HYperfractionated Radiation Therapy Versus Concurrent Chemoradiation for Head and Neck Cancer (HYTC)

Inclusion Criteria: Patients with pathologically (histologically or cytologically) proven diagnosis of HNSCC (larynx, hypopharynx, or oropharynx). Pathologic confirmation may be from either nodal or primary tumour. If a biopsy is obtained from nodal disease, a clinically apparent primary tumour on imaging and/or clinical examination must be present.

Diagnostic tonsillectomy or local excision of the primary without removal of nodal disease is permitted.

Diagnostic lymph node excision or limited neck dissections (retrieving ≤ 4 nodes) are permitted HPV positive or negative (by p16 immunohistochemistry). OPC will be classified as p16 at local sites based on greater than 70% strong diffuse nuclear or nuclear and cytoplasmic staining.

For patients with OPC: analysis of p16 status is required For patients with laryngeal/hypopharyngeal cancer: analysis of p16 status is NOT required

Clinical stage T1-2 N1-2 M0 or T3 N0-2 M0 (UICC/AJCC TNM 8th Edition). Staging will be determined based on clinical examination, axial imaging (CT and/or MRI), and whenever available, PET-CT imaging.

The following radiological investigations must be done within 8 weeks of registration:

CT or MRI of the head and neck; PET-CT scan or chest CT scan (PET-CT scan is strongly preferred and highly recommended to be used for eligibility).

Planned definitive RT. Based on clinical and laboratory evaluation and in keeping with local institutional standards, the treating oncologist must declare upfront, that in the absence of the present clinical trial, the patient would be candidate for treatment with concurrent high dose cisplatin every 3 weeks. This would include:

Adequate hematologic function must be documented within 8 weeks prior to registration:

Hemoglobin levels of > 8g/dL (the use of transfusion or other intervention to achieve hemoglobin ≥ 8 g/dL is acceptable) Platelet count of >100,000 cells/mm3. ANC of > 1500 cells/mm3.

Adequate hepatic function must be documented within 8 weeks prior to registration:

Total bilirubin < 2 X institutional upper limit of normal. AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal. Albumin ≥ 3.0 g/dL.

Adequate renal function must be documented within 8 weeks prior to registration:

Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula

Patients known to be Human Immunodeficiency Virus (HIV)+ are permitted.

Patients with CD4>200 and serum HIV viral load of < 200 copies/mm3 are eligible

HIV+ patients must receive appropriate care and treatment for HIV infection, including antiretroviral medications when clinically indicated, and should be under the care of a physician experienced in HIV management.

HIV testing is not required for eligibility. Must be ≥ 18 years of age.

Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.

Patient is able (i.e. sufficiently fluent) and willing to complete the PRO questionnaires in English or Arabic. The baseline assessment must be completed within required timelines, prior to treatment start. Inability (lack of comprehension in English/Arabic, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the patient ineligible for the study.

Consent to provision of samples of blood and plasma for correlative studies is optional.

The treatment team must be able to commence definitive RT within 6 weeks of randomization.

Women of child bearing potential must use an accepted and effective method of contraception and/or abstain from sexual intercourse while on protocol treatment and for at least 6 months after the last day of RT. Sexually active males must use an accepted and effective method of contraception and/or abstain from sexual intercourse while on protocol treatment and for at least 6 months after the last day of RT.

Women must not be pregnant or breast-feeding (Women in childbearing period will be instructed by treating physician to avoid pregnancy during and 6 months after end of RT). All females of child bearing potential must have a serum or urine pregnancy test to rule out pregnancy within 4 weeks prior to registration. All breastfeeding women should discontinue breastfeeding prior to study registration.

Participants must not be receiving any other standard anti-cancer therapy or experimental agent concurrently with the study drugs.

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Exclusion Criteria:Patients who fulfill any of the following criteria are not eligible for admission to the study:

HNC Patients with any of the following clinical stages/categories:

cT1-2 N0 M0 cT4 cN3 cM1

Patients with primary oral cavity cancer, nasopharynx cancer, or HNC of unknown primary.

Previous HNC or multiple synchronous primary HNCs.

Previous induction or neo-adjuvant chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable, however, any prior exposure to cisplatin is excluded.

Previous RT to the head and neck or neck dissection of at least 3 levels on either side.

Patients with severe, active co-morbidity including any of the following:

Chronic obstructive pulmonary disease or other pulmonary illness requiring hospitalization within 30 days of registration Unstable angina and/or congestive heart failure requiring hospitalization within 6 months of registration Acute myocardial infarction within 6 months of study registration Diseases precluding RT (e.g. scleroderma) Persistent grade 3-4 (CTCAE v5) electrolyte abnormalities that cannot be reversed despite replacement as indicated by repeat testing Active infection requiring IV antibiotics prior to registration; Chronic renal disease e.g., nephrotic syndrome, that could be worsened by cisplatin therapy History of allogenic organ transplantation Any symptomatic peripheral sensory neuropathy grade ≥ 2 (CTCAE v5)

Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (carcinoma in situ of the breast, oral cavity, or cervix are all permissible).

Prior allergic reaction to cisplatin