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Analyses of clinical outcomes following radiotherapy (RT) have advanced our understanding of fundamental radiobiological characteristics in head and neck squamous cell carcinoma (HNSCC). Low fractionation sensitivity appears to be a common feature, as well as susceptibility to changes in overall treatment time (OTT). Large tumors should be harder to cure if a successful RT requires the sterilization of all clonogenic cells. Congruently, primary tumor volume has proven to be an important parameter. However, most findings come from an era when p16-negative HNSCC was the dominant tumor type. HPV-associated, p16-positive, oropharyngeal tumors (OPSCC) are more radiosensitive and have better outcome. The current study aims to investigate the role of primary tumor volume, OTT and estimate α-ratio for p16-positive OPSCC, and to quantify the differences in radiosensitivity depending on p16-status. A cohort of 523 patients treated with RT was studied using a tumor control probability (TCP)-model that incorporates primary tumor volume (V) raised to an exponent  c , OTT and α-estimation. The significance of V was also investigated in Cox-regression models. In the p16-positive cohort ( n  = 433), the volume exponentwas 1.44 (95%CI 1.06–1.91), compared to 0.90 (0.54–1.32) for p16-negative tumors ( n  = 90). Hazard ratios per tumor volume doubling were 2.37 (1.72–3.28) and 1.83 (1.28–2.62) for p16-positive and p16-negative, respectively. The estimated α-ratio was 9.7 Gy (−2.3–21.6), and a non-significant daily loss of 0.30 Gy (−0.17–0.92) was found. An additional dose of 6.8 Gy (interquartile range 4.8-9.1) may theoretically counteract the more radioresistant behavior of p16-negative tumors. Primary tumor volume plays a crucial role in predicting local tumor response, particularly in p16-positive OPSCC. The estimated α/β-ratio for p16-positive oropharyngeal tumors aligns with previous HNSCC studies, whereas the impact of prolonged OTT was slightly less than previously reported. The differences in radiosensitivity depending on p16-status were quantified. The findings should be validated in independent cohorts.

Importance of tumor volume, overall treatment time and fractionation sensitivity for p16-positive and p16-negative oropharyngeal tumors