based chemotherapy, may be considered for both CDDP-fit and unfit patients (that are those with poor renal function, older age, bad performance status or who cannot tolerate forced hydration for example). The limited absolute survival benefit of chemotherapy in advanced GC (few weeks at best), the cumbersome vascular toxicity of CDDP and the activity of several new drugs such irinotecan, oxaliplatin, taxanes and oral fluoropyrimidines make nowadays possible to consider CDDP-free regimens for the treatment of this incurable disease.