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 the oropharynx (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 the oropharynx that would mandate definitive chemoradiation as current standard of care when standard radiation fractionation is applied. Debulking of the disease by resecting the exophytic portion of the tumor for biopsy/sample or symptom alleviation 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 months after treatment.
* Patients must have Karnofsky Performance Status (KPS) ≥ 60 within 8 weeks prior to registration
* Patients must have had a neutrophil:lymphocyte ratio ≤ 5 within 8 weeks of registration.
* Patient must have had a hemoglobin count ≥ 10 within 8 weeks of registration. The patient may receive transfusion to reach this goal.
* Patients must be a current non-smoker (at least 6 months) with ≤ 15 pack-year smoking 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, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating 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 nodal conglomerates that in sum measure \>4cm is allowed)
* Patients with nodal disease clinically fixed to or radiographically invading adjacent neck musculature any single lymph node \> 4cm (multiple lymph nodes including nodal conglomerates that in sum measure \>4cm is allowed)
* Prior history of malignancy diagnosed within 2 years prior to registration, except for nonmelanomatous skin cancer that has completed treatment and the patient is deemed as being disease-free, or Gleason 6 prostate cancer undergoing active surveillance.
* Patients must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.