A Novel Approach to Dose De-Escalation in HPV-Positive Oropharyngeal Chemoradiotherapy Utilizing Adaptive Planning Based on Voxel-Level FDG Response

Abstract

Definitive chemoradiation for HPV-positive oropharyngeal squamous cell carcinoma (HPV+ OPC) is associated with high cure rates, but also with significant patient morbidity. Using previously described techniques to create heterogenous radiotherapy dose level selection, combined with data from patients followed by serial FDG-PET/CT during definitive chemoradiation, we generated hypothetical adaptive radiation plans with the goal of decreasing dose to normal tissues while maintaining equivalent local control.Five patients with HPV+ OPC enrolled on a prospective single-institution protocol with serial FDG-PET/CT imaging during the course of definitive chemoradiation were analyzed. Two radiotherapy plans were then generated for each patient: one in which gross disease was prescribed a uniform dose of 60 Gy, and a second using adaptive tumor response to progressively reduce the prescription dose to gross disease in a heterogenous fashion. Voxel-level changes in FDG avidity were combined with a previously described tumor voxel control probability model to guide dose de-escalation in radiosensitive regions of tumor while maintaining equivalent local control. Dose accumulation to nearby organs at risk (OARs), incorporating changes due to progressive de-escalation, were then compared for the two sets of plans using the paired samples Wilcoxon test.The de-escalated plans created using voxel-level tumor response resulted in treatment plans with significantly reduced dose to all evaluated OARs. Significant improvements included a decreased spinal cord maximum dose, brainstem maximum dose, parotoid gland mean dose, constrictor muscle mean and maximum dose, and mandible maximum dose (P = 0.03). Projected tumor control probability remained high, despite de-escalation of dose in PET-sensitive areas of gross disease.Adaptive FDG-PET response can be used to guide de-escalation to reduce dose to nearby OARs. Using a novel technique for dose selection based on voxel-level tumor response, heterogeneous de-escalation can further reduce toxicity while maintaining optimal local control in most patients with HPV+ OPC. This concept will be used to design a non-randomized prospective trial investigating the role of heterogeneous de-escalation in this patient population.