Small-cell lung cancer accounts for approximately one-fifth of primary lung cancer cases. It possesses different biologic characteristics compared with other types of lung cancers, including rapid tumor growth, early metastases, and high level of sensitivity to chemotherapy and radiotherapy. Since patients with small-cell lung cancer usually present with disseminated disease, combination chemotherapy is the cornerstone of treatment for patients in all disease stages, with major responses in 65% to 85% of cases, including 25% to 50% complete responses.
Most patients experience tumor relapse and die within 2 years, however. With chemotherapy and thoracic radiotherapy, the median survival duration is 10 to 15 months for limited-disease patients, and patients with extensive disease show a median survival time of 7 to 11 months with chemotherapy.
Combination chemotherapy regimens include CAV (cyclophosphamide [Cytoxan, Neosar], doxorubicin(Drug information on doxorubicin) [Adriamycin], and vincristine [Oncovin]); CAE (cyclophosphamide, doxorubicin, and etoposide(Drug information on etoposide) [VP-16, VePesid]); CAVE (cyclophosphamide, doxorubicin, vincristine, and etoposide; PE (cisplatin (Platinol) and etoposide; and CE (carboplatin [Paraplatin] and etoposide). In randomized trials, three regimensCAV, PE, and CAV alternating with PEyielded similar survival rates, but PE resulted in less myelosuppression.[2,3] Therefore, the most widely used regimen is the combination regimen PE.
There have been no major advances in the treatment of small-cell lung cancer during the last decade. The recent advent of new active agents including camptothecins, the taxanes, and gemcitabine(Drug information on gemcitabine) (Gemzar) provides hope for more effective therapies and, among these drugs, irinotecan(Drug information on irinotecan) (CPT-11, Camptosar) is the most promising agent.
Irinotecan is a water-soluble derivative of camptothecin, and exhibits strong antitumor activity in a broad spectrum of experimental models.[4,5] Camptothecin and its derivatives possess a unique mechanism of action that inhibits DNA topoisomerase I. Irinotecan is transformed to an active metabolite (SN-38) by carboxylesterase, an enzyme that is mainly found in the liver, bowel mucosa, and tumor tissue. Clinical studies have now shown that irinotecan possesses significant activity against a variety of malignant diseases, including small-cell lung cancer.
A Japanese phase I trial of irinotecan administered as a weekly IV infusion demonstrated that its dose-limiting toxicities included leukopenia and diarrhea, and the recommended dose for phase II studies was 100 mg/m2. Based on these results, irinotecan was administered at a dose of 100 mg/m2 IV once weekly in two phase II studies.[8,9] The results from four phase II trials of irinotecan monotherapy in small-cell lung cancer are enumerated in Table 1.
In a multi-institutional phase II trial, Negoro and coworkers enrolled 41 patients, 35 of whom were evaluable for response. The overall response rate was 37%, with a median response duration of 7 weeks. The response rate was 33% in 27 previously treated patients and 50% in 8 previously untreated patients. The median survival time was 35 weeks for all patients. The major toxicities were grade 3 or higher leukopenia (31%) and diarrhea (15%).
A single-institution trial by Masuda and colleagues delivered the same dose and schedule of irinotecan to 16 patients with refractory or relapsed small-cell lung cancer, of whom 15 were evaluable for response and toxicity. (All 15 patients had been heavily pretreated with some form of cisplatin(Drug information on cisplatin)-based regimens.) Only one patient was refractory to chemotherapy as defined by tumor growth during chemotherapy. Although there were no complete responses in the 15 patients, a partial response was obtained in 47% of patients, with a median duration of response of 8 weeks (range, 4 to 22 weeks). The median survival time from the onset of irinotecan therapy was 27 weeks.
The most frequent adverse event was myelosuppression: 34% and 0% of patients had severe leukopenia and thrombocytopenia (WHO grade 3 or 4), respectively. Greater than grade 2 nausea and vomiting occurred in 13% of patients, and diarrhea was observed in 7%. One patient (7%) experienced grade 4 paralytic ileus. Grade 3 or 4 pulmonary adverse events occurred in two patients (13%).
A French trial used a different approach with a dosage of 350 mg/m2 every 3 weeks that resulted in a lower overall response rate of 16% in 32 previously treated patients who had received etoposide-cisplatin-based first-line chemotherapy. The median duration of response was 131 days, and median survival was 125 days. The major grade 3 or 4 toxicities were neutropenia (58%), febrile neutropenia (22%), delayed diarrhea (37%), and nausea and vomiting (22%).
Seventeen sensitive-relapse patients (those who initially responded but progressed after a treatment-free interval of at least 90 days) and 27 refractory patients (those who failed first-line treatment, or who initially responded but progressed within 90 days of the end of therapy) were enrolled in a US phase II study conducted by DeVore et al. Patients received irinotecan at an initial dosage of 125 mg/m2 weekly for 4 of 6 weeks. Response rates were 35.3% in patients with sensitive disease and 3.7% in patients with refractory disease, and median survivals were 5.9 and 2.8 months, respectively. Overall survival was 4.8 months. Grade 3 or 4 late diarrhea was reported in 26.6% of patients, and grade 3 or 4 neutropenia in 26.7%.
Overall, single-agent irinotecan exhibited encouraging response rates in pretreated small-cell lung cancer patients, although studies examining irinotecan in first-line therapy were lacking.
Irinotecan and Cisplatin
The preclinical synergism between irinotecan and cisplatin, irinotecan’s lack of cross-resistance, and differing mechanisms of action and toxicity profiles between the two drugs provided a rationale for examining the use of these agents in the treatment of small-cell lung cancer. Masuda and co-workers conducted a phase I trial to determine the maximum tolerated dose of irinotecan together with a fixed dose (60 mg/m2) of cisplatin in patients with advanced lung cancer, and the dose-limiting toxicities of this combination. The maximum tolerated dose of irinotecan was 90 mg/m2 on days 1, 8, and 15, plus cisplatin 60 mg/m2 on day 1, every 4 weeks, with diarrhea being the dose-limiting toxicitiy. In this phase I study, five (36%) partial responses and one (7%) complete response were observed for an overall response rate of 43%. The response rates for non-small-cell lung cancer and small-cell lung cancer were 33% (4 out of 12 patients) and 100% (2 out of 2 patients), respectively. The recommended dosages for phase II studies were irinotecan 80 mg/m2 on days 1, 8, and 15, plus cisplatin 60 mg/m2 on day 1, every 4 weeks.
The West Japan Thoracic Oncology Group (WJTOG) conducted a phase II trial of this combination regimen in previously untreated small-cell lung cancer patients. Kudoh et al initially administered irinotecan at 80 mg/m2 to 10 patients on days 1, 8, and 15, in combination with cisplatin 60 mg/m2 on day 1. The irinotecan dose was reduced to 60 mg/m2 because 3 of the initial 10 patients experienced severe toxicity, and 1 of them died of diarrhea and neutropenia.
Among the 75 patients that were enrolled, 72 were evaluable for response, and all were assessable for toxicity (Table 2). Forty patients with limited disease achieved an overall response rate of 83% and a complete response rate of 30%; 35 patients with extensive disease achieved an overall response rate of 86% and a complete response rate of 29%. The median response duration was 8.0 months for limited-disease patients and 6.6 months for extensive-disease patients. The median survival was 14.3 months for limited-disease patients and 13.0 months for extensive-disease patients. The 2-year survival rate was 21.7% for limited-disease patients and 17.5% for extensive-disease patients. The major grade 3 or 4 toxicities were neutropenia (77%), anemia (39%), and diarrhea (19%).
In a similar study, patients with prior chemotherapy also received irinotecan 60 mg/m2 on days 1, 8, and 15 with cisplatin 60 mg/m2 on day 1. Sixteen patients were enrolled; the chemotherapy-free interval was more than 90 days in nine patients, and less than 90 days in seven patients. The overall response rate was 19%, and the median survival was 5.7 months. The percentage of the projected dose of irinotecan administered was relative low (57%), mainly due to leukopenia.
Other schedules have also been investigated. Both irinotecan (60 mg/m2) and cisplatin (30 mg/m2) were administered together on days 1, 8, and 15, every 4 weeks. Among the five patients with refractory small-cell lung cancer, one achieved a partial response.