Gastroenterology 2017;153:439–447

Interval Colorectal Cancer Incidence Among Subjects

Undergoing Multiple Rounds of Fecal Immunochemical Testing
Manon van der Vlugt,1,* Esmée J. Grobbee,2,* Patrick M. M. Bossuyt,3 Amanda Bos,4
Evelien Bongers,5 Wolfert Spijker,6 Ernst J. Kuipers,2 Iris Lansdorp-Vogelaar,7
Manon C. W. Spaander,2 and Evelien Dekker1

CLINICAL AT
1
Cancer Center Amsterdam, Department of Gastroenterology and Hepatology, and 3Clinical Epidemiology, Biostatistics and
Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; 2Department of
Gastroenterology and Hepatology, and 7Department of Public Health, Erasmus University Medical Centre, Rotterdam, The
Netherlands; 4Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands;
5
Foundation of Population Screening Mid-West, Amsterdam, The Netherlands; and 6Regional Organization for Population
Screening South-West Netherlands, Rotterdam, The Netherlands

compared with persons with colonoscopy interval cancers

See Covering the Cover synopsis on page 335.
BACKGROUND & AIMS: Among subjects screened for colo-
rectal cancer (CRC) by the guaiac fecal occult blood test, in-
terval cancers develop in 48% to 55% of the subjects. Data are
limited on how many persons screened by fecal immuno-
chemical tests (FIT), over multiple rounds, develop interval
cancers. In the Netherlands, a pilot FIT-based biennial CRC
screening program was conducted between 2006 and 2014. We
collected and analyzed data from the program on CRCs detec-
ted during screening (SD-CRC) and CRCs not detected within
the screening program (non–SD-CRC; such as FIT interval
cancers, colonoscopy interval cancers, and cancer in
nonparticipants). METHODS: Screenees with a negative FIT
result received a letter explaining that no blood had been
detected in the stool sample and were re-invited, if eligible, for
screening biennially. Screenees with a positive FIT result (he-
moglobin concentration of 10 mg Hb/g feces) were invited for
consultation and scheduled for colonoscopy; results were
collected. After the fourth round of FIT screening, the cohort
was linked to the Netherlands Cancer Registry, through March
31, 2015; participant characteristics, data on tumor stage,
location (at time of resection), and survival status were
collected for all identified CRC cases. A reference group
comprised all persons with CRC diagnosed in the Netherlands
general population during the same period, in the same age
range (50–76 years), who had not been offered CRC screening.
The median time between invitations (2.37 years) was used as
a cutoff to categorize participants within the FIT interval cancer
category. We compared participant characteristics, tumor
characteristics, and mortality among subjects with SD-CRC and
with non–SD-CRC. RESULTS: A total of 27,304 eligible in-
dividuals were invited for FIT screening, of whom 18,716
(69%) participated at least once. Of these, 3005 (16%) had a
positive result from the FIT in 1 of the 4 screening rounds. In
total, CRC was detected in 261 participants: 116 SD-CRCs and
145 non–SD-CRCs (27 FIT interval cancers, 9 colonoscopy
interval cancers, and 109 CRCs in nonparticipants). The FIT
interval cancer proportion after 3 completed screening rounds
was 23%. Participants with SD-CRC had more early-stage
tumors than participants with non–SD-CRCs (P < .001). Of
persons with SD-CRC and FIT interval cancers, significantly
higher proportions survived (89% and 81%, respectively)
(44% survival) and nonparticipants with CRC (60% survival)
(P < .001). CONCLUSIONS: In an analysis of data from a pilot
FIT-based biennial screening program, we found that among
persons screened by FIT, 23% developed FIT interval cancer.
FIT therefore detects CRC with 77% sensitivity. The proportion
of FIT interval cancers in FIT screening appears to be lower
than that with guaiac fecal occult blood testing. Clinical trial
registry: yes, www.trialregister.nl, trial number: NTR5385.
Keywords: fFOBT; Colon Cancer; Early Detection; Tumor.
C olorectal cancer (CRC) is one of the leading causes of
cancer-related deaths in the Western world.1,2
Approximately 50% of patients die from the disease.3 Sur-
vival is strongly related to tumor stage at time of diagnosis,
with a 5-year survival of 94% for stage I CRC to 8% for stage
IV CRC.3 Population-based CRC screening programs enable
detection of CRC (screen-detected [SD]-CRC) at an earlier
stage. Screening with fecal occult blood tests (FOBT) has
been shown to reduce CRC-related mortality.4–6
Although FOBT screening is effective, not all CRCs will be
detected within a screening program. A number of screening
invitees will develop CRC in time although their cancer was
not detected by FOBT: these are non–screen-detected CRCs
(non-SD-CRCs).7 These cancer cases partially consist of in-
terval cancers: cancer cases detected after a negative
screening examination and before the date of the next rec-
ommended screening.7 Such cancers can be missed by the
first-line screening test or during colonoscopy following a
*Authors share co-first authorship.
Abbreviations used in this paper: BBPS, Boston Bowel preparation scale;
CRC, colorectal cancer; FIT, fecal immunochemical test; FOBT, fecal
occult blood test; gFOBT, guaiac fecal occult blood test; Hb, hemoglobin;
IQR, interquartile range; non–SD-CRC, non–screen-detected CRC;
SD-CRC, screen-detected CRC; SES, socioeconomic status.
Most current article
© 2017 by the AGA Institute
0016-5085/$36.00
http://dx.doi.org/10.1053/j.gastro.2017.05.004
 440 van der Vlugt et al
EDITOR’S NOTES
BACKGROUND AND CONTEXT
Fecal immunochemical test (FIT)-based screening for
colorectal cancer (CRC) is effective, but not all CRCs
are detected within a screening program.
NEW FINDINGS
The FIT interval cancer miss rate is much lower than the
previously reported miss rates for guaiac fecal occult
blood tests (gFOBT).
CLINICAL AT
LIMITATIONS
The study did not perform a head-to-head comparison
with gFOBT.
IMPACT
The results support the superior effectiveness of FIT over
gFOBT.
positive FOBT.7 Other cancer cases will be detected in those
who did not participate in screening.
Monitoring the incidence of interval cancers is regarded
as an indicator of program sensitivity and FIT sensitivity. So
far, most studies have reported interval cancers of programs
using guaiac-based FOBT, showing high proportions of in-
terval cancers. In such programs, the proportion of interval
cancer cases ranged from 48% to 55%.5,6,8,9 These studies
have shown better survival rates in screen-detected cancers
than in interval cancers.10
As fecal immunochemical tests have a better diagnostic
accuracy than guaiac-based FOBTs (gFOBTs), it is conceiv-
able that interval cancer proportions are lower than those
reported in gFOBT-based programs.11 In this study, we
report FIT interval cancers over multiple rounds of FIT
screening.
Methods/Materials
Population and Design
Since 2006, 2 pilot programs of biennial FIT-based CRC
screening have been conducted in the southwest and northwest
regions of the Netherlands. These 2 cohorts were combined for
a fourth pilot round of screening in 2014. Details about the
design of these CRC screening programs have been reported
previously.12,13 In 2006, we selected the initial 2 cohorts based
on postal code areas within our regions, which were both rural
and urban areas with a known average uptake in breast cancer
screening. Since 2006, we used the same inclusion and exclu-
sion criteria for both cohorts. In short, demographic data of all
invitees between 50 and 74 years living in the target areas
were obtained from municipal population registers. See
Supplementary Table 1 for baseline invitee characteristics per
region. No national screening program had been implemented
at the start of this pilot program; the target population was
screening-naive when first contacted. In the Netherlands, a
national FIT-based CRC screening program has been gradually
initiated from January 2014 onward. Invitees for the study
cohort were not invited for the national CRC screening
program.
Gastroenterology Vol. 153, No. 2
Selected persons were invited for each consecutive round,
except for those who had moved out of the area, those who
had passed the upper age limit, institutionalized people, those
with an estimated life expectancy of less than 5 years, those
unable to give informed consent, and those who had tested
positive in a previous screening round and had undergone a
colonoscopy. In our information leaflet, persons with a history
of inflammatory bowel disease or CRC were advised not to
participate in CRC screening and to report this to the
screening organization.
Characteristics
Date of birth, sex, and postal codes of all invitees were
collected from the municipal population register. Socioeco-
nomic status was based on the “social status scores” that are
available through the Netherlands Institute of Social Research
(www.scp.nl). The postal code of the invitee was used to
evaluate social status. The social status score of a postal code
area was based on the unemployment rate, educational level,
average income, and position on the labor market. The average
score is 0 and the 2006 standard deviation in the Netherlands
was used to assign invitees to 1 of 3 categories: high (status
scores >0.96), average (status scores between
0.96 and 0.96),
and low socioeconomic status (SES) (status scores <
0.96).
The first available postal code of the invitee was used to
categorize invitees.
Invitations and Stool Tests
Because of organizational and logistical issues, the time
interval between rounds differed (median time between in-
vitations was 2.37 years; interquartile range [IQR] 2.01 to
2.76). Invitations were sent between June 2006 and December
2014. Two different brands of stool tests were used in our
cohort. In the first, second, and third round, all invitees received
an OC-Sensor (Eiken Chemical Co, Tokyo, Japan). In the fourth
round (executed between March 2014 and February 2015), all
invitees were randomly allocated to receive either an OC-
Sensor or an FOB-Gold (Sentinel Diagnostics SpA, Milan,
Italy).14 A hemoglobin (Hb) value of 10 mg Hb/g feces was used
as the positivity threshold; this corresponds to 50 ng/mL buffer
for OC-Sensor and 58 ng/mL buffer for FOB-Gold.
Test Results
Screenees with a negative FIT result received a letter
explaining that no blood had been detected in the stool sample
and no follow-up was needed at that time. It was emphasized
that the FIT is not 100% sensitive and that vigilance for
symptoms of CRC remained important. Participants were
instructed to contact their general practitioner in case of
symptoms, despite the negative test result.
Screenees with a positive FIT result were invited for a
consultation at the outpatient clinic to discuss the test result.
During the intake at the outpatient clinic, for all person who
were FIT-positive, a colonoscopy was scheduled within 4
weeks. In some cases, patient-related circumstances led to
postponing the colonoscopy. All endoscopies were performed
within 6 months and, therefore, a timeframe of 6 months after a
positive FIT was used for the definition of screen-detected
cancers.
August 2017
Follow-up Colonoscopy and Colorectal Lesions
The colonoscopy was performed per international quality
standards; quality parameters were collected in a database.15
To describe the quality of the bowel preparation, a 4-point
scale was used: excellent, good, fair, poor. Excellent and good
were considered as sufficient and fair and poor were consid-
ered as insufficient bowel preparation. Since 2013, the Boston
Bowel preparation scale (BBPS) was used with BBPS 6
considered as sufficient bowel preparation. Cecal intubation
was confirmed by photo documentation of cecal landmarks. All
endoscopists were experienced, and had performed at least
1000 colonoscopies. Advice regarding surveillance colonoscopy
after removal of adenomatous polyps, large (10 mm) serrated
lesions, or cancer was given to the participant according to the
Dutch guideline colonoscopy surveillance.16 Data on the loca-
tion, size, macroscopic aspects, and morphology, as well as
details on the technique for polypectomy and endoscopic
assessment of radicality were recorded for all colorectal lesions
detected during colonoscopy. Tumor location was categorized
as either proximal or distal to the splenic flexure. Collected
lesions were evaluated by an experienced gastrointestinal
pathologist, using the Vienna criteria.17 Cancers were staged
per the seventh edition American Joint Committee on Cancer
classification.18
Screen-Detected Cancers, Non–Screen-
Detected Cancers, and the General Population
After finishing the fourth screening round, the cohort was
linked to the Netherlands Cancer Registry, managed by the
Netherlands Comprehensive Cancer Organisation (up to date
until March 31, 2015). Since 1989, the Netherlands Cancer
Registry registers all participants diagnosed with cancer in the
Netherlands and provides a unique and fully covered database.
Data on tumor stage, location (at time of resection), and sur-
vival status were collected for all identified CRC cases. Defini-
tion of SD-CRC and non–SD-CRC are depicted in Table 1. A
colonoscopy interval cancer within a FIT screening program
was defined as a cancer diagnosed after negative colonoscopy
after a positive FIT within the surveillance interval. We defined
a reference group consisting of all persons with CRC diagnosed
in the Netherlands general population during the same period
and in the same age range (50–76 years) who had not been
offered CRC screening. The upper range of 76 years was chosen
based on the median time between invitations and the upper
age limit for eligibility (74 þ 2.37 years). Participants with CRC
detected at a scheduled surveillance colonoscopy as well as
CRC in screening participants with a positive FIT who declined
to undergo a subsequent colonoscopy are reported separately.
The median time between invitations (2.37 years; IQR 2.01–
2.76) was used as a cutoff to categorize participants within the
FIT interval cancer category. If a participant had a negative FIT
and developed a CRC but had not yet been invited for the
consecutive round, this was categorized as a FIT interval can-
cer. If a participant had a negative FIT and was not invited for a
consecutive round (due to having passed the upper age limit, or
having moved out of the area) but developed a CRC within the
2.37-year interval (the median time between invitations), this
was categorized as a FIT interval cancer. Those who were not
compliant with the FIT screening program were not defined as
an interval CRC, because there cannot be an interval CRC if the
FIT Interval Cancers in Colorectal Cancer Screening 441
Table 1.Definitions of Cancers
Terminology Definition
SD-CRC Screen-detected colorectal cancer defined as
CRCs detected at colonoscopy following a
positive FIT result
non–SD-CRC Non–screen-detected colorectal cancer defined as
all CRCs that were not diagnosed at a
colonoscopy following a positive FIT result and
are divided into 3 groups:
1. FIT interval cancer defined as cancers diag-
nosed between screening rounds after negative
CLINICAL AT
FIT before the next FIT was due
2. Colonoscopy interval cancer within a FIT
screening program defined as cancers diag-
nosed after negative colonoscopy after a posi-
tive FIT within the surveillance interval
3. Colorectal cancer in nonparticipants defined as
cancers diagnosed in those who did not
respond to their FIT invitation.
General The reference group was defined as all persons
population diagnosed with CRC in the Netherlands
population during the same period and in the
same age range (50–76 years), who were not
offered CRC screening.
individual did not undergo initial testing7 and was not included
in the analysis.
Data on the general population and on nonparticipants
(because there was no informed consent) were anonymously
analyzed and subsequently delivered to us by the Netherlands
Comprehensive Cancer Organisation. Data on follow-up time, in
days after diagnosis, and SES are not available for these groups.
Data Analysis
The proportion of FIT interval cancers was calculated by
dividing the number of FIT interval cancers by the sum of SD-
CRC and FIT interval cancers. The proportion was calculated
over 3 completed screening rounds so SD-CRC cases detected
within the first 3 screening rounds were selected and the total
number of FIT interval cancers occurring after these rounds.
FIT CRC sensitivity was calculated as 1-FIT interval cancer
proportion. Median follow-up for participants with SD-CRC, FIT
interval cancers, and colonoscopy interval cancers was calcu-
lated from date of diagnosis to death or considered censored at
the end of follow-up (March 31, 2015). Median follow-up could
not be calculated for the general population and for non-
participants because no data on follow-up in days after diag-
nosis were available nor was the exact date of diagnosis; only
the year of diagnosis of these cases was provided. Survival after
diagnosis was estimated only for participants with SD-CRC, FIT
interval cancers, and colonoscopy interval cancers.
Differences in proportions between groups were evaluated
for statistical significance using the c2-test statistic. Kaplan-
Meier was used to estimate for survival with accompanying
confidence intervals. P values <.05 were considered to indicate
statistically significant differences. Data analysis was per-
formed using SPSS 23 for Windows (IBM SPSS Statistics,
Chicago, IL). All authors had access to the study data and
reviewed and approved the final manuscript.
 442 van der Vlugt et al
Ethics Approval
Approval for the study was provided by the Dutch National
Health Council (WBO 2642467, 2832758, 3049078, and
161536–112008, The Hague, The Netherlands). All authors had
access to the study data and reviewed and approved the final
manuscript.
Results
A total of 27,304 members of the target population were
eligible for FIT screening, of whom 18,716 (69%) partici-
CLINICAL AT
pated at least once (Figure 1). Of these, 3005 (16%) had a
positive FIT in 1 of the 4 screening rounds and 2762 sub-
sequently underwent a colonoscopy (92% adherence). In
the total cohort of 27,304, CRC was detected in 269 invitees:
in 160 participants (60%) and in 109 who never partici-
pated (40%). The cancers detected in the 160 participants
were 116 SD-CRCs (72%), 27 FIT interval cancers (17%), 9
colonoscopy interval cancers (6%), 5 CRCs in FIT-positive
participants not adhering to colonoscopy (3%), and 3
CRCs detected at surveillance (2%). These last 2 groups,
with a total of 8 CRCs, were excluded from further analyses.
FIT Interval Cancer Proportion and FIT
CRC Sensitivity
The FIT interval cancer proportion was 23% (27 FIT in-
terval cancers versus 89 SD-CRCs after 3 completed
screening rounds), reflecting a FIT sensitivity for detecting
CRC of 77%. FIT levels of participants with SD-CRCs and FIT
interval cancers are shown in Supplementary Table 2; 31% of
those with a SD-CRC had a positive FIT between the range of
10 to 46 mg Hb/g feces. Twelve participants (44%) with a FIT
interval cancer had undetectable hemoglobin concentrations
at the time of the last screening. For FIT interval cancers,
Supplementary Table 3 shows the quantitative FIT level per
case, the total number of rounds in which they participated,
and after which round the FIT interval cancer was diagnosed.
Participant Demographics
Table 2 summarizes the characteristics of SD-CRC and
non–SD-CRC separately. No significant differences were
Gastroenterology Vol. 153, No. 2
found for age at diagnosis between participants with SD-
CRC and individuals with non–SD-CRC (P ¼ .83) (Table 2).
A colonoscopy interval cancer was detected more often in
women than in men (56% vs 44%), but this difference was
not statistically significant. There were also no significant
differences in SES among the groups (P ¼ .76). The age and
sex distribution was comparable with that of the general
population (not tested for statistical significance).
Among the 9 participants with a colonoscopy interval
cancer, the colonoscopies were reported as complete with
cecal intubation. In 6 cases, sufficient bowel preparation
was reported, in 3 cases these data were missing. Three
participants received a colonoscopy surveillance advice, but
developed a CRC within this interval. One person received
an advice of a 3-year interval and 1 person a 6-year interval,
and both recommendations were in agreement with the
Dutch Surveillance Guideline of 2008. One person received
an adjusted advice of a 1-year surveillance interval because
multiple adenomas were removed at index colonoscopy. Six
participants were advised a 10-year screening interval as
per protocol (see Supplementary Table 4).
Tumor Location and Stage Distribution
Tumor location and CRC stage distribution are described
in Table 3 and Figure 2. Screen-detected CRC, FIT interval
cancers, and CRC in nonparticipants were mostly located in
the distal colon (71%, 63%, 62%, respectively), whereas
colonoscopy interval cancers were more often located in the
proximal colon (78%; P ¼ .063).
The stage distribution differed significantly among the 4
groups, with more favorable stages in participants with SD-
CRC (P < .001). Stage distribution was similar for partici-
pants with FIT interval CRC and for nonparticipants with CRC
(P ¼ .39). Participants with FIT interval cancers had more
advanced stages than SD-CRC (P ¼ .019). Tumor location and
stage distribution in nonparticipants with CRC were compa-
rable to those not offered screening (see Table 3).
Survival
Median follow-up after diagnosis for SD-CRC, FIT inter-
val cancers, and for colonoscopy interval cancers was 46.1
Figure 1. Flowchart of the
4 rounds of FIT-based
CRC screening, including
screen-detected and non–
screen-detected CRCs
among participants
(participating at least once)
and nonparticipants (never
participated).
August 2017 FIT Interval Cancers in Colorectal Cancer Screening 443

Table 2.Characteristics of Participants

Non–SD-CRC

FIT interval Colonoscopy CRC in CRC in general

SD-CRC cancer interval cancer nonparticipant P population

Total CRC 116 27 9 109a 72,612

Age at diagnosis, n (%) .831
50–59 28 (24) 6 (22) 1 (11) 21 (19) 14,651 (20)
60–69 50 (43) 11 (41) 6 (67) 49 (45) 31,868 (44)
>70 38 (33) 10 (37) 2 (22) 39 (36) 26,093 (36)
Sex, n (%) .709

CLINICAL AT
Male 73 (63) 16 (59) 4 (44) 69 (63) 42,486 (59)
Female 43 (37) 11 (41) 5 (56) 40 (37) 30,126 (42)
SES score, n (%) .763
Low 13 (11) 2 (7) 2 (22) Unknown Unknown
Average 82 (71) 21 (78) 6 (67) Unknown Unknown
High 21 (18) 4 (15) 1 (11) Unknown Unknown

a
Four cases with 2 incidents, age at diagnosis first incident selected.

months (IQR 18.1 to 72.1 months). There was a significant
difference in survival among SD-CRC, FIT interval cancers,
and colonoscopy interval cancers (P < .001; Figure 3).
Those with colonoscopy interval cancers had the lowest
survival: survival at 24 months was 67% (95% CI, 35%–
88%) compared with 85% (95% CI, 68%–94%) for FIT
interval cancers and 93% (95% CI, 87%–96%) for SD-CRCs.
Survival at 36 months was 56% (95% CI, 27%–81%), 85%
(95% CI, 68%–94%) and 91% (95% CI, 85%–95%),
respectively. Table 4 lists the number of deaths in the
respective groups. The number of deaths among persons
with FIT interval cancers was lower than among non-
participants with CRC and those not offered CRC screening
(19% vs 40% and 35%, respectively).
Discussion
This study confirms that the proportion of interval can-
cers in FIT-based CRC screening seems to be lower than in
gFOBT-based screening. Over 4 rounds of screening, fewer
than 1 in 4 cancer cases comprised FIT interval cancers. We
observed a more favorable survival for participants with FIT
interval cancers than for the population that was not offered
screening (ie, general population). Participants with a colo-
noscopy interval cancer had the worst outcome, which am-
plifies the importance of colonoscopy quality control.
We are the first to describe interval cancers in a FIT-
based screening program with long-term follow-up. Our
cohort is sampled from an average-risk population,
comprising all age ranges commonly invited for CRC
screening programs worldwide, which makes our results
applicable for many countries considering CRC screening.
This population was screen-naive when first approached,
without the presence of any other CRC screening initiatives
in the population. All data were prospectively collected and
all invitees were linked to the Netherlands Cancer Registry
by the Netherlands Comprehensive Cancer Organization to
identify all non–SD-CRCs.

Table 3.Tumor Location and Stage Distribution of CRCs

Non–SD-CRC

FIT interval Colonoscopy CRC in CRC in general

SD-CRC cancer interval cancer nonparticipant P population

Total CRC 116 27 9 109 72,612

Tumor location,a n (%) .063
Proximal 34 (29) 10 (37) 7 (78) 38 (35) 23,976 (33)
Distal 82 (71) 17 (63) 2 (22) 67 (62) 47,290 (65)
Unknown 0 (0) 0 (0) 0 (0) 4 (4) 1346 (2)
Stage, n (%) <.001
I 60 (52) 8 (30) 2 (22) 17 (16) 14,002 (19)
II 16 (14) 6 (22) 0 (0) 31 (29) 18,384 (25)
III 37 (32) 9 (33) 1 (11) 36 (33) 21,819 (30)
IV 3 (3) 4 (15) 6 (67) 23 (21) 16,909 (23)
Unknown 0 (0) 0 (0) 0 (0) 2 (2) 1498 (2)

a
Proximal (¼ splenic flexure and proximal).
 444 van der Vlugt et al
CLINICAL AT
The success of a FIT-based CRC screening program not
only depends on FIT test characteristics (sensitivity and
specificity) but also on adherence to screening with FIT and
to follow-up colonoscopy in persons who are FIT-positive.
Within our pilot study, high participation rates and high
colonoscopy adherence rates were achieved, resulting in a
substantial number of persons diagnosed with SD-CRC. To
fully appreciate the reported data of this research study,
these adherence rates should be confirmed in the setting of
an organized population-based screening program. In 2014,
in the Netherlands, a national FIT-based CRC screening
program was implemented, resulting in even higher
participation rates: 73% in 2015. Excluding those for whom
colonoscopy was not recommended (n ¼ 2637) during
intake, uptake of colonoscopy was 83.1%.19 This confirms
that the high performance indicators achieved within the
pilot study could possibly also be achieved in the setting of
the national organized FIT-based screening program.
To fully appreciate our findings, some limitations also
need to be addressed. Little information was available about
nonparticipants dying of CRC in our cohort, as these data
were delivered anonymously for privacy reasons. Conse-
quently, their SES could not be assessed. Previous studies
have shown that especially socioeconomically deprived
persons are less likely to take part in CRC screening, even
though they presumably are at a higher risk of developing
CRC due to poor general health.20,21 Last, their date of
diagnosis could not be related to the date of invitation. It is
possible that a person had already been diagnosed with CRC
Gastroenterology Vol. 153, No. 2
Figure 2. Stage distribu-
tion for the different types
of CRC as defined by
Sanduleanu et al.7 For
definitions see Table 1.
before being invited for screening. In such case, refraining
from participation would have been a justified decision.
Because FIT is more sensitive in detecting advanced
neoplasia than gFOBT, one would expect lower interval
rates for FIT. A previous Scottish FIT-based study, however,
reported a FIT interval cancer proportion of 51% using a
cutoff of 80 mg Hb/g feces.22 Italian researchers reported a
FIT interval cancer proportion of 31% using a cutoff of 20
mg Hb/g feces after 2 rounds of FIT screening.23 Our lower
proportion of FIT interval cancers could probably be
explained by the substantially lower cutoff (10 mg Hb/g
feces), thereby detecting CRCs already at low Hb concen-
tration. In our study, 31% of all SD-CRCs had low Hb con-
centration of <47 mg Hb/g feces. The Scottish study
investigated the effect of different cutoff levels of fecal Hb
on interval cancer proportions and colonoscopy demand. It
reported an interval cancer proportion of 51% at a cutoff
of 80 mg Hb/g feces vs a proportion of 38% using a cutoff of
10 mg Hb/g feces with a significant increase in number of
required colonoscopies for the latter cutoff.22 Hence,
choosing a very low positivity cutoff leads to a higher
number of SD-CRCs and lower proportion of FIT interval
cancers, at the cost of increased colonoscopy demand and
increased numbers of false positives.22
Our results showed no evidence for gender differences
in interval cancer rates, although previous studies have
shown higher rates of interval cancers among women.8,23–25
As in other studies, CRC was detected less frequently in
women. Notably, more women had a colonoscopy interval
August 2017
Figure 3. Survival curves.
cancer than men (56% vs 44%), yet this difference did not
reach statistical significance. These results are in line with a
Spanish study, reporting SD-CRC and interval cancers dur-
ing 4 rounds of FOBT screening mainly using gFOBT and FIT
in a small proportion of screenees.9 The Scottish researchers
also reported higher rates of FIT interval cancers in women,
without reaching statistical significance.22,24
Previous gFOBT-based studies have shown that most SD-
CRC cases were at an early stage, resulting in a better survival
than observed in non–screen-detected cancer cases.4,5,10,26 In
our study, most screen-detected cases were stage I cancers,
which confirms the findings of previous studies.9,10,24,27
In our FIT-based program, a higher percentage of stage I
CRCs were found than in previously reported gFOBT
screening programs. This could possibly be explained by the
relatively low FIT cutoff and the higher sensitivity of FIT.
FIT Interval Cancers in Colorectal Cancer Screening 445
CLINICAL AT
Comparable early-stage distributions in FIT screening have
been reported.22,26 Most detected tumors were located
distally, except for colonoscopy interval cancers, which were
mainly located in the proximal colon. These findings are also
in line with previous studies.9,28
In contrast to previous literature reporting that prog-
nosis of nonparticipants with CRC is poorer than that of
participants with symptomatically diagnosed CRC, we did
not observe this from our data.5,24 The number of deaths
was significantly lower in participants with FIT interval
cancers than in nonparticipants with CRC. This is in contrast
to findings of an English study, which reported similar
outcomes for gFOBT interval cancers and a control group.8
Persons diagnosed with FIT interval cancers showed bet-
ter survival as compared with nonparticipants and the
general population. This implies that the theoretical risk of
 446 van der Vlugt et al
Table 4.Mortality
FIT interval
SD-CRC cancer
Total CRC 116 27
Deaths, all-cause mortality,a n (%) 13 (11) 5 (19)
Follow-up months after 50 (25 to 76) 40 (15 to 63)
diagnosis CRC, median (IQR)
CLINICAL AT
a
At end of cohort.
persons seeking delayed medical consultation in case of the
development of abdominal symptoms due to false reassur-
ance caused by a recent negative FIT result seems, fortu-
nately, to have no immediate negative effect on all-cause
mortality within our cohort. These findings should be
interpreted with caution because, in theory, FIT participants
could have been in better health than the general popula-
tion, resulting in a selection bias.
In our cohort, 9 colonoscopy interval cancers were
detected between 2006 and 2015, resulting in a colonos-
copy interval cancer rate of 7.2%. Although the surprisingly
high occurrence of colonoscopy interval cancers needs
further attention, the rate is comparable to that in previ-
ously published screening studies, including another
FIT-based program, reporting rates between 2% and
8%.27,29–32 As most colonoscopy interval cancers were
detected in the proximal colon, we should consider proce-
dural factors, especially missed lesions (for instance due to
inadequate bowel preparation). In 30% of all persons
diagnosed with colonoscopy interval cancers in our study,
the bowel preparation score was not mentioned in the
report. Because both FIT interval cancers (reflecting FIT
CRC sensitivity) and colonoscopy interval cancers (partially
reflecting quality of the colonoscopy) are important for the
quality and success of a screening program, both should be
carefully monitored.
Five participants who refused colonoscopy after a posi-
tive FIT were later diagnosed with CRC. Unfortunately, no
information on the reason for refusal was available. To
facilitate early detection of these CRCs, additional strategies
to inform participants about the need for follow-up after a
positive FIT should be developed. Modifiable determinants
for nonadherence to endoscopy, such as embarrassment,
lack of knowledge about CRC, fear of the procedure, or
inconvenience should be discussed. Other strategies could
be built on sending all nonrespondents after a positive FIT
result an additional information leaflet, or to offer them a
consultation by phone.
Overall, our results support the effectiveness of FIT
screening programs with improved survival of screen-
detected cancers and lower proportions of interval cancers
than in gFOBT-based screening. Participants with colonos-
copy interval cancer had the worst outcome, which amplifies
the importance of colonoscopy quality control within
screening programs.
Gastroenterology Vol. 153, No. 2
Non-SD CRC
Colonoscopy CRC in CRC in general
interval cancer nonparticipant P population
9 109 72,612
5 (56) 44 (40) <.001 25,221 (35)
19 (9 to 30) – –
Supplementary Material
Note: To access the supplementary material accompanying
this article, visit the online version of Gastroenterology at
www.gastrojournal.org, and at http://dx.doi.org/10.1053/
j.gastro.2017.05.004.
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Received January 15, 2017. Accepted May 1, 2017.
Reprint requests
Address requests for reprints to: Evelien Dekker, MD, PhD, Department of
Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef
9, 1105 AZ, Amsterdam, The Netherlands. e-mail: e.dekker@amc.uva.nl;
fax: þ31 20 691 7033.
Acknowledgments
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, 200340001). The authors thank all
involved coworkers of the Foundation of Population Screening Mid-West and
South-West (Bevolkingsonderzoek Midden-West, Bevolkingsonderzoek Zuid-
West) for their important contributions to the study. We thank the
gastroenterologists who performed all colonoscopies.
Conflicts of interest
All authors have nothing to disclose.
Funding
The Netherlands Organization for Health Research and Development of the
Dutch Ministry of Health (ZonMW) funded all 4 screening rounds (project
numbers 120710007, 63000004, 200340001). The organization was not
involved in the analysis and interpretation of the data nor in the writing of the
manuscript or decision to submit the paper.
447.e1 van der Vlugt et al Gastroenterology Vol. 153, No. 2

Supplementary Table 1.Basic Characteristics of Invitees Per Round Per Region

Round 1 Round 2 Round 3 Round 4

MW SW MW SW MW SW MW SW

Invitees 5028a 9623 10,198 8185 10,032 9586 9517 9774

Age, median (IQR) 59 (54–65) 60 (55–66) 59 (54–65) 61 (56–66) 60 (55–66) 60 (54–65) 61 (57–67) 61 (56–67)
Sex (male) 2485 (49) 4779 (50) 4981 (49) 3962 (48) 4901 (49) 4648 (49) 4618 (49) 4672 (48)

MW, Midwest region; SW, Southwest region.

a
gFOBT invitees excluded round 1.

Supplementary Table 2.Last Measurement of Hb

Concentration Level Before CRC
Diagnosis

FIT Hb concentration SD-CRC, FIT interval

(mg Hb/g feces) n (%) cancer, n (%)

0 – 12 (44)
1–5 – 7 (26)
6–9 – 5 (19)
10–20 20 (17) –
21–46 16 (14) –
47 80 (69) –
Missing – 3 (11)

The 3 missing cases were FIT-negative (Hb concentration

level <10 mg Hb/g feces) but exact level was not
documented.
August 2017 FIT Interval Cancers in Colorectal Cancer Screening 447.e2

Supplementary Table 3.FIT Interval Cancers

Round Total rounds Total rounds Interval FIT Hb concentration

Case Region incident eligible participated diagnosisa (y) (mg Hb/g feces)b

1 MW 1 1 1 0.94 1.8
2 MW 1 1 1 2.34 –
3 SW 1 1 1 0.5 0.4
4 MW 1 1 1 1.9 0
5 MW 1 1 1 1.53 –
6 SW 1 1 1 0.67 4.8
7 MW 1 1 1 0.48 –
8 SW 2 2 2 0.92 9.6
9 MW 2 2 2 0.94 0
10 MW 2 2 2 2.07 5.0
11 SW 2 2 2 0.67 0
12 MW 2 1 1 1.94 6.0
13 MW 2 2 2 1.93 3.8
14 MW 2 2 2 1.52 0
15 MW 2 2 2 1.59 0
16 SW 2 2 2 0.42 0
17 MW 2 2 2 0.42 9.9
18 MW 2 2 2 1.95 0
19 MW 2 2 1 1.53 3.0
20 MW 3 3 3 1.61 7.6
21 SW 3 3 3 2.24 0
22 MW 3 2 2 1.41 0
23 SW 3 3 3 1.58 0
24 SW 3 3 2 1.08 0
25 MW 3 3 3 2.25 5.4
26 MW 3 3 3 2.29 7.6
27 MW 3 1 1 2.34 0

MW, Midwest region; SW, Southwest region.

a
Interval diagnosis ¼ time between date of last negative FIT result and diagnosis of CRC.
b
Missing FIT Hb concentration ¼ The 3 missing cases were FIT negative (Hb concentration level <10 mg Hb/g feces) but exact
level was not documented.

Supplementary Table 4.Colonoscopy Interval Cancers

Date FIT Date Date Time Endoscopic Bowel Cecal Surveillance

Case Region test endoscopy diagnosis CRC Interval (y) findings prep score intubation advice

1 SW Nov 2008 Jan 2009 June 2011 2.58 8 adenoma with Excellent Yes 3y
1 HGD sigmoid
2 SW Feb 2010 March 2010 Febr 2012 1.92 HP – Yes No FU
3 MW Jan 2007 March 2007 July 2008 1.51 No findings Good Yes No FU
4 SW Nov 2009 Nov 2009 Nov 2012 3.00 One TA <10 mm – Yes 6 y
5 SW April 2009 June 2009 June 2013 4.08 HP Good Yes No FU
6 SW May 2009 July 2009 Sept 2012 3.33 >10 adenomas, 1 TVA Good Yes 1 y
7 SW Nov 2008 Dec 2008 Nov 2009 1.00 HP – Yes No FU
8 MW Feb 2012 April 2012 Nov 2013 1.77 No findings Excellent Yes No FU
9 SW June 2008 July 2008 Jan 2015 6.50 No findings Good Yes No FU

FU, follow up; HGD, high-grade dysplasia; HP, hyperplastic polyp; MW, Midwest region; SW, Southwest region; TA, tubular
adenoma; TVA, tubulovillous adenoma with low-grade dysplasia.