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Individuals screened for Epstein-Barr virus (EBV) infection had a significantly lower risk of nasopharyngeal cancer (NPC) mortality, a large randomized study from China showed.

Screened individuals had a 30% reduction in cancer-specific mortality over a 12-year period versus similar individuals who were not screened, reported Su-Mei Cao, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, and co-authors. Patients ages 50 and older derived the greatest benefit.

The findings added to previous evidence that screening improves NPC detection and survival, Cao and colleagues wrote in the . EBV is a necessary cause for undifferentiated carcinoma, which accounts for approximately 95% of NPCs in endemic regions, they pointed out.

"Screening programs aimed at early detection need to guard against leading to overdiagnosis of nonlethal, indolent forms of the disease being screened for," the authors noted. "As overall NPC incidence was similar across the trial arms, our results suggest this is not a concern."

"Our finding is consistent with the clinical observation that NPC is prone to invasion and metastasis, and that the overdiagnosis of indolent tumors commonly observed for other epithelial cancers is not a common phenomenon."

The 30% reduction in NPC-related mortality tells only part of the study, according to the authors of an . Only 30% of individuals invited to participate in screening actually did so, and fewer than 70% of high-risk individuals adhered to recommended diagnostic follow-up.

On the basis of "some very crude assumptions," several inferences can be made, wrote editorialists Philip E. Castle, PhD, and Paul K.J. Han, MD, both of the National Cancer Institute in Rockville, Maryland.

• The mortality reduction in patients who were actually screened was 54%
• With adherence to diagnostic follow-up, an even greater mortality reduction might have occurred
• The trial appeared to demonstrate effective risk-stratification, based on the assumption that high risk is predictive of NPC-related mortality

"Those categorized as baseline high risk were probably one order of magnitude higher risk than those who were baseline medium risk and two orders of magnitude higher risk than those who were baseline low risk," Castle and Han continued. "This is one of the first demonstrations that a risk-based cancer screening algorithm may be sufficiently sensitive to reduce cancer-related mortality while managing those at lower risk less aggressively."

They offered several suggestions to improve screening participation: decentralized screening through home-based, self-collection sample collection; potential repurposing of lateral flow testing technologies developed for COVID for detection of EBV biomarkers; and use of less invasive methods (such as radiomics and image analysis) to triage high-risk individuals.

"Many more people were biopsied than had NPC," noted Castle and Han. A more sensitive and reasonably specific triage method could allow for broadening the definition of high risk, thereby increasing the sensitivity and mortality reduction of the screening algorithm, they suggested.

"Now the hard work begins," the editorialists argued. "That is, implementing it as a highly effective population-level intervention, which requires more than simply performing blood tests and biopsies. It requires educating both individuals and healthcare providers about the benefits and harms of NPC screening, assessing and integrating individual preferences in screening decisions, and making screening more accessible, user-friendly, and efficient using new technologies."

Screening for NPC has been shown to improve early detection and to be cost-effective in endemic regions, Cao and coauthors noted. To determine whether screening with EBV-based markers can reduce NPC-specific mortality, the investigators organized a randomized trial involving 16 towns within the larger cities of Sihui and Zhongshan, China. Eight towns were randomly assigned to screening and eight to a non-screened control group.

Adults ages 30-69 with no history of NPC were enrolled from Jan. 1, 2008, to Dec. 31, 2015. Residents of the screening towns were invited to undergo serum EBV viral capsid antigen/nuclear antigen 1-immunoglobulin A antibody testing. Follow-up continued through Dec. 31, 2019.

The total study population comprised 186,263 residents of the no-screening towns and 174,943 residents of the screening group towns, among whom 30% actually participated in the screening program. Compliance with endoscopic examination, biopsy, or both was 67.6% (1,703 of 2,518) overall and 65.9% (1,110 of 1,685) among participants ever classified as high risk at baseline.

The data showed an NPC-specific mortality of 8.2 deaths per 1,000 person-years in the screened group versus 12.5 per 1,000 person-years in the unscreened group, representing a rate ratio of 0.70 (95% CI 0.49-0.997, P=0.048). The overall benefit was driven by patients 50 or older, who had a rate ratio reduction of 44% with EBV screening (95% CI 0.37-0.85) versus the nonsignificant 4% reduction among younger participants.

"The optimal age to start NPC screening is unknown, and current recommendations are primarily based on the age-specific incidence rate in high-risk populations," Cao and colleagues noted. "The stronger mortality reduction among individuals screened at 50-69 years might suggest that screening efforts should be focused on this age group."

"However, it is important to note that the reduction in NPC-specific mortality could be overestimated in this subgroup with the lower incidence of NPC," they added.

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