Decitabine in Combination With Standard of Care Therapy for the Treatment of Surgically Resectable HPV-Negative Head and Neck Cancer

Inclusion Criteria:

* REGISTRATION: Age ≥ 18 years
* REGISTRATION: Histologic confirmation of HPV-negative, squamous cell carcinoma of the head and neck that is surgically resectable. HPV-status confirmation by p16, circulating tumor DNA or in-situ hybridization is only required for oropharyngeal primaries

  * Includes mucosal and non-mucosal subsites
  * Includes head and neck of unknown primary origin REGISTRATION: Measurable disease preoperatively, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or equivalent criteria
  * NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; disease that is measurable by physical examination only is not eligible
* REGISTRATION: Absence of distant metastases on standard diagnostic work-up ≤ 16 weeks prior to registration. (chest computed tomography \[CT\] or positron emission tomography \[PET\]/CT)
* REGISTRATION: Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only

  * NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
* REGISTRATION: Hemoglobin ≤ 9.0 g/dL (obtained ≤ 14 days prior to registration)
* REGISTRATION: Absolute neutrophil count (ANC) ≥ 1500/mm\^3 (obtained ≤ 14 days prior to registration)
* REGISTRATION: Platelet count ≥ 100,000/mm\^3 (obtained ≤ 14 days prior to registration)
* REGISTRATION: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 14 days prior to registration)
* REGISTRATION: Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x ULN (≤ 5 x ULN for patients with liver involvement) (obtained ≤ 14 days prior to registration)
* REGISTRATION: Prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN (obtained ≤ 14 days prior to registration) OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy
* REGISTRATION: Provide written informed consent
* REGISTRATION: Ability to complete questionnaire(s) by themselves or with assistance
* REGISTRATION: Willingness to provide mandatory blood specimens for correlative research
* REGISTRATION: Willingness to provide mandatory tissue specimens for correlative research
* REGISTRATION: Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
* RE-REGISTRATION FOR ADJUVANT DOSE ASSIGNMENT: Patient received pre-operative decitabine dose
* RE-REGISTRATION FOR ADJUVANT DOSE ASSIGNMENT: The patient had study-specific surgery
* RE-REGISTRATION FOR ADJUVANT DOSE ASSIGNMENT: Patient meets adjuvant radiation criteria based on investigator choice

Exclusion Criteria:

* REGISTRATION: Any of the following:

  * Pregnant women
  * Nursing women
  * Men or women who are of childbearing potential who are unwilling to employ adequate contraception
* REGISTRATION: Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
* REGISTRATION: Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy

  * NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
* REGISTRATION: Failure to recover from acute, reversible effects of prior therapy regardless of interval since last treatment

  * EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for at least 3 months since completion of prior treatment
* REGISTRATION: Uncontrolled intercurrent illness including, but not limited to:

  * Ongoing or active infection
  * Symptomatic congestive heart failure
  * Unstable angina pectoris
  * Cardiac arrhythmia
  * Or psychiatric illness/social situations that would limit compliance with study requirements
* Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
* REGISTRATION: Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
* REGISTRATION: Other active malignancy ≤ 5 years prior to registration

  * EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix
  * NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer
* REGISTRATION: History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
* REGISTRATION: Prior history of radiation therapy to the affected site
* REGISTRATION: Prior systemic chemotherapy ≤ 5 years prior to registration for other diagnosis not related to study disease
* REGISTRATION: Contraindication to radiation therapy as determined by the treating team
* REGISTRATION: Contraindication to decitabine as determined by the treating team
* RE-REGISTRATION FOR ADJUVANT DOSE ASSIGNMENT: Experienced a dose limiting toxicity (DLT) during pre-operative decitabine therapy