Novel Cytotoxic Agents

Abstract

Picoplatin Picoplatin is a new cisplatin analog designed to avoid the development of platinum resistance. Preclinical studies in human ovarian xenografts showed complete and durable tumor regression with picoplatin, with continued remission even after the cessation of treatment on day 28 at maximum tolerated dose. In comparison, maximum tolerated doses of cisplatin induced partial tumor regression during treatment and rapid regrowth after cessation of treatment. In the same model, picoplatin caused marked volume reduction in cisplatin-resistant tumor xenografts. In a randomized multicenter study, 77 patients with previously treated small cell lung cancer (SCLC) were treated with picoplatin 150 mg/m intravenously every 3 weeks until disease progression. The study population was subdivided into chemotherapy refractory (failure to achieve response or progressive disease during the first-line cisplatin-based chemotherapy), resistant (initial response with relapse within 3 months from the last cycle of therapy), and sensitive (relapse between 3 and 6 months after last cycle of therapy). Most patients had refractory (44 patients) or resistant (27 patients) disease, whereas only six patients had sensitive disease. Response rates were observed in 9% of patients, and median survival was nearly identical for refractory and sensitive patients at 27 and 26 weeks, respectively. The most common toxicity was myelosuppression and most notably, there were no grade 3 to 4 nephrotoxicity, neurotoxicity, or ototoxicity. The Study of Picoplatin Efficacy After Relapse is an ongoing randomized phase III trial comparing overall survival for picoplatin and best supportive care with best supportive care alone in previously treated patients with SCLC. Bendamustine Bendamustine is a cytotoxic agent combining a purinelike benzimidazol and a bifunctional alkylating nitrogen mustard group. This agent, synthesized in the early 1960s, has significant activity against hematological malignancies including chronic lymphocytic leukemia, indolent non-Hodgkin lymphoma, and multiple myeloma, being approved in the United States for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma in 2008. Several ongoing trials are evaluating the efficacy of bendamustine in solid tumors.1 Bendamustine was initially evaluated in two trials for previously untreated patients with lung cancer. In the first trial, 43 patients with lung cancer were treated with single agent bendamustin 70 mg/m for 4 days every 4 weeks to a maximum of six cycles. There were no responses among the 23 patients with non-small cell lung cancer (NSCLC), whereas nine of 22 patients (40%) with SCLC achieved partial response (PR). The treatment was very well tolerated, with the main grade 3 toxicities consisting of nausea and vomiting (7%), diarrhea (4.6%), leukopenia (4.6%), and thrombocytopenia (4.6%). In the second study, 26 patients with extensive disease SCLC received bendamustine 120 mg/m on days 1 and 2 every 3 weeks for a maximum of six cycles. Among the 22 evaluable patients, complete response (CR) was observed in two patients (9%), PR in eight patients (36%), and stable disease (SD) in four patients (19%). Survival time was not reported, and there were no grade 3 or 4 toxicities. The same schedule of bendamustine (120 mg/m on days 1 and 2 every 3 weeks) was tested in 21 patients with extensive disease-SCLC relapsing more than 2 months after completion of first-line treatment. Response rate was 29% with additional 29% achieving SD. Median time to progression, overall survival, and 1-year overall survival were 4 months, 7 months, and 16%, respectively. The main toxicity was neutropenia, including three patients with grade 3, one patient with grade 4, one patient with neutropenic fever, and one treatment-related death due to sepsis. In a multicenter German trial, 56 patients with SCLC were treated with a combination of carboplatin area under the curve of 5 on day 1 and bendamustin 50 mg/m on days 1 and 2 every 3 weeks. Among the 55 evaluable patients, the response rate was 73% with 1 CR (1.8%) and 39 PR (71%). Main toxicities included 46% grade 3 to 4 leukopenia, 26% grade 3 to 4 thrombocytopenia, and 3.6% treatment-related deaths. In summary, bendamustine seems to be a promising agent worthy of further investigation in the treatment of patients with SCLC. However, the role of bendamustine in SCLC may be further defined in randomized phase III stud*Washington University School of Medicine, St. Louis, Missouri; and †Penn State Hershey Cancer Institute, Pennsylvania. Disclosure: The authors declare no conflicts of interest. Address for correspondence: Chandra P. Belani, MD, Penn State Hershey Cancer Institute, PA. E-mail: cbelani@hmc.psu.edu Copyright © 2009 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/09/0411-1082 Santa Monica Supplement Journal of Thoracic Oncology • Volume 4, Number 11, Supplement 3, November 2009