Fecal Occult Blood & Colonoscopy Need in Familial CRC Risk

Alimentary Pharmacology & Therapeutics
Can quantification of faecal occult blood predetermine the need
for colonoscopy in patients at risk for non-syndromic familial
colorectal cancer?
Z. LEVI*, P. ROZEN* , à, R. HAZAZI*, A. VILKIN*, A. WAKED*, E. MAOZ , S. BIRKENFELD
*Gastroenterology Department, Rabin
Medical Center, Beilinson Hospital,
Petach Tikva; Gastroenterology
Units, Clalit Health Services, Tel Aviv;
àTel Aviv University Medical School,
Tel Aviv University, Tel Aviv, Israel
Correspondence to:
Dr P. Rozen, Department of
Gastroenterology, Tel Aviv Medical
Center, 6 Weizmann Street, Tel Aviv
64239, Israel.
E-mail: [email protected]
Publication data
Submitted 17 July 2006
First decision 24 July 2006
Resubmitted 18 August 2006
Resubmitted 8 September 2006
Accepted 8 September 2006
& Y. NIV* , à
SUMMARY
Background
Patients at risk for non-syndromic (Lynch or polyposis) familial colorectal
neoplasia undergo colonoscopic surveillance at intervals determined by
clinically ascertained protocols. The quantitative immunochemical faecal
occult blood test for human haemoglobin is specific and sensitive for significant colorectal neoplasia (cancer or advanced adenomatous polyp).
Aim
To determine immunochemical faecal occult blood test efficacy for identifying significant neoplasia in at-risk patients undergoing elective colonoscopy.
Methods
We retrospectively identified consecutive at-risk patients who provided
three immunochemical faecal occult blood tests before colonoscopy. Quantitative haemoglobin analysis was performed by the OC-MICRO automated
instrument using the 100 ng Hb/mL threshold to determine positivity.
Results
In 252 at-risk patients undergoing colonoscopy; five had cancer, 14 an
advanced adenoma and 46 a non-advanced adenoma. The immunochemical faecal occult blood test was positive in 31 patients (12.3%).
Sensitivity, specificity, positive and negative predictive values for cancer were: 100%, 90%, 16% and 100%, and for all significant neoplasia:
74%, 93%, 45% and 98%. With 88% fewer colonoscopies, all colorectal
cancers and 74% of all significant neoplasia would have been identified
by this one-time immunochemical faecal occult blood test screening.
Conclusions
A sensitive, non-invasive, interval screening test might be useful to predetermine the need for colonoscopy in this at-risk population and minimize unnecessary examinations. This favourable retrospective
evaluation will be extended to a prospective study.
Aliment Pharmacol Ther 24, 1475–1481
ª 2006 The Authors
Journal compilation ª 2006 Blackwell Publishing Ltd
doi:10.1111/j.1365-2036.2006.03152.x
1475
1476 Z . L E V I et al.
INTRODUCTION
Patients and relatives at risk for non-syndromic (Lynch
or polyposis) familial colorectal cancer (CRC) undergo
colonoscopic surveillance at intervals determined by
protocols based on accumulated clinical experience.
Other than for the defined genetic syndromes, which
have established diagnostic and follow-up endoscopy
protocols, the increased risk to the asymptomatic relative is estimated from the youngest age and number of
affected first-degree relatives.1–3 These screening and
follow-up protocols are implemented in order to detect
and treat asymptomatic early CRC and/or all clinically
significant colorectal neoplasia that are of potential
risk to the patient. ‘Significant’ neoplasia includes CRC
or ‘advanced’ adenomatous polyps; this latter category
included adenomas ‡10 mm, or having more than
20% of villous histology or any amount of high-grade
dysplasia independent of size.4
The commonly used guaiac faecal occult bloodscreening test (FOBT) is faulted by its relatively low
sensitivity for significant colorectal neoplasia and low
specificity because of non-specificity for human haemoglobin (Hb).5,6 Published experience using the HemoccultTM (Beckman Coulter, Fullerton, CA, USA) guaiac
FOBT in high-risk patients, showed a modest sensitivity for cancer and low positive predictive value for
any neoplasia.7 Therefore, at present, patients with a
family history of non-syndromic CRC are advised not
only to rely on guaiac FOBT screening, but to undergo
periodic total colonoscopic surveillance.1,3
However, unnecessary colonoscopy examinations
are both a clinical and economic burden with an
associated morbidity. In a recent evaluation of colonoscopy utilization in the United States, it was found
that 22.4% were performed because of a family history of CRC.8 A periodically performed, sensitive and
specific, non-invasive interval screening test might be
useful to predetermine the timing of the need for colonoscopy.
We have an ongoing colonoscopic evaluation of a
quantitative immunochemical faecal occult blood test
for human Hb (I-FOBT) and, like others, found it to be
highly sensitive and specific for significant colorectal
neoplasia, more so than a sensitive guaiac FOBT.6,9–11
The aim of this study was to analyse our initial
results and identify those examinees that had a colonoscopy examination for a family history of non-syndromic CRC, to see whether the I-FOBT had identified
the presence of significant colorectal neoplasia in
these at-risk relatives, and at what sensitivity and specificity. Based on these retrospective results we would
then decide if a prospective study was justified.
MATERIALS AND METHODS
Patients
These were consecutive, ambulatory patients undergoing colonoscopy who were invited to participate in
our ongoing endoscopic evaluation of an I-FOBT. To
date, the overall compliance and successful completion
of the protocol is 54%. We now analysed the subgroup
having a family history of CRC, and volunteering for
the study. The patients, referred by their treating doctor for colonoscopy, had been considered to be at
increased risk because of their family history. All were
interviewed and a two-generation family history of
cancer was taken.
They were grouped, using accepted criteria, as: those
having had a first-degree relative aged £60 years with
colorectal neoplasia or ‡2 such relatives of any age
(Group 1); those who had a single first-degree relative
with colorectal neoplasia but aged >60 years old, and
others who had a family history of a second-degree
relative with colorectal neoplasia (Group 2).1 The 108
patients in Group 1 included 88% who were asymptomatic and the remainder had anaemia (one), change in
bowel habits (six) or abdominal pain (five). Previous
colonoscopy had been performed in 41 (38%), at a
mean 3 2 years before, and colorectal neoplasia had
been diagnosed in 15 (14%). The 144 patients in
Group 2 included 69% who were asymptomatic and
the remainder had anaemia (seven), change in bowel
habits (17) or abdominal pain (21). Previous colonoscopy had been performed in 52 (36%), at a mean
4 3 years before, and colorectal neoplasia had been
diagnosed in 22 (15%).
Exclusions included patients with known or suspected genetic syndromes for colorectal neoplasia, visible
rectal bleeding, a known diagnosis of inflammatory
bowel disease, haematuria, menstruation at that time
and non-co-operation with preparing a faecal test.
Colonoscopy was to the caecum or to an obstructing
carcinoma if present. Otherwise, an incomplete examination was repeated or excluded from analysis. All
lesions were noted, biopsied or removed. Patients’
electronic data files were available from the three participating endoscopy units belonging to the same Medical Organization.
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Numbers of polyps were noted, as were their sites.
Adenomas were grouped by size: <10 mm, ‡10 mm;
number; and also by their histology: tubular, tubulovillous, villous; dysplasia was classified as low- or
high-grade. ‘Significant’ neoplasia included CRC or
‘advanced’ adenomatous polyps; all advanced adenomatous polyps (AP) sized <10 mm were re-examined
to confirm their histology diagnosis.
Faecal sampling
All participants received an oral and/or telephone
explanation of the test and written instructions on
preparing the I-FOBTs. The examinee was requested to
prepare three daily or consecutive samples during the
week before colonoscopy examination, without diet or
medication limitations other than those requested
before colonoscopy, namely stopping aspirin and anticoagulants.
The faecal test sampling device is shaped like a
small test tube with the faecal probe inserted into it
and sealing it after faecal sampling. The probe tip is
then in a closed amount of Hb-stabilizing buffer. Each
sample tube has a unique bar code and before preparing the sample the patient writes on the tube his/her
name and date of sample preparation. Samples were
double closed in zip-lock bags and kept in a refrigerator at 4 C until processing within 2 weeks.11
Instrument for I-FOBT analysis
The I-FOBT and instrument used for faecal Hb evaluation has been previously described in detail.10,11 In
summary, for faecal Hb analysis and quantification of
the I-FOBT the OC-MICROTM instrument (Eiken Chemical Co., Tokyo, Japan) was used. This desktop instrument is self-contained with reagent, buffer, washing
and fluid-disposal bottles, requiring access to a standard power supply. Ten of the patient-prepared faecal
sample tubes are loaded into the sample rack and in
parallel there is another rack with the disposable reaction cells. The instrument automatically mixes the faecal-buffer solution with the latex–antihuman Hb
antibody reagent. The flocculation is read as an optical
change and compared with a standard calibration
curve. Calibration is prepared for each day’s analysis
using the provided known high- and low-value control
test fluids. The range of measurements is 50–2000 ng
Hb/mL, approximately equivalent to 40–400 lg Hb/g
faeces.10,11 For pricing the immunochemical FOBT at
ª 2006 The Authors, Aliment Pharmacol Ther 24, 1475–1481
Journal compilation ª 2006 Blackwell Publishing Ltd
$20, we used the local agent’s price for three tests and
added administration costs. In comparison, our Ministry of Health’s authorized pricing for three guaiac tests
is $13.
Analyses and statistical methods
The diagnostic level of the I-FOBT for significant neoplasia was evaluated by four criteria: sensitivity, specificity and predictive positive and negative values.
The statistical significance level was set to 0.05 and
results are given as mean s.d. and 95% confidence
intervals (CI). The SPSS for Windows Software, version
13.0 was used for analysis.
For clinical correlation with faecal Hb levels, the
most severe pathology finding (histology and polyp
size) recorded was used for each examinee. Subjects
having only hyperplastic polyps were included in the
group not having neoplasia. For correlations of faecal
Hb levels with adenomas, the analysis included APs
and was then repeated without them. For the category
‘significant’ colorectal neoplasia, the analyses included
only CRC or AP or both together.
Receiver operator characteristic (ROC) curves were
drawn in order to determine several faecal Hb cut-off
values of I-FOBT that would discriminate between significant neoplasia and other (non-significant) polyps.
I-FOBT analysis for correlating the highest amount of
faecal Hb in the three tests and presence of neoplasia
at colonoscopy was based on the 100 ng Hb/mL
threshold. This was the threshold suggested both by
the manufacturer and in published experience.12 Additional analyses were performed examining different
threshold levels and also results obtained with just the
first two I-FOBTs prepared by the examinees.13 Association between pathology findings with the I-FOBT
level was examined by non-parametric tests: Mann–
Whitney for two groups and one-way ANOVA on ranks
for more than the two groups, multiple comparisons
between each pair were underwent using the Gabriel,
Dunnet and Games-Howell tests. In addition, several
contrasts were implemented for comparisons between
combinations of categories – all adenomas vs. normal;
significant neoplasia vs. other polyps.
For an evaluation of the clinical utility of the
I-FOBT for detecting significant colorectal neoplasia,
we compared the results to the colonoscopy examinations. We then calculated the number of colonoscopy
examinations that would potentially result from the
positive I-FOBT tests.
1478 Z . L E V I et al.
The Ethics Committee of the Rabin Medical Center
approved the study in 2004. All participants gave an
informed signed consent for the I-FOBT and colonoscopy examination.
Faecal occult blood results
At the Hb threshold of 100 ng Hb/mL, 31 patients had
an elevated I-FOBT so the overall positivity rate was
12.3%. I-FOBT results according to endoscopy and
pathology diagnosis, is given in Table 1. The mean
faecal Hb levels in patients having a normal colonoscopy examination were not different from the mean
level in patients with non-APs. However, the mean
faecal Hb level in patients with AP or CRC was significantly higher than in patients with a normal colonoscopy examinations or having only non-advanced
adenomas (P < 0.001; Table 1, Figure 1).
RESULTS
Patient and colonoscopy results
The data from 252 examinees were analysed. Group 1
had 108 patients and included 87 relatives of adenoma
or CRC patients aged £60 years and 21 having >1 such
relative of any ages. Group 2 had 144 patients and
included 116 who had a single first-degree relative
with colorectal neoplasia but aged >60 years old and
28 who had a family history of a second-degree relative with colorectal neoplasia.1,2 Together, they included 46.2% males and their mean age was
57.7 11.2 years.
Colonoscopy detected significant neoplasia in 19
patients (7.4%). These included one with CRC and two
with an AP in Group 1; four with CRC and 12 with an
AP in Group 2. Altogether, there were five patients
with CRC and 14 with an AP. The mean age of
patients with significant neoplasia was older than that
of patients without significant neoplasia (62.2 10.4
vs. 57.3 11.2, P ¼ 0.07).
Non-APs were detected in a further 46 patients
(18.2%) and hyperplastic polyps in 35 patients
(13.8%). Of all the polyps, 55.8% were tubular adenomas, 7.4% were tubular-villous and the remainder was
hyperplastic polyps. High-grade dysplasia was found
in adenomas of four patients (6.7%). The size of 58.3%
of the adenomatous polyps was <5 mm, 25.0% were
6–9 mm, and 16.7% were ‡10 mm; 40.0% of the
patients with polyps had single adenomas.
Correlations of diagnosis with faecal
haemoglobin levels
At the standard 100 ng/mL faecal haemoglobin
threshold:
Colorectal cancer: Five patients were identified by
colonoscopy; all were identified by the elevated faecal
Hb.
Advanced adenomatous polyps: Fourteen patients
were identified by colonoscopy, nine of them (64.3%)
were identified by the elevated faecal Hb.
Significant neoplasia: These include the five patients
with CRC and 14 with APs identified by colonoscopy,
together 14 of these 19 (74%) were identified by their
elevated faecal Hb.
The I-FOBT sensitivity, specificity, positive and negative predictive results for the detection of CRC were
100%, 90%, 16% and 100%; and for the detection of
all significant neoplasia were 74%, 93%, 45% and
98% (Table 2, Figure 2).
At differing faecal haemoglobin thresholds: We
examined the results obtained by using a lower or
Table 1. Immunochemical faecal Hb levels detected according to colonoscopy and pathology findings (n ¼ 252)
Diagnosis
N
Faecal Hb [ng/mL; mean s.d. (95% CI)]
Normal
Non-AP
AP
Cancer
CRC + AP
187
46
14
5
19
36
69
598
1220
762
114
268
904
881
917
(20–54)
(0–146)
(125–1072)
(448–1992)
(349–1174)
P-value*
N.S.
<0.001
<0.001
<0.001
Hb, haemoglobin; CI, confidence intervals; AP, advanced adenomatous polyps; CRC, colorectal cancer.
* When compared with the normal and non-AP groups.
Includes patients with non-adenomatous (hyperplastic) polyps.
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ROC curves: analysis for OC-MICRO
OC-MICRO Results (Hb) by Diagnostic Category
3500
100%
3000
80%
Sensitivity
ngHb/mL
2500
2000
1500
60%
40%
1000
Cancer (n = 5)
CRC + AP (n = 19)
20%
500
AP (n = 14)
Non-AP (n = 46)
0
–500
Normal, Hyperplastic Non-Advanced
Adenomas (n = 46)
(n = 187)
AP (n = 14)
Cancer (n = 5)
AP + Cancer (n = 19)
0%
0%
10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
1 - Specificity
Diagnosis
Figure 2. Receiver operator characteristic curve for sensitivity and specificity for each diagnostic category at the
ng Hb/mL level of faecal haemoglobin (Hb) measured. At
the 100 ng Hg threshold there is high sensitivity for colorectal cancer (CRC) and also advanced adenomatous polyps (AP) and for both together, with low sensitivity for
non-AP as a category.
Figure 1. Box plots for each diagnostic category of faecal
haemoglobin (Hb) values, at the 100 ng Hb threshold.
Dark line indicates median Hb value, shaded block covers
the upper and adjacent two lower quartiles, and bars are
the maximum and minimum levels measured. Colorectal
cancer (CRC) and/or advanced adenomatous polyp (AP)
measurements are significantly elevated when compared
with the normal hyperplastic polyp and non-AP groups
(P < 0.001).
Estimation of number of colonoscopy
examinations needed
higher faecal Hb threshold and also by utilizing just
the first two I-FOBTs collected (Table 3). Lowering the
threshold to 75 ng Hb/mL, did not improve the sensitivity or specificity for cancer or all significant neoplasia. Conversely, using a higher threshold of 150–
200 ng Hb/mL decreased the sensitivity for cancer by
20% and for all significant neoplasia by 16%. The
improvement in specificity was only 1–2%. Analysing
the first two I-FOBTs collected, the sensitivity at
100 ng Hb/mL for cancer was maintained, but for all
significant neoplasia was reduced by 11% with an
improved specificity of 2–3%.
To identify all the five CRCs, 31 colonoscopy examinations would have been performed for a positive
I-FOBT, i.e. six were needed to identify each cancer.
To identify 14 of all the 19 significant neoplasia, 31
colonoscopy examinations would also have been performed for a positive I-FOBT, i.e. 2.2 colonoscopy
examinations would have been needed for each
significant neoplasm. So, these 14 lesions (74% of all
the significant neoplasia detected by colonoscopy)
could have been identified with 31 colonoscopy examinations, i.e. 88% fewer colonoscopy examinations at
this one-time screening round.
Table 2. Sensitivity, specificity, predictive values and 95% CIs at the faecal haemoglobin threshold of 100 ng/mL*
Group
Pathology
Number
Sensitivity [(%) CI]
Specificity [(%) CI]
PPV [(%) CI]
NPV [(%) CI]
1 (N ¼ 108)
2 (N ¼ 144)
All (N ¼ 252)
CRC + AP
CRC + AP
CRC
CRC + AP
3
16
5
19
33
81
100 (100–100)
74 (54–94)
94
91
90 (86–93)
93 (89–96)
14
54
16 (3–29)
45 (28–63)
98
98
100 (100–100)
98 (96–100)
* Utilizing the highest of the three I-FOBT measurements in each patient.
CI, confidence interval; CRC, colorectal cancer; AP, advanced adenomatous polyps; PPV, positive predictive value; NPV, negative predictive value.
ª 2006 The Authors, Aliment Pharmacol Ther 24, 1475–1481
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1480 Z . L E V I et al.
Table 3. Sensitivity, specificity, predictive values and 95% CIs for cancer (n ¼ 5), cancer + advanced adenomas (n ¼ 19) at
different faecal haemoglobin thresholds* and numbers of tests prepared by the 252 examinees
Threshold (ng/mL)/
number of tests prepared
75/three tests
100/three tests
100/two tests
150/three tests
200/three tests
Pathology
Sensitivity
[% (95% CI)]
Specificity
[% (95% CI)]
PPV
[% (95% CI)]
NPV
[% (95% CI)]
CRC
CRC
CRC
CRC
CRC
CRC
CRC
CRC
CRC
CRC
100
74
100
74
100
63
80
58
80
58
88
92
90
93
93
95
91
93
92
94
15
41
16
45
23
52
15
41
17
46
100
98
100
98
100
97
99.6
96
99.6
97
+ AP
+ AP
+ AP
+ AP
+ AP
(100–100)
(54–94)
(100–100)
(54–94)
(100–100)
(42–85)
(45–100)
(36–80)
(45–100)
(36–80)
(84–92)
(89–95)
(86–93)
(89–96)
(90–96)
(93–98)
(88–94)
(90–96)
(89–95)
(92–97)
(3–27)
(25–58)
(3–29)
(28–63)
(5–39)
(32–73)
(1–28)
(22–59)
(2–32)
(22–66)
(100–100)
(96–100)
(100–100)
(96–100)
(100–100)
(95–99)
(99–100)
(94–99)
(99–100)
(94–99)
* Utilizing the highest of the I-FOBT measurements in each patient.
CI, confidence interval; CRC, colorectal cancer; AP, advanced adenomatous polyps; PPV, positive predictive value; NPV, negative predictive value.
DISCUSSION
This colonoscopy-controlled study allowed for a
detailed retrospective evaluation of a small number
of subjects at familial risk for colorectal neoplasia. It
demonstrated that a one-time quantitative immunochemical determination of the faecal occult blood
level would have led to the identification of 100%
of CRC and 74% of all significant colorectal neoplasia, with significantly fewer colonoscopy examinations.
This I-FOBT has the advantage of having a high
sensitivity for significant neoplasia and not for the
non-advanced adenomas that are not an immediate
medical threat to the screenee. This differentiation
would significantly reduce the number of follow-up
colonoscopy examinations for clinically non-significant adenomas.3,8 The anticipation being that annual
I-FOBT re-examination would eventually identify the
minority of adenomas that progress to significant neoplasia.
Even within a colonoscopy-screening program for
high-risk patients interval neoplasia occurs. This has
been attributed to non-recognition of the neoplastic
lesion or inadequate therapy, e.g. incomplete polypectomy or mucosectomy or the genetically driven rapid
progress to neoplasia in spite of the adequate examination. For these reasons, it has been suggested that
the intervals between colonoscopy examinations be
shortened or interval faecal occult blood testing also
be performed as has already been tried successfully
with the I-FOBT, Inform OBT (Enterix, Sydney, Australia).13,14 The latter approach seemed to us to be worthy
of evaluation both from the aspects of cost–benefit
and practicality. We therefore performed this pilot retrospective evaluation.
The strengths of the study are a complete colonic
examination of the participants and the quantification of the faecal Hb. A limitation of this retrospective study was the clinical criteria of family history
used by the treating doctor to refer patients for colonoscopy, and that some patients also had mild
symptoms. If the published protocols for screening
families at risk had been followed, then a considerable number should not have been referred because
of their family history, but entered into an averagerisk screening or diagnostic protocol.1–3,5 A further
limitation is our definition of advanced adenomas.
We did not include the cases having three or more
adenomas without high-grade dysplasia or villous
elements, but sized <1 cm, as was underwent in
another study.13 We also used colonoscopy as our
‘gold’ standard, even though it too has been shown
to be imperfect occasionally.13,14 However, in our
published short follow-up study of a larger group of
patients, we did not identify missed cancers occurring.10
In this high-risk population, at present we feel that
a high sensitivity for all significant neoplasia is paramount and we accept a moderate specificity with the
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consequent need for colonoscopy examination. From
this small retrospective analysis, we do not want to
draw final conclusions on which is the optimal faecal
Hb threshold and numbers of tests to be requested. We
will learn from a larger, prospective trial, if we need
to change the present policy.
This favourable initial clinical experience will now
be extended to a prospective study of performing the
interval I-FOBT in a larger and asymptomatic population at familial risk undergoing elective colonoscopy
screening and follow-up. Eventually, this approach
might reduce the burden of colonoscopies and could
be more cost-effective in this large number of asymptomatic patients at increased risk for CRC, but having
only a family history of non-syndromic colorectal
neoplasia.3,8
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ACKNOWLEDGEMENTS
We acknowledge the medical and secretarial staff of
the Endoscopy Units and the patients for their cooperation. We thank Dr Ester Shabtai and Doron
Comaneshter for statistical analyses, and Ms Sally
Zimmerman for secretarial assistance. Instrument and
reagents were provided by Eiken – Japan, Alfa Wasserman – Italy and Pharmatrade – Israel. Support for
administration of the study was provided by Eiken and
the Katzman Family Foundation.
Presented in part at the International Society for
Hereditary Tumors (InSiGHT) Meeting, Newcastle, UK,
2005.
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