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

This phase II/III trial compares whether cisplatin given weekly with radiation therapy is better tolerated than cisplatin given every three weeks with radiation therapy for the treatment of head and neck cancer that has spread to other places in the body (advanced). The second part of this study will also help to find out if the cisplatin given weekly approach will extend patients' life by at least the same amount of time as the cisplatin given every three weeks approach. Cisplatin is in a class of medications known as platinum-containing compounds that work by killing, stopping or slowing the growth of cancer cells. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Radiation with low-dose cisplatin given weekly may be effective in shrinking or stabilizing head and neck cancer or preventing its recurrence.

PRIMARY OBJECTIVES:

I. To determine whether radiation with cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with cisplatin every 3 weeks for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). (Phase II) II. To determine whether radiation with cisplatin weekly is non-inferior to radiation with cisplatin every 3 weeks in terms of overall survival (OS) for patients with locoregionally advanced SCCHN. (Phase III) III. To determine whether radiation with cisplatin weekly is superior in terms of acute toxicity, as measured by the T-scores (TAME method), to radiation with cisplatin every 3 weeks for patients with locoregionally advanced SCCHN. (Phase III)

SECONDARY OBJECTIVES:

I. To assess and compare progression-free survival (PFS) between arms. II. To assess and compare locoregional failure and distant metastasis between arms.

III. To assess acute and late toxicity (Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0).

IV. To assess patient-reported outcomes quality of life (PRO/QOL), as measured by the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H\&N) (primary PRO), between arms.

V. To assess hearing loss, as measured by audiograms and the modified TUNE grading scale between arms.

VI. To assess hearing loss, as measured by speech audiometry Consonant-Nucleus-Consonant word scores and tympanometry (subject to the modified TUNE grading scale testing results; otherwise, it will be an exploratory objective).

VII. To assess hearing-related QOL as measured by the Hearing Handicap Inventory-Screening (HHIA-S) (secondary PRO), between arms.

VIII. To assess long-term PFS, OS, and toxicity between arms. IX. To assess 3-year restricted-mean survival time for OS and PFS between arms (if long-term update is warranted).

EXPLORATORY OBJECTIVE:

I. To collect blood and tissue specimens for future translational science studies. For instance, to examine how germline and somatic genetic variants, such as TP53, CDKN2A, PIK3CA, PTEN, NFE2L2, and KEAP1, may influence cisplatin-related efficacy and toxicity, and to assess the effect of regular nonsteroidal anti-inflammatory drugs (NSAIDs) use and genomic activation of PIK3CA (mutation or amplification) or loss of PTEN, the negative regulator of PI3K, on disease-free survival or overall survival.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I (NON-OROPHARYNGEAL CANCER \[OPC\]/p16-NEGATIVE OPC group and p16-NEGATIVE OPC/CANCER OF UNKNOWN PRIMARY \[CUP\] group): Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive cisplatin intravenously (IV) once every 3 weeks (Q3W) (on days 1, 22, and 43) during radiation therapy in the absence of disease progression or unacceptable toxicity.

ARM II (NON-OROPHARYNGEAL CANCER \[OPC\]/p16-NEGATIVE OPC group and p16-NEGATIVE OPC/CANCER OF UNKNOWN PRIMARY \[CUP\] group): Patients undergo radiation therapy over 5 fractions a week for a total of 33-35 fractions in the absence of disease progression or unacceptable toxicity. Patients also receive cisplatin IV once a week (QW) for 7 weeks during radiation therapy in the absence of disease progression or unacceptable toxicity.

Patients undergo computed tomography (CT) scan, or magnetic resonance imaging (MRI) or position emission tomography (PET) scan throughout the study.

Eligibility Criteria:
Inclusion Criteria:

* Pathologically (histologically or cytologically) proven diagnosis of SCCHN of the oropharynx, larynx, hypopharynx, or p16-positive unknown primary prior to registration; specimen from cervical lymph nodes with a well-defined primary site documented clinically or radiologically is acceptable; in patients with carcinoma of unknown primary this will be sufficient for pathologic confirmation without a clinically 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 Improvement Amendments (CLIA)-certified laboratory. A rigorous laboratory accreditation process similar to the United States (U.S.) CLIA certification, such as the provincial accreditation status offered by the Ontario Laboratory Accreditation (OLA) Program in Canada, the College of American Pathologists (CAP), or an equivalent accreditation in other countries, is acceptable.

  * The p16 results must be reported on the pathology report being submitted. The p16 positivity is defined as \> 70% of tumor cells showing strong nuclear and/or cytoplasmic immunostaining with p16 antibody.
  * For patients with laryngeal and hypopharyngeal primaries: Analysis of p16 status is NOT required.

    * Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations. Simple tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site. Limited neck dissections retrieving =\< 4 nodes are permitted and 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 to registration:
* Computed tomography (CT) scan of neck (diagnostic quality with contrast, unless contraindicated) 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 CT component must be of diagnostic quality with contrast, unless contraindicated.

  * Note: A diagnostic quality CT or MRI with contrast or FDG-PET/CT scan of neck performed for the purposes of radiation planning may serve as both staging and planning tools

    * One of the following imaging studies is required within 60 days prior to registration:
* FDG-PET/CT of the chest; FDG-PET/CT scan is strongly preferred and highly recommended to be used for eligibility OR
* Chest CT

  * Exam with laryngopharyngoscopy (mirror or in office direct procedure acceptable) within 70 days prior to registration;
* Eligibility by patient cohort;

  * Non-OPC/p16-negative OPC Cohort; Tumor Site: Larynx/Hypopharynx; Clinical Staging (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, T1-4 N2-3, or T3-4 N0-1
* p16-positive OPC/CUP Cohort;

  * Tumor Site: OPC; Smoking Status: =\< 10 pack-years; Clinical Staging (AJCC, 8th ed.): T1-3 N2-3 or T4 N0-3
  * Tumor Site: OPC; Smoking Status: \> 10 pack-years; Clinical Staging (AJCC, 8th ed.): 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 to 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 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 days prior to registration) (not applicable to patients with known Gilbert's syndrome)
    * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 1.5 x institutional ULN (within 30 days prior to registration)
    * Known human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and CD4 T Cell count \> 200 cells/mm\^3 are eligible for this trial. Testing is not required for entry into protocol
    * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the 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 who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes
    * Willing to use highly effective contraceptives for participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) during therapy and for 14 months (females); for 11 months (males) following last dose of cisplatin; this inclusion is necessary because the treatment in this study may be significantly teratogenic.
    * The patient or a legally authorized representative must provide study-specific informed 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 of unknown 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 a different 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 of radiation 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: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.)
  * Persistent grade 3-4 (CTCAE version 5.0) electrolyte abnormalities that cannot be reversed despite replacement as indicated by repeat testing
  * Patient must not have an active infection requiring IV antibiotics prior to registration;
  * Other chronic renal disease like nephrotic syndrome, that could be worsened by cisplatin 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