This is a single-center, open-label, randomized, controlled, exploratory clinical trial designed to evaluate the efficacy and safety of de-escalated surgery compared with standard surgery in patients with resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC) who achieved a partial response (PR) or complete response (CR) after neoadjuvant immunochemotherapy. Eligible patients will be randomly assigned in a 1:1 ratio to either the de-escalated surgery group (experimental) or the standard surgery group (control). The de-escalated surgery group will undergo limited tumor resection and selective neck dissection based on clinical and imaging response, while preserving important anatomical structures and functions when feasible. The control group will receive standard surgical treatment following NCCN guidelines. All patients will be evaluated using RECIST 1.1 criteria for radiological response and will undergo enhanced CT or MRI at baseline, before the second cycle of neoadjuvant therapy, within one week before surgery, 30 days after surgery, and every 3 months thereafter until 2 years post-surgery, disease recurrence, death, or study completion. The study aims to assess whether de-escalated surgery can achieve similar oncologic outcomes while improving postoperative function and quality of life. The primary endpoints are disease-free survival (DFS), health-related quality of life (HRQoL), and 3- and 5-year overall survival rates (OS rate). A total of 60 patients will be enrolled over a 3-year period, with 30 in each group.
Patients diagnosed with stage III-IVa head and neck squamous cell carcinoma (HNSCC) according to the AJCC 8th edition TNM staging system, who have achieved a partial response (PR) or complete response (CR) after receiving neoadjuvant immunochemotherapy consisting of a PD-1 inhibitor in combination with nab-paclitaxel and carboplatin/cisplatin.
No prior history of other malignant tumors.
Aged between 18 and 75 years.
1.Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L without the use of granulocyte colony-stimulating factor (G-CSF) within the previous 14 days
Diagnosis of another malignant tumor, or the primary lesion at the time of neoadjuvant therapy was not oral cancer.
Active autoimmune disease requiring systemic treatment (e.g., disease-modifying agents, corticosteroids, or immunosuppressants) within 2 years prior to treatment. Replacement therapy (e.g., thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) is not considered systemic treatment.
History of allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation.
Known history of human immunodeficiency virus (HIV) infection (i.e., positive HIV-1/2 antibody).
Parallel
Radical surgery combined with radiotherapy or chemoradiotherapy
Procedure/SurgeryRadical resection of the primary tumor and neck dissection will be performed according to the NCCN guidelines, followed by adjuvant radiotherapy or chemoradiotherapy based on the postoperative pathological features.
Surgical De-escalation After Neoadjuvant Therapy
Procedure/SurgeryThe experimental group will undergo a de-escalated surgical approach, defined as follows: 1. Primary tumor resection: The total diameter of the resection margins will be reduced by ≥30% compared with the pre-neoadjuvant therapy measurement. Resection will be performed with an additional 10-15 mm margin beyond the shrunken tumor boundary. 2. Functional preservation: When appropriate, important anatomical structures and functional components such as the submandibular gland, mandible, epiglottis, oral commissure, parotid duct, eyeball, and major nerves may be preserved after thorough evaluation. 3. De-escalated neck dissection: (1) Patients with clinically node-negative (cN0) neck status both before and after neoadjuvant immunotherapy will be exempted from neck dissection. (2) For midline-crossing lesions (e.g., tongue, hard palate, or soft palate), patients with contralateral clinically node-negative (cN0) neck status both before and after neoadjuvant immunotherapy will be exemp
Disease-Free Survival
The time from randomization (or from the start of treatment in single-arm trials) to disease recurrence or death from any cause, whichever occurs first, will be analyzed. The Kaplan-Meier method will be used to estimate survival curves, and between-group comparisons will be performed using the log-rank test.
Change in Health-Related Quality of Life (HRQoL) Assessed by EORTC QLQ-C30
The EORTC QLQ-C30 is a validated, cancer-specific instrument developed by the European Organisation for Research and Treatment of Cancer (EORTC) to assess quality of life in cancer patients. It contains 30 items measuring global health status, functional domains (physical, role, cognitive, emotional, and social), and symptom scales (fatigue, pain, nausea/vomiting, etc.). Each item is scored on a 4-point Likert scale (1 = Not at all to 4 = Very much), except for two global health items scored from 1 (Very poor) to 7 (Excellent). Higher scores on functional and global health scales indicate better outcomes, whereas higher scores on symptom scales indicate worse outcomes.
Change in Head and Neck Cancer-Specific Quality of Life Assessed by EORTC QLQ-H&N43
The EORTC QLQ-H\&N43 is a supplementary module to the QLQ-C30 designed to assess head and neck cancer-specific symptoms and functions. It includes 43 items covering domains such as pain, swallowing, speech, eating, social contact, and sexuality. Each item is rated on a 4-point Likert scale (1 = Not at all to 4 = Very much). Higher scores on symptom scales indicate worse symptoms or problems.
Major pathological response
MPR was assessed by two independent pathologists based on postoperative resection specimens, and discrepancies were resolved by a senior pathologist.
overall survival rate
Defined as the proportion of subjects who remain alive at 36 months from randomization or treatment initiation. For subjects lost to follow-up before death, the date of last contact will be considered as the censoring time.
Safety Endpoints
During the study and follow-up period, the severity of drug-related adverse events (DRAEs) and radiation-related adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 5.0). Surgery-related adverse events were classified based on the Clavien-Dindo grading system for surgical complications.
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Qunxing Li,MD
Lead sponsor
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Sponsor institution
