Irinotecan Therapy for Small-Cell Lung Cancer

Dr. Sandler has written a thorough and cogent review of the literature on irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) in the treatment of small-cell lung cancer. The most promising data are those from a randomized trial by Noda et al, which showed that irinotecan, compared to etoposide(Drug information on etoposide), in combination with cisplatin(Drug information on cisplatin) resulted in an approximately 3-month survival benefit in patients with extensive disease, good performance status, and an age < 70 years. The results of this trial were published recently in The New England Journal of Medicine and, therefore, will attract wide readership and, presumably, much enthusiasm and excitement.[1]

For emphasis, however, I refer to the final two paragraphs in Dr. Sandler’s review. To paraphrase, a confirmatory trial must be completed before this combination can be considered the standard of care in North America, despite the seemingly firm conclusions reached by the Japan Clinical Oncology Group (JCOG) investigators. Dr. Desmond Carney echoes this sentiment in his editorial, which accompanied publication of the JCOG study.[2]

Reservations About Efficacy

Why are we all so skeptical? Certainly part of the reluctance to accept these data at face value comes from the failed attempts over 2 decades to improve median survival in extensive small-cell lung cancer beyond the 9- to 10-month plateau achieved with new cytotoxins, dose-intense therapy, alternating therapy, or maintenance with biologics. Our efforts have been dogged; the results generally disappointing. Why did the simple substitution of irinotecan for etoposide in combination with cisplatin work when so much else has failed?

There is no obvious answer. One could hypothesize that this effect is related to the enhanced cytoreduction produced by irinotecan. There was, in fact, a 17% increase in the overall response rate with irinotecan/cisplatin; however, complete responses, which dogma holds more likely to have an impact on survival, were more common in the standard etoposide-containing arm (2% vs 9%, P > .05).

Clues to the success of irinotecan-based induction therapy might be found in the experience with its use as second-line therapy. Unlike its sister compound topotecan(Drug information on topotecan) (Hycamtin), which has been studied in a North American phase III randomized trial in patients with recurrent small-cell lung cancer, data with irinotecan in this setting derive from multiple phase II trials. However, a comparison of the activity of the two drugs in this setting, as reviewed by Dr. Sandler, suggests similar efficacy in sensitive relapse and a lack of activity in refractory disease. Topotecan has yet to distinguish itself as an important drug in the front-line setting, and in combination with cisplatin has proven particularly toxic and problematic. Given the similarity of the activity of these two drugs in recurrent small-cell lung cancer, one is again left wondering why irinotecan should be uniquely effective in induction therapy.

Toxicity Issues