Treatment De-Escalation for Favorable Prognosis Human Papilloma Virus (HPV) or p16-Positive Oropharyngeal Cancer Receiving Definitive Radiotherapy

Inclusion Criteria:

• Patients must be ≥ 18 years of age on the day of signing informed consent.

• Patients must have a diagnosis of p16+ and/or HPV+ squamous cell carcinoma of theoropharynx (including base of tongue, glossotonsilar sulcus, tonsil, soft palate,vallecula, and/or posterior oropharyngeal wall).

• clinical stage stage I-II (T1-2 N1 M0, or T3 N0-1 M0 ) (AJCC 8th ed.) SCCA of theoropharynx that would mandate definitive chemoradiation as current standard of carewhen standard radiation fractionation is applied. Debulking of the disease byresecting the exophytic portion of the tumor for biopsy/sample or symptomalleviation will be permitted, as long as gross unresected tumor is left behind.

• Subjects must agree to biopsy of areas that are FDG-avid on PET-CT scan 3-4 monthsafter treatment.

• Patients must have Karnofsky Performance Status (KPS) ≥ 60 within 8 weeks prior toregistration

• Patients must have had a neutrophil:lymphocyte ratio ≤ 5 within 8 weeks ofregistration.

• Patient must have had a hemoglobin count ≥ 10 within 8 weeks of registration. Thepatient may receive transfusion to reach this goal.

• Patients must be a current non-smoker (at least 6 months) with ≤ 15 pack-yearsmoking history

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, forthe duration of study participation, and for 90 days following completion oftherapy. Should a woman become pregnant or suspect she is pregnant whileparticipating in this study, she should inform her treating physician immediately.

• Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

• Patients with gross involvement of level 4 lymph node level

• Endophytic T3 disease, as clinically determined by the principal investigator.

• Patients with any single lymph node > 4cm (multiple lymph nodes including nodalconglomerates that in sum measure >4cm is allowed)

• Patients with nodal disease clinically fixed to or radiographically invadingadjacent neck musculature any single lymph node > 4cm (multiple lymph nodesincluding nodal conglomerates that in sum measure >4cm is allowed)

• Prior history of malignancy diagnosed within 2 years prior to registration, exceptfor nonmelanomatous skin cancer that has completed treatment and the patient isdeemed as being disease-free, or Gleason 6 prostate cancer undergoing activesurveillance.

• Patients must not be pregnant or nursing due to the potential for congenitalabnormalities and the potential of this regimen to harm nursing infants.