Disclaimer
This information collection is a core HTA, i.e. an extensive analysis of one or more health technologies using all nine domains of the HTA Core Model. The core HTA is intended to be used as an information base for local (e.g. national or regional) HTAs.

Fecal Immunochemical Test (FIT ) versus guaiac-based fecal occult blood test (FOBT) for colorectal cancer screening

Fecal Immunochemical Test (FIT) for colorectal cancer screening compared to CRC screening with Guaiac –based fecal occult blood test (gFOBT) in the screening of Adenomas, as non-malignant precursor lesions of ColoRectal Cancer (CRC). in healthy and/or asymptomatic adults and elderly Any adult over 50 years old, both men and women, with average risk of CRC.

(See detailed scope below)

HTA Core Model Application for Screening Technologies 1.0
Core HTA
Published
Tom Jefferson (Agenas - Italy), Marina Cerbo (Agenas - Italy), Nicola Vicari (Agenas - Italy)
Mirjana Huic (AAZ), Agnes Männik (UTA - Estonia), Jesus Gonzalez (ISCIII - Spain), Ingrid Rosian (GÖG - Austria), Gottfried Endel (HVB - Austria), Valentina Rupel (IER - Slovenia), Alessandra Lo Scalzo (Agenas - Italy), Ingrid Wilbacher (HVB - Austria)
Agenas - Agenzia nazionale per i servizi sanitari regionali
AAZ (Croatia), AETSA (Spain), A. Gemelli (Italy), Avalia-t (Spain), CEIS (Italy), CEM (Luxembourg), GÖG (Austria), HAS (France), HVB (Austria), IER (Slovenia), ISCIII (Spain), Laziosanità (Italy), NCPHA (Bulgaria), NIPH (Slovenia), NSPH (Greece), NSPH MD (Romania), Osteba (Spain), Regione Veneto (Italy), SBU (Sweden), SNHTA (Switzerland), THL (Finland), UTA (Estonia).
5.4.2013 13.07.00
31.7.2014 9.21.00
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 24 September 2021]. Available from: http://corehta.info/ViewCover.aspx?id=206

Fecal Immunochemical Test (FIT ) versus guaiac-based fecal occult blood test (FOBT) for colorectal cancer screening

Health Problem and Current Use of the Technology >>

Collection summary

Background

Colorectal cancers (CRCs) arise mostly from previously begin adenomas and have effective treatment if diagnosed early in their evolution. It is for these reasons that they are amenable to screening. Screening can be done via three approaches: imaging, endoscopy and stool-based identification. Two of the techniques used in stool-based based identification are the object of this core HTA, collectively knows as Fecal occult blood tests (FOBT): (guaiac, so-called gFOBT and immunochemical testing, so called FIT, also known as Immunochemical Faecal Occult Blood Test (iFOBTs).

CRC is the 3rd most common cancer worldwide, and the second most frequent in developed countries with an estimated 1,234,000 cases worldwide in 2008. There are large variations between regions. Incidence rates are higher in Australia/New Zealand (39.0 per 100,000), Western Europe (33.1 per 100,000) and Southern Europe (31.1 per 100,000) and lower in Western Africa (4.9 per 100,000), South-Central Asia (4.5 per 100,000) and Middle Africa (3.7 per 100,000) {6}. In 2008 an estimated 8% of total cancer-related deaths was caused by CRC. Incidence and mortality from CRC are higher in men that in women.

Currently screening practices vary considerably across Europe (see assessment element CUR 14),

Several different types and brands of FOB tests are available, with different performance characteristics.

gFOBT is the longest established of the two basic techniques, guaiac and immune based. There are several potential advantages and disavantages of gFOBT use. The advantages are mainly due to the cheapness, acceptability and long standing nature of the procedure. The disadvantages of gFOBT are its lack of automation, laboriousness and lack of specificity for human Haemoglobin, requiring a period of dietary preparation before testing.

FITs are a newer class of Faecal Occult Blood tests compared to gFOBTs and reputedly have improved test characteristics compared to gFOBT. iFOBTs have been used for population CRC screening in Japan since 1992. In the US, the first iFOBT (OC-Sensor) was approved by the FDA (Food and Drug Administration) since 2001. 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, so CRC incidence is reduced) and earlier diagnosis of CRC (at early, curable stage).

A wide range of qualitative and quantitative FITs is presently available, with varying levels of sensitivity and specificity. They all use antibodies raised against human haemoglobin (Hb) to detect human blood present in faeces.

The aim of this core HTA was to compare the diagnostic and clinical performance of FITs with gFOBT for detection of CRC.

Results

Safety of the technology (SAF)

As FIT and gFOBT are non-invasive tests no direct harms are likely. Indirect harms can be caused by a wrong or delayed diagnosis or by harms related to subsequent colonoscopy (such as local trauma). The psychological impact of screening (including consequences of any false-positive and false-negative test results) and patient discomfort related to the procedures are the potential harms to be assessed as the overall number of adverse events depends on sensitivity and specificity of the  screening tests. False-positive results may cause anxiety and distress, overdiagnosis and overtreatment. The false-negative test results may delay the detection of illness and the start of treatment. Organisational factors affecting harms include false-positive test results from gFOBT with a lax dietary preparation and FIT samples should be kept in refrigerated. Personnel experience and dexterity is also a factor.

Harms colonoscopy are estimated at 5% of procedures whereas 68% of people who received a false positive experienced stress and 46% of those who received an invitation to screening were worried and 15% very worried.

Effectiveness of the technology (EFF)

Our searches were unable to identify a direct comparison of the two techniques with meaningful cancer-specific outcomes such as CRC mortality within screening programmes.

However on the basis of several single studies and systematic review FIT have higher detection rates than gFOBT for adenomas, at the expense of a drop in specificity. We concluded that Overall, FIT performance is superior to the standard gFOBT for the detection of CRC and advanced adenomas in a population based screening setting.  

Costs, economic evaluation of the technology (ECO)

FIT lacks evidence of its effect on mortality when used in a screening programme, but both tests are more cost-effective than no screening. Cost-effectiveness models tend to suggest FIT has more favourable ICERs than gFOBT but its higher sensitivity means that there is a need for  higher capacity in undertaking diagnostic colonoscopies with an increased up-front resource use and cost associated with the increased number of colonoscopies.

Ethical aspects of the technology (ETH)

The tests are very similar, making ethical problems around choice less important. Overall there appears to be dominance of FIT over gFOBT and both dominate no screening. However in the absence of a direct clinical comparison the evidence base is unstable as shown by the different ICERs in ECO5. A full assessment should be carried out in context to define the costs and opportunity costs as well as the benefits of choice between the two types of test.

Organisational aspects of the technology (ORG)

CRC screening is carried out with significant variation across the EU in terms of organization and type of screening test. There partial or complete screening programmes in 19 of the 27 EU countries. Organised screening is considered better than opportunistic screening. In 2007, gFOBT was used as the only screening method in twelve countries: Bulgaria, Czech Republic, Finland, France, Hungary, Latvia, Portugal, Romania, Slovenia, Spain, Sweden, and United Kingdom. In six countries, two types of tests were used: FIT and FS in Italy, and gFOBT and colonoscopy in Austria, Cyprus, Germany, Greece, and Slovak Republic. FIT is being used in 6 European countries: Russia, Lithuania, Italy, Scotland, Spain and Slovenia.

National screening programmes use risk-based criteria to define who should receive screening invitations. The target population for a CRC screening programme includes all people eligible to attend screening on the basis of age and geographical area of residence. Altough there are variations, people who are between 50 and 75 are invited to be screened.

Screening programmes with FIT carry an investment penalty including equipment for screening, premises, office material for posting invitations and re-invitations, IT equipment and other office devices such as printers, and human resources including administrative and health personnel, investment in education of personnel and their training. Every country needs to assess their costs independently using cost-effectiveness analyses or other economic evaluation method. Investments that are needed for implementation of FIT are therefore country specific.

Social aspects of the technology (SOC)

We found good evidence that FIT has better compliance than gFOBT in screening. The reasons for this finding are unclear and under researched but may include socio-cultural factors and the need for dietary prepration for gFOBT.

Legal aspects of the technology (LEG)

Legals implications of detecting colorectal cancer include the necessity to provide Sufficient information and informed consent, the right of access to (best) health care once a presumptive diagnosis is made, freedom in taking part, protection of personal data, equal right of access according to need and in the case of regional inequalities, access abroad and the right to charge contributions to the cost of the programme.

Closing Remarks

The Core Model is not intended to provide a cookbook solution to all problems but to suggest a way in which information can be assembled and structured, and to facilitate its local adaptation. The information is assembled around the nine domains, each with several result cards in which questions and possible answers are reported.

The reasons for having a standardised but flexible content and layout are rooted in the way HTA is conducted in the EU and in the philosophy of the first EUnetHTA Joint Action (JA1) production experiment.

HTA is a complex multidisciplinary activity addressing a very complex reality – that of healthcare. Uniformly standardised evidence-based methods of conducting assessments for each domain do not exist (Corio M, Paone S, Ferroni E, Meier H, Jefferson TO, Cerbo M. Agenas – Systematic review of the methodological instruments used in Health Technology Assessment. Rome, July 2011.)). There are sometimes variations across and within Member States in how things are done and which aspects of the evaluation are privileged. This is especially so for the “softer” domains such as the ethical and social domains.

Collection methodology

Objective

To produce a Core Health Technology Assessment (HTA) comparing the performance of fecal occult blood tests (FOBT - guaiac, so-called gFOBT and immunochemical testing, so called FIT, also known as Immunochemical Faecal Occult Blood Test - iFOBT) for colorectal cancers (CRCs) based on the EUnetHTA Core Model.

Methods

The work was based on the HTA Core Model on screening technologies, which was developed during the EUnetHTA Joint Action 1 (JA1).

The first phase was the selection of the technology to be assessed using the Core Model; this phase was carried out through a three-step process that is described in our MSP.

Then there was the check of Partners’ availability to assume responsibility, as an institution, to take the lead in one of the nine evaluation domains. At the same time, the nine domain teams were built-up in accordance with partners’ preferences and some general guidelines (i.e.: “each WP4/B Associated partner AP should be involved in at least one domain, indicating its interest for at least one domain”)

Finally the specific work plan was shared, according with the general WP4 3-year work plan and objectives. This specific work plan included the phases scheduled in the “HTA Core Model Handbook” (Production of Core HTAs and structured HTA information).

An editorial team was set up for discussion and major decisions on basic principles and solutions related to the content of core HTA. The editorial team was chaired by Tom Jefferson (Agenas) and composed of all the primary investigators of the domains.

To allow collaboration between partners a draft protocol for Core Model use was agreed by the researchers involved. The research questions for each of the nine domains of the Core Model were formulated and the corresponding relevant assessment elements (AEs) were selected.

The research strategy was carried out by Agenas with input from the other partners.

Evidence from published and manufacturer sources was identified, retrieved, assessed, and included according to pre-specified criteria, and summarised to answer each AE. Work was carried with domain assessments being made by a single agency and by different investigators from different agencies, in a mixed organisational model.

Introduction to collection

This brief document provides background information on the preparation and development of the Core HTA on CRC detection. The core HTA document was produced during the course of the second EUnetHTA Joint Action (JA2) 2012-2015.

The idea behind EUnetHTA’s Core Model is to provide a framework for structuring relevant HTA information while at the same time facilitating local use and adaptation of the information or guiding its production.

The Model is based on nine dimensions or “domains” of evaluation:

  1. Health Problem and Current Use of the Technology (CUR)
  2. Description and technical characteristics of technology (TEC)
  3. Safety (SAF)
  4. Effectiveness (EFF)
  5. Costs and economic evaluation (ECO)
  6. Ethical analysis (ETH)
  7. Organisational aspects (ORG)
  8. Social aspects (SOC)
  9. Legal aspects  (LEG)

The Core HTA was sent to the Stakeholder Advisory Group (SAG) for feedback before the final Public Consultation and the comments received where included where applicable.

Scope

TechnologyFecal Immunochemical Test (FIT) for colorectal cancer screening
Description

FITs use an antibody (immunoglobulin) specific to human globin, the protein component of haemoglobin, to detect fecal occult blood. Immunochemical tests have improved test characteristics compared to conventional guaiac-based tests for fecal occult blood. FIT should not be subject to interference from dietary blood and it is more specific to bleeding from the distal gastrointestinal tract. They could be analytically and clinically more sensitive and specific, Their measurement can be automated and the user can adjust the concentration at which a positive result is reported. A wide range of qualitative and quantitative tests is presently available, with varying levels of sensitivity and specificity (like Hem-SP/MagStream H, Fujirebio Inc. Japan ; OC-Sensor, Eiken Chemical Co., Tokyo, Japan;    FOB Gold, Medinostics Products Supplier; Sentinel Diagnostics SpA, Milan, Italy).

Intended use of the technologyScreening

CRC screening with faecal inmunochemical test (FIT) for detection of occult blood in the stool associated with colorectal lesions (adenomas and CRC).

The use of the test is considered under conditions of population based colorectal cancer screening, in the context of organised cancer screening programmes as recommended by the EU. Early detection and treatment of colorectal lesions before they become symptomatic has the potential to improve control of the disease, reducing morbidity and mortality associated to CRC. Early treatment of invasive lesions can be generally less detrimental for quality of life. The endoscopic removal of pre-malignant lesions also reduces the incidence of CRC by stopping the progression to cancer. Colorectal cancers and adenomatous polyps bleed has providing fecal blood haemoglobin as the biomarker of choice for current screening programmes. Stool samples could be periodically taken and analyzed for the presence of occult blood, as an early sign of colorectal lesions (adenoma or CRC).

Target condition
Adenomas, as non-malignant precursor lesions of ColoRectal Cancer (CRC).
Target condition description

CRC is the third most common in incidence and the fourth most common cause of cancer death worldwide. CRC is particularly suitable for screening. The disease is believed to develop in a vast majority of cases from non-malignant precursor lesions called adenomas. Adenomas can occur anywhere in the colorectum after a series of mutations that cause neoplasia of the epithelium. At some time , the adenoma may invade the submucosa and become malignant. Initially, this malignant cancer is not diagnosed and does not give symptoms  (preclinical phase). It can progress from localised (stage I) to metastasised (stage IV) cancer, until it causes symptoms and is diagnosed. Only 5–6% of the population actually develop CRC. The average duration of the development of an adenoma to CRC is estimated to be  at least 10 years. This long latent phase provides a window of opportunity for early detection of the disease.

Target population

Target population sex: Any. Target population age: adults and elderly. Target population group: Healthy and/or asymptomatic people.

Target population description

Adults, average risk of CRC, aged 50 years or over.

The best age range for offering gFOBT or FIT 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 .The age range for a national screening programme should at least include people aged 60 to 64 years in which CRC incidence and mortality are high and life-expectancy is still considerable. Only the FOBT for men and women aged 50–74 years has been recommended todate by the EU (Council Recommendation and the European guidelines for quality assurance in CRC screening and diagnosis).

Members of families with hereditary syndromes, previous diagnosis of CRC or pre-malignant lesions should follow specific surveillance protocols and are not included in the target population

ComparisonCRC screening with Guaiac –based fecal occult blood test (gFOBT)
Description

CRC screening with Guaiac–based fecal occult blood test (gFOBT)

The guaiac-based FOBT is still a commonly used method for detecting blood in faeces. To detect hemoglobin the test uses guaiac gum and its efficacy as a colorectal cancer screening test has been analyzed in several randomised controlled trials. The test detects the haem component of haemoglobin, which is identical across human and animal species and is chemically robust and only partially degraded during its passage through the gastrointestinal tract. gFOBTs cannot distinguish between human blood and blood residues from the diet.

Many guaiac-based tests are currently on the market (like Coloscreen, Helena Laboratories,Texas,USA; Hema-screen Immunostics Inc.; Hemoccult, Beckman Coulter Inc.; Hemoccult SENSA, Beckman Coulter Inc.; MonoHaem, Chemicon Europe Ltd; Hema-Check, Siemens PLC; HemaWipe, Medtek Diagnostics LLC)

The use of the test is considered under conditions of population based colorectal cancer screening, in the context of organised cancer screening programmes as recommended by the EU. Population-based programmes have been rolled out nationwide in several European countries. Many member states  haveestablished nationwide non-population-based programmes. Some states are planning or piloting a nationwide population-based programme. These have  adopted only FOBT, some only FIT, some a mix between FOBT and endoscopy, or only colonoscopy.

Outcomes

CUR and TEC

  • Health problems (target condition)
  • Epidemiology
  • Burden of disease
  • Target population
  • Current management of the condition
  • Features of the technology
  • Life-Cycle
  • Regulatory status
  • Utilization
  • Investments and tools required to use the technology
  • Training and information needed to use the technology

SAF

  • Colonoscopy probability of perforation
  • Colonoscopy with polypectomy probability of perforation
  • Colonoscopy probability of death following perforation
  • Probability of bleeding following colonoscopy
  • Psychological harms from false-negatives and false-positives (and generally from participating in screening program)

EFF

  • Test (FIT and gFOBT) sensitivity for adenomas
  • Test (FIT and gFOBT) sensitivity for cancer
  • Test (FIT and gFOBT) specificity for adenomas
  • Test (FIT and gFOBT) specificity for cancer 
  • Adenoma incidence (detection rates)
  • Rectal cancer incidence (detection rates)
  • Colon cancer incidence (detection rates)
  • CRC incidence (detection rates)
  • Stage distribution of detected cancers
  • Rectal cancer specific mortality
  • CRC specific mortality
  • Overall mortality
  • Life years saved

ECO:

  • Model/template for  national pilots  to assess the costs and benefits of the two alternative  technologies FIT and gFOBT  and also no-programmed-screening
  • Systematic literature search of   available models and/or economic  evaluation for screening colorectal cancer with FIT and gFOBT and no screening programme
  • Resource Utilization: Publicly funded health care payer costs (screening tests, further examinations e.g. labor, colonoscopy  and treatments and administration and organisation costs of screening programme) for FIT and gFOBT (in cooperation with ORG)
  • Cost per Case detected (average, marginal, incremental) =  intermediate outcome – optional, not decided yet (relevant for deciding how often a test should be carried out and what are the incremental costs for a “new” detected case
  • Indirect Costs: not for the Core modell (should be decided later on)
  • Test accuracy: from SAF
  • Cost effectiveness analysis: HRQoL measures (both generic and context specific) (EFF and SAF for help, own Lit.research), ICER

 ORG:

  • Responsiveness of target population to invitation
  • Invitation-reminder system
  • Competence of human resources – health professionals
  • Investments needed (material,equipment)
  • Costs of using both tests (FIT, gFOBT)
  • Timeliness of results and future phases
  • Use of tools for process monitoring (completed check lists)
  • Model for Budget Impact Analysis from perspective of the payer

SOC

  • Compliance with the tests (FIT, gFOBT)
  • Anxiety and any psychological effects of using  one test or another
  • Information, counseling, communication (quality of) for the use of tests
  • Satisfaction  
  • Quality of life
  • Equity of access

LEG

  • Information as baseline for an informed consent
  • Harms or inequities that can be taken to court
Health Problem and Current Use of the Technology >>