Modulation of vinblastine resistance in metastatic renal cell carcinoma with cyclosporine A or tamoxifen: a cancer and leukemia group B study

• Published in: Clinical cancer research Vol. 3; no. 11; pp. 1977 - 1984
• Main Authors: SAMUELS, B. L, HOLLIS, D. R, ROSNER, G. L, TRUMP, D. L, SHAPIRO, C. L, VOGELZANG, N. J, SCHILSKY, R. L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-11-1997
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - mortality; Carcinoma, Renal Cell - pathology; Carcinoma, Renal Cell - therapy; Cyclosporine - administration & dosage; Cyclosporine - adverse effects; Cyclosporine - therapeutic use; Drug Resistance, Multiple; Female; General aspects; Humans; Infusions, Intravenous; Kidney Neoplasms - drug therapy; Kidney Neoplasms - mortality; Kidney Neoplasms - pathology; Kidney Neoplasms - therapy; Lymphatic Metastasis; Male; Medical sciences; Middle Aged; Neoplasm Metastasis; Pharmacology. Drug treatments; Survival Rate; Tamoxifen - administration & dosage; Tamoxifen - adverse effects; Tamoxifen - therapeutic use; Vinblastine - administration & dosage; Vinblastine - pharmacokinetics; Vinblastine - therapeutic use; Antineoplastic agent; Carcinoma; Intravenous administration; Toxicity; Antiestrogen; Antihormone; Kidney; Alkaloid; Randomization; Multiple resistance; Phase II trial; Advanced stage; Ciclosporin; Drug interaction; Antimitotic; Non steroid compound; High dose; Kidney disease; Human; Drug combination; Urinary system disease; Vinblastine; Malignant tumor; Tamoxifene; Chemotherapy; Treatment; Immunosuppressive agent
• ISSN: 1078-0432; 1557-3265

Multidrug resistance mediated by P-glycoprotein may be an important cause of chemotherapy failure. Renal cell carcinoma is
a disease known to 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 reverse multidrug resistance
in renal cell carcinoma cell lines in vitro. Phase I studies have defined appropriate doses of cyclosporine A and tamoxifen
that can be combined with continuous-infusion vinblastine and safely achieve serum levels associated in vitro with resistance
reversal. A randomized Phase II study was carried out by the Cancer and Leukemia Group B to evaluate the potential of high
doses of cyclosporine A or tamoxifen to modulate clinical vinblastine resistance in patients with advanced renal cell carcinoma.
Patients were treated initially with continuous-infusion vinblastine alone (1.2 mg/m2/day for 4 days or 1.5 mg/m2/day for
5 days); patients with stable or progressive disease 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 days) or tamoxifen (400 mg/m2 as a loading dose and 300 mg/m2/day
for 13 days). Sixty-three patients were randomized to each arm. Eighty patients 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 cyclosporine A. No responses were observed, although four patients with progressive disease on prior
vinblastine achieved stabilization of disease after cyclosporine A was added. Addition of cyclosporine resulted in more leukopenia
(5% versus 25%) and in transient hyperbilirubinemia (24%) and neurocortical changes (11%). No significant azotemia was observed.
Thirty-five patients received high-dose tamoxifen with continuous-infusion vinblastine. One complete remission was seen in
a patient who had stable disease only with prior vinblastine alone; no other responses 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 neurocortical changes as a result of high-dose tamoxifen therapy, and 11% developed phlebitis.
We conclude that advanced renal cell carcinoma is a highly 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 design and conduct of this study.