Dosimetric Predictors of Hypothyroidism after Combined Modality Therapy ± Immunotherapy for HPV-Related Oropharyngeal Cancer: A Secondary Analysis of Prospective Trials

Purpose/Objective(s) Multiple prospective trials have integrated immune checkpoint blockade (ICB) into treatment paradigms involving radiotherapy (RT) for head and neck cancer. Dosimetric predictors of hypothyroidism after RT is not well understood in this context. In this secondary analysis, we evaluate the association of radiation dose-volume metrics with hypothyroidism after definitive treatment with or without ICB for HPV-related oropharyngeal cancer (OPC). Materials/Methods This was a dosimetric secondary analysis of locally advanced HPV+ OPC treated on two prospective phase II de-escalation trials (OPTIMA / NCT02258659) and OPTIMA II / NCT03107182) and an associated expansion cohort on registry (OPTIMA-like). On OPTIMA and OPTIMA-like, patients received induction chemotherapy (platinum doublet x 3 cycles) followed by response-adapted de-escalated RT (+/- chemotherapy). On OPTIMA II, nivolumab was added to induction chemotherapy and offered adjuvantly for 6 months. After RT, hypothyroidism was defined as elevated TSH and being prescribed levothyroxine or demonstrating clinical signs/symptoms. Demographic and treatment variables were recorded, notably mean thyroid dose (Gy) and thyroid volume receiving a minimum of 30-70 Gy (V30 Gy - V70 Gy). Hypothyroidism was analyzed as a time-to-event outcome using cumulative incidence (with death and salvage reirradiation as competing risks). Optimal dosimetric cut points were defined as those with maximum Youden index. Results 134 patients met inclusion criteria (median follow-up 5.6 years, median age 61 years, 95% men). 50 patients (37%) received ICB. The mean thyroid dose was 23 Gy (median across patients; range: 0.5 – 61 Gy). Hypothyroidism occurred in 26% (n = 35) of patients (median time 0.8 years; range: 0.03 - 4.0 years). For mean thyroid dose, the optimal cut point was 35.5 Gy (31% sensitivity, 89% specificity). Across all dosimetric predictors, the optimal cut point by Youden index was V50 Gy ≥ 31.7% (43% sensitivity, 89% specificity). The cumulative incidence of hypothyroidism is displayed in Table 1. On multivariable Fine-Gray competing risks regression, V50 Gy was associated with hypothyroidism (sHR = 1.02 per % thyroid gland; 95% CI, 1.01 to 1.03; P = 0.001), while ICB (P = 0.15), age (P = 0.41), and sex (P = 0.34) were not. There was no interaction effect between thyroid dose and ICB. Conclusion The percentage of thyroid gland receiving at least 50 Gy was associated with hypothyroidism (optimal cut point V50 Gy > 31.7%). ICB was not significantly associated with hypothyroidism and did not interact with dosimetric predictors. These findings inform potential thyroid dose constraints to utilize in future trials, including those integrating ICB.