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 2 October 2022]. 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

<< SafetyCosts and economic evaluation >>

Clinical Effectiveness

Authors: Jesús González-Enríquez, Francesca Gillespie, Stefania Lopatriello, Iñaki Imaz

Summary

The main objective of this EEF domain is to facilitate summarized information on the effectiveness of the use of Fecal Immunochemical Test (FIT) for detection of occult blood in the stool associated with colorectal lesions (adenomas and CRC), under conditions of population based colorectal cancer screening, comparing with CRC screening with Guaiac –based fecal occult blood test (gFOBT).

We have not identified any study that compares FIT vs gFOBT in terms of mortality. The identified studies that provided mortality information compared screening using FIT vs no screening and reported only colorectal cancer specific mortality. A randomised controlled trial and three observational studies examined the effect of the use of FIT for colorectal cancer screening versus no screening on colorectal cancer mortality, showing a reduction on CRC mortality. The randomised controlled trial obtained no significant differences for colorectal and colon cancer mortality, but significant for rectal cancer mortality, when compared those FIT based screened vs. those no screened In addition, three Japanese observational studies with high risk of bias found a significant reduction in CRC mortality. Therefore no direct evidence comparing FIT vs gFOBT in the context of a population based colorectal cancer screening program is available.

A high-quality level systematic review studying differences in detection rates between FIT and GFOBT has been identified {10}. This systematic review selected five randomized controlled trials comparing detection rate of advanced neoplasm of FIT vs GFOBT for screening of CRC. The five trials were combined in a meta-analysis using random effects. Colonoscopy was the reference standard. The Pooled detection rates intended to screen cancers and significant adenomas were achieved in 2.23% of individuals with FIT and 1.24% of individuals with GFOBT. The pooled Odds Ratio of detection with FIT vs. with GFOBT was 1.50 (IC 95%: 0.94-2.39). Hence, the FIT have a 50%, but not significant, higher detection rate in comparison with gFOBT for advanced adenomas and cancer.

We identified 5 systematic reviews {10,15,16,17,18} and 3 additional diagnostic cohort trials{19,20,21} directly comparing FIT vs gFOBT. Overall 6 out of the 8 studies in the table conclude that FIT is more accurate and preferable to gFOBT for CRC screening.

The most recent and high quality review {15} analyses the performance characteristics of FIT compared with gFOBT, including two randomized control trials {11,12} and two observational studies {13,14}. In summary, the sensitivity of FIT for detecting CRC and AA compared with a standard gFOBT is superior. In the two randomized control trials, specificity was decreased for CRC and Advanced Adenoma when using FIT compared with gFOBT. On the other hand, these two studies reported higher advanced neoplasia detection rates for FIT compared with gFOBT. The PPV for detecting CRC and Advanced Adenoma using FIT is not different from the standard gFOBT. In general, the positivity rates for FIT using the manufacturer’s standard cut-off level in hemoglobin concentration are higher than for gFOBT.

Overall, FIT performance is superior to the standard gFOBT for the detection of CRC and advanced adenomas in a population based screening setting. 

Introduction

The Effectiveness domain in the Core HTA considers all relevant questions related to the efficacy and effectiveness of the technology, focusing in the assessment of the health benefits. We primarily consider patient relevant outcomes (mortality, morbidity, quality of life) and performance characteristics of the intervention (accuracy). Also have considered for assessment other related effects of the intervention (change in management).

We selected the relevant Assessment elements and they were translated into research questions. The assessment elements questions for EFF Domain were selected and adapted using as a model the Core Model for Screening Technologies.

The main objective of this EEF domain is to facilitate summarized information on the effectiveness of the use of Fecal Immunochemical Test (FIT) for detection of occult blood in the stool associated with colorectal lesions (adenomas and colorectal cancer-CRC), under conditions of population based colorectal cancer screening, comparing with CRC screening with Guaiac –based fecal occult blood test (gFOBT).

 

Relevant issues and research questions selected

 

Mortality

D0001. What is the effect of FIT versus gFOBT for CRC screening on overall mortality?

D0002. What is the effect of FIT versus gFOBT for CRC screening on the mortality caused by CRC?

D0003. What is the effect of FIT versus gFOBT for CRC screening due to other causes than CRC?

Morbidity

D0005. How does the use of FIT versus gFOBT for CRC screening modify the symptoms and findings of adenomas and CRC?

D0006. How does FIT versus gFOBT for CRC screening modify the progression of adenomas and CRC?

D0026. How does the use of FIT versus gFOBT for CRC screening technology modify the effectiveness of subsequent interventions?

Change in management

D0020. Does use of FIT versus gFOBT for CRC screening lead to improved detection of adenomas and CRC?

D0022. Does FIT for CRC screening detect other potential health conditions that can impact the subsequent management decisions?

D0023.How does FIT versus gFOBT for CRC screening modifies the need for other technologies and use of resources?

Test accuracy

D1001. What is the accuracy of FIT for CRC screening against reference standard?

D1002. How does FIT compare to gFOBT for CRC screening in terms of accuracy measures?

D1003. What is the reference standard and how likely does it classify adenoma and CRC correctly?

D1005. What is the optimal threshold value of FIT for CRC screening?

D1006. Does FIT for CRC screening reliably rule in or rule out adenomas and CRC?

D1007. How does FIT accuracy vary in different settings?

D1008. What is known about the intra- and inter-observer variation in FIT interpretation?

Methodology

Frame

The collection scope is used in this domain.

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

Assessment elements

TopicIssue RelevantResearch questions or rationale for irrelevance
D0001MortalityWhat is the effect of the intervention on overall mortality?yesWhat is the effect of FIT versus gFOBT for CRC screening on overall mortality?
D0002MortalityWhat is the effect of the intervention on the mortality caused by the target disease?yesWhat is the effect of FIT versus gFOBT for CRC screening on the mortality caused by CRC?
D0003MortalityWhat is the effect of the intervention on the mortality due to other causes than the target disease?yesWhat is the effect of FIT versus gFOBT for CRC screening on the mortality due to other causes than CRC?
D0004MortalityWhat is the mortality related to the diagnostic test?noThere is no mortality directly associated to FIT or gFOBT
D0005MorbidityHow does the use of the technology modify the symptoms and findings of the target condition?yesHow does the use of FIT for CRC screening modify the symptoms and findings of adenomas and CRC?
D0006MorbidityHow does the technology modify the progression of the target condition?yesHow does FIT for CRC screening modify the progression of adenomas and CRC?
D0026MorbidityHow does the technology modify the effectiveness of subsequent interventions?yesHow does the use of FIT versus gFOBT for CRC screening technology modify the effectiveness of subsequent interventions?
D0008MorbidityWhat is the morbidity directly related to the technology?noThere is no morbidity directly related to FIT or gFOBT.
D0020Change-in managementDoes use of the test lead to improved detection of the condition?yesDoes use of FIT versus FOBT for CRC screening lead to improved detection of adenomas and CRC?
D0022Change-in managementDoes the test detect other potential health conditions that can impact the subsequent management decisions?yesDoes FIT for CRC screening detect other potential health conditions that can impact the subsequent management decisions?
D0023Change-in managementHow does the technology modify the need for other technologies and use of resources?yesHow does FIT versus FOBT for CRC screening modify the need for other technologies and use of resources?
D0021Change-in managementHow does the use of the test change physicians' management decisions?noA positive test must be folowed of new invasive tests for diagnosis (colonoscopy). It is not expected that the use of FIT vs gFOBT change the physician’s management decisions. The strategy of performing new invasive diagnostic tests (colonoscopy) following a positive result that is accepted for gFOBT should be applied for FIT.
D0024Change-in managementIs there an effective treatment for the condition the test is detecting?noThere is no a need of key information regarding this question for the specific framing of this CORE HTA. There are clear evidences regarding treatment effectiveness for CRC and adenomas, and this ussue would not affect in a relevant way our specific scope.
D1001Test accuracyWhat is the accuracy of the test against reference standard?yesWhat is the accuracy of FIT for CRC screening against reference standard?
D1002Test accuracyHow does the test compare to other optional tests in terms of accuracy measures?yesHow does FIT compare to gFOBT for CRC screening in terms of accuracy measures?
D1003Test accuracyWhat is the reference standard and how likely does it classify the target condition correctly?yesWhat is the reference standard and how likely does it classify adenoma and CRC correctly?
D1005Test accuracyWhat is the optimal threshold value in this context?yesWhat is the optimal threshold value of FIT for CRC screening?
D1006Test accuracyDoes the test reliably rule in or rule out the target condition?yesDoes FIT for CRC screening reliably rule in or rule out adenomas and CRC?
D1007Test accuracyHow does test accuracy vary in different settings?yesHow does FIT accuracy vary in different settings?
D1008Test accuracyWhat is known about the intra- and inter-observer variation in test interpretation?yesWhat is known about the intra- and inter-observer variation in FIT interpretation?
D1004Test accuracyWhat are the requirements for accuracy in the context the technology will be used?noAlready included within the question G0012 of the ORG domain which is related to quality standards.
D1019Test accuracyIs there evidence that the replacing test is more specific or safer than the old one?noRegarding specificity, it is already included in the effectiveness domain question D1002. Regarding safety, it is already included within SAF domain.
D0027Test accuracyWhat are the negative consequences of further testing and delayed treatment in patients with false negative test result?noConsidered as a relevant question more specifically related to SAF domain (C006)
D0028Test accuracyWhat are the negative consequences of further testing and treatments in patients with false positive test result?noConsidered as a relevant question more specifically related to SAF domain (C006)
D0011FunctionWhat is the effect of the intervention on global function?noAlready included as a relevant outcome within SOC domain
D0014FunctionWhat is the effect of the technology on return to work?noAlready included as a relevant outcome within SOC domain
D0015FunctionWhat is the effect of the technology on return to previous living conditions?noAlready included as a relevant outcome within SOC domain
D0016FunctionHow does use of the technology affect activities of daily living?noAlready included as a relevant outcome within SOC domain
D0012Quality of lifeWhat is the effect of the technology on generic health-related quality of life?noAlready included as a relevant outcome within SOC domain
D0013Quality of lifeWhat is the effect of the technology on disease specific quality of life?noAlready included as a relevant outcome within SOC domain
D0030Quality of lifeDoes the knowledge of the test result affect the patient's non-health-related quality of life?noAlready included as a relevant outcome within SOC domain
D0017Patient satisfactionWas the use of the technology worthwhile?noAlready included as a relevant outcome within SOC domain (Patient satisfaction, global value)
D0018Patient satisfactionIs the patient willing to use the technology?noAlready included as a relevant outcome within SOC and ORG domains (Patient satisfaction, acceptance)
D0029Benefit-harm balanceWhat are the overall benefits and harms of the technology in health outcomes?noThis is a question to be answered with all the information available from all domains. It requires a comprehensive assessment of the overall value of the intervention.

Methodology description

Domain frame/PICO

The project scope is applied in this domain:

Technology

FIT for colorectal cancer screening vs. gFOBT colorectal cancer screening in organized screening program

Description

Procedure of gFOBT: the standard fecal occult blood (FOBT) test can detect small amounts of blood in the stool by submitting a portion of three consecutive bowel movements for testing. The test cannot identify polyps and some diet restrictions need to be considered, as the test is not specific for human blood alone. gFOBT is used for more than 30 years in routine, is widely available and inexpensive. If the test is positive, a colonoscopy will be needed to find the reason for the bleeding.

Procedure of FIT: FIT (Fecal Immunochemical Test) for colorectal cancer screening, also called as iFOBT (immunochemical FOBT) screening, is more accurate than FOBT as it only identifies human blood. It needs only one stool sample, thus is more simple to complete. If the test is positive, a colonoscopy will be needed to find the reason for the bleeding.

Colorectal cancer screening with faecal inmunochemical test (FIT) for detection of occult blood in the stool associated with colorectal lesions (adenomas and CRC) 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. Stool samples could be periodically taken and analysed for the presence of occult blood, as an early sign of colorectal lesions (adenoma or CRC).

To ensure effectiveness, the screening interval in a national screening programme should not exceed two years for gFOBT and three years for FIT.

Purpose of use: detect cancer, polyps, nonpolypoid lesions, which are flat or slightly depressed areas of abnormal cell growth and can also develop into colorectal cancer.

Intended use of the technology

Screening

CRC screening with faecal immunochemical test (FIT)

Target condition

Adenomas, as non-malignant precursor lesions of Colorectal Cancer.

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. Adenoma may invade the submucosa and become malignant. Initially, this malignant cancer is not diagnosed and does not cause 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 general 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: 50-74 years. Target population group: Asymptomatic people.

Target population description

Adults (both men and women), 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. EU Council Recommendations suggests only the faecal occult blood test (gFOBT or FIT) for men and women aged 50–74 for CRC screening.

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.

 

Comparison

CRC 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 haemoglobin the test uses guaiac gum and its efficacy as a colorectal cancer screening test has been analysed 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 have established nationwide non-population-based programmes. Some states are planning or piloting a nationwide population-based programme. These have adopted only gFOBT, some only FIT, some a mix between FOBT and endoscopy, or only colonoscopy.

 

 

EFF domain Outcomes

  • 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

 

Information sources

Answers to the selected research questions of the EFF domain are mainly based in systematic literature search in the following sources {EFF Appendix 1}:

  1. A basic literature search for the technology (FIT_technology) (MEDLINE, EMBASE, Cochrane Library: CDSR, DARE, HTA database, CENTRAL).

 

  1. A specific complementary EFF domain search strategy, using the following sources (MEDLINE, EMBASE, Cochrane Library, SCOPUS).

 

This specific literature search strategy was produced to answer the EEF domain research questions.

We merged the two databases, general and specific, excluding duplicates, and worked with it to answer all research questions. The final selection after deletion of duplicates included a total of 620 studies.

Additional information sources were used to answer specific research questions when the data retrieved through a systematic review did not provide adequate information (hand searching of journals and references in selected studies, trial registers and grey literature).

Retrieved articles were included or excluded according to the PICO adopted for the project scope and related directly to the outcomes selected in the EFF domain. Abstracts resulting from the literature searches were independently assessed by at least two investigators. A final database with 176 selected studies from the merger of the two search strategies used for our EFF domain, after excluding references not directly related to the EFF domain frame and research questions.

Priority was done to the identification of systematic reviews and clinical trials.

For research questions related with issues of mortality, morbidity and change in management the project approach were mainly based in prospective controlled clinical trials, meta-analysis or systematic reviews of clinical trials. Other study types and designs have been considered (observational studies, prognostic studies, registries, statistics) if adequate for some research questions.

For research questions related with test accuracy we searched for diagnostic accuracy reviews, and clinically relevant diagnostic studies comparing FIT and FOBT were selected. Inclusion criteria where: studies that report data on accuracy measures (sensitivity, specificity, positive and negative predictive values, likelihood ratios, SROC and other measures, detection rates), publication date after year 2000, FIT compared with gFOBT or alone, on asymptomatic average risk patients, age 50+ years, data on specific issues relative to selected research questions.

Relevant articles considered to meet inclusion criteria for one selected research question were fully assessed (described, data extraction table, quality assessment) by the investigators. Extraction tables where tailored to research questions issues.

 

Quality assessment tools or criteria

The quality of the selected studies was analyzed by using the Cochrane risk of bias checklist for randomized controlled trials and for non-randomized studies {1}. To evaluate the quality of systematic reviews we used the 11 items of the Revised Assessment of Multiple Systematic Reviews (R-AMSTAR){2}. Test accuracy studies included in systematic reviews and qualified with QUADAS have also been reported.

Analysis and synthesis

Priority is given to reporting summary effects measures from systematic reviews and randomized clinical trials. When quantitative pooling of results is available or possible from meta-analysis it is presented. When the heterogeneity of studies and nature of data available prevent from pooling on a summary estimate, specific data are described and reported.

Summary informative evidence tables of selected studies are presented once reviewed for methodological quality. Data was synthesized in tables were possible and research questions were answered starting from the best quality of available evidence.

Assessing the accuracy of the screening test we report summary measures from the selected systematic reviews and meta-analysis (pooled sensitivity, pooled specificity, predictive values, likelihood ratios or area under receiver operating characteristic curve), and specific results from other prospective studies once reviewed for methodological quality.

Additional descriptive analysis is presented, interpreted and commented if necessary for the EFF assessment elements. 

Result cards

Mortality

Result card for EFF2: "What is the effect of FIT versus gFOBT for CRC screening on overall mortality?"

View full card
EFF2: What is the effect of FIT versus gFOBT for CRC screening on overall mortality?
Method
Result

Importance: Important

Transferability: Completely

Result card for EFF4: "What is the effect of FIT versus gFOBT for CRC screening on the mortality caused by CRC?"

View full card
EFF4: What is the effect of FIT versus gFOBT for CRC screening on the mortality caused by CRC?
Method
Result
Comment

Importance: Important

Transferability: Completely

Result card for EFF6: "What is the effect of FIT versus gFOBT for CRC screening on the mortality due to other causes than CRC?"

View full card
EFF6: What is the effect of FIT versus gFOBT for CRC screening on the mortality due to other causes than CRC?
Method
Result

Importance: Important

Transferability: Completely

Morbidity

Result card for EFF8: "How does the use of FIT for CRC screening modify the symptoms and findings of adenomas and CRC?"

View full card
EFF8: How does the use of FIT for CRC screening modify the symptoms and findings of adenomas and CRC?
Method
Result

Importance: Optional

Transferability: Partially

Result card for EFF10: "How does FIT for CRC screening modify the progression of adenomas and CRC?"

View full card
EFF10: How does FIT for CRC screening modify the progression of adenomas and CRC?
Method
Result
Comment

Importance: Optional

Transferability: Partially

Result card for EFF18: "How does the use of FIT versus gFOBT for CRC screening technology modify the effectiveness of subsequent interventions?"

View full card
EFF18: How does the use of FIT versus gFOBT for CRC screening technology modify the effectiveness of subsequent interventions?
Method
Result

Importance: Optional

Transferability: Not

Change-in management

Result card for EFF12: "Does use of FIT versus FOBT for CRC screening lead to improved detection of adenomas and CRC?"

View full card
EFF12: Does use of FIT versus FOBT for CRC screening lead to improved detection of adenomas and CRC?
Method
Result

Importance: Critical

Transferability: Completely

Result card for EFF14: "Does FIT for CRC screening detect other potential health conditions that can impact the subsequent management decisions?"

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EFF14: Does FIT for CRC screening detect other potential health conditions that can impact the subsequent management decisions?
Method
Result

Importance: Optional

Transferability: Not

Result card for EFF16: "How does FIT versus FOBT for CRC screening modify the need for other technologies and use of resources?"

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EFF16: How does FIT versus FOBT for CRC screening modify the need for other technologies and use of resources?
Method
Result

Importance: Important

Transferability: Partially

Test accuracy

Result card for EFF20: "What is the accuracy of FIT for CRC screening against reference standard?"

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EFF20: What is the accuracy of FIT for CRC screening against reference standard?
Method
Result

Importance: Important

Transferability: Partially

Result card for EFF22: "How does FIT compare to gFOBT for CRC screening in terms of accuracy measures?"

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EFF22: How does FIT compare to gFOBT for CRC screening in terms of accuracy measures?
Method
Result
Comment

Importance: Critical

Transferability: Partially

Result card for EFF24: "What is the reference standard and how likely does it classify adenoma and CRC correctly?"

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EFF24: What is the reference standard and how likely does it classify adenoma and CRC correctly?
Method
Result
Comment

Importance: Critical

Transferability: Completely

Result card for EFF26: "What is the optimal threshold value of FIT for CRC screening?"

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EFF26: What is the optimal threshold value of FIT for CRC screening?
Method
Result

Importance: Important

Transferability: Completely

Result card for EFF31: "Does FIT for CRC screening reliably rule in or rule out adenomas and CRC?"

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EFF31: Does FIT for CRC screening reliably rule in or rule out adenomas and CRC?
Method
Result
Comment

Importance: Important

Transferability: Partially

Result card for EFF28: "How does FIT accuracy vary in different settings?"

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EFF28: How does FIT accuracy vary in different settings?
Method
Result

Importance: Important

Transferability: Completely

Result card for EFF30: "What is known about the intra- and inter-observer variation in FIT interpretation?"

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EFF30: What is known about the intra- and inter-observer variation in FIT interpretation?
Method
Result

Importance: Important

Transferability: Partially

Discussion

With the evidence available for the effectiveness of FIT for CRC screening, it could be argued that it is appropriate to implement FIT instead of gFOBT without direct evidence from high quality RCT on CRC mortality, given that FIT is more sensitive for advanced adenomas and cancer, at least presents equal high specificity and higher detection rates for advanced adenomas and cancer.

Referring to test accuracy assessment, well-designed randomized controlled studies directly comparing FIT and gFOBT are needed. The use the Standards for Reporting of Diagnostic Accuracy guidelines is recommended for reporting future diagnostic accuracy studies. Studies should ideally recruit a representative screening population, use colonoscopy to confirm diagnosis regardless of the FOBT result, measure the detection of CRC and adenomas and report the results separately and combined, and allow outcome assessors access to clinical information that would be available in practice, but blind them to other information. Specimen instability issue must be considered in each setting. The type of FIT and associated costs, the appropriate haemoglobin cut-off to use, and the capacity for follow-up by colonoscopy or flexible sigmoidoscopy may contribute to the evidence of FIT as an appropriate CRC screening tool.

Despite the differences in the design and heterogeneity of selected studies the analysis shows that FIF is more accurate and performs better than gFOBT in detecting advanced adenoma and CRC.

FIT has additional important advantages compared to gFOBT: higher acceptance and screening participation rates, needs a smaller number of stool samples, has no need for dietary restriction, potential for automation in the laboratory and to select the cut-off level of hemoglobin concentration that defines a positive test. However, potential disadvantages are greater specimen instability and possibly higher positivity rates.

Global balance between total health benefits and harms and costs is out of the scope of the EFF domain. The global impact of false positive screening results and false negative screening results, the potential effects of over-diagnosis and over-treatment have not been considered. This global balance could be obtained in a comprehensive view of all pieces of information produced by all domains of the CoreHTA and could need the design of specific analytical modeling.

References

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21.       Wong CKW, Fedorak RN, Prosser CI, Stewart ME, Van Zanten SV, Sadowski DC. The sensitivity and specificity of guaiac and immunochemical fecal occult blood tests for the detection of advanced colonic adenomas and cancer. Int J Colorectal Dis 2012; 27 (12):1657-64.

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24.       Digby J, Fraser CG, Carey FA, McDonald PJ, Strachan JA, Diament RH, et al. Faecal haemoglobin concentration is related to severity of colorectal neoplasia. J Clin Pathol 2013; 66(5): 415-419.

25.       Haug U, Hundt S, Brenner H. Quantitative immunochemical fecal occult blood testing for colorectal adenoma detection: evaluation in the target population of screening and comparison with qualitative tests. Am J Gastroenterol 2010; 105(3):682-90.

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27.       Chiu HM, Lee YC, Tu CH, Chen CC, Tseng PH, Liang JT, et al. Association Between Early-Stage Colon Neoplasms and False-Negative Results from the Fecal Immunochemical Test. Clin Gastroenterol Hepatol 2013; 11(7):832-8.

28.       Denters MJ, Deutekom M, Bossuyt PM, Stroobants AK, Fockens P, Dekker E. Lower risk of advanced neoplasia among patients with a previous negative result from a fecal test for colorectal cancer. Gastroenterology 2012; 142(3):497-504.

29.       Cha JM, Lee JI, Joo KR, Shin HP, Park JJ, Jeun JW, et al. Performance of the fecal immunochemical test is not decreased by high ambient temperature in the rapid return system. Dig Dis Sci 2012; 57(8):2178-83.

30.       Van Rossum LGM, van Rijn AF, Van Oijen MGH, Fockens P, Laheij RJF, Verbeek ALM, et al. False negative fecal occult blood tests due to delayed sample return in colorectal cancer screening. Int J Cancer 2009; 125(4):746-50.

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32.       Haug U, Kuntz KM, Knudsen AB, Hundt S, Brenner H. Sensitivity of immunochemical faecal occult blood testing for detecting left- vs  right-sided colorectal neoplasia. Br J Cancer 2011; 104(11):1779-85.

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Appendices

APPENDIX 1. Search strategies and flow chart.

 

pdf10936.EFF Appendix 1

 

10936.EFF Flow Chart Appendix 1

 

APPENDIX 2. Revised Assessment of Multiple Systematic Reviews (R-AMSTAR)

 

pdf10936.EFF Appendix 2

 

 

APPENDIX 3. Evidence tables of studies, description of studies, quality assessment.

 

pdf10936.EFF Appendix 3

 

 

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