The goal of this clinical trial is to evaluate if short-course radiation therapy (SCRT) can effectively treat high-risk cutaneous squamous cell carcinoma (cSCC) and if active surveillance is a safe alternative to radiation for moderate-risk cSCC in adults with head and neck cSCC who have undergone surgery.

The main questions it aims to answer are:

Does short-course radiation therapy (5 treatments over 2 weeks) effectively prevent cancer recurrence in high-risk patients? Can moderate-risk patients be safely monitored with active surveillance instead of receiving radiation?

Researchers will compare:

Short-course radiation therapy (SCRT) for high-risk patients to historical data on long-course radiation to determine effectiveness.

Active surveillance for moderate-risk patients to expected recurrence rates to assess safety.

Participants will:

High-Risk Group (SCRT): Receive short-course radiation therapy and attend follow-up visits.

Moderate-Risk Group (Active Surveillance): Have regular check-ups, including clinical exams and imaging, to monitor for cancer recurrence.

Optionally provide blood samples for future biomarker research.

This clinical trial investigates two approaches for managing cutaneous squamous cell carcinoma (cSCC) of the head and neck following surgical resection, based on patient risk stratification. The study evaluates short-course radiation therapy (SCRT) as a treatment for high-risk cSCC and active surveillance as a potential alternative to radiation therapy for moderate-risk cSCC.

High-Risk Cohort (Short-Course Radiation Therapy - SCRT) Patients classified as high risk will undergo SCRT, consisting of five fractions of radiation therapy over a two-week period. This approach aims to provide effective local control while minimizing treatment burden compared to conventional long-course radiation therapy (typically 30+ fractions over six weeks). The study will assess the efficacy, safety, and long-term outcomes of SCRT, including recurrence rates, toxicity profiles, and patient-reported quality of life.

Moderate-Risk Cohort (Active Surveillance) Patients meeting moderate-risk criteria will not receive adjuvant radiation therapy but will instead be monitored through regular clinical exams and imaging. This arm evaluates whether active surveillance is a safe alternative to radiation in this population by tracking recurrence rates and overall survival.

Study Design and Assessments Participants will be followed for oncologic outcomes (local, regional, and distant recurrence rates), adverse events, functional outcomes, and patient-reported quality of life. Optional blood sample collection will allow for biomarker analysis and potential future translational research.

By stratifying patients based on risk, this trial aims to refine post-surgical management of head and neck cSCC, potentially reducing unnecessary radiation exposure in moderate-risk patients while ensuring effective treatment for high-risk individuals.

Inclusion Criteria:

• Pathologically confirmed cutaneous squamous cell carcinoma of the head & neck region, defined as extending from vertex of head to supraclavicular region.

• Mohs micrographic surgery with or without further surgery following Mohs to achieve negative margins (i.e. R0 margin status) within 70 days prior to registration

• Appropriate stage for study entry (T1-T3 N0 M0; AJCC 8th ed.) based on the following diagnostic workup:

  • Clinical exam within 60 days prior to registration
  • CT head & neck/soft tissue with IV contrast within 60 days prior to registration or MR face and neck with IV contrast. IV contrast may be held if medically contraindicated.
  • Bilateral neck ultrasound within 60 days prior to registration

• Risk Factors fitting either the High-Risk or Moderate-Risk Categories:

  • Risk Factor Definitions

Major Risk Factors: Microscopic Extensive PNI (defined as PNI for >3 nerves with all involved nerves either >0.1 mm in size and/or deeper than the dermis), Gross PNI (defined as perineural spread evidenced on by MRI imaging, with cranial nerve deficit, or both), Size >6 cm, or Recurrent disease status post prior Mohs

Moderate-Risk Factors: Poor differentiation, 4-6 cm, PNI (defined as >0.1 mm in size)

BWH Risk factors: >2 cm, poor differentiation, deep invasion, PNI (>0.1 mm in size)

• BWH: T2a = 1 risk factor; T2b = 2-3 risk factors, T3 = 4 risk factors

High-Risk Group (Group H) Any 1 major OR 2-3 moderate OR BWH T3

Moderate-Risk Group (Group M) BWH T2b not meeting criteria for High-Risk.

Exclusion Criteria:

• Patients receiving any other investigational agents.

Patients pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

Serious medical comorbidities that, in the opinion of the radiation oncologist, would prevent participation in this study.

Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for different cancer(s) is allowable

Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields

Actively receiving systemic cytotoxic chemotherapy, immunosuppressive, anti-monocyte or immunomodulatory therapy.

Anonymized patient related data will be incorporated into publications and will be made available to other investigators at reasonable request.