PHILADELPHIAIrinotecan (Camptosar) produces response rates in advanced non-small-cell lung cancer (NSCLC) comparable to those of some well-established combination regimens and is being tested as a radiosensitizer in combination with cis-platin and radiotherapy in locally advanced NSCLC. These and other developments using topoisomerase I inhibitors in NSCLC were reviewed by Corey Langer, MD, at a clinical investigators workshop sponsored by the University of Texas M. D. Anderson Cancer Center and Pharmacia Oncology. Dr. Langer is Medical Director, Thoracic Oncology, at Fox Chase Cancer Center in Philadelphia, PA.
Phase II trials of irinotecan(Drug information on irinotecan) in Japan had produced response rates of 32% to 36%, comparable to other regimens used in the United States, Dr. Langer reported. Many of the Japanese studies, however, included stage III patients who would not generally be enrolled in advanced-stage NSCLC studies in the United States.
A Single-Agent Advantage
Data from a phase III study comparing irinotecan/cisplatin to vindesine(Drug information on vindesine)/cisplatin and to irinotecan alone showed that survival is significantly better with irinotecan, Dr. Langer said (see Figure). One-year survival in this study was 47.5% with irinotecan/cis-platin, vs 26.3% with vindesine/cisplatin (P = .004). One-year survival with irinotecan alone was 37.0% vs 26.3% with vindesine/cisplatin (P =.018).
In this study, a single-agent non-platinum regimen looked better than a platinum-based combination therapy, Dr. Langer said. This advantage has not, however, been confirmed by other studies.
Attempts to Reduce Toxicity
A North American phase II study of irinotecan/cisplatin in 52 patients reported an overall response rate of 29%, time to progression of 5.1 months, median overall survival of 9.9 months, and 1-year survival of 37%. In this trial (DeVore et al, Journal of Clinical Oncology 1999;17:2710-2720) irinotecan was given weekly on days 1, 8, and 15, and cisplatin(Drug information on cisplatin) was given monthly on day 1.
Dr. Langer said that this regimen caused substantial toxicity, including grade 3/4 neutropenia in 49.1% of patients, and febrile neutropenia requiring hospitalization in 11.5%. Significant nonhematologic toxicities included grade 3 nausea/vomiting in 32.7%, and grade 3 asthenia in 23.1%.
Irinotecan dose intensity was 75.5% of planned, and 73% of patients required dose reduction, Dr. Langer said.
In an attempt to reduce toxicity and improve efficacy, a follow-up study tested weekly irinotecan combined with weekly cisplatin on a day 1 and 8 schedule in 50 patients with advanced NSCLC. The putative synergy of these agents shown in vitro can be better exploited by same-day administration, and better sequencing of cisplatin plus irinotecan may improve efficacy, Dr. Langer said. Decreased toxicity may result from the ability to decrease the dose of cisplatin per administration.
Monthly vs Weekly Schedule
With the weekly schedule, the response rate was 36%, time to progression was 6.9 months, and 1-year overall survival was 46%. Grade 3/4 neutropenia was the main hematologic toxicity, occurring in 25% of cycles. Grade 3/4 diarrhea occurred in 20% of cycles. Dose intensity was well maintained for both agents, Dr. Langer said, adding that irinotecan dose intensity was 89% with this schedule.
A comparison of toxicities and responses of the weekly and monthly regimens showed that the weekly regimen appears to be more effective and better tolerated, Dr. Langer reported. He called for phase III trials comparing irinotecan/cisplatin to other regimens.
The activity of monthly irinotecan plus cisplatin is comparable to commonly used platinum-based regimens. A survival advantage was seen in stage IV patients with monthly irinotecan plus cisplatin in a meta-analysis of two phase II trials. A weekly irinotecan-plus-cisplatin regimen appears to be more active and better tolerated, Dr. Langer concluded.
The next step will be to combine irinotecan with cis-platin and radiotherapy in locally advanced surgically unresectable, medically inoperable stage II/IIIA, and locally recurrent NSCLC.