Individualized Adaptive De-escalated Radiotherapy for HPV-related Oropharynx Cancer

Inclusion Criteria:

* Patients must have FDG-avid and histologically or cytologically proven squamous cell carcinoma of the oropharynx (tonsil, base of tongue, oropharyngeal wall, soft palate) that is p16 positive by immunohistochemistry or HPV positive by in situ hybridization.
* AJCC eighth edition staging stage 1 and stage 2
* Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup:
* History/physical examination, including documentation of weight within 4 weeks prior to registration;
* FDG-PET/CT scan for staging and RT plan within 4 weeks prior to registration;
* Zubrod Performance Status (A quantification of the functional status of cancer patients that runs from 0 to 5, with 0 denoting perfect health and 5 death) 0-1 within 4 weeks prior to registration;
* Age ≥ 18;
* Able to tolerate PET/CT imaging required to be performed
* CBC/differential obtained within 4 weeks prior to registration on study, with adequate bone marrow function;
* Serum creatinine within normal institutional limits or a creatinine clearance ≥ 45 ml/min within 4 weeks prior to registration;
* Women of childbearing potential and male participants must agree to use a medically effective means of birth control throughout their participation in the treatment phase of the study.
* The patient must provide study-specific informed consent prior to study entry.

Exclusion Criteria:

* cT4, cN3 or cM1 disease
* "Matted nodes" as determined by review with Neuroradiology
* Gross total excision of both primary and nodal disease with curative intent; this includes tonsillectomy, local excision of primary site, and nodal excision that removes all clinically and radiographically evident disease. In other words, to participate in this protocol, the patient must have clinically or radiographically evident gross disease for which disease response can be assessed.
* Carcinoma of the neck of unknown primary site origin (even if p16 positive);
* Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years
* Any prior therapy for the study cancer; note that prior chemotherapy for a different cancer is allowable if \> 3 years prior to study;
* Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;
* Severe, active co-morbidity;
* Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception;
* Poorly controlled diabetes