The Paradoxical Influence of Hyperthermia on Progression‐Free Survival in Recurrent/Metastatic Oral Cancer Treated With Immune Checkpoint Inhibitors

Background Clinical evidence for combining hyperthermia (HT) with immune checkpoint inhibitors (ICIs) in recurrent/metastatic oral cancer (RM‐OC) is lacking. To our knowledge, this is the first study to investigate the clinical impact of this combination therapy in this specific cohort. Methods We retrospectively analyzed 35 patients with RM‐OC treated with ICIs. Patients receiving concurrent HT ( n = 8) were compared to those without HT ( n = 27). Progression‐free survival (PFS) and overall survival (OS) were evaluated using Kaplan–Meier and Cox proportional hazards models. Results A significant discordance between endpoints emerged. Multivariate analysis revealed that concurrent HT was paradoxically associated with significantly worse PFS (hazard ratio, 3.06; 95% confidence interval, 1.08–8.64; p = 0.035). In stark contrast, HT had no corresponding negative impact on OS (median OS: 26.2 vs. 30.2 months; p = 0.53). Conclusion Concurrent HT with ICI therapy was paradoxically associated with diminished PFS without impacting OS. This critical discordance suggests that the observed radiographic progression may reflect intense, HT‐induced immune‐related inflammation (pseudoprogression) rather than true tumor progression. These findings underscore the complexity of interpreting efficacy endpoints for this novel combination therapy and highlight the need to reconsider standard response evaluation criteria.