Anti-EGFR targeted therapy delivered before versus during radiotherapy in locoregionally advanced nasopharyngeal carcinoma: a big-data, intelligence platform-based analysis

Nasopharyngeal carcinoma (NPC) is a special type of head and neck malignancy for its extremely unbalanced geographic distribution and treatment modality. There are 86, 700 new cases reported worldwide in 2012 with the highest incidence in South China [1]. Unlike other head and neck cancers, radiotherapy (RT) is the primary and only cure for non-disseminated disease as a result of the anatomic constrain and sensitivity to radiation. Control of early stage disease with RT alone or chemo-radiation is usually excellent; however, management of locoregionally advanced NPC (LA-NPC) still remain unsatisfactory, with a 5-year overall survival (OS) of 67–77% [2]. Unfortunately, more than 70% of newly cases were locoregionally advanced disease at initial diagnosis [3]. Currently, concurrent chemo-radiation (CCRT) is the main standard care for LA-NPC. Although local and regional control has improved greatly, distant metastasis rates after treatment remain high and is the main source of treatment failure [4]. Therefore, identification of novel and effective therapeutic strategies is urgent and crucial for clinicians.

Epidermal growth factor receptor (EGFR), a transmembrane protein highly expressed in most human epithelial malignancies [5], is a promising therapeutic target in oncology for its correlation with aggressive phenotype, treatment resistance and poor prognosis [6, 7]. EGFR is also highly expressed in NPC [8] and numerous studies have evaluated the efficacy of anti-EGFR targeted therapy [9‐15]. Cetuximab (CTX) or nimotuzumab (NTZ) (anti-EGFR monoclonal antibodies) concurrently with RT could achieved comparable outcomes compared with standard cisplatin-RT [12, 14]. When delivered during CCRT, different results were produced. You et al. and Xia et al. revealed CTX/NTZ additional to CCRT was more effective than CCRT alone [11, 13] while Li et al. did not identified any difference [10]. Regardless of the controversial efficacy, CTX/NTZ significantly increased acute mucositis and acneiform rash during RT [10, 12], resulting in poor quality of life or even disruption of RT. It seems that anti-EGFR therapy concurrent with RT may not be the best choice.

Induction chemotherapy (IC), given before RT, has been proven a promising treatment in LA-NPC for its satisfactory compliance and efficacy in reducing distant metastasis [16‐19]. Possibly, CTX/NTZ in combination with IC may further reduce distant metastasis and improve survival outcomes. Notably, all abovementioned studies focus on the concurrent phase and no relative study to date has been carried out to assess the value of anti-EGFR therapy concurrently with IC. Given this concern, we initiated this retrospective study to evaluate the efficacy and toxicity difference of CTX/NTZ concurrently with IC or RT for LA-NPC.

Managing advanced disease has always been a tough challenge not only in NPC management but also in many other cancers since prognosis of this subgroup is usually poor. Therefore, identification and establishment of novel and effective treatment is urgent and necessary. As far as we know, our study is the first one to compare the efficacy and safety of anti-EGFR therapy (CTX or NTZ) concurrently with IC or RT in LA-NPC treated by IMRT. We found that CTX/NTZ delivered during IC could produce significantly better DFS than administered during RT while no significant difference was achieved with regard to OS, DMFS and LRRFS.

With the wide application of IMRT in NPC, local and regional control has improved greatly and distant metastasis has become the main failure pattern [4, 23]. Although CCRT is effective, it may be not powerful enough to reduce distant metastasis for LA-NPC [24]. Additional cycles of chemotherapy like IC to CCRT is warranted. Although IC followed by CCRT has achieved excellent efficacy [16, 17, 19], further improvement of prognosis is still needed. Therefore, novel and effective treatment strategies should be identified.

EGFR on tumor cells has been established as a factor predicting treatment resistance and poor prognosis [6, 7], making anti-EGFR a potential and promising treatment strategy. Antitumor efficacy of CTX in combination with conventional chemotherapy has been proven in various EGFR-expressing malignancies like colorectal cancer, head and neck cancers and recurrent NPC [25‐27]. In recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), CTX combined with fluorouracil-cisplatin chemotherapy achieved significantly better DFS and OS compared with fluorouracil-cisplatin alone when given as the first-line therapy [28]. It seems that CTX could overcome resistance to previously administered chemotherapy and thereby improved survival outcomes [26]. You et al. [13] and Li et al. [10] enhanced the treatment intensity during concurrent phase by adding CTX/NTZ to standard concomitant cisplatin. However, the efficacy may be unsatisfactory and adverse events significantly increased [10, 12‐14]. It’s likely that concurrent administration of anti-EGFR therapy with cisplatin is a feasible strategy but not the best. These evidence reminded us that CTX/NTZ in combination with IC may be a preferable choice. In our present study, we confirmed this view as patients in the investigational arm achieved significantly better DFS. Our findings provided a new insight in managing LA-NPC by enhancing the treatment intensity during IC.

Reasons contributing to the significantly difference of DFS were complicated. First, treatment intensity during IC was improved by adding CTX/NTZ which could help to further eradicate micro-metastasis lesions prior to RT and thereby reduce treatment failure events. Second, patients receiving CTX/NTZ during RT experienced more severe toxicities than those not. Consequently, these patients had poor quality of life during RT which could adversely affect prognosis [29, 30]. Furthermore, some patients even suffered RT interruption due to severe skin reaction or mucositis. Undoubtedly, the prolonged treatment time had a negative impact on prognosis [31, 32].

Notably, univariate and multivariate analysis only identified the significant difference between the two arms for DFS. As indicated by the survival curves, patients in the investigational arm also achieved better DMFS and LRRFS compared with patients in the control arm, although the difference was not significant. The main reason should be attributed to the small sample size which was not statistically powerful enough to identify the difference. Possibly, the improved DFS should originate from DMFS and LRRFS together. Due to the insufficient follow-up duration, no significant difference was achieved on OS although more patients in the control arm experienced treatment failure. Therefore, future studies with larger sample and longer follow-up duration are warranted to validate our results. Moreover, some other factors like program death ligand 1 (PD-L1) on tumor cells, human papillomavirus (HPV) status and lifetime cigarette smoking (pack-years) may also play important roles in prognosis and have an effect on the insignificant OS. However, these factors were not routinely evaluated in our center. Further studies were needed to evaluate these factors.

Generally, severe toxicities during RT in our study were similar as the findings in previous studies [10, 12‐14]. Overall grade 3–4 toxic events were comparable between the two arms; however, anti-EGFR therapy related toxicities like skin reaction and mucositis significantly varied between the investigational and control arms during IC and RT. In detail, patients in the investigational arm experienced more grade 3–4 skin reaction and mucositis during IC but less during RT. Undoubtedly, CTX/NTZ could aggravate radiation-induced skin and oral mucositis. Another reason for the difference may be that the total dose used in induction phase is less than that used in concurrent phase. As both arms had similar chemotherapy intensity, severe heamatological and gastrointestinal events were parallel.

In our study, patients in the investigational arm had two main advantages compared with those in control arm. First, patients experienced significantly less anti-EGFR therapy related severe toxicities. Therefore, patients had better quality of life during treatment. Second, cycles of CTX/NTZ used during induction phase were usually less than that in concurrent phase. Hence, cost of anti-EGFR therapy is also less. However, limitations of this study should also be acknowledged. Our study is retrospective and the sample size may be small, meaning that potential bias existed and the power of identify difference may be insufficient. Moreover, the follow-up duration may be insufficient. Consequently, we set DFS as the first endpoint to address this. Furthermore, the cycles of IC were not uniform. In light of previous evidence, we recruited patients receiving at least two cycles because two cycles could produce the similar survival outcomes as three or more cycles [21]. Importantly, we balanced this factor between the two groups. The median age of included patients is younger than that in other reports, which should be attributed to the small sample size.

In summary, CTX/NTZ concurrently with IC could achieved better survival outcomes and less severe toxicities compared with CTX/NTZ concurrently with RT in LA-NPC treated by IMRT. Our study provided a new insight into managing LA-NPC for clinicians. However, findings of present study need to be validated in prospective studies.