Randomized Phase III Trial of Cisplatin/Irinotecan Versus Cisplatin/Etoposide in Patients with Extensive-Stage Small-Cell Lung Cancer

Rationale With > 150,000 deaths per year, lung cancer maintains its discouraging > 40-year reign as the most common cause of death from malignancy in the United States. Small-cell lung cancer (SCLC) is a distinct clinicopathologic entity that accounts for approximately 20% of lung cancer cases and deaths. Although it is considered to be more chemotherapy- and radiation therapy (RT)–responsive than non–small-cell lung cancer, residual or recurrent chemotherapy-resistant metastatic disease inevitably leads to the death of > 90% of patients with SCLC. Therefore, the need remains to identify more effective systemic treatments for this highly lethal malignancy. Combination cisplatin/etoposide has been the cornerstone for the treatment of SCLC for nearly 2 decades. After its introduction as sole therapy or alternating with cyclophosphamide, doxorubicin, and vincristine, several large randomized clinical trials confirmed its superiority compared with other regimens in this disease.1-4 As the importance of concurrent chemotherapy and RT in patients with limited-stage disease became established, the facility of using cisplatin and etoposide in this combined modality approach further cemented its position as the treatment of choice for SCLC.5,6 In patients with extensivestage disease, several recent, large, randomized clinical trials comparing cisplatin/etoposide with cisplatin/etoposide/ifosfamide, cisplatin/etoposide/megace, cisplatin/oral etoposide, or cisplatin/etoposide/topotecan demonstrated objective response rates (RRs) of approximately 65%-70% and a median survival in the range of 8.7-10 months.7-10 There have been numerous unsuccessful attempts to improve on the results of standard cisplatin/etoposide in SCLC. These have included strategies to increase dose intensity, add a third or fourth agent, alternate with other multidrug regimens, and modify the schedule of administration.11-14 Although a few randomized trials have suggested a possible small improvement in outcome, all have been at the cost of increased toxicity, and none have been confirmed in a second randomized clinical trial. One randomized trial has indicated that carboplatin can be used in place of cisplatin with a more acceptable toxicity profile and no apparent loss in efficacy.15 In fact, combination cisplatin/etoposide probably represents the US community standard for the treatment of extensive-stage SCLC (ESCLC). Paclitaxel and the topoisomerase I inhibitors topotecan and irinotecan have been shown to have significant activity in patients with SCLC previously treated with chemotherapy, including primarily previous cisplatin/etoposide.16-21 Topotecan’s activity as second-line therapy has been convincingly demonstrated in a randomized clinical trial.22 The activity of these agents in this “salvage” setting has raised the hopes that they might possess sufficient activity in SCLC to positively impact overall survival if used as primary therapy. The most common strategy pursued to test this hypothesis has examined the addition of paclitaxel or topotecan to cisplatin/etoposide, thereby creating a 3-drug combination or the sequential or alternating administration of paclitaxel and/or topotecan with cisplatin/etoposide.23-29 Uncontrolled phase II trials have suggested that ≥ 1 of these approaches might improve therapeutic outcome with increased but acceptable toxicity. Several randomized clinical trials testing these hypotheses have been completed. One trial was closed early because of excess toxicity, and 1 underpowered study could only suggest an improvement in RR and median survival.30,31 An Intergroup trial of cisplatin/etoposide with or without paclitaxel showed no survival benefit to the addition of paclitaxel, but there was enhanced toxicity in patients with ESCLC.32