De-Escalation Surgery After Immunotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma (Neo-Margin)

A Randomized Controlled Clinical Study of De-Escalation Surgery Following Immunotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma

This is a multicenter, randomized, open-label, non-inferiority clinical trial designed to evaluate whether downgraded surgery-guided by post-immunotherapy tumor boundaries-can achieve comparable 3-year overall survival (OS) to standard surgery in patients with Stage III-IVa locally advanced head and neck squamous cell carcinoma (HNSCC) who have responded to neoadjuvant immunotherapy. A total of 356 patients will be randomized 1:1 to receive either downgraded or standard surgery, followed by risk-adapted adjuvant therapy. The primary endpoint is 3-year OS, with secondary endpoints including disease-free survival, quality of life, complication rates, and cost-effectiveness. The study hypothesizes that downgraded surgery will preserve organ function and quality of life without compromising survival outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Squamous Cell Carcinoma of the Head and Neck
• Intervention / Treatment: Procedure: De-escalation surgery; Radiation: radiotherapy; Drug: adjuvant immunotherapy; Procedure: Standard Surgery

• Study Type: Interventional
• Enrollment (Estimated): 356
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Yue He, M.D.; Phone Number: +8613501950200; Email: HEY1683@sh9hospital.org.cn
• Study Contact Backup: Name: Feng Liu, M.D.; Phone Number: +8618917797783; Email: nuanliu@126.com

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200000
      • Shanghai Ninth Peolple's Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age between 18 and 75 years inclusive, with no restriction on gender.
2. Histologically confirmed primary squamous cell carcinoma of the head and neck (excluding nasopharyngeal carcinoma).
3. Clinical stage III-IVa according to the AJCC 8th edition TNM staging system prior to immunotherapy; specifically, stage III-IVa for oropharyngeal squamous cell carcinoma (p16-negative) or stage III for oropharyngeal squamous cell carcinoma (p16-positive).
4. ECOG performance status of 0 or 1.
5. Life expectancy of ≥6 months.
6. Received preoperative immune checkpoint inhibitor therapy, primarily with anti-PD-1 monoclonal antibodies or bispecific antibodies containing an anti-PD-1 arm, regardless of brand, with or without concurrent chemotherapy or targeted therapy, for no more than six cycles.
7. Achieved complete response (CR) or partial response (PR) on imaging assessment after preoperative therapy, according to RECIST 1.1 criteria.
8. Assessed as eligible for de-escalation surgery based on clinical evaluation by the surgeon. Examples include omission of surgery on the primary lesion; preservation of critical structures or functions, such as retaining the mandible initially planned for resection; avoidance of flap reconstruction; or limitation of tongue resection to less than half when hemi-glossectomy was initially indicated.
9. No prior curative surgery or radiotherapy for the current tumor.
10. Willing to undergo surgical treatment.
11. No significant contraindications to surgery.
12. Voluntary participation in the study, signed informed consent, good compliance, and willingness to cooperate with follow-up visits.

Exclusion Criteria:

1. Severe underlying diseases making the patient unable to tolerate surgery.
2. Current tumor is recurrent.
3. Myocardial infarction, severe/unstable angina, NYHA class II or higher heart failure, or symptomatic congestive heart failure within 6 months before randomization.
4. History of psychiatric drug abuse or drug addiction.
5. Pregnant or breastfeeding women.
6. Diagnosis of other malignancies within 5 years prior to study entry, except for locally treated and cured basal cell carcinoma or squamous cell carcinoma of the skin, superficial bladder carcinoma, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, and papillary thyroid carcinoma.
7. Any other severe physical or mental illness, or laboratory abnormalities that might increase the risk associated with participation or interfere with the study results, or any other conditions deemed unsuitable for participation by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: De-escalation surgery; The surgical procedure should be designed and performed based on the tumor boundaries following neoadjuvant therapy.	Procedure: De-escalation surgery; Surgical planning and resection will be conducted based on tumor boundaries assessed after neoadjuvant therapy.; Radiation: radiotherapy; Radiotherapy is recommended within 6 weeks after surgery. Patients achieving a pathological complete response (pCR) may be exempted. For the primary tumor and involved nodes, 60-70 Gy in 30-35 fractions is delivered once daily, Monday to Friday (low risk: 60 Gy; high risk: 66 Gy; residual disease: 70 Gy). Suspected subclinical areas receive 45-50 Gy (2 Gy/f) or 54-63 Gy (1.6-1.8 Gy/f). Concurrent cisplatin is given when extracapsular nodal extension or positive/close margins (<1 mm) are present: 100 mg/m² every 3 weeks ×3, with renal function-based dose adjustment. For patients unsuitable for cisplatin, cetuximab is administered at 400 mg/m² in the first week, then 250 mg/m² weekly.; Drug: adjuvant immunotherapy; Postoperative adjuvant immunotherapy was administered in accordance with the initial treatment plan and clinical indications.; Other Names: postoperative adjuvant immunotherapy
Active Comparator: Standard Surgery; The surgical procedure should be designed and performed based on the tumor boundaries prior to neoadjuvant therapy.	Radiation: radiotherapy; Radiotherapy is recommended within 6 weeks after surgery. Patients achieving a pathological complete response (pCR) may be exempted. For the primary tumor and involved nodes, 60-70 Gy in 30-35 fractions is delivered once daily, Monday to Friday (low risk: 60 Gy; high risk: 66 Gy; residual disease: 70 Gy). Suspected subclinical areas receive 45-50 Gy (2 Gy/f) or 54-63 Gy (1.6-1.8 Gy/f). Concurrent cisplatin is given when extracapsular nodal extension or positive/close margins (<1 mm) are present: 100 mg/m² every 3 weeks ×3, with renal function-based dose adjustment. For patients unsuitable for cisplatin, cetuximab is administered at 400 mg/m² in the first week, then 250 mg/m² weekly.; Drug: adjuvant immunotherapy; Postoperative adjuvant immunotherapy was administered in accordance with the initial treatment plan and clinical indications.; Other Names: postoperative adjuvant immunotherapy; Procedure: Standard Surgery; Surgical planning and resection will be conducted based on tumor boundaries assessed prior to neoadjuvant therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-year overall survival (OS) rate	The proportion of subjects in the intention-to-treat population who are alive at 3 years after randomization.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
5-year overall survival (OS) rate	The proportion of subjects in the intention-to-treat population who are alive at 5 years after randomization.	5 years
3-year and 5-year Event-free survival (EFS) rates	The proportion of subjects in the intention-to-treat population who have not experienced any EFS events at 3 and 5 years after randomization. EFS time is defined as the duration from randomization to the first occurrence of any of the following events: (1) disease recurrence or metastasis in patients who underwent surgery; (2) disease progression per RECIST 1.1, or recurrence/metastasis after non-surgical treatment (e.g., radiotherapy) following neoadjuvant therapy; (3) occurrence of a second primary tumor; or (4) death from any cause. Patients who did not undergo surgery due to clinical complete response (CR) or near CR, as well as those who declined surgery but received other antitumor therapies without experiencing progression, recurrence/metastasis, or death, or who had positive surgical margins without radiographic evidence of progression, are not considered to have reached an EFS event.	5 years
incidence of adverse events	Adverse events observed will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0.	Through study completion, an average of 5 years
Surgical complications	Surgical complications in this study will be assessed according to the Clavien-Dindo classification system, and detailed information on all complications occurring during the perioperative period will be recorded in the eCRF.	Perioperative
Totally quality of life, QoL	Totally Health status and quality of life will be assessed using the European Organization for Research and Treatment of Cancer Quality of Lifer Questionnaire Core 30 (EORTC QLQ-C30) questionnaires.	Baseline, 1 months (±7d) after surgery and prior to radiotherapy, 2 months after radiotherapy, and 6 months (±14d) after randomization, 1year (±14d) after randomization
Quality of life for HNSCC patients	Health status and quality of life will be assessed using the European Organization for Research and Treatment of Cancer Quality of Lifer Questionnaire Head and Neck 35 (EORTC QLQ-H&N35) questionnaires	Baseline, 1 months (±7d) after surgery and prior to radiotherapy, 2 months after radiotherapy, and 6 months (±14d) after randomization, 1year (±14d) after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic complete response rate	The proportion of patients who achieved pCR among the ITT population and the pathologically evaluable population in each group.	Through study completion, an average of 5 years
Major pathologic response rate	The proportion of patients who achieved MPR among the ITT population and the pathologically evaluable population in each group.	Through study completion, an average of 5 years
Surgical resection rates stratified by anatomical subsite and extent of surgical downgrading	The proportion of patients who received that level of surgery among those initially planned for surgical intervention at the corresponding subsite.	Through study completion, an average of 5 years
Primary tumor surgery exemption rate	The proportion of patients who were exempted from primary tumor surgery among the ITT population in that group.	Through study completion, an average of 5 years
Lymph node dissection exemption rate	The proportion of participants spared lymph node dissection among those originally planned for the procedure.	Through study completion, an average of 5 years
Blood loss volume	Intraoperative blood loss volume	Intraoperative
Blood transfusion volume	Intraoperative blood transfusion volume	Intraoperative
Tracheostomy rate	The proportion of patients who underwent tracheostomy among the ITT population in that group.	Through study completion, an average of 5 years
Surgical mortality rate	The proportion of patients who died from any cause within 28 days after surgery among the ITT population in that group.	Through study completion, an average of 5 years
Flap reconstruction exemption rate	The proportion of patients exempted from free flap reconstruction among those who were initially planned to undergo the procedure within the group.	Through study completion, an average of 5 years
Length of hospital stay	Total length of hospital stay was calculated from the day of surgery to the day of discharge (a stay of less than 24 hours was counted as 0.5 day). For patients who did not undergo surgery, the hospital stay was recorded as 0 days.	Through study completion, an average of 5 years
Inpatient surgical costs and radiotherapy/chemotherapy costs	Medical costs incurred during the hospitalization for surgery and during postoperative radiotherapy and chemotherapy.	Through study completion, an average of 5 years

Collaborators and Investigators

• Sponsor: Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2026
• Primary Completion (Estimated): July 1, 2031
• Study Completion (Estimated): July 1, 2031

Study Registration Dates

• First Submitted: November 29, 2025
• First Submitted That Met QC Criteria: December 27, 2025
• First Posted (Actual): January 6, 2026

Study Record Updates

• Last Update Posted (Actual): January 6, 2026
• Last Update Submitted That Met QC Criteria: December 27, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Immunotherapy; Head and Neck Squamous Cell Carcinoma; Locally advanced; De-escalation surgery; Standard surgery
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Therapeutics; Radiotherapy
• Other Study ID Numbers: JYKQ-2025-057; NCRCO2025ZD-01 (Other Grant/Funding Number: Shanghai Ninth Peolple's Hospital)

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