Survival Outcomes Associated with Hypothyroidism Following Cancer Therapies

Hypothyroidism is a recognized adverse effect of cancer therapies such as immune checkpoint inhibitors (ICI), tyrosine kinase inhibitors (TKI), and radiotherapy. Although proposed as an indicator of treatment response, its prognostic significance across cancer types and therapies remains underexplored. This study evaluated survival outcomes associated with treatment-induced hypothyroidism.

We conducted a retrospective cohort study using de-identified electronic health record data from the University of Michigan (2006-2023). Adults (≥18 years) receiving ICIs, TKIs, or radiotherapy, without prior thyroid disease or malignancy, were included. We defined hypothyroidism by institutional laboratory criteria or thyroid hormone initiation. Time-dependent Cox models estimated hazard ratios (HRs) and 95% confidence intervals for overall and cancer-specific survival, adjusting for demographic, clinical, and lifestyle factors. Analyses were stratified by treatment class and cancer sites; sensitivity analyses assessed robustness.

Among 9909 patients (57,772 person-years; median follow-up 4.64 years), 2177 (22.0%) developed hypothyroidism (median onset time: 5.04 months). Treatment-induced hypothyroidism was associated with improved overall (HR = 0.86 [0.79-0.93], p < 0.001) and cancer-specific survival (HR = 0.76 [0.70-0.84], p < 0.001). Stratified analyses showed significant survival benefits with hypothyroidism following ICI (overall HR = 0.75 [0.61-0.92], p = 0.014; cancer-specific HR = 0.75 [0.66-0.94], p = 0.012) and radiotherapy (overall HR = 0.88 [0.81-0.96], p = 0.011; cancer-specific HR = 0.76 [0.68-0.84], p < 0.001), but not for TKI. Site-specific survival benefits were observed in brain/central nervous system (HR = 0.39 [0.26-0.61], p < 0.001), lip/oral cavity/pharyngeal (HR = 0.77 [0.61-0.97], p = 0.032), and lung/bronchus cancers (HR = 0.80 [0.66-0.97], p = 0.034) but higher mortality in colon cancer (HR = 1.82 [1.10-3.02], p = 0.021). Results were consistent across sensitivity analyses.

Hypothyroidism after ICI and radiotherapy was associated with improved survival, supporting its potential as a prognostic biomarker of therapeutic benefit. Future studies should investigate the underlying mechanisms and clinical implications.