**4. Treatment of NPC**

NPC is relatively sensitive to ionizing radiation, and radiation therapy (RT) is the mainstay modality of curative-intent treatment for patients with the nondisseminated disease. The 5-year disease-specific survival rate in stage I NPC is now expected to be around 95% with IMRT alone [36]. By introducing concurrent chemoradiotherapy to patients with locoregionally advanced diseases, the 5-year overall survival rate was around 60-80% recently [37]. Researchers are making exploratory effects on molecular-targeted medicine and immunotherapy in the treatment of NPC. Several encouraging results from clinical trials will be discussed below.

#### **4.1 Radiation therapy**

The ideal modality of RT should fully cover the complex-shaped gross tumor with high doses needed for eradication while providing maximum sparing for adjacent organs. Photon-based radiotherapy techniques have evolved from conventional two-dimensional (2D) radiotherapy to 3D conformal radiotherapy and intensity-modulated radiation therapy (IMRT). Charged particle therapy is gaining more and more attention in the treatment of NPC, especially the locoregionally advanced disease.

IMRT technique allows for the conform radiation dose to deliver precisely to a gross tumor and minimize the dose to adjacent normal tissues by controlling the intensity of the radiation beam. There is compelling evidence from numerous randomized controlled trials (RCTs) reporting a superiority of IMRT over conventional techniques. Over 90% 5-year locoregional control rate and 80% of overall survival rate were achieved, along with significant protection of the saliva gland and reduction of other radiation-induced complications [38–44]. Compared with 2D or 3D radiotherapy, IMRT was significantly associated with better 5-year locoregional control and overall survival [45].

Despite the rapid improvement in radiotherapy techniques, successful RT of NPC relies on precise delineation and accurate dose delivery to the gross tumor volume (GTV), clinical target volume (CTV), and critical organs at risk (OARs) [46]. Advanced imaging techniques, such as MRI, CT, 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/CT, and fusion of images from different techniques with the planning CT images of radiotherapy, together with endoscopy and clinical examination are most commonly used for facilitating primary GTV delineation. The international guidelines and consensus have recently been propounded for the delineation of CTV and OARs, allowing improved consistency and providing helpful references in NPC radiation management [41, 47–49].

Besides, the application of automation, deep learning, and artificial intelligence has been investigated currently [50–52]. It will be an integral piece of RT to improve accuracy, consistency, and cost-efficiency while reducing labor-intensive costs soon.

## **4.2 Chemotherapy in non-metastatic NPC**

While stage I NPC is treated by IMRT alone with little doubt, locoregionally advanced disease (stage II to stage IVB) requires the combination of chemotherapy with comprehensive consideration [53, 54] (**Table 2**). The modalities of chemotherapy include concurrent chemoradiotherapy (CRT), adjuvant chemotherapy, and induction chemotherapy, while the regimens vary between studies/centers.

For stage II NPC, the National Comprehensive Cancer Network (NCCN) guideline suggests RT plus concurrent chemotherapy ± sequential chemotherapy, whereas the EHNS-ESMO-ESTRO clinical practice guideline proposes concurrent chemoradiotherapy (**Table 2**). The controversy between the two guidelines may partly reflect the contentious evidence from numerous clinical trials based on different RT techniques [2, 55–57]. In the IMRT era, many recently retrospective studies and meta-analyses demonstrated that RT alone might be sufficient for patients with stage II disease to achieve desirable long-term outcomes and avoid increased toxicity [58–61].

There is a consensus among guidelines that concurrent chemoradiotherapy ± sequential chemotherapy may be mainstay treatment in stage III to IVB diseases with a remarkable survival benefit [2, 48]. Recently, a study based on 7,940 patients from 27 trials suggests that patients treated with induction-concurrent CRT (IMRT) gained the highest overall survival, progress-free survival, and distant metastasisfree survival [62]. To date, induction-concurrent CRT is becoming more and more important in treating locoregionally advanced NPC and adopted by many treatment centers. Several ongoing trials (NCT01536223, NCT01872962, NCT02512315, NCT 03306121, and NCT03503136) comparing induction-concurrent CRT and concurrent CRT with detailed combinations of different regimens, such as taxane, cisplatin, and 5-fluorouracil are anticipated, which results would provide further evidence for clinical practice.


*a Stage: American Joint Committee on Cancer (AJCC) – TNM Staging System for the Nasopharyngeal Carcinoma (8th ed. 2017).*

*b National Comprehensive Cancer Network (NCCN) Guidelines Version 2.2020.*

*c EHNS-ESMO-ESTRO Clinical Practice Guidelines (2012).*

*d NCCN Categories (1-3) of Evidence and consensus.*

*e Level of evidence (I-V) used in the EHNS-ESMO-ESTRO Clinical Practice Guidelines.*

#### **Table 2.**

*Treatment strategies for different stages.*
