Colorectal cancer screening: An update and South African perspective

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Epidemiology

Colorectal cancer (CRC) accounts for about 10% of all malignancies, making it the third most common cancer worldwide. Furthermore, CRC carries a high mortality with 935,000 deaths recorded in 2020, making it the second leading cause of cancer-related deaths globally.

There is a large geographic variation in incidence rates with a 4-fold higher rate in developed versus developing countries. The lowest incidence rates are noted in Africa and Central Asia.(1) Incidence rates and mortality are, however, increasing in low and middle-income countries while stabilizing in high-income countries.(2) CRC risk increases with advancing age. Internationally there is a tenfold increased risk between those less than 50 years old and patients above 85.(3) In recent years, however, CRC has been diagnosed at an earlier age with patients presenting with more advanced disease.(4) The age-standardized incidence rate (ASIR) per 100,000 in Africa is 5.25, with a higher rate seen in North Africa (8.86) compared to Sub-Saharan Africa (SSA) (5.91).(5) The National Cancer Registry in South Africa (SA) reported an ASIR of 6.84 in females (fifth highest cancer) and 10.85 in males (fourth highest cancer) in 2022. The ASIR has increased in both men and women from 1986 to 2022, with a dip noted before 2011, likely due to poor reporting prior to the declaration of cancer as a reportable disease (Figure 1 and Table 1).(6) The true incidence of CRC in Africa is likely higher than reported due to resource limitations, lack of access to healthcare services, underdiagnosis, and underreporting.

Figure 1:

Temporal trends of the age-standardized incidence rate of colorectal cancer in SA (6)

Table 1:

Average annual percentage change (AAPC) of colorectal cancer in SA

sex	Trend1		Trend2
	period	AAPC (95% CI)	period	AAPC (95% CI)
Female	1986–2006	−1 (−2.4,0.4)	2006–2022	2.7 (1.3,4.2)*
Male	1986–2022	1.4 (0.9,1.9)*
Overall	1986–2006	−0.4 (−1.9,1)	2006–2022	2.5 (1.1,3.9)*

In SA, black patients develop CRC at a younger age than other race groups.(7–9) It has been postulated that this may have a molecular or genetic basis with a higher propensity towards microsatellite instability (MSI) and hereditary non-polyposis CRC (HNPCC) amongst black patients.(9–13) Families with unique mismatch repair mutations resulting in HNPCC have been identified in SA. However, more data is needed to confirm the genetic basis for the younger onset of CRC amongst black patients.(14) The evolving landscape of CRC is likely related to lifestyle changes associated with urbanization. Risk factors for the development of CRC include a family history of CRC, obesity (relative risk (RR) 1.54), hyperlipidaemia (RR 1.62), physical inactivity, diet (increased risk with the consumption of red and processed meats and a protective effect with the intake of calcium, fiber, Vitamin D and fruit and vegetables), smoking (RR 1.35), moderate to heavy alcohol consumption (RR 1.71) and diabetes (hazard ratio 1.18–1.49).(15–18) The risk conferred by a family history of CRC is dependent on the number of affected relatives and the age of diagnosis of the affected family members (younger ages conferring a higher risk) with a twofold increased risk on average. Furthermore, having a first degree relative with CRC confers a higher risk in younger patients with the elevated risk waning with increasing age (relative risk of 3.29 for age <40 years vs 1.42 for age > 40 years).(19) Clinicians should therefore obtain a three generation family history to identify clustering of cancer within families.

The progression towards CRC is typically initiated by multiple genetic mutations and chromosomal instability, leading to microsatellite-stable tumors. This manifests as the progression from an adenoma to CRC, thereby presenting an opportunity to prevent cancer by resecting adenomas detected by screening. In contrast, MSI tumors develop from ineffective DNA repair by the inactivation of mismatch repair genes, resulting in HNPCC (Lynch syndrome). Sessile serrated lesions (SSLs) are the result of mutations in BRAF or KRAS and progress to CRC by methylation of tumour-suppressing genes.(20)

Screening Modalities

Stool Based Tests

Stool-based tests are reliant on the detection of blood within the gastrointestinal tract (GIT). Guaiac faecal occult blood tests (gFOBT) detect haem, whereas faecal immunochemical tests (FIT) detect human globulin. When interpreting these tests, it is important to bear cognizance of the fact that premalignant and malignant lesions are not the only source of blood loss within the GIT. Furthermore, haem is present in some foods, including red meat, necessitating the need for implementing dietary restrictions prior to gFOBT-based testing.(21,22) Stool-based testing with gFOBT requires three samples and annual or biennial testing, decreasing its uptake.(22,23) The sensitivity of gFOBT at detecting CRC and advanced neoplasia is between 13%–50% and 2%–24%, respectively.(22) While gFOBT has been shown to reduce CRC-related mortality, it is limited by a low sensitivity for the detection of premalignant lesions.(22,23)

FIT testing is specific for human globulin and requires one sample, which can be collected at home and posted. The threshold defining a positive test can be adjusted with lower thresholds, increasing the detection of advanced neoplasia but reducing its positive predictive value, leading to the need for more colonoscopies. The FDA-approved cut of value of 20 ug/g results in a sensitivity and specificity for CRC of 79% and 94%, respectively.(22,23) In comparison, at this threshold, the sensitivity for advanced neoplasia is 25%.(23) While colonoscopy remains the gold standard for CRC and advanced adenoma detection, the higher rate of uptake with FIT testing coupled with annual or biennial testing makes the yield comparable to a colonoscopy performed every 10 years.(23)

Stool testing has evolved beyond the detection of haemoglobin to include the detection of methylated and tumour DNA. This detects mutations associated with CRC, advanced adenomas, and SSLs in cells shed within the lumen of the colon. Early models of multitarget stool DNA (MT-sDNA) testing showed an increased sensitivity compared to FIT for the detection of CRC (92.3%), advanced neoplasia (42.4%), high-grade dysplastic polyps (69.2%), and large SSLs (42.4%). Specificity, however, was lower than FIT (86.6% vs 94.9%), resulting in more false positive tests and potentially increasing the need for colonoscopy.(24) Next-generation MT-sDNA tests have recently been developed and evaluated. These tests detect newer biomarkers and have shown higher sensitivities for CRC (93.9%) and advanced neoplasia (43.4%) compared to FIT testing (67.3% and 23.3%, respectively). A lower specificity was noted for advanced neoplasia (90.6%) and a negative colonoscopy (92.7%) compared to FIT testing (94.8% and 95.7%, respectively).(25) Current recommendations are to perform MT-sDNA testing every 3 years, with cost models showing it to be less cost-effective compared to both colonoscopy and FIT.(26) Furthermore, stool collection is more complex with the need for buffers increasing the number of inadequate specimens.(23) In addition to DNA-based stool tests, RNA-FIT tests, which evaluate RNA markers for CRC and advanced neoplasia, are being evaluated.(27)

Blood-Based Tests

Blood-based tests, or liquid biopsies, for detecting CRC and precursors, have been shown to increase screening uptake.(28) They offer a non-invasive, safe, acceptable, and convenient mode of screening but are limited in their ability to detect advanced adenomas. Blood-based tests for CRC are also being incorporated into multi-cancer early detection tests which screen for several different cancers simultaneously. Blood-based tests incorporate artificial intelligence and detect cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) released in the bloodstream by tumor cells. Several newer blood-based modalities additionally detect epigenetic and protein biomarkers.(27,29) A recent study evaluated a cfDNA test relative to colonoscopy in a screening population. The cfDNA test had a sensitivity of 83.1% for CRC and a sensitivity of 13.2% for advanced precursor lesions. The specificity for any advanced neoplasia or CRC was 89.6%.(30)

Imaging

Computed tomographic colonography (CTC) allows for the visualization of premalignant and malignant colorectal lesions through 3D and 4D reconstructions. It is a non-invasive, safe alternative to colonoscopy for CRC screening and is indicated in cases of incomplete colonoscopy.(19,31) Although sedation is not required for CTC, it requires bowel preparation, the instillation of air and gas, patient position changes, and radiation exposure. Access to CTC may be limited by the need for equipment and trained radiologists. There is a high rate of incidental findings during CTC (>60%), the minority of which are clinically relevant (5.2%–16%), thus creating the potential for unnecessary investigations, increasing costs and risk exposure.(31,32) The sensitivity of CTC for the detection of CRC is 92%, while the sensitivity and specificity for small lesions (>10 mm) are 92% and 96%, respectively. Smaller lesions are, however, less accurately detected, with a specificity and sensitivity for lesions >6 mm of 70% and 86%.(23) Other trials have shown an advanced neoplasia detection rate per 100 participants of between 4.9 and 6.1 for CTC compared to 7.2–8.7 for colonoscopy. It is noted, however, that CTC has a higher participant uptake, making it comparable to colonoscopy on this basis. The detection of flat lesions remains a limitation of CTC with colonoscopy having a 5 times higher yield than CTC at detecting SSLs.(31)

MR colonography is a newer imaging modality that avoids radiation exposure but still requires bowel preparation and the instillation of air and gas. While more data is needed, it has shown pooled sensitivities of 98.2%, 82%, and 38% for the detection of CRC, large polyps, and any-sized polyps, respectively.(23)

Colon capsule (CC) is a variation of small bowel video capsule enteroscopy, utilizing a wireless capsule-housed camera to image the large intestine. Advancements in the technology have led to improved image quality and increased diagnostic yields. In the USA, it is approved for imaging patients with incomplete colonoscopy, GIT bleeding and contraindications to colonoscopy. It is a recognized option for CRC screening in individuals unable to undergo other screening modalities.(19) In a multicenter study across the USA and Israel, 79% of patients had a complete CC with most incomplete studies being due to incomplete preparation or short transit times. Using CC, the sensitivity and specificity were 81% and 92% for polyps >6 mm and 80% and 97% for polyps >10mm. Most false negatives were due to flat hyperplastic polyps and SSLs.(33) When compared to CTC, CC had a higher sensitivity and specificity for both small >6 mm (79.2%/96.3% vs 26.8%/98.9%) and large polyps >10 mm (85.7%/98.2% vs 50%/99.1%).(34)

Endoscopy

Colonoscopy is considered the gold standard for the detection of colorectal neoplasia and CRC. It offers a one-step screening process allowing the detection, diagnosis, and treatment of neoplasia. Other non-invasive modalities represent a 2-step process with a positive test still requiring the need for colonoscopy. The capacity to perform colonoscopy with regards to both skill and resources, remains a significant barrier to its use as a primary screening modality. In addition to capacity, colonoscopy is invasive, requires the need for bowel preparation, requires the capability to provide safe sedation, requires support staff (nurses, scope processors, etc), and carries a risk of complications like bleeding and perforation. Colonoscopy, therefore, has a lower uptake than FIT testing.(23) A large, randomized, population-based European trial (NordICC) showed no perforations or colonoscopy-related deaths within 30 days.(35) Multiple studies have shown that colonoscopy can reduce CRC-related mortality in both the proximal and distal colon by between 29% and 68%. Furthermore, through the detection and resection of precursor lesions, colonoscopy has the potential to prevent CRC. Only a small percentage of such lesions, however, progress to CRC, and thus detection through colonoscopy may increase the burden on resources while providing unclear gain.(23) The recently published NordICC trial showed a risk reduction of 18% for CRC in the colonoscopy screening group. In this study, the number needed to invite to screening with colonoscopy to prevent one CRC was 455 patients. The study was, however, performed with an intention to treat analysis, and only 42% of those invited underwent screening with colonoscopy.(35) The number needed to screen to prevent one CRC is therefore likely to be lower with higher uptake. While local data is lacking, surveillance colonoscopy in high-risk SA patients, identified by mismatch repair gene defects, has been shown to improve overall and disease-specific survival.(14) A further barrier to the effectiveness of screening with colonoscopy is training and quality of the colonoscopy.

Flexible sigmoidoscopy is an alternative to colonoscopy for screening. While it is quicker, does not require sedation, and does not require full bowel preparation, it does require similar resources to colonoscopy. Furthermore, the detection of precursor lesions during sigmoidoscopy warrants a full colonoscopy. Sigmoidoscopy has been shown to reduce CRC incidence by up to 23% and mortality from CRC by up to 27%.(23)

Requirements for a Screening Program

Organized screening programs target specific populations at a national level through a systemic and defined process. This is a multi-step process requiring quality control measures at each of the individual steps to ensure effectiveness. The International Agency for Research on Cancer (IARC) provides guidance on the steps needed to implement an organized screening program. Some of these steps include defining target populations, establishing databases and cancer registries, selecting cost-effective screening modalities that are widely available, implementation policies, implementation teams, defining intervals for screening, pathways for invitations to screening, pathways to track clinical outcomes, and access to follow up care for patients with positive screening tests.(22,36) In contrast, opportunistic screening is carried out on an ad hoc basis through healthcare encounters. This is highly dependent on individual healthcare workers and is subject to risks, including underutilization, overutilization, lack of quality control, inappropriate use of resources, and inequitable access.

The IARC guidelines recommend that 95% of the target population should be invited to screening with a minimum uptake rate of 45%, follow-up colonoscopy rates of 85%, and a maximum time of 31 days from a positive screening test to colonoscopy.(37) In the event of positive screening tests or the detection of CRC, access to follow-up care is crucial. Therefore, ensuring capacity and access to ancillary care, including diagnostic imaging, oncology services, interventional endoscopy, surgery, radiation therapy, dietetics, stoma services, and intensive care, are fundamental to the implementation of an organized screening program.

Studies evaluating the cost-effectiveness of CRC screening have shown screening to be cost-effective.(22) Due to a lack of screening programs in SSA, local data is lacking. Mathematical modeling has shown screening colonoscopy in combination with treatment to be potentially cost-effective in SSA. Increasing treatment coverage, however, is needed, and increased treatment coverage on its own is a cost-effective strategy.(38) Treatment for early-stage disease (stage 1) is both cheaper and more effective than treating later-stage disease (stage 2 and beyond).(39) Early diagnosis and management, therefore, enable cost savings. Training and building capacity for the early diagnosis of CRC and establishing referral pathways and access to the multidisciplinary management of CRC is an essential start to implementing a screening program in SA.

Current Recommendations for Colorectal Cancer Screening

The American College of Gastroenterologists (ACG) and the European Society of Gastrointestinal Endoscopy endorse screening with FIT or colonoscopy from the age of 50 in those with an average risk of CRC and younger in those with first degree relatives with CRC.(19,36) Previous ACG guidelines further recommended screening in African Americans start from the age of 45 due to younger mean ages of diagnosis and higher mortality in black patients.(40) This is particularly relevant and congruent with the experience in black patients in SA. In recent years, the incidence of advanced neoplasia and CRC in younger patients has been on the rise, partly because of the increase in obesity. This has prompted multiple societies like the ACG to suggest screening in all race groups from the age of 45 years.(19) CRC incidence rates have doubled in those between the ages of 20 and 49 and screening at age 45 compared to age 50 is expected to result in a gain of 25 life years per 1000 screened patients.(19)

These benefits of colonoscopy are dependent on the training of the endoscopist and quality parameters measured by key performance indicators (KPIs). Frameworks based on the attainment of KPIs to gain and maintain accreditation to perform screening colonoscopies have been implemented in the UK with improvements in quality of care.(41) Unfortunately, no such models exist in SA. Formal endoscopy training, competency-based assessments, and achieving or maintaining KPIs are not needed to perform colonoscopy in SA. The current practice in SA is an individualized risk-based referral for CRC screening.

Capacity for Screening in SA

The lack of local data highlights a dire need to establish databases and registries in SA to define true endoscopic capacity in SA and to maintain quality control measures. This is essential in determining readiness to establish a screening program in SA. It is estimated that there are 0.06 registered gastroenterologists per 100,000 population.(42) This is notably below the recommended minimum of 0.22 per 100,000.(43) The true capacity to perform endoscopy in SA is unknown, but it is estimated that 150,000 colonoscopies are performed annually for patients with medical insurance (9 million people), and 70,000 colonoscopies are performed in public health facilities (approximately 50 million people). In comparison, 650,000 colonoscopies are performed annually in the UK for a population of 60 million people.(43) Furthermore, in South Africa, most endoscopy is performed by general surgeons and surgery medical officers with little to no structured formal training.(42)

Regarding stool-based tests, gFOBT is accessible in both the state and private sectors. In comparison, FIT testing is largely unavailable in the public health sector, which serves most of the population, and is limited to those with access to private health care. Furthermore, fragmented postal services make home-based stool collection challenging. DNA-based stool tests and blood-based tests are still not readily accessible to most of the population. Similarly, CTC, MR colonography, and CC are restricted to some tertiary hospitals, academic centers, and private healthcare institutions. The lack of resources and the large divide between state and private health care remain a substantial limitation to implementing any meaningful form of screening. At present, large private health care funders cover biennial FIT testing between ages 45–75 years and additionally cover screening by means of colonoscopy.(44) There is no such provision in state health care resulting in inequitable access and resulting in potential overutilization.

Recommendations for Screening in South Africa

Because of the limited capacity to perform organized screening, implementation is unlikely soon. We, therefore, recommend that in the interim, opportunistic screening be a more feasible approach by selecting high-risk groups based on risk factors (family history, obesity, diabetes) and genetic susceptibility (polyposis syndromes and HNPCC). We suggest risk-based screening for the general population be considered from age 45. Given the propensity to develop CRC at a younger age in black patients we suggest risk-based screening at age 40 and even younger in those with a family history or genetic susceptibility to CRC. In all patients with a first degree relative with CRC or an advanced adenoma screening should be commenced at age 40 or 10 years before the youngest onset in relatives and younger (35–40) in black patients. with a Risk calculators may facilitate the selection of patients for screening (e.g., https://www.qcancer.org/). Stool-based testing using FIT needs to be made more accessible and is likely to be the most appropriate modality for screening in our setting.

The South African National Cancer Prevention Services (SANCaPS) has advocated for the identification of inherited cancers by associating data processing between the National Health Laboratory Service (NHLS) Corporate Data Warehouse (CDW) and the National Cancer Registry.

Cancer reports from both state and private health care pass through the CDW this enabling identification of high-risk family members through this proposal. Furthermore, SANCaPS recommend mandatory testing for mismatch repair genes in all CRC diagnosed <60 years of age to identify genetic MSI tumors.(45) These measures are an important step to identify high risk individuals in whom opportunistic screening will have a higher gain.

In addition, we advocate for improved endoscopy services through increasing capacity for training, the implementation of competency-based assessments and the establishment of national databases to ensure quality control through the mandatory maintenance of KPIs in order to provide screening endoscopy.

Conclusion

The incidence of CRC is likely to increase in SA and SSA with urbanization, the surge of obesity, and diabetes. The younger age of diagnosis of CRC in black patients has profound fiscal implications by affecting the working age group in SA, thus making it a potential public health crisis in the future. Due to our unique genetic makeup, social circumstances, lifestyles, and challenges in SA, international costing models and policies cannot be extrapolated to our setting. The potential to face epidemic-like proportions of CRC in the coming decades in SA can be averted. There is an urgent need to implement concurrent policies aimed at training and building capacity to reduce incidence through public health initiatives, screening for pre-malignant lesions, early detection of CRC, and facilitating pathways to access care in those with advanced neoplasia and CRC. In order to achieve this, creating awareness and buy in from all stake holders including governmental support is crucial. As the benefits of these initiatives will take over a decade to manifest a meaningful impact, there is a window of opportunity to implement prompt intervention.

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