Endocrine Oncology Unit, Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
Ann Endocrinol (Paris). 2023 May;84(3):374-381. doi: 10.1016/j.ando.2023.03.009. Epub 2023 Mar 22.
Tyrosine kinase inhibitors (TKIs) have improved outcome for many tumors. Although better tolerated than cytotoxic chemotherapy, they may cause several adverse events (AEs) and various endocrine-related toxicities have been reported under TKI treatment. The toxicity profile varies between the different TKI compounds. This review focuses on the main endocrinopathies caused by TKIs. Thyroid dysfunction and, in particular, hypothyroidism are the most frequent and best described. Several potential mechanisms have been hypothesized, including thyroid gland dysfunction, hormone metabolism impairment and hypothalamus-pituitary-thyroid axis imbalance. TKIs have been reported to influence almost all glands. In particular, they are associated with adrenal insufficiency, growth retardation due to growth hormone (GH) and/or insulin-like growth factor-1 (IGF1) deficiency, hypogonadism, and male and female fertility impairment. TKIs may affect bone metabolism, in particular decreasing osteoclastogenesis and bone turnover and, in turn, they may cause secondary hyperparathyroidism. Hypocalcemia has been reported under lenvatinib and vandetanib treatment and parathyroid hormone (PTH)-dependent and PTH-independent mechanisms have been hypothesized. Metabolic alterations during TKI treatment range from hypoglycemia with imatinib and dasatinib to hyperglycemia with nilotinib; dyslipidemia improved with imatinib and worsened with nilotinib, sunitinib, pazopanib, sorafenib, and famitinib. Endocrine-related AEs should be managed by dedicated endocrinologists. Hormone deficiencies are easily managed by replacement therapy, while endocrine hyperfunction may be improved by symptomatic treatment. Severe situations should be managed in coordination with the oncologist, trying to limit the need for TKI dose reduction or interruption.
酪氨酸激酶抑制剂（TKIs）改善了许多肿瘤的预后。虽然与细胞毒性化疗相比，TKIs 的耐受性更好，但它们可能会引起多种不良反应（AEs），并且在 TKI 治疗下已报告了各种与内分泌相关的毒性。不同的 TKI 化合物的毒性谱有所不同。本篇综述重点介绍了 TKI 引起的主要内分泌疾病。甲状腺功能障碍，特别是甲状腺功能减退，是最常见和描述最详细的。已经假设了几种潜在的机制，包括甲状腺功能障碍、激素代谢受损和下丘脑-垂体-甲状腺轴失衡。TKIs 已被报道会影响几乎所有的腺体。特别是，它们与肾上腺功能不全、由于生长激素（GH）和/或胰岛素样生长因子 1（IGF1）缺乏引起的生长迟缓、性腺功能减退以及男性和女性生育能力受损有关。TKIs 可能会影响骨代谢，特别是减少破骨细胞生成和骨转换，从而导致继发性甲状旁腺功能亢进。仑伐替尼和凡德他尼治疗下已报告了低钙血症，并且已经假设了甲状旁腺激素（PTH）依赖性和非依赖性机制。TKI 治疗期间的代谢改变范围从伊马替尼和达沙替尼引起的低血糖到尼罗替尼引起的高血糖；与伊马替尼相关的血脂异常得到改善，与尼罗替尼相关的血脂异常恶化，与舒尼替尼、帕唑帕尼、索拉非尼和法米替尼相关。应通过专门的内分泌学家来管理与内分泌相关的 AEs。激素缺乏可以通过替代疗法来轻松管理，而内分泌功能亢进可以通过对症治疗来改善。严重情况应与肿瘤学家协调管理，尽量减少 TKI 剂量减少或中断的需求。
