Performance of two screening tests and barriers to colorectal cancer screening

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PhD thesis

Performance of two screening tests and barriers to colorectal cancer screening

Anna Lisa Schult

Section for Colorectal Cancer Screening, Cancer Registry of Norway.

Department of Medicine, Bærum Sykehus, Vestre Viken Hospital Trust.

Faculty of Medicine, University of Oslo.

2021

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© Anna Lisa Schult, 2022

Series of dissertations submitted to the Faculty of Medicine, University of Oslo

ISBN 978-82-8377-992-9

reproduced or transmitted, in any form or by any means, without permission.

Cover: Hanne Baadsgaard Utigard.

Print production: Reprosentralen, University of Oslo.

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Screening at the Cancer Registry of Norway between 2015 and 2021. The practical work was performed at the Department of Gastroenterology at Bærum Hospital and Moss hospital. I want to acknowledge the University of Oslo for the cooperation during my PhD fellowship and the Department of Medicine at Bærum Hospital for releasing me from my clinical work during this period.

First of all, I would like to thank my main supervisor, Thomas de Lange. As the head of Gastroenterology at Bærum Hospital, you took me under your wings from my first day as a young doctor in 2010. As often as I had time, I joined you at the endoscopy unit to observe and participate in endoscopies. When Bærum Hospital became one of two centres in a large CRC screening trial, you hired me as one of the endoscopists, an opportunity I always will be grateful for. Later you became the head of the Section for Colorectal Cancer Screening at the Cancer Registry, and thus my main supervisor when I started as a PhD fellow. We have known each other for a long time now. Also, when you at first took a new job and then even moved to Sweden, you have always been there for me. You supported my work with clinical knowledge and research experience, you are both critical and motivating. Last but not least, you had a lot of understanding for various challenges during this PhD period.

I am also most thankful to my co-supervisor Geir Hoff. No matter what and when I asked you, you always answered enthusiastically and constructively and I never had to wait for feedback. You are without a doubt the person in Norway with most experience and knowledge in colorectal cancer screening research. Without you, this project had not been carried out.

Edoardo Botteri, thank you for your support in thousands of statistical analyses, for checking results and discussing confusing concepts of statistics. I am very grateful that you were my co-supervisor.

Øyvind Holme, you replaced Thomas as the head of the Section for Colorectal Cancer Screening at the Cancer Registry and became one of my co-supervisors. I appreciate your honesty and your knowledge. You have been there for everyday questions and challenges, even if you were not my main supervisor.

My co-supervisor Michael Bretthauer, thank you for presenting me to your research group, for giving valuable feedback on analyses and manuscripts and insights into scientific reasoning.

Kristin, my PhD mate, I enjoyed our professional discussions, our teamwork, but also social happenings with and without our families. Particularly, I will not forget the three weeks we spent at the Summer Course in Epidemiology in Firenze.

Additionally, I would like to thank my colleagues at the Section for Colorectal Cancer Screening; Anita, Paula, Markus, Stine, Erik, Therese, Ane, Mona and Bård for the good fellowship and Giske Ursin, the Director of the Cancer Registry, for giving me the opportunity to carry out this work.

I also want to thank all my co-authors for their valuable contributions to the papers. Thanks also to all the nurses, doctors and secretaries at the screening centres as well as bioengineers

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and pathologists involved in the screening trial. I would also like to thank Mona and Marius for their contribution as clinical monitors in the third study.

Svein Oskar, the current head of the Department for Gastroenterology at Bærum Hospital, thank you for keeping in touch all the time and for continuing to give me the opportunity to work for you.

To my family, thank you for always supporting me, even if my decisions have taken me far away from you. The geographical distance has been particularly apparent since the corona pandemic. I miss you a lot!

Finally and most important, Sverre, thank you for being my friend and husband, for sharing home office the last 15 months, for keeping me happy and loving me. To our kids, August, Alfred and Hennie, thank you for being there with your ideas, your disputes, your humour.

You make life colourful and worth living.

Stabekk, July 2021 Anna Lisa Schult

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7 Abbreviations

ACG American College of Gastroenterology ADR Adenoma detection rate

AE Adverse event

APC gene Adenomatous polyposis coli gene APC Adenoma per colonoscopy

ASA American Society of Anesthesiologists BBPS Boston Bowel Preparation Scale CEA Carcinoembryonic antigen CI Confidence interval

CIMP CpG island Methylator Phenotype CIN Chromosomal instability

CIR Cecum intubation rate CRC Colorectal cancer

CTC Computed tomographic colonography

ESGAR European Society of Gastrointestinal and Abdominal Radiology ESGE European Society of Gastrointestinal Endoscopy

EU European Union

FAP Familial adenomatous polyposis FDA US Food and Drug Administration FIT Faecal immunochemical test

FIT1-3 Accumulated three rounds of FIT FOBT Faecal occult blood test

gFOBT Guaiac-based faecal occult blood test HP Hyperplastic polyp

IBD Inflammatory bowel disease IBS Irritable bowel syndrome

iFOBT Immunochemical faecal occult blood test IARC International Agency for Research on Cancer KPI Key performance indicators

LST Lateral spreading tumours MEI Magnetic endoscopic imaging

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8 MMR genes Mismatch repair genes

MSI Microsatellite instability

MSTF Multi-Society Task force on colorectal cancer

NICE Narrow-Band Imaging International Colorectal Endoscopic Classification NSAIDS Non-steroidal anti-inflammatory drugs

OR Odds ratio

PCCRC Post-colonoscopy colorectal cancer PDR Polyp detection rate

PREM Patient reported experience measure PROM Patient reported outcome measure RCT Randomised controlled trial

REC Regional Committee for Medical Research Ethics RR Risk ratio

SAE Serious adverse event SSL Sessile serrated lesion

TNM system Tumour Node Metastasis system TSA Traditional serrated adenoma

USPSTF US Preventive Services Task Force VAS Visual analogue scale

WHO World Health organisation

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Definitions

Advanced adenoma: Advanced adenoma was defined as an adenoma ≥ 10 mm, or an adenoma with presence of high grade dysplasia or ≥ 25% villous components.

Advanced serrated lesion: Advanced serrated lesions were defined as any serrated lesion (HP, SSL or TSA) ≥ 10 mm or with dysplasia.

CRC: CRC was defined as adenocarcinoma localised to the rectum or colon.

Distal lesion: Colonic lesions detected in the rectum, sigmoid and descending colon were defined as distal.

Effectiveness: The extent to which an intervention works under “real world” conditions.

Trials using an effectiveness approach are also called pragmatic trials.

Efficacy: The extent to which an intervention works under ideal and highly controlled conditions. Trials determining efficacy are also called explanatory trials.

Gastronet: The official national quality assurance programme for gastrointestinal endoscopy.

Positive predictive value: The probability of being affected when a test is positive. It is calculated as the quotient of true positives and the sum of true positives and false positives.

Proximal lesion: Colonic lesions detected in the splenic flexure and proximal for it, were defined as proximal.

Sensitivity): The ability of a test to identify affected individuals correctly. It is calculated as the quotient of true positives and the sum of true positives and false negatives.

Specificity: The ability of a test to identify unaffected individuals correctly. It is calculated as the quotient of true negatives and the sum of true negatives and false positives.

Type I error: The rejection of a true null hypothesis.

Type II error: The acceptance of a false null hypothesis.

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Articles in this thesis

Paper I: Randel KR*, Schult AL*, Botteri E, Hoff G, Bretthauer M, Ursin G, Natvig E, Berstad P, Jørgensen A, Sandvei PK, Olsen ME, Frigstad SO, Darre-Næss O, Norvard ER, Bolstad N, Kørner H, Wibe A, Wensaas KA, de Lange T, Holme Ø.

Colorectal cancer screening with repeated fecal immunochemical test versus sigmoidoscopy: baseline results from a randomized trial.

Gastroenterology 2021

*shared first authorship

Paper II: Schult AL, Botteri E, Hoff G, Randel KR, Dalén E, Eskeland SL, Holme Ø, de Lange T.

The proportion of cancers and advanced adenomas in asymptomatic participants in colorectal cancer screening: a cross-sectional study BMJ open 2021

Paper III: Schult, AL, Botteri E, Hoff G, Holme Ø, Bretthauer M, Randel KR, Gulichsen EH, El-Safadi B, Barua I, Munck C, Nilsen LR, Svendsen HM, de Lange T.

Women require routine opioids to prevent painful colonoscopies: a randomised controlled trial

Submitted manuscript

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Norsk vitenskapelig sammendrag

Bakgrunn: Tarmkreft (CRC) har høy forekomst og fortsatt høy dødelighet, særlig i vestlige land selv om behandlingsmulighetene har blitt bedre. Screening mot CRC kan redusere dødelighet og, avhengig av metoden, forekomst av CRC. Endoskopisk screening med sigmoidoskopi eller koloskopi og test for usynlig blod i avføring er de metodene som brukes hyppigst. Fekal immunokjemisk test (FIT) er den av avføringstestene på skjult blod som anvendes hyppigst. Det foregår omfattende forskning for å vurdere effekten av de forskjellige metodene. Effektiviteten av en screeningstest er imidlertid ikke bare avhengig av test

egenskapene men også av deltakelsesraten og at målgruppen for screening blir testet.

Endoskopiske undersøkelser kan være smertefulle og frykt for smerte kan true deltakelse i screeningen. Særlig kvinner har en høy risiko for smertefulle koloskopier. En misoppfatning om at screening er for dem med symptomer fra tarmen kan være en annen årsak til at

målgruppen, nemlig asymptomatiske mennesker, velger å avstå fra deltakelse.

Målet med denne avhandlingen var å beskrive funn ved tidspunkt for screening i en randomisert studie som sammenliknet to forskjellige screeningsmetoder, og å belyse både forekomsten av neoplasi hos asymptomatiske deltakere samt å sammenlikne forskjellige medikamentelle strategier for å redusere smerter under koloskopi hos kvinner.

Material og metoder: Denne avhandlingen er basert på data fra en stor randomisert studie som sammenlikner effektiviteten av engangs sigmoidoskopi med gjentatte runder med FIT for CRC screening. Omtrent 140,000 menn og kvinner ble tilfeldig utvalgt til de to gruppene i en 1:1 ratio. Studie I i denne avhandlingen sammenliknet deltakelsesrater, positivitetsrater, deteksjonsrater for neoplasi, kvaliteten av koloskopiene og alvorlige uønskete hendelser i de to gruppene. Studie II var en tversnittstudie som vurderte andelen av asymptomatiske deltakere blant dem som fikk påvist enten CRC eller avansert adenom ved sigmoidoskopi screening eller ved koloskopi etter en positiv FIT. Studien evaluerte også forekomsten av tarmsymptomer og om det finnes en sammenheng mellom symptomene og neoplasi i de to gruppene. Studie III var en randomisert kontrollert studie blant kvinner som deltok ved koloskopi etter en positiv screeningstest eller var i screeningsalder og deltok ved en klinisk koloskopi. Studien sammenliknet standardbehandlingen ved smerter, nemlig fentanyl ved behov, med to alternative medikamentelle strategier; fentanyl før koloskopien begynner og alfentanil ved behov. Smerter under undersøkelsen var det primære endepunktet.

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Resultater: Studie I viste at deltakelse ved FIT screening var høyere enn ved sigmoidoskopi screening og deltakelsen økte med gjentatte test runder. Studien viste også at gjentatte runder med FIT førte til en høyere positivitetsrate enn engangs sigmoidoskopi. Det ble påvist flere CRC og avanserte adenomer, men færre ikke-avanserte adenomer ved FIT screening enn ved sigmoidoskopi screening. Forekomsten av alvorlige uønskete hendelser var likt fordelt mellom gruppene. Kvaliteten av koloskopiene oppfylte internasjonale målstandarder. Studie II viste at noen tarmsymptomer var assosiert med funn av CRC og avansert adenom, men flertallet av disse neoplasiene ble oppdaget hos asymptomatiske deltakere i begge

screeningsgruppene. I Studie III rapporterte kvinnene som fikk fentanyl i forkant av

koloskopien færre smertefulle koloskopier enn kvinner som fikk fentanyl ved behov. Det var ingen forskjell i uønskete hendelser, behov for observasjon etter undersøkelsen, cøkum intubasjonsrate eller ønsket om å gjenta koloskopi på samme måte.

Konklusjon: Betydningen av resultatene ved screeningstidspunkt i Studie I for det primære endepunktet, CRC dødelighet etter ti års oppfølging, må avventes for å kunne vurdere effektiviteten av de to screeningsmetodene. Likevel har de foreløpige resultatene gitt viktig kunnskap om planlegging og gjennomføring av et screeningsprogram mot CRC og man har sett at begge metodene lar seg gjennomføre i Norge. Studie II understreket viktigheten av å motivere asymptomatiske personer til å delta i screeningen og Studie III viste at man bør tilby fentanyl før koloskopi til alle kvinner i aldersgruppen 55-79 år. Optimalisert

smertebehandling ved koloskopi kan påvirke omdømmet til en screeningskoloskopi og dermed øke deltakelse ved screening.

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Thesis summary

Background: Colorectal cancer (CRC) is a major health burden with a high incidence and mortality rate despite improved treatment options. Screening offers the possibility of reducing both incidence and mortality of this disease. Several screening modalities are currently used in different countries. Endoscopic screening with sigmoidoscopy or colonoscopy, and testing for occult blood in stool are the most frequently applied methods. Among tests analysing stool for occult blood, faecal immunochemical tests (FIT) are most commonly used.

Extensive research seeks to scrutinize the efficacy of screening modalities. However, it is important to realize that a method with high efficacy may have low effectiveness when participation rates in screening programmes are low, or if the target group is not reached.

Potential screening participants often expect endoscopic examinations to be uncomfortable or even painful. This anticipation can jeopardize participation in screening programmes.

Especially women have a higher risk of painful colonoscopies. Another barrier to CRC screening may be the absence of bowel symptoms, as asymptomatic individuals, the target group for CRC screening, show a lower adherence to screening programmes. The overall aim of this thesis was to describe baseline findings of a randomised CRC screening trial

comparing two screening modalities and to shed light on the prevalence of asymptomatic neoplasia in a screening population and on strategies for preventing painful colonoscopies in women.

Material and methods: The present thesis is based on data from a large randomised comparative effectiveness trial comparing once-only sigmoidoscopy with repeated FIT for CRC screening. About 140,000 men and women were randomly assigned 1:1 to the two modalities. Study I was an evaluation of baseline findings including participation rates, positivity rates, detection rates of colorectal neoplasia, quality of colonoscopies and adverse events in the two screening groups. Study II was a cross-sectional study, assessing the proportion of asymptomatic individuals amongst those diagnosed with CRC or advanced adenoma at sigmoidoscopy screening and work-up colonoscopy after positive FIT. It also assessed the prevalence of bowel symptoms in these screening populations and their

association with the above mentioned neoplasia. Study III was a randomised controlled trial comparing the standard analgesic treatment, fentanyl on-demand during colonoscopy, with two alternative treatment options- fentanyl prior to colonoscopy and alfentanil on-demand in women undergoing colonoscopy with procedural pain as the primary outcome.

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Results: Study I showed that the participation rate in FIT screening was higher than in sigmoidoscopy screening and increasing with repeated rounds of testing. It also showed that repeated FIT resulted in more positive screening tests than once-only sigmoidoscopy. More CRCs and advanced adenomas were detected at FIT screening, while more non-advanced adenomas were detected at sigmoidoscopy screening. There was no difference in the rate of serious adverse events (SAEs). Colonoscopy performance met international target standards.

Study II demonstrated that bowel symptoms were frequent in our screening populations. But although some bowel symptoms were associated with a finding of CRC or advanced

adenoma, the majority of these neoplasia were detected in asymptomatic screening participants regardless of the screening modality. Study III showed that women receiving fentanyl prior to colonoscopy reported fewer painful colonoscopies than women treated with fentanyl on-demand. No differences in adverse events, need for recovery, cecum intubation rates or willingness to repeat colonoscopy were observed.

Conclusions: The comparative effectiveness of sigmoidoscopy and FIT screening is unknown. Study I showed that FIT screening was superior to sigmoidoscopy screening in terms of participation and detection of advanced adenomas and CRC. However, the removal of significantly more non-advanced adenomas in sigmoidoscopy screening may have a considerable long-term impact on CRC incidence. To sort out the comparative effectiveness in the Norwegian population we need to evaluate CRC incidence and mortality in the screening groups after long-term follow up. Nevertheless, the present results provided important information about planning and implementing a colorectal cancer screening programme and showed that both screening methods are feasible in Norway. Study II

highlighted the importance of encouraging asymptomatic individuals at average risk for CRC to participate in screening programmes. Study III showed that fentanyl before colonoscopy should be offered to all women aged 55-79. Optimized pain relief during colonoscopy may have impact on the reputation of a screening colonoscopy and thus increase participation rates in colonoscopy screening.

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Background

Colorectal cancer (CRC) Epidemiology of CRC

CRC is a major health burden worldwide. According to the estimates made by the Global Cancer Observatory (owned by the International Agency for Research on Cancer-IARC) it is the third most diagnosed cancer and second most common cause of cancer death (Figure 1).^1,

2 CRC incidence rates are highest in the most developed countries and CRC has been

proposed as a marker of socioeconomic development.² Colon cancer incidence is supposed to increase as developing countries continue to evolve economically.^{2, 3} However, in some high developed countries a decreasing or stabilising incidence and mortality is observed and assumed to be related to both a healthier lifestyle, screening programmes, a generally higher colonoscopy activity and improved treatment options.^3-8

Figure 1: Estimates of CRC incidence (blue) and mortality (red) in 2020. Provided by Global Cancer Observatory, available at https://gco.iarc.fr/, assessed 21 January 2021.¹

CRC in Norway

The CRC incidence is high in Norway and, for unknown reasons, there has been a steeper increase than in the Scandinavian neighbouring countries (Figure 2).

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CRC incidence is higher in men than in women, but compared to women in other countries female Norwegians have the highest age-standardized incidence rates worldwide (Figure 3).^1,

2 It was hypothesised that exposures specific to Norwegian women, e.g. the consumption of brown cheese, could cause this development, but so far, no specific exposures are found.⁹

Figure 2: Age-Standardized CRC incidence rates for men and women aged 0-85 years in Scandinavian countries. Provided by NORDCAN, available at https://nordcan.iarc.fr/en, assessed 21 January 2021.10

Figure 3: Estimates of age-standardized CRC incidence in women in 2020. Provided by Global Cancer Observatory, available at https://gco.iarc.fr/, assessed 21 January 2021.¹

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17 Risk factors for CRC

Individuals with hereditary syndromes are at high risk for CRC. Among these, Lynch syndrome and familial adenomatous polyposis (FAP) are the major ones. However, well defined hereditary syndromes are only responsible for about 5-7% of CRC cases.¹¹ Likewise, a positive family history (two or more first- or second-degree relatives with CRC) without a known mutation is a risk factor. It is assumed that about 20% of CRC cases are familial.¹² Long lasting chronic inflammatory bowel disease (IBD) may also carry an increased risk of CRC.¹³

Consequentially, most CRCs develop sporadically, among average-risk individuals. CRC incidence increases substantially with age.¹⁴ A recent registry-based study showed a strong age gradient for transformation from CRC precursors to CRC for both sexes.¹⁵ An aging population may be one of the major causes of increasing CRC prevalence. Another strong risk factor for CRC is male sex.² Aside from these non-modifiable factors, several lifestyle and dietary factors increase the CRC risk. The World Cancer Research Fund Network runs a Continuous Update Project analysing cancer prevention related to diet, nutrition and physical activity.¹⁶ The major modifiable risk factors for CRC are smoking, alcohol consumption, processed and red meat, overweight and lack of physical activity.^17-25 Furthermore, consumption of wholegrain, dietary fibre, dairy products and calcium supplements may reduce the CRC risk, as well as postmenopausal hormone replacement therapy and long-term use of non-steroidal anti-inflammatory drugs (NSAIDS) are protective.^26-29

Colorectal neoplasia and tumorigenesis

The majority of CRCs are caused by slow-progressing precancerous lesions like adenomas and serrated class polyps, developing on the colon mucosa. Two Norwegian autopsy studies reported a polyp prevalence of about 50% and an adenoma prevalence between 32-40% in adults.^{30, 31} The adenoma prevalence increased with age to 50% in men and 45% in women over 75 years of age,³⁰ respectively to 70% in men and 55% in women aged 80 and older.³¹ Today, polyp prevalence can be determined by colorectal imaging studies. A recent study, that identified polyps by high quality colonoscopy showed an overall polyp prevalence of 76%, an adenoma prevalence of 51% and a serrated class polyp prevalence of 38%.³² The adenoma detection rate increased to over 60% in individuals over 70 years of age.

Considering the high incidence of potential precancerous lesions, and the life time CRC risk of about 4%,³³ only a minority of precursor lesions progress to CRC.^{34, 35}

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18 Histopathological classification

Until the 1990s, most polypous colorectal lesions were assigned to two histopathological groups, namely adenomatous polyps and hyperplastic polyps.³⁶ Colorectal adenomas show intraepithelial dysplasia, which means that there is atypical growth of cells in the epithelium.

Adenomas are classified according to the grade of dysplasia as low-grade or high-grade and, according to their glandular architecture, as tubular, villous or tubulovillous.³⁷ Increasing polyp size and proportion of villous architecture are associated with high-grade dysplasia.^{38, 39} Adenomas with high-grade dysplasia are the clinically relevant precursors of CRC.¹⁵ Apart from isolated points of view, it was formerly believed that hyperplastic polyps had no role in the development of CRC.^{40, 41} In 1990, serrated adenomas differing from the typical

hyperplastic polyps were described, and two years later Jass et al. identified malignant colorectal tumours similar to serrated polyps.^{42, 43}According to the recently updated World Health organisation (WHO) classification, serrated class polyps are differentiated into hyperplastic polyps (HP), sessile serrated lesions (SSL) with or without dysplasia and traditional serrated adenoma (TSA).⁴⁴ About three-fourths of serrated polyps are HPs, while SSLs contribute with about 25%. TSAs are rare. HPs are mainly small and located in the distal colorectum, SSLs are often larger than HPs and found in the proximal colon, while TSAs are typically polypoid and appear primarily in the distal colorectum.⁴⁴ While HPs are considered to rarely have neoplastic potential, it is assumed that SSLs and TSAs are

precursors of 25-30% of CRCs.^{45, 46} Colorectal cancer tumorigenesis

Already in 1887, a correlation between adenoma and CRC was stated and confirmed forty years later.^{47, 48} The term adenoma-carcinoma sequence was introduced in 1951 and the corresponding genetic model for colorectal tumorigenesis was described in 1990.^{49, 50} Later, when the importance of serrated class polyps in CRC tumorigenesis became obvious, the term serrated pathway was introduced.⁵¹ These two precursor lesion pathways cover three specific genetic pathways in colorectal tumorigenesis, the pathway of chromosomal instability (CIN), the microsatellite instability (MSI) pathway and the serrated pathway.⁵² Numerous successive genetic and epigenetic changes cause the malignant transformation to CRC. Which pathway is followed depends not only on the type but also on the timing of the alterations.⁵³

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The CIN, the traditional adenoma-carcinoma sequence, leading to microsatellite stable tumours and responsible for 65-90% of all CRCs begins with inactivation of a tumour suppressor gene (adenomatous polyposis coli gene - APC) followed by secondary genetic alterations (activation of proto-oncogenes and mutation of tumour suppressor genes) and may take 10 years or more.^{52, 54} In contrast, the MSI pathway leads to instability in microsatellite regions via mutations in DNA mismatch repair (MMR) genes.⁵² Mutations are maintained and replicated, resulting in further mutations and a hypermutation phenotype. However, APC mutations are found in up to 50% of MSI tumours pointing to common parts of CIN and MSI.^{55, 56} Almost all CRCs in patients with Lynch syndrome result from this pathway and 15% of sporadic CRCs.^{52, 57} MSI tumours are more likely to be located in the proximal colon, are less invasive, and develop in younger patients.^{58, 59} Especially tumours with a high level of MSI progress much faster than CIN tumours.⁵² Typically for the serrated pathway of tumorigenesis is the CpG island methylator phenotype (CIMP). This route is associated with mutations in the proto-oncogenes BRAF and/or KRAS and causes CpG island methylation which results in silencing of tumour suppressor genes.^{54, 60} Both microsatellite stable and instable tumours can develop. Figure 4 outlines a simplified presentation of the three pathways of CRC tumorigenesis.

Figure 4: The pathways of colorectal cancer tumorigenesis. (Adapted from Dekker E, Tanis PJ, Vleugels JLA, et al. Colorectal cancer. Lancet 2019;394:1467-1480.⁵⁴ Reprinted with permission of Elsevier.)

FAP=familial adenomatous polyposis, APC= adenomatous polyposis coli gene, MMR=mismatch repair, CIMP= CpG island methylator phenotype

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The different molecular features of CRCs have implications for treatment and prognosis.⁵³

Morphological classification

Since it is challenging to identify lesions that would develop into CRC over time, most lesions are removed when they are detected. A thorough assessment of the neoplasia is essential to determine the appropriate treatment. The Paris classification is considered most suitable to characterize the morphology of colorectal lesions.⁶¹ It classifies lesions as

polypoid (either pedunculated or sessile) and superficial (either slightly elevated, flat, slightly depressed or excavated) (Figure 5).

Figure 5: Paris classification of superficial neoplastic lesions. Reprinted with permission from Elsevier.⁶¹

The polyp morphology predicts the likelihood of advanced neoplasia. For example, 30% of depressed type lesions have been found to present infiltration of adenoncarcinoma.⁶² Non- polypoid lesions larger than 10 mm and extending laterally along the colon wall are specified as lateral spreading tumours (LST).^{63, 64} Non-granular LST (LST-NG) and granular LST (LST-G) with a large nodule (≥ 10 mm) are more likely to be malignant than LST-G without a large nodule.^{65, 66}

Recent developments as high-definition endoscopy, narrow-band imaging and

chromoendoscopy facilitate the characterisation of colorectal neoplasia with, for instance, the Kudo pit pattern classification system or the Narrow-Band Imaging International Colorectal

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Endoscopic (NICE) classification system.^{65, 67-69} Both systems were shown to be valid diagnostic tools to differentiate neoplastic colorectal lesions.^{70, 71}

Symptoms and diagnosis

Patients with CRC can be symptomatic or be diagnosed without symptoms at screening or surveillance.

Symptoms and signs

To identify individuals with CRC based on symptoms is challenging. Many countries have taken initiatives to ensure adequate access to diagnosis and treatment for individuals with suspicious symptoms.^{7, 72, 73} Rectal bleeding, change in bowel habits and abdominal pain as well as weight loss and iron deficiency anaemia are reported to be the most common symptoms and signs.^{74, 75} There is evidence of an association between overt rectal bleeding and CRC, although most patient-reported blood in stools is associated with benign lesions - mostly haemorrhoids.^{76, 77} Change in bowel habits and abdominal pain are also considered as potential “alarm symptoms” but their predictive importance is inconsistent.^{78, 79} Early-stage cancers may present with vague symptoms⁸⁰ and many symptoms suspicious for CRC also occur in benign conditions.⁵⁴ Most symptomatic cancers are diagnosed at a late stage with a lower probability of survival and a higher probability of reduced quality of life caused by extensive treatment.^{14, 54, 81}

Detection of neoplasia

Since the development of fiber-optic colonoscopes facilitated the examination of the entire colorectum in the 1960s, outstanding technical improvements have been made and today colonoscopy is the gold standard tool to diagnose colonic disease. It allows for detection, assessment of findings and retrieval of histopathological specimens in one step. With regard to colorectal neoplasia, treatment can often be carried out at the same time as most

precancerous polyps and in some cases even malignant polyps can be completely removed during the procedure.

Staging of colorectal cancer

The currently most used staging system for CRC is the American Joint Committee on Cancer system, known as the T(umour) N(ode) M(metastasis) system.⁸² Based on the information

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about tumour depth, involvement of local lymph nodes and distant metastasis a stage numbered from 0 to IV is given. A stage 0 CRC has not invaded the submucosa (cancer in situ, Cis). Stage I means that the tumour has reached the submucosa or muscularis propria but there are no local lymph nodes or distant metastases. A stage II CRC penetrates the

muscularis propria or invades other organs or structures, but still there is no involvement of local lymph nodes, distant nodes or other organs. At stage III local lymph nodes are invaded but there are no distant metastases, while distant metastasis is detected at stage IV (Figure 6).

Figure 6: Cancer staging and illustration of the layers of the colorectum. (Adapted from Amado NG, Predes D, Moreno MM, et al.⁸³ distributed under the CC-BY licence.)

In addition to the TNM staging system, classification systems for malignant polyps exist. All malignant polyps have in common that the adenocarcinoma infiltration is limited to the submucosa (pT1).⁶⁷ The Haggitt system grades pedunculated polyps as 0 to 4.⁸⁴ Level 0 represents cancer in situ (pTis), with no infiltration of the muscularis mucosa, levels 1-3 describe which part of a pedunculated polyp is affected (head, neck or stalk). All malignant sessile polyps are graded as level 4 as well as malignant pedunculated polyps with malign cells below the stalk. The Kikuchi classification groups malignant sessile polyps into three levels (Sm1-3) depending on the depth of invasion of the submucosa.^{63, 85}

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23 Prognosis of CRC

CRC survival varies geographically. These differences even apply to high income countries.^8,

86 The most important prognostic factors are stage and age at diagnosis.⁸⁶ In Norway, the five-year relative survival for colon cancer and rectum cancer, respectively, is currently 68%

and 71%. For those with localised stage at diagnosis it is 98% for both colon and rectum cancer and 16% and 20%, respectively, for those with distant stage.⁸⁷ Rectal cancer survival has improved more than colon cancer survival since the middle of the 1990’s. This may be due to the introduction of advanced surgical methods, increased specialisation and

preoperative radiation for rectal cancer in addition to increased awareness to early symptoms and diagnosis at a localized stage.^{33, 87}

Treatment

Endoscopic treatment

As a result of increasing screening activity, the proportion of early-stage cancers, including malignant polyps, is increasing.^{33, 65} Polyps are mostly removed by simple polypectomy or endoscopic mucosal resection. Malignant polyps classified as Haggitt level 1-3 can be treated endoscopically by en-bloc resection, while pedunculated malignant polyps level 4 require surgery.⁶⁵ The evaluation if a non-pedunculated malignant polyp is adequately managed endoscopically, is difficult since the muscularis propria is not present in the histological specimen.⁶⁵ In these cases, endoscopic submucosal dissection or full-thickness resection can increase the probability of complete resection and thus prevent recurrence.^{54, 88, 89}

Other treatment

Surgical resection of the affected colon segment accompanied by lymphadenectomy is the basis for a curative treatment.⁵⁴ For liver metastases, surgery and ablative techniques, may give better disease control or even cure.⁹⁰ For lung metastases and peritoneal metastasis, the prognosis is poor and treatment usually only improves disease control.^{91, 92} Especially

systemic CRC treatment, used in metastatic disease, frequently reduces quality of life, due to direct consequences of the cancer itself, but also due to adverse effects and complications of therapy.⁵⁴

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24 Reducing the burden of CRC

Options to reduce the burden of CRC include both better prevention strategies as well as improved diagnostic tools and treatment. A successful approach requires a balance between prevention, diagnosis and treatment.⁹³

Primary prevention

Primary prevention aims to prevent a disease before it occurs. In the case of CRC, this

implies intervention on modifiable risk factors like physical activity, dietary factors, smoking habits and the use of chemopreventive agents. Estimates indicate that 54% of all CRC cases in the USA are attributable to the following life style factors: cigarette smoking, excess body weight, alcohol intake, red and processed meat consumption and low dietary intake of fibre and calcium.⁹⁴ Primary prevention may be less costly than secondary prevention, like

screening, which many developing countries are not able to fund. In addition, these countries often lack diagnostic and treatment resources. Therefore, primary prevention is the preferred approach from a global perspective to reduce the burden of CRC.² Even if primary prevention potentially avoids a high number of CRC cases and thus saves lives, the implementation poses major challenges. First of all, it is demanding to motivate individuals with an unfavourable lifestyle and who would benefit the most of changing their lifestyle.^95-97 Secondly, primary prevention strategies can be associated with the risk of adverse events.

One example is the prophylactic use of low-dose aspirin, as recommended by the US

Preventive Services Task Force (USPSTF)⁹⁸, increasing the risk of gastrointestinal bleeding.

Another example is long-term use of postmenopausal hormone replacement therapy that can increase the risk of breast cancer and endometrial cancer.⁹⁹ Generally, a balance between harms and benefits of primary prevention strategies is required.

Secondary prevention

Secondary prevention means to detect conditions that can lead to disease or to detect disease in a subclinical form. With regard to CRC, this can either be achieved by surveillance of individuals at high risk (individuals with long-term IBD, previous colorectal neoplasia, hereditary syndromes or familial predisposition) or screening of asymptomatic individuals at average risk.^{54, 100} Thus, precancerous lesions or early-stage cancers can be detected and removed. Unlike primary prevention strategies, secondary prevention strategies for CRC are often either invasive in themselves (such as sigmoidoscopy and colonoscopy) or are followed

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by an invasive procedure after a positive non-invasive screening test (such as work-up endoscopy after a positive test for occult blood in stool).¹⁰⁰ Endoscopic procedures are associated with the inherent risk of adverse events.

Screening

Screening intends to identify asymptomatic disease or risk factors in a population and offer early treatment. Cancer screening aims to detect precursors of the disease (like cervical cancer screening) or early-stage cancer (like breast cancer screening). Thus, screening can decrease incidence and cancer related mortality as well as prevent impaired quality of life caused by treatment of late-stage cancer.

Cancer screening is a health service offered to a presumptively healthy population. Therefore, benefits and harms of screening have to be evaluated carefully. In 1968 the major principles of screening were postulated by the WHO by Wilson and Junger and are still followed (Table 1).¹⁰¹

1. The condition should be an important health problem 2. There should be an accepted treatment for the disease 3. Facilities for diagnosis and treatment should be available

4. There should be a recognizable latent or early symptomatic phase 5. There should be a suitable test

6. The test should be acceptable to the population

7. The natural history of the condition should be understood 8. There should be an agreed policy on whom to treat as patients

9. The cost of case-finding should be economically balanced in relation to possible expenditure on medical care as a whole.

10. Case-finding should be a continuous process and not a “once and for all” project.

Table 1: Wilson and Junger’s principles of screening.^{101, 102}

Colorectal cancer screening

CRC is a disease suitable for screening in developed countries according to the WHO criteria.

Depending on the test, CRC screening can be preventive or act through early detection.

Preventive means that precancerous lesions are detected and removed, thus decreasing the CRC incidence. Tests aimed at early-detection identify cancer at an early and therefore curable stage and reduce CRC mortality. Traditionally, endoscopic screening has been

considered preventive, while screening based on occult blood in stools has been considered as early-detection. However, stool test with improved sensitivity for precursor lesions may be

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preventive. Implementation of CRC screening programmes initially increases the incidence of CRC due to an increased detection. Particularly in endoscopic screening, the subsequent incidence reduction is explained by the removal of precancerous lesions.¹⁰³

For the effectiveness of screening, both the performance of the screening test and the

adherence to screening and quality of work-up examinations are crucial. A lot of research on CRC screening is carried out and the evidence is constantly modified.

CRC screening can be opportunistic or programmatic. In opportunistic screening, either the patients ask a health care provider for screening or receive a screening recommendation when visiting a health care provider for something else. In programmatic screening all individuals in a defined target population are invited to screening with a standardised test, making sure that all screen-positives are followed-up and that screen-negatives are re-invited for

subsequent screening rounds. Opportunistic screening is prone to selection bias as individuals have to take responsibility themselves to be screened or their health care provider has to address the issue. Programmatic screening increases screening participation and decreases inequalities and inequities.^104-106 Furthermore, programmatic screening may ease quality assurance and subsequently reduce harms.^107-110 The recent update on CRC screening recommendations from the American College of Gastroenterology (ACG) recommends programmatic screening programs.¹¹¹

A large number of CRC screening guidelines exist and recommendations differ. After

Bernard summarized the current global recommendations in a systematic review in 2018, the ACG and the USPSTF recently updated their guidelines.^111-113 Recommendations from national guidelines depend on whether programmatic or opportunistic screening predominates. The USPSTF do not rank CRC screening tests to maximize screening participation regardless of the test used.¹¹³ In contrast, in Europe, where CRC screening mainly is programmatic, recommendations often depend on the feasibility of the test in a screening programme. The use of tests that need to be repeated in rather short intervals is challenging in opportunistic screening since invitations are not sent automatically and the patient or health care provider themselves are responsible for adherence to screening.¹¹⁴ In programmatic screening a high specificity of the recommended screening tests is often prioritised in order to reduce the risks and costs of false positive primary screening tests.¹¹⁴ This approach can result in ethical challenges, for example, when choosing very strict

definitions for a positive primary screening and thus give screening participants a false sense

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of security. Faecal occult blood testing (FOBT) is often recommended as the primary

screening method for programmatic screening, because there is evidence for a CRC mortality reduction with FOBT screening and because colonoscopy capacity is limited.^{115, 116}

There is broad agreement that individuals offered CRC screening ideally are average-risk people aged 50 to 75 years without a medical history of CRC or precancerous lesions and without symptoms suspicious for CRC.111, 112, 117 There are local, regional and national differences regarding the recommended screening test, test intervals and surveillance.¹¹²

CRC screening modalities

Various CRC screening modalities with their inherent advantages and disadvantages are used worldwide. Endoscopic screening and screening by FOBT are most commonly performed.

Analysis of biomarkers in stool (multi-target stool DNA) and blood (methylated septin 9 DNA), and computed tomographic colonography (CTC) are approved by the US Food and Drug Administration (FDA), while video capsule endoscopy is under investigation.^{114, 118} Since only colonoscopy visualises the entire colorectum and enables lesions to be removed during the same exam, all other positive primary screening tests have to be followed up by a colonoscopy.

Sigmoidoscopy

Sigmoidoscopy (flexible sigmoidoscopy), an endoscopic examination of the distal part of the large bowel after cleansing with a small enema, is a well-documented screening test. Data from up to 17 years of follow-up from four randomised controlled trials (RCT) comparing sigmoidoscopy with no screening are available (the US PLCO trial, the Italian SCORE trial, the Norwegian NORCCAP trial and the UK Flexi Scope trial).^119-122 A CRC incidence reduction of 18-26% and a CRC mortality reduction of 22-31% were shown. The IARC recently concluded that there is sufficient evidence for both reduction in incidence and mortality as well as a sufficient benefit-harm ratio for single screening with

sigmoidoscopy.¹¹⁸ Most guidelines recommend sigmoidoscopy every 5^th or 10^th year, some guidelines recommend to combine sigmoidoscopy with faecal occult blood testing.¹¹² Colonoscopy

Colonoscopy allows for direct visualisation of the mucosa of the entire colorectum with diagnosis and therapy at once. A complete bowel cleansing is required. Colonoscopy has a

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high sensitivity for precancerous lesions and cancer (95% for adenomas ≥ 10 mm and CRC).¹²³ However, to date, there is no evidence from randomised trials for the effectiveness of primary colonoscopy in CRC screening. Three randomised studies comparing FIT versus colonoscopy screening (CONFIRM, COLONPREV, SCREESCO) and one comparing colonoscopy versus no screening (NORDICC) with regard to CRC incidence and mortality are ongoing.^124-127 So far, the efficacy of screening colonoscopy is assessed by cohort and case control studies providing effect on both CRC incidence and CRC mortality.117, 118, 128-132

A meta-analysis of observational studies reported a CRC incidence and mortality reduction of nearly 70% but no significant mortality reduction regarding proximal CRC.¹³³ Colonoscopy is an invasive procedure and is accompanied by adverse events, especially related to

sedation¹³⁴ and polypectomy.¹³⁵ Most complications related to polypectomy occur after resection of large polyps. The IARC concludes that there is sufficient evidence for both CRC incidence and mortality reduction at a sufficient benefit-harm ratio.¹¹⁸ Most guidelines recommend colonoscopy every 10^th year.¹¹²

Faecal occult blood test (FOBT)

Faecal occult blood tests are either guaiac-based (gFOBT) or immunochemical (FIT or iFOBT). gFOBT works by detecting peroxidase activity and human haemoglobin is a

peroxidase catalyst, while FIT detects human globin in stool using antibodies against globin.

Stool tests are performed at home and not accompanied by absence from work. Since FOBTs are non-invasive, no adverse events are associated with the primary test.

Guaiac-based faecal occult blood test

The gFOBT is a qualitative test. Three samples for each screening series are recommended to reduce the number of false negative results for CRC detection.¹³⁶ Dietary restrictions

(avoidance of iron supplements, red meat, poultry, fish, some raw vegetables, NSAIDS and vitamin C) prior to testing are recommended to reduce the number of false positive or negative tests.¹³⁷ A consequence may be a lowered adherence to gFOBT screening.¹³⁸ Thus, dietary restrictions were not applied in all screening trials using gFOBT.¹³⁹ The efficacy of gFOBT as a screening modality is proven by four RCTs from Sweden, Denmark, England and the USA comparing annual or biennial gFOBT with no screening with up to 30 years of follow-up.^139-142 A meta-analysis estimated a CRC mortality reduction of 14 % compared to no screening, but with no evidence of CRC incidence reduction.¹⁴³ The US trial showed a significant incidence reduction, but the colonoscopy referral rate was outstandingly high

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(28% for those screened biennially and 38% for those screened annually). The IARC stated evidence for CRC mortality reduction as well as a positive benefit-harm ratio when gFOBT is performed every or every second year.¹¹⁸

Faecal immunochemical test

FIT can be both a qualitative and a quantitative test. For quantitative tests, a threshold can be set depending on population risk or colonoscopy capacity.¹⁴⁴ In the last years, FIT has largely replaced gFOBT. Meta-analysis and cohort studies reported better sensitivity for the detection of CRC and advanced adenomas than gFOBT.^{136, 145} Lowering cut-off improves the

sensitivity and reduces the specificity: Cut-off values of less than 20 mcg haemoglobin/g faeces (mcg/g) resulted in the best diagnostic accuracy.¹⁴⁴ A meta-analysis estimated a pooled sensitivity of one-time FIT for CRC of 89% and specificity of 91% at cut-off values for a positive test less than 20 mcg/g.¹⁴⁴ These findings were confirmed by another meta-analysis that also estimated the sensitivity for advanced adenoma (25%-40% for cut-off 10mcg/g to 20 mcg/g).¹⁴⁶ Poor sensitivity was reported for serrated lesions.¹⁴⁷ FIT performance for advanced neoplasia was better for distal than proximal lesions in some studies and one meta-

analysis,127, 148, 149 while another study reported similar sensitivity for both localisations.¹⁵⁰ CRC was detected at earlier stage with FIT than with gFOBT in a cohort study.¹⁵¹ Few data exist on the cumulative effectiveness of repeated rounds of FIT testing. A non-randomised prospective trial showed a higher diagnostic yield of CRC and/or advanced adenoma for repeated FIT than for sigmoidoscopy or colonoscopy.¹⁵² Further advantages are the easier sampling: Only one test per screening round is required for many of the FITs currently used, no dietary restrictions are necessary and the quantitative test can be read automatically. A meta-analysis showed that participation rates for FIT screening were higher than for gFOBT.¹⁵³ Thus it is expected that FIT has greater impact on CRC incidence and mortality reduction than gFOBT and in a recent review it was concluded that there is evidence to recommend FIT over gFOBT for CRC screening.¹³⁶ However, to date, there are no results from RCTs reporting CRC incidence or mortality reduction for FIT screening. FIT screening is recommended performed every year or every second year.^{112, 154} It is the preferred method for programmatic screening in many countries^{155, 156} and also ranked as a tier 1 test by the Multi-Society Task Force on colorectal cancer (MSTF).¹¹⁷

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30 Other modalities

FIT-faecal DNA test is a combination of a FIT and markers for abnormal DNA in stool.

Screening every 3^rd year is recommended by the manufacturer.¹¹⁴ In a large prospective trial, all participants underwent both FIT, FIT-faecal DNA test and colonoscopy.¹⁴⁷ This trial demonstrated a higher one-time testing sensitivity for CRC and advanced lesions when using FIT-faecal DNA compared to FIT and also a 40% sensitivity for serrated lesions larger than 1 cm (compared to 5% for FIT). On the other hand, the specificity was inferior compared to FIT and the costs are high (both the test itself and due to a high number of positive tests with need for work-up colonoscopies). A Markov model and three microsimulation models of CRC demonstrated that both annual FIT and colonoscopy every 10^th year are more effective and less expensive than FIT-faecal DNA testing every 3^rd year.^{157, 158} The effects on CRC incidence or mortality reduction are unknown.¹¹⁴ US guidelines recommend FIT-faecal DNA test every 1^st to 3^rd year for individuals declining colonoscopy and FIT while it is not

mentioned in European guidelines.¹¹²

One of two imaging screening modalities is CTC. It has a high sensitivity for large adenomas (≥ 1cm), while the sensitivity for smaller polyps is lower than for colonoscopy.^159-161

Additionally, the insufficient detection of flat and sessile serrated lesions is a drawback. ^162,

163 Finding of polyps larger than 5mm at CTC should entail a work-up colonoscopy. No results on CRC incidence and mortality reduction from RCTs are reported. Based on detection rates for CRC and advanced adenomas stated in one RCT and several tandem studies, there is limited evidence for an effect of CTC screening on CRC incidence and mortality.^{117, 118} Exposure to radiation can be harmful and the IARC stated recently that the evidence for a positive benefit/harm ratio for one round with CTC screening is inadequate.¹¹⁸ Nevertheless, the updated USPSTF guidelines recommend CTC as a primary screening test.¹¹³ The screening interval is suggested to be every 5^th year.¹¹³ The European Society of Gastrointestinal Endoscopy (ESGE) and European Society of Gastrointestinal and Abdominal Radiology (ESGAR) jointly suggest CTC as a screening tool if no programmatic FIT

screening exists on the assumption that screenees receive adequate information about the test performance, benefits and risks.¹⁶⁴

The second possible colorectal imaging method for screening, capsule colonoscopy, was assessed in few studies and results suggested at least non-inferior test performance compared to CTC.^164-166 However, there were many technically inadequate examinations (partly due to

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inadequate bowel cleansing) and the need for extensive bowel cleansing is a main

disadvantage.¹⁶⁶ Capsule colonoscopy is not approved for screening by the FDA and neither recommended by the ESGE/ESGAR as a first-line screening test.^{117, 164}

Furthermore, one blood test is approved by the FDA for CRC screening, the Septin9 assay.

This assay is based on the detection of methylated septin 9, a plasma marker for CRC. It was shown that it is not suitable for polyp detection as its sensitivity for advanced adenoma detection is low (11.2% in a population scheduled for primary colonoscopy screening), it has lower sensitivity for cancer than FIT and it is costly.^167-169 The Septin9 assay is not

recommended as a screening test by any of the approved guidelines due to a large number of superior screening modalities.¹¹²

Adherence to colorectal cancer screening

Beside test performance, several other factors influence the effectiveness of a screening programme. One of the most important factors is adherence to screening by following the current recommendations on the screening test at appropriate intervals.

Adherence to CRC screening is persistently low in numerous countries.¹⁷⁰ According to the second European screening report, overall participation in programmatic screening in the European Union (EU) is 50% when FIT screening is adopted, 33% in gFOBT screening programmes, 25% in sigmoidoscopy screening and only 16% in primary colonoscopy screening.¹¹⁶ It was estimated that between 46%-63% of CRC related deaths in the USA are attributable to non-screening¹⁷¹ and that 80% adherence to screening within 2018 could prevent 200.000 CRC related deaths within 20 years.¹⁷² Adherence to CRC screening in the USA has been increasing the last two decades, but the 2018 goal is still not achieved and currently about two third are screened as recommended.¹⁷³ Both adherence to the initial screening test and the work-up colonoscopy is of relevance. The rate of non-compliance to work-up colonoscopy after a positive stool-based test is considerable and increases risk for CRC related death.¹⁷⁴ Delaying the work-up colonoscopy can also result in a cancer diagnosis at a later stage.¹⁷⁵

For programmatic screening, the European Guidelines for Quality assurance in CRC screening and Diagnosis recommend a minimum participation rate of at least 45% in the primary test, desired target rate of 65% and at least 90% adherence to work-up

colonoscopy.¹⁷⁶ A recent study, using a microsimulation model, found that all approved stool

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based screening modalities, the Septin9 assay and CTC at appropriate intervals would have equivalent effectiveness assuming 100% adherence, comparable to colonoscopy screening every 10^th year, but that colonoscopy is superior to all these methods given the actual reported participation.¹⁷⁷

Great efforts have been made to improve adherence to CRC screening. In RCTs, better adherence was achieved if patients’ general practitioner sent the invitation letters, or when there were written reminders or telephone calls and when kits for stool testing were sent directly to the patients.¹⁷⁸ In opportunistic screening, personal navigation, where patients were contacted by trained navigators to identify and organize performance of their preferred screening test, showed promising results in RCTs.^{179, 180} It is crucial to understand barriers to colorectal cancer screening to improve adherence to already implemented CRC screening.

Strategies to increase screening adherence may differ depending on whether screening is programmatic or opportunistic (e.g. in opportunistic screening the possibility to choose the screening test can increase participation).

Barriers to colorectal cancer screening

Barriers and facilitators to CRC screening exist on different levels. Socio-demographic characteristics, environmental characteristics, health care utilisation, health behavioural characteristics and psychological characteristics are outlined in a systematic review.¹⁸¹ Female sex, young age (<60-65 years), old age (>75 years), low income or low educational level and ethnic minority were associated with lower adherence to CRC screening with both FOBT and endoscopy. To be single was associated with lower adherence in FOBT screening.

Furthermore, living in the countryside was a barrier. In the USA, where opportunistic screening dominates, lack of health insurance was another barrier. To be recommended screening by a physician was a facilitator for adherence and consequently, individuals having little contact with health care providers were less likely to participate. Individuals with health-conscious behaviour took part in screening more often and so did those with chronic diseases or family history of CRC. Psychological factors play a major role in decision making in CRC screening. Considering oneself being at high risk for CRC (e.g. due to the presence of bowel symptoms) was a facilitator for compliance to screening colonoscopy, while a negative view of the screening test lowered adherence to screening. Many of the main barriers to screening were shown to be test-specific.¹⁸² One out of four never-screened individuals

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reported that they were willing to give up 90 days of their life to avoid screening

colonoscopy.¹⁸³ According to a systematic review, one main concern is experiencing pain during colonoscopy.¹⁸⁴ Last but not least, lacking knowledge about CRC screening reduced screening participation.^185-187

Quality of CRC screening

The EU has recommended implementation of CRC screening programmes since 2003.¹⁸⁸ Quality assurance at all steps and regular monitoring of key performance indicators (KPIs) were recommended.¹⁸⁹ In 2012 detailed guidelines were released.¹⁵⁶ Flaws at any single level can jeopardise the success of a screening programme. However, the greatest focus has been on colonoscopy quality.^190-192 Recommendations dedicated to quality indicators for FIT were published in 2015 by the MSTF.¹⁵⁴

Quality of colonoscopy

Colonoscopy is the cornerstone in CRC screening either as a primary screening test, like in the USA, Germany and Poland, or as a work-up examination after other primary screening modalities. It is also the method of choice for surveillance after polypectomy. Thus, high colonoscopy quality is of crucial importance for a successful screening programme. KPIs for screening with colonoscopy have been defined. In addition to the KPIs discussed below, several other factors, such as the adequate removal of precancerous lesions and adequate surveillance, are of considerable importance but will not be explained in detail.

Bowel cleansing

To allow for a high quality colonoscopy, the colorectum has to be cleansed with the aid of laxatives. The validated Boston Bowel Preparation Scale (BBPS) is often used to evaluate cleansing quality and reaching a score of two out of three in each of three colonic segments is considered adequate.¹⁹³ It was shown that the risk of missing polyps larger than 5 mm

increased when BBPS scores were less than two in a segment. The rate of adequate bowel cleansing and the compliance with bowel preparation increased when split-dose regimen was introduced and a higher proportion of participants were willing to repeat the split-dose bowel preparation compared to day-before cleansing.^{194, 195} The ESGE suggests at least 90%

adequate bowel cleansing, the MSTF suggests at least 85%.^{196, 197}

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34 Cecum intubation

To examine the whole colon is crucial. To intubate the cecum means to advance the colonoscope beyond the ileocecal valve allowing for thorough examination of the entire cecum with photo documentation of the appendiceal orifice.^{190, 192} Incomplete colonoscopies are associated with post-colonoscopy CRC (PCCRC).^{198, 199} In CRC screening a cecum intubation rate (CIR) of >95% is recommended.¹⁹²

Adenoma detection rate (ADR)

ADR is the proportion of colonoscopies with at least one adenoma detected and it reflects the degree of adequate mucosa inspection. ADR depends on the characteristics of the population examined and is higher in FIT positive screening participants than in participants of primary colonoscopy screening. ADR is also increasing with age and higher in men than in women.

ADR is inversely correlated with the occurrence of PCCRC and CRC related mortality.^{200, 201} Accordingly, it was shown that a 1% increase in ADR was accompanied with a 3% decrease of PCCRC and a 5% decrease in CRC mortality²⁰⁰, as well as an ADR of 25% or more was correlated with a decreased risk of PCCRC and consecutively CRC related death.²⁰² For a population aged ≥ 50 years, ADR is recommended to be at least 30% in men and 20% in women for primary colonoscopy screening or 25% for both sexes combined.^{190, 192} In FIT screening with a threshold cut-off ≤ 20 mcg/g, the MSTF suggests an ADR >45% in men and

>35% in women.¹⁵⁴ Withdrawal time

Withdrawal time is defined as the time spent moving the colonoscope from the cecum back to the anal canal in colonoscopies without therapy or biopsy.¹⁹⁰ It is a measure for mucosal inspection. A positive correlation between withdrawal time and ADR as well as an inverse association between ADR and PCCRC have been demonstrated.²⁰³ Endoscopists with mean withdrawal time of at least six minutes had higher ADR and advanced neoplasia detection than those with shorter withdrawal time.²⁰⁴ On the other hand, the increase in ADR was minimal when the withdrawal time exceeded ten minutes.²⁰⁵ Therefore, the ESGE defined six minutes as the minimum standard and ten minutes as the target standard for mean withdrawal time.¹⁹⁰ Increasing withdrawal time is particularly recommended to improve performance of endoscopists with insufficient ADR.190, 192, 206

Performance of two screening tests and barriers to colorectal cancer screening

PhD thesis