Endocrine Abstracts

Background: Fatigue is one of the most frequently reported adverse events in patients treated with multikinase inhibitors (MKIs). It is present in about 59% and 24% of patients treated with lenvatinib and vandetanib, respectively, associates with a decreased quality of life and often leads to treatment discontinuation. In 2018, for the first time, a correlation between fatigue and primary adrenal insufficiency (PAI) was demonstrated in 12 patients treated with lenvatinib and vandetanib (Colombo et al., JCEM 2018). These data were confirmed more recently by the evaluation of adrenal function in 13 patients treated with lenvatinib (Monti et al., Thyroid 2022).

Aim: To assess adrenal function in a larger series of patients who developed fatigue during MKIs treatment.

Methods: Adrenal function has been monthly evaluated, for an average follow-up of 38 months (6-161 months), in 32 patients receiving MKIs and developing fatigue during treatment (23 on Lenvatinib, 7 on Vandetanib and 2 on Selpercatinib). In particular, cortisol and ACTH levels were evaluated together with 250-µg ACTH stimulation test (performed at the time of ACTH elevation above the normal limits).

Results: A high percentage of patients with fatigue, 23/31 (74%), had a significant elevation of basal ACTH with normal cortisol levels during MKIs treatment (18/23 on lenvatinib, 4/7 on vandetanib and 1/2 on selpercatinib). Moreover, 8/23 patients (6 on lenvatinib and 2 on vandetanib) showed an impaired response to the ACTH test, thus confirming PAI diagnosis. The onset of PAI occurred after an average period of 14 months (range 3-61) from the start of MKIs treatment. Cortisone acetate (CA) replacement therapy was recommended in 9 patients (all the patients with an impaired cortisol response to ACTH stimulation and in 1 patient with only ACTH elevation and fatigue degree 2 according to the CTCAE version 4.03), and improved fatigue in 6 of them (67%).

Conclusions: Data on a large series confirm that a high percentage of patients on MKIs show ACTH levels above the upper normal limit. Fatigue can be totally or partially related to the development of PAI in these patients. The first evidence of reduced adrenal function is the progressive rise of basal ACTH levels with cortisol values within normal limits. Moreover, a reduced cortisol response to the 250-µg ACTH stimulation test is observed in some of these patients. Replacement therapy with CA improves fatigue and, therefore, adherence to therapeutic regimens, avoiding dose reductions or discontinuation.