Recovery of the Hypothalamic-Pituitary-Adrenal Axis in a Cohort of Patients with Stage I-III Adrenocortical Carcinoma after at Least 2 Years of Adjuvant Mitotane Therapy

Presentation Number: SUN 387
Date of Presentation: April 2nd, 2017

Nadia Gagnon*, Catherine Alguire, Nada El Ghorayeb, Andre Lacroix and Isabelle Bourdeau
Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada

Abstract

Background: Adrenocortical carcinoma (ACC) has a high risk of recurrence, but adjuvant treatment with mitotane was shown to increase recurrence-free survival in patients with radically resected ACC. Actual standard of care recommends adjuvant mitotane at therapeutic levels for at least two years in patients with high recurrence risk; as mitotane has adrenolytic activity, simultaneous replacement with sufficient glucocorticoid is necessary. Data on whether adjuvant mitotane will cause permanent adrenal insufficiency or whether recovery of the hypothalamic-pituitary-adrenal (HPA) axis can occur after mitotane withdrawal is limited.

 Objective: To evaluate the recovery of the HPA axis after at least 2 years of adjuvant mitotane at therapeutic levels in a cohort of patients with ENSAT stage I-III ACC.

 Methods: We performed a retrospective analysis of patients with ACC who had undergone radical surgery in our centre between 1995 and 2016. We collected data on clinical presentation, biochemical investigation, mitotane and hydrocortisone doses, imaging, histology and outcomes of patients with local regional disease that completed at least 2 years of adjuvant mitotane therapy.

Results: Our cohort included 29 ACC with local regional disease (5 ENSAT stage I, 12 stage II and 12 stage III). Adjuvant mitotane was administered in 23 patients and at least 2 years of therapeutic level (14-20 mg/mL) was completed in 9 patients (Stage I n=2, Stage II n=6 and Stage III n=1). Among the others, 3 initially declined mitotane, 3 died following the progression of the ACC disease and 8 are still under treatment. Of those who completed treatment, the duration of adjuvant mitotane was 26-59 months (mean 36.4). The hydrocortisone replacement dose was 30-50mg per day. Two patient also received Fludrocortisone 0.05mg per day. The evaluation of their HPA axis with Cortrosyn stimulation test showed that 4 patients (2 Stage I, 1 Stage II and 1 Stage III) were able to discontinue hydrocortisone supplement, between 5-59 months after last dose of mitotane. Fludrocortisone was also discontinued in the 2 patients. Two patients with Stage II ACC are currently in weaning of hydrocortisone, after 17 and 73 months of stopping mitotane, and 3 patients with Stage II are still under supplement with a morning cortisol <14-76 nmol/L, 13, 26 and 130 months after stopping mitotane. None of these 9 patients showed evidence of recurrence of ACC from their biochemical or imaging follow-up.

 Conclusion: After at least 2 years of therapeutic adjuvant mitotane therapy, a complete recovery of the HPA axis was observed in 4 out of 9 patients (44.4%) with stage I-III ACC demonstrating that mitotane does not permanently destroy the remaining adrenal cortex at least in a subgroup of patients.

 

Nothing to Disclose: NG, CA, NE, AL, IB