**7. Chemotherapy in metastatic NPC**

Being a chemosensitive tumor, chemotherapy is the mainstay of treatment for metastatic NPC. Single-agent chemotherapy was used previously. Standard chemotherapy agents used now are platinum doublets with gemcitabine, 5FU, or paclitaxel [40, 41]. Higher response rates are associated with combination regimens than monotherapy. Cisplatin-5FU continuous infusion regimen resulted in a response rate of 55–65% [42]. Paclitaxel when added to carboplatin resulted in response rates as high as 75% [43]. A Randomized phase 3 trial from China compared Cisplatin gemcitabine (GP) with cisplatin 5FU(FP) in recurrent and metastatic NPC [44]. Gemcitabine plus cisplatin prolonged progression-free survival in patients with recurrent or metastatic NPC. The updated results showed an improvement in OS with Cisplatin -gemcitabine regimen (HR 0.723 (95% CI, 0.578 to 0.904; P = .004). The median OS was 22.1 months with GP versus 18.6 months with FP [45]. Triplet regimens tried in metastatic settings resulted in higher response rates and increased median OS, but with increased toxicities [46]. There is no head-on comparison with the standard doublets and triplet regimens are not recommended for first-line therapy.

These patients eventually progress on platinum-based chemotherapy due to the development of platinum resistance. The selection of second line treatment depends on the chemotherapy agent used in first line. The common second-line agents are 5-FU (including capecitabine), taxanes (paclitaxel, docetaxel), irinotecan, vinorelbine, and gemcitabine [47–50] The response rates are inferior compared to the first-line agents.

## **8. Future directions**

The role of adjuvant chemotherapy according to risk-adapted approach is evolving. Two trials of adjuvant chemotherapy according to post-treatment plasma EBV DNA measurements (NRG-HN001- NCT02135042 and NCT02363400) are underway [51, 52]. The benefit of concurrent chemotherapy in stage II NPC is not clear. NCT02610010, NCT02116231, and NCT02633202 are ongoing randomized phase2/3 trials evaluating the same [53–55]. There is no proven role for targeted therapy or immunotherapy in locally advanced or metastatic NPC [56, 57]. A phase 3 trial (NCT02633176) comparing cisplatin, docetaxel plus cetuximab with cisplatin and docetaxel induction chemotherapy followed by concurrent chemoradiation in previously untreated metastatic NPC is underway [58]. PD-1 antibody Camrelizumab

is being compared with best supportive care after Chemoradiotherapy in Locoregionally Advanced NPC in a phase 3 trial [59]. Camrelizumab in combination with chemotherapy is tested against chemotherapy alone in recurrent and metastatic NPC in another randomized phase 3 trial [60].
