Commentary (Johnson): Integration of Vinorelbine into Chemotherapy Strategies for Non-Small-Cell Lung Cancer

Dr. Vokes provides information about integrating a new chemotherapeutic agent, vinorelbine (Navelbine), into the current treatment regimens for patients with advanced-stage non-small-cell lung cancer. He reviews the phase II activity of vinorelbine and summarizes the large phase III studies showing a prolongation of survival in patients treated with vinorelbine in combination with cisplatin (Platinol). Dr. Vokes is careful about applying this information and appropriately concludes that vinorelbine in combination with cisplatin should be considered as the initial therapy for stage IV non-small-cell lung cancer.

The author then comments on four meta-analyses performed on eight small studies, which showed that the survival of patients with disseminated non-small-cell lung cancer treated with supportive care is shorter than the survival of patients treated with combination chemotherapy. The most recent meta-analysis demonstrated that cisplatin-based combinations prolong survival while the other regimens do not, when compared to the survival of patients treated with supportive care [1]. However, a study comparing survival of patients with disseminated non-small-cell lung cancer treated with cisplatin-containing combinations and those given regimens not containing cisplatin showed similar median survivals [2]. Therefore, it is currently unresolved as to whether it is important to include cisplatin as one of the agents in chemotherapy regimens for patients with disseminated non-small-cell lung cancer.

I do agree with the author's assertions that (1) patients similar to those treated in the randomized studies should be offered combination chemotherapy, (2) a best regimen has not been identified, and (3) not all physicians agree that the magnitude of survival benefit makes combination chemotherapy a standard treatment for patients with disseminated non-small-cell lung cancer.

Preclinical, Phase I, and Phase II Studies of Vinorelbine

The bulk of the article deals with studies of vinorelbine as an agent for non-small-cell lung cancer. Vinorelbine is the fourth drug to be approved by the Food and Drug Administration for the treatment of non-small-cell lung cancer. Dr. Vokes does an excellent job reviewing the structure, mechanism of action, and preclinical studies of vinorelbine. It is worth noting that the Japanese phase II study of vinorelbine in patients with disseminated non-small-cell lung cancer (objective response rate of 32%) [3] confirms the objective response rate of 29% quoted for the other phase II study.

Phase III Studies of Vinorelbine and Combinations

The initial phase III study on vinorelbine combinations examined by Vokes was the important trial reported by Le Chevalier and colleagues, which compared the combination of vindesine (Eldisine) and cisplatin to vinorelbine alone and vinorelbine plus cisplatin [4]. The survival advantage for vinorelbine/cisplatin compared to vinorelbine alone and vindesine/cisplatin was significant. However, the effect of vinorelbine/cisplatin shown in this large trial was not great (prolongation of median survival of 2 months) and did not appear to influence the outcome of patients after 1 year.

The selection of vindesine plus cisplatin as one of the arms for this study was useful. This regimen had previously been shown to prolong survival in patients with disseminated non-small-cell lung cancer compared to supportive care in the National Cancer Institute of Canada study [5]. Therefore, the prolonged survival of patients treated with vinorelbine/cisplatin compared to vindesine/cisplatin provides indirect evidence that vinorelbine/cisplatin is better than supportive care. Dr. Vokes does not point out that the median survival of the patients treated with vindesine/cisplatin in the European study was nearly identical to that observed in the NCIC Study (32 vs 33 weeks), suggesting reproducible survival results with this combination in these patient populations.

The other two phase III trials were small and do not provide very convincing data. The trial comparing vinorelbine to vinorelbine plus cisplatin involved only 131 patients and did not assess the contribution of vinorelbine to survival because both arms received vinorelbine. The study with fluorouracil and leucovorin has been reported only in abstract form. Dr. Vokes appropriately points out the fluorouracil/leucovorin regimen was an unusual choice for the control arm of this study because it is not typically used in patients with advanced-stage non-small-cell lung cancer.

The median survival of patients with disseminated non-small-cell lung cancer treated with vinorelbine as a single agent in both phase II studies and the three phase III studies is remarkably similar (30 to 33 weeks). This is quite favorable compared to the median survival of approximately 20 weeks seen in patients with disseminated non-small-cell lung cancer receiving supportive care.

This article is very helpful in defining the current role of vinorelbine, summarizing the ongoing studies and describing potential future directions. Dr. Vokes is to be commended for putting together this information in a useful format. Phase II studies of vinorelbine in patients with advanced-stage non-small-cell lung cancer show response rates of greater than 30% and median survivals in excess of 30 weeks. Vinorelbine/cisplatin treatment provides a survival advantage for patients with disseminated non-small-cell lung cancer compared to vindesine/cisplatin. Indirect comparisons suggest that vinorelbine/cisplatin is likely to provide a survival advantage for patients with advanced non-small-cell lung cancer compared to those treated with supportive care. Thus, I agree with Dr. Vokes' statement that vinorelbine in combination with cisplatin should be considered as the initial therapy for stage IV non-small-cell lung cancer.

References:

1. Stewart LA, Pignon JP, Parmar MKB: A meta-analysis using individual patient data from randomized clinical trials of chemotherapy in non-small cell lung cancer: Survival in the supportive care setting (abstract). Proceedings of the American Society of Clinical Oncology 13:337, 1994.

2. Jett JR: Current treatment of unresectable lung cancer. Mayo Clin Proc 68:603-611, 1993.

3. Yokoyama A, Furuse K,Niitani H: Multi-institutional phase II study of navelbine (vinorelbine) in non-small cell lung cancer (abstract). Proceedings of the American Society of Clinical Oncology 11:287, 1992.

4. Le Chevalier T, Brisgand D, Douillard JY, et al: Randomized study of vinorelbine and cisplatin verus vindesine and cisplatin versus vinorelbine alone in advanced non-small cell lung cancer: Results of a European multicenter trial including 612 patients. J Clin Oncol 12:360-367, 1994.

5. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong survival in patients with advanced non-small cell lung cancer-report of a Canadian multicenter randomized trial. J Clin Oncol 6:633-641, 1988.