The current study evaluated the therapeutic effect of nimotuzumab combined with concurrent chemoradiotherapy in stage III-IVa nasopharyngeal carcinoma patients, and demonstrated that this combination achieved better prognosis compared with CCRT alone, with similar toxicity rates between the two regimens. Furthermore, we constructed nomogram models to assess the survival probability according to the clinical characteristics of individual patients.
Although nasopharyngeal tumors are sensitive to radiotherapy, some patients still develop recurrence and metastases after treatment. EGFR is over-expressed in most NPC patients, and its high expression level is an indication of strong invasion and drug resistance (Fortunato Ciardiello & Tortora, 2001). Several reports have examined the efficacy of NTZ treatment for NPC patients, but the conclusions are discrepant (Fangzheng et al., 2018; Jian-feng Huang et al., 2017; F. Wang et al., 2018; Yao et al., 2018; Zhi-gang Liu et al., 2016; Zhi-Qiang et al., 2019). For example, Li et al. conducted a retrospective study and found that NPC patients receiving cisplatin and radiotherapy achieved better survival than those receiving NTZ combined with radiotherapy, while NTZ plus radiotherapy caused less toxicity. They suggested NTZ plus radiotherapy is an optional treatment for the stage II or older NPC patients (H. M. Li et al., 2016). However, NPC patients in stage II rarely receive anti-EGFR drugs treatment in our cancer center. Therefore, only stage III-IVa NPC patients are discussed in the current study, and the therapeutic effect of the NTZ combination for stage II NPC patients remains elusive. Liu et al. conducted a study retrospectively and concluded that NTZ combined with CCRT was an effective treatment option for locoregionally advanced NPC (Zhi-gang Liu et al., 2016). Similarly, Yao et al. suggested that NTZ in addition to the standard CCRT regimen was more effective for long-term survival in locoregionally advanced NPC patients in comparison to CCRT alone. Nevertheless, only 42 and 31 patients treated with CCRT plus NTZ were included in the two previous studies, and the results are thus inconclusive (Yao et al., 2018; Zhi-gang Liu et al., 2016).
Our cancer center previously documented the efficacy of combination anti-EGFR targeted treatment. You et al. first reported that significantly longer survival rates were not observed in patients receiving CTX/NTZ treatment concurrently with IMRT compared to those in the standard cisplatin-IMRT combination. Furthermore, the subgroup analysis revealed frustrating loco-regional control in N3 stage patients treated with CTX/NTZ. Additionally, G3-G4 hematologic toxicities and an increased rate of CTX-related mucositis were observed in the CTX/NTZ group (You, Sun, et al., 2017). You et al. then compared the efficacy of CTX or NTZ and CCRT, and CCRT treatment alone, in stage II-IVa NPC patients. They suggested that the combination of CTX/NTZ with CCRT yielded better OS in patients with stage II-IVa NPC compared with CCRT alone. In addition, the positive effect of the combined CTX/NTZ treatment was also evident in DFS and DMFS (You, Hua, et al., 2017).
Our data are partially consistent with these previous findings. In the current study, the combination of NTZ and CCRT improved OS, PFS, and LRFS for stage III-IVa NPC patients without increasing the incidence of acute toxicity. However, DMFS did not benefit from the addition of NTZ treatment (Fig. 2 and Fig. 3). We hypothesize that the inconsistent results might be due to a discrepancy in patient enrollment. Specifically, the analysis by You et al. included patients between January 2009 and December 2013, with 189 patients in the CTX/NTZ plus CCRT arm. In addition, the molecularly-targeted drug was CTX or NTZ, not specifically NTZ, and eligible patients received only one treatment cycle. In the current study, we enrolled NPC patients from 2015 to 2017, and focused on the efficacy of NTZ specifically. Patients receiving at least six doses of NTZ were included, and 213 eligible patients were assigned to each cohort using the PSM method. In addition, Sun et al. conducted a study to investigate the efficacy of anti-EGFR drugs added to palliative chemotherapy in patients with de novo metastatic NPC. They reported that de novo metastatic NPC patients might not benefit from the addition of anti-EGFR drug treatment, and adding CTX to CCRT might exacerbate the acute mucositis and skin reactions (X.-S. Sun et al., 2019). Collectively, the efficacy of anti-EGFR drugs on suppressing distant metastasis remains to be determined.
NTZ is a recombinant humanized IgG1 monoclonal antibody that binds to EGFR directly (Cristina Mateo et al., 1997). Therefore, NTZ can inhibit the binding of EGF and transforming growth factor alpha to the EGFR, and thereby block the EGFR signaling pathway. In addition, NTZ is reported to induce apoptosis, and inhibit the cell cycle and angiogenesis in tumors (Crombet-Ramos, Rak, Perez, & Viloria-Petit, 2002). Furthermore, NTZ has high safety and low toxicity, with a relatively low risk of skin and mucosa toxicities commonly caused by other EGFR-targeting antibodies (Lin et al., 2018; Zhi-Qiang et al., 2019). These factors suggest that NTZ has advantages over other EGFR inhibitors, such as CTX, in terms of less toxicity (Lin et al., 2018). In addition, the affinity constant of NTZ is low, which leads to highly specific tumor uptake and low normal tissue absorption.
Previous clinical trials that studied the efficacy of NTZ combined with radiotherapy in patients with locally advanced head and neck squamous cell carcinoma reported that the addition of NTZ caused mild toxicity and may improve the radiation sensitivity of unresectable head and neck tumors (Talavera et al., 2009). Randomized studies that enrolled Indian patients with advanced head and neck squamous cell carcinoma concluded that concurrent use of NTZ with radiotherapy or chemoradiotherapy was safe and provided long-term survival benefits (Patil et al., 2019; Reddy et al., 2014). In NPC, CCRT significantly increased radiotherapy- and chemotherapy-related adverse events such as mucositis, skin reactions, and organ toxicity (Chen et al., 2012). Therefore, it is essential to clarify the adverse side effects of combination treatments with NTZ. Wang et al. concluded that long-term usage of NTZ did not increase the incidence of radiation-related toxicities; no skin rashes or infusion reactions were observed in the treated NPC patients (Fangzheng et al., 2018). Consistent with this finding, Wang et al. conducted a 1:3 PSM analysis in III-IVa stage NPC patients that received IMRT with or without NTZ, and no significant differences were observed between the two regimens in terms of acute toxicities (Zhi-Qiang et al., 2019). We made similar observations in the current analysis (Table 2), demonstrating that NTZ plus CCRT may be a safe therapy regimen for locally advanced NPC patients.
The nomogram models showed favorable predictive accuracy and discriminative ability. Some studies have established a nomogram model for predicting NPC survival (J. Li et al., 2018; W.-Z. Li et al., 2021; Tang et al., 2015). In the present study, we constructed models for predicting the OS, PFS, LRFS, and DMFS. We included potential prognostic biomarkers in the nomogram models. The models showed that the combination of NTZ and CCRT treatment contributed to better predict prognosis for stage III-IVa NPC patients.
Although our analysis verified the positive efficacy of the NTZ plus CCRT regimen for local advanced NPC patients, and the nomogram models provided useful tools for clinical decision-making, the current study still had several limitations. Firstly, as a retrospective study, potential selection bias was unavoidable, even though the bias was minimized by recruiting consecutive NPC patients and using the PSM analysis. Secondly, information of the EGFR expression level is missing; therefore, the relationship between the EGFR expression level and the efficacy of NTZ is unclear. Finally, the study population was enrolled from a single center. Therefore, external validation, including a prospective and randomized study, is needed to verify our findings.