To prospectively investigate and integrate radiomic and immunologic signatures in patients with nasopharyngeal carcinoma (NPC) treated with either proton or photon radiotherapy, with the aim of identifying biomarkers associated with treatment response, toxicity, and long-term outcomes.

This is a non-randomized, single-center, phase II prospective trial enrolling patients with stage I-III NPC undergoing definitive proton or photon chemoradiotherapy. Participants will be followed for ≥2 years after treatment completion to evaluate clinical outcomes and longitudinal biomarker dynamics, including radiomic and immunologic signatures.

Radiotherapy target delineation was performed according to established consensus guidelines. The gross tumor volume (GTV) included all radiologically visible primary tumors and involved lymph nodes. The clinical target volume receiving 69.96 Gy encompassed the GTV with a 0-5 mm margin and may also include the entire nasopharynx. The clinical target volume receiving 59.4 Gy was optionally delineated at the discretion of the treating physician to encompass regions at high risk for microscopic disease spread, including the nasopharynx, nasal cavity, maxillary sinuses, pterygoid plates, parapharyngeal space, retropharyngeal lymph nodes, clivus, skull base, sphenoid sinus, and bilateral upper cervical lymph nodes. The elective neck volumes, receiving 50-54.12 Gy , encompassed the bilateral cervical lymphatic drainage regions. The detailed contour definitions followed the International Consensus Guidelines on Delineation of Clinical Target Volumes at Different Dose Levels for Nasopharyngeal Carcinoma.

Concurrent Chemotherapy Regimens:

1. Cisplatin Based Regimens

   o Dosage: Cisplatin 100 mg/m² IV on Day 1 every 3 weeks during radiotherapy (total 2-3 cycles); Cisplatin 50 mg/m² IV on Day 1 every 2 weeks during radiotherapy (typically 6-8 weeks); Cisplatin 40 mg/m² IV weekly during radiotherapy (typically 6-7 weeks)

2. Carboplatin-Based Regimens o Dosage: Carboplatin AUC 5-6 IV every 3 weeks

The use of induction chemotherapy is allowed in locally advanced NPC

1. TPF Regimen (Docetaxel + Cisplatin + 5-Fluorouracil)

   • Docetaxel: 75 mg/m² IV on Day 1
   • Cisplatin: 75 mg/m² IV on Day 1
   • 5-FU: 750-1000 mg/m²/day continuous IV infusion on Days 1-5
   • Cycle: Every 3 weeks × 2-3 cycles

2. GP Regimen (Gemcitabine + Cisplatin)

   • Gemcitabine: 1000 mg/m² IV on Days 1 and 8
   • Cisplatin: 80 mg/m² IV on Day 1
   • Cycle: Every 3 weeks × 2-3 cycles

3. TP Regimen (Docetaxel + Cisplatin)

   • Docetaxel: 75 mg/m² IV on Day 1
   • Cisplatin: 75 mg/m² IV on Day 1
   • Cycle: Every 3 weeks × 2-3 cycles

Inclusion Criteria:

1. Willingness to provide written informed consent.

2. Pathologically confirmed diagnosis of nasopharyngeal carcinoma

3. Age ≥18 years

4. ECOG performance status 0-1

5. Patients with AJCC v.9 stage I-III disease who undergo chemoradiotherapy

6. Adequate bone marrow, liver, and renal function within 4 weeks before study registration

   • Hemoglobin ≥ 9.0 g/dL
   • Absolute neutrophil count (ANC) ≥ 1,000/mm3
   • Platelet count ≥ 50,000/μL
   • Total bilirubin < 2.5 mg/dL
   • Serum albumin >2.8 g/dL
   • Serum creatinine ≤ 1.5 mg/dL

Exclusion Criteria:

1. Presence of distant metastasis
2. Patients with AJCC v.9 cT1N0M0 disease who undergo radiotherapy alone.
3. Synchronous or prior invasive malignancy, unless disease-free for at least 2 years.
4. Prior radiotherapy to the head and neck region
5. Presence of severe major organ dysfunction
6. Pregnant women or women of childbearing potential who are unwilling to use medically acceptable contraception.

Patients with AJCC 9th edition stage I-III nasopharyngeal carcinoma undergoing definitive chemoradiotherapy using either proton or photon radiotherapy.

The sharing of individual participant data (IPD) will be conducted only after obtaining approval from the Institutional Review Board (IRB) and in accordance with applicable ethical and data protection regulations.