Survival outcomes associated with hypothyroidism following cancer therapies

Background: Hypothyroidism is a recognized adverse effect of cancer therapies such as immunotherapy (immune checkpoint inhibitors, ICIs), chemotherapy (tyrosine kinase inhibitors, TKIs), and radiotherapy. Although proposed as an indicator of treatment response, its prognostic significance across cancer types and therapies remains under-explored. This study evaluated survival outcomes associated with treatment-induced hypothyroidism. Methods: We conducted a retrospective cohort study using de-identified electronic health record data from the University of Michigan between 2006 and 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 (CIs) for overall and cancer-specific survival, adjusting for demographic, clinical, and lifestyle factors. Analyses were stratified by treatment class and cancer site; sensitivity analyses assessed robustness. Results: Among 9,909 patients (57,772 person-years; median follow-up 4.64 years), 2,177 (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 immunotherapy (overall HR = 0.75 [0.61-0.92], p = 0.01; cancer-specific HR = 0.75 [0.66-0.94], p = 0.01) and radiotherapy (HR = 0.88 [0.81-0.96], p = 0.01; cancer-specific HR = 0.76 [0.68-0.84], p <0.001), but not for chemotherapy. Site specific survival benefits were observed in brain/CNS (HR = 0.39 [0.26-0.61], p < 0.001), lip/oral cavity/pharyngeal (HR = 0.77 [0.61-0.97], p = 0.03) and lung/bronchus cancers (HR = 0.80 [0.66-0.97], p = 0.03) but higher mortality in colon cancer (HR = 1.82 [1.10-3.02], p = 0.02). Results were consistent across sensitivity analyses. Conclusion: Hypothyroidism after immunotherapy 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.