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Pharyngeal Diseases

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Otorhinolaryngologic Diseases

Jin-Ching Lin, MD.PhD.

No previous study reported the treatment outcome of stage III nasopharyngeal carcinoma (NPC) patients. The investigators try to investigate the long-term treatment outcome of stage III NPC patients and do risk grouping by plasma Epstein-Barr virus (EBV) DNA assay for future therapy improvement.

The stage III NPC patients were the majority group of the patient population of NPC. But most clinical trials focused on the treatment of American Joint Committee on Cancer (AJCC) 7th edition stage IVA/IVB treatment for high risk of recurrence or metastasis. No previous study reported the treatment outcome of stage III NPC patients. The investigators tried to investigate the long-term treatment outcome of stage III NPC patients and do risk grouping by plasma EBV DNA assay for future therapy improvement.

We collected the pre-treatment and post-treatment plasma EBV DNA. The plasma EBV DNA assay was analyzed by real time PCR.

Long-term Treatment Outcome for Stage III NPC Patients and Risk Grouping by Plasma EBV DNA

Long-term Treatment Outcome for Stage III Nasopharyngeal Carcinoma Patients and Risk Grouping by Plasma Epstein-Barr Virus DNA

Diagnosis to death to recurrence or metastasis

Diagnosis to death to locoregional failure

Taichung Veterans General Hospital

Symptoms and General Pathology

Communicable Diseases

Herpesviridae Infections

DNA Virus Infections

Tumor Virus Infections

Plasma EBV DNA quantification by quantitative polymerase chain reaction (qPCR) assays in different medical centers.

Peripheral blood will be collected from each subject into an EDTA tube for the isolation of plasma.

Plasma EBV DNA qPCR test

Ming-Yuan Chen, MD, PhD

Si-Yuan Chen, MD

Plasma Epstein-Barr virus (EBV) DNA will be measured in native plasma samples of nasopharyngeal carcinoma (NPC) patients, respectively, by three medical centers and a qualified laboratory in Southern China, the highest endemic area of NPC. Passing-Bablok regression and difference plots will be used to compare results from each center to the all-method median and mean values. Agreement among methods will be evaluated against bias derived from a biological variation.

The investigators intend to collect EBV DNA positive plasma samples of NPC patients, distribute the samples to four test centers and compare the measurement results to obtain the current status of the agreement of plasma EBV DNA measuring at different centers with various measurement systems in the endemic regions of NPC. A series of statistical analyses including Cohen's Kappa, intraclass correlation coefficient, and Passing-Bablok regression will be adopted for the consistency test. A harmonization study by using the same calibrators will be conducted.

Peripheral blood will be collected into ethylenediaminetetraacetic acid (EDTA)-coated tubes and centrifuged, the plasma will be recovered and frozen at -80℃ until the test.

Verification of Harmonization of Plasma Epstein-Barr Virus DNA Measurements

Verification of Harmonization of Plasma Epstein-Barr Virus DNA Measurements at Multiple Centers in NPC Epidemic Regions

Wuzhou Red Cross Hospital

Zhongshan People's Hospital, Guangdong, China

Sun Yat-sen University

professor & chief physician

Victor Lee, FRCR

Ka-On Lam, FRCR

Dora Kwong, MD

Chi-Chung Tong, FRCR

Chun-Kin Sze, FRCR

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.

Serial Plasma EBV DNA for Nasopharyngeal Carcinoma

Serial Plasma EBV DNA for Patients With Nasopharyngeal Carcinoma

Overall survival is calculated from the date of diagnosis of NPC to the date of death from any cause

Cancer-specific survival is calculated from the date of diagnosis of NPC to the date of death due to cancer

Progression-free survival is calculated from the date of diagnosis of NPC to the date of progression of NPC or the date of death from any cause, whichever comes earlier.

Distant metastasis-free survival is calculated from the date of diagnosis of NPC to the date of distant metastasis or date of death from any cause, whichever comes earlier.

Regional failure-free survival is calculated from the date of diagnosis of NPC to the date of regional nodal failure or date of death from any cause, whichever comes earlier.

Local failure-free survival is calculated from the date of diagnosis of NPC to the date of local failure or date of death from any cause.

The University of Hong Kong

Clinical Assistant |Professor

Patients enrolled in this observational cohort would have regular blood taking for EBV DNA examination at baseline, after every cycle of chemotherapy, every week during radiotherapy, and 1-3 months after chemo-radiotherapy until EBV DNA becomes undetectable for at least two times.

Parameters analyzed will include (1) the changing pattern of plasma EBV DNA concentrations during chemotherapy and radiotherapy (2) half-life values (t1/2) of plasma EBV DNA clearance rate

Plasma EBV DNA

Endemic nasopharyngeal carcinoma (NPC) is invariably associated with Epstein-barr virus (EBV) infection. Plasma EBV DAN detected by polymerase chain reaction (PCR)-based assays can provide important informations of disease screening, disease relapse, and risks classification. In this study, the investigators will explore the impact of serial plasma EBV DNA during chemotherapy and radiotherapy on initial tumor response and long-term survival in patients with non-metastatic nasopharyngeal carcinoma

Serial Epstein-Barr Virus DNA Surveillance in Nasopharyngeal Carcinoma Patients

Serial Epstein-Barr Virus DNA Surveillance During Treatment in Non-metastatic Nasopharyngeal Carcinoma Patients

not to share individual participant data (IPD) available to other researchers unless reasonably required, and only the PI has the whole access to the complete data

Local or regional failure-free survival is calculated from the date of diagnosis of NPC to the date of regional nodal failure or date of death from any cause, whichever comes earlier.

The half-life value (t1/2) of plasma EBV DNA clearance was calculated using the equation of \[t1/2 = 0.693/k\].

Vice-president

Kwan-chee Allen Chan, MD, PhD

The purpose of this study is to determine if the screening of nasopharyngeal carcinoma using plasma Epstein-Barr virus DNA analysis would result in the detecting NPC cases at earlier stages and improve survival.

Epstein-Barr virus (EBV) infection is an important etiological factor for nasopharyngeal carcinoma (NPC). In a pilot study, we have shown that the analysis of Epstein-Barr virus (EBV) DNA in blood can detect early and asymptomatic NPC. However, it is unlcear if NPC screening can improve the prognosis of the screened NPC subjects.

20,000 male subjects aged from 40 to 62 will be recruited because the incidence of NPC is higher in this target group. Twenty millilitres of venous blood will be collected from each subject at enrolment for plasma EBV DNA analysis.

Subjects who have initial positive results for plasma EBV DNA will have another testing at approximately 4 weeks. Subjects who have persistently positive results for the two plasma EBV DNA analyses will be investigated using nasal endoscopic examination and MRI of the nasopharynx.

After the initial screening, all participants will be phone interviewed yearly to update their cancer status.

A second round of screening will be carried out at 3 to 5 years after the initial round of screening. Subjects will be screened with plasma EBV DNA as in the first round of screening. Subjects with initial positive results will be retested and those with persistently positive results will be investigated using nasal endoscopic examination and MRI of the nasopharynx.

Plasma samples are retended for future study to evaluate the accuracy of sequencing-based biomarkers

Prospective Nasopharyngeal Carcinoma Screening Using Plasma Epstein-Barr Virus DNA Analysis

Prospective 20,000-person Nasopharyngeal Carcinoma (NPC) Screening Programme Using Plasma Epstein-Barr Virus (EBV) DNA Analysis

All the participants will be subjected to the screening of nasopharyngeal carcinoma (NPC) at the time of recruitment using plasma EBV DNA analysis. Subjects with positive results will be investigated using endoscopic examination and MRI. If the subject is confirmed of having NPC, the stage of the disease would be recorded.

Participants who are screened negative will be followed up yearly for 5 years after the screening. The incidence of NPC will be recorded.

The relative risk of developing nasopharyngeal carcinoma for subjects with negative, transiently positive and persistently positive plasma Epstein-Barr virus DNA at enrolment will be determined.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Long-term Treatment Outcome for Stage III NPC Patients and Risk Grouping by Plasma EBV DNA	NCT03314051	Nasopharyngeal ... EBV Related Car...		20 Years - 80 Years	Taichung Veterans General Hospital
Verification of Harmonization of Plasma Epstein-Barr Virus DNA Measurements	NCT05037357	Nasopharyngeal ...	Plasma EBV DNA ...	18 Years - 70 Years	Sun Yat-sen University
Serial Plasma EBV DNA for Nasopharyngeal Carcinoma	NCT02476669	Nasopharyngeal ...		-	The University of Hong Kong
Serial Plasma EBV DNA for Nasopharyngeal Carcinoma	NCT02476669	Nasopharyngeal ...		-	The University of Hong Kong
Serial Epstein-Barr Virus DNA Surveillance in Nasopharyngeal Carcinoma Patients	NCT03855020	Nasopharyngeal ...	Plasma EBV DNA	18 Years -	Sun Yat-sen University
Prospective Nasopharyngeal Carcinoma Screening Using Plasma Epstein-Barr Virus DNA Analysis	NCT02063399	Nasopharyngeal ...		40 Years - 62 Years	Chinese University of Hong Kong
Serial Plasma EBV DNA for Nasopharyngeal Carcinoma	NCT02476669	Nasopharyngeal ...		-	The University of Hong Kong
Prospective Nasopharyngeal Carcinoma Screening Using Plasma Epstein-Barr Virus DNA Analysis	NCT02063399	Nasopharyngeal ...		40 Years - 62 Years	Chinese University of Hong Kong
Verification of Harmonization of Plasma Epstein-Barr Virus DNA Measurements	NCT05037357	Nasopharyngeal ...	Plasma EBV DNA ...	18 Years - 70 Years	Sun Yat-sen University

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