MITOTANE ASSOCIATED WITH ETOPOSIDE, DOXORUBICIN, AND CISPLATIN IN THETREATMENT OF ADVANCED ADRENOCORTICAL CARCINOMA

BACKGROUND. The use of either mitotane or chemotherapy in the treatmen t of advanced adrenocortical carcinoma (ACC) has led to scanty and con troversial results. The recent finding that mitotane is able to revers e in vitro multidrug resistance has provided a rational basis for comb ining this agent with cytotoxic drugs. The association of mitotane wit h etoposide, doxorubicin, and cisplatin (EDP) in the treatment of pati ents with advanced, inoperable ACC was tested in an Italian multicente r Phase II trial. METHODS. Twenty-eight patients (18 women and 10 men; median age, 47 years; range, 27-65 years) with measurable disease wer e enrolled in the study and evaluated for toxicity and response. There were 18 patients with clinical and/or biochemical evidence of steroid hypersecretion. An EDP schedule (etoposide 100 mg/m(2) on Days 5-7, d oxorubicin 20 mg/m(2) on Days 1 and 8, and cisplatin 40 mg/m(2) on Day s 1 and 9) was administered intravenously every 4 weeks; concomitantly , patients were given up to 4 g/day of oral mitotane or the maximum to lerated dose, without any interruption between chemotherapy cycles. RE SULTS. According to World Health Organization criteria, complete respo nse was achieved in 2 patients and partial response in 13, for an over all response sate of 53.5% (95% CI, 35-72%). Stable disease was observ ed in 8 patients and progressive disease in 5. Responses occurred in p atients with both functioning and nonfunctioning tumors, and more ofte n in those bearing lymph node and lung metastases. Time to progression in responding patients was 24.4 months. Generally, the EDP regimen wa s well tolerated. Only 4 patients received reduced doses, whereas 3 di scontinued early chemotherapy due to toxicity. The addition of mitotan e increased neurologic and gastrointestinal side effects. Due to these additional toxicities, only 9 patients regularly took the drug at the planned dose (4 g/day); 11 received the maximum tolerated dose of 3 g /day, 6 received 2 g/day, and 1 received 1 g/day. Mitotane was also re sponsible for raised serum levels of cholesterol and triglycerides. A complete hormone response (normalization of altered biochemical parame ters) was observed in 9 of 16 evaluable patients with functioning tumo rs. CONCLUSIONS. EDP plus mitotane combination chemotherapy appears to be active and manageable treatment for patients with advanced ACC. Ca ncer 1998;83: 2194-200. (C) 1998 American Cancer Society.