Treatment modality and anatomic site as determinants of mortality in second primary cancers after head and neck cancer: A SEER analysis.

e18100 Background: Second primary malignancies (SPMs) are a major contributor to late mortality among survivors of head and neck cancer (HNC). However, the extent to which initial HNC treatment modality and the anatomic site of subsequent non-synchronous SPMs influence overall, and cancer-specific mortality remains incompletely characterized. We evaluated the independent association of prior HNC treatment and SPM site with survival outcomes in a large population-based cohort. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified adults diagnosed with primary squamous cell HNC who subsequently developed a non-synchronous SPM occurring ≥2 years after HNC diagnosis, a threshold chosen to minimize misclassification of synchronous disease and early recurrence. Modified Poisson regression with robust variance was used to estimate unadjusted and adjusted relative risks (aRRs) for overall mortality and cancer-specific mortality. Multivariable models adjusted for age at HNC diagnosis, race/ethnicity, tumor grade, latency interval, anatomic site of the SPM, and receipt of surgery, chemotherapy, and radiation for the index HNC. Results: Among 19,686 HNC survivors with non-synchronous SPMs, overall mortality occurred in 68.6% of patients, and 42.2% died from cancer-related causes. Survival outcomes varied by initial HNC treatment modality. Patients who had undergone surgical management of the index HNC had lower overall mortality (aRR 0.85, 95% CI 0.81–0.88) and cancer-specific mortality (aRR 0.91, 95% CI 0.85–0.98), whereas those treated with radiation had higher overall (aRR 1.08, 95% CI 1.06–1.11) and cancer-specific mortality (aRR 1.11, 95% CI 1.07–1.15), consistent with differences in baseline disease characteristics and treatment selection. Chemotherapy was not independently associated with cancer-specific mortality after adjustment. Marked heterogeneity in mortality risk was observed across SPM sites. Compared with second primary head and neck cancers, pancreatic (aRR 1.66), esophageal (aRR 1.53), lung (aRR 1.39), and stomach (aRR 1.27) SPMs were associated with substantially higher overall and cancer-specific mortality, whereas prostate, breast, melanoma, bladder, and kidney SPMs were associated with more favorable outcomes. Conclusions: Among survivors of head and neck cancer who develop non-synchronous second primary malignancies, long-term mortality risk varies substantially according to both initial treatment modality and the anatomic site of the subsequent cancer. These associations likely reflect underlying disease severity and biologic heterogeneity rather than treatment efficacy alone. Together, these findings highlight the importance of treatment-aware and site-specific survivorship risk assessment.