A Phase I study of paclitaxel, etoposide, and cisplatin in extensive stage small cell lung cancer

This Phase I study was designed to determine the maximally tolerated dose (MTD) of paclitaxel with standard doses of cisplatin and etoposide for patients with untreated extensive stage small cell lung cancer (SCLC). Secondary objectives were to determine the toxicities, response rate, response duration, and overall survival in this cohort. Twenty-eight SCLC patients were enrolled into four dose levels. All patients received a fixed dose of cisplatin at 80 mg/m², i.v., day 1. The first group received etoposide 50 mg/m², i.v. day 1 and 100 mg/m² p.o., days 2-3, whereas all subsequent groups received etoposide 80 mg/m², i.v., day 1 and 160 mg/m², p.o., days 2-3. The paclitaxel starting dose was 135 mg/m², i.v., over a 3-h period and was escalated to 175 and 200 mg/m². Cycles were repeated every 21 days for a maximum of six cycles. Granulocyte-colony stimulating factor was not given prophylactically but was allowed in subsequent cycles according to the American Society of Clinical Oncologists guidelines. All 28 SCLC patients were evaluable for toxicity, and 23 patients were evaluable for response. Myelosuppression was the major toxicity, with grade 4 neutropenia occurring in 23 of 28 patients (82%), but febrile neutropenia was uncommon and developed in 4 patients (14%). Grade 4 thrombocytopenia and anemia were rare, occurring as isolated events in one patient each. Dose-limiting peripheral neuropathy was observed at a paclitaxel dose of 200 mg/m². Grade 4 nausea/vomiting and diarrhea were also noted at this dose level. Five patients had complete responses (22%), and 14 patients had partial responses (61%). The overall response rate was 83% with a median time to progression of 7.5 months, a median survival of 10 months, and a 1-year survival rate of 39%. This three-drug combination of paclitaxel with cisplatin and etoposide is active with acceptable toxicity. Neurotoxicity was dose limiting at 200 mg/m² of paclitaxel. Neutropenia was frequent but not associated with significant morbidity. The recommended doses for future clinical trials are 175 mg/m² paclitaxel, i.v., over a 3-h period on day 1 with 80 mg/m² cisplatin, i.v., on day 1 and 80 mg/m² etoposide, i.v., on day 1 and 160 mg/m² p.o. on days 2 and 3 with growth factor support. The Southwestern Oncology Group has instituted a Phase II study with this dose schedule.