Impact of an Epstein-Barr Virus Serology-Based Screening Program on Nasopharyngeal Carcinoma Mortality: A Cluster-Randomized Controlled Trial

Academic Background

Nasopharyngeal carcinoma (NPC) is a malignant tumor that is highly prevalent in Asia, particularly in southern China. Approximately 85% of NPC cases occur in Asia, with the incidence being especially high in southern China. The early symptoms of NPC are often nonspecific, leading to most patients being diagnosed at an advanced stage, with a five-year survival rate of around 50%. However, if detected and treated at an early stage, the five-year survival rate can be as high as 95%. Therefore, early screening is crucial for improving the survival rate of NPC patients.

The Epstein-Barr virus (EBV) is one of the primary causative factors of NPC, particularly in undifferentiated NPC, where EBV infection is present in almost all cases. Therefore, EBV-based serological marker screening is considered a potential method for early detection of NPC. Although previous studies have shown that EBV antibody screening can improve the early detection rate of NPC, whether it can reduce NPC mortality still lacks evidence from randomized controlled trials. This study aims to evaluate the impact of an EBV serology-based screening program on NPC mortality through a cluster-randomized controlled trial.

Source of the Paper

This paper was co-authored by Wen-Jie Chen, Xia Yu, Yu-Qiang Lu, and others, from institutions such as the Sun Yat-sen University Cancer Center, Zhongshan People’s Hospital, and Sihui Cancer Institute. The paper was published on October 1, 2024, in the Journal of Clinical Oncology (JCO), with the DOI: https://doi.org/10.1200/jco.23.01296.

Study Design and Methods

Study Design

This study adopted a cluster-randomized controlled trial design, selecting 16 towns in Sihui City and Zhongshan City, Guangdong Province, China, as the study units. Eight towns were randomly assigned to the screening group, while the other eight served as the control group. The study participants were aged 30 to 69 years and had no history of NPC. Residents in the screening group were invited to undergo EBV viral capsid antigen (VCA) and nuclear antigen 1 (EBNA1) immunoglobulin A (IgA) antibody testing, while the control group received no intervention. The study began on January 1, 2008, and continued until December 31, 2015, with follow-up until December 31, 2019.

Study Procedure

1. Randomization and Grouping: Random numbers were generated using SAS software to assign the 16 towns to the screening and control groups.
2. Serological Testing: Residents in the screening group had blood samples collected at town hospitals, which were then sent to city hospitals for VCA-IgA and EBNA1-IgA antibody testing. Participants were classified into high-risk, medium-risk, and low-risk groups based on a predefined risk prediction algorithm.
3. Further Examination for High-Risk Individuals: High-risk participants were referred for nasopharyngeal endoscopy and/or biopsy, while medium-risk and undiagnosed high-risk participants were retested annually.
4. Follow-Up and Endpoint Assessment: The primary endpoint was NPC-specific mortality over a 12-year follow-up period, with secondary endpoints including NPC incidence, all-cause mortality, early diagnosis rate, and NPC survival.

Data Analysis

Nonparametric tests and Poisson regression models were used to assess the impact of screening on NPC mortality, taking into account the cluster-randomized design. Statistical analyses were performed using SAS 9.4 and R 4.1.2 software.

Main Results

Baseline Characteristics

The baseline characteristics of the screening and control groups were similar. The screening group included 174,943 residents, while the control group had 186,263 residents. In the screening group, 52,498 residents (30.0%) participated in the EBV antibody testing.

NPC Incidence and All-Cause Mortality

The NPC incidence and all-cause mortality were similar between the screening and control groups. There were 706 NPC cases in the screening group and 776 in the control group. No significant difference was observed in all-cause mortality between the two groups.

NPC-Specific Mortality

The NPC-specific mortality in the screening group was significantly lower than in the control group, with a standardized mortality rate of 8.2 per 1,000 person-years in the screening group compared to 12.5 in the control group. The adjusted risk ratio (RR) was 0.70 (95% CI, 0.49-0.997; p=0.048). This benefit was more pronounced in individuals aged 50 and older (RR, 0.56; 95% CI, 0.37-0.85; p=0.007), while it was not significant in those younger than 50 (RR, 0.96; 95% CI, 0.64-1.46; p=0.856).

Early Diagnosis and Survival Rate

The proportion of early-stage diagnoses (stages I/II) was significantly higher in the screening group than in the control group (30.5% vs. 20.5%; p<0.0001). The survival rate of patients in the screening group was also significantly higher than in the control group (log-rank p=0.0034).

Conclusion

In this 12-year cluster-randomized controlled trial, EBV serology-based screening significantly reduced NPC mortality, particularly in individuals aged 50 and older. The early diagnosis rate and survival rate were also significantly improved in the screening group. The results suggest that EBV antibody screening has significant public health value in NPC-endemic regions.

Highlights of the Study

1. Significant Reduction in Mortality: NPC-specific mortality in the screening group was reduced by 30%, with a 44% reduction in individuals aged 50 and older.
2. Significant Improvement in Early Diagnosis: The proportion of early-stage diagnoses was significantly higher in the screening group, indicating that screening effectively improves the early detection rate of NPC.
3. Cluster-Randomized Design: The study adopted a cluster-randomized controlled trial design, ensuring the reliability and generalizability of the results.

Significance and Value of the Study

This study is the first to confirm, through a large-scale randomized controlled trial, that an EBV serology-based screening program can significantly reduce NPC mortality. This finding provides important scientific evidence for public health policies in NPC-endemic regions, demonstrating that EBV antibody screening can be an effective strategy for NPC prevention and control. Future research should further explore ways to improve screening participation and compliance and assess the cost-effectiveness of screening in different age groups.