Nasopharyngeal carcinoma (NPC) is an endemic malignancy in Southern China, Hong Kong, Taiwan, Singapore and Malaysia. It is highly associated with Epstein-Barr virus (EBV). Radiation therapy alone is indicated for early stage I to II diseases while concurrent chemoradiation is required for more advanced stage III to IVB diseases. Intensity-modulated radiation therapy (IMRT) is the standard radiation technique for NPC, in virtue of its superior target coverage and dose sparing to adjacent critical organs-at-risks.

Plasma EBV DNA and other novel plasma biomarkers have been extensively investigated in NPC. Previous studies have proven their predictive and prognostic values in NPC diagnosis, surveillance and survival outcomes.

We would like to investigate the roles of plasma biomarkers including plasma EBV DNA on treatment response evaluation, survival and prognosis on NPC, in the modern era of precision radiation therapy. This will provide important information on refining on the current edition of AJCC/UICC staging classification.

Patients with histologically confirmed previously untreated NPC are be recruited to join tis study. The study has obtained approval from local institutional review board.

After written informed consent, baseline investigations including blood tests for routine hematology, biochemistry and plasma EBV DNA will be taken. Only 3ml of EDTA blood will be taken for plasma EBV DNA and other potential biomarkers. They will also undergo baseline imaging investigations including positron-emission tomography with integrated computed tomography (PET-CT) and magnetic resonance imaging (MRI) of the head and neck regions. An routine nasoendoscopy and nasopharyngeal biopsies will be obtained to confirm and delineate the mucosal extent of the disease.

If confirmed non-metastatic, patients will be treated with IMRT using 7-9 radiation beams. A total dose of 70Gy in 33-35 fractions over 6.5 to 7 weeks will be given. For advanced stage III to IVB diseases, concurrent chemoradiation using cisplatin 100mg/m2 on Day 1, 22 and 43 of IMRT followed by 3 cycles of adjuvant chemotherapy with cisplatin 80mg/m2 on Day 1 and 5-FU 1000mg/m2 from Day 1 to Day 4 every 4 weeks for 3 more cycles starting 4 weeks after completion of IMRT will also be given. Some patients will also receive induction chemotherapy with either (1) cisplatin 100mg/m2 on Day 1 and 5-FU 1000mg/m2 on Day 1 to 5, or cisplatin 100mg/m2 on Day 1 and gemcitabine 1000mg/m2 on Day 1 and Day 8, administered every 3 weeks for 3 cycles before commencement of chemoradiation, at the discretion of treating oncologists if their primary tumours are close to critical organs e.g. brainstem, optic chiasm or optic nerves.

After treatment patients will undergo nasopharyngeal biopsies, patients will undergo nasopharyngeal biopsies again at 8 weeks after completion of IMRT to confirm histological complete local remission. Blood will be taken again on the same day for plasma EBV DNA and other potential biomarkers. Additional biopsies and salvage local treatment e.g. brachytherapy, stereotactic or IMRT boost will be offered to patients who have persistent local disease at 12 weeks after completion of IMRT. If complete local remission is confirmed, patient will have regular follow up every 3 to 4 months for surveillance and survival outcomes. Regular imaging with MRI and CT scans every 3 to 4 months will also be arranged as well. Plasma EBV DNA will be measured again at 6 months and 1 year after completion of IMRT and then as clinically indicated afterwards.

For those with metastatic diseases at diagnosis, systemic chemotherapy (platinum-based chemotherapy with cisplatin and gemcitabine) will be offered. Blood taking for plasma EBV DNA and other potential biomarkers at baseline before chemotherapy commencement and then after every 3 cycles will be arranged. Plasma EBV DNA measurement and imaging examinations with CT and MRI scans will be arranged at baseline and then after 3-4 cycles of chemotherapy for tumour response evaluation. If the disease does not show progression according to RECIST 1.1, patients will receive up to 6 cycles of chemotherapy followed by consolidation IMRT to the nasopharynx and the neck with 60-70Gy in 33-35 fractions over 6-7 weeks. Additional stereotactic body radiation therapy (SBRT) will be offered to patients who have oligo-progression/oligo-metastasis (up to 3 lesions). Patients will have regular follow up every 3-4 months afterwards. Further salvage palliative chemotherapy or radiation therapy or best supportive care depending on the patients' wish and performance status will be offered to those who develop further relapse after first-line chemotherapy and/or consolidation IMRT.

The trend of baseline and serial plasma EBV DNA and other potential biomarkers will be monitored prospectively.

Inclusion Criteria:

• Patients with histologically confirmed previously untreated nasopharyngeal carcinoma

Exclusion Criteria:

• Patients who are pregnant or lactating
• Patients who are not mentally capable of giving written informed consent
• Patients with performance status ECOG=3 or above or patients who are expected not able to tolerate radiation therapy and/or chemotherapy
• Patients who refuse active treatment for their nasopharyngeal carcinoma
• Patients who cannot comply with radiation therapy and/or chemotherapy for their nasopharyngeal carcinoma

Patients with histologically confirmed previously untreated nasopharyngeal carcinoma (NPC) will be invited to join this study.