CONTEXT: Treatment of refractory adrenocortical carcinoma (ACC) is not established. Animal experiments pointed toward adrenal toxicity of sunitinib. OBJECTIVE: The objective of the study was to determine the antitumor effects of sunitinib in refractory ACC. DESIGN: This was a phase II, open-label trial using a two-stage accrual design. SETTING: The study was conducted at two tertiary referral centers. PATIENTS: Thirty-eight patients with refractory ACC progressing after mitotane and one to three cytotoxic chemotherapies participated in the study. INTERVENTION: The intervention included sunitinib at a standard dose (50 mg/d, 4 wk on, 2 wk off). MAIN OUTCOME MEASURE: Response was defined as progression-free survival (PFS) of 12 wk or longer (first tumor evaluation). RESULTS: Thirty-five patients could be evaluated for response. Five patients experienced stable disease, 24 had progressive disease, and six patients died from ACC before the first evaluation (naïve estimate five of 35=14.3%, median unbiased response rate 15.4%, 95% confidence interval 5.0-33.4%). The median PFS was 2.8 months. In responders, PFS ranged between 5.6 and 11.2 months and overall survival between 14.0 and 35.5 months. Of 36 serious adverse events, only nine were possibly related to sunitinib. Concomitant mitotane appeared to negatively impact on outcome. Furthermore, a negative correlation between the serum concentrations of sunitinib plus its active metabolite N-desethylsunitinib (SU12662) and mitotane (r=-0.650; P=0.114) was observed in seven evaluable patients suggestive of a relevant drug interaction. CONCLUSION: Sunitinib has modest activity in advanced refractory ACC, which compares favorably with other targeted treatments in these patients. Sunitinib serum levels might have been profoundly reduced by mitotane induced cytochrome P450-3A4 activity attenuating its antitumor activity and adverse effects. Together these findings suggest that sunitinib deserves further investigation in mitotane-naïve ACC patients.
CONTEXT: Treatment of refractory adrenocortical carcinoma (ACC) is not established. Animal experiments pointed toward adrenal toxicity of sunitinib. OBJECTIVE: The objective of the study was to determine the antitumor effects of sunitinib in refractory ACC. DESIGN: This was a phase II, open-label trial using a two-stage accrual design. SETTING: The study was conducted at two tertiary referral centers. PATIENTS: Thirty-eight patients with refractory ACC progressing after mitotane and one to three cytotoxic chemotherapies participated in the study. INTERVENTION: The intervention included sunitinib at a standard dose (50 mg/d, 4 wk on, 2 wk off). MAIN OUTCOME MEASURE: Response was defined as progression-free survival (PFS) of 12 wk or longer (first tumor evaluation). RESULTS: Thirty-five patients could be evaluated for response. Five patients experienced stable disease, 24 had progressive disease, and six patients died from ACC before the first evaluation (naïve estimate five of 35=14.3%, median unbiased response rate 15.4%, 95% confidence interval 5.0-33.4%). The median PFS was 2.8 months. In responders, PFS ranged between 5.6 and 11.2 months and overall survival between 14.0 and 35.5 months. Of 36 serious adverse events, only nine were possibly related to sunitinib. Concomitant mitotane appeared to negatively impact on outcome. Furthermore, a negative correlation between the serum concentrations of sunitinib plus its active metabolite N-desethylsunitinib (SU12662) and mitotane (r=-0.650; P=0.114) was observed in seven evaluable patients suggestive of a relevant drug interaction. CONCLUSION:Sunitinib has modest activity in advanced refractory ACC, which compares favorably with other targeted treatments in these patients. Sunitinib serum levels might have been profoundly reduced by mitotane induced cytochrome P450-3A4 activity attenuating its antitumor activity and adverse effects. Together these findings suggest that sunitinib deserves further investigation in mitotane-naïve ACC patients.
Authors: A Stigliano; I Chiodini; R Giordano; A Faggiano; L Canu; S Della Casa; P Loli; M Luconi; F Mantero; M Terzolo Journal: J Endocrinol Invest Date: 2015-07-14 Impact factor: 4.256
Authors: André P Fay; Aymen Elfiky; Gabriela H Teló; Rana R McKay; Marina Kaymakcalan; Paul L Nguyen; Anand Vaidya; Daniel T Ruan; Joaquim Bellmunt; Toni K Choueiri Journal: Crit Rev Oncol Hematol Date: 2014-06-04 Impact factor: 6.312
Authors: Tobias Else; Alex C Kim; Aaron Sabolch; Victoria M Raymond; Asha Kandathil; Elaine M Caoili; Shruti Jolly; Barbra S Miller; Thomas J Giordano; Gary D Hammer Journal: Endocr Rev Date: 2013-12-20 Impact factor: 19.871
Authors: Nitya Raj; Youyun Zheng; Virginia Kelly; Seth S Katz; Joanne Chou; Richard K G Do; Marinela Capanu; Dmitriy Zamarin; Leonard B Saltz; Charlotte E Ariyan; Brian R Untch; Eileen M O'Reilly; Anuradha Gopalan; Michael F Berger; Kelly Olino; Neil H Segal; Diane L Reidy-Lagunes Journal: J Clin Oncol Date: 2019-10-23 Impact factor: 44.544