The eligible patients for this study were required to meet all of the following criteria: 1) Histologically or cytologically confirmed SCLC, 2) progressive disease after one first-line chemotherapy not including camptothecin analogues, 3) age 18~80 years inclusive, 4) ECOG Performance score below 2, 5) life expectancy above 3 months, and 6) written informed consent, 7) presence of at least one bidimensionally measurable disease, 8) WBC count greater than 3,500×10⁹/L, absolute granulocyte count ≥1,500×10⁹/L, hemoglobin ≥9.0 g/dl, platelet ≥100×10⁹/L, 9) total bilirubin level ≤1.5 mg/dl, AST and ALT ≤two times the upper normal limit in absence of liver metastasis, creatinine level ≤1.5 mg/dl and a calculated creatinine clearance >60 ml/min. Patients with increased bilirubin (up to 2.5 times the upper normal limit) because of liver metastases were also considered eligible. Patients must have been off all previous systemic chemotherapy at least 3 weeks before study entry and must have recovered from the side effects of prior therapy. Patients with brain metastases were eligible provided that neurologic symptoms were under control with radiotherapy or steroid treatment, and the brain was not the only site of assessable disease.

Belotecan (CKD-602) was administered intravenously, 0.5 mg/m²/d (diluted in 100 ml of 5% dextrose water) as a 30-minute infusion for 5 consecutive days. Chemotherapy treatment schedule were repeated every 3 weeks if neutrophil count was more than or equal to 1.5×10⁹/L, the platelet count was more than or equal to 100×10⁹/L and recovery to Common Toxicity Criteria (CTC) grade I nonhematologic toxicity had occurred. Belotecan dose reduction 0.1 mg/m²/d was to be performed in case of grade IV neutropenia complicated by fever or lasing 7 days or longer, grade III neutropenia lasting beyond day 21 of the treatment cycle, or grade IV thrombocytopenia. Also same dose reduction were applied to grade III or IV nonhematologic toxicity (excluding grade III Nausea), or the patient could be withdrawn from the study.

To evaluate the Responses of tumor lesions and toxicity profiles, we monitored chest radiography, computed tomography (CT) scans, complete blood cell counts, and blood chemistries. The response could be evaluated in 42 patients who were treated with belotecan above 1 cycle. And we observed overall response rate, survival and toxicities of belotecan monotherapy (0.5 mg/m² for 5 days every 21 days) after failure of etoposide and platinum (EP).

Statistical analyses were done using SPSS for Window version 12.0 (SPSS Inc., Chicago, IL, USA). Descriptive statistics, frequency tables, x² tests were used.

Survival time and time to progression were recorded as days from the beginning of belotecan treatment. Kaplan-Meier method was used to calculate survival and time to progression according to predictors were done using a log-rank test.

From Aug 2004 to Oct 2006, the 49 patients were entered onto the study and 44 patients could be evaluated the response and toxicity profiles. 5 patients could not follow up on the response. Reason for loss to follow-up were death and poor physical status. The characteristics of enrolled patients are summarized in Table 1. The mean age of 64.5±7.6 (mean±SD) years. All of patients were treated by etoposide and platinum combination chemotherapy (EP) as first-line chemotherapy. Responses to previous first-line chemotherapy (etoposide/platinum) were partial remission (PR) in 29, stable disease (SD) in 7, progression (PD) in 9, and not evaluable in 4 cases. 21 patients showed relapse more than 90 days after prior EP therapy (sensitive relapse, SR) and 28 patients relapsed within 90 days after prior chemotherapy (refractory relapse, RR).

Dose intensity was calculated as the sum of the daily doses delivered during the course divided by the duration of the course in weeks. Relative dose intensity was 78±15% in responders and 83±13% in non-responders (p=0.03).

Within the 49 eligible patients, 5 patients could not be evaluated for response because of inadequate radiologic assessment. After receiving belotecan above at least 1 cycle of the 44 assessable patients, 11 patients showed partial remission, 19 patients remained stable, and 10 patients showed progression of their disease. The overall response rate was 25% (11/44) and the disease control rate (partial remission+stable disease) was 75%. There were no significant difference in response rate between sensitive and refractory patients group (6 PRs, 10 SDs and 4 PDs in sensitive relapses; 5 PRs, 12 SDs and 7 PDs in refractory patients).

Median survival time (MST) from the beginning of belotecan treatment was 10.3 months (290 days). MST of non-responders were 186 days (95% CI; 67~305), while responders were 401 days (95% CI; 234~568, p=0.07) (Figure 1). MST was not different between SR (290 days) and RR (376 days). Median progression free survival (MPFS) was 73 days (95% CI; 48~98 days). MPFS of responders was 112 days in contrast to 61 days of non-responders (p=0.06, Figure 2). MPFS was not different between SR (79 days) and RR (67 days).

Grade III~IV neutropenia, anemia, and thrombocytopenia were experienced by 59.6%, 12.8% and 23.4% of belotecan patients. And the severity of nonhematologic toxicity is generally mild. In our study, the grade III~IV nausea, vomiting, and myalgia have not been experienced.