MODULATION OF VINBLASTINE RESISTANCE IN METASTATIC RENAL-CELL CARCINOMA WITH CYCLOSPORINE-A OR TAMOXIFEN - A CANCER AND LEUKEMIA GROUP-B STUDY

Multidrug resistance mediated by P-glycoprotein may be an important ca use of chemotherapy failure. Renal cell carcinoma is a disease known t o demonstrate a high degree of intrinsic chemotherapy drug resistance, and this has been shown to be related to intrinsic overexpression of P-glycoprotein. Cyclosporine A and tamoxifen have been shown to revers e multidrug resistance in renal cell carcinoma cell lines in vitro. Ph ase I studies have defined appropriate doses of cyclosporine A and tam oxifen that can be combined with continuous-infusion vinblastine and s afely achieve serum levels associated in vitro with resistance reversa l. A randomized Phase II study was carried out by the Cancer and Leuke mia Group B to evaluate the potential of high doses of cyclosporine A or tamoxifen to modulate clinical vinblastine resistance in patients w ith advanced renal cell carcinoma. Patients were treated initially wit h continuous-infusion vinblastine alone (1.2 mg/m(2)/day for 4 days or 1.5 mg/m(2)/day for 5 days); patients with stable or progressive dise ase were then treated with the same vinblastine regimen, combined with a high-dose regimen of either cyclosporine A (12.5 mg/kg/day for 5 da ys) or tamoxifen (400 mg/m(2) as a loading dose and 300 mg/m(2)/day fo r 13 days). Sixty-three patients were randomized to each arm. Eighty p atients on both arms were evaluable for response to vinblastine alone; of these, only one patient achieved a partial response. Thirty-three patients went on to be treated with vinblastine and high-dose cyclospo rine A. No responses were observed, although four patients with progre ssive disease on prior vinblastine achieved stabilization of disease a fter cyclosporine A was added. Addition of cyclosporine resulted in mo re leukopenia (5% versus 25%) and in transient hyperbilirubinemia (24% ) and neurocortical changes (11%). No significant azotemia was observe d. Thirty-five patients received high-dose tamoxifen with continuous-i nfusion vinblastine. One complete remission was seen in a patient who had stable disease only with prior vinblastine alone; no other respons es were observed. Leukopenia was not more severe with the addition of tamoxifen to vinblastine, nor was hyperbilirubinemia observed. However , 9% of patients developed transient ataxia with or without neurocorti cal changes as a result of high-dose tamoxifen therapy, and 11% develo ped phlebitis. We conclude that advanced renal cell carcinoma is a hig hly chemoresistant tumor, that continuous-infusion vinblastine has no appreciable activity in the therapy of this disease, and that addition of high doses of cyclosporine A or tamoxifen was not able to modulate this resistance in these patients. Suggestions regarding study design for future drug resistance modulation trials were made based on the d esign and conduct of this study.