Irinotecan Produces Responses in Small-Cell and Non-Small-Cell Lung Cancer

NASHVILLE, Tennessee—The failure of current chemotherapy to make much of an impact on lung cancer mortality makes the need for more effective chemotherapy obvious and data on active new agents was presented at the Vanderbilt University Symposium by Alan Sandler, MD.

"Lung cancer accounts for more deaths than breast, colon, and prostate cancer combined," Dr. Sandler noted. Among the approximately 135,000 patients diagnosed with non-small-cell lung cancer (NSCLC) annually, about 30% to 40% have metastatic disease at presentation, and untreated patients have a median survival of about 5 months. Cisplatin-based therapy improves median survival by only about 2 months, and 1-year survival improves from 10% without treatment to approximately 20%-25%, although it does relieve symptoms and improve quality of life (QOL) in 66% to 78% of patients with stage III/IV disease.

Widely Used Combinations

Most of the drugs reviewed, including paclitaxel (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), and gemcitabine (Gemzar), are in clinical trials of combination therapy (Figure 1). A number of combinations are already being widely used in the clinic. "Cisplatin/paclitaxel, cisplatin/gemcitabine, and cisplatin/vinorelbine are approved by the Food and Drug Administration for advanced NSCLC due to a demonstrated increase in survival," Dr. Sandler said. "Cisplatin/irinotecan has produced comparable results in two Japanese trials."

Dr. Sandler, who is associate professor of medicine and medical director of thoracic oncology at Vanderbilt University Medical Center in Nashville, Tennessee, cited a phase II study by Fukuoka et al. That study showed a 31.9% response rate to irinotecan at 100 mg/m² weekly, with a median survival of 42 weeks in 72 untreated patients with advanced NSCLC. Principal toxicities were grade 3/4 leukopenia in 25% and grade 3/4 diarrhea in 21% of patients.

Negoro et al reported similar results: responses were seen in 23 of 67 untreated patients (34%) with advanced NSCLC. "A comparison of irinotecan/cisplatin, vinorelbine/cisplatin, and single-agent irinotecan in NSCLC showed a response rate of 44% with irinotecan/cisplatin median survival of 50 weeks, and 1-year overall survival of 46%," Dr. Sandler stated.

"Future directions in NSCLC include evaluating irinotecan in other combinations including doublets (with taxanes or gemcitabine) and triplets such as paclitaxel/carboplatin/irinotecan. Other future studies should include combinations with noncytotoxics such as angiogenesis inhibitors, tyrosine kinase inhibitors, or metalloprotease inhibitors," Dr. Sandler said. "There should also be continued evaluation of irinotecan in locally advanced NSCLC."

Small-Cell Lung Cancer

Small-cell lung cancer constitutes 15% to 25% of the 171,000 new lung cancer cases diagnosed each year in the United States. Irinotecan used as a single agent in previously untreated extensive small-cell lung cancer (SCLC) has produced response rates of 50% (4/8) as first-line treatment and 14% to 47% as second-line treatment, according to Dr. Sandler. Irinotecan combined with cisplatin produced complete response rates of 29% to 30% (overall response rate > 80%) and median survival of 13.0 to 14.3 months.

Irinotecan/cisplatin has been compared to etoposide/cisplatin as first-line therapy in a Japanese phase III trial in extensive disease SCLC. "Two-year survival as of March 2000 was 18.9% with irinotecan/cisplatin vs 6.5% with etoposide/cisplatin (P = .0021)," Dr. Sandler said.

Dr. Sandler will be one of the principle investigators in a multicenter trial led by Vanderbilt University, University of Colorado, Indiana University, and Fox Chase Cancer Center comparing cisplatin/etoposide to cisplatin/irinotecan. This study will utilize a 3-week regimen of cisplatin/irinotecan as hematologic toxicity often resulted in reduced or missed doses of irinotecan on day 15 in the Japanese trial.

"Future directions for studies in SCLC will be to evaluate irinotecan in doublet and triplet combinations and in combinations with noncytotoxics including angiogenesis inhibitors, tyrosine kinase inhibitors, and metalloprotease inhibitors," Dr. Sandler said. "Irinotecan should also be evaluated in limited SCLC."