Phase II study of dose-intense chemotherapy with sequential topoisomerase-targeting regimens with irinotecan/oxaliplatin followed by etoposide/carboplatin in chemotherapy naive patients with extensive small cell lung cancer

IntroductionTopoisomerase inhibitors are active agents in small cell lung cancer (SCLC), and preclinical models indicate that sequential administration of a topoisomerase I inhibitor followed by a topoisomerase II inhibitor can result in enhanced cytotoxicity.Patients and methodsIn this phase II study, patients with extensive SCLC were treated with two sequential topoisomerase-based regimens: irinotecan (150 mg/m2)/oxaliplatin (85 mg/m2) [regimen A] on day 1 followed by etoposide (100 mg/m2 × 3)/carboplatin (AUC 6) [regimen B] on day 15. Regimen A was repeated 3 weeks later. The primary objective was objective response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and exploratory correlative analysis of the tumor expression of the excision repair cross complementing (ERCC1) and topoisomerase II-α. Patients received a maximum of 5 cycles of sequential therapy of regimen A → B.ResultsThe overall response rate was 96%, the 6-month PFS was 76.9%, the median PFS was 8.95 months, and OS was 12.9 months in 26 evaluable patients. Grade 4 neutropenia (23%) and thrombocytopenia (58%) were observed with regimen B; and grade 2/3 nausea-vomiting (54%) and diarrhea (46%) with regimen A. Seven patients required dose reductions in regimen A and 19 patients in regimen B. The dose intensity, delivered during the first three cycles was 89%. No significant correlations were observed between the tumor expression of the ERCC1 and topoisomerase II-α and clinical outcomes (PFS or OS).ConclusionsAlthough cross-study comparisons are difficult to make, our data suggests that sequential topoisomerase-targeting regimens may enhance the efficacy of chemotherapy in newly diagnosed SCLC patients (Clinical Trial Registration Number, 9 NCT00240097; Clinical Trials.gov number, NCT00240097).