Proton Therapy for Recurrent Nasopharyngeal Carcinoma

Radiotherapy is the main treatment for nasopharyngeal carcinoma (NPC). Currently, the 5-year local control rate for NPC is 80% to 85% . However, some patients inevitably experience local recurrence. For early recurrent tumors, salvage surgery can achieve satisfactory tumor control and improve the quality of life for patients, thus being a reasonable treatment option. However, many recurrent tumors are too advanced to be resected. For these unresectable tumors, high-dose re-irradiation is the only potentially curative method. Intensity-modulated radiotherapy (IMRT), as the main treatment for NPC, has achieved encouraging results in local control, survival, and tolerable toxicity. However, there are still two problems with the treatment plan of IMRT for unresectable recurrent NPC: first, the survival of patients is still poor. It has been reported that the 2-year local progression-free survival rate of locally recurrent NPC patients treated with IMRT combined with chemotherapy is approximately 56% to 76.9%, and the 2-year overall survival rate is only 44% to 68%. Second, severe adverse reactions caused by re-irradiation are the most important cause of treatment failure. About 64.9% of patients experience grade 3 to 5 late radiation-related toxicities such as mucosal necrosis and temporal lobe necrosis . Therefore, in recent years, researchers have been trying more advanced radiotherapy techniques to improve the efficacy of patients with unresectable locally recurrent NPC and reduce radiotherapy-related complications.

Proton radiotherapy is currently recognized as the cutting-edge radiotherapy technology internationally, mainly through particle beam irradiation of tumors. Particles enter with low energy and gradually increase energy deposition until a rapid increase occurs within the "Bragg peak", that is, the energy is elevated and released entirely when reaching the tumor site, achieving a "directed explosion" on the tumor, and then rapidly decreases after passing through the tumor site, decaying to 0 within a very short distance, resulting in minimal radiation to the surrounding normal tissues and reducing the occurrence of long-term adverse reactions. Therefore, proton radiotherapy is an ideal and preferred choice for recurrent NPC. However, there are currently few studies on proton and heavy ion therapy for recurrent NPC, and most are retrospective and observational studies. Although some studies have included patients with unresectable locally recurrent NPC who received re-irradiation with protons, they have not provided detailed information on the specific outcomes of these patients . On the other hand, Linda et al.'s historical study reported that the 2-year overall survival (OS) and local progression-free survival rates of 16 patients with recurrent NPC who received proton beam re-irradiation (median dose of 60.1 Gy relative biological effectiveness (RBE)) were both 50%, and it caused minimal side effects on the central nervous system. Meanwhile, Dionisi et al. reported that 17 patients (12 of whom were rT4 patients) received proton re-irradiation, with a median follow-up of 10 months: 23.5% of the patients experienced grade ≥ 3 late toxicities; the 18-month OS and local control rates were 54.4% and 66.6%, respectively.

The above studies show that most of the supportive evidence for the reduction of toxicity and improvement of efficacy of proton therapy for recurrent NPC comes from various observational and retrospective studies, lacking high-level evidence-based medical evidence. The conduct of this study will explore the safety and efficacy of intensity-modulated proton radiotherapy for recurrent NPC and provide more high-quality evidence-based medical evidence for proton therapy of recurrent cancer.