A Phase III Trial in NPC With Post-radiation Detectable Plasma EBV DNA

Phase III Randomized Trial of Immediate Adjuvant Chemotherapy or Delayed Salvage Chemotherapy in Nasopharyngeal Carcinoma Patients With Post-radiation Detectable Plasma EBV DNA

Nasopharyngeal carcinoma (NPC) is a geographically endemic, Epstein-Barr virus (EBV)-associated carcinoma of epidermoid origin. It occurs most commonly in Southern China and Southeast Asia. The NPC cells are poorly differentiated or undifferentiated with a high incidence of lymphatic and hematological dissemination. Because of the inherent anatomic constraints and a high degree of radiosensitivity, radiotherapy (RT) has been the primary treatment for NPC patients.

NPC is also a chemosensitive tumor. Various modes of combined chemoradiotherapy have been used to treat NPC patients with advanced-stage diseases during recent 20 years. However, treatment outcome for locoregionally advanced NPC is still unsatisfactory.

Study Overview

• Status: Terminated
• Conditions: Nasopharyngeal Carcinoma
• Intervention / Treatment: Drug: MEP

Detailed Description

The current NCCN guidelines recommend that CCRT + adjuvant chemotherapy for advanced (stage III-IV) NPC, originated from the results of the Intergroup study [69]. However, all meta-analysis reported no any benefit in using adjuvant chemotherapy for NPC patients [82-85]. These contradictions puzzle most oncologists for decades. In our opinion, routine delivery of post-radiation adjuvant chemotherapy after RT±induction/concurrent chemotherapy for "all" advanced-stage NPC patients should be re-considered. The major goal of adjuvant chemotherapy in NPC is to reduce the occurrences of distant failure. But, not all advanced NPC patients need adjuvant chemotherapy. In our previous phase III study, only 19.1% (27/141) NPC patients with 1988 AJCC stage III-IV disease developed distant failure after CCRT . In another study of 210 NPC patients with 1997 AJCC stage IIB-IVB treated by induction chemotherapy + RT, 55 patients (26.2%) suffered from subsequent distant metastasis [67]. We should remember that unnecessary adjuvant therapy is frequently used. For example, if the target patients have as high as 50% subsequent distant failure rate, and the adjuvant therapy protocol has a 50% control rate for the subclinical disease. When we treat all target patients, only 25% patients benefit from the adjuvant therapy because of unnecessary treatment in 50% and ineffective treatment in another 25% patients. Thus, adjuvant therapy should be designed for "selected" patients. For NPC patients, pEBV DNA-guided adjuvant therapy trial is very reasonable. We plan to prove that adjuvant chemotherapy is beneficial for post-radiation detectable pEBV DNA patients in this prospective multi-center trial. We will conduct another trial to investigate (compare) which adjuvant chemotherapy regimen is the best one in the future.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 3

Contacts and Locations

Study Locations

• Taiwan
  • Kaohsiung, Taiwan
    • Kaohsiung Veterans General Hospital.
  • Taichung, Taiwan, 40447
    • China Medical University Hospital
  • Taichung, Taiwan, 407
    • Taichung Veterans General Hospital
  • Tainan, Taiwan
    • National Cheng-Kung University Hospital
  • Taipei, Taiwan, 104
    • Mackay Memorial Hospital
  • Taipei, Taiwan
    • Sun Yat-sen University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1.Histological proven NPC.

2.2010 AJCC stage II-IVB.

3.Age ≧ 20 years old.

4.Performance status of ECOG ≦ 2.

5.Finished RT ≧ 66 Gy (± induction and/or concurrent chemotherapy).

6.pEBV DNA > 0 copy/ml at 1±1 week post-RT.

7.Re-staging work-ups at 10±2 weeks post-RT showing no active lesions.

8.Adequate liver, renal, and bone marrow function 4 weeks before randomization.

9.Signed informed consent.

Exclusion Criteria:

1. Pathologically-proven the presence of locoregional disease and/or distant metastasis.
2. Unequivocally-shown active NPC (locoregional/distant) by imaging studies.
3. Inadequate RT.
4. Received any post-RT adjuvant chemotherapy.
5. pEBV DNA = 0 copy/ml at 1±1 week post-RT.
6. Previous delivery of cisplatin dose > 600 mg/m2.
7. Previous delivery of epirubicin > 360 mg/m2.
8. History of a malignancy except those treated with curative intent for skin cancer (other than melanoma), in situ cervical cancer, ductal carcinoma in situ (DCIS) of breast.
9. Severe cardiopulmonary diseases (unstable angina and/or congestive heart failure or peripheral vascular disease requiring hospitalization within the last 12 months; chronic obstructive pulmonary disease exacerbation other respiratory illness requiring hospitalization) or clinically significant psychiatric disorders.
10. Female patients who are pregnant or lactating.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adjuvant Chemotherapy; MEP followed by oral Tegafur-uracil	Drug: MEP; Adjuvant Chemotherapy; Other Names: cisplatin; epirubicin; oral Tegafur-uracil; mitomycin-C
No Intervention: control arm; closely followed with frequency similar to the experiemental arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to progression	5 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	5 years
Progression-free survival and relapse rate	5 years
Toxicity profile and tolerance, according to CTCAE 4.1	5 years
Predicting value of plasma EBV DNA	5 years

Collaborators and Investigators

• Sponsor: National Health Research Institutes, Taiwan
• Collaborators: Mackay Memorial Hospital; China Medical University Hospital; National Cheng-Kung University Hospital; Taichung Veterans General Hospital; Kaohsiung Veterans General Hospital.; Koo Foundation Sun Yat-Sen Cancer Center
• Investigators: Study Chair: Jin-Ching Lin, MD, PHD, Taichung Veterans General Hospital; Study Director: Tsang-Wu Liu, MD, National Health Research Institutes, Taiwan; Principal Investigator: Jin-Ching Lin, MD, PhD, Taichung Veterans General Hospital; Principal Investigator: Yi-Fang Chang, MD, PhD, Mackay Memorial Hospital; Principal Investigator: Ching-Yun Hsieh, MD, China Medical University Hospital; Principal Investigator: Chia-Jui Yen Yen, MD. PhD, National Cheng-Kung University Hospital; Principal Investigator: Yaoh-Shiang Lin, MD, Kaohsiung Veterans General Hospital.; Principal Investigator: Stella Yu-Chen Tsai, MD, Sun Yat-sen University; Principal Investigator: Hsiao-Hui Tsou, PhD, National Health Research Institutes, Taiwan

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2014
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: December 4, 2014
• First Submitted That Met QC Criteria: February 9, 2015
• First Posted (Estimated): February 16, 2015

Study Record Updates

• Last Update Posted (Actual): August 19, 2025
• Last Update Submitted That Met QC Criteria: August 14, 2025
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Nasopharyngeal carcinoma (NPC); Adjuvant Chemotherapy; radiotherapy (RT); Epstein-Barr virus (EBV); Plasma EBV DNA(pEBV DNA); PET-CT scan at Pre-Tx restaging
• Additional Relevant MeSH Terms: Stomatognathic Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Otorhinolaryngologic Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Nasopharyngeal Diseases; Pharyngeal Diseases; Nasopharyngeal Neoplasms; Nasopharyngeal Carcinoma; Carcinoma; Antibiotics, Antineoplastic; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Nucleic Acid Synthesis Inhibitors; Topoisomerase Inhibitors; Alkylating Agents; Topoisomerase II Inhibitors; Cisplatin; Mitomycins; Mitomycin; Tegafur; Epirubicin
• Other Study ID Numbers: T1313

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No