Platinums in Lung Cancer: Sufficient or Necessary?

Abstract

This issue of the Journal of Clinical Oncology presents two articles that address the role of cisplatin and carboplatin in the treatment of advanced non–small-cell lung cancer (NSCLC). The first of these studies is a meta-analysis of the published literature comparing platinum-based regimens to non–platinum-based regimens. The second is a randomized study comparing vinorelbine plus cisplatin to the non–platinum-containing regimen of docetaxel plus gemcitabine. These analyses support the current American Society of Clinical Oncology (ASCO) guidelines for the treatment of advanced NSCLC, which state, “Firstline chemotherapy given to patients with advanced NSCLC should be a two-drug combination regimen. Non–platinumcontaining chemotherapy regimens may be used as alternatives to platinum-based regimens in the first line.” Cisplatin was shown to have activity in advanced NSCLC in studies from Memorial Sloan-Kettering Cancer Center and other institutions more than 20 years ago. When combined with a variety of other agents, these combinations were shown to prolong survival compared with best supportive care in randomized trials and in a metaanalysis of these randomized trials. These results led to the original 1997 ASCO guidelines for the treatment of advanced NSCLC, which stated, “In stage IV disease, chemotherapy prolongs survival and is most appropriate for individuals with good performance status. Chemotherapy given to NSCLC patients should be a platinum-based combination regimen.” During the 1990s, several new agents were shown to be active in the treatment of advanced NSCLC, including paclitaxel, docetaxel, vinorelbine, and gemcitabine. In randomized trials comparing either paclitaxel or docetaxel with best supportive care, both were shown to produce a significant survival advantage. In the paclitaxel study, the hazard ratio (HR) was 0.68, which was somewhat better than the 0.73 HR reported with cisplatin regimens. Randomized trials showed that combinations of cisplatin plus gemcitabine and cisplatin plus vinorelbine were superior to cisplatin alone. Other randomized trials showed that the combination of vinorelbine and cisplatin was superior to vinorelbine, paclitaxel plus carboplatin was superior to paclitaxel, gemcitabine plus carboplatin was slightly superior to gemcitabine, and docetaxel plus cisplatin was slightly superior to docetaxel. Many randomized trials compared doublets containing these new agents plus either cisplatin or carboplatin. These randomized trials invariably found equivalent efficacy with somewhat differing toxicity profiles. A smaller number of randomized trials compared combinations of these new agents with the new agent plus either cisplatin or carboplatin. These trials also showed equivalent efficacy results. These randomized trials led to the current ASCO guidelines stating that platinum doublets or nonplatinum doublets are the standard for advanced NSCLC patients with good performance status. The study of D’Addario et al in this issue of the Journal of Clinical Oncology was a literature-based meta-analysis designed to compare the efficacy and toxicity of platinumbased to non–platinum-based chemotherapy in advanced NSCLC patients. However, the analysis did not use individual patient data. The primary efficacy end points were objective response rates and one-year survival rates. Overall survival could not be assessed because the authors did not collect individual data. The analysis included both randomized phase II and randomized phase III studies of varying designs. Many of these studies compared a platinum doublet with a nonplatinum single agent. No subset analysis was performed comparing these trials, though most favored the doublet. A subset analysis was performed in trials using third-generation agents. For the entire group of studies, the authors report that the platinum-based therapies had a significantly higher response rate and 1-year survival compared with the nonplatinum combinations. The toxicity of platinum-based regimens was significantly higher for hematologic toxicity, nephrotoxicity and nausea and vomiting. In the subset of trials with third-generation agents, there was no significant increase in survival compared with platinum combinations. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 13 MAY 1 2005