Clinical validation of a prognostic preclinical magnetic resonance imaging biomarker for radiotherapy outcome in head-and-neck cancer

Purpose: To retrain a model based on a previously identified prognostic imaging biomarker using apparent diffusion coefficient (ADC) values from diffusion-weighted magnetic resonance imaging (DW-MRI) in a preclinical setting and validate the model using clinical DW-MRI data of patients with locally advanced head-and-neck cancer (HNC) acquired before radiochemotherapy.

Material and methods: A total of 31 HNC patients underwent T2-weighted and DW-MRI using 3 T MRI before radiochemotherapy (35x2Gy). Gross tumor volumes (GTV) were delineated based on T2-weighted and b500 images. A preclinical model previously revealed that the size of high-risk subvolumes (HRS) defined by a band of ADC-values was correlated to radiation resistance. To validate this model, different bands of ADC-values were tested using two-sided thresholds on the low-ADC histogram flank to determine HRSs inside the GTV and correlated to treatment outcome after three years. The best model was used to fit a logistic regression model. Stratification potential regarding outcome was internally validated using bootstrap, receiver-operator-characteristic (ROC)-analysis, Kaplan-Meier- and Cox-method, and compared to GTV ADC_mean and clinical factors.

Results: The best model was defined by 800<ADC<1100∙10^-6mm²/s and correlated significantly to treatment outcome (p = 0.003). Optimal HRS cut-off value was found to be 5.8 cm³ according to ROC-analysis. This HRS demonstrated highly significant stratification potential (p < 0.001, bootstrap AUC ≥ 0.84) similar to GTV size (p < 0.001, AUC ≥ 0.79), in contrast to ADC_mean (p = 0.361, AUC = 0.53).

Conclusions: A preclinical prognostic model defined by an ADC-based HRS was successfully retrained and validated in HNC patients treated with radiochemotherapy. After thorough external validation, such functional HRS based on a band of ADC values may in the future allow interventional response-adaptive MRI-guided radiotherapy in online and offline approaches.