Small-cell lung cancer differs from other types of lung cancer in its more aggressive clinical course and in its superior responsiveness to chemotherapy and radiotherapy. Chemotherapy is currently the main treatment for all stages of small-cell lung cancer.
In phase III investigations by the Japan Clinical Oncology Group (JCOG) in extensive disease (JCOG 9106), current combination chemotherapy regimens such as etoposide(Drug information on etoposide)/cisplatin (Platinol) produced response rates of 60% to 80%, complete response rates of 15% to 20%, and a median survival of 10 to 12 months (N = 227). In a phase III study of 228 evaluable patients with limited disease (JCOG 9104), a regimen of etoposide/cisplatin with early concurrent thoracic radiotherapy twice daily (30 fractions, 45 Gy each) produced response rates of 85% to 95%, complete response rates of 40% to 60%, and a median survival of 24 months. However, these therapeutic outcomes still leave substantial room for improvement.
One of the most important approaches in the treatment of small-cell lung cancer is new drug development. In the 1990s, drugs with novel mechanisms of actionsuch as paclitaxel(Drug information on paclitaxel) (Taxol), irinotecan(Drug information on irinotecan) (Camptosar, CPT-11), and gemcitabine(Drug information on gemcitabine) (Gemzar)were introduced (see Table 1). Irinotecan, a water-soluble camptothecin derivative developed in Japan, acts by inhibition of topoisomerase I; it is one of the most active agents against small-cell lung cancer.
In a phase II multicenter study of irinotecan in small-cell lung cancer on a weekly schedule at a dose of 100 mg/m2, Negoro and colleagues reported response rates of 33% in 27 previously treated patients and 50% in 8 previously untreated patients, resulting in an overall response rate of 37.1%. Two complete and 13 partial responses were observed. The major toxicities were leukopenia and diarrhea (which were dose limiting, but reversible), nausea/vomiting, anorexia, and alopecia. The authors concluded that irinotecan was highly effective against small-cell lung carcinomas.
In a prospective nonrandomized phase II single-institution study, Masuda and collaborators assessed irinotecan at 100 mg/m2/wk in 16 patients who had been pretreated heavily with cisplatin(Drug information on cisplatin)-based combination chemotherapy. In 15 assessable patients (14 relapsed and 1 refractory), investigators reported an overall response rate of 47% (95% confidence interval: 21.4% to 71.9%), with seven partial responses. The major toxicities were myelosuppression (predominantly grade 3/4 leukopenia in 33%), diarrhea, and pulmonary toxicity. The authors concluded that irinotecan was an active agent against refractory or relapsed small-cell lung cancer, and the data warranted further study in single-agent and combination therapy.
In a phase II trial, the combination of irinotecan at 60 mg/m2 on days 1, 8, and 15 (80 mg/m2 for the first 10 patients), and cisplatin at 60 mg/m2 on day 1, every 4 weeks, was assessed in previously untreated small-cell lung cancer patients. The overall response rate was 84%, with a complete response rate of 29%. The median survival time was 14.3 months for 40 limited-disease patients and 13.0 months for 35 extensive-disease patients. Two-year survival rates were 17.5% for limited-disease patients and 21.7% for extensive disease. The response rates are enumerated in Table 1. Major grade 3/4 toxicities were neutropenia (77%), leukopenia (45%), anemia (39%), and diarrhea (19%). The authors concluded that the combination of irinotecan/cisplatin was a new active regimen for small-cell lung cancer (especially extensive disease), with acceptable toxicity.
Based on these results, the JCOG conducted a phase III study of irinotecan/cisplatin vs etoposide/cisplatin in extensive-disease small-cell lung cancer (JCOG 9511, Chairman Nagahiro Saijo).[6,7] The primary end point was survival. Patients in the study arm received a combination of irinotecan at 60 mg/m2 on days 1, 8, and 15, and cisplatin at 60 mg/m2 on day 1, on an every-4-week schedule. The standard arm consisted of etoposide at 100 mg/m2 on days 1, 2, and 3, and cisplatin at 80 mg/m2 on day 1, every 3 weeks, for four courses.
After accrual of 154 patients between November 1995 and November 1998, the study was stopped in December 1998 because of a large, statistically significant difference in survival at the second interim analysis. Median survival was 411 days for the new combination of irinotecan/cisplatin and 282 days for standard etoposide/cisplatin. Also, there was a trend toward a higher response rate in patients receiving the irinotecan-containing regimen (83.1% vs 67.5%), as well as significant increases (P = .0021) in both 1-year (58.4% vs 37.7%) and 2-year survival (18.9% vs 6.5%) with the new combination. A summary of these responses is shown in Table 2.
Hematologic toxicity was less pronounced in patients receiving irinotecan/cisplatin compared to etoposide/cisplatin, with significantly less JCOG grade 3/4 leukopenia (27% vs 52%; P = .003), grade 3/4 neutropenia (66% vs 92%; P = .0002), and grade 3/4 thrombocytopenia (5% vs 19%; P = .0001). Among nonhematologic toxicities, only the incidence of grade 3/4 diarrhea was increased in the irinotecan/cisplatin arm (16% vs 0%; P = .0001); others did not differ significantly between the two arms.
The authors concluded that in patients with extensive-disease small-cell lung cancer, the four cycles of irinotecan plus cisplatin regimen every 4 weeks yielded a significant improvement in survival over standard etoposide/cisplatin, and resulted in less myelosuppression.
Two North American randomized phase III trials are being planned that will attempt to reproduce and extend these promising results. One will utilize the JCOG 9511 trial design, and the second will employ a study arm in which the schedule is modified to irinotecan at 65 mg/m2 on days 1 and 8, plus cisplatin at 30 mg/m2 on days 1 and 8, every 3 weeks.
Irinotecan/cisplatin is superior to etoposide/cisplatin in survival with tolerable toxicity, and irinotecan/cisplatin regimens are a new standard treatment for extensive-disease small-cell lung cancer (see Table 3).