A Multicenter, Prospective, Phase III Clinical Study of Proton Intensity-modulated Radiotherapy Versus Photon Intensity-modulated Radiotherapy for Untreated Non-metastatic Nasopharyngeal Carcinoma

A Multicenter, Prospective, Phase III Clinical Study of Proton Intensity-modulated Radiotherapy Versus Photon Intensity-modulated Radiotherapy for Untreated Non-metastatic Nasopharyngeal Carcinoma

Proton therapy for nasopharyngeal carcinoma can reduce radiotherapy-related toxic reactions, and some retrospective studies have found that proton therapy improves the survival of patients with nasopharyngeal carcinoma. However, high-level prospective clinical evidence is still lacking. This study aims to investigate the efficacy and side effects of proton therapy compared with photon intensity-modulated radiotherapy for nasopharyngeal carcinoma through a multicenter, prospective, phase III clinical trial, providing more high-quality evidence-based medical evidence for proton therapy of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck. The incidence of nasopharyngeal carcinoma is high in China, accounting for 47% of cases worldwide, and the incidence in southern China is 20 times the global rate. Among these, the incidence in Guangdong is one of the highest in the world, which is why nasopharyngeal carcinoma is also referred to as the 'Guangdong tumor'. Because the growth site of nasopharyngeal carcinoma is adjacent to the base of the skull, it easily invades the skull base. Its pathology is mainly moderately to poorly differentiated squamous cell carcinoma, which is sensitive to radiation; therefore, radiotherapy is the first-choice treatment for nasopharyngeal carcinoma.

In recent years, with the widespread application of intensity-modulated radiotherapy (IMRT) technology and the development of targeted therapy and immunotherapy, the 5-year survival rate of patients with nasopharyngeal carcinoma has exceeded 80%, and many patients survive long-term. Therefore, while further attention is paid to improving efficacy, it is even more important to focus on the long-term quality of life of nasopharyngeal carcinoma patients. Due to the dosimetric limitations of conventional photon radiotherapy, patients treated with IMRT often experience some late complications that seriously affect quality of life, such as dry mouth, restricted mouth opening, radiation-induced caries, radiation-induced cranial nerve injury, brain injury, spinal cord injury, and pituitary dysfunction. In addition, due to the large area of low-dose irradiation, the incidence of second primary tumors in the head and neck caused by radiotherapy is approximately 0.5-3%.

Proton therapy is a new technology that uses the unique 'Bragg peak' characteristic of proton beams to treat tumors, and it has been widely applied in many developed countries in Europe and America. Photon beams gradually lose energy after penetrating to a certain depth in the human body. By the time they reach the lesion, the dose intensity has already significantly decreased, while surrounding normal tissues (OARs) such as the brainstem, spinal cord, salivary glands, and skin are exposed to relatively high doses of radiation, leading to radiotherapy side effects. In contrast, proton therapy, due to its special 'Bragg peak' characteristic, maintains a roughly stable dose after entering the body, then increases and reaches a peak to release all its energy when irradiating the lesion, achieving a 'targeted blast' on the tumor, and rapidly decreases after passing through the lesion, resulting in minimal radiation to the surrounding normal tissues and thus reducing the occurrence of long-term adverse reactions. An early study explored the clinical outcomes of 17 T4 stage NPC patients treated with a combination of proton and photon therapy. At three years, patients had a local control (LC) rate of 92%, disease-free survival rate of 75%, and overall survival (OS) rate of 74%. Late toxic reactions included one patient with temporal lobe imaging changes, one patient with mandibular radiation osteonecrosis, and two patients with endocrine dysfunction. Researchers indicated that combined proton and photon therapy could achieve good local control in T4 NPC patients, regardless of whether chemotherapy was also used. A case-control study on NPC patients published in 2015 showed that 20% of patients receiving intensity-modulated proton therapy (IMPT) required gastric tube insertion, while 65% of patients receiving intensity-modulated radiation therapy (IMRT) with photons required it. Additionally, the incidence of vomiting, nausea, gastrointestinal, and other radiotherapy side effects in the IMPT group was much lower than in the IMRT group.The Trento Proton Therapy Center in Italy published in 2019 the efficacy and toxicity of proton plus photon radiotherapy for locally advanced NPC. The study included 17 previously untreated patients with stage III-IVa NPC, who received photon radiotherapy with dose-escalated proton therapy combined with concurrent chemotherapy. The results showed 2-year, 5-year, and 10-year local recurrence-free rates of 94%, 86%, and 86%, respectively. Regarding acute toxicities, one patient required parenteral nutrition due to difficulty swallowing (16% weight loss) and was hospitalized for a short period (10 days). Two other patients experienced treatment interruptions of 5 and 6 days due to acute mucositis and having to undergo tympanostomy for otitis media. Regarding late toxicities, six patients showed temporal lobe necrosis on brain MRI, and one of them developed corresponding symptoms. A 2023 study on the use of photon and proton radiotherapy in definitive treatment of nasopharyngeal carcinoma included 80 non-metastatic NPC patients treated at their institution from 2012 to 2022; 48 received photon radiotherapy, and 32 received proton therapy. The photon and proton cohorts were compared. The median follow-up was 30 months. The results showed that the 2-year progression-free survival was 63.9% in the photon group and 90.3% in the proton group; the 2-year overall survival was 86.8% in the photon group and as high as 96.8% in the proton group. A 2025 retrospective study from Taiwan, China showed that compared with intensity-modulated photon radiotherapy, proton therapy improved survival in patients with nasopharyngeal carcinoma.

Inclusion Criteria:

1. Diagnosed by histology and/or cytology as non-keratinizing carcinoma of the nasopharynx (differentiated or undifferentiated type, i.e., WHO type II or III).

2. Clinical stage: T1-4N0-3M0, I-III stage (AJCC 9th edition).

3. Age: ≥ 18 years old, ≤ 70 years old.

4. Gender: No restrictions.

5. ECOG ≤ 1.

6. Good organ function:

   Normal bone marrow function: WBC ≥ 4×109/L, Platelet ≥ 100×109/L, HGB ≥ 90g/L Total bilirubin, AST, ALT ≤ 2.0× upper limit of normal value; Creatinine clearance rate ≥ 60ml/min or Creatinine ≤ 1.5× upper limit of normal value.

7. The patient has signed the informed consent form and is willing and able to comply with the study visit schedule, treatment plan, laboratory tests and other research procedures.

Exclusion Criteria:

1. The patient has a poor general condition and is in a state of poor health; or the patient has already experienced metastasis.
2. The patient has an uncontrolled severe infectious disease.
3. The patient has severe diseases or complications in the heart, lungs, liver, kidneys or other systems, and the investigator judges that they cannot complete the clinical trial.
4. There are implants such as artificial ears or dentures within the radiotherapy range, and the investigator judges that they are not suitable for proton therapy.
5. The patient has a history of radiotherapy in the head and neck region.
6. The patient has mental illness, drug abuse or alcohol dependence.