Reduced-dose Versus Conventional-dose Intensity-modulated Radiation Therapy for Locally Advanced Nasopharyngeal Carcinoma With Remission After Induction Chemotherapy and Immunotherapy

Reduced-Dose Versus Conventional-Dose Intensity-Modulated Radiation Therapy in Locally Advanced Nasopharyngeal Carcinoma With Remission After Induction Chemotherapy and Immunotherapy: A Multicenter, Phase III Clinical Trial

To explore the efficacy and safety of reduced-dose radiotherapy combined with concurrent chemotherapy and immunotherapy in stage Ⅳa (AJCC 8th,) locally advanced nasopharyngeal carcinoma patients who are sensitive to induction chemoimmunotherapy (assessed as complete response [CR]/partial response [PR] by imaging, with EBV DNA copy number reduced to zero or below the lower limit of detection), so as to provide a new treatment option for these patients.

Study Overview

• Status: Recruiting
• Conditions: Nasopharyngeal Carcinoma (NPC)
• Intervention / Treatment: Drug: Concurrent Chemotherapy; Drug: Cisplatin-based induction chemotherapy; Drug: Full course of PD-1blockades; Radiation: Reduced-dose radiotherapy; Radiation: Standard-dose radiotherapy

Detailed Description

In a prospective clinical trial, under full-course immunotherapy, a platinum-based chemotherapy combined with immunotherapy regimen is used as the induction treatment protocol. Patients with stage Ⅳa (AJCC 8th,) nasopharyngeal carcinoma who achieve partial response (PR) or complete response (CR) after induction treatment, with EBV DNA reduced to zero or below the lower limit of detection, are randomized at a 1:1 ratio. One group receives reduced-dose radiotherapy combined with concurrent chemoimmunotherapy, while the other group receives conventional-dose radiotherapy combined with concurrent chemoimmunotherapy.

Through follow-up, the differences in survival prognosis, incidence of complications, and quality of life between the two groups are observed. The aim is to evaluate whether, on the premise of ensuring non-inferior 3-year progression-free survival (PFS), reduced-dose radiotherapy shows superiority or significant improvement in ≥ grade 3 radiotherapy-related toxicities (especially xerostomia, dysphagia, and hearing loss) and quality of life. Thereby, it explores whether the treatment strategy of further reduced-dose radiotherapy is suitable for patients with locally advanced nasopharyngeal carcinoma who achieve CR/PR on imaging evaluation and have EBV DNA reduced to zero after neoadjuvant therapy.

• Study Type: Interventional
• Enrollment (Estimated): 456
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ming-Yuan Chen, MD,PhD; Phone Number: +86-20-87343361; Email: chenmy@sysucc.org.cn
• Study Contact Backup: Name: Rui You, MD,PhD; Phone Number: +86-13580439820; Email: your5@mail.sysu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China
      • Recruiting
      • Sun Yat-Sen University Cancer Center
      • Contact: Peiyu Huang; Phone Number: +86-13632396200; Email: huangpy@sysucc.org.cn
    • Guangzhou, Guangdong, China, 516000
      • Recruiting
      • The Fifth Affiliated Hospital of Guangzhou Medical University
      • Contact: Mingyuan Chen, PhD.; Phone Number: +86-13878480806; Email: chmingy@mail.sysu.edu.cn
    • Guangzhou, Guangdong, China
      • Recruiting
      • Cancer Center of Guangzhou Medical University
      • Contact: Bin Qi; Phone Number: +86-13580580985
    • Guangzhou, Guangdong, China
      • Recruiting
      • The Second Affiliated Hospital of Sun Yat-sen University (SYSU)
      • Contact: Yimin Liu; Phone Number: +86-13802501812
    • Shantou, Guangdong, China
      • Recruiting
      • Cancer Hospital of Shantou University Medical College
      • Contact: Kai Chen; Phone Number: +86-13005222990; Email: chenkai89@126.com
    • Zhongshan, Guangdong, China
      • Recruiting
      • Zhongshan City People's Hospital
      • Contact: Feng Lei; Phone Number: +86-13528227676
  • Guangxi
    • Nanning, Guangxi, China, 530021
      • Recruiting
      • The People's Hospital of Guangxi Zhuang Autonomous Region
      • Contact: Shen-Hong Qu, MD, PhD; Phone Number: +86-15807813816; Email: qshdoctor@163.com
    • Wuzhou, Guangxi, China
      • Recruiting
      • Wuzhou Red Cross Hospital
      • Contact: Jinhui Liang; Phone Number: +86-13878480806
  • Hubei
    • Wuhan, Hubei, China
      • Recruiting
      • Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology
      • Contact: Guangyuan Hu; Phone Number: +86-13886000095
  • Hunan
    • Changsha, Hunan, China
      • Recruiting
      • Xiangya Hospital of Central South University
      • Contact: Yuxiang He; Phone Number: +86-13786112914; Email: heyuxiang88@163.com
    • Changsha, Hunan, China
      • Recruiting
      • Central South University Cancer Hospital
      • Contact: Yaqian Han; Phone Number: +86-18673176667; Email: hanyaqian@hnca.org.cn
  • Zhuhai
    • Guangdong, Zhuhai, China, 519000
      • Recruiting
      • The Fifth Affiliated Hospital of Sun Yat-sen University
      • Contact: Ming-Yuan Chen, MD,PhD; Phone Number: +86-13903052650; Email: chenmy@sysucc.org.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Histologically and/or cytologically confirmed nasopharyngeal non-keratinizing carcinoma (differentiated or undifferentiated type, i.e., WHO classification Type II or Type III).
2. Clinical stage: AJCC 8th edition staging: T4N0-2M0, T1-4N3M0 (stage IVa); AJCC 9th edition staging: T4N0-2M0, T1-4N3M0 (stage III).
3. After 3 courses of platinum-based chemotherapy combined with immunotherapy as induction treatment, the efficacy is assessed as PR or CR by nasopharyngoscopy and enhanced MRI of nasopharynx + neck, with EBV DNA reduced to zero or below the lower limit of detection.
4. Age: 18-70 years old.
5. PS/ECOG score (performance status score of 0 or 1).

6. Adequate organ function:

   1. Hematology: White blood cell count ≥ 4000/μL, neutrophil count ≥ 2000/μL, hemoglobin ≥ 9 g/dL, platelet count ≥ 100000/μL;
   2. Liver function: Bilirubin ≤ 1.5 × upper limit of normal (ULN) (patients with known Gilbert's disease and serum bilirubin level ≤ 3 × ULN are eligible), AST and ALT ≤ 1.5 × ULN, and alkaline phosphatase ≤ 1.5 × ULN; albumin ≥ 3 g/dL;
   3. Renal function: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min calculated by the Cockcroft-Gault formula.
   4. Proteinuria: Urine protein/creatinine ratio (UPC ratio) < 1.0. For those with UPC ratio ≤ 0.5, no further examination is required; for those with UPC ratio > 0.5, further testing showing 24-hour urine protein < 1000 mg is eligible.

   Note: The UPC ratio of random urine is an estimate of 24-hour urine protein quantification, and the two have a good correlation. The UPC ratio can be calculated using the following formulas:

   i. Urine protein/urine creatinine (if both protein and creatinine are in mg/dL); ii. (Urine protein) × 0.088/urine creatinine (if urine creatinine is in mmol/L).

   e) Coagulation function: International normalized ratio (INR) ≤ 1.5, activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.

7. Patients have signed the informed consent form and are willing and able to comply with the study's scheduled visits, treatment plans, laboratory tests, and other study procedures

Exclusion Criteria:

1. Patients whose laboratory test results within 7 days before enrollment do not meet the relevant standards.
2. Patients with efficacy evaluation of stable disease (SD) or progressive disease (PD) after 3 courses of platinum-based chemotherapy combined with immunotherapy as induction treatment, or whose EBV DNA has not been reduced to zero or below the lower limit of detection.
3. Patients who have received any of the following for primary lesions and/or cervical metastatic lesions: chemotherapy, immunotherapy, targeted therapy, or surgical treatment (excluding diagnostic treatment).
4. Patients with tumors accompanied by obvious liquefaction necrosis, which are unsuitable for radiotherapy or may lead to radioresistance.
5. Patients with tumors invading the brain parenchyma.
6. Patients with a history of severe allergic reactions to any components of other monoclonal antibodies or PD-1/PD-L1 monoclonal antibodies.
7. Patients with known or suspected autoimmune diseases, including dementia and epileptic seizures.
8. Patients with recurrence, distant metastasis, or concurrent other malignant tumors.
9. Patients with severe heart disease, pulmonary dysfunction, or cardiac/pulmonary function grade 3 or lower (including grade 3).
10. Patients with previous use of anti-PD-1/PD-L1 antibodies, anti-CTLA-4 antibodies, or any other antibodies acting on T-cell costimulatory or checkpoint pathways.
11. Patients with comorbidities requiring long-term treatment with immunosuppressive drugs or systemic/local use of corticosteroids at immunosuppressive doses before enrollment.
12. Patients with HIV positivity; HBsAg positivity with positive HBV DNA copy number (quantitative detection ≥ 1000 cps/ml); positive screening for chronic hepatitis C (HCV antibody positivity).
13. Patients with a history of allergic reactions to the drugs used in this study (gemcitabine, docetaxel, taxanes, cisplatin).
14. Patients with active tuberculosis (TB) who are receiving anti-tuberculosis treatment or have received anti-tuberculosis treatment within 1 year before screening.
15. Patients who, within 4 weeks before enrollment: have received systemic or local glucocorticoid treatment, been vaccinated with any anti-infective vaccines (such as influenza vaccine, varicella vaccine, etc.), or used traditional Chinese herbal medicines with anti-tumor effects.
16. Women of childbearing age with positive pregnancy test results and lactating women.
17. Other patients deemed unsuitable for inclusion by the attending physician.

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
Active Comparator: Induction chemotherapy plus conventional concurrent chemoradiotherapy	Drug: Concurrent Chemotherapy; Cisplatin 100mg/m2 every 3 weeks for 2 cycles; Drug: Cisplatin-based induction chemotherapy; Cisplatin-based induction chemotherapy will be given every 3 weeks for 3 cycles before radiotherapy.; Drug: Full course of PD-1blockades; Toripalimab 240 mg, once every 3 weeks (Q3W), intravenous infusion (iv). A total of 12 courses of treatment will be administered, including 3 courses during the induction chemotherapy phase, 3 courses during the radiotherapy phase, and 6 courses during the post-radiotherapy maintenance phase. Administration will start on Day 1 of induction chemotherapy and continue after the end of radiotherapy until the occurrence of intolerable toxicities, disease progression, withdrawal of consent, determination by the investigator that the patient needs to withdraw from treatment, or the completion of 12 courses, whichever comes first.; Radiation: Standard-dose radiotherapy; GTVnx/nd:69.96Gy/33Fr/2.12Gy CTV1: 59.4Gy/33Fr/1.8Gy CTV2: 54.12Gy/33Fr/1.64Gy
Experimental: Induction chemotherapy plus reduced-dose radiotherapy and concurrent chemotherapy	Drug: Concurrent Chemotherapy; Cisplatin 100mg/m2 every 3 weeks for 2 cycles; Drug: Cisplatin-based induction chemotherapy; Cisplatin-based induction chemotherapy will be given every 3 weeks for 3 cycles before radiotherapy.; Drug: Full course of PD-1blockades; Toripalimab 240 mg, once every 3 weeks (Q3W), intravenous infusion (iv). A total of 12 courses of treatment will be administered, including 3 courses during the induction chemotherapy phase, 3 courses during the radiotherapy phase, and 6 courses during the post-radiotherapy maintenance phase. Administration will start on Day 1 of induction chemotherapy and continue after the end of radiotherapy until the occurrence of intolerable toxicities, disease progression, withdrawal of consent, determination by the investigator that the patient needs to withdraw from treatment, or the completion of 12 courses, whichever comes first.; Radiation: Reduced-dose radiotherapy; GTVnx/nd:63.6Gy/30Fr/2.12Gy CTV1: 54Gy/30Fr/1.8Gy CTV2: 49.2Gy/30Fr/1.64Gy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progress-Free Survival (PFS)	Defined as time from randomization to locoregional or distant metastasis relapse or death from any cause, whichever occurred first.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Defined as the time interval from randomization to death due to any cause.	3 years
Distant Metastasis-Free Survival (DMFS)	Defined as the time interval from randomisation to the date of first distant metastases.	3 years
Locoregional Relapse-Free Survival (LRRFS)	Defined as the time from randomisation to the date of first locoregional relapse.	3 years
Score of survival quality according to the EORTC Quality of Life Questionnaire (QLQ)-C30 (V3.0)	Score of survival quality according to the EORTC Quality of Life Questionnaire (QLQ)-C30 (V3.0) before treatment, during treatment, after treatment.	3 years
Score of survival quality according to the EORTC Quality of Life Questionnaire Head and Neck (The QLQ-H&N35)	Score of survival quality according to the EORTC Quality of Life Questionnaire Head and Neck (The QLQ-H&N35) before treatment, during treatment, after treatment.	3 years
The proportion of patients with treatment related acute complications	The proportion of patients with treatment related acute complications according to NCI-CTC5.0 criteria and RTOG criteria.	1 year
The proportion of patients with treatment related late complications	The proportion of patients with treatment related late complications according to NCI-CTC5.0 criteria and RTOG criteria.	3 years
Objective Response Rate (ORR)	Defined as the proportion of patients with tumor reduction achieving complete response (CR) or partial response (PR), assessed at 3 months after the end of concurrent chemoradiotherapy.	assessed at 3 months after the end of concurrent chemoradiotherapy

Collaborators and Investigators

• Sponsor: Ming-Yuan Chen
• Investigators: Principal Investigator: Ming-Yuan Chen, MD,PhD, Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2025
• Primary Completion (Estimated): June 30, 2030
• Study Completion (Estimated): June 30, 2032

Study Registration Dates

• First Submitted: December 27, 2025
• First Submitted That Met QC Criteria: December 27, 2025
• First Posted (Actual): January 9, 2026

Study Record Updates

• Last Update Posted (Actual): January 9, 2026
• Last Update Submitted That Met QC Criteria: December 27, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Locally Advanced; Nasopharyngeal Carcinoma; Concurrent chemoradiotherapy; partial response; complete response; Randomized non-inferiority trial; PD-1inhibitor; Epstein-Barr Virus DNA; EBV DNA clearance; undetectable EBV DNA; reduced-dose radiotherapy
• Additional Relevant MeSH Terms: Stomatognathic Diseases; Pathologic Processes; Neoplasms by Site; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Carcinoma; Otorhinolaryngologic Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Nasopharyngeal Neoplasms; Disease Progression; Pathological Conditions, Signs and Symptoms; Nasopharyngeal Carcinoma; Pathologic Complete Response; Therapeutics; Radiotherapy
• Other Study ID Numbers: ZDWY.BYAFZZX.043

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No