Induction Chemoimmunotherapy Followed by Deescalated Definitive Radiotherapy in Head and Neck Cancer

Background Induction chemoimmunotherapy has demonstrated marked response rates in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Conventional "expanded and escalated " radiotherapy to lymph node regions may reduce the systemic immune responses. Therefore, de-escalated radiotherapy after a good response to induction therapy may reduce accumulated toxicity while preserving efficacy and maintain the functional state of anti-tumor immune niche.

Objectives Primary: To determine if de-escalated radiotherapy is non-inferior to standard radiotherapy for 2-year PFS in LA-HNSCC patients with deep response (≥50% tumor regression) after induction chemoimmunotherapy.

Secondary: To compare overall survival (OS), local-regional control (LRC), distant metastasis-free survival (DMFS), treatment-related adverse events (AEs, irAEs, SAEs), and quality of life (ECOG, EQ-5D-5L, MDADI) between the two groups.

Study Design Multicenter (8 sites in China), prospective, phase II, randomized (1:1), open-label, non-inferiority trial.

Eligibility Criteria:

• Age 18-75 years
• Histologically confirmed HNSCC (non-nasopharyngeal), HPV/P16 negative
• AJCC 8th stage T1-2N2-3M0 or T3-4N0-3M0
• ECOG 0-1
• Completed 2-3 cycles of induction chemotherapy (platinum-based) plus PD-1 inhibitor, achieving deep response (≥50% tumor reduction by RECIST) assessed by MDT
• Adequate organ function
• No prior immunotherapy

Interventions:

Induction (all patients) : 2-3 cycles of chemotherapy (cisplatin/carboplatin based) + PD-1 inhibitor.

Randomization (1:1):

• Experimental (de-escalated RT):

GTV (post-induction residual): 60 Gy/25 fractions GTVtb (pre-induction tumor bed): not specified CTV1 (GTVtb + 1 cm): 50 Gy/25 fractions CTV2 (high-risk nodal stations + one station beyond): 45 Gy/25 fractions

• Control (standard RT):

GTV (post-induction residual): 69.96 Gy/33 fractions GTVtb (pre-induction tumor bed): not specified CTV1 (GTVtb + 1-1.5 cm + high-risk nodal stations): 60.06 Gy/33 fractions CTV2 (intermediate/low-risk nodal stations): 50.96 Gy/28 fractions

• Maintenance: Camrelizumab 200 mg IV Q3W for 8 cycles

Follow-up: Every 3 months for 2 years post-RT.

Sample Size: 180 participants, 90 patients in each arm.

Statistical Analysis: Baseline comparisons using Mann-Whitney U test; survival analysis using log-rank test and Cox regression; non-inferiority testing for PFS.

Study Period: June 2026 (anticipated start) to December 2031 (completion).

Ethics: Approved by the Ethics Committee of Cancer Hospital, Chinese Academy of Medical Sciences (26/057-0382). Written informed consent will be obtained from all participants.

Inclusion criteria

• Patients with head and neck squamous cell carcinoma (HNSCC) who have completed 2-3 cycles of induction chemotherapy plus PD-1 inhibitor and achieved deep response.
• Within 1 month of achieving deep response, subsequent concurrent chemoradiotherapy is determined by integrating MDT recommendation and patient's discretion.

• Age 18 to 75 years (including 75). 3. Histopathologically confirmed HNSCC (excluding nasopharyngeal carcinoma). 4. Clinical stage T1-2N2-3M0 or T3-4N0-3M0 (AJCC 8th edition). 5. HPV or P16 negative. 6. ECOG performance status 0 or 1. 7. No contraindications to immunotherapy or radiotherapy. 8. Adequate organ function as defined by:

• WBC ≥ 3.0×10^9/L, ANC ≥ 2.0×10^9/L, PLT ≥ 100×10^9/L, HGB ≥ 90 g/L (no transfusion or G-CSF within 14 days).
• TBIL ≤ 2.0×ULN, ALT/AST ≤ 2.5×ULN, BUN/CRE ≤ 1.5×ULN or creatinine clearance ≥ 60 mL/min.
• INR or PT ≤ 1.5×ULN (or within therapeutic range for anticoagulation).
• Myocardial enzymes within normal limits. 9. For women of childbearing potential: negative pregnancy test within 7 days prior to enrollment and use of effective contraception during treatment and for 2 months after last dose. Male participants must agree to use effective contraception for the same period.

• Willing to sign informed consent and comply with follow-up.

Exclusion criteria

• Occurrence of ≥ G4 toxicities during induction therapy and not suitable to receiving subsequent concurrent chemoradiotherapy or immunotherapy.
• History of another active malignancy within 5 years, except cured basal cell carcinoma of skin, cervical carcinoma in situ, papillary thyroid carcinoma, or superficial bladder cancer.
• Active or history of autoimmune disease (e.g., interstitial pneumonia, uveitis, colitis, hepatitis, hypophysitis, vasculitis, myocarditis, nephritis, hyperthyroidism/hypothyroidism requiring hormone replacement). Exceptions: vitiligo, childhood asthma fully resolved without intervention; asthma requiring bronchodilator medical intervention is excluded.
• Uncontrolled cardiovascular disease: myocardial ischemia grade II or higher, myocardial infarction, poorly controlled arrhythmia (including QTc ≥ 470 ms), NYHA class III-IV heart failure, LVEF < 50%, or myocardial infarction within 1 year.
• Active infection or unexplained fever >38.5°C during screening (tumor fever allowed if judged by investigator).
• Congenital or acquired immunodeficiency (e.g., HIV infection), active hepatitis B (HBV-DNA ≥ 10^4 copies/mL), or active hepatitis C (HCV-RNA above lower limit of detection).
• Prior treatment with any PD-1/PD-L1 inhibitor.
• Allergy to cisplatin, macromolecular protein preparations, or any component of anti-PD-1 antibodies.
• Major surgery for non-tumor reasons without full recovery of toxicity/complications before starting study treatment.
• Pregnancy or breastfeeding.
• Any other condition that, in the investigator's judgment, would interfere with study participation or data collection (e.g., severe psychiatric illness, abnormal laboratory values, family or social factors).