Patients with human papillomavirus (HPV)-related oropharyngeal cancer generally have very good outcomes. Patients' treatment responses depend more on their individual cancer characteristics and personal risk factors than on the specific type of treatment they receive. However, the different treatments used for this cancer can cause significant side effects. Because outcomes are often favorable regardless of treatment type, reducing treatment-related side effects should be a priority when choosing care.

Studies have reported that lowering radiation doses for some patients can reduce side effects while still effectively controlling the cancer.

Patients with this type of head and neck cancer typically receive either surgery or radiation as their first treatment.

For patients who receive surgery first, radiation to the surgical area and nearby neck lymph nodes is often recommended afterward. In these patients, the study will test whether lowering the radiation dose to low-risk lymph nodes on the side of the neck opposite the tumor can reduce side effects while still effectively controlling the cancer (Method A).

For patients who receive radiation as their first treatment, the study will test one or both of two radiation approaches aimed at reducing both short-term and long-term side effects. These approaches include reduced lymph node radiation (Method A, described above) and a tumor dose reduction approach (Method B), which lowers the radiation dose delivered directly to the tumor.

Information such as tumor size, the number of cancerous or suspicious lymph nodes, and risk factors like smoking history will be used to determine which patients may be eligible for reduced lymph node radiation (Method A), reduced tumor radiation (Method B), or both. Patients who may qualify for tumor dose reduction (Method B), either alone or combined with Method A, will need an additional blood test called a circulating tumor DNA (ctDNA) test to determine eligibility.

The ctDNA test measures small amounts of tumor-related DNA in the blood, which are often elevated at the time of diagnosis. Studies have shown that cancer is more likely to return when ctDNA levels remain positive after treatment. This study will evaluate whether ctDNA levels measured before and during treatment can help identify patients who can safely receive lower radiation doses to the tumor (Method B).

Overall, this study aims to safely evaluate two radiation de-escalation approaches in order to lessen short- and long-term side effects while maintaining excellent cancer control.

This research study is designed for people with HPV-related head and neck cancer who are being treated with either surgery followed by radiation or radiation as their first treatment. Patients with this type of cancer generally have excellent outcomes, but the treatments can cause significant short- and long-term side effects. Because cancer control is often very good regardless of the specific treatment approach, this study focuses on whether radiation doses can be safely reduced to lessen side effects while still effectively controlling the cancer.

Most patients receive either surgery or radiation as their initial treatment, based on discussions with their medical team. For patients who have surgery first, radiation is often recommended afterward to the surgical area and nearby lymph nodes in the neck. Traditionally, this includes radiation to lymph nodes on both sides of the neck, even the side opposite the tumor. This study will evaluate whether lowering the radiation dose to low-risk lymph nodes on the side opposite the tumor can reduce side effects without compromising cancer control. This approach is called reduced lymph node radiation (Method A).

For patients who receive radiation as their first treatment, radiation is typically given to both the tumor and lymph nodes on both sides of the neck. In these patients, the study will evaluate one or two radiation-reduction strategies. In addition to reduced lymph node radiation (Method A), the study will also examine tumor dose reduction (Method B), which lowers the amount of radiation delivered directly to the tumor itself. Some patients may receive one of these approaches, while others may be eligible for both. Eligibility for these radiation-reduction approaches is based on individual cancer characteristics, such as tumor size, the number of involved lymph nodes, and risk factors like smoking history.

For patients who may qualify for tumor dose reduction (Method B), an additional blood test called a circulating tumor DNA (ctDNA) test is used. This test measures small amounts of tumor DNA in the blood. Studies suggest that patients whose ctDNA levels are negative after treatment are less likely to have their cancer return. In this study, ctDNA testing before treatment and partway through radiation will help identify patients who may be able to safely stop radiation earlier than usual (Method B).

Participants in the study are followed closely as part of their routine cancer care. This includes regular clinic visits, imaging, and physical exams. This also includes research procedures such as questionnaires about symptoms and quality of life. Some participants will also provide additional research-related blood samples to help researchers better understand which factors may predict treatment response and long-term outcomes in the future.

Up to 132 patients will take part in this study at the University of Maryland Medical System. Participation is voluntary, and treatment decisions-such as whether to have surgery or radiation and whether to receive chemotherapy-are made by the patient and their medical team, not determined by the study. However, the study procedures will determine participants' eligibility for and use of one or both of the two radiation reduction approaches.

The goal of this research is to improve future care by identifying safe ways to reduce radiation and treatment-related side effects while maintaining excellent cancer control.

4.1 Step 1 Registration 4.1.1 Step 1 Inclusion

(Y) 1. Is there pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma) of the oropharynx or squamous cell carcinoma unknown primary? Note: 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.

(Y) 2. Is the patient ≥ 18 years of age?

(Y) 3. Did the patient provide study specific informed consent prior to study entry, including consent for mandatory submission of tissue for required p16 review?

(Y) 4. Clinical TNM staging criteria by cohort (AJCC 8th edition):

TORS candidate patients must be:

• cT0-4 and N0, N1, N3

Non-TORS candidate patients must be either:

• cT1-4 N0, N1, N3
• cT1-3 N2 with < 10 pack years

4.1.2 Step 1 Exclusion

(N) 1. Patient who are clinical N2 and have ≥10 pack years smoking history

(N) 2. Patients who are clinical T4N2

(N) 3. Patients with distant metastasis (M1)

4.2 Step 2 Registration 4.2.1 Step 2 inclusion

(Y) 1. Does the patient have pathologically (histologically or cytologically) proven P16+ status?

(Y) 2. Does the patient have appropriate imaging (PET/CT preferred, CT neck with IV contrast and CT chest without contrast as recommended alternative to PET/CT) completed within 90 days of enrollment?

(Y) 3. Does the patient have clinical or pathological M0 staging? (Y) 4. Patients who have undergone TORS must have pathological stage pT1-4 N0, N1 or N3. TORS patients found to be clinical N2 post TORS or have contralteral neck dissection and positive nodes will be excluded.

(Y) 5. Is the patient a candidate for bilateral radiation based on evaluation by ENT, Rad Onc, or Med Onc and review at multi-disciplinary tumor board?

(Y) 6. Non-TORS patients who are cT1-3 N0, N1, N2 and have <10 PY must have completed a ctDNA evaluation prior to Step 2 enrollment.

(Y) 7. Non-TORS patients who are cT1-3 N2 must have a positive ctDNA result prior to Step 2 enrollment.

(Y) 8. Was a general history and physical examination performed by a radiation oncologist, medical oncologist, or head and neck surgeon within 60 days prior to registration?

(Y) 9. Was the patient's Zubrod Performance Status 0-1 within 30 days prior to registration?

(Y) 10. If a woman of child-bearing potential or sexually active male, is the patient willing to use effective contraception throughout their participation in the treatment phase of the study and at least 180 days following the last study treatment.

4.2.2 Step 2 Exclusion

(N) 1. Does the patient have cancer considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge, buccal or lip), nasopharynx, hypopharynx, or larynx?

(N) 2. Does the patient have distant metastasis?

(N) 3. Does the patient have prior invasive malignancy (except non-melanomatous skin cancer and low/intermediate risk prostate cancer) unless disease free for a minimum of 3 years?

(N) 4. Did the patient have prior systemic chemotherapy for the study cancer (prior chemotherapy for a different cancer is allowable)?

(N) 5. Did the patient have prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields?

(N) 6. Did the patient have prior cancer-related surgeries of curative intent of the head and neck excluding superficial removal of cutaneous skin malignancies?

(N) 7. Does the patient have any co-morbid condition or concern that may interfere with follow up per experimental arm?

(N) 8. Does the patient have an active drug or alcohol dependency that in the opinion of the investigator would limit compliance with study requirements?

(N) 9. Is the patient pregnant or nursing (an exception will be made for nursing patients that are not receiving chemotherapy)?