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  • CUR22: What are the other evidence-based alternatives to CRC screening with FIT?
  • CUR27: What are the technical characteristics and analytical validity of guaiac-based fecal occult blood test (FOBT), as main CRC screening comparator in this assessment? Jump to
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What are the other evidence-based alternatives to CRC screening with FIT?

Authors: Mirjana Huic, Eleftheria Karampli, Silvia Florescu, Cipriana Mihaescu-Pintia

Internal reviewers: Laura Cacciani, Sophie Brunner, Esther Kraft

Several screening tests for CRC are available, classified according to three categories {61}:

Stool-based techniques: Fecal occult blood test (FOBT) (either guaiac, so called gFOBT and immunochemical, so called FIT); Fecal DNA testing.   Endoscopic techniques: Optical colonoscopy; Flexible sigmoidoscopy (FS).   Imaging techniques: Virtual colonoscopy techniques using: a) Computed tomographic colonography (CT colonography), b) Magnetic resonance colonography (MR colonography); Wireless capsule endoscopy (PillCam Colon); Double-contrast barium enema (DCBE).   gFOBT (Please see Result card CUR 27 in this Domain for details) FOBT is an alternative name for the Guaiac-based faecal occult blood test (gFOBT), a class of faecal occult blood test which detects non-visible blood in the faeces associated with colorectal cancer (CRC) and adenomas. It detects the peroxidase reaction of haemoglobin, which causes the detection paper impregnated with guaiac resin to turn blue. Dietetic provisions are necessary to exclude false-positive results. A recent study showed limited sensitivity of this test for both, advanced adenomas (11%) and carcinomas (13%) ({69} cited in {5}). With the use of gFOBT, a decrease in mortality for CRC by 15 to 33% has been proved ({70}cited in {5}).   Stool DNA testing (Please see  also Result cards CUR 23 in this Domain and TEC 3 in the Domain Technical description and characteristics of the technology) Faecal DNA tests represent new group of faecal tests designed to detect molecular abnormalities in cancer or precancerous lesion that are shed into the stool. Two faecal DNA tests were commercially available: PreGen Plus, from 2003 to 2008, and ColoSure (single marker faecal DNA assay for methylated vimentin) intended for individuals who are not eligible for more invasive CRC screening. New test showed evolution in the composition of the test, as well in pre-analytical factors and analytic factors in comparison with older faecal DNA tests. Recent systematic review on evidence on faecal DNA testing to screen for CRC in adults at average risk for CRC {71} concluded that faecal DNA tests have insufficient evidence about its diagnostic accuracy to screen for colorectal cancer in asymptomatic, average-risk patients; insufficient evidence for the harms, analytic validity, and acceptability of testing in comparison to other screening modalities also. Existing evidence has little or no applicability to currently available faecal DNA testing.   Sigmoidoscopy According to the EU Guidelines {2}: "There is reasonable evidence from one large RCT that flexible sigmoidoscopy (FS) screening reduces CRC incidence and mortality if performed in an organised screening programme with careful monitoring of the quality and systematic evaluation of the outcomes, adverse effects and costs (II). The available evidence suggests that the optimal interval for FS screening should not be less than 10 years and may even be extended to 20 years (IV - C).   There is limited evidence suggesting that the best age range for FS screening should be between 55 and 64 years (III – C). After age 74, average-risk FS screening should be discontinued, given the increasing co-morbidity in this age range (V - D).   The impact on CRC incidence and mortality of combining sigmoidoscopy screening with annual or biennial FOBT has not yet been evaluated in trials. There is currently no evidence for extra benefit from adding a once-only FOBT to sigmoidoscopy screening (II). "   Recent meta-analysis {72} of randomized controlled trials demonstrates that FS-based screening significantly reduces the incidence and mortality of CRC in average-risk patients. By intention to treat analysis, FS-based screening was associated with an 18% relative risk reduction in the incidence of CRC (0.82, 95% CI 0.73–0.91, p,0.001, number needed to screen [NNS] to prevent one case of CRC = 361), a 33% reduction in the incidence of left sided CRC (RR 0.67, 95% CI 0.59–0.76, p,0.001, NNS = 332), and a 28% reduction in the mortality of CRC (relative risk [RR] 0.72, 95% CI 0.65–0.80, p,0.001, NNS = 850).   Colonoscopy   The EU Guideline {2} states: "Limited evidence exists on the efficacy of colonoscopy screening in reducing CRC incidence and mortality (III). However, recent studies suggest that colonoscopy screening might not be as effective in the right colon as in other segments of the colorectum (IV).   Limited available evidence suggests that the optimal interval for colonoscopy screening should not be less than 10 years and may even extend up to 20 years (III - C).   Indirect evidence suggests that the prevalence of neoplastic lesions in the population below 50 years of age is too low to justify colonoscopic screening, while in the elderly population (75 years and above) lack of benefit could be a major issue. The optimal age for a single colonoscopy appears to be around 55 years (IV - C). Average risk colonoscopy screening should not be performed before age 50 and should be discontinued after age 74 (V - D)."   Recent interim report of RCT {73} involving asymptomatic adults 50 to 69 years of age comparing the one-time colonoscopy in 26,703 subjects with FIT every 2 years in 26,599 subjects and primary outcome - the rate of death from colorectal cancer at 10 years, showed that subjects in the FIT group were more likely to participate in screening than were those in the colonoscopy group (34.2% vs. 24.6%, P<0.001). On the baseline screening examination, the numbers of subjects in whom colorectal cancer was detected were similar in the two study groups, but more adenomas were identified in the colonoscopy group. Advanced adenomas were detected in 514 subjects (1.9%) in the colonoscopy group and 231 subjects (0.9%) in the FIT group (odds ratio, 2.30; 95% CI, 1.97 to 2.69; P<0.001), and non-advanced adenomas were detected in 1109 subjects (4.2%) in the colonoscopy group and 119 subjects (0.4%) in the FIT group (odds ratio, 9.80; 95% CI, 8.10 to 11.85; P<0.001).   CT colonography (CTC) Computed tomographic colonography (CTC) is a potential technique for CRC screening. With CTC, two- and three-dimensional digital images are constructed to investigate the presence of lesions in the colon and rectum. Studies on the impact of CTC screening on CRC incidence or mortality have not yet been conducted.   Capsule endoscopy Colon capsule endoscopy is a new technique to visualize the colon. Compared with full colonoscopy, the accuracy of colon capsule is considerably lower and an even more extensive bowel cleansing is needed. Capsule endoscopy has not yet been evaluated in an average risk screening population. With capsule endoscopy, a camera with the size and shape of a pill is swallowed to visualise the gastrointestinal tract. No studies have reported on CRC incidence and mortality reduction from capsule endoscopy.   New screening technologies under evaluation {2} There currently is no evidence on the effect of new screening tests under evaluation on CRC incidence and mortality (VI). New screening technologies such as CT colonography, stool DNA testing and capsule endoscopy should therefore not be used for screening the average-risk population (VI - D).  
Important
Partially
Huic M et al. Result Card CUR22 In: Huic M et al. Health Problem and Current Use of the Technology In: Jefferson T, Cerbo M, Vicari N [eds.]. Fecal Immunochemical Test (FIT ) versus guaiac-based fecal occult blood test (FOBT) for colorectal cancer screening [Core HTA], Agenas - Agenzia nazionale per i servizi sanitari regionali; 2014. [cited 16 June 2021]. Available from: http://corehta.info/ViewCover.aspx?id=206

What are the technical characteristics and analytical validity of guaiac-based fecal occult blood test (FOBT), as main CRC screening comparator in this assessment?

Authors: Mirjana Huic, Eleftheria Karampli, Silvia Florescu, Cipriana Mihaescu-Pintia

Internal reviewers: Laura Cacciani, Sophie Brunner, Esther Kraft

Results {2,74,75,76}

FOBT is an alternative name for the Guaiac-based faecal occult blood test (gFOBT), a class of faecal occult blood test which detects non-visible blood in the faeces associated with CRC and adenomas. They represent one out of few different screening options for CRC. The aim of population-based screening for CRC is to reduce morbidity and mortality from CRC through both, prevention (by the removal of adenomas before they had a chance to become malignant) and earlier diagnosis of CRC (at early, curable stage).

The gFOBT has been shown to be clinically and economically effective when used for CRC screening and is at present the most frequently used method in screening programs. It detects the peroxidase reaction of haemoglobin, which causes the detection paper impregnated with guaiac resin to turn blue. Dietetic provisions are necessary to exclude false-positive results. A recent study showed limited sensitivity of this test for both, advanced adenomas (11%) and carcinomas (13%) ({69} cited in {5}). With the use of gFOBT, a decrease in mortality for CRC by 15 to 33% has been proved ({70} cited in {5}).

 

Potential advantages and disadvantages of gFOBT are presented in Table 1.

Table 1. Potential advantages and disadvantages of gFOBT {74}

Advantages of gFOBT

Disadvantages of gFOBT

The collection card and reagent are cheap

Testing is not automated, is labour intensive and involves subjective visual reading

The card based collection system is easy to pack using automated machinery and easy to send by post

The participants is required to prove samples from three separate bowel motions

Easy to print patients details on the cards

Not specific for human Hb

The samples are considered to be stable on the cards for up to 21 days

Not as sensitive as iFOBT to human Hb

The system has been validated in numerous RCTs, has been implemented in a number of bowel cancer screening programmes and work successfully

Not possible to adjust the cut-off Hb concentration of the test

 

 

 

Several different types and brands of tests are available (Table 2). Still it is not possible to adjust the analytical sensitivity of gFOBT, with the exception of the simple adjunct of hydrating the specimen prior the testing with Hemoccult SENSA: hydration increases test  sensitivity and decrease specificity and positive predictive value.

 

Table 2. Different types, brands and some characteristics of Guaiac-based faecal occult bleeding test (gFOBT)

Product names of Guaiac-based fecal occult bleeding test (gFOBT)

 

Manufacturer/Supplier

Analytical Sensitivity

Coloscreen

Helena Laboratories, Texas,USA

0.9 mg Hb/g

Hema-screen

Immunostics Inc. New Jersey,07712, USA

0.6 mg Hb/g

Hemoccult

Beckman Coulter Inc. Fullerton,CA 92835, USA

30% positivity at 0.3 mg Hb/g

Hemoccult SENSA

Beckman Coulter Inc. Fullerton,CA 92835, USA

75% positivity at 0.3 mg Hb/g

MonoHaem

Chemicon Europe Ltd

1.05 mg Hb/g

Hema-Check

Siemens PLC

6 mg Hb/g

HemaWipe

Medtek Diagnostics LLC/BioGnosis Ltd

2 mg Hb/g

 

 

EU Guideline 2010 {2}

“Evidence for efficacy in CRC screening

There is good evidence that gFOBT screening reduces CRC mortality by 14%. 16% in people of appropriate age invited to attend screening. The observed, modest reduction in CRC mortality has not been shown to impact overall mortality (Level of the evidence I).

 

Evidence for the interval

Both annual and biennial screening with gFOBT has been shown to be effective methods for significantly reducing CRC mortality (Level of the evidence I). The results of the Minnesota trial imply that the benefit from annual screening appears to be greater than for biennial screening (Level of the evidence II). No clear recommendation regarding the best time interval for offering screening by gFOBT can be drawn. To ensure effectiveness, the screening interval in a national screening programme should not exceed two years (Level of the evidence II - B).

 

Evidence for the age range

The best age range for offering gFOBT screening has not been investigated in trials. Circumstantial evidence suggests that mortality reduction from gFOBT is similar in different age ranges between 45 and 80 years (Level of the evidence IV). The age range for a national screening programme should at least include 60 to 64 years in which CRC incidence and mortality are high and life-expectancy is still considerable. From there the age range could be expanded to include younger and older individuals, taking into account the balance between risk and benefit and the available resources (Level of the evidence VI - B).“

According a report for the Ontario Ministry of Health and Long-Term Care (41) persons in whom age is the only risk factor for CRC are considered to be at average risk. Factors that place individuals at higher risk include a family history of CRC or adenoma, personal history of CRC or adenoma, and inflammatory bowel disease. There is evidence endorsing the provision of CRC screening to average-risk individuals, beginning at age 50, to detect cancers at a favourable stage before they have advanced to a potentially lethal disease state.

Evidence on risks vs. Benefit {2}

gFOBT screening is a safe screening method with no direct adverse health effects. However, it is associated with false-positive test results, leading to anxiety and unnecessary follow-up colonoscopies. No colonoscopy-related deaths were reported in any of the RCTs, or in the UK pilot programme. In a well-organised, high-quality screening programme using unrehydrated gFOBT, the risks of adverse effects are limited (Level of the evidence I).

 

gFOB tests have proven characteristics that make them suitable for population CRC screening. Despite the known disadvantages of gFOBT they could be more practicable and affordable than iFOBT in some settings which depend on local labour costs, the mechanism of kit distribution and collection and the reduced sample stability of iFOBT (Level of evidence I, Grade of recommendation B).

 

Quality assurance of gFOBT {75}

Countries with CRC screening programmes that adopt a traditional gFOBT need to apply additional laboratory quality procedures to minimise variability and error associated with visual tests reading including manual results input. These procedures include use of appropriate temperature for artificial lighting and neutral-coloured walls un the reading laboratory; use of a national laboratory training programme to prosper consistency of interpretation; a blinded internal QC check each day for each analyst prior to commencing testing; adoption of a monitoring programme to identify operator related analytical performance; double entry of test results. (Level of evidence VI, Grade of recommendation B).

 

Despite the fact that dietary constituents present potential interference in gFOBT, dietary restriction has not been demonstrated to significantly increase screening specificity and risks reducing participation rate.  The potential for dietary interference is significantly less for iFOBT. With the qualification that a diet peculiar to a particular country or culture may not have been tested or reported, dietary restriction is not indicated for programmes using either gFOBT or iFOBT (Level of evidence II, Strength of recommendation D).

 

Some drugs which could cause GI bleeding like aspirin, NSAIDs and anticoagulants present potential interference in gFOBT and iFOBT, drug restriction is not recommended for population screening programmes using either gFOBT or iFOBT (Level of evidence III, Strength of recommendation  D).

 

Since many factors influence the uptake and reliability of sample collection, a local pilot study should be undertaken to ensure that the chosen device and associated distribution, sampling and labelling procedures are acceptable (Level of evidence VI, Grade of recommendation A).

 

All laboratories providing population screening should be led by a qualified clinical chemist trained and experienced in the techniques used for analysis and with clinical quality assurance procedures (Level of evidence VI, Grade of recommendation B).

 

All laboratories providing screening service should be associated with a laboratory accredited to ISO 15189:2007 Medical laboratories-Particular requirements for quality and competence. Also they should perform Internal Quality Control procedures and participate in appropriate External Quality Assessment Scheme (Level of evidence VI, Grade of recommendation B).

 

Distribution of FOBT kits by mail, using local postal service is an effective way of reaching the designated population (Level of evidence II, Grade of recommendation B).

 

Automated check protocols should be implemented to ensure correct identification of the screen population and complete and accurate recording of individual screening participation and test results.  Protocols should be implemented to ensure standardised and reliable classification of the test results (Level of evidence VI, Grade of recommendation A).

 

All laboratory performance outcomes like uptake, undelivered mail, time from collection to analysis, analytical performance, positivity rates, lots and spoilt kits and technical failure rate, technical performance variability and bias should be each subject to rigorous monitoring (Level of evidence VI, Grade of recommendation A).

 

The proportion of unacceptable tests received for measurement is influenced by the ease of use of the test kit and the quality of the instructions for use. This proportion should not exceed 3% of all kits received; less than 1% is desirable (Level of evidence III, Grade of recommendation A).

Important
Partially
Huic M et al. Result Card CUR27 In: Huic M et al. Health Problem and Current Use of the Technology In: Jefferson T, Cerbo M, Vicari N [eds.]. Fecal Immunochemical Test (FIT ) versus guaiac-based fecal occult blood test (FOBT) for colorectal cancer screening [Core HTA], Agenas - Agenzia nazionale per i servizi sanitari regionali; 2014. [cited 16 June 2021]. Available from: http://corehta.info/ViewCover.aspx?id=206

References