酪氨酸激酶抑制剂治疗期间的甲状腺功能减退症与晚期非甲状腺癌患者的生存时间延长相关。

Hypothyroidism During Tyrosine Kinase Inhibitor Therapy Is Associated with Longer Survival in Patients with Advanced Nonthyroidal Cancers.

机构信息

1 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts.

2 Thyroid Section, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts.

出版信息

Thyroid. 2018 Apr;28(4):445-453. doi: 10.1089/thy.2017.0587.

DOI:10.1089/thy.2017.0587

PMID:29652597

Abstract

BACKGROUND

Tyrosine kinase inhibitor (TKI)-induced thyroid dysfunction is recognized as a common adverse effect of treatment, but the importance of incident hypothyroidism during TKI therapy remains unclear. This study analyzed the prognostic significance of hypothyroidism during TKI therapy in cancer patients.

METHODS

This was a retrospective cohort study of adult patients with advanced nonthyroidal cancer treated with TKI and available thyroid function testing at three affiliated academic hospitals from 2000 to 2017. Patients with preexisting thyroid disease were excluded. Demographic, clinical, and cancer treatment data were collected. Thyroid status with TKI treatment was determined from thyroid function testing and initiation of thyroid medication, and classified as euthyroid (thyrotropin [TSH] normal), subclinical hypothyroidism (SCH; TSH 5-10 mIU/L, or higher TSH if free thyroxine normal), or overt hypothyroidism (OH; TSH >10 mIU/L, low free thyroxine, or requiring replacement). Multivariate models were used to evaluate the effect of TKI-related hypothyroidism on overall survival (OS).

RESULTS

Of 1120 initial patients, 538 remained after exclusion criteria. SCH occurred in 72 (13%) and OH in 144 (27%) patients with TKI therapy. Patients with hypothyroidism had significantly longer OS, with median OS in euthyroid patients of 685 days [confidence interval (CI) 523-851] compared to 1005 days [CI 634-1528] in SCH and 1643 days [CI 1215-1991] in OH patients (p < 0.0001). After adjustment for age, sex, race/ethnicity, cancer type, cancer stage, ECOG performance status, and checkpoint inhibitor therapy, OH remained significantly associated with OS (hazard ratio = 0.561; p < 0.0001), whereas SCH did not (hazard ratio = 0.796; p = 0.165). Analysis of hypothyroid patients (SCH and OH) with TSH >5 and <10 mIU/L stratified by hormone replacement status showed improved survival associated with hormone replacement.

CONCLUSIONS

New hypothyroidism in cancer patients treated with TKI is associated with significantly improved OS, should not necessitate TKI dose reduction or discontinuation, and may provide independent prognostic information.

摘要

背景

酪氨酸激酶抑制剂（TKI）诱导的甲状腺功能障碍被认为是治疗的常见不良反应，但 TKI 治疗期间发生的甲状腺功能减退症的重要性尚不清楚。本研究分析了 TKI 治疗期间甲状腺功能减退症对癌症患者的预后意义。

方法

这是一项回顾性队列研究，纳入了 2000 年至 2017 年期间在三家附属医院接受 TKI 治疗且可获得甲状腺功能检测的晚期非甲状腺癌成年患者。排除了患有甲状腺疾病的患者。收集了人口统计学、临床和癌症治疗数据。根据甲状腺功能检测和甲状腺药物的开始情况来确定 TKI 治疗时的甲状腺状态，并分为甲状腺功能正常（促甲状腺激素[TSH]正常）、亚临床甲状腺功能减退症（SCH；TSH 5-10mIU/L，或游离甲状腺素正常时更高的 TSH）或显性甲状腺功能减退症（OH；TSH>10mIU/L，游离甲状腺素低，或需要替代治疗）。采用多变量模型评估 TKI 相关甲状腺功能减退症对总生存期（OS）的影响。

结果

在排除标准后，1120 名初始患者中有 538 名仍符合入选标准。72 名（13%）和 144 名（27%）患者在接受 TKI 治疗期间发生 SCH 和 OH。甲状腺功能减退症患者的 OS 明显延长，甲状腺功能正常患者的中位 OS 为 685 天[置信区间（CI）523-851]，而 SCH 患者为 1005 天[CI 634-1528]，OH 患者为 1643 天[CI 1215-1991]（p<0.0001）。在校正年龄、性别、种族/民族、癌症类型、癌症分期、ECOG 表现状态和检查点抑制剂治疗后，OH 仍与 OS 显著相关（风险比=0.561；p<0.0001），而 SCH 则无关（风险比=0.796；p=0.165）。对 TSH>5 且<10mIU/L 的甲状腺功能减退症患者（SCH 和 OH）进行分析，并根据激素替代状态进行分层，结果显示激素替代与生存改善相关。