The purpose of this study is to demonstrate that participants with HPV positive and hypoxia negative T1-2, N1-2c (AJCC, 7th ed.) oropharyngeal squamous cell carcinoma receiving a major de-escalated radiation therapy with 2 cycles of standard chemotherapy is not inferior to comparable subjects treated with the current standard chemoradiation.

Accrual for Cohort A has been completed.

Cohort B is active and continues to enroll participants where surgery is optional and proton is allowed.

This non-randomized non-inferiority study will enroll HPV associated oropharyngeal carcinoma subjects. Subjects who also have no evidence of hypoxia will undergo a major de-escalated radiation therapy concurrent with standard chemotherapy. Hypoxia status will be determined by 1 BF-FMISO PET /CT imaging. If this baseline scan shows no evidence of hypoxia, the subject will receive 30Gy concurrent with 2 cycles of chemotherapy. If this baseline scan shows evidence of hypoxia, a repeat 1 BF-FMISO scan will be done 5-10 treatment days after start of radiation therapy. If the repeat 1 BF-FMISO scan PET /CT demonstrates no evidence of hypoxia, the subject will receive 30Gy concurrent with 2 cycles of chemotherapy. If the repeat 1 BF-FMISO scan PET /CT demonstrates hypoxia, the subject will receive 70Gy concurrent with 2 cycles of chemotherapy. At 4 (+/- 4 weeks) months after chemoradiation, a neck dissection will be done unless the subjects FDG PET /CT scan at that time shows no evidence of disease of which the subject can be observed as per current standard of care.

Inclusion Criteria:

- Cohort A: Pathologically (histologically or cytologically) proven diagnosis of HPV associated squamous cell carcinoma of the oropharynx (tonsil, base of tongue, or oropharyngeal walls) from surgical resection or excisional biopsy regardless of margin status.

• Squamous cell carcinoma of the neck of unknown primary is allowed with excision biopsy of a lymph node (or core biopsy) and consent from the PI or co-PIs

  • Cohort B: Pathologically (histologically or cytologically) proven diagnosis of HPV associated squamous cell carcinoma of the oropharynx (tonsil, base of tongue, or oropharyngeal walls). Surgical removal of primary site is no longer required.

• Squamous cell carcinoma of the neck of unknown primary is allowed with excision biopsy of a lymph node (or core biopsy) and consent from the PI or co-PIs

  • Subjects must have clinically or radiographically evident measurable disease at nodal stations.
  • Clinical stage T1-2, N1-2c without evidence of distant metastasis based on FDG PET/CT.

• Patients who have squamous cell carcinoma of the neck of unknown primary, and thus, are T0, are allowed with excision biopsy of a lymph node (or core biopsy) or consent from the PI or co-PI

  • CT or MRI of the neck with and without contrast Note: A CT scan of neck and/or a PET/CT performed for the purposes of radiation planning may serve as planning tools.
  • ECOG Performance Status of 0-2 or Karnopsky Performance Status >/= 50
  • Age ≥ 18
  • Adequate hematologic function within 30 days prior to registration, defined as follows:

• White Blood Count (WBC) >/= 2 K/mcL

• Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3

• Platelets ≥ 100,000 cells/mm3

• Hemoglobin ≥ 8.0 g/dl; Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is acceptable

  • Adequate renal function within 30 days prior to registration, defined as follows:

• Serum creatinine ≤ 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula

CCr male = [(140 - age) x (wt in kg)] [(Serum Cr mg/dl) x (72)] CCr female = 0.85 x (CrCl male)

• Adequate hepatic function within 30 days prior to registration, defined as follows:

  • Bilirubin ≤ 2 mg/dl
  • AST or ALT ≤ 3 x the upper limit of normal

• Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential

• The subject must provide study-specific informed consent prior to study entry

Exclusion Criteria:

• Subjects with prior head and neck radiation therapy

• Subjects with simultaneous primary cancers outside of the oropharynx

• Note: Exceptions can be made for patients with simultaneous primaries outside the oropharynx if determined by the PI/Co-PI the patient can proceed with protocol activities

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 3 years or if cure rate from treatment at 5 years to be 90% or greater

• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable

• No particle therapy such as but not limited to proton therapy is allowed in Cohort A. For Cohort B, this exclusion is removed.

• Severe, active co-morbidity defined as follows:

  • Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  • Transmural myocardial infarction within the last 6 months
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration
  • Hepatic Insufficiency resulting in clinical jaundice and/or coagulation defects