Assessment of the Hypothalamic Pituitary Adrenal Axis in Patients Receiving Adjuvant Mitotane Treatment after Radical Resection of Adrenocortical Carcinoma

Presentation Number: SUN 389
Date of Presentation: April 2nd, 2017

Giuseppe Reimondo*1, Soraya Puglisi2, Barbara Zaggia1, Vittoria Basile3, Laura Saba1, Paola Carla Giuseppina Perotti4, Silvia De Francia5, Maria Chiara Zatelli6, Salvatore Cannavo7 and Massimo Terzolo1
1Medicina Interna 1 - AOU San Luigi, Orbassano (TO), Italy, 2Endocrinology Unit, Messina, 3Dpto di Scienze Cliniche e Biologiche, Medicina Interna 1, Università di Torino, Italy, Orbassano (TO), Italy, 4Medicina Interna 1 - AOU San Luigi, Orbassano (To), ITALY, 5Pharmacology, Orbassano (TO), Italy, 6University of Ferrara, Ferrara, Italy, 7University of Messina, Messina, Italy

Abstract

BACKGROUND: Mitotane, used in the treatment of adrenocortical cancer (ACC), is able to inhibit multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency (AI) and requiring high-dose cortisol replacement. Recent studies in vitro have also documented a direct inhibitory effect of mitotane at the pituitary level.

AIMS: Assessment of the hypothalamic pituitary adrenal (HPA) axis in patients receiving mitotane as adjuvant treatment after radical resection of ACC with the aim of getting insights on how mitotane affects the HPA axis and looking for markers to assessing AI.

PATIENTS AND METHODS: We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical removal of ACC, who were on stable mitotane dose and cortisol replacement therapy for at least 6 months and were disease free at the time of evaluation. Patients underwent standard hormone evaluation and stimulation test with h-CRH. A group of 10 patients with Addison’s disease served as controls for the h-CRH test.

RESULTS: At the time of the study, 6 patients had mitotane levels within the therapeutic range, 1 had levels >20 mg/L, while 9 had levels <14 mg/L. The median dose of cortisone acetate was 62.5 mg daily. Basal serum cortisol was reduced in 14 patients (87.5%), being undetectable in 7 of them (43.8%), and in the normal range in only 2 patients (12.5%); one of them had low mitotane concentrations. Only a non-significant trend between mitotane dose and either serum or salivary cortisol was evident. We demonstrated a close correlation between CBG levels and plasma mitotane levels (r = 0.80, p = 0.003) and between serum cortisol levels and salivary cortisol levels (r = 0.71, p = 0.005), while ACTH levels were inversely correlated with the daily dose of cortone acetate (r = -0.67, p = 0.006). ACTH levels were significantly higher in the Addison group than in ACC patients, both in baseline conditions (p=0.036) than following CRH (p=0.041).

CONCLUSIONS: Measurement of salivary cortisol did not add useful information for assessing AI in mitotane-treated ACC patients. Assessment of ACTH levels may be of some aid, since levels that are not frankly elevated may herald over-replacement. The observation of lower ACTH levels in ACC patients than in patients with Addison, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary level. However, an effect of high-dose cortisol replacement should not be ruled out.

 

Nothing to Disclose: GR, SP, BZ, VB, LS, PCGP, SD, MCZ, SC, MT