Dissociation Between Acute and Late Radiation Toxicity in Locally Advanced Head and Neck Cancer: A Secondary Analysis

Background and objective Intensity-modulated radiotherapy (IMRT) reduces both acute and late toxicity in head and neck squamous cell carcinoma (HNSCC) compared with three-dimensional conformal radiotherapy (3D-CRT). However, whether the severity of a patient's acute treatment toxicity predicts subsequent late toxicity remains uncertain. If such an association exists, acute toxicity could identify survivors who need closer late-effect surveillance, particularly where routine dosimetric review is not feasible. Based on radiobiological differences between acute and late normal-tissue responses, we hypothesized that acute and late toxicities would be largely dissociated and prespecified this analysis to test that hypothesis. The primary objective of this study was to determine whether peak acute mucositis predicts grade ≥2 late xerostomia at 12 months. Other acute-to-late, dosimetric, and multivariable analyses were secondary or exploratory. Methods We reanalyzed data from 78 patients with locally advanced HNSCC treated with definitive chemoradiotherapy between 2017 and 2018. Peak acute toxicity grades, such as mucositis, dysphagia, dermatitis, and nasogastric tube requirement, were linked at the individual-patient level to 12-month late toxicity assessed using Radiation Therapy Oncology Group (RTOG)/European Organisation for Research and Treatment of Cancer (EORTC) criteria. The mean parotid dose was extracted from each treatment plan. Associations were evaluated using Fisher's exact test and Spearman's rank correlation, with logistic regression for exploratory analyses. A prespecified minimum detectable effect was used to assess statistical power. Results At 12 months, grade ≥2 late xerostomia occurred in 23.1% of IMRT patients vs 51.3% of 3D-CRT patients (p = 0.019). No acute toxicity measure significantly predicted any late endpoint; the smallest p-value was 0.142, and all CIs included the null value. However, statistical power was limited: the primary analysis had 80% power to detect only a large association (OR ≈4.1 or greater) and approximately 18% power for the observed OR of 1.69. Thus, a moderate association cannot be excluded. Patients treated with 3D-CRT had more severe acute mucositis than those treated with IMRT (43.6% vs 17.9%) and received higher mean parotid doses (35.2 vs 23.7 Gy). Although a weak correlation was observed between acute mucositis and late xerostomia (Spearman ρ = 0.23, p = 0.042), it was no longer significant after adjustment for radiotherapy technique. Both exploratory regression models failed their global significance tests and should be interpreted cautiously. Conclusions In this cohort, we found no convincing evidence that the severity of acute treatment toxicity predicts subsequent late toxicity, although the limited sample size means moderate associations cannot be confidently excluded. Late xerostomia was more clearly associated with radiotherapy technique and parotid dose than with the severity of the acute reaction. Acute toxicity should not be used in isolation to estimate an individual patient's risk of late toxicity; delivered dose and treatment technique remain more informative determinants of late normal-tissue injury.