Prospective validation of diffusion-weighted MRI as a biomarker of tumor response and oncologic outcomes in head and neck cancer: Results from an observational biomarker pre-qualification study

Purpose/Objective(s) To determine diffusion-weighted imaging (DWI) MRI parameters associated with tumor response and oncologic outcomes in head and neck (HNC) patients treated with definitive radiation therapy (RT). Materials/Methods Eighty-six HNC patients enrolled in an active prospective imaging study at The University of Texas MD Anderson Cancer Center were included in the analysis. Patients had MRIs pre-, mid-, and post-RT completion. Inclusion criteria included adults with histologic evidence of malignant head and neck neoplasm indicated for curative-intent treatment with RT with/without chemotherapy, good performance status (ECOG score 0-2), and with no contraindications to MRI. Patients were scanned using a MAGNETOM Aera 1.5T MR scanner (Siemens Healthcare, Germany) with two large four-channel flex phased-array coils. We used fat-suppressed T2-weighted turbo spin echo sequences for tumor segmentation which were co-registered to respective DWIs for extraction of apparent diffusion coefficient (ADC) measurements. Treatment response was assessed at mid-RT and at 8-12 weeks post-RT using RECIST 1.1 criteria and was defined as: complete response (CR) vs. non-complete response (non-CR). Pre-RT ADC was correlated with RT response (CR vs. non-CR) at mid- and post-RT. The Mann-Whitney U test was used to compare ADC values between the mid-treatment CR group and the non-CR group. Recursive partitioning analysis (RPA) was performed to identify ADC threshold associated with relapse. Cox proportional hazards models were done for clinical vs. clinical and imaging parameters and internal validation was done using bootstrapping technique. Results Eighty-one patients were included in this analysis. Median follow-up was 31 months. Pre-treatment ADC was not correlated with tumor response or oncologic outcomes (P>0.05). For patients with post-RT CR, there was a significant increase in mean ADC at mid-RT compared to baseline ((1.8 ± 0.29) × 10 −3 mm 2 /s versus (1.37 ± 0.22) × 10 − 3 mm 2 /s, p 0.05). RPA identified GTV-P delta (Δ) ADC mean <7% at mid-RT as the most significant parameter associated with worse LC and RFS ( p =0.01). Univariable and multivariable analysis of prognostic outcomes showed that GTV-P ΔADC mean at mid-RT ≥7% was significantly associated with better LC and RFS. The addition of ΔADC mean significantly improved the c-indices of LC and RFS models compared with standard clinical variables (0.85 vs. 0.77 and 0.74 vs. 0.68 for LC and RFS, respectively, p <0.0001 for both). Conclusion ADC change at mid-RT is a strong predictor of oncologic outcomes in HNC patients. Patients with no significant increase of primary tumor site ADC at mid-RT relative to baseline values are at high risk of disease relapse. Multi-institutional data are needed for validation of our results.