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Patients with untreated, stage IV, non small cell lung cancers (NSCLC); aged ≤ 75; WHO PS ≤ I; normal hematologic renal and hepatic baseline value have been selected for (treatment with the new Topolsomerase I inhibitor CPT 11 delivered as a 30’ IV infusion every 3 weeks at the dose of 350 mg/m2. Nineteen patients have been so far entered (M/F: 15/4; median age 62 (41–75); PS 0: 26%, 1: 63%,2: 11%); median number of involved organs: 3 (1–6) with lung in 30%, mediastinum in 21%, bone in 8% and liver in 5% of patients. All patients but one were chemotherapy naive. Patients have received 74 cycles (96% at the planned dose) and the median Relative Dose Intensity was 0.99. Efficacy (Preliminary Results) PR: 4; NC: 5; PD: 6; not evaluable: 4. Safety The following grade 3 or 4 toxicities have been observed: (% of patients) neutropenia: 28%; delayed diarrhea:. 26%; nausea/vomiting: 26%; anemia: 22%. An early cholinergic-like syndrome, never severe, was frequently observed. The most common symptom was diffuse sweating in 16% of patients. One toxic death occurred due to the combination of diarrhea and infection. Conclusion Severe neutropenia combined to severe diarrhea is the limiting toxicity. From these preliminary results, CPT 11 could be an effective drug in NSCLC, as formerly shown in Japanese studies.

A 25%–33% increase in initial doses of cisplatin (CDDP) and cyclophosphamide (CPM), when combined with standard doses of doxorubicin and etoposide, has been found sufficient to significantly improve both disease free and overall survival in patients with limited SCLC (NEJM 1993, 329, 1148–1152). In this following trial, we are testing whether or not an increase in dose-intensity of a quite similar 4drug regimen leads to an improvement in survival. From October 1991 to December 1994, 123 patients with untreated SCLC were enrolled in this study comparing “standard dose” (SD) PEVEP for 6 cycles versus “high dose” (HD) PEVEP + rh-GMCSF (E. Coli derived) for 4 cycles. SD PEVEP consisted of: Epirubicin 40 mg/m2 dl, CDDP 100 mg/m2 d2, Etoposide 75 mg/m2/d dl-3, CPM 400 mg/m2/d dl-3. In the HD PEVEP arm the intended doses for each cycle were increased by 50%, except for CDDP: 25%. This HD PEVEP arm was supported by a systematic use ofrh-GMCSF (5 μg/hg/d s. c.) administered from d4 to dl3. Thus, the cumulative doses in both arms were roughly similar. Responding patients with residual disease confined to the chest were eligible for thoracic radiation. Complete responders were eligible for prophylactic cranial radiation. An interim analysis was performed as planned by the protocol after the inclusion of 50% of 200 patients required to demonstrate a 50% improvement in median survival. Accrual has been closed prematurely on 12/23/94 due to a significant survival difference between the two arms. An updated analysis will be presented.

The standard combination chemotherapy of SCLC is an etoposide based regimen. After failure of this regimen the prognosis is very poor although the use of a rescue regimen still displays clinical activity. It has been already suggested that investigational new drugs should to be assessed in second line therapy in SCLC and that a RR ≥ 10% among 29 patients would be relevant for the screening of active new compounds. CPT11 is a new DNA topoisomerase I inhibitor active in colorectal cancer and other solid adult tumors. 22 patients with progressive extensive SCLC after a prior response on a VP16-based chemotherapy have been so far entered onto the study. Sex ratio M/F = 19/3; median age = 57.2 (43–72). Performance Status 0 = 14%; 1 = 45%; 2 = 41%. Median number of involved organ 4 (1–6) with liver (27%), lung (22%), lymph nodes (16%) and brain (11% of patients). 57 cycles at the planned dose of 350 mg/m 2 every 3 weeks have been delivered with a median Relative Dose Intensity of 0.95 (0.78–1. 03). Efficacy: One CR and three PR have been observed among the 15 evaluable patients. Safety: The incidence of grade 3 and 4 toxicity per cycle has been: neutropenia: 49% (with febrile neutropenia sepsis in 14%), delayed diarrhea: 18%, nausea vomiting: 14%. Conclusion The activity of CPT 11 in SCLC is likely to be attractive on the basis of these preliminary data. Neutropenia is clearly the dose limiting toxicity in this population of pretreated patients with frequent occult bone marrow involvement.