Small-cell lung cancer accounts for approximately 20% to 25% of all cases of lung cancer and has an especially poor prognosis, resulting in about 25% of all lung cancer deaths.[1-3] Small-cell lung cancer is characterized by an aggressive clinical course with early dissemination of regional and distant metastases. Tumors are initially chemosensitive but acquire drug resistance during disease progression. About 30% to 40% of small-cell lung cancer patients present with limited-stage disease that is 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 extensive-stage disease. The 5-year survival rate for small-cell lung cancer is only about 5% overall, and is negligible for patients with extensive-stage disease.
Combination chemotherapy is the most effective treatment modality for small-cell lung cancer. For patients with extensive-stage small-cell lung cancer, chemotherapy can increase median survival from approximately 1.5 months to 7 to 11 months, with 2-year survival uncommon.[1,5] Standard chemotherapy regimens for small-cell lung cancer include cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar), doxorubicin(Drug information on doxorubicin) (Adriamycin), and vincristine (CAV); cisplatin or carboplatin(Drug information on carboplatin) (Paraplatin) plus the DNA topoisomerase II inhibitor etoposide(Drug information on etoposide); or alternating these two combinations (eg, CAV followed by cisplatin(Drug information on cisplatin)/etoposide). Cisplatin/etoposide is the most widely used first-line regimen for patients with extensive-stage small-cell lung cancer, and results in survival comparable to that obtained with CAV or other early combinations (median overall survival: 7 to 11 months), but with a more favorable toxicity profile.
Several new agents, including paclitaxel(Drug information on paclitaxel), topotecan(Drug information on topotecan) (Hycamtin), gemcitabine(Drug information on gemcitabine) (Gemzar), and irinotecan(Drug information on irinotecan) (CPT-11, Camptosar), have exhibited significant activity as single agents against small-cell lung cancer (Table 1). This review will focus on the treatment of extensive-stage small-cell lung cancer with the topoisomerase I inhibitor irinotecan when used alone and in combination with cisplatin.
Irinotecan hydrochloride, a semisynthetic derivative of the plant alkaloid camptothecin, inhibits topoisomerase I activity. During DNA replication, the enzyme topoisomerase I relieves torsional strain by inducing reversible single-strand breaks.[7,8] Irinotecan, and to a much greater extent its active metabolite SN-38, prevents religation of those breaks by binding to the topoisomerase I/DNA complex. Irinotecan-induced cytotoxic death may occur through interaction of replication enzymes with this ternary molecular complex, possibly by arresting DNA replication and leading to lethal double-strand DNA breaks.
Antitumor activity of irinotecan has been demonstrated in preclinical studies with a variety of mouse tumors and human tumor xenografts, including drug-resistant tumors, when administered either intravenously or orally.[11,12] Irinotecan also complements the antitumor activity of agents that act through other effects on DNA replication (eg, cisplatin or gemcitabine) or interfere with other vital cell functions (eg, the taxanes), either additively or synergistically.[13,14]
Single-agent irinotecan has demonstrated antitumor activity as second-line therapy in several phase II studies of patients with extensive-stage small-cell lung cancer, achieving overall response rates of 13.6% to 47% with doses of 100 to 125 mg/m² weekly and 350 mg/m² every 3 weeks (Table 2).[15-17]
In a recent U.S. phase II study involving previously treated small-cell lung cancer patients, 45 patients received irinotecan at 125 mg/m² weekly for 4 weeks, followed by a 2-week rest; the majority of patients received only one treatment course. The response rate was 14% overall, but 29% among 17 patients with sensitive-relapse disease (ie, relapse more than 90 days after completing chemotherapy). Similarly, topotecan, another camptothecin analog, achieved a 38% response rate among chemosensitive patients, but only 6% of refractory patients responded (ie, patients not initially responding to chemotherapy, or those with relapse less than 90 days after completing chemotherapy).