This phase II trial studies how well personalized neck radiation therapy directed by sentinel lymph node biopsy (SLNB) works in treating patients with oral cavity squamous cell carcinoma (OCSCC). SLNB can be performed as part of standard care for OCSCC. During SLNB, a radiotracer is injected around the tumor. The lymph nodes are then biopsied and tested to see if the tracer injected into the tumor traveled to and is present in the sentinel lymph nodes (SLNs). Results of the SLNB are used to determine whether lymph nodes should be removed in both sides of the neck or just on the same side as the primary tumor. Standard treatment then involves radiation therapy to both sides of the neck, regardless of SLNB results. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. Studies have shown only a small number of patients develop a return of the cancer (recurrence) in the opposite side of the neck after radiation therapy. In addition, radiation therapy can negatively impact patient outcomes like saliva production, speech and swallow function, increased risk of radiation induced cancers, and chronic pain. Standard of care SLNBs may be effective in determining whether radiation therapy only needs to be administered to one side of the neck or both sides. This may help spare tissue on the opposite side of the neck from receiving radiation if there is no indication of lymph node involvement there.

Inclusion Criteria:

• Patient must have biopsy-proven squamous cell carcinoma of the oral cavity

• Clinical stage cT1-4a N0-2b M0 within 42 days of study enrollment based on the following work-up:

  • History and physical examination within 42 days of study enrollment; must include documentation of lateralized primary tumor site
  • Cross-sectional imaging of the head and neck within 42 days of study enrollment
  • Cross-sectional imaging of the chest within 42 days of study enrollment

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 within 42 days of study enrollment

• Age > 18

• Recommended treatment plan is surgical resection with ipsilateral neck dissection and SPECT-CT-guided sentinel node biopsy. Flap reconstruction is allowed

• Patient is willing and able to provide informed consent. Patient provides study-specific informed consent prior to study entry

• Women of childbearing potential and male participants must agree to use medically effect means of birth control throughout their participation in the treatment phase of the study

Exclusion Criteria:

• Evidence of distant metastatic disease based on clinical or radiologic evaluation
• Evidence of contralateral neck disease on staging imaging
• Prior non-head and neck invasive malignancy (except non-melanomatous skin cancer, including effectively treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or cervix) unless disease free for ≥ 2 years
• Diagnosis of head and neck squamous cell carcinoma (SCC) in the oropharynx, nasopharynx, hypopharynx, and larynx
• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowed. Prior immunotherapy for the study cancer is allowed.
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• Patient with severe, active co-morbidity that would preclude an elective or completion neck dissection
• Pregnant and breast-feeding patients
• Excisional biopsy for study cancer
• Prior surgery involving the lateral neck, including neck dissection or gross injury to the neck that would preclude surgical dissection for this trial. Prior thyroid and central neck surgery is permissible; incisional biopsy is permitted
• Underlying or documented history of hematologic malignancy (e.g., chronic lymphocytic leukemia [CLL]) or other active disease capable of causing lymphadenopathy (sarcoidosis or untreated mycobacterial infection)
• Actively receiving systemic cytotoxic chemotherapy, immunosuppressive, anti-monocyte or immunomodulatory therapy
• Currently participating in another investigational therapeutic trial