Comparing Cisplatin Every Three Weeks to 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 N2-3Note: Cigar and pipe tobacco consumption is not included in calculating thelifetime pack-years. Marijuana consumption is likewise not considered in thiscalculation. There is also no clear scientific evidence regarding the role ofchewing tobacco-containing products in oropharyngeal cancer, although this ispossibly more concerning given the proximity of the oral cavity and oropharynx.In any case, investigators should not count use of non-cigarette tobaccoproducts 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 priorto registration)

• 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 achievehemoglobin [Hgb] >= 8.0 g/dL is acceptable)

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

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

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5x institutional 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 andCD4 T Cell count > 200 cells/mm^3 are eligible for this trial. Testing isnot required for entry into protocol

• Patients with a prior or concurrent malignancy whose natural history ortreatment does not have the potential to interfere with the safety orefficacy assessment of the investigational regimen are eligible for thistrial

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

• Willing to use highly effective contraceptives for participants ofchildbearing potential (participants who may become pregnant or who mayimpregnate a partner) during therapy and for 14 months (females); for 11months (males) following last dose of cisplatin; this inclusion isnecessary because the treatment in this study may be significantlyteratogenic.

• The patient or a legally authorized representative must providestudy-specific informed consent prior to study entry and, for patientstreated in the United States (U.S.), authorization permitting release ofpersonal 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