Endocrine Toxicities of Antineoplastic Therapy: The Adrenal Topic

Abstract

Immune checkpoint inhibitors (ICIs) have improved survival in patients affected by several solid tumours at the cost of new autoimmune adverse events. Endocrine toxicity is frequently reported in patients treated with these agents, mainly as thyroid dysfunction and hypophysitis. Primary adrenal insufficiency is reported in 1–2% of patients receiving a single ICI, but its rate is approximately 5% in patients treated with a combination of two ICIs. The clinical presentation of adrenal insufficiency may be insidious due to symptoms that are not specific. The same symptoms in cancer patients are frequently multifactorial, rendering the early diagnosis of adrenal insufficiency challenging in this group of patients. As adrenal insufficiency can be fatal if not rapidly diagnosed and treated, oncologists should be aware of its clinical presentations to timely involve endocrinologists to offer patients the appropriate management. In parallel, it is essential to educate patients, their caregivers, and relatives, providing them with detailed information about the risk of adrenal insufficiency and how to manage alarming symptoms at their onset. Finally, large collaborative trials are needed to develop appropriate tests to assess better the personal risk of drug-induced adrenal insufficiency and its early diagnosis and treatment, not only in cancer patients.

Adrenal Insufficiency with Anticancer Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor Receptor: Analysis of the FDA Adverse Event Reporting System

“…The available clinical evidence on AI by VEGFR-TKIs is scant, jeopardized and limited to cases reports and small case series [ 4 , 5 ], including a recent pharmacovigilance study on axitinib [ 30 ]. In a small prospective study, the analysis of basal and stimulated adrenal function in 12 patients receiving lenvatinib and vandetanib for advanced radioiodine refractory differentiated or medullary thyroid cancer, respectively, revealed a gradual ACTH increase with normal cortisol levels in 10 patients complaining of fatigue.…”

“…Minor imbalances were noted in a KEYNOTE-426 trial for pembrolizumab plus axitinib (0.7% vs. 0.2% for sunitinib) [ 34 ], and a CLEAR trial for lenvatinib plus pembrolizumab (1.1% vs. 0% for sunitinib) [ 35 ]. Our real-world data found a median latency of three months for the combination regimen, with remarkable high rates of discontinuation and dechallenge, thus suggesting the importance of implementing dedicated guidelines and screening protocols (ACTH test) through a close collaboration among pharmacologists, internists, oncologists and endocrinologists [ 4 , 36 , 37 ].…”

“…Notably, chronic severe fatigue in oncology may be a cancer-related complication but also possibly subtend underlying adrenal dysfunctions, thus leading to drug discontinuation. However, the effects of VEGFR inhibitors on adrenal function are incompletely characterized [ 4 , 5 ]. To the best of our knowledge, only a few case reports/series have described adrenal insufficiency (AI) during bevacizumab [ 6 , 7 ], sunitinib [ 8 , 9 ], pazopanib [ 10 ], lenvatinib [ 11 ], and vandetanib therapy [ 12 , 13 ].…”

Addison’s Disease: Diagnosis and Management Strategies

“… 124 1–2% of patients under a single ICP develop AD, while those under 2 different types of ICPs have a 5% risk of suffering from AD. 125 Primary and secondary AI might not be reflected by random cortisol measurement, thus the importance of periodic dynamic tests. 126 Among the complex constellation of various side effects, AD is mandatory to be taken into consideration due to its severity.…”

Endocrine toxicity of immune checkpoint inhibitors: a network meta-analysis of the current evidence

“…The enhanced therapeutic effects are attributed to the concurrent blockade of CTLA-4 and PD-1/PD-L1 pathways, thereby fostering synergistic anti-cancer effects. Nonetheless, although these combination therapies may offer synergistic benefits, they can also significantly increase toxicity levels [17]. This concern is particularly relevant to ICI-induced endocrine toxicity: focused research has extensively explored this toxicity, yet current studies have often been constrained by their narrow scope and methods, thus limiting their applicability to the diverse and evolving array of ICI treatments.…”