Commentary on “Interim Analysis of a Phase III Trial Comparing Cisplatin, Gemcitabine, and Vinorelbine vs. Either Cisplatin and Gemcitabine or Cisplatin and Vinorelbine in Advanced Non–Small-Cell Lung Cancer (NSCLC)”

Abstract

The report in this issue by Comella et al1 of a randomized trial of cisplatin/gemcitabine/vinorelbine (PGV) versus cisplatin/ gemcitabine (PG) or cisplatin/vinorelbine (PV), showing a response and survival superiority for the three-drug combination, points out a number of successes we have achieved in the clinical management of advanced NSCLC in the last few years. Nevertheless, it also highlights some of our relative limitations in the treatment of this disease that warrant comment as well, and should not be interpreted as establishing a new of care just yet. Taken at face value, this study is an example of a relatively large, multicenter, randomized trial with survival as the primary endpoint. We need these phase III trials in this era of rapidly expanding therapeutic options in advanced NSCLC. In this clinical setting with such a poor prognosis, too often clinical decisions are made and new standards set based on preliminary phase I and II trials that may demonstrate encouraging early results. This trial takes as its control arms two well-studied regimens, PG and PV, based on large randomized phase III trials showing superiority over single-agent cisplatin, arguably the most important single agent in NSCLC identified to date.2,3 The PV regimen has also been proven superior to single agent vinorelbine or a European regimen of cisplatin-vindesine.4 Similarly, the regimen is worthy of comparison based on encouraging results from this same group in a prior phase II trial with a response rate of 57% and a 50-week median survival.5 Therefore, based on a well-designed trial with proper control arms and a promising investigational regimen, the preliminary response and survival data favoring PGV over PV (although not over PG, at least so far) does warrant close attention. Nonetheless, we also need to consider a few caveats in interpreting these results and how they can be applied clinically. The patient group in this study is highly selected with a better-than-average prognosis as patients over age 70 were excluded, as were those with an ECOG performance status > 1, or patients with prior surgery or radiation. Forty-two percent had stage IIIB disease, only 25% had weight loss, and only 15% had more than one site of metastasis. Only 3% of the population had CNS metastases. Therefore, these data cannot necessarily be applied to a wider, more diverse, and less healthy patient population characteristic of a typical United States oncology practice. It is unclear if the response and survival benefit, or the relatively favorable toxicity profile, would stand up in more general use. Despite these limitations, a 16-week improvement in survival of PGV over PV (51 weeks vs. 35) is impressive in a randomized trial. And in an environment with cisplatin as the preferred platinum analog, this threedrug regimen of PGV certainly would have to be considered as one new option. But current patient desires, treatment goals, and clinical practice in the United States preclude this regimen from becoming such a standard. If the proof of the pudding is in the eating, few US oncologists or patients are hungry for cisplatin and its associated toxicities and inconveniences. Whether driven by patient preferences, clinic time and space limitations, tighter external restrictions, or financial incentives, there has been widespread rejection of cisplatin with substitution of carboplatin. In fact, in the SWOG trial evaluating the experimental carboplatin-paclitaxel versus the standard cisplatin-vinorelbine regimen, response, survival, and quality of life were virtually identical.6 Yet SWOG chose to adopt a new based on the feasibility and convenience of the carboplatin regimen. The need to include any platinum compound at all remains largely untested with our new generation of chemotherapy agents. One randomized trial suggested the combination of docetaxel and gemcitabine was comparable to the cisplatin-docetaxel in that trial.7 Finally, the role of adding a third drug is not yet clear. Previous