For early, locally recurrent NPC, endoscopic surgery is the recommended treatment modality [8]. However, it can only be used for minor, superficial lesions in specific sites. According to Li et al., only about 25% of NPC patients with initial IMRT developed local recurrence disease at the rT1-2 stage [18]. For most NPC patients with unresectable local recurrence, re-irradiation remains the only curative option. A meta-analysis demonstrated that rT1-2 NPC had a 5-year LFFS of 85% (95% CI, 79–91%), a 5-year DFFS of 95% (95% CI, 90–99%), and a 5-year OS of 62% (95% CI, 51–74%). In contrast, rT3-4 NPC h IMRT ad lower rates with a corresponding 5-year LFFS of 68% (95%CI, 61–76%), a 5-year DFFS of 82% (95%CI, 80–84%), and a 5-year OS of 38% (95%CI, 34–42%) [19]. Tian et al. also reported that patients with rT3-T4 NPC achieved only a modest LRFFS rate of 60.9% and DFFS of 78.3%, along with an OS rate of 27.5% [10]. The limited survival benefit of re-irradiation for patients with unresectable locally recurrent NPC may be attributed to unsatisfactory dose distribution caused by the large size and extensive invasion of the recurrent tumor, as well as constraints on organs at risk. Additionally, the radioresistance of recurrent NPC and the high toxicity associated with re-irradiation could also contribute to this limitation. Severe late complications, such as necrosis of the nasopharyngeal mucosa, hemorrhage, temporal lobe necrosis, and cranial neuropathy, are the primary causes of mortality in patients with recurrent NPC after re-irradiation. These patients can achieve a reduction in gross tumor volume by induction chemotherapy, thereby reducing the clinical tumor volume and facilitating target coverage and dose distribution while decreasing the dose delivered to adjacent critical structures. In addition, induction chemotherapy can also be used as a bridge to re-irradiation for patients whose tumors recur less than 1 year after the initial radiotherapy. Several studies have reported a partial response rate of approximately 64–75% for induction chemotherapy with gemcitabine in combination with cisplatin prior to re-irradiation [20–23]. Wang et al. also found that a regimen of induction chemotherapy with cisplatin, fluorouracil, and paclitaxel resulted in a high response rate of 66.7% for locally recurrent NPC [24]. However, re-irradiation combined with chemotherapy may result in increased toxicities [10, 25]. Therefore, a prospective multicenter Phase 3 randomized clinical trial is needed to investigate the efficacy and safety of induction chemotherapy in combination with radiation therapy in locally advanced recurrent NPC.
NPC is thought to be a highly immuno-inflammatory tumor associated with EBV infection, dense lymphocyte infiltration, and high expression of PDL-1 [13]. Chemotherapy may enhance anti-tumor immunity by promoting antigen presentation, enhancing T cell response and trafficking, alleviating immunosuppression in the tumor microenvironment (TME), and inducing immunogenic cell death [26–28]. Thus, PD-1 inhibitors combined with chemotherapy have a synergistic anti-tumor effect [29, 30]. Over the past few years, a growing body of literature has reported the role of antiPD-1 checkpoint inhibitors in combination with chemotherapy in the treatment of R/M NPC. The results of multiple Phase 3 clinical trials (CAPTIN-1st, JUPITER-02, and RATIONALE 309) have shown that anti-PD-1 checkpoint inhibitors in combination with chemotherapy result in better PFS and are well tolerated [14–16]. Whereas, these studies all included a mixture of local relapses and/or distant metastases. Accordingly, the role of anti-PD-1 checkpoint inhibitors in combination with chemotherapy in the treatment of locally advanced recurrent NPC remains worthy of further exploration. In the current study, we found higher tumor response rates but a lower overall survival rate in the RI group than in the IC group. Severe late complications caused by re-irradiation may limit the survival benefit of re-irradiation.
Changing the fractionation method of radiotherapy may be a way to reduce late-stage complications associated with radiotherapy and improve survival in recurrent NPC patients. Recently, You et al. conducted a prospective phase III clinical study of hyperfractionated IMRT compared with conventionally fractionated IMRT in the treatment of locally advanced recurrent NPC [31]. The study showed that hyperfractionated IMRT significantly reduced the late toxicity of re-irradiation in patients with recurrent nasopharyngeal carcinoma compared with conventionally fractionated IMRT (34% vs. 57%, P = 0.023) and improved the 3-year overall survival rate (74.6% vs. 55%, P = 0.014) and quality of life of patients. This research suggests that hyperfractionated IMRT can be used as a standard treatment for locally advanced recurrent NPC. In our study, 3 of the 24 patients in the RI group received hyperfractionated IMRT. Unfortunately, two patients died of nasopharyngeal necrosis. Hyperfractionation did not show a significant survival benefit in our study, which could be related to the small sample size in this retrospective study.