**5.4 Palliative chemotherapy for metastasis and relapses NPC**

Palliative chemotherapy is very important and plays role in control of disease and keep patients in good conditions as well as in extending survival of patients with NPC metastases as NPC is very sensitive to chemotherapy cancer. Standard treatment includes chemotherapy with platinum in combination with other drugs such as 5-FU with cisplatin/carboplatin and paclitaxel with gemcitabine. Patients treated for long time with platinum chemotherapy, can achieve a significant response with rates of up to 80% and an average survival rate of 12 to 18 months [77]. There is a significant correlation between higher response rates with a combination therapy regimen than monotherapy, and platinum is a good treatment, but it is not the main criterion or standard treatment. Regardless of the treatment regimen chosen for the first line, the average progression time after 7 to 10 months remains relatively constant [78, 79]; This is related to the development of platinum resistance. The response rates for a triple therapy with paclitaxel/carboplatin/ gemcitabine are impressive and close to 80%. However, the average response time is about 8 months, similar to two drug regimens [80].

#### **5.5 Novel therapies: molecular-targeted agents**

The past 10 years have seen the development of new treatments for NPC and this has been somewhat simultaneous with the development of treatment for other cancers. Little progress has been made in recent years beyond the usual cytotoxic approaches. EGFR-mediated signaling pathways inhibited by the molecular factors that lead to inhibition of cell growth and cell apoptosis which include tyrosine kinase inhibitors, for example gefitinib and monoclonal antibodies [81].

In a number of centers, Ueda and colleagues [82] investigating a combination treatment of carboplatin, paclitaxel and cetuximab in patients with metastatic or recurrent or with repeated platinum-resistant NPC showed good survival benefit, an overall response rate reach to 64 % and a median OS of 29.1 months with follow up for 30 months. The treatment with gefitinib had little response rates in

metastatic and recurrent NPC treated previously with platinum-based chemotherapy. The symptomatic improvement and disease stabilization were observed in some cases [83].

Multikinase inhibitors target tyrosine kinases such as fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) and drugs such as pazopanib (VEGFR, PDGFR, FGFR, c-KIT), sorafenib (VEGFR, PDGFR, Raf kinases), and sunitinib (PDGFR, VEGFR, C-KIT), have been evaluated in NPC [84, 85].
