Clinical Trials of Low-Dose Metronomic Chemotherapy in Castration-Resistant Prostate Cancer

Abstract

Low-dose metronomic (LDM) chemotherapy is the continuous or near-continuous use of conventional chemotherapeutic agents at doses that do not necessitate cyclic treatment interruptions. Recently, LDM chemotherapy has gained traction for the treatment of castration-resistant prostate cancer (CRPC). Its excellent safety profile and relatively low rate of severe (i.e., grade 3/4) toxicities make it an enviable treatment, especially for elderly and frail CRPC patients. By searching the MEDLINE, EMBASE, and CENTRAL databases, we identified fifteen published prostate cancer LDM chemotherapy trials comprising 471 patients. The trials were stratified and analyzed according to three common types of LDM regimens: (1) cyclophosphamide monotherapy, (2) cyclophosphamide plus corticosteroid, and (3) complex combination regimens. Oral cyclophosphamide was part of all LDM regimens. Collectively, LDM chemotherapy was found to be beneficial in almost 60 % of patients (mean clinical benefit rate of 58.08 ± 20.30). Severe treatment-associated side effects were rarely seen, with anemia being the most commonly reported. One comparative single-center study showed a superior safety profile and comparable benefit of LDM cyclophosphamide therapy compared to conventional, maximum tolerated dose (MTD) docetaxel chemotherapy. Another study highlights that prior LDM chemotherapy does not negatively impact on the subsequent use of MTD docetaxel chemotherapy. In addition, five studies document the benefit of LDM chemotherapy in CRPC patients that have undergone MTD docetaxel chemotherapy. Randomized phase III trials will be needed to allow definitive conclusions as to the clinical utility of the LDM approach in CRPC. Unfortunately, the metronomic use of off-patent drugs such as cyclophosphamide faces unique commercial and regulatory hurdles that are slowing down the clinical development of LDM chemotherapy in prostate cancer and other malignancies.