Phase III Non-Inferiority Trial of Proton Versus Photon Therapy for Nasopharyngeal Carcinoma

Proton Therapy Versus Photon Therapy for the Treatment of Nasopharyngeal Carcinoma: A Prospective, Open-Label, Multicenter, Phase III Non-Inferiority Clinical Trial

This study is a prospective, open-label, multicenter, cohort, phase III non-inferiority clinical trial comparing proton therapy with photon radiotherapy for nasopharyngeal carcinoma. It intends to enroll histologically confirmed newly diagnosed nasopharyngeal carcinoma patients without distant metastasis (M0). Through a prospective 1:1 matched cohort study design, patients will be divided into the intensity-modulated proton therapy (IMPT) group and the intensity-modulated radiation therapy (IMRT) group. Systemic treatment regimens are formulated according to clinical guidelines.

This is a prospective, open-label, multicenter, cohort, phase III non-inferiority clinical trial comparing proton therapy with photon radiotherapy for nasopharyngeal carcinoma. Histologically confirmed newly diagnosed nasopharyngeal carcinoma patients without distant metastasis (M0) will be enrolled and allocated to the intensity-modulated proton therapy (IMPT) group or intensity-modulated radiation therapy (IMRT) group via a prospective 1:1 matched cohort design. Systemic treatment regimens are formulated according to clinical guidelines.

Study Phase： Phase III Study Endpoints：

Primary Endpoint:

2-year locoregional recurrence-free survival (LRFS).

Secondary Endpoints:

2-year overall survival (OS), 2-year progression-free survival (PFS), 2-year distant metastasis-free survival (DMFS), radiation-related adverse reactions, and quality of life.

Inclusion Criteria：

Patients must meet all the following criteria:

Signed written informed consent before any trial-related procedures; Aged ≥18 and ≤75 years, regardless of gender; Histologically confirmed nasopharyngeal carcinoma, including keratinizing carcinoma, non-keratinizing differentiated carcinoma, and undifferentiated carcinoma (latest WHO classification); Clinically diagnosed as nasopharyngeal carcinoma (cT1-4N0-3M0, AJCC 9th edition); No prior systemic antitumor therapy for locally advanced disease; ECOG performance status 0-1;

Sufficient organ function with the following laboratory parameters:

Absolute neutrophil count (ANC) ≥1.5×10⁹/L; Platelets ≥75×10⁹/L; hemoglobin ≥9 g/dL (90 g/L or ≥5.6 mmol/L); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN; Serum creatinine ≤1.5×ULN and creatinine clearance ≥60 ml/min (calculated by Cockcroft-Gault formula); Normal coagulation function and myocardial enzymes without clinical significance.

Exclusion Criteria：

Patients with any of the following will be excluded:

Distant metastasis (M1); Head and neck squamous cell carcinoma originating from non-nasopharyngeal sites; Pathological types other than nasopharyngeal keratinizing carcinoma and non-keratinizing carcinoma; Currently participating in an interventional clinical trial; Contraindications to radiotherapy;

Active hepatitis B infection (defined as HBsAg-positive with HBV-DNA copy number above the upper limit of normal), except:

HBV viral load <1000 copies/ml (200 IU/ml) with anti-HBV therapy throughout the study; Anti-HBc(+), HBsAg(-), anti-HBs(-), and HBV viral load (-) (requires close monitoring for reactivation); Active HCV infection (HCV antibody-positive with HCV-RNA above the lower limit of detection); Pregnant women;

Severe or uncontrolled systemic diseases, such as:

Significant cardiac arrhythmias (e.g., complete left bundle branch block, ≥Grade II heart block, ventricular arrhythmia, atrial fibrillation); Unstable angina, congestive heart failure (NYHA ≥ Class 2); Arterial thrombosis, embolism, or ischemia within 6 months before enrollment; Interstitial lung disease requiring glucocorticoid therapy within 1 year or current active disease; Active tuberculosis; Active or uncontrolled infection requiring systemic treatment; Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction; Severe liver diseases (e.g., cirrhosis, decompensated liver disease, acute/chronic active hepatitis); Mental disorders precluding study participation; Medical history, diseases, treatments, or laboratory abnormalities interfering with trial results, or other conditions deemed unsuitable by the investigator.

Evaluation Criteria

Efficacy Evaluation:

Primary and secondary endpoints are assessed by investigators according to RECIST 1.1:

LRFS: Time from randomization to locoregional recurrence (primary/lymph node recurrence or death from any cause); OS: Time from randomization to death from any cause; PFS: Time from enrollment to disease progression, recurrence, or death; DMFS: Time from randomization to distant metastasis or death.

Toxicity Assessment:

Acute and late radiation-related adverse reactions (e.g., mucosal/skin reactions, gastrointestinal reactions, myelosuppression, xerostomia, hearing loss) are graded per NCI CTCAE v5.0.

Quality of Life:

Assessed using EORTC QLQ-C30(V3.0) and QLQ-H&N35(V1.0) at baseline, weekly during treatment, post-treatment, and follow-ups.

Safety Evaluation:

Adverse events (AEs), treatment-emergent AEs (TEAEs), serious AEs (SAEs); Proportion of patients discontinuing treatment due to AEs; Changes in vital signs, physical examinations, and laboratory parameters. Statistical Plan and Sample Size

Sample Size Calculation:

Non-inferiority design assuming 2-year LRFS of 85% for IMRT. With one-sided α=0.025, power=0.8, 1:1 ratio, and non-inferiority margin δ=8%, PASS software estimates 193 patients per group (386 total), accounting for 5% loss to follow-up.

Statistical Methods:

Efficacy analyzed in Intention-to-Treat (ITT) and Per Protocol (PPS) populations; safety in Safety Set (SS). Survival curves estimated by Kaplan-Meier, compared by log-rank test. Multivariate analysis uses Cox proportional hazards model. LRFS is one-sided test (α=0.025); others are two-sided (α=0.05).

Inclusion Criteria:

Signed written informed consent prior to the implementation of any trial-related procedures; No gender restriction, age ≥18 years and ≤75 years; Histologically confirmed, according to the latest WHO classification, including keratinizing carcinoma, non-keratinizing differentiated carcinoma, and undifferentiated carcinoma; Investigator-assessed nasopharyngeal carcinoma (cT1-4N0-3M0, AJCC 9th Edition); No prior systemic anti-tumor therapy for locally advanced disease; ECOG performance status 0-1;

Adequate organ function, subjects must meet the following laboratory parameters:

Absolute neutrophil count (ANC) ≥1.5x10⁹/L. Platelets ≥75×10⁹/L. Hemoglobin ≥9 g/dL (90 g/L) or ≥5.6 mmol/L; Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤2.5×ULN (Upper Limit of Normal) Serum creatinine ≤1.5×ULN AND creatinine clearance (calculated using Cockcroft-Gault formula) ≥60 ml/min; Good coagulation function: simple laboratory abnormalities judged by the investigator to be without clinical significance; Myocardial enzyme spectrum: simple laboratory abnormalities judged by the investigator to be without clinical significance; (Note: The document lists this as criteria 8 under 3.2.1 in the main text, but the synopsis table formatting places it slightly differently though it appears to be the last point of item 7 in structure. For clarity, listing as a separate main point as per the detailed protocol structure.)

Exclusion Criteria:

Presence of distant metastatic lesions (M1). Primary squamous cell carcinoma of the head and neck not originating in the nasopharynx.

Diagnosis of types other than nasopharyngeal keratinizing carcinoma and non-keratinizing carcinoma; (Note: The inclusion criteria state WHO types: keratinizing, non-keratinizing differentiated, and undifferentiated. This exclusion seems to narrow it further or implies a nuance. This is a direct translation of the source.) Currently participating in an interventional clinical research treatment; Contraindications to radiotherapy;

Untreated active hepatitis B (defined as HBsAg positive with HBV-DNA copy number greater than the upper limit of normal at the respective study center's laboratory); Note: Hepatitis B subjects meeting the following criteria may also be enrolled:

HBV viral load <1000 copies/ml (200 IU/ml) before the first dose; subjects should receive anti-HBV therapy throughout the study drug treatment period to avoid viral reactivation.

For subjects who are anti-HBc (+), HBsAg (-), anti-HBs (-), and HBV viral load (-), prophylactic anti-HBV therapy is not required, but close monitoring for viral reactivation is necessary.

Active HCV infection (HCV antibody positive and HCV-RNA level above the lower limit of detection); Pregnant women;

Presence of any severe or uncontrolled systemic diseases, for example:

Significant and symptomatically severe, difficult-to-control abnormalities in rhythm, conduction, or morphology on resting electrocardiogram, such as complete left bundle branch block, second-degree or higher heart block, ventricular arrhythmias, or atrial fibrillation[cite: 2]; Unstable angina, congestive heart failure, chronic heart failure of New York Heart Association (NYHA) class ≥ 2; Any arterial thrombosis, embolism, or ischemia within 6 months prior to enrollment, such as myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack[cite: 2]; History of non-infectious pneumonitis requiring glucocorticoid therapy within 1 year prior to the first dose, or currently active interstitial lung disease; Active pulmonary tuberculosis; Active or uncontrolled infection requiring systemic therapy; Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction; Liver diseases such as severe cirrhosis, decompensated liver disease, acute or chronic active hepatitis; Patients with mental disorders who cannot cooperate with treatment; History of illness or disease, treatment, or abnormal laboratory values that could interfere with study results, hinder the subject's full participation in the study, or other situations deemed unsuitable for enrollment by the investigator; or if the investigator believes there are other potential risks making the subject unsuitable for this study