Radiation Therapy and Chemotherapy De-escalation Prior to Neck Dissection Surgery for the Treatment of Laryngeal, Hypopharyngeal, or p16-Negative Oropharyngeal and Unknown Primary Head and Neck Squamous Cell Cancers

Inclusion Criteria

• Histologically confirmed diagnosis of squamous cell carcinoma (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; fine-needle aspiration (FNA) may be acceptable only with principal investigator [PI] and/or co-PI approval) * If the primary site is oropharynx or unknown primary, P16 immunohistochemistry (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 T0-4 N1-2C M0 (American Joint Committee on Cancer [AJCC] 7th edition) without evidence of distant metastasis based on staging fludeoxyglucose (FDG) PET/CT
• 18 years of age or older
• Must not have received prior radiation therapy or chemotherapy for head and neck carcinoma (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 * Note: A CT scan of the neck and/or a PET/CT performed for the purposes of radiation planning may serve as planning tools
• White blood count (WBC) >= 2,000 cells/uL (within 30 days prior to registration)
• Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 (within 30 days prior to registration)
• Platelets >= 100,000 cells/mm^3 (within 30 days prior to registration)
• Hemoglobin >= 8.0 g/dL (within 30 days prior to registration) * Note: The use of transfusion or other interventions to achieve hemoglobin (Hgb) >= 8.0 g/dL is acceptable
• Serum creatinine =< 1.5 mg/dL or creatinine clearance (CrCl) >= 50 mL/min determined by 24-hour collection or estimated by Cockcroft-Gault formula (within 30 days prior to registration)
• Patients with serum creatinine > 1.5 mg/dL can be eligible for carboplatin-based chemotherapy with approval of co-PI (within 30 days prior to registration)
• Bilirubin =< 2 mg/dL (within 30 days prior to registration)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x the upper limit of normal (within 30 days prior to registration)
• 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-head and neck (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 * 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-human chorionic gonadotropin [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