**4.4 Management of metastatic disease**

Patients with metastatic NPC have various clinical characteristics and outcomes. Around 10% of newly diagnosed NPC patients present with synchronous distance metastases. Unfortunately, up to 15%-30% of the non-metastatic NPC patients will experience distant failure after primarily curative treatment [2, 48]. Compelling evidence suggests these patients may achieve a median overall survival of 10-15 months by receiving palliative chemotherapy. The overall survival can be improved among those who are indicated for locoregional RT and local treatment of metastatic lesions [63, 75–81]. Thus, a personalized treatment strategy is necessary for metastatic NPC. Researchers and clinicians have made a hard effort to build up predictive models for prognosis to stratify risk groups and provide treatment strategies accurately [82–87].

Recommending by NCCN guideline, the first-line regimens of systemic therapy for NPC patients with recurrent, or unresectable, or metastatic disease are cisplatin plus gemcitabine. Other recommended regimens include the combination of cisplatin/5-fluorouracil, cisplatin or carboplatin/docetaxel or paclitaxel, carboplatin/cetuximab, gemcitabine/carboplatin, as well as the single-use of them. A recent view suggests that neither VEGFR nor EGFR targeting therapies are recommended as high priority for recurrent and/or metastatic NPC, with unimpressive response rates around 10% or less [67, 88–93]. Reported toxicities of anti-VEGF therapy and anti-EGFR therapy can be severe and life-threatening, which should not be neglected.

Remarkably, several single-arm trials evaluating immunotherapy targeted the programmed death 1/programmed death-ligand 1 (PD1/PD-L1) pathway in recurrent/metastatic NPC patients have shown promising outcomes [94–96]. In principle, NPC tumors are featured by high PD-L1 expression and abundant infiltration of non-malignant lymphocytes, suggesting the feasibility of immune checkpoint blockade therapies in NPC patients [97–100]. Some ongoing phase 3 trials investigating anti-PD-1 therapies among treatment naïve locoregionally advanced disease, recurrent, or metastatic disease, will improve clinical practice [2]. Likewise, a phase 1 trial of a recombinant vaccinia virus (MVA-EL), which encodes an EBNA1/LMP2 fusion protein designed to boost T-cell immunity to these antigens, has shown clinical efficacy in heavily pretreated NPCs [101]. Evidence from phage 2/3 RCTs on immunotherapies targeting EBV and/or PD1/PD-L1 is awaited to manage locoregional, recurrent, and metastatic NPC in the near future.
