Palliative systemic therapy for recurrent or metastatic nasopharyngeal carcinoma – How far have we achieved?

Accepted Manuscript Title: Palliative systemic therapy for recurrent or metastatic nasopharyngeal carcinoma − how far have we achieved? Authors: Victor Lee, Dora Kwong, To-Wai Leung, Ka-On Lam, Chi-Chung Tong, Anne Lee PII: DOI: Reference:

S1040-8428(16)30405-X http://dx.doi.org/doi:10.1016/j.critrevonc.2017.03.030 ONCH 2368

To appear in:

Critical Reviews in Oncology/Hematology

Received date: Accepted date:

3-1-2017 28-3-2017

Please cite this article as: Lee Victor, Kwong Dora, Leung To-Wai, Lam Ka-On, Tong Chi-Chung, Lee Anne.Palliative systemic therapy for recurrent or metastatic nasopharyngeal carcinoma − how far have we achieved?.Critical Reviews in Oncology and Hematology http://dx.doi.org/10.1016/j.critrevonc.2017.03.030 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Palliative systemic therapy for recurrent or metastatic nasopharyngeal carcinoma – how far have we achieved?

Victor Lee, Dora Kwong, To-Wai Leung, Ka-On Lam, Chi-Chung Tong, Anne Lee Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong

Corresponding author Dr. Victor Lee Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong 1/F, Professorial Block, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong Email address: [email protected] Telephone number: 852-2255-4352 Fax number: 852-2872-6426

Conflict of interest None.

Contents 1. Introduction and epidemiology 2. Palliative chemotherapy 2.1. Single-agent chemotherapy 2.2. Doublet combination chemotherapy 2.3. Polychemotherapy 3. Targeted therapy 3.1 Various types of targeted therapy for NPC 3.2 New targets for NPC 4. Immuno-oncology for nasopharyngeal carcinoma 4.1 Immunotherapy 4.2 Immune checkpoint inhibitors References Biography

Abstract Nasopharyngeal carcinoma (NPC) is endemic in Southern China, Taiwan, Malaysia, Singapore, North Africa and Alaska. About 30% of NPC patients develop recurrence or metastasis despite initial radical treatment. Palliative chemotherapy is the first-line treatment for inoperable recurrence or distant metastatic disease. However the standard first-line chemotherapeutic regimen is yet to be established until recently gemcitabine and cisplatin has been proven superior to traditional regimen with 5-FU and cisplatin shown in a phase III randomized-controlled trial.

Further palliative systemic treatment options including other chemotherapeutic regimens, targeted therapy and more recently immunotherapy have gradually evolved. We provided a comprehensive review on different traditional chemotherapeutic regimens and highlighted the latest chemotherapeutic treatments as well as the latest development of targeted therapies, immune checkpoint inhibitors and other immunotherapeutic options in this setting.

Keywords: Nasopharyngeal

carcinoma;

recurrent;

metastatic;

chemotherapy;

targeted

therapy;

immunotherapy; checkpoint inhibitors

1. Introduction and epidemiology Nasopharyngeal carcinoma is distinctive in terms of geographical distribution and the histology. It is an endemic malignancy in Southern China, followed by Taiwan, Malaysia, Singapore, North Africa and Alaska, with a peak incidence of 30 per 100,000 persons (Jia et al., 2006; Parkin et al., 2002). The undifferentiated type (WHO Type III), strongly associated with Epstein-Barr virus (EBV) infection, is the most common histological type in the endemic areas whereas squamous cell type (WHO Type I) is the predominant type in the low-incident regions. Radiotherapy with contemporary techniques like intensity-modulated radiation therapy (IMRT) is the mainstay of treatment for early stage NPC, while concurrent chemoradiation with or without adjunct chemotherapy is indicated for locoregionally advanced disease, as shown in the first metaanalysis in 2006 and a recent update in 2015 with inclusion of 19 trials and 4806 patients (Baujat et al., 2006; Blanchard et al., 2015). Nevertheless, about 30% of cases relapse locoregionally or

distantly, despite intensive definitive treatment (Lee et al., 2005). Though most of these relapsed patients have an unfavorable survival outcome, their survival can be significantly prolonged with palliative chemotherapy and more recently targeted therapy has demonstrated encouraging objective responses and treatment outcomes. In this review, we comprehensively presented the treatment outcomes of the previous studies on palliative chemotherapy, targeted therapy, immunotherapy and the future directions on the use of novel treatments for recurrent or metastatic NPC.

2. Palliative chemotherapy Systemic chemotherapy has been the mainstay of first-line treatment for incurable recurrent or metastatic NPC. For the past 30 years, trials investigating the efficacy and safety were all retrospective or small-scale phase II clinical trials and there have been few phase III randomizedcontrolled trials comparing efficacy and safety of different chemotherapeutic regimens and no evidence pertaining to prolongation of survival compared to best supportive care. Moreover, these trials consisted of a heterogeneous population treated in different settings (first-line, second-line or beyond). In addition, quality-of-life evaluations before and after chemotherapy were often neglected. Instead of summarizing the published trials treated in different lines of settings, we now described their treatment outcomes according to the number of chemotherapeutic agents used, namely monotherapy, doublet combination chemotherapy and polychemotherapy.

2.1. Single-agent chemotherapy

Anecdotal publications consisting mainly of retrospective studies have demonstrated that the use of old agents like methotrexate, bleomycin, 5-fluorouracil (5-FU), epidoxorubicin, mitoxantrone, and platinum compounds produced an objective response rates between 15 and 30% (Shiu and Tsao 1989, Dugan et al. 1993, Ma and Chan 2005). More recent clinical trials have also investigated the efficacy of newer agents including gemcitabine, irinotecan, paclitaxel, capecitabine, and docetaxel (Table 1) (Dugan et al., 1993; Au et al., 1998; Foo et al., 2002; Ma et al., 2002; Chua et al., 2003; Poon et al., 2005; Chua et al., 2008; Ciuleanu et al., 2008; Zhang et al., 2008; Ngeow et al., 2011). Notably, gemcitabine and capecitabine are the foci of recent studies, offering an objective response rates between 24 and 48% and median progression-free survival (PFS) between 4 and 14 months (Foo et al., 2002; Ma et al., 2002; Chua et al., 2003; Chua et al., 2008; Ciuleanu et al., 2008; Zhang et al., 2008). Docetaxel, as a single agent, also produced a response rate of 37% and a median PFS of 5 months (Ngeow et al., 2011).

There has been no standard third-line treatment or beyond as the performance status of these patients gradually decline brought by the side effects attributed to the use of prior first-line and second-line treatment. Lee et al has recently published the use of metronomic oral cyclophosphamide as third-line treatment or beyond for recurrent/metastatic disease (Lee et al., 2016). Metronomic oral chemotherapy may provide an ideal choice to patients treated in this setting by shifting the targets from tumor cells to tumor vasculature so as to reduce the chance of drug resistance as well as offering a relatively low toxicity profile to them who have been significantly jeopardized by the long-term complications brought by prior courses of radiation therapy, surgery and chemotherapy (Gnoni et al., 2015; André et al., 2014; Sarmiento et al., 2008). In this prospective phase II study, 56 patients received oral cyclophosphamide 50 to

150mg daily until progressive disease or unacceptable toxicity. Thirty-three (58.9%), 13 (23.2%), 6 (10.7%), 3 (5.4%) and 1 (1.8%) patients received cyclophosphamide as third, fourth, fifth, sixth and seventh line of therapy respectively. One (1.8%), 17 (30.4%) and 38 (67.9%) patients received 50mg, 100mg and 150mg daily as the starting dose. After a median follow-up duration of 9.95 months, the objective response rate was 8.9% seen in 5 patients. The disease control rate was 57.1%, observed in 32 patients. The median PFS for the whole study population was 4.47 months (95% confidence interval [CI], 3.18–5.76 months). Those with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 enjoyed a longer median PFS (5.49 months, 95% CI, 0.42–10.56 months) compared to those with ECOG PS 2 (3.75 months, 95% CI, 3.05– 4.45 months, P = 0.011). In addition, those who had locoregionally advanced recurrent disease had better median PFS (8.97 months, 95% CI, 0.53–17.41 months) compared to those who suffered from distant metastases (4.14 months, 95% CI, 2.53–5.75 months, P = 0.020). Plasma EBV deoxyribonucleic acid (DNA) titers were also measured before and after chemotherapy. The biochemical PFS for the whole study population was 3.75 months (95% CI 2.11–5.38 months). Those who had better PS 1 enjoyed a longer median biochemical PFS (5.45 months, 95% CI, 4.57–6.34 months) than patients whose ECOG PS was 2 (3.42 months, 95% CI, 1.97– 4.87, P = 0.007). Similarly, those who had locoregionally advanced recurrent disease enjoyed longer biochemical PFS (8.97 months, 95% CI, 3.01–14.92 months) as compared to those who had distant metastases (3.42 months, 95% CI, 2.01–4.83 months; P = 0.004). Treatment-related adverse events were observed in 34 (60.7%) patients. Sixteen (28.6%) patients developed grade 3 adverse events, including malaise (5.4%), hematological (8.9%), gastrointestinal (3.6%) and feverish (3.6%) and hemorrhagic (1.8%) events. Treatment interruption secondary to adverse events were observed in 25 (44.6%) patients. Dose reduction was necessary in 23 (41.1%)

patients because of these grade 3 adverse events. Two (3.6%) patients were permanently discontinued from cyclophosphamide because of persistent unresolving grade 3 malaise for more than 3 weeks, though it subsided completely without sequelae after cyclophosphamide termination.

2.2. Doublet combination chemotherapy Platinum doublets have been regarded as the principal regimen of choice for medically fit patients with recurrent/metastatic NPC. Clinical trials entailing platinum doublets have exhibited response rates from 20 to 76%; one study showed that all patients with recurrent disease only responded to cisplatin and 5-fluorouracil (Table 2) (Wang and Tan, 1991; Au and Ang, 1994; Chi et al., 1994; Stein et al., 1996; Yeo et al., 1996; Yeo et al., 1998; Tan et al., 1999; Chua et al., 2000; Huang et al., 2002; Ma et al., 2002; McCarthy et al., 2002; Ngan et al., 2002; Altundag et al., 2004; Ciuleanu et al., 2004; Chua et al., 2005; Wang et al., 2006; Li et al., 2008; Wang et al., 2008; Ma et al., 2009; Chen et al., 2012; Chua et al., 2012; Dede et al., 2012; Yau et al., 2012). Platinum and 5-fluorouracil combination therapy (known as PF regimen) has once been the most popular among doublet regimens widely practiced in Asian countries where the disease is endemic. The dose of cisplatin is 100 mg/m2 on day 1 and that for 5-FU is 1000 mg/m2 over 3 to 5 days, given every 3 weeks. This popular regimen produced an overall response (OR) rate between 66 and 78% and a median survival of 12 to 14 months (Wang and Tan, 1991; Au and Ang, 1994; Chi et al., 1994) In particular, Chi et al revealed that all patients with locally recurrent disease responded to PF and leucovorin producing a median survival of 34 months, while 80% of those with metastatic disease responded with a median survival of 14 months (Chi et al, 1994). This regimen was found effective even in patients who had received prior

chemotherapy. All five patients who had received mitoxantrone previously still responded, suggesting a lack of cross-resistance between mitoxantrone and PF. Another 4 patients with good responses to prior induction chemotherapy with PF followed by radiotherapy who then developed metastatic disease with disease-free intervals greater than 1 year still, nevertheless, responded to the same regimen (Chi et al., 1994). Moreover, the toxicity profile was favorable with mild immunosuppression and peripheral neuropathy. However, cisplatin-induced nephrotoxicity and ototoxicity were of concern, especially in patients who had also received cisplatin during their previous definitive chemoradiation with high-dose radiation to their middle and inner ears. Commonly, carboplatin has been used as a substitute of cisplatin for advanced head and neck cancers including NPC (Lokich and Anderson 1998). Two older randomizedcontrolled studies on advanced head and neck cancers demonstrated that cisplatin was superior to carboplatin in terms of improved response rate (Forastiere et al., 1992; De Andrés et al., 1995). One of these showed cisplatin conferred superior disease-free survival (DFS) and overall survival (OS) compared to carboplatin when both were used in conjunction with 5-FU (De Andrés et al., 1995). However, this study did not recruit patients with recurrent or metastatic diseases. More recently, carboplatin has been tested with concurrent chemoradiation against cisplatin-based concurrent chemoradiation in a randomized-controlled non-inferiority study (Chitapanarux et al., 2007). Patients with locally advanced NPC were randomized to receive cisplatin chemoradiation versus carboplatin chemoradiation followed by adjuvant chemotherapy using the same platinum compound as in the concurrent phase coupled with 5-FU. No difference in 3-year DFS (p = 0.9613) and OS (p = 0.9814) was demonstrated. In 2013, a retrospective Malaysian study compared PF with carboplatin and 5-FU in 41 patients with recurrent and metastatic squamous-cell head and neck cancer and NPC (Kua et al. 2013). The results revealed

that carboplatin and 5-FU (median OS, 12 months) was not inferior to PF (median OS, 10 months; p = 0.110). However, the drawbacks of this study were that no subgroup analysis was performed for NPC patients only and there were 6 treatment-related mortalities (14.6%) — four in the carboplatin + 5-FU group and two in the cisplatin + 5-FU group.

Other active agents for recurrent and metastatic NPC include gemcitabine, capecitabine, oxaliplatin and taxanes (Chan et al., 2010). One Hong Kong study published in 2002 tested gemcitabine with platinum as first-line chemotherapy for metastatic NPC in 44 patients. (Ngan et al., 2002). The objective response rate was 73% and the median PFS was 11 months. Gemcitabine together with oxaliplatin (a third-generation platinum compound) was also evaluated in another Hong Kong study. This multi-center study demonstrated that first-line gemcitabine and oxaliplatin produced an objective response rate of 57% and a median PFS of 9 months (Ma et al., 2009). Gemcitabine together with a non-platinum compound in patients pretreated with platinum was also found to be feasible and promising. A Chinese study including patients all with disease progression while still on previous platinum-based chemotherapy demonstrated an objective response rate of 36% and a median PFS of 6 months after gemcitabine and vinorelbine (Wang et al., 2006). Another Chinese study, in which about 15% of 61 patients had progressive disease while still on platinum-based chemotherapy, demonstrated an objective response rate of 38%, and a median PFS of 5 months; and the median OS being 14 months following treatment with a median of 4 cycles of gemcitabine and vinorelbine (Chen et al., 2012). Use of capecitabine, an oral pro-drug of 5-FU, in combination with cisplatin as first-line treatment was also comprehensively evaluated. Chua et al (2012) published a multi-center study on such treatment in 44 patients with previously untreated metastatic NPC. Of the 39 patients

evaluable for efficacy, the objective response rate was 54% including 1 patient (3%) showing a complete response. The median time to progression was 7 months and the median OS was 28 months. In addition, this study specially emphasized quality-of-life assessment using FACT-G and disease specific FACT-H&N questionnaires (Chua et al., 2012). They reported mild decline in quality-of-life scores after chemotherapy, which was likely due to side-effects and hospitalization. Docetaxel and ifosphamide doublet chemotherapy regimens were also extensively studied (Huang et al., 2002; Altundag et al., 2004; Chua et al., 2005; Li et al., 2008). When used with platinum or non-platinum compounds, the objective response rates were between 22 and 68% and the median PFS ranged between 6 and 8 months. More recently a Hong Kong study investigated the role of pemetrexed when combined with cisplatin for patients with recurrent or metastatic NPC (Yau et al., 2012). Fifteen patients were recruited into this study, 6 of whom had locoregional recurrence while the rest had distant metastases with or without locoregional recurrence. Three patients were previously treated with cisplatin-based chemotherapy as prior first-line therapy, while the rest received cisplatin during their initial definitive chemoradiation. Plasma EBV DNA was also measured in this study. The objective response rate was 20% and 1 patient (7%) enjoyed complete response. Another 8 patients (53%) had their disease stabilized, giving an overall clinical benefit rate of 73%; 3 patients (21%) had undetectable plasma EBV DNA after treatment. Pemetrexed was welltolerated with only one patient who experienced grade 4 anemia. The most common grade 3 toxicities included neutropenia (27%) and anemia (20%).

It is still under debate whether patients can be safely re-challenged with cisplatin if they were exposed to it during previous induction chemotherapy, definitive cisplatin-based chemoradiation

or prior palliative chemotherapy. An older study revealed that all 4 patients with a disease-free interval of more than 1 year after induction PF and radiotherapy still responded to the same regimen (Chi et al., 1994). In their study on doublet regimen using cisplatin and capecitabine for previously untreated metastatic NPC, Chua et al (2012) demonstrated that prior adjunctive (neoadjuvant, concurrent, or adjuvant) chemotherapy given at least 6 months before study entry had a longer PFS (9 vs. 7 months) and OS (30 vs. 28 months), though the differences were not statistically significant (Chua et al., 2012). Recently, molecular medicine has played an important role in the prediction of chemosensitivity. Some light has been shed on the discovery of excision repair cross complementation group 1 (ERCC1) and xeroderma pigmentosum complementation group F (XPF) involved in the repair cisplatin-DNA adducts via different pathways. These have a bearing on the nucleotide excision repair pathway, double-strand break repair, and repair of interstrand crosslinks (Lee et al., 2010; Chan et al., 2011; Sun et al., 2011; Huang et al., 2012; Chen et al., 2013; Jagdis et al., 2013). When associated with ERCC1, XPF forms a heterodimer which functions as a structure-specific endonuclease. The ERCC1 also binds and stabilizes XPF, which enhances the latter’s endonuclease to create an incision 5’ to the DNA lesion, thus allowing DNA to be repaired. Four studies confirmed that high expression levels of ERCC1 conferred poor treatment outcomes in NPC when cisplatin was administered as induction treatment, concurrently with radiation therapy or palliative setting (Lee et al., 2010; Sun et al., 2011; Huang et al, 2012; Chen et al., 2013). Another study showed that high ERCC1 levels predicted poor locoregional control, but did not predict resistance to cisplatin (Chan et al., 2011). One more recent study showed that neither ERCC1 nor XPF predicted locoregional recurrence, DFS and OS in 142 patients with NPC treated with curative intent (Jagdis et al.,

2013). Perhaps one of the solutions to these conflicting results is to re-biopsy the recurrent/metastatic lesions to evaluate chemosensitivity to platinum.

A phase III randomized-controlled trial on the best chemotherapeutic regimen as first-line treatment has been eagerly awaited for long. Zhang et al published their pivotal phase III trial using gemcitabine and cisplatin (GP) as first-line treatment for recurrent or metastatic NPC (Zhang et al, 2016). This is the first multi-center randomized-controlled trial investigating the replacement of 5-FU with gemcitabine in combination with cisplatin as first-line treatment, performed in endemic areas of NPC in 22 hospitals in China. The primary study endpoint was PFS, while secondary endpoints were objective response rate, disease control rate, safety profiles and overall survival (OS). Altogether 362 patients were equally randomized to either GP or PF regimen. After a median follow-up of 19.4 months, the median PFS was statistically longer in the GP regimen (median 7.0 months) as compared to PF (5.6 months, hazard ratio 0.55, p < 0.0001). Subgroup analysis demonstrated that PFS advantage was observed in all pre-specified subgroups except non-Type-III histology and chemotherapy with 5 cycles. A higher objective response rate was achieved in the GP regimen (64%) compared to PF regimen (42%), while disease control was similar between the two arms (90% versus 86%). With respect to safety profiles, more grade ≥3 hematological adverse events were seen in patients treated with GP, whereas more mucosal inflammation was reported in those who received PF. Finally, OS was also significantly longer with GP compared to PF (median 29.1 months vs. 20.9 months, p = 0.0025), though event follow-up is still yet to mature.

While this is the first head-to-head randomized-controlled trial demonstrating the superiority of GP to PF, there are some caveats pertaining to this study. First of all, no stratification factor was employed during the randomization process. It has been previously shown that liver metastasis is a poor prognostic factor while lung metastasis is a favorable factor (Hui et al., 2004; Winter et al., 2008; Ong et al., 2003). Secondly, the dose of cisplatin was set at 80mg/m2 in both arms in this study instead of 100mg/m2 in the usual sense. It is not known if this slightly diminished dose of cisplatin would carry any impact on tumor response and efficacy. Though induction chemotherapy was allowed in this study, only agents including platinum, 5-fluorouracil, docetaxel and paclitaxel but not gemcitabine were permitted in this trial. The study results might be insignificant if gemcitabine was also allowed in the induction setting, as it is getting popular shown in recent studies (Tan et al., 2015; Lim et al., 2013; Yau et al., 2006). The current drug of choice may be further complicated by the recently published phase III RCT comparing induction chemotherapy

with

docetaxel,

cisplatin

and

5-FU

(TPF)

followed

by

concurrent

chemoradiotherapy versus concurrent chemoradiotherapy (Sun et al., 2016). The more exposure to 5-FU in the induction setting may diminish the efficacy when used in recurrent/metastatic diseases. Overall, this randomized-controlled trial has established GP as the new standard of first-line therapy in recurrent/metastatic NPC.

2.3. Polychemotherapy Use of more than two drugs has not been shown to be superior to doublet counterparts. Several trials reported on polychemotherapy for recurrent NPC which demonstrated encouraging response rates but also more treatment-related toxicities (Table 3) (Boussen et al., 1991; Su et al., 1993; Azli et al., 1995; Siu et al., 1998; Hasbini et al., 1999; Taamma et al., 1999; Huang et al.,

2008; Leong et al., 2008). More importantly, they have not been compared with the standard PF or GP doublet regimen. One study, CAPABLE, incorporating five compound (cisplatin, methotrexate, bleomycin, cyclophosphamide, and doxorubicin), was associated with a response rate of 80% but also an extraordinarily high treatment-related mortality of 12% (Siu et al., 1998) Another phase II study, using 5-FU, mitomycin, epirubicin, and cisplatin demonstrated a response rate of 52% at the expense of iatrogenic death of 9% (Hasbini et al., 1999). In general, polychemotherapy entailing three or more agents is not routinely recommended.

3. Targeted therapy Targeted therapy against one or several genetic mutations, aberrant growth factor pathways or angiogenesis has been broadly investigated and evaluated in head and neck squamous cell carcinoma. Of them, cetuximab was proven to be the most promising agent when combined with PF compared to the same chemotherapy regimen alone (Vermorken et al., 2007). Unfortunately, none of the studies targeted therapy has been found successful in NPC, as elaborated further below.

3.1. Various types of targeted therapy for NPC A number of studies have tested the efficacy of targeted therapy for recurrent/metastatic NPC (Table 4). First of all, like other squamous-cell head and neck cancers, epidermal growth factor receptor (EGFR) is also highly expressed in NPC (Sheen et al., 1999; Fujii et al., 2002; Leong et al., 2004). Thus, several studies investigated the role of EGFR tyrosine kinase inhibitors and monoclonal antibodies in metastatic NPC. A small phase II study in Hong Kong showed that none of 19 patients responded to gefitinib in previously heavily pretreated NPC, with median

time to progression and OS of 4 and 16 months, respectively (Chua et al., 2008). Another Hong Kong study was terminated due to lack of efficacy following treatment with gefitinib (Ma et al., 2008). Similarly, a phase II study, using erlotinib as maintenance treatment after 6 cycles of GP in chemo-naïve patients with metastatic NPC, revealed stable disease in only three out of 12 evaluable patients (You et al., 2012). Use of cetuximab, a monoclonal antibody against EGFR, in combination with carboplatin was also evaluated. Seven (12%) out of 59 patients enjoyed partial response with a median PFS of 3 months and median OS of 8 months, but at the expense of significant toxicities (grade ≥3 toxicities in 52% of the patients) (Chan et al., 2005).

Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are also potential targets of treatment in NPC. Its overexpression was found in 60 to 67% of patients and also conferred a shorter survival (Hui et al., 2002; Krishna et al., 2006). The use of sorafenib, an oral multikinase inhibitor, was also not shown to be more efficacious than systemic chemotherapy (Elser et al., 2007). A more recently published phase II study on sorafenib in combination with standard cisplatin and 5-FU regimen in the induction phase followed by maintenance sorafenib until disease progression demonstrated a high response rate of 78% and median PFS of 7 months and median OS of 12 months (Xue et al., 2013). However, this regimen was also accompanied by a high frequency of hand-foot-skin reactions (83% in all and 19% in grade ≥3), leucopenia (78% in all and 7% in grade ≥3), and hemorrhagic events (22% in all and 2% in grade ≥3). Another multikinase tyrosine kinase inhibitor sunitinib was also tested in metastatic NPC in Hong Kong (Hui et al., 2011) Of the 10 patients who had post-treatment radiological assessment for tumor response, one patient had a partial response and another three remained stable for at least 12 months. Meanwhile, the hemorrhagic events also deserve attention (64% in all, 29% in grade 3/4,

and 14% in grade 5) and included epistaxis, hemoptysis, and hematemesis in 6, 3, and 2 patients, respectively. Two patients with tumor invasion to the carotid sheath suffered a fatal epistaxis/hematemesis which was likely secondary to carotid blowout after tumor shrinkage. Pazopanib, another orally available multikinase inhibitor against VEGFR-1, -2, and -3, plateletderived growth factor (PDGF)-α, PDGF-β and c-kit tyrosine kinases was also evaluated in NPC (Lim et al., 2011). Two (6%) out of 33 patients enjoyed a partial response and another 16 (48%) patients had stable disease. Treatment was fairly tolerated; fatigue and hand-foot syndrome were the most common grade ≥3 toxicities. One patient died of epistaxis and myocardial infarction. At around the same time, bevacizumab, an anti-angiogenic monoclonal antibody, was also shown to produce promising responses when combined with cisplatin chemoradiation as the definite treatment for locally advanced NPC (Lee et al., 2012). Whether the effect of bevacizumab and systemic chemotherapy can also accrue in a metastatic setting will depend on the results of an ongoing phase II study (NCT02250599) comparing paclitaxel and carboplatin with bevacizumab or chemotherapy alone.

Axitinib, another VEGF receptor inhibitor, was also evaluated in a Hong Kong phase II trial after progression to at least 1 line of platinum-based palliative chemotherapy (Hui et al., 2016). The final result demonstrated that the clinical benefit rate was 78.4% out of 37 evaluable patients, including 1 patient with partial response, 6 patients with unconfirmed partial response and 22 patients with stable disease. The median time to progression was 5.0 months and the median overall survival was 10.4 months. The most common adverse events were hand-foot syndrome (50%; all grades), hypothyroidism (48%), fatigue (40%), hypertension 38%, diarrhea 30%, pain 28% and mucositis (28%).

3.2 New targets for NPC New genes and/or growth factor pathways have been identified as potential targets of novel targeted therapies. For instance, the PI3K/Akt pathway was recently revealed to be frequently involved in NPC tumorigenesis and progression (Xu et al., 2004; Pedrero et al., 2005). Apart from that, microRNAs (miRNAs), a diverse class of 20- 24–nucleotide non-coding RNAs were also found upregulated in NPC compared with non-tumorous nasopharyngeal tissues (Choy et al., 2008; Sengupta et al., 2008; Shi et al., 2010; Xia et al., 2010; Zhang et al., 2010; Zhang et al., 2013). A local study found that upregulation of miRNA-144 promoted malignant progression by repressing the expression of a tumor suppressor gene phosphatase and tensin homologue (PTEN), which is partially responsible for upregulation of the PI3K/Akt pathway in NPC.65 In-vitro cellline studies have demonstrated that Akt inhibitors can suppress tumor growth. Hopefully the efficacy of these inhibitors can be further verified in phase II and III clinical trials (Lo et al., 2013; Ma et al., 2013; Ma et al., 2015).

Besides, nuclear factor-κB (NF-κB) signaling pathways have been also extensively investigated in NPC. Verhoeven et al revealed that EBV latent membrane protein-1 (LMP-1) upregulated BART expression through NF-κB signaling and that BART miRNAs were capable of downregulating LMP-1 expression (Verhoeven et al., 2016). It was apparent that aberrant NF-κB signaling and expression of BARTs is autoregulatory to maintain EBV latency in NPC cells. In another recent study on the use of whole-exome sequencing in 135 NPC tumors, multiple lossof-function mutations were identified in several NF-κB signaling negative regulators NFKBIA, CYLD, and TNFAIP3 (Zheng et al., 2016). In addition, functional studies confirmed that

inhibition of NFKBIA brought a significant impact on NF-κB activity and NPC cell proliferation. Indeed, bortezomib, the first NF-κB inhibitor, was found to have anti-tumor effect on NPC cells (Jiang et al., 2016; Hui et al., 2013). Hopefully these new preclinical findings may provide and reveal new hopes on the treatment for NPC confirmed in clinical trials.

It is observed from above that almost all of the evidence on the use of targeted therapy is limited to phase II studies only. The most common reason of failures in phase II study is mainly attributed to the drug-related toxicities including tumor bleeding and other hemorrhagic events. Another important obstacle and challenge in the development of new targeted agents lies in the lack of reliable and reproducible NPC cell models for preclinical testing. Only a few cell lines including C666-1 and a very few patient-derived xenografts have demonstrated stable EBV genome expression in culture (Busson et al., 1988; Huang et al., 1989; Cheung et al., 1999; Chan et al., 2008; Gullo et al., 2008). Such scarcity of NPC cell models also leads to the difficulty of identifying accurate biomarkers to predict drug efficacy.

4. Immuno-oncology for NPC The spotlight has now switched, for the past few years, from targeted therapy to immunotherapy or immune checkpoint inhibitors which have appeared as novel alternatives for various types of solid tumors. It has been known for long that patients who have been receiving immunosuppressive therapy after transplantation are at a higher risk of cancer development. By means of different immunosuppressive mechanisms, head and neck cancers and probably NPC, also manage to evade immunosurveillance and continue to proliferate. One of these mechanisms concerns the targeting of immune checkpoints including cytotoxic T-lymphocyte-associated

protein-4 (CTLA-4) and programmed death-1 (PD-1) pathway. Targeting these immune checkpoints with the use of monoclonal antibody is a recent breakthrough which emerges as a new treatment option for head and neck cancers and also NPC. Other approaches of cancer immunotherapy include EBV-directed adoptive and active immunotherapies, antibodies and EBV lytic cycle induction.

4.1. Immune checkpoint inhibitors Immunotherapy with immune checkpoint inhibitors has gradually emerged as a promising treatment modality for head and neck squamous cell carcinoma and NPC. Pembrolizumab in Keynote-012 phase Ib study, was shown to produce an objective response rate of 18%, a median PFS of 2 months and a median OS of 13 months in the intention-to-treat population (Seiwert et al., 2016). This promising result has led to accelerated approval by Food and Drug Administration of the United States in August this year for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. More recently, nivolumab in the multi-center phase III randomized-controlled trial was superior to standard single-agent systemic therapy (methotrexate, docetaxel or cetuximab) (Ferris et al., 2016). OS as the primary study endpoint was reached (7.5 months vs. 5.1 months, p = 0.01). Though median PFS was similar between the two arms (2.0 months vs. 2.3 months, p = 0.32), the rate of PFS at 6 months was higher with nivolumab (19.7% vs. 9.9%). The objective response rate was also more promising (13.3% vs. 5.8%). Perhaps it is prime time for these immunotherapeutic agents to be tested in NPC. The first phase I study on NPC demonstrated an objective response in 22.2% and disease control in 77.8% of a total of 44 patients (Hsu et al., 2015). A least 4 phase II trials are ongoing

to investigate the safety and efficacy of these immune check inhibitors (including nivolumab, pembrolizumab, PDR001 and avelumab) in the recurrent/metastatic setting as second-line treatment or beyond after prior failure to platinum-based chemotherapy (NCT02339558, NCT02611960 and NCT02605967, NCT02875613) (Table 5). Hopefully they will provide a new paradigm of treatment which can be further extended in the first-line setting.

4.2. Other approaches of cancer immunotherapy Immunotherapy has also evolved gradually in the treatment of recurrent/metastatic NPC. The immunological approach encompasses various strategies namely Epstein-Barr virus (EBV)directed adoptive and active immunotherapy, administration of antibodies and induction of EBV lytic cycle (Chua et al., 2001; Comoli et al., 2005; Straathof et al., 2005; Smith et al., 2012; Chia et al., 2014; Lin et al., 2002; Chia et al., 2012; Li et al., 2013; Hui et al., 2013).

Most of the antigens presented by EBV-infected NPC, including EB nuclear antigen-1 (EBNA1), LMP-1 and LMP-2 are poorly immunogenic. Compared to LMP-1, LMP-2 may be a better target antigen for CD8 +ve cytotoxic T-lymphocytes (CTLs) therapy. Though NPC cells were found to have preserved the antigen processing function which can be recognized by the major histocompatibility complex class I–restricted virus-specific CTLs in vitro, the downregulation of major histocompatibility complex class I peptide expression in NPC cells, the low incidence of T cells in patients which can recognize HLA-restricted epitopes in LMP2 and EBNA and the inactivation of tumor-infiltrating lymphocytes by the tumor microenvironment make the developing of effective EBV-specific immunotherapy difficult.

For the past 2 decades, there have been quite a number of clinical trials on the use of CD8 +ve CTLs through autologous transfer or vaccination with dendritic cells or peptides in patients with recurrent/metastatic NPC who had failed prior systemic therapy (Chua et al., 2001; Comoli et al., 2005; Straathof et al., 2005; Smith et al., 2012; Chia et al., 2014; Lin et al., 2002; Chia et al., 2012; Li et al., 2013; Hui et al., 2013). The results demonstrated favorable LMP-2 specific immune responses and some durable tumor regression in some patients in earlier studies (Comoli et al., 2005; Straathof et al., 2005). One pilot study conducted by Secondino et al showed an objective response rate of 27% and disease control rate of 55% in a series of 11 patients (Secondino et al., 2012). Other studies have also investigated sequencing T-cell therapy with chemotherapy and the use of novel adenovirus vector for more optimal T-cell expansion (Chia et al., 2014; Smith et al., 2012). An updated result of the use of adenovirus vector for T-cell adoptive therapy in patients with active disease and no/minimal residual recurrent or metastatic disease showed that the median PFS and OS were 5.5 months and 38.1 months respectively (Smith et al., 2016). In particular, it was further revealed that disease stabilization in patients with active disease was significantly associated with the functional and phenotypic composition of in vitro-expanded T-cell immunotherapy. These included a higher proportion of effector CD8 +ve T-cells and increased number of EBV-specific T-cells with broader antigen specificity. Hui et al also reported the experience of using a non-cell recombinant vaccinia virus-based vaccine which encodes a functionally inactive fusion protein containing the CD4 epitope–rich C-terminal half of EBNA1 and CD8epitope–rich LMP-2A, showing favorable T-cell response in >80% of patients (Hui et al., 2013). This will be further evaluated in the ongoing phase II study (NCT01094405).

Though preliminary results are encouraging and safe, these approaches are still experimental, costly and only limited to specialized tertiary institutions with expertise and comprehensive laboratory infrastructure.

5. Conclusion In summary, a platinum-based doublet chemotherapy regimen especially gemcitabine and cisplatin is recommended as the first-line treatment for recurrent/metastatic NPC. Cisplatin is preferred over carboplatin based on its long history with much accumulated experience by oncologists. Newer chemotherapeutic agents like capecitabine and taxanes can be safely combined with platinum compounds either as first-line or subsequent-line therapy. Combination chemotherapy using three or more agents has not been shown superior to doublet regimens. For second-line or subsequent treatment of recurrence/metastasis, whether platinum-based chemotherapy was given previously is a consideration. For patients treated with platinum-based chemotherapy, subsequent treatment depends on performance status, toxicity, and the interval to recurrence after previous platinum-based regimen. Re-challenge with platinum-based doublets can be considered in patients who enjoyed a good initial response to the same regimen with an intervening disease-free period of more than 1 year. Carboplatin is an acceptable substitute producing similar responses and outcomes when cisplatin is contraindicated, though it generally gives rise to more hematological toxicities. For patients who fail platinum-based doublet chemotherapy or whose disease relapse within a year of such a regimen, second-line treatment including gemcitabine, capecitabine, or taxanes with or without platinum can be considered. The role of targeted therapy in NPC remains to be deciphered. New targets and growth factor pathways have been gradually identified and new compounds against these targets are awaited.

Current attention is also focused on cancer immunotherapy especially immune checkpoint inhibitors, awaiting the results of the ongoing phase II randomized-controlled trials.

Conflict of interest None.

Acknowledgement None.

References Altundag, K., Aksoy, S., Gullu, I., Altundag, O., Ozyar, E., Yalcin, S., et al., 2004. Salvage ifosfamide-doxorubicin chemotherapy in patients with recurrent nasopharyngeal carcinoma pretreated with Cisplatin-based chemotherapy. Med. Oncol. 21 (3), 211–215 [Medline]. André, N., Carré, M., Pasquier, E., 2014. Metronomics: towards personalized chemotherapy? Nat. Rev. Clin. Oncol. 11 (7), 413–431 [Medline]. Au, E., Ang, P.T., 1994. A phase II trial of 5-fluorouracil and cisplatinum in recurrent or metastatic nasopharyngeal carcinoma. Ann. Oncol. 5 (1), 87–89 [Medline]. Au, E., Tan, E.H., Ang, P.T., 1998. Activity of paclitaxel by three-hour infusion in Asian patients with metastatic undifferentiated nasopharyngeal cancer. Ann. Oncol. 9 (3), 327–329 [Medline]. Azli, N., Fandi, A., Bachouchi, M., Rahal, M., Lianes, P., Wibault, P., et al, 1995. Final report of a phase II study of chemotherapy with bleomycin, epirubicin, and cisplatin for locally advanced

and metastatic/recurrent undifferentiated carcinoma of the nasopharyngeal type. Cancer. J. Sci. Am. 1 (3), 222–229 [Medline]. Basso, S., Zecca, M., Merli, P., Gurrado, A., Secondino, S., Quartuccio, G., et al., 2011. T cell therapy for nasopharyngeal carcinoma. J. Cancer. 2, 341–346 [Medline]. Baujat, B., Audry, H., Bourhis, J., Chan, A.T., Onat, H., Chua, D.T., et al. (2006). "Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data metaanalysis of eight randomized trials and 1753 patients." Int. J. Radiat. Oncol. Biol. Phys. 64 (1), 47–56 [Medline]. Blanchard, P., Lee, A., Marguet, S., Leclercq, J., Ng, W.T., Ma, J., et al., 2015. Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol 16 (6), 645–655 [Medline]. Boussen, H., Cvitkovic, E., Wendling, J.L., Azli, N., Bachouchi, M., Mahjoubi, R., et al, 1991. Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin, and fluorouracil. J. Clin. Oncol. 9 (9), 1675–1681 [Medline]. Busson, P., Ganem, G., Flores, P., Mugneret F, Clausse B, Caillou B, et al, 1988. Establishment and characterization of three transplantable EBV-containing nasopharyngeal carcinomas. Int. J. Cancer 42 (4), 599-606 [Medline]. Chan, A.T., Gregoire, V., Lefebvre, J.L., Licitra, L., Felip, E., Group E-E-EGW, 2010. Nasopharyngeal cancer: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 21 Suppl 5, v187–189 [Medline]. Chan, A.T., Hsu, M.M., Goh, B.C., Hui, E.P., Liu, T.W., Millward, M.J., et al., 2005. Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. J. Clin. Oncol. 23 (15), 3568–3576 [Medline].

Chan, S.H., Cheung, F.M., Ng, W.T., Choi, C.W., Cheung, K.N., Yiu, K.H., et al., 2011. Can the analysis of ERCC1 expression contribute to individualized therapy in nasopharyngeal carcinoma? Int. J. Radiat. Oncol. Biol. Phys. 79: 1414–1420 [Medline]. Chan, S.Y., Choy, K.W., Tsao, S.W., Tao, Q., Tang, T., Chung, G.T., et al, 2008. Authentication of nasopharyngeal carcinoma tumor lines. Int. J. Cancer 122 (9), 2169–2171 [Medline]. Chen, C., Wang, F., Wang, Z., Li, C., Luo, H., Liang, Y., et al., 2013. Polymorphisms in ERCC1 C8092A predict progression-free survival in metastatic/recurrent nasopharyngeal carcinoma treated with cisplatin-based chemotherapy. Cancer. Chemother. Pharmacol. 72 (2), 315–322 [Medline]. Chen, C., Wang, F.H., Wang, Z.Q., An, X., Luo, H.Y., Zhang, L., et al., 2012. Salvage gemcitabine-vinorelbine chemotherapy in patients with metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral. Oncol. 48 (11), 1146–1151 [Medline]. Cheung, S.T., Huang, D.P., Hui, A.B., Lo, K.W., Ko, C,W., Tsang, Y.S., et al, 1999. Nasopharyngeal carcinoma cell line (C666-1) consistently harbouring Epstein-Barr virus. Int J Cancer 83 (1), 121-126 [Medline]. Chi, K.H., Chan, W.K., Cooper, D.L., Yen, S.H., Lin, C.Z., Chen, K.Y., 1994. A phase II study of outpatient chemotherapy with cisplatin, 5-fluorouracil, and leucovorin in nasopharyngeal carcinoma. Cancer 73 (2), 247–252 [Medline]. Chia, W.K., Wang, W.W., Teo, M., Tai, W.M., Lim, W.T., Tan, E.H., et al., 2012. A phase II study evaluating the safety and efficacy of an adenovirus-ΔLMP1-LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma. Ann. Oncol. 23 (4), 997–1005 [Medline].

Chia, W.K., Teo, M., Wang, W.W., Lee, B., Ang, S.F., Tai, W.M., et al., 2014. Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol. Ther. 22 (1), 132–139 [Medline]. Chitapanarux, I., Lorvidhaya, V., Kamnerdsupaphon, P., Sumitsawan, Y., Tharavichitkul, E., Sukthomya, V., et al., 2007. Chemoradiation comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-inferiority, open trial. Eur. J. Cancer. 43 (9), 1399–1406 [Medline]. Choy, E.Y., Siu, K.L., Kok, K.H., Lung, R.W., Tsang, C.M., To, K.F., et al., 2008. An EpsteinBarr virus-encoded microRNA targets PUMA to promote host cell survival. J. Exp. Med. 205 (11), 2551–2560 [Medline]. Chua, D., Huang, J., Zheng, B., Lau, S.Y., Luk, W., Kwong, D.L., et al., 2001. Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T cells for nasopharyngeal carcinoma. Int. J. Cancer. 94 (1), 73–80 [Medline]. Chua, D., Wei, W.I., Sham, J.S., Au, G.K., 2008. Capecitabine monotherapy for recurrent and metastatic nasopharyngeal cancer. Jpn. J. Clin. Oncol. 38 (4), 244–249 [Medline]. Chua, D.T., Kwong, D.L., Sham, J.S., Au, G.K., Choy, D., 2000. A phase II study of ifosfamide, 5-fluorouracil and leucovorin in patients with recurrent nasopharyngeal carcinoma previously treated with platinum chemotherapy. Eur. J. Cancer. 36 (6), 736–741 [Medline]. Chua, D.T., Sham, J.S., Au, G.K., 2003. A phase II study of capecitabine in patients with recurrent

and

metastatic

nasopharyngeal

carcinoma

chemotherapy. Oral. Oncol. 39 (4), 361–366 [Medline].

pretreated

with

platinum-based

Chua, D.T., Sham, J.S., Au, G.K., 2005. A phase II study of docetaxel and cisplatin as first-line chemotherapy in patients with metastatic nasopharyngeal carcinoma. Oral. Oncol. 41 (6), 589– 595. Chua, D.T., Wei, W.I., Wong, M.P., Sham, J.S., Nicholls, J., Au, G.K., 2008. Phase II study of gefitinib for the treatment of recurrent and metastatic nasopharyngeal carcinoma. Head. Neck. 30 (7), 863–867 [Medline]. Chua, D.T., Yiu, H.H., Seetalarom, K., Ng, A.W., Kurnianda, J., Shotelersuk, K., et al., 2012. Phase II trial of capecitabine plus cisplatin as first-line therapy in patients with metastatic nasopharyngeal cancer. Head. Neck. 34 (9), 1225–1230 [Medline]. Ciuleanu, E., Irimie, A., Ciuleanu, T.E., Popita, V., Todor, N., Ghilezan, N., 2008. Capecitabine as salvage treatment in relapsed nasopharyngeal carcinoma: a phase II study. J. BUON. 13 (1), 37–42 [Medline]. Ciuleanu, T.E,, Fountzilas, G., Ciuleanu, E., Plataniotis, M., Todor, N., Ghilezan, N., 2004. Paclitaxel and carboplatin in relapsed or metastatic nasopharyngeal carcinoma: a multicenter phase II study. J. BUON. 9 (2), 161–165 [Medline]. Comoli, P., Pedrazzoli, P., Maccario, R., Basso, S., Carminati, O., Labirio, M., et al., 2005. Cell therapy of stage IV nasopharyngeal carcinoma with autologous Epstein-Barr virus-targeted cytotoxic T lymphocytes. J. Clin. Oncol. 23 (35), 8942–8949 [Medline]. De Andrés, L., Brunet, J., López-Pousa, A., Burgués, J., Vega, M., Tabernero, J.M., et al., 1995. Randomized trial of neoadjuvant cisplatin and fluorouracil versus carboplatin and fluorouracil in patients with stage IV-M0 head and neck cancer. J. Clin. Oncol. 13 (6), 1493–1500 [Medline].

Dede, D.S., Aksoy, S., Cengiz, M., Gullu, I.,Altundag, K., 2012. Ifosfamide and doxorubicin combination chemotherapy for recurrent nasopharyngeal carcinoma patients. Asian. Pac. J. Cancer. Prev. 13 (5), 2225–2228 [Medline]. Dugan, M., Choy, D., Ngai, A., Sham, J., Choi, P., Shiu, W., et al., 1993. Multicenter phase II trial of mitoxantrone in patients with advanced nasopharyngeal carcinoma in Southeast Asia: an Asian-Oceanian Clinical Oncology Association Group study. J. Clin. Oncol. 11 (1), 70–76 [Medline]. Elser, C., Siu, L.L., Winquist, E., Agulnik, M., Pond, G.R., Chin, S.F., et al., 2007. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J. Clin. Oncol. 25 (24), 3766–3773 [Medline]. Ferris, R.L., Blumenschein, G. Jr., Fayette, J., Guigay, J., Colevas, A.D., Licitra, L., et al., 2016. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 375 (19), 1856–1867. Foo, K.F., Tan, E.H., Leong, S.S., Wee, J.T., Tan, T., Fong, K.W., et al., 2002. Gemcitabine in metastatic nasopharyngeal carcinoma of the undifferentiated type. Ann. Oncol. 13 (1), 150–156 [Medline]. Forastiere, A.A., Metch, B., Schuller, D.E., Ensley, J.F., Hutchins, L.F., Triozzi, P., et al., 1992. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group Study. J. Clin. Oncol. 10 (8), 1245–1251 [Medline]. Fujii, M., Yamashita, T., Ishiguro, R., Tashiro, M., Kameyama, K., 2002. Significance of epidermal growth factor receptor and tumor associated tissue eosinophilia in the prognosis of patients with nasopharyngeal carcinoma. Auris. Nasus. Larynx. 29 (2), 175–181 [Medline].

Gnoni, A., Silvestris, N., Licchetta, A, Santini, D., Scartozzi, M., Ria, R., et al., (2015). Metronomic chemotherapy from rationale to clinical studies: a dream or reality? Crit. Rev. Oncol. Hematol. 95 (1), 46–61 [Medline]. Gullo, C., Low, W.K., Teoh, G., 2008. Association of Epstein-Barr virus with nasopharyngeal carcinoma and current status of development of cancer-derived cell lines. Ann. Acad. Med. Singapore 37 (9), 769–777 [Medline]. Hasbini, A., Mahjoubi, R., Fandi, A., Chouaki, N., Taamma, A., Lianes, P., et al., 1999. Phase II trial combining mitomycin with 5-fluorouracil, epirubicin, and cisplatin in recurrent and metastatic undifferentiated carcinoma of nasopharyngeal type. Ann. Oncol. 10 (4), 421–425 [Medline]. Hsu, C., Lee, S.H., Ejadi, S., Even, C., Cohen, R., LeTourneau, C., et al., 2015. Antitumor activity and safety of pembrolizumab in patients with PD-L1-positive nasopharyngeal carcinoma: Interim results from a phase 1b study. Ann Oncol 26 (Supplement 9), ix93. Huang, D.P., Ho, J.H., Chan, W.K., Lau WH, Lui M, 1999. Cytogenetics of undifferentiated nasopharyngeal carcinoma xenografts from southern Chinese. Int. J. Cancer 43 (5), 936–939 [Medline]. Huang, H.Q., Cai, Q.Q., Lin, X.B., Wang, A.L., Bu, Q., Hu, X.H., et al., 2008. Preliminary result of multicenter clinical trial on the docetaxel, 5-Fu and DDP in the treatment of advanced, recurrent or metastatic nasopharyngeal carcinoma. Zhonghua. Zhong. Liu. Za. Zhi. 30 (4): 314– 316 [Medline]. Huang, H.Q., Zhou, Z.M., Li, Y.H., Jiang, W.Q., He, Y.J., Teng, X.Y., et al., 2002. Preliminary results of ifosfamide and doxorubicin regimen in treatment of patients with recurrent and metastatic nasopharyngeal carcinoma. Ai. Zheng. 21 (4), 409–411 [Medline].

Huang, P.Y., Li, Y., Mai, H.Q., Luo, R.Z., Cai, Y.C., Zhang, L., 2012. Expression of ERCC1 predicts clinical outcome in locoregionally advanced nasopharyngeal carcinoma treated with cisplatin-based induction chemotherapy. Oral. Oncol. 48 (10), 964–968 [Medline]. Hui, E.P., Chan, A.T., Pezzella, F., Turley, H., To, K.F., Poon, T.C., et al., 2002. Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin. Cancer. Res. 8 (8), 2595–2604 [Medline]. Hui, E.P., Leung, S.F., Au, J.S., Zee, B., Tung, S., Chua, D., et al., 2004. Lung metastasis alone in nasopharyngeal carcinoma: a relatively favorable prognostic group. A study by the Hong Kong Nasopharyngeal Carcinoma Study Group. Cancer 101 (2), 300–306 [Medline]. Hui, E.P., Ma, B.B., King, A.D., Mo, F., Chan, S.L., Kam, M.K., et al., 2011. Haemorrhagic complications in a phase II study of sunitinib in patients of nasopharyngeal carcinoma who has previously received high-dose radiation. Ann. Oncol. 22 (6), 1280–1287 [Medline]. Hui, E.P., Taylor, G.S., Jia, H., Ma, B.B., Chan, S.L., Ho, R., et al., 2013. Phase 1 trial of recombinant modified vaccinia ankara (MVA) encoding Epstein-Barr viral tumor antigens in nasopharyngeal carcinoma patients. Cancer Res. 73 (6), 1676–1688 [Medline]. Hui, E.P., Ma, B.B., Mo, F., Kam, M.K., Chan, S.L., Loong, H.H., et al., 2016. Axitinib in recurrent or metastatic nasopharyngeal carcinoma (NPC): final result of a phase 2 clinical trial with pharmacokinetic (PK) correlation. Ann. Oncol. 27 (Supplement 6), vi328–vi350 [Medline]. Hui, K.F., Lam, B.H., Ho, D.N., Tsao, S.W., Chiang, A.K., 2013. Bortezomib and SAHA synergistically induce ROS-driven caspase-dependent apoptosis of nasopharyngeal carcinoma and block replication of Epstein-Barr virus. Mol. Cancer Ther. 12 (5), 747–758 [Medline].

Jagdis, A., Phan, T., Klimowicz, A.C., Laskin, J.J., Lau, H.Y., Petrillo, S.K., et al., 2013. Assessment of ERCC1 and XPF protein expression using quantitative immunohistochemistry in nasopharyngeal carcinoma patients undergoing curative intent treatment. Int. J. Radiat. Oncol. Biol. Phys. 85 (5), 1340-1345. Jia, W.H., Huang, Q.H., Liao, J., Ye, W., Shugart, Y.Y., Liu, Q., et al., 2006. Trends in incidence and mortality of nasopharyngeal carcinoma over a 20-25 year period (1978/1983-2002) in Sihui and Cangwu counties in southern China. BMC Cancer. 6, 178 [Medline]. Jiang, G.M., Wang, H.S., Du, J., Ma, W.F., Wang, H., Qiu, Y., et al., 2016. Bortezomib relieves immune tolerance in nasopharyngeal carcinoma via STAT1 suppression and indoleamine 2,3dioxygenase downregulation. Cancer Immunol. Res. Dec 6. doi: 10.1158/2326-6066. [Medline]. Krishna, S.M., James, S., Balaram, P., 2006. Expression of VEGF as prognosticator in primary nasopharyngeal cancer and its relation to EBV status. Virus. Res. 115 (1), 85–90 [Medline]. Kua, V.F., Ismail, F., Chee Ee Phua, V., Aslan, N.M., 2013. Carboplatin/5-fluorouracil as an alternative to Cisplatin/5-fluorouracil for metastatic and recurrent head and neck squamous cell carcinoma and nasopharyngeal carcinoma. Asian Pac J Cancer Prev. 14 (2), 1121–1126 [Medline]. Lee, A.W., Sze, W.M., Au, J.S., Leung, S.F., Leung, T.W., Chua, D.T., et al., 2005. Treatment results for nasopharyngeal carcinoma in the modern era: the Hong Kong experience. Int. J. Radiat. Oncol. Biol. Phys. 61 (4), 1107–1116 [Medline]. Lee, H.W., Hwang, Y.H., Han, J.H., Choi, J.H., Kang, S.Y., Jeong, S.H., et al., 2010. High expression of excision repair cross-complementation group 1 protein predicts poor outcome in patients with nasopharyngeal cancer. Oral. Oncol. 46 (3), 209–213 [Medline].

Lee, N.Y., Zhang, Q., Pfister, D.G., Kim, J., Garden, A.S., Mechalakos, J., et al., 2012. Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial. Lancet. Oncol. 13 (2), 172–180 [Medline]. Leong, J.L., Loh, K.S., Putti, T.C., Goh, B.C., Tan, L.K., 2004. Epidermal growth factor receptor in undifferentiated carcinoma of the nasopharynx. Laryngoscope. 114 (1), 153–157 [Medline]. Leong, S.S., Wee, J., Rajan, S., Toh, C.K., Lim, W.T., Hee, S.W., et al., 2008. Triplet combination of gemcitabine, paclitaxel, and carboplatin followed by maintenance 5-fluorouracil and folinic acid in patients with metastatic nasopharyngeal carcinoma. Cancer. 113 (6), 1332– 1337 [Medline]. Li, F., Song, D., Lu, Y., Zhu, H., Chen, Z., He, X., et al., 2013. Delayed-type hypersensitivity (DTH) immune response related with EBV-DNA in nasopharyngeal carcinoma treated with autologous dendritic cell vaccination after radiotherapy. J. Immunother. 36 (3), 208–214 [Medline]. Li, Y.H., Wang, F.H., Jiang, W.Q., Xiang, X.J., Deng, Y.M., Hu, G.Q., et al., 2008. Phase II study of capecitabine and cisplatin combination as first-line chemotherapy in Chinese patients with metastatic nasopharyngeal carcinoma. Cancer. Chemother. Pharmacol. 62 (3), 539–544 [Medline]. Lin, C.L., Lo, W.F., Lee, T.H., Ren, Y., Hwang, S.L., Cheng, Y.F., et al., 2002. Immunization with Epstein-Barr Virus (EBV) peptide-pulsed dendritic cells induces functional CD8+ T-cell immunity and may lead to tumor regression in patients with EBV-positive nasopharyngeal carcinoma. Cancer. Res. 62 (23), 6952–6958 [Medline].

Lim, A.M., Corry, J., Collins, M., Peters, L., Hicks, R.J., D'Costa I., et al., 2013. A phase II study of induction carboplatin and gemcitabine followed by chemoradiotherapy for the treatment of locally advanced nasopharyngeal carcinoma. Oral. Oncol. 49 (5), 468–74 [Medline]. Lim, W.T., Ng, Q.S., Ivy, P., Leong, S.S., Singh, O., Chowbay, B., et al., 2011. A Phase II study of pazopanib in Asian patients with recurrent/metastatic nasopharyngeal carcinoma. Clin. Cancer. Res. 17 (16), 5481–5489 [Medline]. Lo, M.C., Yip, T.C., Ngan, K.C., Cheng, W.W., Law, C.K., Chan, P.S., et al., 2013. Role of MIF/CXCL8/CXCR2 signaling in the growth of nasopharyngeal carcinoma tumor spheres. Cancer. Lett. 335 (1), 81–92 [Medline]. Lokich. J., Anderson. N., 1998. Carboplatin versus cisplatin in solid tumours: an analysis of the literature. Ann. Oncol. 9 (1), 13–21 [Medline]. Louis, C.U., Straathof, K., Bollard, C.M., Ennamuri, S., Gerken, C., Lopez, T.T., et al., 2010. Adoptive transfer of EBV-specific T cells results in sustained clinical responses in patients with locoregional nasopharyngeal carcinoma. J. Immunother. 33 (9), 983–990 [Medline]. Louis, C.U., Straathof, K., Bollard, C.M., Gerken, C., Huls, M.H., Gresik, M.V., et al., 2009. Enhancing the in vivo expansion of adoptively transferred EBV-specific CTL with lymphodepleting CD45 monoclonal antibodies in NPC patients. Blood. 113 (11), 2442–2450 [Medline]. Ma, B., Hui, E.P., King, A., To, K.F., Mo, F., Leung, S.F., et al., 2008. A phase II study of patients with metastatic or locoregionally recurrent nasopharyngeal carcinoma and evaluation of plasma Epstein-Barr virus DNA as a biomarker of efficacy. Cancer. Chemother. Pharmacol. 62 (1), 59–64 [Medline].

Ma, B.B., Chan, A.T., 2005. Recent perspectives in the role of chemotherapy in the management of advanced nasopharyngeal carcinoma. Cancer. 103 (1), 22–31 [Medline]. Ma, B.B., Hui, E.P., Wong, S.C., Tung, S.Y., Yuen, K.K., King, A., et al., 2009. Multicenter phase II study of gemcitabine and oxaliplatin in advanced nasopharyngeal carcinoma-correlation with excision repair cross-complementing-1 polymorphisms. Ann. Oncol. 20 (11), 1854–1859 [Medline]. Ma, B.B., Lui, V.W., Hui, C.W., Lau, C.P., Wong, C.H., Hui, E.P., et al., 2013. Preclinical evaluation of the AKT inhibitor MK-2206 in nasopharyngeal carcinoma cell lines. Invest. New. Drugs. 31 (3), 567–575 [Medline]. Ma, B.B., Goh, B.C., Lim, W.T., Hui, E.P., Tan, E.H., Lopes Gde, L., et al., 2015. Multicenter phase II study of the AKT inhibitor MK-2206 in recurrent or metastatic nasopharyngeal carcinoma from patients in the mayo phase II consortium and the cancer therapeutics research group (MC1079). Invest. New. Drugs. 33 (4), 985–991 [Medline]. Ma, B.B., Tannock, I.F., Pond, G.R., Edmonds, M.R., Siu, L.L. 2002. Chemotherapy with gemcitabine-containing regimens for locally recurrent or metastatic nasopharyngeal carcinoma. Cancer. 95 (12), 2516–2523 [Medline]. McCarthy, J.S., Tannock, I.F., Degendorfer, P., Panzarella, T., Furlan, M., Siu, L.L. 2002., A Phase II trial of docetaxel and cisplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. Oral. Oncol. 38 (7), 686–690 [Medline]. Ngan, R.K., Yiu, H.H., Lau, W.H., Yau, S., Cheung, F.Y., Chan, T.M., et al., 2002. Combination gemcitabine and cisplatin chemotherapy for metastatic or recurrent nasopharyngeal carcinoma: report of a phase II study. Ann. Oncol. 13 (8), 1252–1258 [Medline].

Ngeow, J., Lim, W.T., Leong, S.S., Ang, M.K., Toh, C.K., Gao, F., et al., 2011. Docetaxel is effective in heavily pretreated patients with disseminated nasopharyngeal carcinoma. Ann. Oncol. 22 (3), 718–722 [Medline]. Ong, Y.K., Heng, D.M., Chung, B., Leong, S.S., Wee, J., Fong, K.W., et al., 2003. Design of a prognostic index score for metastatic nasopharyngeal carcinoma. Eur J Cancer 39 (11), 1535– 1541 [Medline]. Parkin, D.M., Bray, F. Ferlay, J., Pisani, P., 2005. Global cancer statistics. CA. Cancer J. Clin. 55 (2), 74–108 [Medline]. Pedrero, J.M., Carracedo, D.G., Pinto, C.M., Zapatero, A.H., Rodrigo, J.P., Nieto, C.S., et al., 2005. Frequent genetic and biochemical alterations of the PI3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int. J. Cancer. 114 (2), 242–248 [Medline]. Poon, D., Chowbay, B., Cheung, Y.B., Leong, S.S., Tan, E.H., 2005. Phase II study of irinotecan (CPT-11) as salvage therapy for advanced nasopharyngeal carcinoma. Cancer. 103 (3), 576–581 [Medline]. Sarmiento, R., Gasparini, G., 2008. Antiangiogenic metronomic chemotherapy. Onkologie. 31 (4), 161–162 [Medline]. Secondino, S., Zecca, M., Licitra, L., Gurrado, A., Schiavetto, I., Bossi, P., et al., 2012. T-cell therapy

for

EBV-associated

nasopharyngeal

carcinoma:

preparative

lymphodepleting

chemotherapy does not improve clinical results. Ann. Oncol. 23 (2), 435–441 [Medline]. Seiwert, T.Y., Burtness, B., Mehra, R., Weiss, J., Berger, R., Eder, J.P., et al., 2016. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 17 (7), 956–965 [Medline].

Sengupta, S., den Boon, J.A., Chen, I.H., Newton, M.A., Stanhope, S.A., Cheng, Y.J., et al., 2008. MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Proc. Natl. Acad. Sci. U. S. A. 105 5874–5878 [Medline]. Sheen, T.S., Huang, Y.T., Chang, Y.L., Ko, J.Y., Wu, C.S., Yu, Y.C., et al., 1999. Epstein-Barr virus-encoded latent membrane protein 1 coexpresses with epidermal growth factor receptor in nasopharyngeal carcinoma. Jpn. J. Cancer. Res. 90 (12), 1285–1292 [Medline]. Shi, W., Alajez, N.M., Bastianutto, C., Hui, A.B., Mocanu, J.D., Ito, E., et al., 2010. Significance of Plk1 regulation by miR-100 in human nasopharyngeal cancer. Int. J. Cancer. 126 (9), 2036– 2048 [Medline]. Shiu, W.C.T., Tsao, S.Y., 1989. Efficacy of 4-epidoxorubicin in advanced nasopharyngeal carcinoma. Clin. Trials. J. 26, 149–152 [Medline]. Siu, L.L., Czaykowski, P.M., Tannock, I.F., 1998. Phase I/II study of the CAPABLE regimen for patients with poorly differentiated carcinoma of the nasopharynx. J. Clin. Oncol. 16 (7), 2514– 2521 [Medline]. Smith, C., Tsang, J., Beagley, L., Chua, D., Lee, V., Li, V., et al., 2012. Effective treatment of metastatic forms of Epstein-Barr virus-associated nasopharyngeal carcinoma with a novel adenovirus-based adoptive immunotherapy. Cancer. Res. 72 (5), 1116–1125 [Medline]. Smith, C., Lee, V., Schuessler, A., Beagley, L., Rehan, S., Tsang, J., et al, 2016. Pre-emptive and therapeutic adoptive immunotherapy for nasopharyngeal carcinoma: phenotypic and effector function of T cells impact on clinical response. Oncoimmunology (published online) [Medline]. Stein, M.E., Ruff, P., Weaving, A., Fried, J., Bezwoda, W.R., 1996. A phase II study of cisplatin/ifosfamide in recurrent/metastatic undifferentiated nasopharyngeal carcinoma among young blacks in southern Africa. Am. J. Clin. Oncol. 19 (4), 386–368 [Medline].

Straathof, K.C., Bollard, C.M., Popat, U., Huls, M.H., Lopez, T., Morriss, M.C., et al., 2005. Treatment of nasopharyngeal carcinoma with Epstein-Barr virus-specific T lymphocytes. Blood. 105 (), 1898–1904 [Medline]. Su, W.C., Chen, T.Y., Kao, R.H., Tsao, C.J., 1993. Chemotherapy with cisplatin and continuous infusion of 5-fluorouracil and bleomycin for recurrent and metastatic nasopharyngeal carcinoma in Taiwan. Oncology. 50 (4), 205–208 [Medline]. Sun, J.M., Ahn, M.J., Park, M.J., Lee, H.Y., Ahn, J.S., Lee, S., et al., 2011. Expression of excision repair cross-complementation group 1 as predictive marker for nasopharyngeal cancer treated with concurrent chemoradiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 80 (3), 655–660 [Medline]. Sun, Y., Li, W.F., Chen, N.Y., Zhang, N., Hu, G.Q., Xie, F.Y., et al.. 2016. Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol. 17 (11), 1509–1520 [Medline]. Taamma, A., Fandi, A., Azli, N., Wibault, P., Chouaki, N., Hasbini, A., et al., 1999. Phase II trial of chemotherapy with 5-fluorouracil, bleomycin, epirubicin, and cisplatin for patients with locally advanced, metastatic, or recurrent undifferentiated carcinoma of the nasopharyngeal type. Cancer. 86 (7), 1101–1108 [Medline]. Tan, E.H., Khoo, K.S., Wee, J., Fong, K.W., Lee, K.S., Lee, K.M., et al., 1999. Phase II trial of a paclitaxel and carboplatin combination in Asian patients with metastatic nasopharyngeal carcinoma. Ann. Oncol. 10 (2), 235–237 [Medline]. Tan, T., Lim, W.T., Fong, K.W., Cheah, S.L., Soong, Y.L., Ang, M.K., et al., 2015. Concurrent chemo-radiation with or without induction gemcitabine, carboplatin, and paclitaxel: a

randomized, phase 2/3 trial in locally advanced nasopharyngeal carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 91 (5), 952–960 [Medline]. Verhoeven, R.J., Tong, S., Zhang, G, Zong, J, Chen, Y, Jin, D.Y., et al., 2016. NF-κB signaling regulates expression of Epstein-Barr virus BART microRNAs and long noncoding RNAs in nasopharyngeal carcinoma. J. Virol. 90 (14), 6475–6488. Vermorken, J.B., Mesia, R., Rivera, F., Remenar, E, Kawecki, A., Rottey, S., et al., 2008. Platinum-based chemotherapy plus cetuximab in head and neck cancers. N. Engl. J. Med. 359 (11), 1116–1127 [Medline]. Wang, C.C., Chang, J.Y., Liu, T.W., Lin, C.Y., Yu, Y.C., Hong, R.L., 2006. Phase II study of gemcitabine plus vinorelbine in the treatment of cisplatin-resistant nasopharyngeal carcinoma. Head. Neck. 28 (1), 74–80 [Medline]. Wang, J., Li, J., Hong, X., Tang, W., Hu, X., Wang, B., et al., 2008. Retrospective case series of gemcitabine plus cisplatin in the treatment of recurrent and metastatic nasopharyngeal carcinoma. Oral Oncol 44 (5), 464–470 [Medline]. Wang, T.L., Tan, Y.O., 1991. Cisplatin and 5-fluorouracil continuous infusion for metastatic nasopharyngeal carcinoma. Ann. Acad. Med. Singapore. 20 (5), 601–603 [Medline]. Williams, H., Crawford, D.H., 2006. Epstein-Barr virus: the impact of scientific advances on clinical practice. Blood. 107 (3), 862–869 [Medline]. Winter, H., Meimarakis, G., Hoffmann, G., Hummel, M., Rüttinger, D., Zilbauer, A., et al., 2008. Does surgical resection of pulmonary metastases of head and neck cancer improve survival? Ann. Surg. Oncol. 15 (10), 2915–2926 [Medline].

Xia, H., Ng, S.S., Jiang, S., Cheung, W.K., Sze, J., Bian, X.W., et al., 2010. miR-200a-mediated downregulation of ZEB 2 and CTNNB1 differentially inhibits nasopharyngeal carcinoma cell growth, migration and invasion. Biochem. Biophys. Res. Commun. 391 (1), 535–541 [Medline]. Xu, X., Yang, H., Huo, X., 2004. Expression and significance of PTEN in nasopharyngeal carcinoma. Lin. Chuang. Er. Bi. Yan. Hou. Ke. Za. Zhi. 18 (11), 658–659 [Medline]. Xue, C., Huang, Y., Huang, P.Y., Yu, Q.T., Pan, J.J., Liu, L.Z., et al., 2013. Phase II study of sorafenib in combination with cisplatin and 5-fluorouracil to treat recurrent or metastatic nasopharyngeal carcinoma. Ann. Oncol. 24 (4), 1055–1061 [Medline]. Yau, T.K., Lee, A.W., Wong, D.H., Pang, E.S., Ng, W.T., Yeung, R.M., et al., 2006. Treatment of Stage IV(A-B) nasopharyngeal carcinoma by induction-concurrent chemoradiotherapy and accelerated fractionation: impact of chemotherapy schemes. Int. J. Radiat. Oncol. Biol. Phys. 66 (4), 1004–1010 [Medline]. Yau, T.K., Shum, T., Lee, A.W., Yeung, M.W., Ng, W.T., Chan, L., 2012. A phase II study of pemetrexed combined with cisplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. Oral. Oncol. 48 (5), 441–444 [Medline]. Yeo, W., Leung, T.W., Chan, A.T., Chiu, S.K., Yu, P., Mok, T.S., et al., 1998. A phase II study of combination paclitaxel and carboplatin in advanced nasopharyngeal carcinoma. Eur. J. Cancer. 34 (13), 2027–2031 [Medline]. Yeo, W., Leung, T.W., Leung, S.F., Teo, P.M., Chan, A.T., Lee, W.Y., et al., 1996. Phase II study of the combination of carboplatin and 5-fluorouracil in metastatic nasopharyngeal carcinoma. Cancer. Chemother. Pharmacol. 38 (5), 466–470 [Medline]. You, B., Le Tourneau, C., Chen, E.X., Wang, L., Jarvi, A., Bharadwaj, R.R., et al., 2012. A Phase II trial of erlotinib as maintenance treatment after gemcitabine plus platinum-based

chemotherapy in patients with recurrent and/or metastatic nasopharyngeal carcinoma. Am. J. Clin. Oncol. 35 (3), 255–260 [Medline]. Zhang, L., Deng, T., Li, X., Liu, H., Zhou, H., Ma, J., et al., 2010. microRNA-141 is involved in a nasopharyngeal carcinoma-related genes network. Carcinogenesis 31 (4), 559–566 [Medline]. Zhang, L., Zhang, Y., Huang, P.Y., Xu, F., Peng, P.J., Guan, Z.Z., 2008. Phase II clinical study of gemcitabine in the treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-based chemotherapy. Cancer. Chemother. Pharmacol. 61 (1), 33–38 [Medline]. Zhang, L., Huang, Y., Hong, S., Yang, Y., Yu, G., Jia, J., et al., 2016 Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet 388 (10054), 1883–1892. Zhang, L.Y., Lee, V.H.F., Wong, A.M., Kwong, D.L., Zhu, Y.H., Dong, S.S., et al., 2013. MicroRNA-144 promotes cell proliferation, migration and invasion in nasopharyngeal carcinoma through repression of PTEN." Carcinogenesis 34 (2), 454–463 [Medline]. Zheng, H., Dai, W., Cheung, A.K., Ko, J.M., Kan, R., Wong, B.W., et al., 2016. Whole-exome sequencing identifies multiple loss-of-function mutations of NF-κB pathway regulators in nasopharyngeal carcinoma. Proc. Natl. Acad. Sci. U. S. A. 113 (40), 11283–11288 [Medline].

Table 1 Single-agent chemotherapy in recurrent and/or metastatic nasopharyngeal carcinoma as first-line and/or subsequent line setting. Study

Setting

Phase

Number of Patients

Phase II

25 M pretreated

Regimen

OR Rate (%)

CR Rate (%)

Median PFS

Median OS

G

28

4

3.6 months

7.2 months

48

3.7

5.1 months

10.5 months

1st line or beyond Foo

1st line or beyond

27 M untreated Ma

1st line or beyond

Retrospective

18 R + M

G

34

6

31% (1-month)

48% (1-year)

2nd line or beyond Dugan

2nd line or beyond

Phase II

108 R + M

MIT

25

NR

4.5 months

13 months

Au

2nd line or beyond

Phase II

24 M

PAC

21.7

0

7.5 months

12 months

Poon

2nd line or beyond

Phase II

28 M

IRI

14

0

3.9 months

11.4 months

Chua

2nd line

Phase II

17 R + M

CAP

23.5

5.9

4.9 months

7.6 months

Chua

2nd line or beyond

Retrospective

49 R + M

CAP

37

6

5 months

14 months; 54% (1-year)

Ciuleanu

2nd line or beyond

Phase II

26 R + M

CAP

48

9

14 months

62% (1-year)

Zhang

2nd line or

Phase II

32 R + M

G

43.8

0

5.1 months

16 months; 63%

beyond

(1-year)

Ngeow

2nd line or beyond

Phase II

30 R + M

DOC (weekly)

37

0

5.3 months

12.8 months

Zhang

2nd line or beyond

Phase II

35 R + M

PEM

2.9

0

1.5 months

13.3 months

Peng

2nd line or beyond

Retrospective

39 R + M

S-1

30.7

2.6

5.6 months (median TTP)

13.9 months

Tsao

2nd line

Phase II

13 M

TAS-106

0

0

48 days

280 days

Lee

3rd line or beyond

Phase II

11 R

CYC

8.9

0

9.0 months

14.5 months

4.1 months

8.4 months

45 M

CAP = capecitabine, CR = complete response, CYC = cyclophosphamide, DOC = docetaxel, G = gemcitabine, IRI = irinotecan, M = metastatic, MIT = mitoxantrone, NR = not reported, OR = objective response, OS = overall survival, PAC = paclitaxel, PEM = pemetrexed, PFS = progression-free survival, R = recurrent, TTP = time to progression.

Table 2 Doublet combination chemotherapy regimens in recurrent and/or metastatic nasopharyngeal carcinoma as first-line or subsequent line setting. Study

Setting

Phase

Number of Patients

Regimen

OR Rate (%)

CR Rate (%)

Median PFS

Median OS

1st line or beyond Wang

UNK

Retrospective

25 M

P+F

76

8

NR

NR

Au

1st line

Phase II

24 R + M

P+F

66

13

8 months

11 months

Stein

1st line

Phase II

18 R + M

P+I

59

15

NR

NR

Yeo

1st line or beyond

Phase II

42 M

C+F

38

17

NR

12.1 months

Yeo

1st line or beyond

Phase II

27 R + M

C + PAC

59

11

6 months

13.9 months

Tan

1st line

Phase II

32 M

C + PAC

75

3

7 months

12 months

Ciuleanu

1st line

Phase II

40 M

C + PAC

27.5

7.5

3.5 months

11.5 months

Ngan

1st line or beyond

Phase II

44 R + M

P+G

73

20

10.6 months

15 months

Wang

1st line or beyond

Retrospective

75 R + M

P+G

42.7

5.3

5.6 months

9 months

Ma

1st line or beyond

Phase II

14 R + M

P+G

64

14

13% (1-year)

68% (1-year)

Ma

1st line

Phase II

40 R + M

O+G

56.1

0

9 months

19.6 months

McCarthy

1st line

Phase II

9R+M

P + DOC

22

0

8.4 months

76% (1-year)

Chua

1st line

Phase II

19 M

P + DOC

62.5

6.3

5.6 months

12.4 months

Li

1st line

Phase II

48 M

P + CAP

62.5

6.3

7.7 months

13.3 months

Huang

1st line or beyond

Phase II

34 R + M

I + DOC

67.6

14.7

6 months

NR

Yau

1st line or beyond

Phase II

15 R + M

P + PEM

20

7

30 weeks (median TTP)

NR

Chua

1st line

Phase II

44 M

P + CAP

53.8

2.6

7.3 months (median TTP)

28.0 months

Jin

1st line

Retrospective

822 R + M

P+F

60.2

2.8

5.0 months

19.5 months

PAC + P

61.7

4.2

5.5 months

21.0 months

P+G

71.1

6.9

6.6 months

21.5 months

B+P+F

69.1

4.6

5.5 months

19.0 months

PAC + P +F

74.0

5.8

6.0 months

21.0 months

Ji

1st line

Phase II

47 R + M

DOC + P

70.2

12.8

9.6 months

28.5 months

Long

1st line or beyond

Phase II

39 R + M

LOB + DOC

61.5

7.7

10 months

NR

Zheng

1st line or beyond

Phase II

33 M

P + NOL or

31.3%

0

3.4 months (median

9.5 months

P+F

35.3%

0

TTP)

10.0 months

3.8 months (median TTP) Peng

1st line

Phase II

78 R + M

NED + DOC

65.8

6.8

7.9

15.7

(median TTP) Hsieh

1st line

Phase II

52 R + M

Phase II

20 R

P+G

56.2

NR

9.8 months

14.6 months

P+F+ LV

100

15

NR

34 months

80

13

NR

14 months

2nd line or beyond Chi

2nd line or beyond

15 M Chua

2nd line

Phase II

18 R + M

I+F+ LV

56

6

6.5 months

51% (1-year)

Altundag

2nd line or beyond

Phase II

21 R + M

I + DOC

33.3

0

7 months

NR

Wang

2nd line or beyond

Phase II

39 M

G+V

36

3

5.6 months

11.9 months

Dede

2nd line or beyond

Retrospective

30 R + M

I+D

30

0

4 months (median TTP)

NR

Chen

2nd line or beyond

Phase II

61 R + M

G+V

37.7

1.6

5.2 months

5.2 months

Peng

2nd line or beyond

Phase II

48 R + M

NED + CAP

41.7

4.2

5.8 months (median TTP)

12.4 months

B = bleomycin, CAP = capecitabine, C = carboplatin, CR = complete response, DOC = docetaxel, D = doxorubicin, F = 5-fluorouracil, G = gemcitabine, I = ifosphamide, LOB = lobaplatin, LV = leucovorin, M = metastatic, NED = nedaplatin, NOL = nolatrexed, NR = not reported, OR = objective response, OS = overall survival, O = oxaliplatin, P = cisplatin, PAC = paclitaxel, PEM = pemetrexed, PFS = progression-free survival, R = recurrent, TTP = time to progression, UNK = unknown, V = vinorelbine.

Table 3 Polychemotherapy in recurrent and/or metastatic nasopharyngeal carcinoma as first-line or subsequent line setting. Study

Setting

Phase

Number of Patients

Regimen

OR Rate (%)

CR Rate (%)

Median PFS

Median OS

Boussen

1st line or beyond

Phase II

49 R + M

P+B+F

79

19

50 months

NR

Su

1st line

Phase II

25 R + M

P+B+F

40

3

NR

NR

Azli

1st line or beyond

Phase II

44 R + M

B+E+P

45

20

53 months

NR

Siu

1st line

Phase I/II

17 R

CAPABLE

41

23.5

NR

16 months

80

6.8

NR

14 months

44 M Taamma

1st line

Phase II

23 R + M

F+B+E+P

78

39

42 months

NR

Hasbini

1st line

Phase II

44 R + M

F + MIC + E + P

52

13

9 months

14 months

Leong

1st line

Phase II

28 M

C + G + PAC + F + LV

86

11

8 months

22 months

Huang

1st line or beyond

Phase II

56 R + M

DOC + P + F

72.5

9.8

NR

NR

Xue

1st line

Phase II

54 R + M

SOR + P + F

77.8

1.9

7.2 months

11.8 months

Jin

1st line

Phase II

30 M

ENDO + P + G

85.7

50

19.4 months

90.2% (1year)

Hsieh

1st line

Phase II

22 R + M

P + TEG/URA

59.1

13.6

10 months (median

16 monhts

+ LV + MIC

TTP)

2nd line or beyond Chen

2nd line or beyond

Phase II

95 R+ M

PAC + P + F

78.9

0

9.1 months

27.2 months

B = bleomycin, CAPABLE = cyclophospamide + bleomycin + doxorubicin + cisplatin, C = carboplatin, CR = complete response, DOC = docetaxel, E = epirubicin, ENDO = endostar, F = 5-fluorouracil, G = gemcitabine, I = ifosphamide, LV = leucovorin, M = metastatic, MIC = mitomycin C, NR = not reported, OR = objective response, OS = overall survival, P = cisplatin, PAC = paclitaxel, PFS = progression-free survival, R = recurrent, SOR = sorafenib, TEG/URA = tegafur-uracil.

Table 4 Results for targeted therapy for recurrent and/or metastatic nasopharyngeal carcinoma as 2nd line treatment or beyond. Study

Setting

Phase

Chua

3rd line or beyond

Phase II

Ma

2nd line or beyond

You

Number of Patients

Regimen

OR Rate (%)

CR Rate (%)

Median PFS or TTP (months)

Median OS (months)

19

Gefiinib

0

0

4

16

Phase II

16

Gefitinib

0

0

2.7

12

2nd line

Phase II

20

Erlotinib after 6 cycles of GP

0

0

6.9

Not reached

Chan

2nd line

Phase II

60

Cetuximab + carboplatin

11.7

0

81 days

233 days

Elser

2nd line

Phase II

27

Sorafenib

3.7

0

3.2

7.7

Xue

1st line

Phase II

54

Sorafenib + cisplatin + 5FU

77.8

7.2

11.8

Hui

2nd line or beyond

Phase II

13

Sunitinib

10.0

0

3.5

10.5

Lim

2nd line or beyond

Phase II

33

Pazopanib

6.1

0

4.4

10.8

Hui

2nd line or beyond

Phase II

40

Axitinib

18.9% (confirmed + unconfirmed)

0

5.0

10.4

Table 5 Trials on the use of immune checkpoint inhibitors for recurrent/metastatic nasopharyngeal carcinoma. Trial

Phase

Setting

Randomization

N

Agent

Chemotherapy

Objective response (%)

Disease control (%)

Median PFS

NCT020548 06

Ib

R/M

No

44

Pembrolizumab

No

22.

77.8

5.6 months

NCT023395 58

II

R/M

No

40

Nivolumab

No

Ongoing

Ongoing

Ongoing

NCT026119 60

II

R/M

Yes

124

Pembrolizumab

Gemcitabine, capecitabine or docetaxel in control arm

Ongoing

Ongoing

Ongoing

NCT026059 67

II

R/M

Yes

114

PDR001

Gemcitabine, capecitabine or docetaxel in control arm

Ongoing

Ongoing

Ongoing

NCT028756 13

II

R/M

No

39

Avelumab

No

Ongoing

Ongoing

Ongoing

M = metastatic, N = number of patients, R = recurrent, PFS = progression-free survival.