Patients with SCLC usually present with disseminated disease; therefore, treatment strategies have focused on systemic therapy. SCLC commonly responds to treatment with multiple chemotherapeutic agents, both as single agents and in combination. Response rates of 80% to 100% (50% to 70% complete response) in limited disease and 60% to 80% (8% to 30% complete response) in extensive disease have been achieved with chest radiation plus chemotherapy or with combination chemotherapy. The tumor response to the treatment has a median duration of approximately 6 to 8 months. The median survival rates from the time of diagnosis for limited-stage and extensive-stage disease are 14 to 20 months and 8 to 13 months, respectively. After disease recurs, median survival is about 4 months. About 40% of patients with limited-stage disease survive for 2 years, whereas fewer than 5% of those with extensive-stage disease survive for 2 years. Chest radiotherapy improves actuarial local control rates from 10% to about 40% to 60% in limited-stage disease patients and is associated with improved survival.

Many different chemotherapeutic agents are active against SCLC in both untreated and relapsed patients. The initial chemotherapeutic drugs administered include etoposide, cisplatin, carboplatin, irinotecan (also known as CPT-11), ifosfamide, cyclophosphamide, vincristine, and doxorubicin. The most commonly used initial combination is etoposide and cisplatin (EP). Agents used for second-line chemotherapy include ifosfamide, paclitaxel, docetaxel, gemcitabine, topotecan, irinotecan, CAV (cyclophosphamide, doxorubicin [Adriamycin], and vincristine), etoposide, and vinorelbine. Many different chemotherapy regimens are used including those that are in clinical trials. Substantial antitumor activity has been achieved by administering the taxanes (paclitaxel, docetaxel), topoisomerase Iinhibitors (topotecan, irinotecan), gemcitabine, and vinorelbine.

A phase III trial performed in Japan has shown that patients with extensive-stage SCLC who were treated with irinotecan plus cisplatin achieved a median survival of 14 months compared to 10 months for patients treated with etoposide/cisplatin. At 2 years, the proportion of patients surviving was 19.5% in the irinotecan-pluscisplatin group and 5.2% in the etoposide-plus-cisplatin group; three treatment-related deaths occurred in the irinotecan-plus-cisplatin group, which were due to hematologic toxicity. A confirmatory trial in the United States and Europe has completed accrual, and the results will be reported within 1 year.

Several conclusions have been reached. Etoposide is the major agent that provides a benefit when added to a cisplatin or carboplatin regimen. The EP combination was developed because of preclinical synergy and has become the most frequently used combination for SCLC. EP appears to be superior to CAV alone and is now the regimen of choice to combine with concurrent chest radiotherapy for patients with limited-stage disease. Cisplatin and etoposide have a favorable therapeutic index because they cause little mucosal toxicity, the risk of developing interstitial pneumonitis is low, and hematologic toxicity is modest. In clinical practice, substituting carboplatin for cisplatin is common, especially for patients with extensive-stage disease, to reduce emesis and neuropathy; however, increased myelosuppression is to be expected. The substitution of carboplatin for cisplatin in limited-stage patients being treated with combined-modality therapy has not been adequately evaluated. The addition of ifosfamide or cyclophosphamide plus an anthracycline to EP has provided a modest survival advantage for patients with extensive disease. In two trials of patients with extensive-stage disease, survival improved with the addition of ifosfamide or cyclophosphamide and the anthracycline. However, improved results using ifosfamide have not been uniformly observed, and ifosfamide also increases toxicity. Maintenance chemotherapy beyond 4 to 6 cycles produces a minor prolongation of response without improving survival. Cumulative toxicity is seen, and, therefore, maintenance chemotherapy is not recommended.