This phase II trial investigates how well sodium thiosulfate works in preventing ototoxicity (hearing loss/damage) in patients with squamous cell cancer of the head and neck that has spread to nearby tissue or lymph nodes (locally advanced) who are undergoing a chemoradiation. Sodium thiosulfate is a type of medication used to treat cyanide poisoning and to help lessen the side effects from cisplatin. Chemotherapy drugs, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy with radiation therapy may kill more tumor cells. The purpose of this trial is to find out whether it is feasible to give sodium thiosulfate 4 hours after each cisplatin infusion along with standard of care radiation therapy in patients with head and neck cancer. Giving sodium thiosulfate after cisplatin may help decrease the risk of hearing loss.

PRIMARY OBJECTIVE:

I. To establish feasibility of intravenous sodium thiosulfate (STS) after each dose of concurrent cisplatin in patients with locally advanced head and neck squamous cell carcinoma undergoing definitive radiotherapy.

SECONDARY OBJECTIVES:

I. To determine the rate of grade >= 2 hearing impairment based on Common Terminology Criteria for Adverse Events (CTCAE) version 5 with use of STS after concurrent chemoradiation with cisplatin 3 months post-treatment.

II. To determine the rate of tinnitus measured by Patient Reported Outcomes (PRO)-CTCAE with use of STS 3 months post-treatment.

III. To describe patient reported outcomes with STS measured with PRO-CTCAE for selected oral, gastrointestinal (GI), neurologic and perceptual symptoms.

IV. To describe patient reported outcomes measured with Hearing Handicap Inventory for Adults - Screening (HHIA-S) compared to results from standard NRG Oncology head and neck trials (such as Radiation Therapy Oncology Group (RTOG) 1016).

OUTLINE:

Patients undergo standard of care radiation therapy in combination with cisplatin therapy for up to 6-7 weeks. Cisplatin treatment repeats weekly for up to 7 cycles, or every 21 days for up to 3 cycles. After each cisplatin infusion, patients also receive an infusion of sodium thiosulfate. The dosing schedule for cisplatin will be at the discretion of the treating physician.

After completion of study treatment, patients are followed up every 3 months for up to 3 years.

Inclusion Criteria:

1. Participants must have histologically or cytologically confirmed locoregionally advanced squamous cell carcinomas of mucosal surfaces of head and neck who are being treated with concurrent chemoradiation with cisplatin

2. Participants must be eligible for cisplatin-based concurrent chemotherapy in conjunction with at least 6 weeks of daily fractionated radiation therapy

3. Age >=18 years

4. Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)

5. Demonstrates adequate organ function as defined below:

   1. Absolute neutrophil count >= 1,000/microliter (mcL)
   2. Platelets >= 100,000/mcL
   3. Total bilirubin within normal institutional limits, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits
   4. Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase (SGOT)) =< 3 X institutional upper limit of normal
   5. Alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT)) =< 3 X institutional upper limit of normal
   6. Creatinine =< 1.5 x within institutional upper limit of normal OR creatinine clearance glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2, calculated using the Cockcroft-Gault equation, unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2

6. Ability to understand a written informed consent document, and the willingness to sign it

7. Individuals 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

8. The effects of sodium thiosulfate (STS) on the developing human fetus are unknown. For this reason and because cisplatin used in this trial are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception such as hormonal and/or barrier method of birth control for the duration of study participation and for 3 months after last administration of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after last administration of study treatment

Exclusion Criteria:

1. Participants that are not eligible for cisplatin-based chemoradiation for reasons such as chronic kidney disease, severe hearing loss, and severe peripheral neuropathy
2. Uncontrolled inter-current illness or psychiatric illness/social situation that would limit compliance with study requirements
3. Has known hypersensitivity to cisplatin, sodium thiosulfate or any of its excipients
4. Has profound hearing impairment at baseline and cannot hear a sound below 90 decibels (dB)
5. Participants with uncompensated congestive heart failure New York Heart Association (NYHA) class 3 or above
6. Participants who cannot get secure venous access using either a Mediport or a peripherally inserted central catheter (PICC) line for safe administration of intravenous sodium thiosulfate
7. Pregnant women are excluded from this study because cisplatin is a cytotoxic agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cisplatin or sodium thiosulfate, breastfeeding should be discontinued if the mother is treated with either agent