Background
Colorectal cancer (CRC) is one of the most prevalent causes of cancer-related morbidity and mortality in Western countries [
1]. Both can be reduced by the detection of cancers at early, curable stages and by the detection and removal of colorectal adenomas, the most important CRC precursor lesions [
2,
3]. Colonoscopy is the reference standard for the detection and removal of adenomas and its associated CRC mortality reduction is why CRC screening is implemented in many Western countries [
2‐
4]. CRC screening programs can be divided in primary colonoscopy screening programs in which all participants undergo a screening colonoscopy, and screening programs in which the screening colonoscopy is preceded by a triage modality, such as non-invasive stool tests [
4]. Only test-positives will undergo colonoscopy. The effectiveness of all CRC screening programs therefore relies on the quality of the colonoscopy, of which the adenoma detection rate (ADR) is the most established quality indicator [
5‐
8]. In primary screening colonoscopy cohorts lower ADRs were associated with higher post-colonoscopy CRC and CRC mortality risks [
5,
6].
An increasing body of evidence suggests that serrated polyps (SPs) also contribute to CRC oncogenesis [
9‐
11]. Of all post-colonoscopy CRCs, a significant proportion seems to arise from proximal located SPs, presumably because of high lesion miss rates [
12,
13]. As such, the detection of proximal SPs is of importance and the proximal serrated polyp detection rate (PSDPR) has been proposed as a screening colonoscopy quality indicator as well [
14‐
17]. However, the PSPDR is not an established quality indicator, as the association between the PSDPR and the occurrence of post-colonoscopy CRCs has not been established yet [
14,
17].
Both the ADR and the PSPDR are known to vary among endoscopists [
5,
6,
14,
17‐
23]. Nonetheless, little is known about the effect of these variations in ADR and PSPDR on the effectiveness of a screening program using biennial fecal immunochemical testing (FIT) as a triage modality. Therefore, this study aimed to evaluate the effect of variation in ADR and PSPDR on the long-term impact of a biennial FIT-based CRC screening program using the Adenoma and Serrated pathway to Colorectal CAncer (ASCCA) model.
Discussion
Based on the ASCCA model, an increase in ADR will gradually reduce CRC incidence and mortality in a biennial FIT-based CRC screening program, whereas an increase of the PSPDR does only minimally impact CRC burden at a population-level. Similar results were found when an alternative strategy of FIT screening without surveillance was evaluated. The impact of an increased PSPDR on long term-outcomes only slightly increased when assuming a 30% instead of 15% contribution of the serrated pathway and under the assumption that FIT would have a comparable sensitivity for adenomas and SPs. The maximum impact of changing either the PSPDR (from 3 to 15%) or ADR (from 44 to 62%) on mortality reduction due to screening was observed when a colonoscopy screening programme with perfect compliance was modelled. In that case, mortality reductions varied with 4.6 and 15% when varying the PSPDR and ADR over its plausible range.
There are two explanations for the limited influence of an increased PSPDR on the model-predicted effectiveness of FIT-based screening. Firstly, only 15–30% of all CRCs originate from the serrated pathway [
11]. When assuming a 30% contribution of the serrated pathway to CRC incidence, CRC mortality reduction due to screening varied with 3.8% when increasing the PSPDR over its plausible range compared to 1.3% in the base-case scenario wherein a 15% contribution was assumed. Secondly, under the assumption that FIT has a comparable sensitivity for both adenomas and SPs, a 4.0% difference in mortality reduction by increasing the PSPDR over its plausible range was found. FIT is known to be ineffective to detect clinically relevant SPs, such as larger and/or proximally located HPs and SSLs, since these lesions seldom bleed [
9,
11,
38,
39]. This is also supported by our calibration analysis in which equal detection rates per SP led to similar PSPDRs for FIT-screening and colonoscopy screening. In other words, FIT-screening does not lead to a subgroup of individuals referred for colonoscopy that has an increased SP prevalence. Contrastingly, the ADR was considerably higher after preselection with FIT compared to colonoscopy screening when assuming equal detection rates per adenoma. Positivity of FIT in individuals having relevant SPs is most likely due to the frequent co-occurrence of synchronous advanced adenomas or CRC [
40].
The majority of individuals harbouring relevant SPs without concurrent adenomas will therefore not benefit from FIT-based screening. Particularly these individuals are at risk of developing a FIT interval cancer, as it is suggested that SPs, once dysplastic may evolve relatively quickly into malignancy [
41]. Improved detection of proximal SPs during colonoscopy is only effective for improving the effectiveness of a CRC screening program, if colonoscopy is used as a primary screening modality or when a triage test would preselect individuals at increased risk for relevant SPs as well as for advanced adenomas and CRC. Molecular stool testing has shown promising results. However, costs, test specificity, and ease to perform should improve to become a realistic alternative to FIT [
32]. Currently, whole stool samples are needed to enable molecular testing. This could be burdensome for screenees and will influence adherence rates, which is crucial for population-based screening programs [
32].
Irrespective of the used triage modality, colonoscopy will remain the reference standard to detect and resect adenomas, SPs and cancer. To ensure the effectiveness of a screening program, quality assurance and monitoring the quality of colonoscopy is of paramount importance. To obtain and assure high quality within the Dutch national CRC screening program, national requirements were set for professionals performing screening colonoscopies. Only endoscopists satisfying pre-defined quality requirements are accredited to perform screening colonoscopies. During the accreditation process, the knowledge and skills of endoscopists are tested by an e-learning, by measuring evidence-based quality indicators and by evaluating the practical skills during colonoscopy [
42].
The ADR is endorsed as the most important (screening) colonoscopy quality indicator, since it is inversely correlated with the occurrence of post-colonoscopy CRCs cancers and CRC mortality in large primary screening colonoscopy cohorts [
5,
6]. However, ADR is criticized as being slightly imprecise, as it does not provide information about incremental adenomas detected besides the first, resulting in the ‘one and done phenomenon’[
43]. Ideally, reporting of the ADR would be combined with a quality indicator reporting on the total number of detected adenomas [
43]. In contrast to these data on ADR, no prospective studies evaluating the association between the PSPDR and the risk of interval cancers have been performed and recommendations for PSPDR thresholds are yet to be determined [
14,
17]. As a consequence it can be hypothesized that the ‘one and done phenomenon’ currently does not apply to the PSPDR. Furthermore, both ADR and PSPDR do not select for neoplastic lesions having a higher neoplastic potential. The histopathological subtyping of SPs tends to be difficult, resulting in a broad diagnostic variability between pathologists [
44]. However, by choosing the total group of SP located in the proximal colon, this interobserver variability among pathologists should not influence the results.
Both ADR and PSPDR vary widely, suggesting important lesion miss rates in low detecting endoscopists [
5,
6,
14,
17‐
23]. Up to date, no studies have assessed interventions to improve the PSPDR. In contrast, several strategies aimed to improve ADR, including simple feedback, involvement of endoscopy nurses and mandating longer colonoscope withdrawal times, as well as multifaceted strategies involving education, audit and feedback. However, all methods had limited effect on ADR [
45‐
49]. The minor impact and poor performance of most interventions may be caused by the paucity of evidence on appropriate factors to target for modification [
50].
The interpretation of detection rates is difficult. This is due to the fact that besides endoscopy skills, detection rates are also influenced by the primary screening test and by the characteristics of the screening population, such as age, gender, screening history and prevalence of neoplastic lesions [
18]. Thus, detection rates can only be interpreted in the context of the same screening setting. The calibrated detection rates in this study are based on one round of FIT-screening in previously unscreened, asymptomatic individuals aged 55–75 years. It should be noted that this differs from the Dutch CRC screening program which includes a phased implementation. During the implementation phase, selective cohorts are invited for screening starting with primarily older cohorts.
To the best of our knowledge this is the first microsimulation study investigating the influence of both the ADR and the PSPDR on the effectiveness of a biennially FIT-based as well as a primary colonoscopy screening program. Three other microsimulation studies estimated the effectiveness of primary colonoscopy screening at different levels of adenoma detection, also showing that higher ADRs were associated with important CRC incidence and mortality reductions [
51‐
53]. The study by Meester et al. also investigated the effectiveness of annual FIT-based screening, showing a higher CRC related mortality in lower ADR settings [
53]. An important difference between these models and the ASCCA model is the fact that both the adenoma-carcinoma pathway and the serrated pathway are included in the ASCCA model, whereas the other models only incorporate the adenoma-carcinoma pathway. This enabled us to also evaluate the impact of improvements in the PSPDR on CRC incidence and mortality reductions.
However, important limitations have to be acknowledged as well. First, we assumed a 10% lower detection rates rated for SPs than for adenomas to estimate the base-case PSPDR. Currently, the exact miss rates of SPs remain to be determined. However it is possible that the actual miss rates of SPs are higher than assumed in our base-case analysis, caused by the flat appearance, proximal location and pale color of SPs hampering detection [
35]. On the other hand, the adenoma miss rates of colonoscopies performed nowadays may potentially be lower than miss rates reported by Van Rijn et al [
7]. Since the publication of this study, the awareness of high quality colonoscopy has increased, accompanied by important improvements in the colonoscopy equipment, such as the application of high-definition colonoscopes and advanced imaging techniques. However, recently no new back-to-back studies have been published. To account for the uncertainty regarding this parameter however, we have evaluated a range of miss rates for both adenomas and SPs.