The fecal immunochemical test (FIT) may substantially reduce deaths from colorectal cancer (CRC), according to a new 21-year population study from Spain’s Basque Country.

Luis Bujanda, MD, PhD, of the Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute-Donostia University Hospital, University of the Basque Country, Donostia-San Sebastián, Spain, and colleagues found that CRC mortality fell by almost 50% among adults aged 50-69 years following the rollout of a FIT screening program, with the decline becoming apparent about 3 years after screening began.

“Organized FIT-based screening was associated with substantial and sustained reductions in CRC mortality, suggesting there are population-level benefits for its use,” the authors concluded.

The study was published in JAMA Network Open.

‘Limited’ Understanding

CRC, a leading cause of cancer-related mortality worldwide, is “well suited for population-based screening, given its relatively high burden, the presence of an identifiable premalignant phase, and the availability of effective interventions enabling early detection or prevention,” the authors wrote.

Many countries have implemented CRC screening programs, primarily using FIT or endoscopy, to target asymptomatic individuals at average risk. These programs have been “associated with substantial reductions in CRC mortality,” with decreases ranging from 13% to 37%, depending on participation, screening modality, and follow-up duration.

However, evidence regarding the long-term population-level impact of FIT-based screening in community-based settings “remains limited,” with few studies evaluating how CRC mortality “evolves across different phases of program implementation, from prescreening to full rollout and long-term maturation.”

Furthermore, the extent to which these mortality trends are sustained in the context of demographic changes and external disruptions (eg, the COVID pandemic) remains “insufficiently characterized.”

The researchers therefore decided to analyze data from a population-based CRC screening program that utilizes FIT. The program, launched in the Basque Country (n = ~2.2 million), targeted individuals aged 50-69 years and was progressively implemented, achieving high participation rates over time.

The current study examined CRC mortality trends over a 21-year period (2004-2024) that encompassed all phases of the process: prescreening, implementation, and postimplementation. Individuals younger than 50 years were included in the study as a nonscreening reference group. Screening took place on a biennial basis, using single-sample FIT.

The researchers used age-standardized mortality rates (ASMRs) and segmented regression approaches to examine the association between the program’s implementation and changes in CRC mortality, accounting for underlying population dynamics and external factors, including the COVID pandemic.

‘Robust Association’

Of 438,134 deaths during the study period, 3.7% were attributable to CRC, with CRC-related ASMRs declining by 29.6% (P = .002). The result was even more impressive in those aged 50-59 years, in whom CRC mortality declined by 50.1% (from 39.7 to 19.8 deaths per 100,000).

A “significant inflection point” was identified in 2012 — 3 years after screening implementation (95% CI, 2011-2014; P < .001). There was an estimated 46.2% relative reduction in CRC mortality in those between the ages of 50 and 59 compared with projected trends without screening. “These trends persisted through the post-COVID period despite substantial demographic aging, supporting a robust association between screening implementation and reduced CRC mortality,” the authors stated.

Among those aged ≥ 70 years, CRC mortality declined by 19.6%, which corresponded to a 45.4% relative reduction compared with projected rates. Notably, 70.8% of CRCs detected through screening during the study period were diagnosed at stage I or II.

“The mortality benefit of CRC screening is well established, through both the removal of advanced adenomas before malignant transformation and the earlier diagnosis of invasive cancers,” the authors commented.

Previous studies conducted in the Basque setting found that the proportion of early-stage tumors increased from 54% to 71% after screening program implementation, while stage at diagnosis remained associated with mortality. The current findings are consistent with this, with long-term evidence also suggesting that “polypectomy itself contributes to CRC mortality reduction.”

Taken together, these proposed mechanisms “provide a biologically plausible explanation for the population-level mortality trends observed in this study.”

Highly Impactful Intervention

In an accompanying editorial, Uri Ladabaum, MD, MS, of the Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, noted that although causality can’t be definitively “proven” in observational studies, the current study “strengthens the evidence that population-based screening decreases CRC mortality” at the population level.

He described the Basque program as an “exemplar,” with 72% FIT participation and > 91% colonoscopy completion after an abnormal FIT. However, he warned, these results may “reflect an upper end” of what a typical biennial FIT program can achieve.

Ladabaum contextualized these findings by referencing the NordICC trial, which found reduced CRC incidence with colonoscopy screening but no significant mortality reduction at 13 years — an outcome he referred to as a “conundrum,” with “outlier results” that lack a satisfactory explanation. Bujanda and colleagues therefore make a “valuable contribution” to the evidence that mature FIT programs deliver substantial reductions in CRC mortality.

With CRC incidence rising globally, “this is not a time to reconsider” whether screening is worthwhile, Ladabaum emphasized. Rather, the evidence “compels us to consider how this highly impactful intervention can be optimized around the world.”

Lessons for the US

Commenting for Medscape Medical News, Cedrek McFadden, MD, medical advisor, Colorectal Cancer Alliance, Washington, DC, said the study “looks beyond whether people complete screening and asks the question that ultimately matters: Does an organized screening program translate into fewer deaths from colorectal cancer?”

McFadden, clinical associate professor of surgery at the University of South Carolina School of Medicine Greenville, regards the findings as “compelling real-world evidence supporting organized screening” but cautioned that they don’t constitute “proof” that FIT alone caused the entire reduction. This was an observational study, not a randomized trial, and CRC treatment and overall cancer care “improved considerably during the 21-year study period.” Additionally, the investigators “didn’t have individual patient data linking participation in screening directly with subsequent mortality.”

The findings are nevertheless “important,” and the “overall message is very relevant to the US” — although McFadden wouldn’t necessarily “assume we would see exactly the same magnitude of mortality reduction in the US” for several reasons.

The Basque program was “highly organized,” with patients “systematically invited to participate, screening was repeated, and positive tests were followed by colonoscopy at very high rates,” he noted. “The US healthcare system is considerably more fragmented, and access to screening and follow-up varies widely.”

The lesson for the US thus isn’t “simply that we need more FIT testing. The lesson is that FIT works particularly well when it’s part of an organized system that identifies eligible patients, gets the test into their hands, reminds them to complete it, tracks abnormal results, and gets those patients to colonoscopy,” McFadden said.

The findings have important implications for health systems, according to McFadden. “The larger message is that CRC screening doesn’t succeed because of a test alone. It succeeds when patients participate, abnormal results are acted upon, and the health system makes sure nobody gets lost between a positive FIT and a colonoscopy.”

This study was funded by grants from the Instituto de Salud Carlos III (ISCIII), cofunded by the European Union; CIBERehd (ISCIII), Department of Education of the Basque Government; the Department of Health of the Basque Country; Euskadi RIS3; Elkartek; the Scientific Foundation of the Spanish Association Against Cancer; the Department of Education of the Basque Country; the Asociación Española Para el Estudio del Hígado; and the Fundación HNA. Bujanda reported receiving personal fees from Norgine and Alfasigma during the conduct of the study. The other authors’ disclosures are listed on the original paper.Ladabaum reported equity in UniversalDx, Cylinder, SanguiBio, and Lumiinus and receiving personal fees from Kohler Ventures, Freenome, Guardant, Neptune Medical, Medtronic, Medacorp, William Blair, Guidepoint, Medial EarlySign, and Geneoscopy outside the submitted work. McFadden reported having no relevant financial relationships.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books.