A phase II study of topotecan and docetaxel in patients with sensitive relapse small cell lung cancer

To the Editor

Although small cell lung cancer (SCLC) is considered highly responsive to chemotherapy, the vast majority of patients succumb to the disease within 2 years. Patients without response or who relapse within 3 months from the completion of first-line chemotherapy have highly resistant tumors and are considered to have refractory disease. Salvage chemotherapy in this setting has limited success and prognosis is very poor. Patients with treatment-free interval greater than 3 months or sensitive relapse on the other hand, have an increased probability of responding to subsequent chemotherapy [1]. Topotecan is a topoisomerase I inhibitor commonly utilized in the second-line treatment for SCLC, particularly after it was found to be at least as effective as the combination of cyclophosphamide, doxorubicin and vincristine (CAV) in this setting [2]. Topotecan resulted in improved control of several symptoms including dyspnea, anorexia, and fatigue. Response rate was 24% and median survival 25 weeks in the topotecan arm. Docetaxel has documented single agent activity in relapsed SCLC with response rate of 19% in a combined analysis of two small phase II studies [3]. The combination of topotecan and docetaxel for the treatment of patients with solid tumors has been previously evaluated in two phase I trials where the dose-limiting toxicity was neutropenic fever [4], [5].

We designed a trial to evaluate the efficacy and toxicity for the combination of topotecan and docetaxel in patients with sensitive relapse SCLC. Patients aged 18 or more, with histologically proven SCLC progressing at least 3 months following response to one or more previous chemotherapy regimens, not previously treated with topotecan or taxanes, ECOG performance status 0 to 2, and adequate cardiac, renal, and hepatic function were enrolled from two different cancer centers between May 2000 and February 2002. Treatment consisted of docetaxel 60 mg/m² intravenously over 60 min followed by topotecan 0.75 mg/m² intravenously over 30 min on day 1. Topotecan was repeated at the same doses on days 2 to 4. Patients received subcutaneous filgrastim starting on day 5 until the achievement of absolute neutrophil count (ANC) greater than 10 000/mm³ for 2 consecutive days and dexamethasone 8 mg orally twice a day for 3 consecutive days, starting 24 hours before the first day of chemotherapy. Cycles were repeated every 21 days. Patients were evaluated before each cycle of therapy for toxicity according to the national cancer institute (NCI) common toxicity criteria and evaluated for response by the RECIST criteria. Patients with neutropenic fever or grade IV myelotoxocity, including neutropenia or thrombocytopenia, lasting one week or longer had the docetaxel dose reduced to 45 mg/m², while maintaining the original dose of topotecan. A second episode of severe myelosuppression despite dose reduction resulted in withdraw from the study. The primary endpoint of the study was response rate. To allow for early stopping in the event that few responses were observed, a Simon minimax two-stage design was used [6]. Since the literature indicates an approximately 30% response rate for second-line chemotherapy in patients with sensitive SCLC, this target was chosen as the smallest probability of response justifying investigation of this experimental drug combination. We planned to recruit 19 patients and terminate the trial in case of 6 or fewer responses or accrue an additional 20 patients in case of seven or more initial responders. The analyses were performed with SAS version 7. Sample size was calculated with the STPLAN version 4.1.

The study was closed after the enrollment of the first eight patients. There were four males and four females with ages between 40 and 79. Performance status was ECOG 0 in three patients, ECOG 1 in four patients, and ECOG 2 in one patient. Two patients received previous chemotherapy only and six patients received both chemotherapy and irradiation, including prophylactic brain irradiation in three patients. Six patients were evaluable for response. Two patients were removed from the study, the first one due to allergy to filgrastim and the second one due to refusal to continue on therapy after the first cycle. Of the six evaluable patients, four patients had stable disease and two had progressive disease. Only one patient was able to complete six cycles of chemotherapy. The most common grade 3 or 4 toxicity was neutropenia, occurring in five patients. Other severe toxicities included thrombocytopenia in three patients, anemia in one patient, dehydration in two patients, fatigue in two patients, and malaise in one patient. The lack of responses, poor accrual, and increased toxicity leading to early withdrawal of therapy in three of the four patients with ongoing stable disease resulted in the premature closure of the study for patient safety. It is unclear why this treatment was so toxic and ineffective in our population. The treatment was administered with the lower doses and identical sequence to the regimen previously tested by Tkaczuk et al. [5]. The only difference was the administration of docetaxel on day 4 in the even cycles of the phase I study. The lack of responses in the first patients may be attributed at least in part to the significant toxicity leading to dose delay and early discontinuation from the study. The combination of topotecan and docetaxel at the doses utilized in our study cannot be recommended as a second-line therapy for patients with chemotherapy-sensitive relapsed SCLC.

Conflict of interest

The authors have no conflict of interest to report.