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

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.