Locoregional failure remains the principal mode of mortality in head and neck squamous cell carcinomas (HNSCCs) treated with conventional chemoradiation therapy over 7 weeks. Radiation dose escalation with hypofractionation has shown unparalleled local control in many other malignancies, such as non-small cell lung cancer, but has been stymied in HNSCCs due to toxicity concerns. MR-guided radiation therapy (MRgRT) allows for adaptive radiation dose escalation based on tumor response, which may improve therapeutic outcomes while limiting toxicities. Our proposal, titled Dose-Escalated Hypofractionated Adaptive Radiotherapy (DEHART), evaluates a novel framework for radiation delivery using MRgRT with concurrent PD-1/PD-L1 targeted immunotherapy in patients with advanced HNSCCs. Unlike conventional radiotherapy, DEHART modifies radiation dose using MRgRT by adapting the radiation plan weekly during the course of treatment, escalating radiation dose to residual tumor while deescalating radiation dose to areas of tumor regression. We hypothesize that DEHART will safely deliver ablative radiation doses in 15 fractions over 3 weeks while limiting both toxicity and the effect of tumor repopulation by resistant clonogens, thus resulting in an improved therapeutic ratio.
We aim to test this hypothesis through a Phase I clinical trial with the following specific aims: (1) Determine the maximum tolerated dose (MTD) of the DEHART regimen delivered using MRgRT with concurrent immunotherapy in a population of patients who are not candidates or unsuitable for definitive chemoradiation therapy; (2) Evaluate the toxicity and functional outcomes of the DEHART regimen including changes in baseline speech, swallow and quality of life; and (3) Assess the efficacy of DEHART and obtain volumetric and functional imaging correlates of efficacy using MRgRT to serve as hypothesis-generating data for future trials of radiation dose adaptation. To determine the MTD of the DEHART regimen, we propose an 18 patient study using a modified Time-to Event Continual Reassessment (TITE-CRM) Phase I Design with three radiation dose levels delivered to regressing disease: 50 Gy in 15 fractions, 55 Gy in 15 fractions and 60 Gy in 15 fractions. If DEHART is found to be safe and shows a signal of efficacy in this study, we will conduct a future Phase II trial to compare this novel treatment strategy to standard-of care conventionally fractionated chemoradiation in patients with locally advanced HNSCCs.
Despite optimal treatment with standard-of-care chemoradiation therapy, failure to control local and regional disease rather than distant metastasis, remains the principal cause of mortality in patients with head and neck squamous cell carcinomas (HNSCCs). DEHART, a novel radiation treatment strategy, may realize the therapeutic potential of hypofractionated radiation in HNSCCs which has previously been limited due to toxicity concerns. We seek to determine the maximum tolerated dose, safety, efficacy and quality-of-life outcomes of the DEHART regimen in a Phase I trial, with the ultimate future goal of comparing such an approach to standard-of-care chemoradiation in patients with HNSCCs.
