A Randomized Phase II/III Trial of De-Intensified Radiation Therapy for Patients With Early-Stage, P16-Positive, Non-Smoking Associated Oropharyngeal Cancer

• Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma but not neuroendocrine phenotype) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls); cytologic diagnosis from a cervical lymph node is sufficient in the presence of clinical evidence of a primary tumor in the oropharynx. Clinical evidence should be documented, may consist of palpation, imaging, or endoscopic evaluation, and should be sufficient to estimate the size of the primary (for T stage)

• Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations. Simple tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site. Limited neck dissections retrieving =\< 4 nodes are permitted and considered as non-therapeutic nodal excisions

• P16-positive based on local site immunohistochemical tissue staining (defined as greater than 70% strong diffuse nuclear or nuclear and cytoplasmic staining of tumor cells). Fine needle aspiration (FNA) biopsy specimens may be used as the sole diagnostic tissue. Centers are encouraged to contact the pathology chair for clarification

‣ Note: Institutions must screen patients, whose tumors must be p16-positive by immunohistochemistry (IHC) in order to be eligible for the trial using a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. A rigorous laboratory accreditation process similar to the United States (U.S.) CLIA certification, such as the provincial accreditation status offered by the Ontario Laboratory Accreditation (OLA) Program in Canada, the College of American Pathologists (CAP), or an equivalent accreditation in other countries, is acceptable. The p16-positive results must be reported on the pathology report being submitted

⁃ Note: If p16 result is equivocal, positive HPV deoxyribonucleic acid (DNA) test of tumor specimen is acceptable and fulfills the eligibility criteria

• Clinical stage T1-2, N1, M0 (American Joint Committee on Cancer \[AJCC\], 8th edition \[ed.\]) or T3, N0-N1, M0 (AJCC, 8th ed.) including no distant metastases based on the following diagnostic workup:

‣ General history and physical examination within 56 days prior to registration;

⁃ Exam with laryngopharyngoscopy (mirror or in office direct procedure acceptable) within 70 days prior to registration;

⁃ One of the following imaging studies is required within 56 days prior to registration:

• FDG-PET/CT of the neck and chest (with or without contrast); FDG-PET/CT scan is strongly preferred and highly recommended to be used for eligibility OR

∙ Chest CT (with or without contrast)

⁃ One of the following imaging studies is required within 28 days prior to registration:

• A diagnostic CT scan of neck (with contrast and of diagnostic quality) OR

∙ An magnetic resonance imaging (MRI) of the neck (with contrast and of diagnostic quality)

∙ Note: A diagnostic quality CT or MRI with contrast or FDG-PET/CT scan of neck performed for the purposes of radiation planning may serve as both staging and planning tools

• Patients must provide their personal smoking history prior to registration. The lifetime cumulative history cannot exceed 10 pack-years. The following formula is used to calculate the pack-years during the periods of smoking in the patient's life; the cumulative total of the number of pack-years during each period of active smoking is the lifetime cumulative history

‣ Number of pack-years = \[Frequency of smoking (number of cigarettes per day) x duration of cigarette smoking (years)\] / 20

⁃ Note: Twenty cigarettes is considered equivalent to one pack. The effect of non-cigarette tobacco products on the survival of patients with p16-positive oropharyngeal cancers is undefined. While there are reportedly increased risks of head and neck cancer associated with sustained heavy cigar and pipe use (Wyss 2013), such sustained use of non-cigarette products is unusual and does not appear to convey added risk with synchronous cigarette smoking. Cigar and pipe tobacco consumption is therefore not included in calculating the lifetime pack-years. Marijuana consumption is likewise not considered in this calculation. There is no clear scientific evidence regarding the role of chewing tobacco-containing products in this disease, although this is possibly more concerning given the proximity of the oral cavity and oropharynx. In any case, investigators are discouraged from enrolling patients with a history of very sustained use (such as several years or more) of non-cigarette tobacco products alone

• Zubrod performance status of 0-1 within 14 days prior to registration

• Age \>= 18

• Absolute neutrophil count \>= 1,500/mcL (within 14 days prior to registration)

• Platelets \>= 100,000/mcL (within 14 days prior to registration)

• Hemoglobin \>= 8.0 g/dL (within 14 days prior to registration) (Note: use of transfusion or other intervention to achieve hemoglobin \[Hgb\] \>= 8.0 g/dL is acceptable)

• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (within 14 days prior to registration)

• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase \[SGOT\]) or alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) =\< 3.0 x institutional ULN (within 14 days prior to registration)

• Serum creatinine =\< 1.5 x ULN OR creatinine clearance (CrCl) \>= 50 mL/min (if using the Cockcroft-Gault formula) (within 14 days prior to registration)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

‣ Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B)

• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment for the hepatitis, they are eligible if they have an undetectable HCV viral load.

‣ Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy

• For women of childbearing potential (WOCBP), negative serum or urine pregnancy test within 24 hours prior to registration

‣ Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL

• Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP must be willing to use an adequate method of contraception during and after treatment

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry

• Only English, Spanish, or French speaking patients are eligible to participate as these are the only languages for which the mandatory dysphagia-related patient reported instrument (MDADI) is available