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.
Age between 18 and 75 years inclusive, with no restriction on gender.
Histologically confirmed primary squamous cell carcinoma of the head and neck (excluding nasopharyngeal carcinoma).
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).
ECOG performance status of 0 or 1.
Severe underlying diseases making the patient unable to tolerate surgery.
Current tumor is recurrent.
Myocardial infarction, severe/unstable angina, NYHA class II or higher heart failure, or symptomatic congestive heart failure within 6 months before randomization.
History of psychiatric drug abuse or drug addiction.
Parallel
De-escalation surgery
Procedure/SurgerySurgical planning and resection will be conducted based on tumor boundaries assessed after neoadjuvant therapy.
Standard Surgery
Procedure/SurgerySurgical planning and resection will be conducted based on tumor boundaries assessed prior to neoadjuvant therapy.
radiotherapy
RadiationRadiotherapy 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.
adjuvant immunotherapy
DrugPostoperative adjuvant immunotherapy was administered in accordance with the initial treatment plan and clinical indications.
3-year overall survival (OS) rate
The proportion of subjects in the intention-to-treat population who are alive at 3 years after randomization.
5-year overall survival (OS) rate
The proportion of subjects in the intention-to-treat population who are alive at 5 years after randomization.
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.
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.
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.
Pathologic complete response rate
The proportion of patients who achieved pCR among the ITT population and the pathologically evaluable population in each group.
Major pathologic response rate
The proportion of patients who achieved MPR among the ITT population and the pathologically evaluable population in each group.
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.
Primary tumor surgery exemption rate
The proportion of patients who were exempted from primary tumor surgery among the ITT population in that group.
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