UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)

UvA-DARE (Digital Academic Repository)

Population-based colorectal cancer screening by fecal immunochemical testingover multiple rounds

van der Vlugt, M.

Publication date2017Document VersionOther versionLicenseOther

Link to publication

Citation for published version (APA):van der Vlugt, M. (2017). Population-based colorectal cancer screening by fecalimmunochemical testing over multiple rounds.

General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an opencontent license (like Creative Commons).

Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, pleaselet the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the materialinaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letterto: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as possible.

Download date:08 May 2021

5The risk of missing upper gastrointestinal cancer in

FIT-positives in a colorectal cancer screening program

Manon van der Vlugt, Esmée J Grobbee, Patrick M. Bossuyt, Amanda C.R.K. Bos, Ernst J. Kuipers, Iris Lansdorp-Vogelaar, Manon C.W. Spaander, Evelien Dekker

Submitted

84

5

CHAPTER 5

ABSTRACT

Objective

Current European guidelines recommend colorectal cancer (CRC) screening using faecal

immunochemical testing (FIT), followed by colonoscopy for test-positives. However, over

half of the FIT-positive participants do not have advanced neoplasia at colonoscopy. As faecal

occult blood might also come from the upper gastrointestinal (GI) tract, one could consider

esophagogastroduodenoscopy (EGD) in those persons to detect upper GI cancers. We assessed

the number of proximal cancers (i.e oral cavity, throat, esophageal, gastric and small bowel cancer)

diagnosed within two years after a FIT test in FIT-positive and FIT-negative participants in a FIT-based

screening program.

Design

Proximal cancers were identified through linkage with the National Cancer Registry in participants

of three rounds of biennial FIT-based CRC screening. We classified proximal cancers in three

groups: FIT-positives with a negative colonoscopy (no advanced neoplasia), FIT-positives with

a positive colonoscopy (advanced neoplasia), and FIT-negatives. We compared incidence rates

between groups.

Results

Among 16,165 screening participants, linkage identified 40 persons with a proximal cancer diagnosed

within two years after a FIT test. No significant difference in incidence rates was found; 7 proximal

cancers in FIT-positives (0.33%; 95%CI 0.16-0.68) and 33 in FIT-negatives (0.24%; 95%CI 0.17-0.34:

P = 0.43). Of the seven FIT-positive persons with proximal cancer, five persons had a diagnosis

after a negative colonoscopy and two after a positive colonoscopy. When focusing on gastric and

esophageal cancers only (those cancers that could be diagnosed by EGD), 0.1% of FIT-positives had

a corresponding diagnosis within two years.

Conclusions

As few patients with a positive FIT were found to have a diagnosis of proximal cancers within two

years, routine additional investigation by EGD in FIT-positive screenees with a negative colonoscopy

is not recommended. Only clinical symptoms, anemia or other risk factors for upper GI cancer could

warrant additional investigations in those persons.

85

5

RISK OF UPPER GI CANCER AFTER A POSITIVE FIT

INTRODUCTION

Colorectal cancer (CRC) screening programs using faecal occult blood testing are based on

the assumption that colorectal carcinoma or its advanced precursor lesions (together defined as

advanced neoplasia) have a tendency to bleed. Detection of blood in stool can be done with guaiac

faecal occult blood tests (gFOBT) and with faecal immunochemical tests (FIT). One of the important

differences between the tests is that gFOBT detects haem (also present in ingested red meat) while

FIT only detects human globin.

At this moment, FIT is recommended for CRC screening because of a higher diagnostic accuracy

for advanced neoplasia than gFOBT and since it is easier to use [1,2]. However, over half of the FIT-

positive participants do not have advanced neoplasia at colonoscopy [3]. As faecal blood might

also come from the upper GI tract, one could therefore consider esophagogastroduodenoscopy

(EGD) in FIT-positives for whom no indication for blood in the colorectum was found, to detect

upper GI cancers. Prior studies have reported conflicting results on the yield of EGD in patients with

a positive faecal occult blood test (FOBT). These studies were mainly based on gFOBT or did not

solely include average risk subjects. This led to the conclusion that there is not enough evidence

to recommend for or against routine EGD in patients with a positive FOBT followed by negative

colonoscopy [4]. However, no data on long-term follow-up of FOBT-positive screening participants

have been published. Besides, as FIT-testing is based on detecting human globin in feces, which has

a more rapid degradation than haem, the detection of blood from upper GI-tract abnormalities has

been controversial, as the globin might already be degradated and not be detectable in stool [5].

We aimed to assess the incidence of proximal cancers (i.e. oral cavity, throat, esophageal,

gastric and small bowel cancer) within two years after FIT testing in FIT-positive and FIT-negative

screenees participating in a large biennial FIT-based screening program in the general population.

Results were stratified according to the FIT results and colonoscopy findings. Colonoscopy was only

performed in FIT-positives.

METHODS

Population and design

Since 2006, a pilot program of biennial FIT-based CRC screening has been conducted in two regions

in the west of the Netherlands. Details about the design of the CRC screening program have been

reported previously [6,7]. In short, demographic data of all invitees between 50 and 74 years

living in the target areas were obtained from municipal population registers. Screening data was

prospectively collected. Persons were invited for each consecutive round, except for those who had

moved out of the area, those that had passed the upper age limit, institutionalized people, those

with an estimated life expectancy of less than 5 years, invitees unable to give informed consent,

and those who had tested positive in a previous screening round and had undergone a subsequent

colonoscopy. In our information leaflet, persons with a history of inflammatory bowel disease or

CRC were asked not to participate CRC screening.

Invitations were sent between June 2006 and October 2012, for a total of three rounds of

screening (see Appendix 1). During the first round, invitees from the northwest region were randomly

86

5

CHAPTER 5

allocated to receive either a gFOBT or a FIT as screening test. Invitees in the southwest region as

included in this analysis were offered a FIT only. Invitees received an OC-sensor (Eiken Chemical

Co, Tokyo, Japan). A hemoglobin value of 10 µg Hb/g feces was used as the positivity threshold.

Screenees with a positive test result were invited for a consultation at the outpatient clinic to discuss

the test result and follow-up by colonoscopy. For this study, all invitees who had participated at

least once were identified and were selected for analysis, except for those with a diagnosis of

proximal cancer (i.e. oral/throat, esophageal, gastric or small bowel cancer) before participating in

the screening program, FIT-positive participants who had undergone an incomplete colonoscopy,

had a contra-indication for coloscopy, or refused colonoscopy, and persons with a medical history

of IBD or CRC (as in those persons a colonic reason for FIT-positivity could not be ruled out) and

participants screened only once with gFOBT.

Follow-up colonoscopy

Colonoscopy was performed according to international quality standards. Quality parameters were

collected in a database [8]. All endoscopists were certified gastroenterologists who had performed

at least 1,000 colonoscopies. For all colorectal lesions detected during colonoscopy, data on

the location, size, macroscopic aspect and morphology were recorded. All lesions were evaluated

by an experienced gastrointestinal pathologist, using the revised Vienna criteria [9]. A positive

colonoscopy after a positive FIT was defined as a colonoscopy with a diagnosis of advanced neoplasia.

Advanced neoplasia (AN) included advanced adenoma and CRC, with advanced adenomas defined

as an adenoma with a diameter ≥10 mm, and/or with a ≥25% villous component, and/or high-

grade dysplasia [10]. A negative colonoscopy was defined as a colonoscopy without a diagnosis

of advanced neoplasia, including a normal colon as well as non-advanced adenomas and serrated

lesions, as these are regarded as coincidental findings [11]. Surveillance recommendations for

adenomatous polyps, large (≥10 mm) serrated lesions or cancer were given according to the Dutch

Guideline Colonoscopy Surveillance [12]. After a negative colonoscopy, no additional investigations

were advised.

Identification of cancers of the upper GI tract

All participants (i.e. those who participated at least once) were linked to the National Cancer

Registry, which is managed by the Netherlands Comprehensive Cancer Organization (up to date

until 31 March 2015). Since 1989, the National Cancer Registry registers all Dutch citizens diagnosed

with cancer in the Netherlands and provides a unique and fully covered database. Registration staff

records the data of all persons diagnosed with cancer. They use the National Pathology Archive,

medical registries in hospitals and hematological laboratories as sources. Over 95% of all cases with

cancer in the Netherlands are registered in the Cancer Registry. For all persons that participated

in the FIT-based screening program and were identified in the registry with cancer, data on tumor

type, location, tumor stage, date of diagnosis were collected. To rule out post-colonoscopy CRC

as an explanation for the positive FIT, all FIT-positive participants with proximal cancers were also

linked to the Cancer Registry to detect a potential concurrent CRC. Proximal cancers diagnosed

87

5

RISK OF UPPER GI CANCER AFTER A POSITIVE FIT

within two years after the last performed FIT were considered ‘potentially detectable by FIT’ and

were selected for additional analysis. Tumors diagnosed after more than two years after the last FIT

was performed were not considered potentially related and were not selected for additional analysis

concerning incidence and PPV.

For the definition of oral and throat malignancies we included the cavum oris (tonsills, tongue

palate, floor of the mouth, cheeck mucosa, retromolar trigone), oropharynx, nasopharynx,

epiglottis, supraglottis, glottis, sinus piriformis, hypopharynx and pharynx. For the definition of

small bowel cancers we included duodenum, jejunum, ileum, Meckels’ diverticulum as well as ‘small

bowel not otherwise specified’. All types of cancerous morphologies that can occur in the oral/

throat and upper gastrointestinal (GI) tract were linked (for instance squamous cell carcinoma,

lymphoma, neuro-endocrine tumors).

Statistical analysis

We estimated the cumulative incidence of proximal cancers in FIT-positives with a positive

colonoscopy, in FIT-positives with a negative colonoscopy, and in FIT-negatives. Differences between

groups were evaluated for statistical significance using the χ2-test statistic. P-values < 0.05 were

considered to indicate statistically significant differences. Data analysis was performed using SPSS

23 for Windows (Chicago, Ill). We additionally calculated a hypothetical number needed to scope,

assuming all gastric or esophageal cancer cases could have been detected with EGD immediately

after the FIT test. This was defined as the number of EGD needed in those with a positive FIT and

a negative colonoscopy to detect one person with gastric or esophageal cancer.

Ethics approval

Ethical approval for the study was provided by the Dutch National Health Council (WBO 2642467,

2832758, 3049078 and 161536-112008, The Hague, The Netherlands). When returning the FIT, all

screening participants had provided written informed consent for linkage with the Cancer Registry.

RESULTS

After three completed rounds of CRC screening, the cohort invited for screening consisted of

25,475 persons of whom 9,310 had to be excluded for this study: 8,257 invitees never participated

in the screening program, 691 were only screened with gFOBT and 362 persons met one or more

of the exclusion criteria. Basic characteristics of the remaining 16,165 participants are shown in

Appendix 2. These remaining 16,165 participants were linked to the National Cancer Registry. Of

these participants, 14,025 (87%) were FIT-negative in all rounds they had participated in, while 2,140

(13%) were FIT-positive. A subsequent colonoscopy was performed in 2,096 FIT-positives; in 65% of

them the colonoscopy was negative (see Figure 1).

Linkage with the National Cancer Registry identified 90 proximal cancers between 2006 and 2015

in our study group (see Appendix 3). Nineteen were diagnosed before the corresponding persons

first participated in FIT-screening and five were FIT-positives that had not undergone a subsequent

colonoscopy. Of the 66 remaining cancers identified in screening participants, 40 were diagnosed

88

5

CHAPTER 5

within two years after the FIT: 33 in FIT-negative participants (33/14,025; 0.24%; 95%CI 0.17-0.34) and

7 in FIT-positive participants (7/2140; 0.33%;95%CI 0.16-0.68). This difference in cumulative incidence

between FIT-positives and FIT-negatives was not significant (P = 0.43). Of the seven persons

diagnosed with a proximal cancer within two years after a positive FIT, five persons were diagnosed

after a negative colonoscopy (0.37%; 95%CI 0.16-0.86) and two after a positive colonoscopy (0.27%;

95%CI 0.07-0.99; Figure 1). When comparing the three groups (e.g. FIT-positives with a negative

colonoscopy, FIT-positives with a positive colonoscopy, and FIT-negative), also no significant

differences was found (P=0.65). Table 1 summarizes the cancers diagnosed per location for each

group. As expected, most oral/throat cancers originated from squamous epithelium and most

upper GI cancers originated from glandular epithelial cells.

When only focusing on gastric and esophageal cancers diagnosed within 2 years after FIT (i.e.

those cancers that can be diagnosed by EGD), 22 esophageal (n=15) and gastric (n=7) cancers were

diagnosed in FIT-negative screenees (0.16%;95%CI 0.1-0.24) and 2 esophageal cancers and no gastric

cancers in FIT-positive screenees (0.09%; 95%CI 0.02-0.33). The difference between FIT-positives

and FIT-negatives is not significant (P= 0.48). The hypothetical number needed to scope with EGD

to detect one gastric or esophageal cancer in FIT-positive screenees with a negative colonoscopy

was 1,367 (1 over 1367).

Figure 1. Flow chart cohort

89

5

RISK OF UPPER GI CANCER AFTER A POSITIVE FIT

Subgroup characteristics

Table 2 summarizes the characteristics of all persons with proximal cancer within the three groups.

Median age at diagnosis was similar; 68 years (IQR 59-73), 61 years and 65 years (IQR 58-73),

respectively. Proximal cancers were more often diagnosed in men, but no statistically significant

differences were seen between the three groups (P = 0.92). Two small bowel cancers were diagnosed

among FIT-positives (0.09%) and none among FIT-negatives. These cancers were located in

the jejunum or ileum and would therefore not have been diagnosed with routine EGD.

Among the FIT-positives, five participants had a negative colonoscopy of whom four had

no findings and one had a tubular adenoma of less than 10 mm at endoscopy. Among the two

participants with a positive colonoscopy, the most advanced lesion was a tubulovillous adenoma.

After linkage to the National Cancer Registry no colonoscopy interval cancers were identified

among these FIT-positives.

DISCUSSION

In our study concerning three completed biennial FIT-based screening rounds with long-term

follow-up, FIT-positive and FIT-negative participants had a similar but low risk of a diagnosis of

proximal cancer within two years. When only focusing on gastric and esophageal cancers diagnosed

within 2 years after FIT (i.e. those cancers that can be diagnosed by EGD), also no difference was

found between FIT positive and FIT-negative participants.

Table 1. Histopathology and location of all proximal cancers according to baseline FIT and colonoscopy results

Positive FIT,

negative colonoscopy

Positive FIT,

positive colonoscopy Negative FIT

Oral/Throat*

carcinoma unspecified

squamous cancer

0

2

0

1

1

10

Esophagus

squamous cancer

adenocarcinoma

Gastric

adenocarcinoma

linitis plastica

GIST

0

1

0

0

0

1

0

0

0

0

4

11

5

1

1

Small bowel

adenocarcinoma

carcinoid

GIST

1

0

1

0

0

0

0

0

0

Total number of cancers 5 2 33

*Oral/throat locations include cavum oris (tonsills, tongue, palate, floor of mouth, retromolar trigone), oropharynx,

epiglottis, supraglottis, glottis, sinus piriformis, hypopharynx, pharynx.

90

5

CHAPTER 5

To our knowledge, this is the first study to report the risk of proximal cancers (oral cavitiy,

throat, esophagus, gastric and small bowel cancer) among persons participating in a FIT-based

CRC screening program with long-term follow-up. Our cohort was sampled from an average-risk

population, comprising all age-ranges commonly invited for CRC screening programs worldwide.

This makes our results applicable for many Western countries that have implemented a FIT-based

screening program. The Dutch National Cancer Registry provides a high quality, unique and fully

covered database, enabling us to identify all proximal cancers occuring among participants.

To fully appreciate our findings, some limitations also need to be addressed. Identifying benign

causes for FIT-positivity (such as a gastric ulcers or erosions) could not be investigated since linkage

with the National Cancer Registry only identifies cancers. Some previously published studies

found an increased incidence of benign gastric lesions and stated that EGD should be additionally

performed to detect these. Linkage to the National Cancer Registry revealed only a small number

of proximal cancers, hampering the statistical precision of comparisons between subgroups. As

previous studies have shown that screening participants are in general healthier and have better

health literacy than non-participants, we chose not to compare our results to the incidence of

proximal cancers in the general population [13,14]. Lastly, tumors diagnosed after more than two

years after the last FIT were not considered potentially related and were not included in the analysis.

It could be that by choosing this 2-year time interval, intermittent bleeding (pre) malignant lesions

are unjustly not included in the analysis.

We did not observe a difference in our cohort in the occurrence of proximal cancers between FIT-

positive and FIT-negative screenees, nor in terms of gastric or esophageal cancers. The cumulative

incidence of diagnosed gastric or esophageal cancer after FIT-testing was extremely low, even lower

Table 2. Characteristics of patients with proximal cancers diagnosed within 2 years after FIT

Positive FIT,

negative

colonoscopy

Positive

FIT, positive

colonoscopy Negative FIT P-value

Total number of cancers 5 2 33 0.645

Age at diagnosis, median (IQR)

50-59 yr

60-69 yr

≥70 yr

68 (59-73)

2 (40%)

1 (20%)

2 (40%)

61

1 (50%)

1 (50%)

0 (%)

65 (58-73)

9 (27%)

13 (39%)

11 (33%)

0.864

Sex (male, n (%)) 4 (80%) 1 (50%) 22 (67%) 0.918

Hb concentration (median, IQR) 65 (37-140) 190 0.6 (0-1.6) <0.001

Type of cancer (n)

Oral/Throat

Esophagus/gastric

Small bowel

2 (40%)

1 (20%)

2 (40%)

1 (50%)

1 (50%)

0 (0%)

11 (33%)

22 (67%)

0 (0%)

0.014

Time between test and diagnosis cancer

(mean, ±SD, yr)

1.11 (0.51) 0.6 (0.01) 1.2 (0.6) 0.237

91

5

RISK OF UPPER GI CANCER AFTER A POSITIVE FIT

for gastric or esophageal cancer in FIT-positives with a negative colonoscopy (0.07%; 1 esophageal

cancer/1,367).

It has been hypothesized that FIT has a low sensitivity for proximal bleeding lesions, as it is based

on detecting human globin, which deteriorates rapidly and may not be traceable [5]. This theory

seems to be strengthened by our findings, as no difference in incidence between oral/throat,

esophageal and gastric cancers was observed between FIT-positives and FIT-negatives. Because of

the doubt whether FIT can detect small bowel cancers, we included these in the linkage. During

follow up, linkage revealed one jejunal gastrointestinal stromal tumor and one ileal adenocarcinoma

in FIT-positive participants. Among FIT-negative participants, no small bowel tumors were found.

Due to their location, these lesions would not have been detected with standard EGD.

Although a significant difference between the distribution in tumor location was observed,

these results must be interpreted with caution due to the very small numbers. A Japanese study

investigated small bowel lesions using capsule endoscopy among FIT-positive screenees with no

findings at colonoscopy and found no abnormalities explanatory for bleeding, and concluded that

additional small bowel evaluation is not recommended in asymptomatic non-anemic participants

[15]. Based on our results we would also not advise additional small bowel evaluation, but further

studies should be performed.

No other studies have looked at throat cancers as a possible cause for a positive FIT.

Our data showed no difference in occurrence of these cancers between FIT-positive and

FIT-negative screenees.

Similar previous studies mainly concerned gFOBT screening programs. In line with our findings,

these studies reported a low positive predictive value (PPV) for upper GI cancers. Zappa et al., who

identified gastric cancers after linkage to a local cancer registry, reported a PPV for FOBT of 0.4%

(22/5580 within 3 years after FOBT) for gastric cancer in FIT-positives (including positives with

a negative or positive colonoscopy). A PPV for FOBT of 0.4% (14/3555 within 3 years after FOBT) for

gastric cancer in FOBT-positives with a negative colonoscopy was reported, resulting in a number

needed to scope of 254. They only identified gastric cancers and did not select esophageal cancers

or other proximal cancers [16]. Rasmussen et al reported a significant difference in incidence

between gastric and esophageal cancers between gFOBT positives and gFOBT negatives in a Danish

population, but also reported a low PPV of 0.52% (within two years of a gFOBT) among persons with

an negative colonoscopy [17]. They detected only 3 upper GI cancers among 20,671 persons during

a 15 year follow up and concluded that the number needed to scope to detect one upper GI cancer

would be unjustified [18].

Several studies analysed the diagnostic yield of EGD among FOBT-positives with a negative

colonoscopy. A review by Allard et al. described studies in gFOBT screening and was inconclusive

[4]. The studies included heterogeneous group of persons, different study designs and different

definitions for positive colonoscopy [4,19,20]. Studies in FIT-based screening programs also

had conflicting results. Most were performed among symptomatic persons, including young

persons from age 18, while other studies included screenees that were willing to undergo both

92

5

CHAPTER 5

colonoscopy and EGD, introducing an important selection bias [17,21-23]. Notably, most of

these studies originate from Asia and, as expected, according to a study published by Day et al.

the detection rates of gastric cancer at EGD among gFOBT-positive screenees was higher in Asians

than Caucasians [24]. Moreover, an important difference in these studies compared to our results

is that benign findings at EGD, like ulcers, gastritis or reflux disease, were defined as significant

pathology and were interpretated as a justifiable reason to perform EGD. Due to the low incidence

of esophageal and gastric findings in the Western world, as well as the decreasing prevalence

of Helicobacter pylori, the benefit of EGD will be probably less than previously reported Asian

studies [25]. Hence, these findings together with the high number needed to scope to diagnose

one gastric or esophageal cancer, make the routine use of EGD in FIT-screenees followed by

a negative colonoscopy not justifiable. Routine EGD-screening in FIT-positives is not without harm.

Complications such as perforations and sedation related complications have been reported [26].

Based on the small numbers, implementing additional EGD will reduce the cost-effectiveness of CRC

screening programs.

In summary, this study provides strong support that EGD should not be routinely performed

in FIT-positive screening participants without advanced neoplasia at subsequent colonoscopy.

Only clinical symptoms, anemia or other risk factors for upper GI cancer could warrant additional

investigations in those persons.

ACKNOWLEDGEMENTS

The authors thank the registration teams of the Netherlands Comprehensive Cancer Organisation for

the collection of data for the Netherlands Cancer Registry and the scientific staff of the Netherlands

Comprehensive Cancer Organisation. We thank the Netherlands Organization for Health Research

and Development of the Dutch Ministry of Health (ZonMW) for funding (project numbers 120710007,

63000004). The authors thank all involved co-workers of the Foundation of Population Screening

Mid-West and South-West (Bevolkingsonderzoek Midden-West, Bevolkingsonderzoek Zuid-West)

for their important contributions to the study.

93

5

RISK OF UPPER GI CANCER AFTER A POSITIVE FIT

REFERENCES

1. Council of the European Union. Council

Recommendation of 2 December 2003 on

cancer screening (2003/878/EC) Off J Eur

Union. 2003:34–38.

2. Von Karsa L, Patnik J, Segnan N, et al. European

guidelines for quality assurance in colorectal

cancer screening and diagnosis: overview and

introduction to the full supplement publication.

Endoscopy. 2013;45: 51–59.

3. van Turenhout ST, Oort FA, Terhaar sive

Droste JS, et al. Hemorrhoids detected at

colonoscopy: an infrequent cause of false-

positive fecal immunochemical test results.

Gastrointest Endosc. 2012;76:136-143.

4. Allard J, Cosby R, Del Giudice ME, et al.

Gastroscopy following a positive fecal occult

blood test and negative colonoscopy:

systematic review and guideline. Can J

Gastroenterol. 2010;24(2):113-120.

5. Young GP, St John DJ, Rose IS, et al. Haem in

the gut. Part II. Faecal excretion of haem and

haem-derived porphyrins and their detection.

J Gastroenterol Hepatol 1990;5:194–203.

6. Stegeman I, van Doorn SC, Mundt MW, et al.

Participation, yield, and interval carcinomas in three

rounds of biennial FIT-based colorectal cancer

screening. Cancer Epidemiol. 2015;39:388-393.

7. Kapidzic A, Grobbee EJ, Hol L, et al. Attendance

and yield over three rounds of population-

based fecal immunochemical test screening.

Am J Gastroenterol 2014;109:1257-1264.

8. Rembacken B., Hassan C., Riemann J.F. et al. Quality

in screening colonoscopy: position statement

of the European Society of Gastrointestinal

Endoscopy (ESGE). Endoscopy 2012;33:957-968.

9. Schlemper RJ, Riddell RH, Kato Y, et al.

The Vienna classification of gastrointestinal

epithelial neoplasia. Gut 2000;47:251-255.

10. Bosman FT. WHO classification of tumours of

the digestive system. International Agency for

Research on Cancer 2010; 4th ed. Lyon.

11. van Doorn SC, Stegeman I, Stroobants AK, et al. Fecal

immunochemical testing results and characteristics

of colonic lesions. Endoscopy 2015;47:1011-1017.

12. Nederlandse richtlijn coloscopie surveillance

NVMDL nov 2013. https://www.mdl.nl/

sites/www.mdl.nl/files/richlijnen/Richtlijn_

Coloscopie_Surveillance_definitief_2013.pdf

13. Moss SM, Campbell C, Melia J, et al. Performance

measures in three rounds of the English bowel

cancer screening pilot. Gut 2012;61:101-107.

14. Hardcastle JD, Chamberlain JO, Robinson MH,

et al. Randomised controlled trial of faecal-

occult-blood screening for colorectal cancer.

Lancet 1996;348:1472-1477.

15. Chiba H, Sekiguchi M, Ito T, et al. Is it

worthwhile to perform capsule endoscopy

for asymptomatic patients with positive

immunochemical faecal occult blood test? Dig

Dis Sci. 2011;56:3459-62.

16. Zappa M, Visioli CB, Ciatto S, et al. Gastric

cancer after positive screening faecal occult

blood testing and negative assessment. Dig

Liver Dis. 2007;39:321-326.

17. Levi Z, Vilkin A, Niv Y. Esophago-gastro-

duodenoscopy is not indicated in patients

with positive immunochemical test and

nonexplanatory colonoscopy. Eur J

Gastroenterol Hepatol. 2010;22:1431-1434.

18. Rasmussen M, Kronborg O. Upper gastrointestinal

cancer in a population-based screening program

with fecal occult blood test for colorectal cancer.

Scand J Gastroenterol. 2002;37:95-98.

19. Bini EJ, Rajapaksa RC, Valdes MT, et al. Is

upper gastrointestinal endoscopy indicated

in asymptomatic patients with a positive fecal

occult blood test and negative colonoscopy?

Am J Med. 1999;106:613-618.

20. Hisamuddin K, Mowat N, Phull P. Endoscopic

findings in the upper gastrointestinal tract of

faecal occult blood-positive, colonoscopy-

negative patients. Dig Liver Dis. 2006;38:503-507.

21. Choi JS, Choi JY, Cho HG, et al. Is

esophagogastroduodenoscopy necessary

in patients with positive fecal occult blood

tests and negative colonoscopy? Scand J

Gastroenterol. 2013;48(6):657-662.

94

5

CHAPTER 5

22. Chiang T, Lee Y, Tu C, et al. Performance of

the immunochemical fecal occult blood test in

predicting lesions in the lower gastrointestinal

tract. CMAJ. 2011;183:1474-1481.

23. Ng JY, Chan DK, Tan KK. Is gastroscopy for

fecal immunochemical test positive patients

worthwhile? Int J Colorectal Dis. 2017;32:95-98.

24. Day L, Cello J, Somsouk M, et al. Prevalence

of gastric cancer versus colorectal cancer in

Asians with a positive fecal occult blood test.

Indian J Gastroenterol 2011;30:209–16.

25. van Blankenstein M, van Vuuren AJ, Looman

CW, et al. The prevalence of Helicobacter

pylori infection in the Netherlands. Scand J

Gastroenterol. 2013;48:794-800.

26. Ben-Menachem T, Decker GA, Early DS, et

al. Adverse events of upper GI endoscopy.

Gastrointest Endosc. 2012;76:707-18.

95

5

RISK OF UPPER GI CANCER AFTER A POSITIVE FIT

SUPPLEMENTARY DOCUMENTS

Appendix 1. Schematic figure of all three completed rounds including observational period of two years after

last FIT was performed to identify all occurring proximal tumors after performing a FIT test. Follow up data till

October 2014 was included.

Appendix 2. Basic characteristics of FIT screening cohort

Round 1 Round 2 Round 3

Invitees 14,651 18,383 19,618

Age (median, IQR) 59 (54-65) 60 (55-66) 60 (55-66)

Sex (male;%) 50 49 49

96

5

CHAPTER 5

Appendix 3. All identified cancers after linkage to Cancer Registry