De-Escalation Radiotherapy in Patients With Low-Risk HPV-Related Oropharyngeal Squamous Cell Carcinoma

Inclusion Criteria: * Patients with pathologically proven diagnosis of HPV-related OPSCC * Clinical stage T1-3 N0-1 M0 (UICC/AJCC 8th Ed.) * Patients must be eligible for definitive RT or CRT * Must be ≥ 18 years of age * Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life and health economics questionnaires in either English or French * Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate * Patients must be accessible for treatment and follow-up. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up. * In accordance with CCTG policy, protocol treatment is to begin within 3 weeks of patient registration * Women/men of childbearing potential must have agreed to use a highly effective contraceptive method * The following radiological investigations must be done within 8 weeks of randomization: CT or MR of head and neck (MRI is recommended for base-of-tongue primary tumors); PET-CT scan. * Patient must consent to provision of, and investigator(s) must confirm location and commit to obtain a representation of formalin-fixed paraffin block of non-cytology tumour tissue in order that the specific correlative marker assays described in Section 12 (Correlative Studies) may be conducted. Please see the Correlative Manual for details * Patient must consent to provision of samples of blood and plasma (for circulating cell free DNA) in order that the specific correlative marker assays described may be conducted. * Patients with prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Exclusion Criteria: * Previous chemotherapy or radiotherapy treatment for head and neck cancer * Patients with an unknown primary.