De-Escalation Surgery After Immunotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma

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.

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.