Omission of Postoperative Radiation in HPV-Associated Oropharyngeal Cancer Using ctHPVDNA Surveillance (OPERATION)

Omission of Immediate Postoperative Radiation in Patients With Intermediate Pathological Risk Features and Negative Two-Week Post-Operative ctHPVDNA (OPERATION Trial)

This single-arm Phase II trial evaluates whether omission of postoperative radiotherapy is feasible and oncologically safe in select patients with HPV-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC). Eligible patients undergo transoral robotic surgery (TORS) and are observed without adjuvant radiation if they demonstrate low or intermediate pathological risk features and have negative circulating tumor HPV DNA (ctHPVDNA) two weeks post-operatively. Patients are followed with standard clinical surveillance combined with serial ctHPVDNA testing (NavDx®) to facilitate early detection of recurrence and prompt salvage therapy as needed.

Study Overview

• Status: Recruiting
• Conditions: Squamous Cell Carcinoma; Human Papilloma Virus (HPV); Oropharyngeal Squamous Cell Carcinoma (OPSCC)
• Intervention / Treatment: Other: Active Surveillance With ctHPVDNA (NavDx®)

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: HCC Clinical Trials Office; Phone Number: 843-792-9321; Email: hcc-clinical-trials@musc.edu

Study Locations

• United States
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Recruiting
      • Medical University of South Carolina
      • Contact: HCC Clinical Trials Office; Phone Number: 843-792-9321; Email: hcc-clinical-trials@musc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Provision of signed and dated informed consent form.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Male or female, ≥ 18 years of age (no upper age limit).
• Biopsy proven squamous cell carcinoma.
• p16 positive (diffuse ≥ 70% tumor cell expression, with at least moderate (2/3+ staining intensity).
• NavDx positive, HPV16 TTMV only.
• AJCC 8th edition cT0-2 N1 M0.
• Well lateralized tonsil (>1 cm from midline, tonsil, base of tongue, glossotonsillar sulcus primary tumors.
• ≤ 2 lymph nodes, each ≤ 3cm, -OR- 1 lymph node >3 but < 6 cm.
• ≤10 pack-years of cigarette smoking or no cigarette smoking for ≥ 5 years (regardless of pack years).
• Anatomically (e.g. adequate exposure) and physically amenable to TORS per the judgement of the operating surgeon.
• Radiologic confirmation of the absence of hematogenous metastasis within 12 weeks prior to surgery; at a minimum CT imaging of the chest. PET/CT is acceptable.
• ECOG Performance Status 0-1.

• CBC with differential obtained within 8 weeks prior to surgery, with adequate bone marrow function defined as follows:

  • Platelets ≥ 100,000 cells/mm3
  • Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dl is acceptable. Transfusion must be completed within 2 to 4 weeks prior to enrollment.)

• Adequate renal and hepatic function within 8 weeks prior to surgery, defined as follows:

  • Serum creatinine < 2.0 mg/dl.
  • Total bilirubin ≤ 1.5 x the institutional ULN.
• Negative pregnancy test within 2 weeks prior to surgery for women of childbearing potential.
• Eligible for platinum chemotherapy. Chemotherapy drugs allowed: cisplatin, carboplatin/paclitaxel, carboplatin/abraxane, per treating physician (cisplatin preferred, 2nd preference carboplatin/paclitaxel or carboplatin/abraxane).
• For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional year after surgery per MD discretion. Acceptable forms of birth control include hormonal contraceptives (such as birth control pills, skin patch, vaginal ring, injection, and/or implant), intrauterine devices (IUDs), and barrier devices (such as condoms, diaphragm, cervical cap, and sponge).

Exclusion Criteria:

• Prior history of surgery to the head and neck that in the opinion of the investigators would modify prognostic significance of pathology results.
• Prior history of radiation therapy to the head and neck, with the exception of skin cancer treated with a small (≤ 9cm3) field with 6 - 9 MeV electron beam or 50 - 250 kVp photon beam.

• Prior history within 5 years of cancer with the exception of:

  • Basal cell carcinoma of the skin
  • Squamous cell carcinoma of the skin, stage 1-2
  • Prostate cancer without distant metastases (stage M0)
  • Thyroid cancer without distant metastases (stage M0)
• Prior history of squamous cell carcinoma of a mucosal site in the head or neck treated with surgery alone.
• Currently taking Disease Modifying Rheumatoid Drugs (DMRDs) or immunosuppressive medication, for example as for organ transplant or multiple sclerosis.

• Current smoker or tobacco user.

  • Severe, active co-morbidity, defined as one or more of the following:
  • Unstable angina and/or congestive heart failure requiring inpatient hospitalization within the last 6 months.
  • Transmural myocardial infarction within the last 6 months.
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration.
  • Chronic Obstructive Pulmonary Disease (COPD) exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration

  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects.

    --- Note, however, coagulation parameters are not required for entry into this protocol.

  • Evidence of active systemic lupus or scleroderma.
  • Psoriatic arthritis.

• Known HIV positivity. HIV positive patients are known to have worse clinical outcomes especially for local, regional, and distant cancer control. This poorer prognosis is thought to be secondary to a compromised immune system. Thus, de-intensification of radiation and chemotherapy is not justifiable in this population.

  -- Note: HIV testing at the time of enrollment is not required.

• Subjects of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for the immediate post-op period (1-2 weeks). Females will be determined to be not of child-bearing potential with a history of hysterectomy or with postmenopausal status of >12 months.
• Pregnant or breastfeeding, or expecting to conceive within the projected duration of the study, starting one month prior to screening and for one year after surgery per MD discretion.
• Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active Surveillance With ctHPVDNA After Surgery; Participants with negative postoperative ctHPVDNA are observed without adjuvant radiation and followed with routine clinical surveillance and serial ctHPVDNA testing.	Other: Active Surveillance With ctHPVDNA (NavDx®); Active surveillance without postoperative radiation using routine clinical follow-up and serial ctHPVDNA testing to detect recurrence.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local-Regional Control	Proportion of participants without local or regional recurrence above the clavicles at 2 years following definitive surgery, including participants who recur but are successfully salvaged with radiation or chemotherapy during the 2-year postoperative period.	2 years post-surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Time from surgery to disease progression or death from any cause.	2 years after definitive surgery
Distant Metastasis-Free Survival (DMFS)	Time from surgery to development of distant metastatic disease or death.	2 years after definitive surgery
Overall Survival (OS)	Time from surgery to death from any cause.	2 years after definitive surgery
Swallowing Function (Functional Oral Intake Scale - FOIS)	Change in swallowing function measured using the Functional Oral Intake Scale (FOIS).	Baseline through 24 months post-surgery
Swallowing-Related Symptoms (Eating Assessment Tool-10 - EAT-10)	Change in patient-reported swallowing symptoms measured using the EAT-10 questionnaire.	Baseline through 24 months post-surgery
ctHPVDNA Detection of Recurrence	Proportion of recurrences first detected by ctHPVDNA positivity prior to clinical or radiographic recurrence.	Up to 5 years
Time From ctHPVDNA Positivity to Clinical Detection	Number of days between initial ctHPVDNA positivity and clinical or radiographic confirmation of recurrence.	Up to 5 years

Collaborators and Investigators

• Sponsor: Medical University of South Carolina
• Investigators: Principal Investigator: Bhishamjit Chera, MD, Medical University of South Carolina

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): July 1, 2030

Study Registration Dates

• First Submitted: April 1, 2026
• First Submitted That Met QC Criteria: April 1, 2026
• First Posted (Actual): April 7, 2026

Study Record Updates

• Last Update Posted (Actual): May 20, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Neoplasms, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Squamous Cell; Health Services Administration; Quality of Health Care; Outcome Assessment, Health Care; Outcome and Process Assessment, Health Care; Watchful Waiting
• Other Study ID Numbers: 104270

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes