Understanding the impact of radiotherapy fractionation on overall survival in a large head and neck squamous cell carcinoma dataset: a comprehensive approach combining mechanistic and machine learning models.

INTRODUCTION

Treating head and neck squamous cell carcinomas (HNSCC), especially human papillomavirus negative (HPV-) and locally advanced cases, remains difficult. Our previous analyses of radiotherapy-only HNSCC clinical trials data using mechanistically-motivated models of tumor repopulation and killing by radiotherapy predicted that hyperfractionation with twice-daily fractions, or hypofractionation involving increased doses/fraction and reduced treatment durations, both improve tumor control and reduce late normal tissue toxicity, compared with standard protocols using 35×2 Gy. Here we further investigated the validity of these conclusions by analyzing a large modern dataset on 3,346 HNSCC radiotherapy patients from the University Health Network in Toronto, Canada, where 42.5% of patients were also treated with chemotherapy.

METHODS

We used a two-step approach that combines mechanistic modeling concepts with state-of-the-art machine learning, beginning with Random Survival Forests (RSF) for an exploratory analysis and followed by Causal Survival Forests (CSF) for a focused causal analysis. The mechanistic concept of biologically effective dose (BED) was implemented for the standard dose-independent (DI) tumor repopulation model, our alternative dose-dependent (DD) repopulation model, and a simple model with no repopulation (BED). These BED variants were included in the RSF model, along with age, stage, HPV status and other relevant variables, to predict patient overall survival (OS) and cause-specific mortality (deaths from the index cancer, other cancers or other causes).

RESULTS

Model interpretation using Shapley Additive Explanations (SHAP) values and correlation matrices showed that high values of BED or BED, but not BED, were associated with decreased patient mortality. Targeted causal inference analyses were then performed using CSF to estimate the causal effect of each BED variant on OS. They revealed that high BED (>61.8 Gy) or BED (>57.6 Gy), but not BED, increased patient restricted mean survival time (RMST) by 0.5-1.0 years and increased survival probability (SP) by 5-15% several years after treatment. In addition to population-level averages, CSF generated individual-level causal effect estimates for each patient, facilitating personalized medicine.

DISCUSSION

These findings are generally consistent with those of our previous mechanistic modeling, implying the potential benefits of altered radiotherapy fractionation schemes ( 25×2.4 Gy, 20×2.75 Gy, 18×3.0 Gy) which increase BED and BED and counteract tumor repopulation more effectively than standard fractionation. Such regimens may represent potentially useful hypofractionated options for treating HNSCC.