A Pilot Study of Radiation De-Escalation for p16 Negative Oropharyngeal Cancer and p16-Negative or Positive Laryngeal and Hypopharyngeal Cancers

Inclusion Criteria: * Histologically confirmed diagnosis of SCC of the head and neck (excluding nasopharynx, nasal cavity/paranasal sinus, oral cavity, salivary, thyroid, and cutaneous primary malignancies). * Any unknown primary SCC of the head and neck with radiographically detectable gross nodes is allowed (core or excisional biopsy acceptable; if excisional biopsy is performed, there must be residual radiographically detectable nodal disease; FNA may be acceptable only with PI and/or co-PI approval) * If the primary site is oropharynx or unknown primary, P16 IHC must be negative. * If the primary site is hypopharynx or larynx, any P16 status is acceptable (positive, negative, or unknown). P16 IHC is strongly encouraged when possible. * Clinical stage T0-3 N1-2C M0 (AJCC 7th edition) without evidence of distant metastasis based on staging FDG PET/CT. * 18 years of age or older. * Must not have received prior radiation therapy or chemotherapy for HNC. * Patients who have had their primary site tumor removed by surgery but still have residual grossly enlarged, radiographically detectable lymph nodes are eligible for this study. * Karnofsky Performance Status (KPS) ≥ 70. * CT or MRI of the Neck with and without contrast o Note: A CT scan of the Neck and/or a PET/CT performed for the purposes of radiation planning may serve as planning tools. * Adequate hematologic function within 30 days prior to registration, defined as follows: * White Blood Count (WBC) ≥ 2,000 cells/µL * 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 interventions 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 (CrCl) ≥ 50 mL/min determined by 24-hour collection or estimated by Cockcroft-Gault formula: CrCl male = \[(140 - age) x (weight in kg)\] / \[(Serum Cr mg/dL) x (72)\] CrCl female = 0.85 x (CrCl male) * Patients with serum creatinine \> 1.5 mg/dL can be eligible for carboplatin-based chemotherapy with approval of co-PI (Dr. Eric Sherman * 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/legally authorized representative (LAR) must provide study-specific informed consent prior to study entry. Exclusion Criteria: * All nasopharyngeal, nasal cavity/paranasal sinus, oral cavity, salivary gland, thyroid, and cutaneous primary malignancies. * Any T4 or N3 patients * Any prior radiotherapy to the head and neck region. * Any prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different non-H\&N cancer is permissible. * Prior chemotherapy or radiotherapy within the last three years. * Patients who underwent previous surgical resection for the same disease (except for biopsy or surgery removing primary site tumor but still present with grossly enlarged, radiographically detectable lymph nodes). * Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 3 years or if cure rate from treatment at 5 years estimated to be ≥ 90%. * Subjects with simultaneous primary cancers outside of the oropharynx o Note: Exceptions can be made for patients with simultaneous primaries outside the H\&N if determined by the PI/Co-PI that the patient can proceed with protocol activities. * Pregnant (confirmed by serum b-HCG in women of reproductive age) or breastfeeding. * Severe, active co-morbidities 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.