The Value of Immunochemical Faecal Occult Blood tests in Clinical

POC
The Value of Immunochemical
Faecal Occult Blood tests in Clinical Use
POC
The Value of Immunochemical
Faecal Occult Blood tests in Clinical Use
Disclaimer
This booklet is intended to provide healthcare practitioners with an overview of QuikRead go iFOBT and QuikRead
FOB quantitative, as well as the diagnostic potential of immunochemical Faecal Occult Blood tests.
Although every effort has been made to provide accurate information, Orion Diagnostica accepts no responsibility whatsoever for the accuracy, correctness or completeness of the information contained in this booklet. It is
the responsibility of the healthcare practitioner to evaluate the contents of this booklet and to verify the information presented. The ultimate judgment regarding the care and appropriate treatment of a particular individual
must always be made by the healthcare practitioner in the light of all the clinical information available about the
individual.
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Contents
Introduction .......................................................................................................... 7
Gastrointestinal bleeding..................................................................................... 8
Normal physiological bleeding........................................................................... 8
Age and gender................................................................................................. 9
Sites of bleeding and intraluminal metabolism of Hb....................................... 10
Colorectal Cancer (CRC)...................................................................................... 11
Progression and survival rates................................................................................ 12
Screening programmes .......................................................................................... 12
Faecal Occult Blood tests (FOBTs)............................................................................... 14
Methods.................................................................................................................. 15
gFOBTs ..................................................................................................... 15
iFOBTs............................................................................................................... 18
Quantitative iFOBTs................................................................................... 19
Further investigations...................................................................................... 23
Guidelines and recommendations.................................................................... 24
QuikRead .......................................................................................................... 26
References.......................................................................................................... 28
Introduction
The purpose of this booklet is to describe how Orion Diagnostica’s QuikRead
go® iFOBT and QuikRead® FOB quantitative can be used as aid in diagnostics, and explain how the user can benefit from the test features. Both tests
are quantitative immunochemical tests intended for measuring Faecal Occult
Blood (FOB), i.e. haemoglobin (Hb) concentrations in human faeces.
A small amount of blood is lost every day in healthy persons due to intestinal physiological bleeding 1−3. In some conditions, such as e.g. iron-deficiency
anaemia (IDA) and colorectal cancer (CRC) 3, 4 the amount of bleeding may
however be greater and a more thorough investigation, such as colonoscopy
or sigmoidoscopy
3, 5
, is required to clarify the origin of bleeding. As FOB
tests measure the amount of Hb in faeces they are useful when suspecting
excess bleeding in the gastrointestinal tract.
Traditionally FOB testing has been performed using qualitative chemical guaiac-based tests (gFOBTs), but the value of immunochemical FOB
tests (iFOBTs) is becoming increasingly recognised 5. iFOBTs have enabled a
significant improvement in analytical specificity 6. Besides offering objective
results, quantitative iFOBTs enable the user to perform FOB testing according
to case-specific parameters as well as national guidelines.
QuikRead go iFOBT and QuikRead FOB quantitative are user-friendly
tests for fast and reliable measurement of occult blood in faeces. The faeces
sample is collected in a QuikRead FOB Sampling vial, which is suitable for
transportation and enables home sampling. The measurement is performed on
an instrument that provides objective results within minutes. With QuikRead
go iFOBT, operated on Orion Diagnostica’s next generation Point-of-Care
test system, the users’ various needs are taken even further into account by
flexible choice of result presentation: Hb concentrations can be displayed
either as qualitative or as quantitative, obtained as ng/ml in buffer or as µg/g
in faeces, whichever is preferred by the user.
7
Gastrointestinal bleeding
There are many causes of and possible clinical scenarios associated with
gastrointestinal bleeding. Bleeding might be massive or small-scaled, obvious
or hidden and originate from e.g. the upper or lower gastrointestinal tract.
The main focus in this booklet is on occult, i.e. hidden bleeding from the
lower gastrointestinal tract.
Occult gastrointestinal bleeding is defined as bleeding that is unknown to
the patient. It is the most common form of gastrointestinal bleeding, and can
be caused by various lesions in the gastrointestinal tract. Significant amounts
of blood can be hidden in faeces; patients losing up to 100 ml of blood per
day may have normal-appearing faeces 7−10. Faecal occult bleeding might be
identified during routine laboratory testing, in screening of asymptomatic
subjects for colon cancer, or as part of a physical examination
11
.
Occult bleeding itself is not a disease, but it might be a symptom of various conditions, such as CRC or chronic iron loss
leading to IDA. Most people to date are not tested for FOB
or IDA, and the incidence of occult bleeding is most likely
underestimated 4.
Occult bleeding
is not visible to
the naked eye.
Occult gastrointestinal bleeding differs significantly
from obscure gastrointestinal bleeding, which is characterised by evident and recurrent bleeding. Visible blood is easily detected as
melena or as bright blood in faeces 12. Obscure bleeding accounts for only
approx. 5% of clinically evident gastrointestinal bleeding, and is commonly
caused by bleeding from a difficult to identify source, such as the small intestine. The diagnostic and therapeutic challenges with obscure bleeding are
great, and the site of haemorrhage should be identified as soon as possible 4.
Normal physiological bleeding
The human gastrointestinal tract consists of the oesophagus, stomach, small
intestine, colon and rectum. These form a digestive system with the main
purpose to utilise nutrients in ingested food and contain the waste until it is
8
defaecated
13
. The normal physiological bleeding from the gastrointestinal
tract is 0.5−1.5 ml/day in healthy persons
1, 2, 14−16
. Bleeding can be caused
by many non-neoplastic reasons and gastric irritants 3, 4, some of which are
listed in table 1 below.
Table 1. Non-neoplastic factors causing gastrointestinal bleeding
• Aspirin
• Peptic ulcer disease (PUD)
• Nonsteroidal anti-inflammatory drugs
• Vascular ecstasias
• Gum disease
• Haemorrhoids
• Gastritis and oesophagitis
• Portal hypertensive gastropathy (PHG)
• Gastroduodenal and oesophageal ulcers
• Various gastrointestinal parasites
Aspirin and anticoagulant therapy have been associated with occult gastrointestinal bleeding 3, 17, but the statement has been challenged 18, 19. A combination
of aspirin and warfarin leads to slightly increased levels of occult blood, but
neither one alone seems to cause positive FOB tests. The increase is most likely
minimal 18, 19. The yield of gastrointestinal evaluation may, however, be small
in patients with too high a degree of anticoagulation or chronic bleeding e.g.
in cases of intrinsic coagulopathy 20.
Age and gender
Recent research in various parts of Europe has shown that physiological faecal haemoglobin concentrations vary significantly with gender and age 21−27.
The concentrations are higher in men than in women, and increase by age
regardless of gender (figure 1). Possible explanations to difference observed
between genders are higher blood Hb concentrations and a faster colonic
transit time in men 21, 27 .
9
350
Female
300
Male
ng Hb/ml
250
200
150
100
50
0
50-54
55-59
60-64
65-69
70-74
Age (years)
Figure 1. Faecal Hb values for the 95th percentile in Scottish men and women of various ages. Data shows that
95% of subjects have faecal Hb concentrations below the indicated values. Men have higher Hb values than
women, and the concentrations increase with age regardless of gender 21.
Sites of bleeding and intraluminal metabolism of Hb
Gastrointestinal bleeding can theoretically originate from all parts of the gastrointestinal tract, but the site of bleeding affects the intraluminal metabolism
of Hb. Therefore, Hb, and its moieties haem and globin, appear in different
forms in faeces depending on the source of the bleeding 20.
Hb originating from the upper gastrointestinal tract is cleaved to haem
and globin by gastric pepsin and pancreatic proteases when it reaches the
proximal small intestine. Part of the haem that is not reabsorbed in the small
intestine is converted to porphyrins and iron 20. Partially degraded haem can
thus be present in the faeces if the site of bleeding is in the upper or middle gastrointestinal tract 1, 2, 7, 9, 20, whereas the haem in faeces is intact if the
bleeding site is in the lower gastrointestinal tract 20.
The globin moiety of human Hb is degraded by pepsin as well as pancreatic
and intestinal proteases in the upper gastrointestinal tract. Partially degraded
globin can be present in faeces if bleeding originates from the middle gastrointestinal tract, and intact globin can be found if bleeding appears in the lower
gastrointestinal tract 7, 20. As globin is degraded in the upper gastrointestinal
tract, it is a better marker for bleeding from the lower gastrointestinal tract
than haem or porphyrins 20.
10
Colorectal Cancer (CRC)
CRC is a cancer from uncontrolled cell growth in the colon, rectum or appendix and it affects mainly elderly. It is the most common cancer and the
second most common cause of cancer deaths in Europe; about 432 000
new cases are reported annually, and in 2012 approx. 212 000 deaths were
reported 28. Worldwide CRC is the third most common cancer with approx.
1.2 million cases, and fourth most common cause of cancer death with 0.6
million deaths annually
. CRC occurs with equal frequency in men and
28−30
women, but some racial differences in CRC survival have been observed 31−33.
CRC mortality rates have decreased in recent years, possibly due to increased
awareness, more accurate diagnosis and earlier detection and removal of premalignant polyps 3, 34. Although mortality rates are decreasing, the incidence
of CRC continues to increase 34, probably due to the aging population and
lifestyle choices.
Many factors and conditions that elevate the risk of CRC are known, and
some of these are listed in table 2. The conditions include hereditary disorders
which lead to multiple noncancerous growths in the intestines, whereas the
listed other factors are mainly associated with lifestyle and diet.
Table 2. Conditions and factors elevating the risk of CRC 3, 35, 36
Conditions
Other factors
• Ulcerative colitis
• Age
• Crohn’s disease
• Nicotin
• Hereditary nonpolyposis colorectal
• Alcohol
cancer (HNPCC)
• Overweight
• Familial adenomatous polyposis (FAP)
• Inactivity
• Peutz–Jeghers syndrome (PJS)
• Large consumption of red meat
• Juvenile Polyposis Syndrome (JPS)
• High calorie intake, low fibre content
• Previous CRC or polyps
• Diabetes mellitus type 2
Typical symptoms of CRC include gastric dysfunction such as stomach pain,
constipation, occasional diarrhoea and difficulties with defaecation. Visible
blood can appear in faeces, and patients also often suffer from anaemia 3, 13,
37
. These symptoms are common in other diseases as well, and therefore only
nonspecific indicators of CRC 3.
11
Progression and survival rates
CRC forms when normal cells or benign mucosal tumours (polyps or bulges)
in the colorectal area become malignant. The disease is classified in stages
according to its progression (Stage 0−4, Dukes A−D CRC). Survival of CRC
is related to the clinical and pathological stage of the disease at the time of
diagnosis. The 5-year survival rate for patients with cancer limited to the
bowel wall is 83−95% 34, 38, whereas it is only 35−65% in those with involvement of lymph nodes and <10% in patients with metastatic disease
Detecting CRC or its precursors early is possible
13
.
34, 36, 39
, which emphasises the
need of proper diagnostics.
Polyps are mucosal masses in the colon and rectum. Hyperplastic polyps
and mucosal tags are generally small and of no clinical importance, whereas
adenomatous polyps are premalignant. Adenomatous polyps account for
approx. half to two thirds of colorectal polyps and are found throughout
the colon and rectum 3. It is generally accepted that most CRCs develop from
adenomatous polyps, but the transformation occurs slowly and the estimated
rate of polyps progressing to cancer is only 2.5 polyps per 1000 per year 40.
The progression from normal mucosa to adenocarcinoma usually takes about
8−10 years 36. It is associated with accumulation of genetic alterations as well
as environmental factors such as fat and fibre intake 3.
About two thirds of cancers bleed in the course of a week 41 and approx.
90% of these will be detected with repeated testing 42. Adenomatous polyps
≥1−1.5 cm in size are more likely, whereas hyperplastic polyps are less likely
to bleed 43, 44.The bleeding caused by cancer tends to be intermittent and the
blood is often unevenly distributed in faeces. Irregular bleeding and uneven
distribution leads to challenges in testing, and a clean faecal sample can thus
not completely rule out the possibility of cancer or benign polyps 13.
Screening programmes
CRC screening is recommended by the Council of the European Union
(2003/878/EC) and the number of European countries that are implementing national CRC screening programs is growing 36. In 2009, 19 of the 27
12
European Union countries implemented screening for CRC 36. The population
usually invited to screening programmes is asymptomatic average-risk men
and women of approx. 50−74 years 3, 6, 36, 45.
CRC screenings are performed in order to lower the burden of cancer in
the population by discovering disease in its early stages 46. Early discovery
reduces the incidence of CRC and enables more effective treatment, e.g. removal of lesions. It also affects the costs of treatment; disease detected when
the cancer has spread to other organs of the body (stage 4, Dukes D CRC) is
twice as expensive to treat in the first year as disease detected when malignancies are restricted on the inner mucous surface (stage 1, Dukes A CRC) 34.
The two main types of CRC and high-risk adenoma screening strategies are bowel visualisation (e.g.
colonoscopy or flexible sigmoidoscopy) and measurement
of faecal markers (e.g. FOB or DNA marker)
47, 48
. The
pros and cons of different screening strategies need to be
taken into account when preparing recommendations
CRC is preventable
if caught in the
pre-cancerous stages.
and screening. National guidelines have chosen different
approaches; some countries perform visual preliminary
screening by colonoscopy or flexible sigmoidoscopy 36, 49,
but performing FOB tests (FOBTs) is the most widely used strategy. Several
studies have shown that using FOBTs in population screening can reduce
mortality from colorectal neoplasia 42, 50−53. Compared to visualisation techniques, the testing of faecal markers is safe, less expensive and non-invasive,
and sampling is possible to do at home 45. The European Group on Tumor
Markers recommends screening with FOBTs to be performed at least biennially 45, whereas The American Gastroenterological Association recommends
that persons at average risk should be tested for FOB annually 3. Annual
investigations and removal of polyps are also recommended for individuals
who have conditions that lead to an elevated risk of CRC 13.
As bleeding might be caused by many physiological and disease-related
factors, FOBTs are not specific for colorectal neoplasia. FOBTs provide information on excessive bleeding and are thus merely indications of the possible
presence of cancers and polyps. Finding of occult blood in faeces therefore
mandates further investigations of the gastrointestinal tract, starting typically
13
with the colon 4. Investigations are needed to locate the source of bleeding.
Using a FOBT in deciding on which patients are in need of further examination
can aid in lowering the number of persons undergoing unnecessary further
examinations, in preventing or decreasing the rates of possible complications,
and therefore leading to cost savings. There are, however, significant differences between FOBTs as well as between further examination techniques.
These are presented in more detail in the following chapter.
Faecal Occult Blood tests (FOBTs)
FOBTs are used for example in colorectal cancer screening programmes 42, 51,
, in the course of clinical evaluation 4, and when investigating possible causes
52
of anaemia 20. The concept of detecting occult bleeding in CRC screening is
based on the observations that cancers bleed more than mucosa. The bleeding
increases gradually with growing size of polyps and advancing stage of CRC,
and FOBTs can potentially detect both CRC and its preliminary stages 3.
FOBT cut-off concentrations are set to detect excess bleeding and do
not typically detect normal physiological bleeding 20. In qualitative tests the
cut-off concentration set by the manufacturer dictates which individuals
will get a positive respective negative result, and thus who will be sent for
further investigation. The most often used cut-off concentration is 100 ng
haemoglobin/ml buffer (1:200 dilution ratio), but it has been challenged by
more recent studies, see page 20.
The likelihood that FOBTs will detect gastrointestinal bleeding depends
on many factors, such as the anatomical level of the bleeding, faecal transit
time, faecal mixing and intraluminal Hb metabolism and degradation
4, 20
.
Additionally the features of the bleeding, e.g. its irregularity, pattern and rate
, as well as the sensitivity and characteristics of the chosen FOBT affect
54
the results 20.
14
Methods
The test method traditionally most used for detecting occult blood in faeces is
the guaiac-based FOB test (gFOBT) 55−58. However, an ongoing change towards
favouring immunochemical FOB tests (iFOBTs, or faecal immunochemical
tests [FITs]) is evident 21, 36. iFOBTs have enabled a significant improvement
in analytical specificity 6, and have many advantages that speak both to
patients and healthcare personnel. The fundamental differences between the
two methods, as well as a review of current recommendations and further
investigation techniques, are presented below.
gFOBTs
Guaiac-based tests for detection of blood in faeces measure pseudoperoxidase
activity of haem in Hb 7, 20. The tests have been available for decades, and are
widely evaluated 48, 59, 60. The haem component of Hb is identical across human
and animal species, chemically robust and only partially degraded during its
passage through the gastrointestinal tract 17. Advantages of gFOBTs include an
affordable price and suitability to screening programs. The main drawbacks,
in turn, concern the specificity of source of bleeding, dietary restrictions, test
interpretation and performance.
During sampling a small amount of faeces is smeared onto a filter paper
on a test card, incorporating the guaiac reagent. Because of intermittent or
low-volume bleeding or heterogeneous sample material, obtaining many
samples is preferred. The sensitivity of gFOBTs increase with the numbers of
samples per faeces as well as with number of faeces sampled 3. One or two
samples are usually taken from each of three separate bowel movements of
every tested person 3, 45. Samples smeared on gFOBT test cards are fairly stable
, and the test card can be returned to the healthcare provider e.g. by mail.
61
When a gFOBT is performed hydrogen peroxidase reagent is added on
the faeces samples. A positive result is registered if a blue colour appears as
a result of oxidation by peroxidases 20, in any of the sample windows after
addition of the reagent. gFOBTs are visually interpreted qualitative tests.
Interpretation of gFOBTs is not always unequivocal and might lead to false
15
negative results, especially if proper training is not given
. The result in-
3, 62
terpretation must be done immediately as the colour may fade. Additionally,
dietary iron supplements, bismuth, or other factors turning faeces dark, green
or black might lead to difficulties in interpreting the blue colour change of
a positive gFOBT 3.
Sources of bleeding and dietary restrictions
Due to the intraluminal metabolism of haem, gFOBTs measure bleeding from
both the upper and lower gastrointestinal tract 2, 9, 20. The test is therefore not
specific for colorectal neoplasia, and might reflect upper gastrointestinal tract
bleeding caused by other reasons 3, 20 (see table 1). Research has shown that
many lesions in the upper gastrointestinal tract bleed sufficiently to produce
positive gFOBT results 1, 9. Use of gFOBTs in CRC screening is therefore likely
to be associated with some false positive results due to bleeding in the upper
gastrointestinal tract 9.
The use of gFOBTS is heavily affected by dietary factors 3, 20. Due to haem,
peroxidase or pseudoperoxidase activity in other substances than human Hb,
gFOBTs do not recognise human occult blood specifically. There is a risk of
false positive and false negative gFOBT results if e.g. the factors in table 3
are present in faeces of persons under investigation 3. Persons being tested
are requested to take into consideration dietary restrictions two days prior to
FOB sampling and throughout the test period 3, 42. Some evidence do although
exist that false positive samples might be avoided with a delay of over 48
hours before analysing the gFOBT 45. False negative results can be avoided
by ingestion of fibres that increase the transit time of faeces 3.
16
Table 3. Factors that may cause false positive or false negative results when using gFOBTs. For more detailed
information see Gnauck et al. (1984). 3
Factors that may cause false positive results
Factors that may cause false negative results
• Red meat
• Vitamin C
• Bacteria
• Citrus fruits
• Turnips
• Horseradish
• Hyperoxides in various fruits and
vegetables
Test performance
The sensitivity and specificity for colorectal neoplasia is highly variable
between different gFOBTs
60, 63
. The reported sensitivities vary between
51−100%, the specificities between 90.4−97% and the positive predictive
value between 2.4−17% 63. The likelihood that a gFOBT will be positive is
in general related to the size and location of the bleeding lesion 2, 64. gFOBTs
are far less sensitive for detecting polyps than CRC, mainly due to the smaller
or insignificant amount of bleeding from polyps
3
or the heterogeneity of
sample material. The low clinical sensitivity and specificity of gFOBTs also
leads to many normal colonoscopies
. Various trials have, however, shown
45
a 16% reduction in the relative risk of CRC mortality when using gFOBTs
in screening 65.
If faecal samples collected on gFOBTs are rehydrated the sensitivity of the
test is increased, on expense of specificity and positive predictive value of the
test. The proportion of cancers found increases, but as does the proportion
of persons who receive a false positive result and must undergo further diagnostic tests in vain 3. According to the European Group on Tumor Markers
rehydration of samples should not be performed 45.
17
iFOBTs
Immunochemical FOBTs exist both as qualitative and quantitative. Qualitative iFOBTs are visually interpreted. Quantitative tests in turn are often
instrument-read and have thus enhanced quality while eliminating the potential for visual bias by the observer 5. iFOBTs use antibodies to detect the
human globin epitopes present in occult blood 17. The antibodies are attached
to latex particles, dye or an enzyme that in the presence of human globin
forms a detectable complex. Detecting methods include turbidity, latex agglutination, haemagglutination, colloidal gold agglutination or coloured dye
produced by an enzyme.
iFOBTs are rapidly replacing gFOBTs because of their many advantages.
These include greater clinical and analytical sensitivity
single sample
28, 45
, collection of a
, simple and hygienic sampling devices , higher specific-
36, 66−68
36
ity for lower gastrointestinal tract bleeding 1, 9, 20, and no dietary restrictions
. The use of iFOBTs results in improved clinical performance and higher
5, 36
participation rates in screenings 45, 69, 70. Compared to gFOBTs, iFOBTs might,
however, require a larger initial investment and have slightly weaker sample
stability after collection 6, 17, 45, 71, 72.
Sources of bleeding and dietary restrictions
Due to the intraluminal degradation of the Hb moiety globin, iFOBTs specifically detect gastrointestinal bleeding from the lower gastrointestinal tract.
Small amounts of bleeding from the upper gastrointestinal tract remain undetected 1, 9. Therefore, it can be stated that iFOBTs have a theoretical advantage
over gFOBTs in localising bleeding to the lower gastrointestinal tract 20, 45.
Antibodies that are used in iFOBTs are directed towards human globin
epitopes 17. As globin is species-specific iFOBTs should not be subject to interference from dietary blood 17. As the potential for dietary interference is small
no dietary restrictions are needed prior to or during sampling for iFOBTs 17, 36.
18
Test performance
Even though iFOBTs are not as widely evaluated as traditional gFOBTs,
adequate population-based comparative studies have been made 45. Overall,
the sensitivity of iFOBTs for CRC is stated to be 61−91% and the specificity
91−98% 73. iFOBTs enable detection of Hb in faeces at lower concentrations than gFOBTs, and therefore increase clinical sensitivity
by detecting small or intermittently bleeding lesions 17. The
superiority of iFOBTs over gFOBTs has been confirmed
by several recent studies 74−76, some indicating even a two
or three times higher sensitivity at increased specificity
77
. There is, however, not yet any direct evidence of a
iFOBTs can detect as little as
0.3 ml of blood added to
a faecal sample 78.
decrease in CRC mortality in prospective randomised
trials 45.
Adequate clinical sensitivity and specificity can be
obtained using a single iFOBT test per subject
17, 66, 67
.
Likely due to the improved clinical performance, the use of only one or two
samples and simpler sample collection and handling techniques 45, screening programmes with iFOBTs has been shown to have a participation rate
higher than gFOBTs 69, 70.
Even though gFOBTs are more affordable than iFOBTs, studies have
shown that use of iFOBTs is a more cost-effective strategy in CRC screening
. This is likely due to the increased sensitivity of the tests as well as the
79−81
higher participation rate 45. The higher test costs are also balanced by use
of automated analysers that lead to reduced staff costs, and by the need of
performing fewer tests per patient 17. Cost-analyses do, however, need to be
made separately in each country, as e.g. test and personnel costs, logistics
and preferences of screening vary 45.
Quantitative iFOBTs
An increasing amount of structured screening programmes use automated
iFOBTs for quantitative measurements of faecal Hb concentrations
. In
82
addition to the advantages of qualitative iFOBTs, quantitative iFOBTs offer
the user a numerical result of the Hb concentration in the sample, can be
19
automated and thus objectively interpreted. These are considerable improvements compared to qualitative tests that cannot provide objective information
on the amount of bleeding. Clinically relevant advantages are described in
more detail below.
• Possibility to adjust cut-off concentration according to study settings,
national guidelines, available local resources, as well as age and gender
of subjects
• Patient-specific follow-up and screening strategies based on additional
knowledge of amount and variability of occult bleeding or underlying
conditions elevating the risk of CRC
Adjustable cut-off concentration
The most prominent advantage of a quantitative FOB test is that the user can
select the cut-off concentration in order to decide on further investigation 5.
This means that the analytical sensitivity of the test can be adjusted according
to e.g. screening settings, national guidelines or local requirements 5, 28. The
goal with choosing a cut-off concentration is to provide an adequate positivity
rate with acceptable trade-off between detection rate and unnecessary colonoscopies performed. The choice depends on the test device, sampling, number
of samples used, intended detection rate, prevalence of CRC in population,
and political issues such as availability of colonoscopy 17, 83.
Several studies on methods and FOB cut-off values have been performed, and some
of the results have been applied to routine use on national level
. Most studies
84, 85
recommend a cut-off concentration of 75−100 ng Hb/ml (15−20 µg Hb/g faeces) 66−68,
83−91
and a one sample strategy 36, 66−68 in order to reach optimum cost-effectiveness.
As described on page 9 and in figure 1, faecal Hb concentrations are not
comparable between men and women of different age. The differences
emphasise that one, by the manufacturer predetermined, Hb cut-off value
is not appropriate in FOB testing. When using one cut-off value more men
20
and elderly people will get positive test results, even though their faecal Hb
concentration might be completely normal. More tailored strategies for
screening programs are thus needed 21, 92, and it is possible that different cutoff concentrations are appropriate to use as criteria for further investigation
for specific groups of individuals 21.
Table 4. The measuring range and result presentation units of QuikRead go iFOBT and QuikRead FOB quantitative.
QuikRead go iFOBT
QuikRead FOB quantitative
Measuring
range
75−1000 ng/ml (15−200 µg/g)
100−1000 ng/ml (20−200 µg/g)
Result unit
As quantitative: ng/ml and/or µg/g
As qualitative: positive / negative
ng/ml, convertible to µg/g
Knowing the total amount of Hb in the faecal mass, enables comparison
of FOB results obtained with different methods. Test manufacturers use
various sampling devices and buffers, collect various masses of faeces and
report Hb concentrations in different ways. Therefore FOB results expressed
in ng Hb/ml buffer are not comparable between different methods 93.
A suggestion on standardisation of units for reporting faecal
Hb concentrations has been made
. The only unit that
94
allows comparison of FOB results between test devices
and across clinical studies is µg Hb/g faeces. The unit
can be calculated if the dilution ratio of the sample is
known, but sophisticated automated iFOBTs provide
iFOBTs typically have limits
of detection <200 μg Hb/g
faeces 78.
the user with results expressed in µg/g automatically.
Patient-specific follow-up and screening
strategies
Occult bleeding increases gradually with growing size of polyps and advancing
stage of CRC (figure 2), and FOB tests can potentially detect both CRC and
its preliminary stages
. Qualitative test indicating only that the result
3, 66, 95
is positive, do not give any information on the amount of occult bleeding.
Risk stratification based on the exact numerical Hb concentration might
help clinicians in identifying subjects with alarmingly high FOB concentra-
21
tions that should undergo further examinations immediately. The interval
between screen-detected disease and the start of definitive management is an
unpleasant time for the patient and it presents the opportunity for disease
progression 28, 96.
ng Hb/ml
1000
800
709 (536-881)
600
559 (199-918)
400
200
0
155 (84-226)
45 (28-63)
Normal
Adenoma
Adv. adenoma
Cancer
Figure 2. Faecal Hb concentrations and 95% Confidence Intervals according to stage of adenomas and cancer in
815 patients (mean age 57.4 years). Study performed with quantitative iFOBT and colonoscopy investigation 66.
Irregular bleeding patterns and rates 54 as well as many other factors might
cause varying faecal Hb concentrations. There is a risk of false results in case
a qualitative test is used and the subject’s average Hb concentration in faeces
is very variable and/or close to the cut-off concentration of the FOB test. In
these cases a quantitative test would clarify the situation significantly, thus
eliminating guess-work, false positives and unnecessary further examinations.
Patients with FOB concentrations close to the cut-off concentration might
benefit from more active follow-up even though such strategies are not yet
implicated in screening programmes 97. According to Chen et al. 97 high-risk
subjects (80−99 ng Hb/ml) could be offered screening with shorter intervals
compared to low-risk subjects (0−19 ng Hb/ml). This approach would be
cost-effective; even if reducing the screening interval of high- and very-high
risk individuals from two to one years, the number of positive FOB tests and
thus colonoscopies would be lower 97. The same risk categorisation has been
used when comparing faecal Hb concentrations by age and gender, and could
also according to McDonald et al. be useful in screening programme planning
. The threshold for screening might additionally differ in populations with
21
high-risk of CRC 84, 98. Clinicians could want to detect even small amounts of
22
bleeding and perform more aggressive screening for patients with e.g. FAP,
HNPCC or family history of CRC 98.
Further investigations
If a FOB test is positive, an investigation is performed to identify the source
of bleeding. The most common techniques for further investigations include
colonoscopy, flexible sigmoidoscopy, air-contrast barium enema, molecular
markers, virtual colonoscopy or colon capsule endoscopy 20, 36. Colonoscopy
is considered the most effective visualisation technique to detect CRC and
high-risk adenomas 45, and the recommended method to evaluate the colon
in patients with increased FOB concentrations
. All diagnostic tools for
20
examining the colon can, however, miss clinically serious lesions 4, 99−101.
Colonoscopy directly visualises the entire colon
for mucosal lesions
102−104
, has high sensitivity
49
and allows intervention . It offers the potential
4
to find and remove lesions throughout the colon and rectum 3. The spread
of the tumour as well as the general condition of the patient affect choice
of treatment and chances of recovery
cost-effectiveness of CRC screening
13
. Several studies have covered the
. As a primary screening method
105−108
colonoscopy is limited by low adherence of the population, high costs and
risks 36. Screening with FOBT alone is stated to be more cost-effective than
computed-tomography-colonoscopy and optical-colonoscopy alone 108.
Flexible sigmoidoscopy involves direct visualisation of the distal colonic
mucosa 49. Reaching approx. 50 cm far from the anal sphincter 36, it is not
an as broad and extensive examination as colonoscopy. Screening with sigmoidoscopy alone is less effective than combining it with FOB testing
3, 105
.
Pre-screening for FOB combined with sigmoidoscopy leads to cancer being
detected in an earlier stage, and to patients surviving longer compared to
screening with sigmoidoscopy alone 109. Air-contrast barium enema together
with flexible sigmoidoscopy
adenomas
111
110
accurately detects colon cancer and large
but is less accurate than colonoscopy
. With advances in
99, 109
technology, air-contrast barium enemas are being used less often, and are
rarely indicated by physicians in screening 36.
23
Virtual colonoscopy or computed tomographic studies of the colon might
be useful in colonic evaluation 112, but clinical experience as of today is limited
. The technique does not detect small lesions or allow polypectomy 36. Using
20
molecular DNA markers is expensive and time-consuming; it requires skills
and a suitable panel of markers. It might not suit mass population screening
and has not undergone validations
. Capsule endoscopy in turn involves
45
swallowing an endoscopic capsule with a built-in micro camera. The technique
is at the stage of testing for use in screening, it is non-invasive and painless 36.
Many factors are of importance when choosing a CRC examination
method. These are e.g. accuracy of the procedure, costs, patient acceptance,
safety and availability of diagnostic tools, and complication rates of the
methods 4, 20. Due to colonoscopy being costly, invasive and scarce it should
only be undertaken in subjects at increased risk of CRC
. Complication
28
deaths from colonoscopies, perforations, major bleeding episodes and minor
complications have been reported 3, 109. For the patient the investigation might
be painful or uncomfortable 13. It is important to ensure that subjects involved
in screening are fully informed about the risks of CRC and the importance of
detecting cancer early. Healthcare providers should be able to give details of
the screening procedure and the risks associated with different investigations 3.
Guidelines and recommendations
As indicated previously, using FOB tests in population screening can reduce
mortality from colorectal neoplasia
42, 50−53
. There are variations in national
guidelines and practices concerning FOBTs; some still favour the established
gFOBTS, whereas others are up to speed and recommend iFOBTs and quantitative tests. In the light of the previously discussed differences between various
FOB testing methods, recommendations are still needed e.g. regarding which
methods and cut-off concentrations to use and how many samples to obtain.
The European Guidelines for quality assurance in colorectal cancer screening and diagnosis
6
state that an ideal biochemical test for CRC screening
would use a biomarker that is specific and sensitive for cancer and advanced
pre-cancer. The sample should be easily collected and could be safely and
24
cheaply transported for automated analysis. Both iFOBTs and gFOBTs fulfil
these criteria 17, 28. iFOBTs are, however, both analytically and clinically more
sensitive and specific for detection of Hb than gFOBTs. The guidelines additionally emphasise the value of automated measurement and adjustable
cut-off concentration. Quantitative iFOBTs are currently the test of choice
for population screening and adequate clinical sensitivity and specificity can
be obtained using a single iFOBT per subject 17.
Also the European Group on Tumor Markers recommends the use of
quantitative iFOBTs with adjustable cut-off value for colorectal neoplasia
screening in average-risk populations. The recommendation is based on
the significant amount of advantages of iFOBTs compared to gFOBTs. For
countries not yet using FOB tests, iFOBTs should be considered the standard
for CRC screening 45.
”The dilemma for a population screening programme is where to draw the line between
detection rates, cost and the inconvenience and morbidity associated with colonoscopy.”
“Adaption of a test device and the selection of a cut-off concentration should follow
a local pilot study to ensure that the chosen test, test algorithm and transport
arrangements work together to provide a positivity rate that is clinically, logistically and
financially acceptable.”
European guidelines for quality assurance in colorectal cancer screening and diagnosis 17
25
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References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
28
Ahlquist, DA. et al. Fecal blood levels in health and
disease. A study using HemoQuant. N Engl J Med.
1985;312:1422−8.
Dybdahl, JH. et al. Occult faecal blood loss determined by chemical tests and a 51 Cr method. Scand
J Gastroenterol. 1981;16:245−52.
Winawer, SJ et al. Colorectal Cancer Screening:
Clinical Guidelines and Rationale. Gastroenterology. 1997;112:594−642.
Rockey, DC. Occult and obscure gastrointestinal
bleeding: causes and clinical management. Nat Rev
Gastroenterol Hepatol. May 2010;7:265−279.
Fraser CG et al. Newer Fecal Tests: Opportunities for
Professionals in Laboratory Medicine. Clin Chem.
2012;58(6):963−5.
European Union. European guidelines for quality
assurance in colorectal cancer screening and diagnosis. 1st ed. Luxembourg: Publications Ofiice of
the European Union; 2010.
Ahlquist, DA. Approach to the patient with occult
gastrointestinal bleeding. In: Yamada T, ed. Textbook
of gastroenterology. Vol I. 2nd ed. Philadelphia: J.B.
Lippincott; 1995.
Schiff, L. et al. Observations on the oral administration of citrate blood in man. Am J Med Sci.
1942;203:409.
Rockey, DC et al. Detection of upper gastrointestinal
blood with fecal occult blood tests. Am J Gastroenterol. 1999;94:344−50.
Izak, G et al. Quantitative determination of gastrointestinal bleeding using Cr51-labeled red blood cells.
Amer J Dig Dis. 1960;5:24.
American Gastroenterological Association. AGA
Technical Review on the Evaluation and Management of Occult and Obscure Gastrointestinal Bleeding. Gastroenterology. 2000;118:201−221.
Stephens F, Lawrenson K. The Pathologic Significance of Occult Blood in Feces. Dis Col & Rect.
1970;13(6):425−8.
Syöpäjärjestöt. Paksu- ja peräsuolen syövät. Available at: http://www.cancer.fi/tietoasyovasta/syopataudit/suolistosyovat/. Accessed November 27, 2013.
St John D, Young G. Evaluation of radiochromium
blood loss studies in unexplained iron-deficiency
anemia. Aust N Z J. 1978;8:121−6.
Ebaugh, FG et al. Quantitative measurement of
gastrointestinal blood loss. I. The use of radioactive
Cr51 with gastrointestinal hemorrhage. Amer J Med.
1958;169:25.
Roche, M et al. Study of urinary and fecal excretion
of radioactive chromium51 in man; its use in the
measurement of intestinal blood loss associated with
hookworm infection. J Clin Invest. 1957;36:1183.
Halloran, SP et al. European guidelines for quality assurance in colorectal cancer screening and
diagnosis. First Edition. Faecal occult blood testing.
Endoscopy. 2012;44:1−23.
Blackshear, JL et al. Fecal hemoglobin excretion in
elderly patients with atrial fibrillation: combined
aspirin and low-dose warfarin vs conventional warfarin therapy. Arch Intern Med. 1996;156:658−60.
Greenberg, PD et al. Asymptomatic chronic gastrointestinal blood loss in patients taking aspirin
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
or warfarin for cardiovascular disease. Am J Med.
1996;100:598−604.
Rockey, DC. Occult Gastrointestinal bleeding. N
Engl J Med. June 1999;341(1):38−46.
McDonald, PJ et al. Faecal haemoglobin concentrations by gender and age: implications for populationbased screening for colorectal cancer. Clin Chem Lab
Med. 2012;50(5):935−40.
Steele, RJ et al. Effects of age, gender and deprivation on key performance indicators in a FOBTbased colorectal cancer screening programme. J Med
Screen. 2010;17:68−74.
Steele, RJ et al. Results from the first three rounds of
the Scottish demonstration pilot of FOBT screening
for colorectal cancer. Gut. 2009;58:530−5.
Moss, SM et al. Performance measures in three
rounds of the English bowel cancer screening pilot.
Gut. 2012;61:101−107.
Lee, TJ et al. High yield of colorectal neoplasia detected by colonoscopy following a positive faecal
occult blood test in the NHS Bowel Cancer Screening
Programme. J Med Screen. 2011;18:82−6.
Goulard, H et al. French colorectal cancer screening
pilot programme: results of the first round. J Med
Screen. 2008;15:143−8.
Brenner, H et al. Sex differences in performance
of fecal occult blood testing. Am J Gastroenterol.
2010;105:2457−64.
von Karsa, L et al. European guidelines for quality
assurance in colorectal cancer screening and diagnosis: Overview and introduction to the full Supplement publication. Endoscopy. 2013;45:51−9.
Parkin, DM et al. Global cancer statistics. CA Cancer
J Clin. 2005;55:74−108.
Davies, RJ et al. Colorectal cancer screening: prospects for molecular stools analysis. Nature Rev Cancer. 2005;5:199−209.
Howard, J et al. A collaborative study of differences
in the survival rates of black patients and white patients with cancer. Cancer. 1992;69:2349−60.
Mayberry, RM et al. Determinants of black/white
differences in colon cancer survival. J Natl Cancer
Inst. 1995;87:1686−93.
Baquet C, Hunter C. Patterns of minorities and special populations. In: Greenwald L, Kramer B, Weed
D, eds. Cancer prevention and control. New York:
Dekker; 1995.
European Diagnostic Manufacturers Association.
EDMA FACTSHEET. Screening for Colorectal Cancer (CRC). June 2010. Available at: https://www.
apifarma.pt/areas/div/Documents/Cancro%20ColoRectal.pdf. Accessed December 13, 2013.
Marbet U, Regli H. Es ist nicht Schicksal, am
Kolonkarzinom zu sterben! Präventionsstrategien
beim kolorektalen Karzinom. Schweiz Med Forum.
2011;11(13):227−232.
Seifert B. Colorectal Cancer Screening. Prague: Maxdorf Publishing; 2013.
Beard, CM et al. Trends in colorectal cancer over
half a century in Rochester, Minnesota, 1940-89.
Ann Epidemiol. 1995;5:210−4.
Canadian Task Force on the Periodic Health Examination. The periodic health examination. Can Med
Assoc J. 1979;121:1193−1254.
39. Wingo, PA et al. Cancer statistics 1995. Cancer.
1995;45:8−30.
40. Elde, TJ. Risk of colorectal cancer in adenomabearing individuals within a defined population. Int
J Cancer. 1985;38:173−6.
41. Young, GP et al. Selecting an occult blood test for
use as a screening tool for large bowel cancer. Fron
Gastrointest Res. 1991;18:135−56.
42. Mandel, JS et al. Reducing mortality from colorectal
cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med.
1993;328:1365−71.
43. Macrae F, St John D. Relationship between patterns
of bleeding and hemoccult sensitivity in patients with
colorectal cancers or adenomas. Gastroenterology.
1982;82:891−8.
44. Foutch, PG et al. Risk factors for blood loss from
adenomatous polyps of the large bowel: a colonoscopic evaluation with histopathologic correlation. J
Clin Gastroenterol. 1988;10:50−6.
45. Duffy, MJ et al. Use of faecal markers in screening
for colorectal neoplasia: a European Group on Tumor Markers (EGTM) position paper. Int J Cancer.
2011;128:3−11.
46. Lansdorp-Vogelaar I, von Karsa L. European guidelines for quality assurance in colorectal cancer
screening and diagnosis. First edition - Introduction.
Endoscopy. 2012;44:SE15−30.
47. Lieberman, DA. Screening for colorectal cancer. N
Engl J Med. 2009;12:1179−87.
48. Huang, CS et al. Colorectal cancer screening in
average risk individuals. Cander Causes Control.
2005;16:171−88.
49. Swan, H et al. International Colorectal Cancer
Screening Programs: Population Contact Strategies,
Testing Methods and Screening Rates. Practical
Gastroenterology. August 2012. http://www.practicalgastro.com/pdf/August12/Swan.pdf. Accessed
December 12, 2013.
50. Towler, B et al. A systematic review of the effects of
screening for colorectal cancer using the faecal occult
blood test, Hemoccult. Br Med J. 1998;317:559−65.
51. Kronborg, O et al. Randomised study of screening
for colorectal cancer with faecal-occult-blood test.
Lancet. 1996;348:1467−71.
52. Hardcastle, JD et al. Randomised controlled trial of
faecal-occult-blood screening for colorectal cancer.
Lancet. 1996;348:1472−7.
53. Kewenter, J et al. Results of screening, rescreening,
and follow-up in a prospective randomized study for
detection of colorectal cancer by fecal occult blood
testing. Results for 68,308 subjects. Scand J Gastroenterol. 1994;29:468−73.
54. Ahlquist, DA et al. Patterns of occult bleeding in asymptomatic colorectal cancer. Cancer.
1989;63:1826−30.
55. Zuckerman G, Benitez J. A prospective study of
bidirectional endoscopy (colonoscopy and upper
endoscopy) in the evaluation of patients with occult gastrointestinal bleeding. Am J Gastroenterol.
1992;87:62−6.
56. Rockey, DC et al. Relative frequency of upper gastrointestinal and colonic lesions in patients with
positive fecal occult blood tests. N Engl J Med.
1998;339:153−9.
57. Rockey D, Cello J. Evaluation of the gastrointestinal
tract in patients with iron deficiency anemia. N Engl
J Med. 1993;329:1691−5.
58. Mandel, JS et al. Sensitivity, specificity and positive
predictive value of the hemoccult test in screening
for colorectal cancers. The University of Minnesota's colon cancer control study. Gastroenterology.
1989;97:597−600.
59. Halloran, SP. Bowel cancer screening. Surgery.
2009;27:397−400.
60. Allison, JE et al. A comparison of fecal occult-blood
tests for colorectal-cancer screening. N Engl J Med.
1996;334:155−9.
61. Young, GP et al. Influence of delay in stool sampling on fecal occult blood sensitivity. Clin Chem.
1996;42:1107−8.
62. Fleisher, M et al. Accuracy of fecal occult blood test
interpretation. Ann Intern Med. 1991;114:875−6.
63. Rabaneck, L et al. Cancer Care Ontario guaiac fecal
occult blood test (FOBT) laboratory standards: evidentiary base and recommendations. Clin Biochem.
2008;41:1289−305.
64. Herzog, P et al. Fecal blood loss in patients
with colonic polyps: a comparison of measurements with 51chromium-labeled erythrocytes
and with the Haemoccult test. Gastroenterology.
1982;83:957−62.
65. Hewitson, P et al. Screening for colorectal cancer
using the fecal occult blood test, Hemoccult. Art
no. CD001216. Cochrane Database Syst Rev. January 2007(1).
66. Kovarova, JT et al. Improvements in colorectal
cancer screening programmes - quantitative immunochemical faecal occult blood testing - how to set
the cut-off for a particular population. Biomed Pap
Med Fac Univ Palacky Olomouc Czech Repub. June
2012;156(2):143−50.
67. Castiglione, G et al. Basic variables at different
positivity thresholds of a quantitative immunochemical test for faecal occult blood. J Med Screen.
2002;9(3):99−103.
68. Fenochi, E et al. Screening for colorectal cancer in
Uruguay with an immunochemical faecal occult
blood test. Eur J Cancer Prev. 2006;15:384−90.
69. van Rossum, LG et al. Random comparison of guaiac and immunochemical fecal occult blood tests for
colorectal cancer in a screening population. Gastroenterology. 2008;135:82−90.
70. Hol, L et al. Screening for colorectal cancer; randomised trial comparing guaiac-based and immunochemical faecal occult blood testing and flexible
sigmoidoscopy. Gut. 2010;59:62−8.
71. van Rossum, LG et al. False negative fecal occult
blood tests due to delayed saqmple return in colorectal cancer screening. Int J Cancer. 2009;125:746−50.
72. Brown L, Fraser C. Effect of delay in sampling on
haemoglobin determined by faecal immunochemical
tests. Ann Clin Biochem. 2008;45:604−5.
73. Ehitlock, EP et al. Screening for colorectal cancer: a targeted. updated systematic review for the
U.S. preventive services task force. Ann Int Med.
2008;149:638−58.
74. Guittet, L et al. Comparison of a guaiac based and an
immunochemical faecal occult blood test in screening for colorectal cancer in a general average risk
population. Gut. 2007;56:210−4.
75. Guittet, L et al. Comparison of a guaiac and an immunochemical faecal occult blood test for the detection of colonic lesions according to the lesion type
and location. Br J Cancer. 2009;100:1230−5.
76. Dancourt, V et al. Immunochemical faecal occult
blood tests are superior to guaiac-based tests for
29
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
30
the detection of colorectal neoplasms. Eur J Cancer.
2008;44:2254−8.
Brenner H, Tao S. Superior diagnostic performance
of faecal immunochemical tests for haemoglobin
in a head-to-head comparison with guaiac based
faecal occult blood test among 2235 participants
of screening colonoscopy. Eur J Cancer. September
2013;49(14):3049−54.
Saito, H. Screening for colorectal cancer by immunochemical fecal occult blood testing. Jpn J Cancer
Res. 1996;87:1011−24.
Berchi, C et al. Cost-effectiveness analysis of two
strategies for mass screening for colorectal cancer in
France. Health Econ. 2004;13:227−38.
Berchi, C et al. Cost-effectiveness analysis of the optimal treshold of an automated immunochemical test
for colorectal cancer screening. Int J Technol Assess
Health Care. 2010;26:48−53.
Grazzini, G. et al. Cost evaluation in a acolorectal cancer screening programme by faecal occult
blood test in the District of Florence. J Med Screen.
2008;15:175−81.
Halloran, S et al. Faecal Occult Blood Testing. In:
Segnan N, Patnick J, von Karsa L, eds. European
guidelines for quality assurance in colorectal cancer
screening and diagnosis. 1st ed. Luxembourg: Publications Office of the European Union; 2010.
van Rossum, LG et al. Cutoff value determines
the performance of a semi-quantitative immunochemical faecal occult blood test in a colorectal
cancer screening programme. Br J Cancer. October
2009;101(8):1274−81.
Levi, Z et al. A quantitative immunochemical fecal
occult blood test for colorectal neoplasia. Ann Int
Med. 2007;146:244−55.
Zorzi, M et al. Screening for colorectal cancer in
Italy. Epidemiol Prev. 2008;32(1):55−68.
Hol, L et al. Screening for colorectal cancer: random
comparison of guaiac and immunochemical faecal
occult blood testing at different cut-off levels. Br J
Cancer. 2009;101:1103−10.
Grazzini, G et al. Immunochemical faecal occult
blood test: number of samples and positivity cutoff.
What is the best strategy for colorectal cancer screening? Br J Cancer. 2009;100:259−65.
Guittet, L et al. Performance of immunochemical
faecal occult blood test in colorectal cancer screening in average-risk population according to positivity treshold and number of samples. Int J Cancer.
2009;125:1127−33.
Nakama, H et al. Evaluation of the optimum cut-off
point in immunochemical occult blood testing in
screening for colorectal cancer. Eur J Cancer. February 2001;37(3):398−401.
Nakama, H et al. A cost-effective analysis of the
optimum number of stool specimens collected for
immunochemical occult blood screening for colorectal cancer. Eur J Cancer. 2000;36:647−50.
Fu, W-P et al. Screening for colorectal cancer using
a quantitative immunochemical faecal occult blood
test: a feasibility study in an Asian population. Tech
Coloproctol. 2009;13:225−30.
Khalid-de Backer, CA et al. Test performance of fecal
occult blood testing and sigmoidoscopy compared
with colonoscopy creening for colorectal advanced
adenoma. Camcer Prev Res. 2011;4:1563−71.
Allison, JE et al. Comparing Fecal Immunochemical
Tests: Improved Standardization Is Needed. Gastroenterology. 2012;142:422−31.
94. Fraser, CG. A Proposal to Standardize Reporting
Units or Fecal Immunochemical Tests for Hemoglobin. JNCI. June 2012;104(11):810−4.
95. Digby, J et al. Faecal haemoglobin concentration
is related to severity of colorectal neoplasia. J Clin
Pathol. 2013;66:415−9.
96. NHS Quality Improvement Scotland. Bowel Screening Programme. Clinical Standards February 2007.
2007. Available at: http://www.bowelscreening.scot.
nhs.uk/wp-content/uploads/2007/06/bowelsc_stnf_
feb07.pdf. Accessed December 11, 2013.
97. Chen, L-S et al. Baseline immunochemical faecal occult blood test (iFOBT) concentration as a predictor
of incident colorectal neoplasia: longitudinal followup of a Taiwanese population-based colorectal cancer screening cohort. Lancet Oncol. 2011;12:551−8.
98. Imperiale T. Tailoring Screening Colonoscopy to
High-Risk Groups…and away from low-risk groups.
Paper presented at: WEO Colorectal Cancer Screening Meeting, May 17, 2013, 2013; Orlando.
99. Rex, DK et al. Relative sensitivity of colonoscopy and
barium enema for detection of colorectal cancer in
clinical practice. Gastroenterology. 1997;112:17−23.
100.Haseman, JH et al. Failure of colonoscopy to detect
colorectal cancer: evaluation of 47 cases in 20 hospitals. Gastrointest Endosc. 1997;45:451−5.
101.Rex, DK et al. Colonoscopic miss rates of adenomas
determined by back-to-back colonoscopies. Gastroenterology. 1997;112:24−8.
102.Winawer, SJ et al. A comparison of colonoscopy and
double-contrast barium enema for surveillance after
polypectomy. National Polyp Study Work Group. N
Engl J Med. 2000;342:1766−72.
103.Rockey, DC et al. Analysis of air contrast barium
enema, computed tomographic colonography, and
colonoscopy: prospective comparison. Lancet.
2005;365:305−11.
104.Rockey, DC et al. Prospective comparison of aircontras barium enema and colonoscopy in patients
with fecal occult blood: a pilot study. Gastrointest
Endosc. 2004;60:953−8.
105.Wagner, JL et al. Cost-effectiveness of colorectal
cancer screening in average-risk adults. In: Young
G, Levin B, eds. Prevention of early detection of colorectal cancer. London: Saunders; 1996.
106.Eddy, DM. Screening for colorectal cancer. Ann Intern Med. 1990;113:373−384.
107.Lieberman, DA. Cost-effectiveness model for
colon cancer screening. Gastroenterology.
1995;109:1781−90.
108.Lucidarme, O et al. Cost-effectiveness modeling of
colorectal cancer: computed tomography colonography vs colonoscopy or fecal occult blood tests. Eur J
Radiol. June 2012;81(7):1413−9.
109.Winawer, SJ et al. Screening for colorectal cancer
with fecal occult blood testing and sigmoidoscopy. J
Natl Cancer Inst. 1993;85:1311−8.
110.Kewenterm J et al. The yield of flexible sigmoidoscopy and double-contrast barium enema in the
diagnosis of neoplasms in the large bowel in patients with a positive Hemoccult test. Endoscopy.
1995;27:159−63.
111.Ott, DJ et al. Barium enema examination: sensitivity
in detecting colonic polyps and carcinomas. South
Med J. 1989;82:197−200.
112.Hara, AK et al. Detection of colorectal polyps
by computed tomographic colography: feasibility of a novel technique. Gastroenterology.
1996;110:284−90.
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