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Page 1: The Value of Immunochemical - Roche  · PDF fileThe Value of Immunochemical Faecal Occult Blood tests in Clinical Use POC

POC

The Value of Immunochemical Faecal Occult Blood tests in Clinical Use

Page 2: The Value of Immunochemical - Roche  · PDF fileThe Value of Immunochemical Faecal Occult Blood tests in Clinical Use POC
Page 3: The Value of Immunochemical - Roche  · PDF fileThe Value of Immunochemical Faecal Occult Blood tests in Clinical Use POC

The Value of Immunochemical Faecal Occult Blood tests in Clinical Use PO

C

Page 4: The Value of Immunochemical - Roche  · PDF fileThe Value of Immunochemical Faecal Occult Blood tests in Clinical Use POC

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 respon-

sibility 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 informa-

tion 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.

Orion Diagnostica therefore accepts no liability for any injury or damage to person or property resulting from

acceptance of the information in this booklet. Hence, liability claims regarding possible injury or damage will be

rejected.

The information in this booklet may contain references to products that are not available or approved by the

regulatory authorities in your country. Orion Diagnostica assumes no responsibility for you accessing information

that may not comply with legislation, regulations or usage applicable in your country. You are advised to consult

Orion Diagnostica’s local business contact or marketing partner for information about the availability of Orion

Diagnostica products in your country.

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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

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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 diagnos-

tics, 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 intes-

tinal 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 chemi-

cal 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.

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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 symp-

tom 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 gastrointestinal bleeding differs significantly

from obscure gastrointestinal bleeding, which is charac-

terised 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 in-

testine. 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

Occult bleeding is not visible to the naked eye.

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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 and anticoagulant therapy have been associated with occult gastroin-

testinal 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 fae-

cal 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 .

• Aspirin

• Nonsteroidal anti-inflammatory drugs

• Gum disease

• Gastritis and oesophagitis

• Gastroduodenal and oesophageal ulcers

• Peptic ulcer disease (PUD)

• Vascular ecstasias

• Haemorrhoids

• Portal hypertensive gastropathy (PHG)

• Various gastrointestinal parasites

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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 gas-

trointestinal 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 mid-

dle 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 gastroin-

testinal 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.

250

200

150

100

50

ng

Hb

/ml

Age (years)

050-54 55-59 60-64 65-69

300

Female

Male

70-74

350

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Colorectal Cancer (CRC)

CRC is a cancer from uncontrolled cell growth in the colon, rectum or ap-

pendix 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 28−30. CRC occurs with equal frequency in men and

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 pre-

malignant 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

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.

• Ulcerative colitis

• Crohn’s disease

• Hereditary nonpolyposis colorectal

cancer (HNPCC)

• Familial adenomatous polyposis (FAP)

• Peutz–Jeghers syndrome (PJS)

• Juvenile Polyposis Syndrome (JPS)

• Previous CRC or polyps

• Age

• Nicotin

• Alcohol

• Overweight

• Inactivity

• Large consumption of red meat

• High calorie intake, low fibre content

• Diabetes mellitus type 2

Conditions

Other factors

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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 involve-

ment of lymph nodes and <10% in patients with metastatic disease 34, 36, 39.

Detecting CRC or its precursors early is possible 13, 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 implement-

ing national CRC screening programs is growing 36. In 2009, 19 of the 27

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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. re-

moval 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 malig-

nancies are restricted on the inner mucous surface (stage 1, Dukes A CRC) 34.

The two main types of CRC and high-risk adeno-

ma 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

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 tech-

niques, 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 bienni-

ally 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 infor-

mation 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

CRC is preventable if caught in the

pre-cancerous stages.

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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 differ-

ences 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,

52, in the course of clinical evaluation 4, and when investigating possible causes

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 54, as well as the sensitivity and characteristics of the chosen FOBT affect

the results 20.

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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 61, and the test card can be returned to the healthcare provider e.g. by mail.

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

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negative results, especially if proper training is not given 3, 62. The result in-

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.

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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

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 45. Various trials have, however, shown

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 diag-

nostic tests in vain 3. According to the European Group on Tumor Markers

rehydration of samples should not be performed 45.

• Red meat

• Bacteria

• Turnips

• Horseradish

• Hyperoxides in various fruits and

vegetables

• Vitamin C

• Citrus fruits

Factors that may cause false positive results Factors that may cause false negative results

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iFOBTs

Immunochemical FOBTs exist both as qualitative and quantitative. Quali-

tative iFOBTs are visually interpreted. Quantitative tests in turn are often

instrument-read and have thus enhanced quality while eliminating the po-

tential 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 ag-

glutination, 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 28, 45, collection of a

single sample 36, 66−68, simple and hygienic sampling devices 36, higher specific-

ity for lower gastrointestinal tract bleeding 1, 9, 20, and no dietary restrictions 5, 36. The use of iFOBTs results in improved clinical performance and higher

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 specifi-

cally detect gastrointestinal bleeding from the lower gastrointestinal tract.

Small amounts of bleeding from the upper gastrointestinal tract remain unde-

tected 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 inter-

ference 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.

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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 concen-

trations 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

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, screen-

ing 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 79−81. This is likely due to the increased sensitivity of the tests as well as the

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 82. In

addition to the advantages of qualitative iFOBTs, quantitative iFOBTs offer

the user a numerical result of the Hb concentration in the sample, can be

iFOBTs can detect as little as 0.3 ml of blood added to

a faecal sample 78.

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automated and thus objectively interpreted. These are considerable improve-

ments 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 colo-

noscopies 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 84, 85. Most studies

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

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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 cut-

off 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.

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 94. The only unit that

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

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 3, 66, 95. Qualitative test indicating only that the result

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-

iFOBTs typically have limits of detection <200 μg Hb/g

faeces 78.

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/gAs qualitative: positive / negative

ng/ml, convertible to µg/g

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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.

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 21. The threshold for screening might additionally differ in populations with

high-risk of CRC 84, 98. Clinicians could want to detect even small amounts of

1000

800

600

400

200

ng

Hb

/ml

0Normal Adenoma Adv. adenoma Cancer

45 (28-63)

155 (84-226)

559 (199-918)

709 (536-881)

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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 20. All diagnostic tools for

examining the colon can, however, miss clinically serious lesions 4, 99−101.

Colonoscopy directly visualises the entire colon 49, has high sensitivity

for mucosal lesions 102−104 and allows intervention 4. It offers the potential

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 13. Several studies have covered the

cost-effectiveness of CRC screening 105−108. As a primary screening method

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 sig-

moidoscopy 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 110 accurately detects colon cancer and large

adenomas 111 but is less accurate than colonoscopy 99, 109. With advances in

technology, air-contrast barium enemas are being used less often, and are

rarely indicated by physicians in screening 36.

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Virtual colonoscopy or computed tomographic studies of the colon might

be useful in colonic evaluation 112, but clinical experience as of today is limited 20. The technique does not detect small lesions or allow polypectomy 36. Using

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 45. Capsule endoscopy in turn involves

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 28. Complication

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 quanti-

tative 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 screen-

ing 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

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25

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 ad-

ditionally 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

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112. Hara, AK et al. Detection of colorectal polyps by computed tomographic colography: feasi-bility of a novel technique. Gastroenterology. 1996;110:284−90.

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