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