Topotecan and Paclitaxel in Previously Treated Patients with Relapsed Small Cell Lung Cancer: Phase II Trial of the North Central Cancer Treatment Group

Abstract

Small cell lung cancer (SCLC) is one of the most aggressive and lethal cancers in humans. It constitutes approximately 15 to 25% of all cases of primary lung cancers.1 Initial response rates of 70 to 90% for both limited and extensive stages of SCLC may be achieved using standard combination cytotoxic chemotherapy agents. The 5-year survival for limited-state SCLC is 15 to 25%, but patients with extensivestage SCLC rarely survive 5 years. Even among patients who achieve a complete response, there is a high rate of relapse.2 Until recently, there has been no well-established treatment available for patients with recurrent SCLC.3 Topotecan is a camptothecin analogue that stabilizes the covalent adduct between topoisomerase I and DNA. In S-phase cells, these topo I-DNA adducts are converted into double-strand breaks that seem to be responsible for cytotoxicity.4 Several phase II5–8 trials as well as a phase III trial3 have demonstrated antitumor efficacy, manageable toxicities, and acceptable safety profile of topotecan in both chemo-naive and previously treated patients with SCLC. Patients in the topotecan group derived significant palliative benefits in general symptoms (e.g., anorexia, fatigue, interference with daily activities, and pulmonary symptoms) over CAV chemotherapy in a randomized trial.3 Although topotecan is currently approved for second-line therapy in SCLC at a starting dose of 1.5 mg/m by a daily 30-minute intravenous infusion for 5 consecutive days of a 21-day cycle, advanced age, extensive pretreatment, prior platinum therapy, prior radiotherapy, and renal impairment are potential risk factors for increased myelosuppression during topotecan therapy. Several studies suggest that the 1.0and 1.25-mg/m doses of topotecan may be appropriate for patients with such high-risk factors.9–11 Paclitaxel is a chemotherapeutic agent that promotes the assembly and stabilization of microtubules. Such binding causes cells to form abundant arrays of disorganized and dysfunctional microtubules, leading to apoptosis. Although there is documented single-agent activity of paclitaxel in phase II studies among chemo-naive patients with SCLC with extensive disease,12,13 response duration is short, which suggests that paclitaxel is not sufficient as a single agent. It is also widely accepted that combinations of cytotoxic drugs produce higher response rates and survival rates in patients with SCLC compared with single-agent therapy. The combination of topotecan and paclitaxel is rational as they have non-overlapping mechanisms of action and are both active agents in SCLC, as discussed previously. Moreover, there is demonstrable in vitro synergy of this combination in SCLC cell lines,14,15 although there are insufficient data on sequence-specific synergy. Phase II trials of the combination of topotecan and paclitaxel that have been reported used a 5-day topotecan schedule as first-line treatment in patients with extensive SCLC.16–19 A randomized phase II study evaluating four treatment combinations17 showed that paclitaxel (230 mg/m on day 1) plus topotecan (1 mg/m on days 1-5) produced excessive toxicity, with toxic deaths occurring in 25% of patients. Objective response rate was 54% with a median survival of 13.8 months. The toxicities were ameliorated in the treatment arm using an attenuated paclitaxel dose of 175 mg/m, with treatment-related death occurring in 3% of patients. Objective response rate in this arm was 69% with a median survival of 9.9 months and 1-year survival of 40%, similar to standard etoposide plus cisplatin chemotherapy. Another phase II trial in patients with chemo-naive extensive SCLC used topotecan 1 mg/m (first three patients received 1.25 mg/m) daily for 5 days and paclitaxel (135 mg/m) on day 5 via a 24-hour infusion every 4 weeks.16 Despite prophylactic G-CSF administration, this combination was associated with a high incidence of myelosuppression *Mayo Clinic and Mayo Foundation, Rochester, Minnesota, †Illinois Oncology Research Association CCOP, Peoria, Illinois; ‡Cedar Rapids Oncology Project CCOP, Cedar Rapids, Iowa; §Carle Cancer Center CCOP, Urbana, Illinois; Missouri Valley Cancer Consortium, Omaha, Nebraska; ¶Duluth CCOP, Duluth, Minnesota; **Wichita Community Clinical Oncology Program, Wichita, Kansas; ††Siouxland HematologyOncology Associates, Sioux City, Iowa. Address correspondence to: Grace K. Dy, MD, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. E-mail: Dy.Grace@mayo.edu Copyright © 2006 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/06/0103-0211