Clin Cancer Res
The Cleveland Clinic Taussig Cancer Center, and Department of Gynecology/Obstetrics, The Cleveland Clinic Foundation, Ohio 44195, USA.
Published: November 2000
Increased expression of P-glycoprotein has been proposed as one important mechanism for inherent or acquired drug resistance of malignant disease to cytotoxic chemotherapy. In experimental systems, hormonal agents, including megestrol acetate (MA), have been shown to be capable of reversing P-glycoprotein-mediated multidrug resistance to natural products, including paclitaxel. Because paclitaxel is one of the most active cytotoxic agents in ovarian cancer (OC), we sought to determine whether retreating patients with well-defined paclitaxel-resistant OC with a combination of paclitaxel and MA would result in clinically relevant reversal of that resistant state. In this Phase I trial, 44 patients with OC or primary peritoneal carcinoma received paclitaxel (135-175 mg/m2 over 3 h) plus an oral loading dose (800-9600 mg over 24 h) and subsequent maintenance dose (800-3200 mg/day x 3 days) of micronized MA. Both the loading dose and maintenance therapy were delivered in four equal daily doses. Therapy was repeated every 21 days, assuming recovery from the toxicity of the prior course. There were no intrapatient dose escalations. The major toxicity of the regimen was peripheral neuropathy (32% of patients; 11% grade 2-3), although four individuals developed major venous blood clots and one suffered a stroke. Four patients exhibited biological evidence of antineoplastic effects, although only one patient experienced improvement in clinically relevant symptoms. Although pharmacokinetic studies were not performed as a component of this study, prior evaluation of MA pharmacokinetics and in vitro data examining the concentrations of the agent required to reverse P-glycoprotein-mediated paclitaxel resistance suggest that the majority of our patient population achieved levels of MA theoretically capable of producing this desired effect. We conclude that the level of activity and toxicity pattern observed in this trial, associated with the combination of paclitaxel and MA, does not provide strong support for further exploration of the regimen as a treatment strategy to overcome paclitaxel resistance in OC.
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