ORIGINAL RESEARCH article
Front. Endocrinol.
Sec. Cancer Endocrinology
This article is part of the Research TopicAdvances in Management of Aggressive Thyroid Cancer: Medullary and Advanced Thyroid CancerView all 12 articles
Effects of Lenvatinib treatment for advanced differentiated thyroid cancer on Cortisol Deficiency
Provisionally accepted
Salvatore Monti*
Beatrice Fazzalari
Valerio Renzelli
Claudia BongerminoMaria Francesca LioniMaria Grazia Deiana
Maurizio PoggiFedra Mori
Giuseppe Pugliese- Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy
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ABSTRACT Background: Lenvatinib has shown remarkable efficacy and improvement in progression-free survival (PFS), although its use is associated with a variety of side effects. Among them, adrenal insufficiency (AI) remains under-recognized and potentially underestimated, and it may be involved in fatigue. In this prospective study, we report the incidence, development, and time course of primary AI (PAI) during Lenvatinib treatment in patients with RR-DTC followed at a single tertiary care center. Methods: The study was conducted on 39 patients with RR-DTC. Eight patients were excluded because they had a follow-up of less than 6 months or were receiving glucocorticoids for RR-DTC-related indications. We studied 31 patients selected for Lenvatinib therapy. Adrenal function was assessed by measuring serum cortisol and adrenocorticotropic hormone (ACTH) levels, and through 250 μg ACTH stimulation test. Peak cortisol levels below 500 nmol/L (18.1 µg/dL) after ACTH injection were indicative of adrenal insufficiency (AI) (PAI-18.1). A cutoff of 386.2 nmol/L (14 µg/dL) has also been used (PAI-14). In patients with primary AI (PAI), steroid replacement therapy with cortisone acetate (CA) was initiated at doses ranging from 25 to 37.5 mg/day. Throughout follow-up, the ACTH stimulation test was repeated every 3 to 9 months, with a 72-hour discontinuation of CA prior to testing. Results: During Lenvatinib treatment, 24 of 31 patients (77.4%) developed PAI-18.1, and 14 of 31 patients (45.2%) developed PAI-14. Patients with a cortisol peak below 646.6 nmol/L at the initial ACTH stimulation test demonstrated a higher risk of developing both PAI-18.1 and PAI-14 during treatment. Patients who developed PAI during Lenvatinib treatment had significantly lower cortisol peak levels on the initial ACTH stimulation test performed before treatment initiation compared to those who did not develop PAI. Fatigue was observed in 28 of 31 patients (90%) during Lenvatinib treatment. Among patients who developed PAI, a significant improvement in fatigue was observed following initiation of CA therapy. Conclusions: Our findings suggest a higher occurrence of PAI, which may contribute to fatigue associated with Lenvatinib treatment. Routine adrenal function testing and early recognition of PAI are essential to improve tolerability and adherence during Lenvatinib treatment.
Keywords: Adrenal Insufficiency, Fatigue, Iodine-refractory differentiated thyroid cancer, Lenvatinib, thyroid cancer
Received: 24 Aug 2025; Accepted: 08 Dec 2025.
Copyright: © 2025 Monti, Fazzalari, Renzelli, Bongermino, Lioni, Deiana, Poggi, Mori and Pugliese. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Salvatore Monti
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