Tyrosine kinase inhibitors (TKI) belong to a new class of molecular multi-targeted anticancer therapy which targets different growth factor receptors and hence attenuates cancer cell survival and growth. TKI-induced thyroid dysfunction is recognized as a common adverse effect of treatment., but the onset of thyroid dysfunction is variable. This study analysed correlation between initiation of TKIs and the onset of thyroid dysfunction in non-thyroid cancers patients without any background thyroid dysfunction.
This was a retrospective cohort study to evaluate thyroid dysfunction in adult patients (n=227, M:F=153:74) with non-thyroidal cancers treated with TKIs. Patients having pre-existing thyroid disease including euthyroid goitres were excluded. Demographic, clinical, and cancer treatment data were collected. Thyroid function tests (TFTs) were done prior to initiation, at 2 months, 6 months and at 1 year. TFTs were classified as euthyroid (thyrotropin [TSH] normal), subclinical (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).
Of the 227 patients in the study, OH occurred in 57 patients (25.1%)(M:F = 19:38) and SCH occurred in 89 patients (39.2%) (M:F=39:50) with TKI therapy at the end of 12 months. 37 patients (M:F=13:24) developed OH in first 6 months after initiation of TKIs. Female patients were more likely to have OH in the first 6-month period following TKIs irrespective of type of TKI or the cancers. SCH was also more common after 2 months in female patients (n=23) (M:F=6:17) but the conversion of SCH to OH was more common in male patients at the end of 12 months. The symptoms were variable and most the patients did have any thyroid specific symptoms. After adjustment for age, sex, cancer type, cancer stage, performance status, and type of TKI, OH remained significantly associated with survival at 1-year (hazard ratio=0.461; p<0.0001), whereas SCH did not (hazard ratio=0.591; 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, although 1 year follow-up is too short to comment on overall survival rates.
New onset hypothyroidism, both OH and SCH is common in non-thyroidal cancer patients treated with TKI. SCH is more common after 2 months and OH after 6 months following TKI initiation. Female sex is more predisposed to develop thyroid dysfunction irrespective of underlying cancer or type of TKI used but male patients progressed to OH at the end of 12 months.