Small-cell lung cancer (SCLC) accounts for approximately 20% to 25% of all lung cancer cases and is associated with an especially poor prognosis, resulting in about 25% of all lung cancer deaths.[1-3] The disease is characterized by an aggressive clinical course with early dissemination of regional and distant metastasis. Tumors are initially chemosensitive but become drug-resistant during treatment. About 30% to 40% of SCLC patients present with limited-stage disease confined to one hemithorax and regional lymph nodes without pericardial or pleural effusion. The majority of patients are initially diagnosed with more advanced and less treatment-sensitive disease. The 5-year survival for limited-stage SCLC is about 20% to 25% and is negligible for patients with extensive disease.
Combination chemotherapy is the most effective treatment modality for SCLC. For patients with extensive-stage SCLC, chemotherapy can increase the median survival from about 1.5 months to 7 to 11 months, with 2-year survival uncommon.[1,6] Standard chemotherapy regimens for SCLC include CAV (cyclophosphamide [Cytoxan, Neosar], doxorubicin(Drug information on doxorubicin) [Adriamycin], vincristine; cisplatin (or carboplatin(Drug information on carboplatin) [Paraplatin]) and the DNA topoisomerase II inhibitor etoposide(Drug information on etoposide); or the alternation of these two combinations (eg, CAV followed by cisplatin(Drug information on cisplatin)/etoposide). For patients with extensive SCLC, etoposide/cisplatin is most commonly used as first-line treatment. Survival with this regimen is comparable to that achieved with CAV and other early combinations (median overall survival: 7 to 11 months), but with a more favorable toxicity profile.
Over the past 2 decades, randomized clinical trials have established some of the limits of combination chemotherapy for SCLC in terms of a survival benefit for patients with extensive disease (Table 1).[8-20] These limits include the following observations: (1) Improvements have been modest, and no combination regimen has emerged as consistently superior, either in pre-1990 trials or in trials of new agents over the past decade; (2) neither high-dose chemotherapy, increased dose intensity, nor the addition of a third agent (ie, ifosfamide(Drug information on ifosfamide) [Ifex] or paclitaxel(Drug information on paclitaxel)) have improved survival; (3) chemotherapy for up to six treatment cycles is as effective as longer-term treatment or the addition of maintenance therapy.[3,7,21-24]
Several new agents, including carboplatin, ifosfamide, and the taxanes, have been shown to be active against SCLC but have not produced an improvement in overall survival (Table 1). Among the most active to date has been the topoisomerase I inhibitor irinotecan(Drug information on irinotecan) (CPT-11, Camptosar). This review focuses on first- and second-line treatment of extensive SCLC with irinotecan-containing regimens.
Irinotecan hydrochloride is a semisynthetic derivative of the plant alkaloid camptothecin that inhibits topoisomerase I activity. During DNA replication, topoisomerase I relieves torsional strain by inducing reversible single-strand breaks.[26,27] Irinotecan, and to a much greater extent its active metabolite SN-38, prevent relegation of these breaks by binding to the topoisomerase I-DNA complex. Irinotecan-induced cytotoxic death may occur through the interaction of replication enzymes with this ternary molecular complex, possibly by arresting DNA replication and leading to lethal double-strand DNA breaks.
When administered either intravenously or orally, irinotecan has demonstrated antitumor activity in preclinical studies in a variety of mouse tumors and human tumor xenografts, including drug-resistant tumors.[30-32] Irinotecan also complements the antitumor activity of agents that act through other effects on DNA replication (eg, cisplatin or gemcitabine(Drug information on gemcitabine) [Gemzar]) or interfere with other vital cell functions (eg, the taxanes), either additively or synergistically.[33-38] In addition, irinotecan is being evaluated for its radiosensitizing properties.
In several phase II studies, single-agent irinotecan has shown antitumor activity as second-line therapy in patients with extensive SCLC. Overall response rates in these trials have ranged from 13.6% to 47%, with doses of 100 to 125 mg/m² weekly and 350 mg/m² every 3 weeks (Table 2).[40-45] In two of these studies, response rates were substantially higher than the approximately 20% response rate typically achieved with single-agent etoposide; however, one study included some previously untreated patients, and the other study was conducted mostly in patients who were considered sensitive relapses to first-line therapy.
In a recent US phase II study involving previously treated SCLC patients, 45 patients received irinotecan at 125 mg/m²/wk for 4 weeks, followed by 2 weeks of rest. The majority of patients received only a single course of treatment. The overall response rate was 14%, but 29% among 17 patients with sensitive-relapse disease (ie, relapse > 90 days after completing chemotherapy). Similarly, another camptothecin analog, topotecan(Drug information on topotecan) (Hycamtin), produced a response rate of 38% among chemosensitive patients but of only 6% among refractory patients (ie, patients not initially responding to chemotherapy, or those who relapsed less than 90 days after completing chemotherapy). Thus, when used alone in the second-line setting, topoisomerase I inhibitors appear to have activity only in patients with sensitive SCLC.
The combination of irinotecan and cisplatin has been studied in patients with previously treated SCLC. In a phase II trial in such patients, Nakanishi et al established significant activity with irinotecan, 60 mg/m², administered on days 1, 8, and 15 of each 4-week cycle, together with either 30 or 60 mg/m² of cisplatin every 28 days (Table 2). In an earlier investigation that used the higher dose of cisplatin, unspecified reductions in the dose of irinotecan were required due to the occurrence of leukopenia.
Masuda and colleagues reported a phase II trial of the combination of irinotecan and etoposide that included 17 eligible patients with previously treated SCLC. Treatment consisted of irinotecan, 70 mg/m², on days 1, 8, and 15 of each 28-day cycle, plus etoposide, 80 mg/m², on days 1 to 3, with granulocyte colony-stimulating factor (G-CSF, Neupogen) support. The overall response rate was 71%, with 25% complete responses. Median survival was 8.2 months, and the 1-year survival was 29%. The median survival for patients with relapsed SCLC receiving second-line chemotherapy was approximately 5 monthsan encouraging result. It should be noted that at least 80% of patients in the study were considered sensitive relapses, which may account for some of the improved responsiveness.
A phase I study in patients with extensive SCLC evaluated second-line irinotecan/paclitaxel following induction therapy with, or relapse from, cisplatin/etoposide. A weekly regimen of irinotecan, 60 mg/m², plus dose-escalated paclitaxel, 15 to 60 mg/m², for 3 weeks achieved responses in 5 of 7 patients, including 3 complete remissions. Based on these results, a phase II study is currently under way, with paclitaxel being administered at 50 mg/m² in previously untreated patients.