Comparing High-Dose Cisplatin Every Three Weeks to Low-Dose Cisplatin Weekly When Combined With Radiation for Patients With Advanced Head and Neck Cancer

Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of SCCHN of theoropharynx, larynx, hypopharynx, or p16-positive unknown primary prior toregistration; specimen from cervical lymph nodes with a well-defined primary sitedocumented clinically or radiologically is acceptable; in patients with carcinoma ofunknown primary this will be sufficient for pathologic confirmation without aclinically or radiographically defined primary site

• For patients with oropharyngeal cancer (OPC)/cancer of unknown primary (CUP):

P16 status based on local site immunohistochemical tissue staining is required. A cell block obtained from a fine needle aspiration (FNA) biopsy specimen may be used as the sole diagnostic tissue. Centers are encouraged to contact the pathology chair for clarification

• Note: Institutions must screen patients for p16 status by immunohistochemistry (IHC)in order to be eligible for the trial using a Clinical Laboratory ImprovementAmendments (CLIA)-certified laboratory. A rigorous laboratory accreditation processsimilar to the United States (U.S.) CLIA certification, such as the provincialaccreditation status offered by the Ontario Laboratory Accreditation (OLA) Programin Canada, the College of American Pathologists (CAP), or an equivalentaccreditation in other countries, is acceptable.

• The p16 results must be reported on the pathology report being submitted. Thep16 positivity is defined as > 70% of tumor cells showing strong nuclear and/orcytoplasmic immunostaining with p16 antibody.

• For patients with laryngeal and hypopharyngeal primaries: Analysis of p16status is NOT required

• Patients must have clinically or radiographically evident measurabledisease at the primary site or at nodal stations. Simple tonsillectomy orlocal excision of the primary without removal of nodal disease ispermitted, as is excision removing gross nodal disease but with intactprimary site. Limited neck dissections retrieving =< 4 nodes are permittedand considered as non-therapeutic nodal excisions

• Clinical stage (American Joint Committee on Cancer [AJCC], 8th ed.),including no distant metastases based on the following diagnostic workup:

• History/physical examination within 60 days prior to registration

• One of the following imaging studies is required within 60 days prior toregistration:

• Computed tomography (CT) scan of neck (diagnostic quality with contrast, unlesscontraindicated) OR

• Magnetic resonance imaging (MRI) of the neck (diagnostic quality with contrast,unless contraindicated) OR

• Fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/CT of the neck; the CTcomponent must be of diagnostic quality with contrast, unless contraindicated.

• Note: A diagnostic quality CT or MRI with contrast or FDG-PET/CT scan of neckperformed for the purposes of radiation planning may serve as both staging andplanning tools

• One of the following imaging studies is required within 60 days prior toregistration:

• FDG-PET/CT of the chest; FDG-PET/CT scan is strongly preferred and highlyrecommended to be used for eligibility OR

• Chest CT

• Exam with laryngopharyngoscopy (mirror or in office direct procedureacceptable) within 70 days prior to registration;

• Eligibility by patient cohort;

• Non-OPC/p16-negative OPC Cohort; Tumor Site: Larynx/Hypopharynx; ClinicalStaging (AJCC, 8th ed.): T3-4 N0 or T1-4 N1-3 T2 N0 (hypopharynx only)

• Tumor Site: p16-negative OPC; Clinical Staging (AJCC, 8th ed.): T2N1, T1-4N2-3, or T3-4 N0-1

• p16-positive OPC/CUP Cohort;

• Tumor Site: OPC; Smoking Status: =< 10 pack-years; Clinical Staging (AJCC, 8thed.): T1-3 N2-3 or T4 N0-3

• Tumor Site: OPC; Smoking Status: > 10 pack-years; Clinical Staging (AJCC, 8thed.): T1N2-3, T2N1-3 or T3-4 N0-3

• Tumor Site: CUP; Smoking Status: Any; Clinical Staging (AJCC, 8th ed.): T0 N2-3

Note: Cigar and pipe tobacco consumption is not included in calculating the lifetime pack-years. Marijuana consumption is likewise not considered in this calculation. There is also no clear scientific evidence regarding the role of chewing tobacco-containing products in oropharyngeal cancer, although this is possibly more concerning given the proximity of the oral cavity and oropharynx. In any case, investigators should not count use of non-cigarette tobacco products in the pack-years calculation.

• Age >= 18

• Zubrod (Eastern Cooperative Oncology Group [ECOG]) performance status of 0-1 within 14 days prior to registration

• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 30 days prior toregistration)

• Platelets >= 75,000 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 intervention to achieve hemoglobin [Hgb] >= 8.0 g/dL is acceptable)

• Calculated creatinine clearance (CrCl) >= 50 mL/min by the Cockcroft-Gault formula (within 30 days prior to registration)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 30 daysprior to registration) (not applicable to patients with known Gilbert's syndrome)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 xinstitutional ULN (within 30 days prior to registration)

• Known human immunodeficiency virus (HIV) infected patients on effectiveanti-retroviral therapy with undetectable viral load within 6 months and CD4 T Cellcount > 200 cells/mm^3 are eligible for this trial. Testing is not required forentry into protocol

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration. Childbearing potential is defined as any person whohas experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause isdefined clinically as 12 months of amenorrhea in a woman over 45 in the absence ofother biological or physiological causes

• Willing to use highly effective contraceptives for participants of childbearingpotential (participants who may become pregnant or who may impregnate a partner)during therapy and for 14 months (females); for 11 months (males) following lastdose of cisplatin; this inclusion is necessary because the treatment in this studymay be significantly teratogenic

• The patient or a legally authorized representative must provide study-specificinformed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Patients with oral cavity cancer, nasopharynx cancer, or p16-negative cancer ofunknown primary (CUP)

• Recurrence of the study cancer

• Definitive clinical or radiologic evidence of distant metastatic disease

• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for adifferent cancer is allowable, however, any prior exposure to cisplatin is excluded

• Prior radiotherapy to the region of the study cancer that would result in overlap ofradiation therapy fields

• Severe, active co-morbidity defined as follows:

• Unstable angina requiring hospitalization in the last 6 months

• Myocardial infarction within the last 6 months

• New York Heart Association Functional Classification III/IV (Note: Patientswith known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment ofcardiac function using the New York Heart Association FunctionalClassification.)

• Persistent grade 3-4 (CTCAE version 5.0) electrolyte abnormalities that cannotbe reversed despite replacement as indicated by repeat testing

• Patient must not have an active infection requiring IV antibiotics prior toregistration;

• Other chronic renal disease like nephrotic syndrome, that could be worsened bycisplatin therapy

• History of allogenic organ transplantation

• Any symptomatic peripheral sensory neuropathy grade >= 2 (CTCAE version 5.0);

• Pregnancy and individuals unwilling to discontinue nursing

• History of hypersensitivity to cisplatin or platinum-containing compounds