Current colorectal cancer screening in developing countries: Identifying optimal approaches

Abstract

Colorectal cancer (CRC) screening has proven effective in reducing cancer-related mortality through early detection. Emerging epidemiological patterns, particularly the rising incidence of early-onset CRC and aging, call for changes for current inadequate CRC screening programs in developing countries. The benefits of CRC screening have come out in developed countries, while more prevailing environmental risk factors coupled with a gap in CRC screening implementation are observed in developing countries. Conventional screening modalities like fecal immunochemical tests are more acceptable, but lack sensitivity for advanced adenomas. Authoritative colonoscopy manifests high efficacy but suffers from poor adherence. Meanwhile, novel screening modalities require optimization. Comparatively high-adherence non-invasive tools could sort high-risk sets for colonoscopy. Growing evidence highlights the potential role of risk stratification approach beyond conventional age, which may refine colonoscopy referral. And microsimulation modeling is valuable for optimizing and evaluating screening strategies before and after screening. It suggests that an adaptive and organized screening framework may offer optimal population-level benefits.

Key Words: Colorectal cancer screening; Risk stratification; Microsimulation modeling; Fecal immunochemical test; Colonoscopy; Early-onset colorectal cancer

Core Tip: Socioeconomic transition and associated shifts toward unhealthy lifestyles are reshaping the global epidemiology of colorectal cancer. While many developed nations have benefited from healthier lifestyle adoption and screening implementation, numerous developing countries now face a rising burden of risk factors alongside scare screening programs. We herein discussed related factors and potential frameworks for implementing effective colorectal cancer screening in developing countries.

INTRODUCTION

Ranking the third in terms of incidence and the second in terms of mortality among all kinds of cancers, colorectal cancer (CRC) represents a heavy burden globally[1]. Demographic shifts, including population growth and aging, are projected to increase annual CRC diagnoses from 1900000 in 2020 to 3200000 in 2040, with corresponding mortality rising from 930000 in 2020 to 1600000 in 2040 during the same period[2]. CRC screening implementation has demonstrated substantial success in developed nations, for instance, the incidence rate and the mortality rate are obviously declining in the United States since 2000[3,4]. Nonetheless, studies have observed rising incidence rates in countries that are generally undergoing major socioeconomic development such as Eastern Europe, South Central Asia, and South America[5]. Gathered evidence further connects human development index (HDI) transitions with CRC risk escalation, since transforming from low to high HDI countries inevitably brings modifiable CRC risk factors like high dietary fat intake and sedentariness[6]. Consequently, dozens of developing countries, who are undergoing rapid socioeconomic transition coupled with more prevailing environmental risk factors, lack comprehensive national screening programs and evidence-based implementation guidelines for effective risk prediction and prevention strategies.

CRC RISK PREDICTION

Age

Currently, CRC risk is generally decided by a “one-size-fits-all” approach according to disease burden observed over time: Objects that older than 50 years are regarded as average risk, who are recommended a colonoscopy then[7,8]. However, CRC diagnosis is rapidly accumulating among generations that younger than 50 years, which is called early-onset CRC (EOCRC)[9]. To date, CRC is the first leading cause of cancer-related death in men and the second in women under 50 years in United States[10]. In response, the American Cancer Society proposed to initiate screening at age 45 years in 2018, a decision supported by microsimulation modeling indicating a favorable, and affordable deal between reduced disease burden and the increased demand for colonoscopy[11]. However, the adoption of this threshold in developing countries must be carefully weighed, in terms of population burdens and healthcare resources[5,12], even though a similar trend of EOCRC has been reported there[13]. From 1990 to 2019, the disability-adjusted life years (DALYs) due to EOCRC increased by 67.8%, with East Asia, Southeast Asia, and Southern Latin America bearing the heaviest burdens. Notably, while developed regions have higher incidence rates, the increase in DALYs over the past 30 years has occurred primarily in middle- and low-socio-demographic index regions[14]. The etiology of EOCRC is not fully understood, but is strongly linked to socioeconomic transitions accompanied by the adoption of westernized lifestyles, and a pronounced birth-cohort effect. Furthermore, the natural history and time to metastasis of EOCRC remain unclear, complicating the design of optimal screening strategies[9]. As to the ending point, most countries chose 75 years considering the increased screening complications and comorbidity burden[15].

Family history and polygenic risk scores

Serving as an essential supplement of age, family history is better received as having one or more first-degree relatives with a CRC diagnosis. To address limitations such as recall bias in reporting family history and the confounding effects of prophylactic polyp removal in relatives, polygenic risk scores (PRS), derived from Genome-wide association studies, have been proposed as an objective, quantifiable alternative[16,17]. Given that the majorities of CRC risk loci being identified from European-ancestry populations, PRSs stemmed from target population need extra attention. Moreover, study showed that only with a greater than 0.50 increase in area under curve value (0.65), a greater than 30% reduction in costs, or a greater than 5% increase in adherence can PRS be cost-effective[18].

Potential factors

Being more pragmatic, lifestyle factors like increased body mass index (BMI), western diet, physical activity, smoking, drinking, ethnicity and powerful positive fecal immunochemical test (FIT) results were integrated in certain CRC prediction models[19,20]. The validated Asia-Pacific Colorectal Screening score exemplified this approach in asymptomatic Asian populations, which incorporates age, sex, family history, smoking, and BMI[21]. Additionally, abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia are useful red-flag signs[22].

Microsimulation modeling

Microsimulation modeling provides a powerful methodological framework for evaluating cancer prevention and surveillance strategies, helping with the lack of empirical data on long-term screening outcomes[3,4,11,23]. Among established models, authoritative MISCAN-Colon model simulates a set of fictitious individuals with life-course trajectories mirroring American demographic patterns based on adenoma-carcinoma sequence[24]. Nevertheless, its assumption of perfect adherence to screening protocols lacks real-world applicability, and lacks generalizability to other populations[11,25]. Given local conditions with respect to demographic characteristics, resource availability, the epidemiology and natural history of CRC, calibrated model might achieve enhanced performance for specific populations other than American[26]. Another widely adopted paradigm, “memoryless” Markov approach, where the probability of transitioning to a future state depends solely on the current state (health behaviors, health care utilization, and disease states), using transition probabilities derived from similar epidemiological data sources[27].

SCREENING MODALITIES

All of the screening modalities discussed here had proved to decrease the CRC screening incidence and mortality, and no study or hypothesis had discussed the harms of noninvasive stool or blood tests[28]. The incremental cost-effectiveness ratios calculated as either cost per life-year-gained (LYG) or cost per qualified-adjusted-life-years (QALY) between two strategies, like (Costs_FIT - Costs_colonoscopy)/(QALY_FIT - QALY_colonoscopy), presenting valuable for economic evaluation, yet being not widely conducted in real world thus far. Commonly-used threshold is United States $50000 per LYG despite regional variations.

Guaiac-based fecal occult blood test

Serving as the earliest screening tool, guaiac-based fecal occult blood test (G-FOBT) detects bleeding through guaiac peroxidase activity with cheap price but poor diagnostic performance[29]. Given the discrepant sensitivity manifested in clinical research, study based on microsimulation modeling denoted that FOBTs show 0.51 in the stage of clinical diagnosis and merely 0.19 in earlier stages[30]. High-sensitivity G-FOBT (Hemoccult II Sensa^®), however, yields excessive false positives, resulting in an unacceptable number of colonoscopies[31]. In addition to dietary restriction, adherence to sequential high-sensitivity G-FOBT rounds was suboptimal compared with a single screening colonoscopy[32]. And qualitative tests appear to be inapt to the modern diagnostic laboratory and high-throughput screening programs[29,33]. All of these call for the revolutionary emergence of I-FOBT, or FIT[34].

FIT

Unlike G-FOBT, FIT detects antibodies specifically for human haemoglobin with improved adherence and diagnostic performance, eliminating dietary restrictions[35]. FIT could be semiquantitative, which allows shifting the positive threshold in certain situations to attain ideal diagnostic levels and eligible screening scope[36]. Meta-analysis revealed that diversified brands with diversified thresholds of FIT will manifest low to high heterogeneity for sensitivity but generally high positivity for both CRC and advanced adenoma. At the threshold that approved by Food and Drug Administration (FDA) of 20 μg/g, the pooled sensitivity and specificity of FIT for CRC was 0.77 and 0.94, while 0.26 and 0.95 for advanced adenomas[37]. However, single-application FIT fell short of desirable detection rates for advanced adenomas, and serrated neoplasia even less so[37,38]. Although it was proclaimed that cumulative detection rates over 5 rounds of FIT gained detection rates for advanced adenoma similar to colonoscopy[39,40], achieving such results in practice appears challenging.

In the United States (opportunistic colonoscopy-dominant), first-round participation of colonoscopy was 62.6%, rising slightly to 63.2% and 68.3% in subsequent rounds, and accomplished 73% in total[40]. In contrast, an organized screening program in China demonstrated markedly higher and more consistent adherence, with rates of 94.0%, 86.8%, and 91.3% across the first three rounds, respectively, and achieving 99.3% in total[41]. Subjects adhere to all procedures occupied less, and many with positive FIT results failed to undergo subsequent colonoscopy.

A study followed 25 years and found that annually or biennially FIT were more cost-effective compared with colonoscopy every 10 years, and FIT group obtained higher participation rate (41.6% vs 21.9%, P < 0.01), lower detection rate for any adenomas (3.82% vs 31.32%, P < 0.01) and comparable detection rate for CRC (0.30% vs 0.65%, P = 0.16)[41].

Multi-target stool DNA test

Provided the limited sensitivity for advanced adenoma of FIT, optimum biomarkers of advanced adenoma and serrated neoplasia appear attractive, among which multi-target stool DNA (mt-sDNA) stood out[42]. Based on the fact that accumulated genetic and epigenetic alterations generate CRC and DNA is stable, mt-sDNA detects quantitative molecular assays (KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, etc.), plus a hemoglobin immunoassay (namely, FIT). Only Cologuard mt-sDNA test (Exact Sciences) was critically approved by the FDA and marketed[38]. Pooled sensitivity of mt-sDNA for CRC detection was 0.93 (95%CI: 0.87-1.0) and pooled specificity was 0.84 (95%CI: 0.84-0.86), with lower pooled sensitivity [0.43 (95%CI: 0.40-0.46)] and pooled specificity for advanced adenomas [0.89 (95%CI: 0.86-0.92)][28]. Imperiale et al[43] compared next-generation mt-sDNA with FIT, the sensitivity for CRC (93.9% vs 67.3%), for advanced adenomas (43.4% vs 23.3%), and the specificity for CRC and advanced adenomas (92.7% vs 95.7%) were all significantly different.

Nevertheless, mt-sDNA every 3 years was suboptimum in cost-effective evaluation than colonoscopy, sigmoidoscopy, computed tomographic colonography (CTC) every 5 years, and annually FIT, though it beat no screening[44,45].

Traditional colonoscopy

Remaining the diagnostic gold standard, colonoscopy, allows for direct vision of the entire colon and rectum and instant removal when detect lesions, yet accompanied by capacity problems and potential complications. Post-colonoscopy CRC well describes the imperfectness of this highly operator-dependent test, owing to inadequate bowel preparation and serrated neoplasia[46]. The painful sedation and bowel preparation as well as complications of this invasive modality led to its low participation rate (14.0%) even in high-risk sets in certain regions[47]. Participation rate for direct colonoscopy was 42.4%, while over 70% among FIT-positive subjects[48]. Serious adverse events from colonoscopy were estimated at 3.1 perforations (95%CI: 2.3-4.0) per 10000 procedures and 14.6 major bleeding events (95%CI: 9.4-19.9) per 10000 procedures[28].

Colonoscopy every 10 years and single colonoscopy both manifested cost-effectiveness compared with no screening, especially single colonoscopy[49,50]. Single sigmoidoscopy outperformed single colonoscopy in cost-effectiveness, except that colonoscopy could deliver 50% protection in the proximal colon[44,51]. Meta-analysis also discovered that the majority of benefits were gained from the distal colon[52].

The theoretical and technological advanced deep learning led to the development of computer-aided polyp detection (CADe) systems, which has been introduced to CRC screening[53]. The adenoma detection rate significantly raised 14.4% when used CADe in a randomized controlled trial (RCT)[54]. Marketed artificial intelligence detection tools cost $19 per procedure, which is more available than training operators[55].

Flexible sigmoidoscopy

Despite its limited scope, flexible sigmoidoscopy (FS) can achieve polyp removal comparable to colonoscopy. It was validated that a single FS provided consecutive protection at least 17 years[56]. A study followed over a period of 22 years and found that multivariate hazard ratios for CRC were 0.60 (95%CI: 0.53-0.68) after negative sigmoidoscopy, 0.44 (95%CI: 0.38-0.52) after negative colonoscopy, and 0.57 (95%CI: 0.45-0.72) after polypectomy, which indicates that once-only FS might be enough for CRC prevention[57]. Serious adverse events from FS were far less common, with a pooled estimate of 0.7/10000 procedures[28]. Sigmoidoscopy every 5 years and single sigmoidoscopy manifested cost-effectiveness compared with no screening[44,50]. Four out of five studies showed that annual FIT outperformed sigmoidoscopy every 5 years in cost-effectiveness[58], while single sigmoidoscopy beat single colonoscopy[44,51].

CTC

Non-invasive CTC obtains 2- or 3-dimensional views through special X-ray machine, which avoids discomfort caused by invasiveness and provides examinations for neighboring organs. Laxative-free CTC was accurate in detecting adenomas 10 mm or larger with diagnostic performance close to optical colonoscopy, yet was poor in detecting smaller lesions, sensitivity and specificity of detecting adenomas 6 mm or larger were 0.59 and 0.94, respectively[59]. By contrast, for CTC with bowel preparation, the sensitivity in detecting adenomas 6 mm or larger ranged from 0.73 to 0.98 and the specificity ranged from 0.80 to 0.93[28]. Little to no risk of serious adverse events for screening CTC was reported, though low-dose ionizing radiation (0.8-5.3 mSv) exposure and potential allergy to contrast media are inevitable[28]. Notably, CTC every 5 years was not cost-effective compared with FIT, sigmoidoscopy and colonoscopy, except no screening[44].

Novel screening modalities

Circulating tumor DNA is a prognostic biomarker shed by tumors in bloodstream, which was intensively described for residual disease and early detection of CRC[60], since Genome-wide alterations in DNA methylation hinted at multiple pathways to develop CRC[61]. Coronado et al[62], reported that commercially available blood test had a 17.5% boosted participation rate over point-of-care FIT reminders, since blood draw is more preferred than stool draw generally. Methylated Septin9 test (Epi proColon), the only FDA-approved blood-based test, is a quantitative real-time PCR assay that detects methylated v2 promoter of Septin9[63]. Reported sensitivity and specificity of Epi proColon was 0.68 (95%CI: 0.53-0.80) and 0.80 (95%CI: 0.78-0.82) for CRC[64,65]. Latest marketed Epi proColon 2.0 (sensitivity: 0.71-0.95, specificity: 0.81-0.99) exhibited a lower sensitivity (0.68 vs 0.79 for FIT; 0.68 vs 0.92 for mt-sDNA) and lower specificity (0.80 vs 0.94 for FIT; 0.80 vs 0.86 for mt-sDNA) than stool tests[66]. However, data varied in existing scarce trials, since the concentration of cfDNA in plasma is low. The only prospective screening program aimed at average-risk people demonstrates a sensitivity of 48.2% for CRC and 11.2% for advanced adenoma[67]. Another cfDNA assay Shield (from Guardant Health, United States) manifested a sensitivity of 83.1% for CRC and 13.2% for advanced adenomas, with a specificity of 89.6% for advanced neoplasia in ECLIPSE clinical trials[68]. However, it would have to reduce 66% costs to be more cost-effective than no screening in Markov modeling[23].

To this end, CRC screening programs dominantly utilizing a two-step approach: Initial noninvasive fecal test followed by a colonoscopy for individuals with positive results[69]. Combined screening modalities, for example, annual FIT/colonoscopy once, demonstrated favorable outcomes in improving QALYs and reducing costs[70]. While FOBT/FIT and colonoscopy remain the more widely used conventional modalities, recommendations for other novel tests remain controversial due to unresolved questions regarding performance, cost-effectiveness, and availability, particularly in low-resource settings.

The colonoscopy-vs-FIT debate persists as both modalities constitute first-tier options. While direct comparative data on CRC incidence/mortality reduction remain unavailable, microsimulation modeling (assuming 100% adherence) favor colonoscopy for maximal efficacy[71]. It is concluded that FIT is more accessible and more well-received which requires frequent application, thus adapts to large, organized programmatic applications ideally. In contrast, colonoscopy is more sensitive but less accessible so that requires much less frequent application and was better structured for opportunistic settings like America[72]. Although the high participation yield of FIT and the high diagnostic yield of colonoscopy could be combined, optimal implementation strategies for population-based screening await further exploration[73].

Furthermore, the challenges inherent to pragmatic studies remain poorly characterized. Scaling up FIT-based screening creates immediate demands on health system capacity, requiring not only a reliable supply chain for test kits but also a sufficient endoscopic workforce to handle the increased volume of colonoscopy referrals for positive results[74]. Real-world adherence might also vary across awareness, insurance types, urban or rural communities and socioeconomic levels[75]. Outreach efforts (e.g., notification, reminders, and mailed kits) had been shown to significantly enhance 1-time CRC screening adherence[76,77] (Table 1).

Table 1 Summarized characteristics of colorectal cancer screening modalities.

Modality	Sensitivity & specificity of advanced adenoma	Sensitivity & specificity of colorectal cancer	Participation rate (organized program)	Cost in United States dollars	Cost-effective analysis	Features
G-FOBT	Sensitivity: 0.19[30]	Sensitivity: 0.50-0.75 (95%CI: 0.09-1.0). Specificity: 0.96-0.98 (95%CI: 0.95-0.99)[28]	G-FOBT vs FIT: 46.9% vs 59.6%[35]	$4[92]	-	Qualitative tests. Samples from 3 days are needed. Diet restriction. Repeat applications are needed. It could be mailed
FIT	Sensitivity: 0.23 (95%CI: 0.20-0.25; I2 = 47.4%). Specificity: 0.96 (95%CI: 0.95-0.97; I2 = 94.8%) (at a threshold of 20 μg/g)[28]	Sensitivity: 0.74 (95%CI: 0.64-0.83; I2 = 31.6%). Specificity: 0.94 (95%CI: 0.93-0.96; I2 = 96.6%)[28]	From the first round to subsequent rounds: 48.2%, 75.3%, 83.4% and 86.1%[93]. FIT vs colonoscopy: 41.6% vs 21.9% (P < 0.01)[41]	$18[92]	ICER: Annual FIT: $14300/QALY, biennial FIT: $3970/QALY[45]	Repeat applications are needed. It could be mailed
mt-sDNA	Sensitivity: 0.43 (95%CI: 0.40-0.46). Specificity: 0.89 (95%CI: 0.86-0.92)[28]	Sensitivity: 0.93 (95%CI: 0.87-1.0). Specificity: 0.84 (95%CI: 0.84-0.86)[28]	71%[94]	$509[92]	ICER: $27500 per QALY[45]. Lower cost-effectiveness compared with no screening, but higher than colonoscopy, FS, CTC every 5 years, and annually FIT[44,45]	Repeat applications are needed
Colonoscopy	Sensitivity: 0.95 (95%CI: 0.77-1.00). Specificity: 0.89 (95%CI: 0.86-0.91) (compared with a reference standard of CTC for adenomas 10 mm or larger)[59]	-	21.9%[41]	$1891[92]	Lower cost-effectiveness compared with no screening[49,50]. ICER for single colonoscopy: $28071 per LYG[23]	Serious adverse events: 3.1 perforations (95%CI: 2.3-4.0) per 10000 procedures; 14.6 major bleeding events (95%CI: 9.4-19.9) per 10000 procedures[28]. Require bowel preparation
FS	-	-	63.1%[95]	$789[92]	Lower cost-effectiveness compared with no screening[44,50]. ICER for FS: Below $28,000 per QALY[44]	Serious adverse events: 0.7/10000 procedures[28]
CTC	Laxative-free CTC, ≥ 10 mm: Close to optical colonoscopy; ≥ 6 mm: Sensitivity: 0.59, specificity: 0.94[59]. CTC with bowel preparation, ≥ 6 mm: Sensitivity: 0.73-0.98; specificity: 0.80-0.93[28]	-	5.78%[59]	$477 (without contrast). $573 (with contrast)[92]	Lower cost-effectiveness compared with no screening. Higher cost-effectiveness compared with FIT, FS and colonoscopy[44]	Little to no risk of serious adverse events. low-dose ionizing radiation (0.8-5.3 mSv) exposure allergy[28]
mSeptin9	Epi proColon: Sensitivity: 0.64 (95%CI: 0.48-0.77)[64,65]	Epi proColon: Sensitivity: 0.68 (95%CI: 0.53-0.80). Specificity: 0.80 (95%CI: 0.78-0.82)[64,65]. Epi proColon 2.0: Sensitivity: 0.71-0.95. Specificity: 0.81-0.99[66]	-	$192[68]	-	-
Cell-free DNA blood-based test (Shield)	Sensitivity: 0.13. Specificity: 0.89[68]	Sensitivity: 0.83[68]	-	$949[23]	Higher cost-effectiveness than no screening. ICER: $377538 per LYG[23]	-

G-FOBT: Guaiac-based fecal occult blood test; FIT: Fecal immunochemical test; FS: Flexible sigmoidoscopy; CTC: Computed tomographic colonography; ICER: Incremental cost-effectiveness ratio; QALY: Qualified-adjusted-life-year; LYG: Life-year-gained.

DISCUSSION

The adenoma-carcinoma sequence typically requires 15-20 years for precursor adenomas to germinate into cancer in average-risk people, implying a critical window for early intervention[78]. Colonoscopic polypectomy has accomplished significant mortality reduction by detecting and removing premalignant lesions at an early, curable stage[79]. CRC incidence rates are three to four times higher in transitioned relative to transitioning countries, although less variation is seen for mortality given a relatively higher case fatality in the latter countries[1]. Distinct socioeconomic gradients correlated with CRC incidence and mortality rates were observed across regions in recent decades: (1) Rapidly transitioning countries (e.g., medium and high HDI countries including those in the Baltics, as well as Russia, China and Brazil) suffered increases in both incidence and mortality, mainly due to behavioral and dietary changes; (2) Increases in incidence and concomitant decreases in mortality was seen in very high HDI countries (e.g., Canada, United Kingdom, Denmark and Singapore); and (3) Decreases in both incidence and mortality, as observed in a number of the highest HDI countries including the United States, Japan and France, which might benefit from the adoption of a healthier lifestyle and the implementation of screening[80]. The rising EOCRC rates linked to adjustable environmental and metabolic factors[11,28], as well as the growth and aging of the population, necessitate urgent intervention to stop this trend[2,15].

Established CRC screening programs in the United States and Europe represented two different organized CRC screening setting. The CRC screening in United States started in 1980 with opportunistic colonoscopy setting, and admirable efficacy were observed since 2000[81]. It has taken the initiative to increase CRC screening rates from 58% in 2013 to 80% in 2018, which expects to avert approximately 280000 new cancer cases and 200000 cancer deaths within 20 years[82]. Although it did not reach that goal, annual CRC incidence declined by 1.3%-1.5% and mortality by 1.8% during this period[10]. The Council of European Union first formally recommended CRC screening in 2003[83]. Annual or biennial FIT (FOBT at the beginning) followed by colonoscopy dominated in most countries, with randomized programme-based screening accepted only, which allows easier quality assurance[84,85]. Studies based on 21 European countries from 2000 to 2020 shew that the divergent CRC trends tended to be explained by divergent levels of screening implementation, the largest declines in CRC mortality were occurred in countries with the most long-standing screening programs[85].

In contrast, it was estimated that 1416426 cases of CRC occurred in China in 2020, accounting for 27% of all prevalent CRC cases globally, yet lacks nationwide CRC screening programs[5]. Early efforts date to 1989 in Jiashan County, where FS after risk assessment reduced rectal cancer mortality by 31.7%, validating risk-assessment model in populous settings[86]. The 2012 Cancer Screening Program in Urban China (CanSPUC) first combine risk stratification with subsequent colonoscopy, yet with low participation rate (14%)[47]. The CanSPUC later in 2018, also the first RCT in large-scale to compare colonoscopy, FIT, and risk-adapted screening arms for 3 consecutive rounds, found the participation rates were 42.4%, 99.3%, and 89.2%, respectively, and detecting 1 advanced neoplasm needed 15.4, 7.8, 9.2 colonoscopies, respectively, with comparable detection rates and costs[48]. Follow up and applications of other strategies are still under way, leading to sparse data for reliable risk stratification and CRC screening recommendations in populous China. Microsimulation modeling in China is just hitting the road otherwise[87,88].

Currently, organized screening is recommended in regions with the highest incidence of CRC (> 30 per 100000)[81]. Incidence and mortality of CRC double or more than double in 157 and 129 of 204 countries and territories, and multiple low to middle HDI countries are experiencing large increases and risk factors proliferation[89]. Some East Asian countries have organized screening programs in place, including Japan, Korea, China, Hong Kong, and Bangkok[81]. While most countries in Africa, South America, and the Middle East even do not have organized screening programs[15]. Average adherence rates varied from 19% in Croatia and the Czech Republic, 55% in Canada to 69% in the Basque of Spain[90]. Significant heterogeneities in adherence were observed in view of screening year, continents, GDP, and incidence of CRC[91] (Table 2).

Table 2 Summarized guidelines for colorectal cancer screening from different regions.

Country/association	Target group	Recommendation	Average risk person definition
USPTF, 2021[28]	Asymptomatic adults at average risk of colorectal cancer. 50-75 years (A recommendation). 45-49 years (B recommendation)	High-sensitivity G-FOBT or FIT every year. sDNA-FIT every 1 to 3 years. CTC every 5 years. Flexible sigmoidoscopy every 5 years. Flexible sigmoidoscopy every 10 years + FIT every year. Colonoscopy screening every 10 years	No prior diagnosis of colorectal cancer, adenomatous polyps, or inflammatory bowel disease; no personal diagnosis or family history of known genetic disorders that predispose them to a high lifetime risk of colorectal cancer (such as Lynch syndrome or familial adenomatous polyposis)
MTSTF, 2022[96]	Average-risk adults aged 45-75 years	High-quality colonoscopy every 10 years or an annual FIT (strong recommendation; moderate-quality evidence). Flexible sigmoidoscopy every 5 years to 10 years (strong recommendation; high-quality evidence). CTC every 5 years (strong recommendation, low-quality evidence). FIT–fecal DNA every 3 years (strong recommendation, low-quality evidence) in individuals who decline colonoscopy and a FIT	Those aged 50-75 years with no history of CRC or adenoma, with no first-degree relatives with CRC, and who are not up to date with CRC screening according to other methods (that is, sigmoidoscopy within 5 years or colonoscopy within 10 years)
ACP, 2023[92]	Asymptomatic average-risk adults aged 50-75 years	A FIT or high-sensitivity G-FOBT every 2 years, colonoscopy every 10 years, or flexible sigmoidoscopy every 10 years plus a FIT every 2 years	No prior diagnosis of CRC, adenomatous polyps, or inflammatory bowel disease, and no personal diagnosis or family history of known genetic disorders that predispose a person to a high lifetime risk for CRC (for example, Lynch syndrome)
ACS, 2018[11]	Average-risk adults aged 45-75 years	Annual FIT. Annual high-sensitivity G-FOBT. mt-sDNA test every 3 years. Colonoscopy every 10 years. CTC every 5 years. Flexible sigmoidoscopy every 5 years	Persons without a history of adenomatous polyps or CRC and not at increased risk for CRC due to a family history of CRC, a confirmed or suspected hereditary CRC syndrome (such as familial adenomatous polyposis or Lynch syndrome), a personal history of abdominal or pelvic radiation for a previous cancer, or a personal history of inflammatory bowel disease
NCCN, 2024[97]	Adults aged 45-70 years	For individuals at average risk, the choice of a particular screening modality should include a conversation with the patient concerning their preference and availability, for individuals at increased risk, colonoscopy is the preferred method	Aged 45-75 years; no personal history of adenoma or SSP/SSL or CRC; no personal history of IBD; no personal history of high-risk CRC genetic syndromes (list of syndromes on CSCR-2); no personal history of cystic fibrosis; no personal history of childhood cancer; negative family history for confirmed advanced adenoma (i.e., high-grade dysplasia, 21 cm, villous tubulovillous histology) or an advanced SP/SSL, (≥ 1 cm, any dysplasia) in first-degree relatives. Negative family history for CRC
The Asia-Pacific region, 2022[98]	Adults aged 50-year. Using age alone as a cut-off point for CRC screening is insufficient. Decision should be made by patients and clinicians together based on a patient’s overall health status, prior screening history and patient’s preferences	Quantitative FIT (every year or every 2 years) or colonoscopy (every 10 years)	-
The European Colorectal Cancer Screening Guidelines Working Group, 2013[99]	Adults aged 50-74 years residing in the target area	Recommendation based on good evidence for G-FOBT, reasonable evidence for FIT and flexible sigmoidoscopy, and limited evidence for colonoscopy	-
National Cancer Center of China, 2020[100]	Low-to-average-risk adults aged 50-75 years (strong recommendation, moderate-quality evidence). High-risk adults aged 40-75 years (strong recommendation, moderate-quality evidence)	-	No first-degree relatives with a CRC diagnosis; no personal diagnosis of adenomatous polyps or CRC; no history of inflammatory bowel over 8-10 years; no positive G-GOBT results
The Canadian Association of Gastroenterology, 2018[101]	All individuals with a family history of CRC or documented adenoma. 50-75 years	Colonoscopy is suggested (recommended in individuals with ≥ 2 first-degree relatives), with FIT as an alternative	-
The Saudi Arabian Ministry of Health, 2015[102]	Average-risk adults aged 45-70 years	Colonoscopy alone every 10 years is the recommended modality; however, if unavailable, flexible sigmoidoscopy every 5 years coupled with annual G-FOBT or FIT should be considered. FIT is preferred over G-FOBT	-

USPTF: United States Preventive Services Task Force; MTSTF: The United States Multi-Society Task Force; ACP: The American College of Physicians; ACS: American Cancer Society; NCCN: The National Comprehensive Cancer Network; CRC: Colorectal cancer; G-FOBT: Guaiac-based fecal occult blood test; FIT: Fecal immunochemical test; IBD: Inflammatory bowel disease; SSP/SSL: Sessile serrated polyp/sessile serrated lesion; SP/SSL: Serrated polyp/sessile serrated lesion; mt-sDNA: Multi-target stool DNA.

This review has several limitations that should be acknowledged. Primarily, it is a narrative, non-systematic synthesis of the literature. While efforts were made to include key and recent studies, the selection process may not have captured all relevant publications, potentially introducing selection bias. Furthermore, the findings and conclusions were not derived from a formal, protocol-driven systematic review with meta-analysis, which limits the objectivity and generalizability of our interpretations.

CONCLUSION

Provided the different socioeconomic levels and different population scales, tailored CRC screening system deserves deliberation. The establishment of a cost-effective, stepwise screening system is imperative, especially in regions with large population or limited healthcare resource: Strengthen cancer registries and screening infrastructure to improve timely diagnosis and treatment, and begin with organized programs in high-incidence regions before gradual expansion; in resource-limited settings, priority should be given to primary screening methods such as FIT followed by confirmatory colonoscopy for positive results; Integrate quality control and evaluation, gather long-term statistics to inform future microsimulation modeling and the development of optimized, risk-stratified algorithms. Concurrently, raise awareness of modifiable risk factors (e.g., obesity, smoking) and raise willingness to participate in screening programs among people.