Proton vs Photon IMRT in Locally Advanced Nasopharyngeal Carcinoma: A Phase III Trial

Official title

A Prospective, Randomized, Open-Label, Multicenter Phase III Clinical Study Comparing Intensity-Modulated Proton Therapy and Intensity-Modulated Photon Radiotherapy in Locally Advanced Nasopharyngeal Carcinoma

Overview

This multicenter, open-label, randomized Phase III trial evaluates intensity-modulated proton therapy (IMPT) versus intensity-modulated photon radiotherapy (IMRT) in patients with newly diagnosed, high-risk, locoregionally advanced nasopharyngeal carcinoma. All patients receive induction chemotherapy followed by concurrent chemoradiotherapy combined with immunotherapy and are randomized 1:1 to IMPT or IMRT during the concurrent treatment phase. The primary endpoints are the incidence of grade ≥3 acute treatment-related toxicities and the 3-year progression-free survival (PFS) rate. Secondary endpoints include overall survival, locoregional relapse-free survival, distant metastasis-free survival, objective response rate, late toxicities, and quality of life.

Detailed description

This is a multicenter, open-label, randomized Phase III clinical trial designed to compare the safety and efficacy of intensity-modulated proton therapy (IMPT) versus intensity-modulated photon radiotherapy (IMRT) in patients with newly diagnosed, high-risk, locoregionally advanced nasopharyngeal carcinoma.

Eligible patients are adults aged 18 to 70 years with histologically confirmed non-keratinizing nasopharyngeal carcinoma (WHO type II or III) and clinical stage T4 or N3 disease without distant metastasis (M0), according to the AJCC staging system.

All enrolled patients will receive three cycles of induction chemotherapy consisting of gemcitabine plus cisplatin. This will be followed by concurrent chemoradiotherapy combined with immunotherapy. During the concurrent treatment phase, patients will be randomized in a 1:1 ratio to receive either IMPT or IMRT, delivered according to protocol-defined target delineation, dose prescription, and fractionation schedules.

The first primary endpoint is the incidence of grade ≥3 acute treatment-related toxicities, defined as treatment-related adverse events of grade 3 or higher occurring from the initiation of radiotherapy to 90 days after completion of radiotherapy. Toxicities will be graded according to CTCAE version 5.0 and RTOG criteria. Ototoxicity, including hearing loss or tinnitus, will be further evaluated using the ASHA (1994) significant change criteria for pure-tone audiometry.The second primary endpoint is the 3-year progression-free survival (PFS) rate, defined as the proportion of patients who remain alive without documented disease progression within 3 years after randomization. Disease progression is defined as locoregional recurrence, distant metastasis, or death from any cause, whichever occurs first.

Secondary endpoints include overall survival (OS), defined as the time from randomization to death from any cause; locoregional relapse-free survival (LRRFS), defined as the time from enrollment to the first occurrence of locoregional recurrence; distant metastasis-free survival (DMFS), defined as the time from randomization to the first occurrence of distant metastasis; objective response rate (ORR), defined as the proportion of patients achieving complete response (CR) or partial response (PR), assessed at 2 weeks after completion of induction chemotherapy and at 3 months after completion of radiotherapy; incidence of grade \<3 acute toxicities; and incidence and severity of late treatment-related toxicities assessed according to CTCAE version 5.0.Quality of life will be evaluated using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30, version 3.0) and the Head and Neck Cancer-specific module QLQ-H\&N35 (version 1.0), administered at baseline, at the end of treatment, and during follow-up visits.

The trial aims to determine whether IMPT can reduce treatment-related toxicities while maintaining or improving disease control and survival outcomes compared with IMRT.

Interventions

• Radiation Intensity-Modulated Proton Therapy (IMPT)
  Participants assigned to this arm receive intensity-modulated proton therapy (IMPT) according to the protocol-defined dose and fractionation schedule. Radiotherapy is delivered using the same target delineation and prescription principles as IMRT, with dose converted to Gy(RBE) for proton therapy. IMPT is administered concurrently with cisplatin-based chemotherapy and toripalimab as specified in the study protocol.
• Radiation Intensity-Modulated Radiation Therapy (IMRT)
  Participants assigned to this arm receive intensity-modulated radiation therapy (IMRT) according to the protocol-defined dose and fractionation schedule. Radiotherapy is delivered to the primary tumor and involved lymph nodes following the target delineation and prescription principles specified in the study protocol. IMRT is administered concurrently with cisplatin-based chemotherapy and toripalimab, consistent with the protocol.
• Drug Cisplatin
  Cisplatin is administered during induction chemotherapy and concurrent chemoradiotherapy as specified in the protocol: 80 mg/m² IV on Day 1 every 21 days for 3 cycles during induction (GP regimen), and 100 mg/m² IV on Day 1 and Day 22 for 2 cycles during concurrent chemoradiotherapy.
• Biological Toripalimab
  Toripalimab 240 mg is administered every 3 weeks during induction, concurrent chemoradiotherapy, and maintenance therapy for a total of 12 cycles unless disease progression or unacceptable toxicity occurs.

Primary outcome measures

• Incidence of treatment-related grade ≥3 acute toxicities [Time frame: From the start of radiotherapy to 90 days after completion of radiotherapy]
• 3-year Progression-Free Survival (PFS) Rate [Time frame: 3 years]

Secondary outcome measures (8)

• Overall Survival (OS) [Time frame: 3 years]
• Locoregional Recurrence-Free Survival (LRRFS) [Time frame: 3 years]
• Distant Metastasis-Free Survival (DMFS) [Time frame: 3 years]
• Objective Response Rate (ORR) [Time frame: 2 weeks after induction chemotherapy and 3 months after completion of radiotherapy]
• Incidence of Grade <3 Acute Treatment-Related Toxicities [Time frame: From the start of radiotherapy to 90 days after completion of radiotherapy]
• Incidence of treatment-related late toxicities [Time frame: From 90 days after completion of radiotherapy up to 3 years]
• Score of quality of life according to the EORTC Quality of Life Questionnaire (QLQ)-C30 (V3.0) [Time frame: Up to 3 years]
• Score of quality of life according to the EORTC Quality of Life Questionnaire Head and Neck Module (QLQ-H&N35) [Time frame: Up to 3 years]

Eligibility criteria

Inclusion criteria

• Age 18 to 70 years
• Histologically confirmed nasopharyngeal carcinoma (WHO type II or III)
• High-risk locoregionally advanced disease defined as clinical stage T4 or N3, M0, according to the AJCC staging system
• No prior anti-tumor therapy for nasopharyngeal carcinoma, including radiotherapy, chemotherapy, targeted therapy, or immunotherapy
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Adequate organ function as defined in the study protocol
• Eligible to receive induction chemotherapy followed by concurrent chemoradiotherapy combined with immunotherapy as specified in the protocol
• Ability to understand and willingness to sign written informed consent

Exclusion criteria

• Evidence of distant metastasis (M1 disease)
• Prior radiotherapy, chemotherapy, targeted therapy, or immunotherapy for nasopharyngeal carcinoma
• Active autoimmune disease requiring systemic therapy
• Uncontrolled infection or severe comorbidities that may affect treatment tolerance
• Pregnancy or breastfeeding
• Known allergy, hypersensitivity, or contraindication to study medications as defined in the protocol
• Any other condition that, in the investigator's judgment, makes the patient unsuitable for participation

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Aca — Jinan

Identifiers

NCT: NCT07340515 · 2025XH13

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗