This is a Phase I study looking to evaluate the safety of dose escalated stereotactic radiotherapy (SRS) without exceeding the maximum tolerated dose in patients with high-risk human papilloma virus (HPV)- unassociated oropharyngeal squamous cancer.

Human Papilloma Virus (HPV) is frequently found within tumor cells removed from patients diagnosed with oropharynx cancer. Tumors which do not contain HPV virus (termed "HPV-Negative") are not cured as frequently by radiation therapy. Tumors which do contain HPV in patients who have a history of cigarette smoking also are not cured as frequently by radiation.

One way to potentially overcome this challenge is to deliver a more intense dose of radiation treatment to the tumor. The standard way to deliver radiation, termed Intensity Modulated Radiotherapy (IMRT), can protect normal tissues near tumors to a certain degree but not completely. Stereotactic radiosurgery (SRS) is a technique which can deliver radiation more precisely.

This trial will test the safety of treating HPV-unassociated oropharynx tumors to higher radiation doses wth SRS (termed a "boost") after a standard course of IMRT has been given. In addition, the investigators will look at whether magnetic resonance imaging (MRI) scanning can detect treatment response in oropharynx tumors earlier than with standard tests.

Inclusion Criteria:

• Patients older than 18 years of age with histologically proven squamous cell carcinoma of the oropharynx
• HPV-negative disease status by routine p16 immunohistochemical (IHC) staining or in situ hybridization (ISH) of biopsied tumor tissue or >10 pack-year cigarette smoking history
• Stage T1-4, N0-3 disease, as defined by American Joint Committee on Cancer (AJCC) criteria
• Eastern Cooperative Oncology Group (ECOG) (Zubrod) Performance Status 0-2.

Exclusion Criteria:

• Patients who have undergone resection of primary disease
• Patients who have received induction chemotherapy for their oropharynx cancer diagnosis
• Prior cancer diagnosis within 5 years, except appropriately treated localized epithelial skin cancer or cervical cancer
• Prior radiation therapy to the head and neck region
• Women of childbearing potential (a woman of child-bearing potential is a sexually mature woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 24 consecutive months [i.e., who has had menses at any time in the preceding 24 months]) and male participants must practice effective contraception (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study
• Patient unable to tolerate MRI or having an estimated Glomerular Filtration Rate (GFR) <60 ml/min/1.73 m2.
• 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 before registration
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol
• Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control (CDC) definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immuno-compromised patients
• History or treatment with potent immunosuppressive drugs for such conditions as organ transplant, severe rheumatoid arthritis, etc. within the past 6 months.