Cancer Therapy: Preclinical Effective Treatment of Advanced Human Melanoma Metastasis in Immunodeficient Mice Using Combination Metronomic Chemotherapy Regimens

Purpose: The development of effective therapeutic approaches for treatment of metastatic melanoma remains an immense challenge. Present therapies offer minimal benefit. Although dacarbazine chemotherapy remains the standard therapy, it mediates only low response rates, usually of short duration, even when combined with other chemotherapeutic agents. Thus, new therapeutic strategies are urgently needed. Experimental Design: Using a newly developed preclinical model, we evaluated the efficacy of various doublet metronomic combination chemotherapy against established advanced melanoma metastasis and compared these with the standard maximum tolerated dose dacarbazine (alone or in combination with chemotherapeutic agents or vascular endothelial growth factor receptor–blocking antibody). Results: Whereas maximum tolerated dose dacarbazine therapy did not cause significant improvement in median survival, a doublet combination of low-dose metronomic vinblastine and low-dose metronomic cyclophosphamide induced a significant increase in survival with only minimal toxicity. Furthermore, we show that the incorporation of the low-dose metronomic vinblastine/low-dose metronomic cyclophosphamide combination with a low-dose metronomic dacarbazine regimen also results in a significant increase in survival, but not when combined with maximum tolerated dose dacarbazine therapy. We also show that a combination of metronomic vinblastine therapy and a vascular endothelial growth factor receptor 2–blocking antibody (DC101) results in significant control of metastatic disease and that the combination of low-dose metronomic vinblastine/DC101 and low-dose metronomic dacarbazine induced a significant improvement in median survival. Conclusions: The effective control of advanced metastatic melanoma achieved by these metronomic-based chemotherapeutic approaches warrants clinical consideration of this treatment concept, given the recent results of a number of metronomic-based chemotherapy clinical trials. Metastatic melanoma is generally associated with poor prognosis. The aggressiveness of the disease is compounded by the lack of effective treatment, with only modest progress being made over the last few decades in the discovery of chemotherapeutic drugs or other therapies, showing a meaningful clinical survival benefit in randomized clinical trials. Although singleagent chemotherapy with dacarbazine has long been the standard systemic treatment formetastaticmelanoma, it is associated with low response rates of short duration (1, 2). Various combinations of chemotherapeutic agents, some of which have inclu‐ ded dacarbazine, have also shown only very modest effects on increasing response rates and with little or no effect on improving median survival times (3–6). All of these approaches have involved conventional maximal tolerated dose regimens in which prolonged breaks are used between treatments to allow recovery from induced toxic side effects. Significant efforts have been made to enhance the efficacy of dacarbazine therapy by using it in combination with other chemotherapeutic agents. In the face of the disappointing results achieved thus far with such maximum tolerated dose approaches, it is obvious that new drugs and/or treatment strategies are needed. In this regard, the effectiveness of metronomic chemotherapy, in which drugs are given in low, minimally toxic doses at frequent regular intervals with no prolonged breaks, usually over long periods of time (7, 8), has been assessed in only a few situations in patients with metastatic or primary melanoma, thus far (9–12). Metronomic chemotherapy regimens have several potential advantages, Authors' Affiliation: Sunnybrook Health Sciences Centre, Molecular and Cellular Biology Research, Toronto, Ontario, Canada Received 12/18/08; revised 3/9/09; accepted 4/8/09; published OnlineFirst 7/21/09. Grant support: NIH (CA-41233), the National Cancer Institute of Canada, and the Canadian Institutes for Health Research (R.S. Kerbel). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Robert S. Kerbel, Sunnybrook Health Sciences Centre, Molecular and Cellular Biology Research, S-217, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada. Phone: 416-480-5711; Fax: 416-4805884; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-3275 4867 Clin Cancer Res 2009;15(15) August 1, 2009 www.aacrjournals.org Published Online First on July 21, 2009 as 10.1158/1078-0432.CCR-08-3275 Research. on July 17, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst July 21, 2009; DOI: 10.1158/1078-0432.CCR-08-3275