FIT (Faecal Immunochemical test) is an alternative name for Immunochemical Faecal Occult Blood Test (iFOBT), a class of occult blood tests introduced in the US market in 2001, which represents one out of few different screening options for colorectal cancer (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 become malignant) and earlier diagnosis of CRC (at early, curable stage) {1-3,5,69}.

CRC is usually polypoid mass with ulceration, spreads by direct infiltration through bowel wall, and involves lymphatic and blood vessels with subsequent spread, commonly to the liver and lung. Rectosigmoid tumors may spread to lungs early because of systemic paravertebral venous drainage of this area. Histology is nearly always adenocarcinoma; 75% located distal to the splenic flexure. May be polypoid, sessile, fungating, or constricting {1-3}.

Degree of invasiveness at surgery (Dukes classification) is single best predictor of prognosis (Table 1). Other predictors of poor prognosis are preoperative serum CEA >5 mg/ml (>5 µg/l), poorly differentiated histology, bowel perforation, venous invasion, adherence to adjacent organs, aneuploidy, specific deletion in chromosome 5, 17, 18, and mutation of ras proto-oncogene. 15% have defects in DNA repair {1-3}.

 

Table 1. Staging and survival of colorectal cancers {1}

TNM classification			Modified Dukes classification	5-year survival (%)
Stage I (N0, M0)	Tumours invade submucosa Tumours invade muscularis propria	T1 T2	A	90
Stage II A (N0,M0) Stage II B	Tumours invade into subserosa Tumours invade directly into other organs	T3 T4	B	70 65
Stage II (M0)   IIIB   IIIC	T1,T2+1-3 regional lymph nodes involved T3, T4+1-3 regional lymph nodes involved Any T+4 or more regional lymph nodes	N1   N1   N2	C	60   35   25
Stage IV	Any T, any N+distant metastases	M1	D	7

 

ICD-10: the ICD-10 (2010 version) codes for CRC are C18-21. Specifically,

 

C18 Malignant neoplasm of colon;

C19 Malignant neoplasm of rectosigmoid junction;

C20 Malignant neoplasm of rectum;

C21 Malignant neoplasm of anus and anal canal.

 

The above codes are those adopted by the World Health Organization International Agency for Research in Cancer (IARC) (http://globocan.iarc.fr/), which includes code C21 anal cancer. Codes included may differ, depending on guidelines that apply.

 

EU Guideline 2010 {2}

“Due to the improved diagnostic reproducibility of the revised Vienna classification, use of this classification in a format modified for lesions detected in screening is recommended to ensure consistent international communication and comparison of histopathology of biopsies and resection specimens (IV – B). Only two grades of colorectal neoplasia (low grade and high grade) should be used, to minimise intraobserver and interobserver error (V - B). The terms

intra-mucosal adenocarcinoma or in-situ carcinoma should not be used (VI - B).

 

The WHO definition of colorectal adenocarcinoma should be used: “an invasion of neoplastic cells through the muscularis mucosae into the submucosa” (VI - A).

 

Adenocarcinomas should be reported according to the TNM classification. The version of TNM

to be used should be decided nationally and should be stated e.g. pT1 pN0 pMX (Version 5) or

pT4 pN2 pM1 (Version 7). These can be further abbreviated to pT1N0MX (v5) or to pT4N2M1

(v7) (VI - B).

 

The WHO classification of adenomas into tubular, tubulo-villous and villous should be used

(VI - A).

 

Due to the increased risk of colorectal cancer associated with flat and/or depressed lesions they should be reported as non-polypoid lesions (III), and further classified by the Paris classification

(V - B).

 

Sub-staging of T1 cancers should be performed to determine the risk of residual disease. Consideration should be given to the appropriate method, which may vary depending on the morphology of the lesion (Kikuchi/Haggitt or measurement). For non-polypoid lesions the Kikuchi stage and for pedunculated lesions Haggitt are currently recommended (VI - C). High-risk features for residual disease such as lack of margin clearance (≤1 mm), poor differentiation and lymphatic and vascular invasion should be reported (V - B). The multidisciplinary team should be consulted on whether or not surgical resection of pT1 adenocarcinoma is recommended; if surgical resection is recommended, consideration should be given to obtaining an opinion from a second histopathologist as variation exists in evaluating high-risk features (VI - A).”

 

Adaptation of the revised Vienna classification¹ for colorectal cancer screening {2}   1. NO NEOPLASIA:² Vienna Category 1 (Negative for neoplasia)   2. MUCOSAL LOW GRADE NEOPLASIA: Vienna Category 3 (Mucosal low-grade neoplasia, Low-grade adenoma, Low-grade dysplasia); Other common terminology mild and moderate dysplasia; WHO: low-grade intra-epithelial neoplasia   3. MUCOSAL HIGH GRADE NEOPLASIA: Vienna: Category 4.1–4.4 (Mucosal high grade neoplasia, High-grade adenoma/dysplasia, Non-invasive carcinoma (carcinoma in situ), Suspicious for invasive carcinoma, Intramucosal carcinoma); Other common terminology severe dysplasia; high-grade intraepithelial neoplasia; WHO: high-grade intraepithelial neoplasia TNM: pTis   4. CARCINOMA invading the submucosa or beyond: 4a. Carcinoma confined to submucosa Vienna: Category 5 (Submucosal invasion by carcinoma); TNM: pT1 4b. Carcinoma beyond submucosa TNM: pT2-T4   ¹ For revised Vienna classification see Dixon (2002), for WHO classification see WHO (2000), for TNM see (TNM classification of malignant tumours, 5th edition 1997; TNM Classification of malignant tumours, 6th edition 2002; TNM Classification of Malignant Tumours, 7th edition 2009). ² Category 2 of the Vienna Classification (indefinite) is not recommended for screening.

Different factors could increase or decrease risk for colorectal cancer (CRC) {1,3,4}.

Factor which increased risk for CRC are: environmental factors (prevalence is increased in developed countries, urban areas); advantaged socioeconomic groups; hypercholesterolemia; coronary artery diseases; low-fiber, high-animal-fat diets; obesity; smoking; acromegaly; sugar consumption; family history (risk is increased in first-degree relatives of patients, families with increased prevalence of cancer, patients with breast or gynaecologic cancer, familial polyposis syndromes);>10-year history of ulcerative colitis or Crohns colitis;>15-year history of uretherosygmoidostomy.

Risk is decreased with long term dietary calcium supplementation, vegetable, garlic, exercise, daily aspirin ingestion (after 5 years daily aspirin there is a 35% reduction in all GI cancers) and other NSAIDs.

 

Most colon cancers arise from non-malignant adenomas in form of adenomatous polyps. Genetic steps from polyp to dysplasia to carcinoma in situ is defined (the adenoma-carcinoma sequence) (point mutation in K-ras proto-oncogene, hypomethylation of DNA leading to enhanced gene expression, allelic loss of tumour suppressor APC gene, allelic loss at DCC gene (deleted in colon cancer) on chromosome 18, and loss and mutation of p53 on chromosome 17 {1-3}.

 

Due such natural course, CRC is particularly suitable for screening. Adenomas can occur anywhere in the colorectum after a series of mutations that cause neoplasia of the epithelium. Adenomas are most often polypoid, but can also be sessile or flat. An adenoma grows in size and can develop high-grade neoplasia. At a certain point in time, the adenoma can invade the submucosa and become malignant. Initially, this malignant cancer is not diagnosed and does not give symptoms yet (preclinical). It can progress from localised (stage I) to metastasised (stage IV) cancer, until it causes symptoms and is diagnosed {1-3}.

 

In developed countries, approximately, 40.50% of the population develop one or more adenomas in a lifetime, but the majority of these adenomas will never develop into CRC. Only 5.6% of the population actually develop CRC. The average duration of the development of an adenoma to CRC is unobserved, but is estimated to take at least 10 years. This long latent phase provides an excellent window of opportunity for early detection of the disease. When detected in the adenoma-phase, removal of the adenoma can prevent the incidence of CRC. But even when detected as an early-stage cancer, prognosis is considerably better than for late-stage cancer {1-3}.

 

An adenoma is benign, dysplastic tumour of columnar cells or glandular tissue. They have tubular, tubulovillous or villous morphology. The likelihood of an adenoma being present increase with age. At the age of 60-70, 5% of asymptomatic subject will have a polyp of >1 cm, or cancer with no symptoms, and up to 50% will have at least one small<1cm adenoma {1-3}.

Removal of adenoma at colonoscopy and subsequent surveillance reduces the risk of development of colon cancer by approximately 80%. The remaining 20% are either newly formed, missed, or difficult to detect, e.g. flat adenoma.

 

About 5% of CRC have well defined single gen basis. Onset of cancer is earlier than in sporadic cases, at age 40-50 or younger {1-3}.

Symptoms of adenomas

 

Polyps in the rectum and sigmoid often present with rectal bleeding. More proximal lesion rarely produce symptoms and most are diagnosed on barium enema, CT colonography or on colonoscopy performed for screening. Large villous adenomas can present with profuse diarrhoea with mucus and hypocalcaemia {1-3}.

 

Colon cancer symptoms

Colon cancer of left-side presents most commonly with rectal bleeding, altered bowel habits (constipation, intermittent diarrhoea, tenesmus, narrowing), abdominal or back pain. Cecal and ascending colon cancers more frequently present with symptoms of anaemia (50% of right-sided lesions), occult blood in stool or weight loss. Possible complication varied from perforation, fistula, volvulus, inguinal hernia {1-3}.

 

Anal cancer accounts for 1-2% of large-bowel cancer. Women are more commonly affected than men. Presents with bleeding, pain, and perianal mass {1-3}.

 

Incidence, prevalence, survival

Colorectal cancer (CRC) is the 3^rd most common cancer worldwide, and the second most frequent in developed countries {5}. In 2008, there were 1,234,000 estimated cases of CRC worldwide, the majority of which (60%) occurred in the most developed countries {6}. The disease is more common in westernized countries than Asia or Africa. The estimated age-standardized incidence rate [world age standardization (ASR-W)] of CRC in 2008 was 17.2 per 100,000 inhabitants; however, 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}. The number of deaths due to CRC worldwide in 2008 was estimated at 608,000, equivalent to 8% of total cancer-related deaths. CRC was the third cause of cancer-related death in women (after breast and lung cancer) and the fourth (after lung, liver and stomach cancer) in men {6}. Estimated CRC age-standardized mortality rates (world age standardization) in both sexes were highest in Central and Eastern Europe (15.1 per 100,000) and lowest in Middle Africa (3.1 per 100,000) {6}. As the case in incidence, mortality from CRC is higher in men that in women.

Focusing on Europe, in 2008, CRC accounted for 12.4% of deaths caused by malignancy in European countries (11.5% and 13.5% of total cancer deaths in men and women respectively)  {6}.  It represented the second cause of cancer death for the total population, lung cancer being the first. The number of deaths attributed to CRC in Europe in 2008 was 212,219. According to estimates on cancer incidence in Europe {6}, in 2008 CRC was the most frequent malignancy in both sexes, comprising 13.5% of all newly-diagnosed carcinomas in the European population (men 13.5%, women 13.5%). Breast cancer and lung cancer were the 2nd and 3rd most frequent malignancies respectively (13.2% and 12.1% of all malignancies in both sexes). Overall, 432,414 people were estimated to have been newly diagnosed in 2008 with CRC in Europe. A more detailed analysis of individual diagnoses from 96 individual cancer registries in Europe for the period 1998-2002 identified malignant disease of the colon as the most frequent, accounting for 57% of all cases (> 35 cases/100,000 inhabitants), followed by malignant diseases of the rectum and rectosigmoid {5}.

Variations are observed in CRC incidence and mortality rates among European countries {6}. Age-standardized incidence rates estimates (European age standard) range from 106 per 100,000 in Hungary to 13.6 per 100,000 in Albania for men and from 55.6 per 100,000 in Switzerland to 21.3 per 100,000 in Greece for women. Estimated age-standardized mortality rates (ASR-W) were higher in Hungary, the Czech Republic and Slovakia and lowest in Iceland, Albania and Cyprus. The mortality rate for Europe was 13.3 per 100,000 population {6}. Part of the differences in CRC incidence and mortality can be explained by differences in lifestyle, screening practices and treatment patterns between countries {2}. However, a detailed comparison of data for European countries is made difficult because of the absence of unified data, as not all countries maintain population and cancer registers {5}. European funded projects such as EUROCARE have aimed at collecting standardised information.

In addition to CRC incidence and mortality, population-based survival is an important indicator for evaluating management of CRC {7}. Survival rates are strongly associated with stage of CRC at diagnosis (see related Table in CUR2). Data on cancer survival for European countries are available through various national and/or regional cancer registries and through the EUROCARE (European cancer registry-based study of cancer patients’ survival and care) study. 5-year relative CRC survival rates in 2004-2009 for European countries for which data were available varied from 38.6% in Latvia to 66.1% in Iceland as is depicted in Table 1. There are significant differences in relative survival rates between European countries. CRC survival disparities have also been observed within countries between geographical regions and ethnic or racial groups {7-9}.

Table 1: Colorectal cancer five-year relative survival rate, 2004-2009 (or nearest period)

Age-sex standardised rate per 100 patients
	2004-2009
	Value		95% CI deviation
Belgium	64.7		1.8
Austria	63.1		1.9
Finland	61.8	2003-08	1.1
Netherlands	61.0		1.2
Sweden	60.7		1.0
Germany	60.4	2003-08	0.8
Portugal	57.4		0.0
Slovenia	55.8		3.2
Denmark	55.5		2.1
United Kingdom	53.3		0.6
Ireland	52.9		1.6
Czech Republic	49.6	2003-08	0.7
Latvia	38.6		4.2
Norway	63.1		1.7
Iceland	66.1	2003-08	9.5
Source: OECD Health Data 2012

 

An important source of information regarding CRC survival rates in Europe are the findings of the EUROCARE study, which began in 1989 and is the most extensive population study monitoring relative survival rate (RSR) {5}. Its aim is to measure and explain international differences in cancer survival in Europe, by using standard definitions, quality control and standard analytic techniques and taking into consideration the demographic variables and background mortality in the participating countries {10}. The indicator that is predominantly used is the 5-year relative CRC survival rate, defined as "the ratio of the recorded survival to the expected survival in the general population of the same age and sex" {7}. The most recent publications include data up to the EUROCARE-4 round, which collected information from 83 cancer registries in 23 European countries on adults diagnosed with cancer in 1995–99 and followed up to December 2003. According to the study results {7}, mean European age-adjusted 5-year relative survival of both sexes for colorectal cancer was 53.8% [95% CI 53.3-54.1]. CRC 5-year survival was >57% in the Nordic countries (except Denmark) and some countries of central and southern Europe, but 51% in the UK. Relative survival rates in eastern European countries were lower (<45%). Survival, however, presents a continuous increase over the period of 1991–2002 in all countries, with the largest improvements observed in eastern European countries, thus, decreasing the gap between the various European areas {11}.

 

Trends in incidence, mortality and survival

In Europe, an increasing trend in average incidence of CRC has been observed in recent years (2001-2005) {5}. However, these trends have not been uniform. Analysis of cancer registries' data in 21 European countries from the mid-1990s to approximately 2005 {12} showed a modest increase on average in CRC incidence among males, whereas in women CRC incidence rates remained stable and even decreased in some countries. Internationally, CRC incidence rates have been stabilizing or declining in historically high-risk areas (United States, New Zealand, Canada), but rapidly increasing in several historically low-risk countries, including Japan, Korea, China, and Eastern European countries {13}.

Observed increases in cancer incidence might relate to increasing risk factors or improvements in the diagnosis and recording of cancer cases and early detection through population screening {12}. For example, the increase in incidence rates in several Asian and Eastern European countries as well as in Spain has been attributed largely to changes in risk factors (changes in dietary and physical activity patterns, smoking) that are most likely related to their westernization {12, 13}. In Japan both increased screening and the transition to a more westernized lifestyle with changes in dietary intake have been reported as the main explanatory factors for the increases in CRC incidence {14}. On the contrary, in the US the decrease in CRC incidence observed in the most recent time period is mainly attributed to detection and removal of precancerous lesions through screening {13}.

Regarding tends in CRC mortality, according to Eurostat data {15}, average mortality rates from CRC in 25 EU member-states fell from 22.2 per 100,000 population in 2000 to 20.5 per 100,000 in 2010. Inequalities, however, exist between European countries also in CRC mortality trends. Mortality rates decreased since the mid-1990s for men and women almost in all countries, the exceptions been Croatia, Poland, Lithuania (men), Slovenia (men) and Spain (men) {12}. The least favourable trends in those countries (in which CRC mortality was lowest in the past) probably reflect a convergence of lifestyle and dietary habits towards those in other European countries {16}. Tends in mortality rates reflect the effect of cancer care, screening and diagnosis as well as changes in incidence {17} .

Regarding CRC survival, data from the EUROCARE rounds have revealed  improvements in average survival in the long-term {18}, {11}, {19}. Disparities in survival rates observed in earlier rounds seemed to narrow {7}. An analysis of data from 25 cancer registries in 16 European countries covering years of diagnosis from 1984 to 2002 {20}, concluded that for time periods from 1988–1990 to 2000–2002, CRC survival substantially increased over time in all European regions under study^[1] and for both sexes. Increase in survival was observed also for all age groups (15–59, 60–74 and 75+ years), with the exception of Eastern European countries were 5-year relative survival in those over 75 years fell. However, the increase in survival was less pronounced for older patients (75+ age group) than for younger ones (aged 15–59 and 60–74) in all other European regions except Central Europe. Data from six countries in which registries included information on site and stage of diagnosis suggest that survival benefits were also larger for patients in earlier than in more advanced cancer stages and for rectum than for colon cancer. However, the substantial variation of CRC survival between European countries that was observed in earlier EUROCARE studies (highest levels of 5-year relative survival in Central and Northern Europe, followed by South European countries and UK and England, and lowest levels in Eastern Europe), were found to have persisted.

Differences in survival and trends over time depend on several reasons including increased access to more effective treatment, better management of co-morbidity, treatment being more effective due to earlier diagnosis, and lead-time bias or over diagnosis {21}, {10}. During the last two decades both early detection and treatment of CRC have improved {15), {22}. Accuracy and utilization of diagnostic technologies have increased as well as awareness among patients and primary care physicians {20}. Technological advances in the treatment and perioperative care of CRC (for example adjuvant chemotherapy, new surgical techniques, preoperative radiotherapy) that became available have also contributed to improvements in CRC survival {22, 23}.

In the framework of EUROCARE, high resolution studies were undertaken in an effort towards interpreting the impact of the aforementioned factors. The rationale adopted is that, if survival differences persist after adjustment for stage at diagnosis, there is evidence to suggest that differences in treatment significantly affect survival {21}. These studies brought forward the impact on CRC survival of (between and within countries) variations in  disease stage at diagnosis as well as variations in availability and use of effective diagnostic technologies and treatments {24-26} as referenced in {10}).

In the future, the number of new cases and deaths related to CRC are expected to increase. In specific, the International Agency on Research for Cancer (IARC) estimates the number of new CRC cases in Europe (in all ages) to rise to 502,000 in 2020, whereas the annual deaths from CRC in Europe are expected to rise to 248,000 {6}.

 

Burden of disease and Quality of life

According to WHO estimations {27}, in 2004, cancers were responsible for 151,461,000 Disability Adjusted Life Years (DALYs) in the European Region (11.3% of total DALYs). Trachea/bronchus/lung cancers, CRC and breast cancer were the main contributors, accounting for 19.1%, 11.1% and 10.2% of total DALYs due to cancer. Analysing the two components of DALYs, premature mortality was the main component for all cancer sites. DALYs in the European Region are projected to decrease to 116,729,000 in 2030, mainly due to the shift in age at death to older ages. The burden of disease due to CRC is estimated to follow this trend and decrease to 1,862,000 DALYs, corresponding to 11.7% of the total cancer burden.

Taking into consideration that both cancer and its treatment affect the physical and psychosocial condition of patients, policy-makers have been increasingly interested in evaluating the impact of cancer on patients' and survivors' quality of life (QoL) {28}. Until recently, there has been little research on the effects of long-term (≥5 years) survival from colon cancer on survivors' health status {29, 30}. Available evidence relates mainly to studies on patients during the treatment phase or the first years after diagnosis {31, 11}. Cross-sectional studies have shown that during the early years of diagnosis and treatment, CRC patients have poorer outcomes in terms of QoL, productivity losses and self-rated health than similar individuals with no history of cancer. They also report higher levels of psychological disability and problems with activities of daily living than controls {32,33,28, 34}.

In long-term (≥5 years) CRC survivors considered as cured (without recurrence or metastasis), overall QoL is similar to that of the general population; nevertheless, specific physical and psychosocial problems such as fatigue, dyspnea, insomnia,  bowel problems and deficits in emotional and social functioning persist over time and are also reported by survivors even 10 years after diagnosis {35,29, 36,37,38}.

In a prospective population-based cohort study from Germany {30}, long-term development of QoL depended on age at diagnosis. Younger survivors were found to report continuously substantial deficits in role, cognitive, emotional, and social functioning as well as presence of long-lasting symptoms in comparison to controls throughout the study period. In older survivors QoL was comparable to that of the general population during the first (1 to 3) years after diagnosis, however, QoL dimensions related to functioning, symptoms and problems worsened significantly between 3 and 10 years after diagnosis which suggests that detriments in older survivors become apparent in the long run. Global QoL scores of survivors were comparable to population norms regardless of duration of follow-up and despite the presence of limitations.

 

  [1] Northern Europe: Sweden, Norway, Finland, Iceland; Southern Europe: Italy, Slovenia; Central Europe: Austria, France, Germany, the Netherlands, Switzerland; Eastern Europe: Poland,  Slovakia; UK: Scotland, England, Wales.

 

As was noted, not all countries maintain population and cancer registers, therefore detailed comparisons are difficult. Data on incidence and mortality were extracted from the database of the GLOBOCAN project (International Agency for Research on Cancer), which provides contemporary estimates of these measures {6}. The most recent estimates are for 2008. Incidence data also derive from population-based cancer registries. More information on the GLOBOCAN data and sources are available on the project’s website. Regarding CRC survival, results of the EUROCARE project were preferred as it is a projects that aims to describe and interpret differences in cancer patient survival in Europe. However, there are limitations to the project, already acknowledged by the researchers {21}. The reader should keep in mind that not all European countries are involved in the EUROCARE project. Furthermore, for several countries cancer registration covers only a fraction of the total national population. The first round (EUROCARE-1) included 30 cancer registry populations diagnosed from 12 European countries. During the rounds that followed more regional and national registries participated. The current, fifth round (EUROCARE-5) includes data from 116 Cancer Registries in 30 European countries and for patients diagnosed during 2000-2007 {39}. Strengths, limitations and the value of findings are discussed in detail by the researchers {21, 40}.

CRC screening in general aims to reduce morbidity and mortality from CRC through both, prevention (by the removal of adenomas before they become malignant) and earlier diagnosis of CRC (at early, curable stage). CRC is particularly suitable for screening due to natural course of disease (adenoma-carcinoma sequence). When detected in the adenoma-phase, removal of the adenoma prevents the incidence of CRC; when detected as an early-stage cancer, prognosis is considerably better than for late-stage cancer. An increase in incidence in the target age range may be observed immediately after the introduction of a CRC screening programme, however, incidence rates should return to background level at re-screening apart from the advancement of the age of diagnosis by screening {43}. For the individual, CRC screening in general can prevent the negative impact of CRC morbidity on quality-of-life {44}. As cancer treatment also represents a significant economic cost for the health system, CRC screening also results in cost-savings ({45} cited by {5}).

There are various methods available for colorectal cancer screening (see Result card CUR22). They can be broadly divided into endoscopic and radiologic methods (for example colonoscopy) and stool-based tests (guaiac-based or immunochemical Faecal occult blood tests - FOBTs, Faecal DNA testing) {42}. Routine screening of stool for occult blood may facilitate early detection.

Guaiac-based Faecal Occult Blood (gFOBT) tests are those mostly studied in RCTs as screening test for CRC and are an established screening strategy for CRC. Several large randomized studies have demonstrated a reduction in cancer-related mortality. In three systematic reviews of RCTs using gFOBT for CRC screening, a reduction of 14 - 16 % in CRC mortality was found {46, 47, 48}  as referenced in {49}. In a matched-cohort study in Scotland, a reduction of 10% in CRC mortality was found {50}. The disadvantage of screening with gFOBT is relatively low sensitivity (many negative colonoscopies). gFOBT sensitivity is only around 50% for carcinoma; specificity for tumour or polyp around 25-40%. In FOBT screen-positive patients in the UK National Bowel Cancer Screening Programme (NHS BCSP) about 10% have cancer, 40% have adenomas and the colon is normal in 50%. False positive results of gFBOT tests are related to ingestion of red meat, iron, aspirin, upper GI bleeding. False negatives can be produced by vitamin C ingestion, intermittent bleeding. The dietary requirements for people preparing for screening with gFBOT may limit patient acceptance {51}.

As it the case with gFOBTs, a range of immunochemical tests are available with varying sensitivity and specificity (5). It has been argued that, since efficacy of gFOBT has already been demonstrated, decisions on screening with FITs can be based on the performance characteristics of the tests (sensitivity, specificity, positive predictive values) {44}. Performance characteristics are addressed in subsequent domains FITs can also be used as a "reflex" test, after primary screening with gFOBT. Available data on this screening strategy, from either research studies or screening programmes is limited {44} .

Target population for CRC screening includes asymptomatic people at average risk, of both genders, age 50-74. Similar age range is currently recommended by the Council of the EU for CRC screening (50-74 years), taking into account that over 100 million men and women in EU are in this age group. Persons in whom age is the only risk factor for CRC are considered to be at average risk {41}. 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. Individuals in higher risk are not included in the target population in the present report. Recommendations may slightly differ for specific population groups, for example, in the US; the Institute for Clinical Systems Improvement (ICSI) recommends routine colorectal cancer screening for all average-risk patients 45 years of age and older for African Americans or American Indians {42}. In some cases, upper age limits are recommended. The U.S. Multi-Society Task Force on Colorectal Cancer (USMSTF), recommends routine colorectal cancer screening continuing until age 75 years {42} .

In the absence of additional evidence, the age range for a screening programme with iFOBT can be based on the limited evidence for the optimal age range in gFOBT trials {2}. According to the EU Guidelines {2}, 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).

The data about number of target population for colorectal cancer screening in Europe are retrieved from already published literature data and EUnetHTA JA2 Surveys conducted in 2013.

In EUnetHTA Partners Survey, data from only 9 countries was available, including data for two Italy regions. Only 1 Manufacturer responded on EUnetHTA JA2 Manufacturers survey.

According to the 2008 Report on the Implementation of the Council Recommendation on Cancer Screening (58), in 2008 the target group included approximately 136 million individuals suitable for CRC screening (aged 50 to 74 years). Of this number, 43% individuals came from 12 countries where CRC population screening was performed or being prepared on either national or regional levels; 34% came from 5 countries where national population screening has been implemented (Finland, France, Italy, Poland, and United Kingdom). In 7 EU countries, national non-population based screening was carried out, which covered 27% of the target population.

The target population in the countries for which information was provided through the EUnetHTA JA2 Survey (2013) is :

Croatia ≈ 1,320,000	Italy (Lazio region) 1,649,561 (2012)	Italy (Veneto Region) 1,210,000 (2012)	Slovenia ≈  540.000	France 16-17 million
Romania 4,926,951 for the 2013 plan	Spain 10,851,924 (2013)	Lithuania 904,872	Luxembourg at least 185,000	Russia About 1/3 of the population 45+

 

• Data for Greece were added by one of the domain Investigators (EK).

A number of countries have organised CRC screening programmes (see CUR14), utilising different strategies. FOB testing is a widely implemented strategy, however there are differences in the type of tests used (gFOBT or iFOBT). From the information provided via the EUnetHTA members’ survey, use of immunochemical testing (FIT) was reported in 5 out of 11 (i. e. Austria, Russia, Luxembourg, Lithuania, Italy, Scotland, Spain, Romania, France, Croatia and Slovenia) European countries. In specific, FIT is used in the Regions of Veneto and Lazio in Italy, Lithuania, Russia, Slovenia and Spain. In Austria, FIT is used only in one province (Burgenland).

According to data (May 2008) from the International Cancer Screening Network {52}, CRC screening programmes utilising immunochemical techniques had been implemented in Hungary (2 pilots) and Italy. In Italy, the majority of programmes use FIT, a limited number offer flexible sigmoidoscopy (FS) once in a lifetime and FIT for non-responders to FS {53}.

Outside of Europe, FIT is the preferred method for CRC screening in Japan {54} and Australia {51}. In Canada, 3 out of 7 provinces (B. Columbia, Saskatchewan and Nova Scotia) implementing CRC screening programs with FOBTs as the entry method were utilising a FIT test {55}.

Please see also ORG Domain.

Uptake or participation rate is defined in the European guidelines on CRC screening as "the number of people who have been screened, within a defined time frame following an invitation, as a proportion of all people who are invited to attend for screening" {43}. Participation rate is an early performance indicator as it is important for the overall effectiveness and cost-effectiveness of the CRC screening programme. European Guidelines {43} consider a minimum uptake of at least 45% as acceptable, however, it is recommended to aim for a participation rate of at least 65%.

Participation rates in FIT-based screening

 

Participation rates in various CRC screening programmes (pilot programmes, established programmes) in Europe and abroad are presented in the following Table 1.

 

Table 1: Participation rates in CRC screening with FIT

Country/Region	Participation rate	Source
Established population - based CRC screening programmes
Burgenland, Austria	35%	EUnetHTA Members Survey
Japan	17% (2002)	(54)
Tuscany, Italy	41% (1st round) (2001)	(44)
Lazio Region, Italy	30% (2011)	EUnetHTA Members Survey
Veneto Region, Italy	63.8% (2012)	EUnetHTA Members Survey
Lithuania	16.4%	EUnetHTA Members Survey
Russia	n.a. (programme established in 2013)	EUnetHTA Members Survey
Slovenia	1st screening round: 49.8%	EUnetHTA Members Survey
Spain	Catalonia 2000-2008: 14.4% adherence to screening recommendations, 18.4% were occasionally adherent	EUnetHTA Members Survey
Pilot CRC screening programmes
Australia	45.5% (2002-2004)	(56)
Netherlands	60% (1st round; 2006-2007)	(44)

 

Participation rates in gFOBT-based screening

In a review by the Irish Health Information and Quality Authority {44},  uptake (the proportion of individuals who complete a screening test in a particular screening round) of CRC screening using the gFOBT in the 1st round of pilot screening programmes ranged from 47% in the Netherlands to 55% in Scotland. Uptake increased to 53% and 55% in the 2nd and 3rd round respectively in the pilot from Scotland. Similar rates were reported in a 3-round pilot in France.

Data from the survey conducted in the framework of the present report provided additional information on participation rates in national population-based CRC screening programmes in France (for the period 2010-2011 participation rate was approximately 32%) and Croatia (19.9%).

 

Population-based screening requires the identification and personal invitation of each person in the eligible target population (by an office or special agency). There are a number of established CRC screening programmes worldwide. Other countries are implementing pilots or considering the introduction of screening programmes {52, 57}. Several variations exist among the various programmes. Dimensions in which the programmes may differ include for example: population targeted (age groups targeted most often include persons aged ≥50 years), screening interval, monitoring mechanisms, methods of contacting eligible population, location of testing etc. The primary method used for screening also varies between countries. The following Table provides an overview of the screening strategies employed in European countries. It is based on data from First Report on the implementation of the European Council Recommendation on cancer screening {58}. Data were updated in the cases where more recent information was found.

Table 1: Overview of CRC screening practices in European countries

Country	CRC screening programme	Target population (eligible age in years)	Screening strategy	Screening interval (years or times in LT)	Source
Austria	Natw, opp	50+	colonoscopy	10	EUnetHTA Survey 2013
			FOBT (gFOBT)	1 or 2	EUnetHTA Survey 2013
	Pop-b (province of Burgenland)	50+	FOBT (FIT)	1	EUnetHTA Survey 2013
Belgium	Natw, pop-b	n.a.	FOBT/CS	n.a.	(59) (status in 2011)
Bulgaria	Natw, opp	31+	FOBT	1	(58) (status in 2007)
Cyprus	Natw, pop-b	n.a.	colonoscopy	n.a.	(59) (status in 2011)
		n.a.	FOBT (gFOBT)	n.a.
Croatia	Natw, pop-b	50-74	FOBT (gFOBT)	2	EUnetHTA Survey 2013
Czech Republic	Natw, opp	50-54	FOBT	1	(57) (status in 2009)
		55+	FOBT (gFOBT)	2
		55+	colonoscopy	10
Denmark	Natw, pop-b	n.a.	FOBT/CS	n.a.	(59) (status in 2011)
Estonia	Pop-b, planned	n.a.	FOBT	n.a.	(60)
Finland	Natw, pop-b	60-69	FOBT	2	(58) (status in 2007)
France	Natw, pop-b	50-74 with no symptoms of CRC and moderate risk of CRC.	FOBT (gFOBT*)	2	EUnetHTA Survey 2013
Germany	opp	50-55	FOBT (gFOBT)	1	(57) (status in 2009)
		55+	FOBT (gFOBT)	2
		50+	colonoscopy	10
Greece	opp	50-70	FOBT	2	Ministerial Decision (Government Gazette Β 3054/2012)
		50+	Colonoscopy	10
Hungary	Pop-b, natw pilot	50-70	FOBT	2	(58) (status in 2007)
Ireland	Pop-b	n.a.	FOBT	n.a.	(59) (status in 2011)
Italy	Regional variations	50-69 (70-75)	FOBT   οnly 1 out of 21 programmes proposes flexible sigmoidoscopy (FS) once in a lifetime to subjects 60+ and FIT for non-responders to FS	2	(58) (status in 2007)
Italy (Lazio Region)	Pop-b	50-74	FOBT (FIT)	2	EUnetHTA Survey 2013
Italy (Veneto Region)	Pop-b	50-69	FOBT (FIT)	2	EUnetHTA Survey 2013
Latvia	Natw, opp	50+	FOBT	1	(58) (status in 2007)
Lithuania	Natw, pop-b	50-75	FOBT (FIT)	2	EUnetHTA Survey 2013
Luxembourg	Opp  natw pop-b planned	50+	FOBT	2	EUnetHTA Survey 2013
		50+	colonoscopy	10
Malta	Pop-b	n.a.	FOBT	n.a.	(59) (status in 2011)
Netherlands	No prog				(58) (status in 2007)
Poland	Natw, pop-b	50-65	colonoscopy	10	(58) (status in 2007)
Portugal	Pop-b, natw planned	50-70	FOBT	2	(58) (status in 2007)
Romania	Pop-b, natw planned	50-47	FOBT	2	EUnetHTA Survey 2013
Russia	Pop-b	Certain age groups 45+ The programme is planned to cover the total population over 45 y. o. in 2016.	FOBT (FIT)		EUnetHTA Survey 2013
Scotland	Pop-b	50-74	FOBT (gFOBT) FIT as a reflex test	2	EUnetHTA Survey 2013
Slovak Republic	Opp, natw	50+	FOBT		(58) (status in 2007)
	Opp, natw planned	50+	colonoscopy	10
Slovenia	Natw, pop-b	50-69	FOBT (FIT)	2	EUnetHTA Survey 2013
Spain	Pop-b: Catalonia, Valencia, Murcia, Canary Islands, La Rioja and Basque Country opp: rest of Spain	50-69	FOBT (FIT)	2	EUnetHTA Survey 2013
Sweden	Pop-b, regional planned	60-69	FOBT	2	(58) (status in 2007)
England	Pop-b, natw	50-75	FOBT	2	(57) (status in 2009)
* France: Although gFOBT is still considered as the reference test, a switch to FIT is recommended and encouraged by national authorities. The Cancer plan 2009-2013, sets the goal odf "Gradually roll out use of the immunological test for colorectal cancer screening to the whole of the country". 7 regions tried using FIT for the national screening programme: Alsace, Aquitaine, Lorraine, Midi-Pyrénées, Pays de la Loire, Picardie, Rhône-Alpes. Abbreviations: pop-b (population-based), opp (opportunistic), no prog (no programme), natw (nationwide), pilot (piloting), plan (planning)

 

In CUR 14-Appendix 1, epidemiological data on CRC are presented for groups of countries according to CRC screening practices.

The text in this Assessment Element describes CRC screening programmes targeting individuals at average risk for CRC (which is the scope of the current report). Screening programmes for high-risk individuals are not discussed.

Various technologies are available for the diagnosis of adenomas and CRC {1-3}.

Colonoscopy is the gold standard and allows biopsy for histology. Biopsy is mandatory, usually at endoscopy. Double-contrast barium enema can visualize the large bowel; now it is superseded by CT colonography. Endoanal ultrasound and pelvic MRI are used for staging rectal cancer. Chest, abdominal and pelvic MRI scanning are utilised to evaluate tumour size, local spread and liver and lung metastases. PET scanning is performed for detecting occult metastases and for evaluation of suspicious lesions found on CT or MR. MR is also useful for evaluating suspicious lesion found on CT or US, especially in the liver. CEA is useful for follow-up, rising level suggest recurrence {1-3}.

 

FOBTs are used for mass population screening and are of value in hospital or general practice. Early diagnosis by screening asymptomatic persons with FOBT, >50% of all colon cancers are within reach of a 60-cm flexible sigmoidoscope; air-contrast barium enema will diagnose around 85% of colon cancer not within reach of sigmoidoscope; colonoscopy is most sensitive and specific, permits tumour biopsy and removal of synchronous polypus, but is more expensive. Radiographic or virtual colonoscopy has not been shown to be better diagnostic method than colonoscopy {1-3}.

Annual digital rectal exam and FOBT are recommended for patients over age 40, screening by flexible sigmoidoscopy every 3 years after age 50; careful evaluation of all patients with positive occult blood test (flexible sigmoidoscopy and air-contrast barium enema or colonoscopy alone) reveals polyps in 20-40% and carcinoma in around 5%.

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

Stool-based techniques: Faecal occult blood test (FOBT) (either guaiac, so called gFOBT and immunochemical, so called FIT); Faecal 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).   Faecal DNA tests represent a new group of fecal 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. Authors of the 2012 AHRQ HTA Report 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. Existing evidence has little or no applicability to currently available faecal DNA testing {62}.  

Results {1-3}

EU Guideline 2010 {2}

According the EU Guideline 2010, "iFOBT have improved test characteristics than gFOBT, and they are currently the test of choice for population CRC screening. In different settings, individual device characteristics like ease of use by participant and laboratory, suitability for transport, sampling reproducibility and sample stability are important and should be all taken into account when selecting the iFOBT most appropriate for CRC screening programme (Level of evidence II, Grade of recommendation A).

 

Adoption of test device and the selection of a cut-off concentration should follow a local pilot study to ensure that chosen test, test algorithm and transport arrangements work together to provide a positivity rate that is clinically, logistically and financially acceptable (Level of evidence VI, Grade of recommendation A).

 

Maximum period between collection and analysis is significantly shorter  than for gFOBT (14-21 days), and screening programmes should adopt the conditions and period of storage described in manufacturer’s Instructions for use and should be appropriate for local conditions which might expose samples to high temperatures for long period of time (Level of evidence III, Grade of recommendation A).

 

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).

 

The number of laboratory sites (analytical centres) should be minimised with automated analytical systems utilised whenever possible and agreed common testing procedures adopted by each centre, since the analysis need to be reproducible across screening population. The samples should be analysed without delay to avoid further sample denaturation and avoid an increase in false negative results. Inter-laboratory analytical imprecision can be observed through established external quality assurance schemes. Common analytical platforms, analytical and quality standards and shared staff training will improve consistency. (Level of evidence VI, Grade of recommendation B).

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).

 

Quality assurance of iFOBT

Manufacturer’s Instructions for Use must be followed. Daily checks of analytical accuracy and precision across the measurement range with particular emphasis at the selected cut-off limit should be performed. Sufficient instrumentation should be available to avoid delays in analysis due to instrument failure or maintenance procedures. Performance data (both internal quality control and external quality assessment data) should be shared and reviewed by a Quality Assurance team working across the programme. (Level of evidence VI, Grade of recommendation B).

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)."

 

Box 1. Some published Guidelines on adenomas/CRC screening and diagnosis

EU Guideline 2010 {2}
Screening	iFOBT have improved test characteristics than gFOBT, and they are currently the test of choice for population CRC screening. In different settings, individual device characteristics like ease of use by participant and laboratory, suitability for transport, sampling reproducibility and sample stability are important and should be all taken into account when selecting the iFOBT most appropriate for CRC screening programme (Level of evidence II, Grade of recommendation A).
Diagnosis	Colonoscopy as recommended test for follow-up investigation for individuals who have tested positive with other CRC screening tools (FOBT, Flexible sigmoidoscopy (FS), and also in experimental studies assessing potential screening tools, e.g. DNA faecal markers and CT colonography).
NICE Guideline 2011 {63}
Screening	NA
Diagnosis	Colonoscopy for patients without major comorbidity, to confirm a diagnosis of colorectal cancer; a biopsy to obtain histological proof of diagnosis (unless it is contraindicated); Flexible sigmoidoscopy then barium enema for patients with major Comorbidity; Computed tomographic (CT) colonography as an alternative to colonoscopy or flexible sigmoidoscopy then barium enema, if the local radiology service can demonstrate competency in this technique (if a lesion suspicious of cancer is detected on CT colonography, a colonoscopy with biopsy should be offered to confirm the diagnosis (unless it is contraindicated)
SIGN Guideline 2011 {64}
Screening	Screening colonoscopy for all patients with ulcerative colitis or Crohn’s colitis of 10 years duration; Surveillance colonoscopies should be performed yearly, 3-yearly or 5-yearly according to risk-stratification; Patients who have undergone colonoscopic polypectomy for adenomas should be offered follow-up colonoscopy based on risk stratification; Patients with one or two adenomas <1 cm in size without high-grade dysplasia are at low risk and only require follow-up colonoscopy at five years if other factors indicate the need for further surveillance (if no polyps are found, further surveillance is not required); The presence of either 3-4 small adenomas (<1 cm), or one adenoma >1 cm in size confers an intermediate risk, and surveillance colonoscopy should be undertaken at three years (if surveillance colonoscopy is subsequently normal on two consecutive occasions, it may cease); Patients with ≥5 small adenomas or ≥3 adenomas with at least one polyp ≥1 cm in size are at high risk, and should undergo colonoscopy at one year.
Diagnosis	Colonoscopy is recommended as a very sensitive method of diagnosing colorectal cancer, enabling biopsy and polypectomy.
	CT colonography can be used as a sensitive and safe alternative to colonoscopy.
Canadian Guideline 2011 {65}
Screening	For opportunistic colorectal cancer screening: annual or biennial FIT, flexible sigmoidoscopy every 10 years and colonoscopy every 10 years. Faecal DNA testing, computed tomography (CT) colonography, and double-contrast barium enema are not recommended for either programmatic or opportunistic colorectal cancer screening.
USA Guidelines {66-68}
Screening	The US Preventive Services Task Force (66) and American College of Gastroenterology (67) recommendations similar the Canadian; the US Multi-Society Task Force (68) differs from Canadian by including faecal DNA testing and CT colonography; flexible sigmoidoscopy is recommended at an interval of every five years

 

In the majority of jurisdictions in the EUnetHTA survey in 2013, local and/or regional guidelines or recommendations on CRC screening were reported (Box 2).

 

Box 2. EUnetHTA survey (2013) about adenomas/CRC screening/diagnosis in different MSs

Austria               No national guideline. A voluntary quality assurance program for screening colonoscopy is in place (partners: Main Association of Social Security Institution and Austrian Society for Gastroenterology and Hepatology OeGGH).                Russia Russian Gastroenterology Association Guidelines.                Luxembourg  European guidelines for quality assurance in colorectal cancer screening and diagnosis.                Lithuania         National guidelines.                Italy (Lazio and Veneto Region)      National and regional recommendations on the basis of European guidelines.   Scotland           Guidance is provided by the UK National Screening Committee.               Spain  Grupo de trabajo de la guía de práctica clínica de prevención del cáncer colorrectal. Actualización 2009. Guía de práctica clínica. Barcelona: Asociación Española de Gastroenterología, Sociedad Española de Medicina de Familia y Comunitaria, y Centro Cochrane Iberoamericano; 2009. Programa de Elaboración de Guías de Práctica Clínica en Enfermedades Digestivas, desde la Atención Primaria a la Especializada: 4               France               Guidance for good practice by HAS (updated in June 2013). The document contains epidemiological data, general description of the screening programmes, algorithms for different groups at risk.   Croatia              National Programme for CRC Screening.              Slovenia 2003 guidelines (currently being updated).    

 

Results {1-3}

Treatment

 

Adenoma

Removal of adenoma at colonoscopy and subsequent surveillance reduces the risk of development of colon cancer by approximately 80%. The remaining 20% are either newly formed, missed, or difficult to detect, e.g. flat adenoma.

 

CRC

Treatment of CRC should be taken by multidisciplinary teams working in special units.

Long-term survival relates to the stage of the primary tumour and the presence of metastatic disease. Long-term survival is only likely when the cancer is completely removed by surgery with adequate clearance margins and regional lymph node clearance.

 

Local disease

Surgical resection of colonic segment containing tumor (preoperative evaluation to assess prognosis and surgical approach includes full colonoscopy, chest RTG, biochemical liver tests, plasma CEA level, and possible abdominal CT). Resection of isolated hepatic metastases possible in selected cases.

 

Rectal carcinoma

Adjuvant radiotherapy to pelvis (with or without concomitant 5FU chemotherapy) decreases local recurrence rate of rectal carcinoma, radiation may improve resectability and local control in patients with rectal cancer. Total mesorectal excition is more effective than conventional anteroposterior resection in rectal cancer.

 

Adjuvant chemotherapy (5FU/leucovorin plus oxaliplatin, or FOLFOX plus bevacizumab, or 5FU/leucovorin plus irinotecan, or FOLFIRI) decreases recurrence rate and improves survival in stage C (III); survival benefit is not clear in stage B (II) tumours; periodic determination of serum CEA level useful to follow up therapy and assess recurrence.

Follow up after curative resection: yearly liver tests, complete blood count, follow-up radiologic or routine screen interim; if polyps detected, repeat 1 year after resection.

 

Advanced tumours (locally unresectable or metastatic)

 

Systemic chemotherapy (5FU/leucovorin plus oxaliplatin plus bevacizumab), irinotecan usually in second treatment; antibodies to the EGF receptor (cetuximab, panitumumab for those with wild type KRAS and BRAF genes) appear to enhance the effect of chemotherapy to 68% and the median survival from 14 to 24 months; intraarterial chemotherapy (floxuridine (FUDR) and/or radiation therapy may palliate symptoms from hepatic metastases.

 

With appropriate selection of patients with a good performance status and in whom MRI and PET-CT scans do not demonstrate extrahepatic disease local treatment can prolong good quality survival (with surgical resection to gamma knife irradiation, radiofrequency, or cryoablation, or hepatic artery embolization. Small lesion can be ablated; larger lesions are best managed by partial hepatectomy or a combination approach: embolization is followed by hepatic regeneration before final resection. Long-term survival without recurrence is reported up to 20% of patients at 5-years with a single <4 cm lesion.

 

Advanced CRC is successfully palliated with little toxicity by 5FU and folinic acid regiments or oral capecitabine in approximately 30% of patient with a median of 12-14 months. The addition of irinotecan or oxaliplatin increases the proportion that benefit to 55% and extended median survival to 18 months but with increased toxicity.

 

Anal cancer

Radiation therapy plus chemotherapy (5FU and mitomycin) leads to complete response in 80% when the primary lesion is <3 cm.  For patients with large lesions or whose disease recurs after chemoradiotherapy, abdominoperineal resection with permanent colostomy is reserved.

 

Based on responses from the survey in EUnetHTA members in 8 countries for which information was available (Russia, Luxembourg, Lazio and Veneto Region in Italy, Spain, Romania, France, Croatia, Slovenia), management involves the treatment approaches described in the European guidelines for quality assurance in colorectal cancer screening and diagnosis. In 4 cases direct reference to European and/or international guidelines was made.

 

Answers could be found also in previous Results card, CUR 18.

Standard treatment options for Stage 1 and II colon cancer include wide surgical resection and anastomosis. The potential value of adjuvant chemotherapy for patients with Stage II colon cancer remains controversial. Standard treatment options for Stage III colon cancer include surgery and adjuvant chemotherapy. Chemotherapy is also used for Stage IV and recurrent colon cancer treatment. Different drugs are available that are used alone and in combination with other drugs in different chemotherapy regiments. The best way to combine and sequence these agents is still not established. Management according to some guidelines {2,63,64}

 is summarised in the following Table 1. Due the fact that the best way to combine and sequence these agents is still not established, guidelines described below are slightly different according regiments used in 1^st-  or 2^nd -line treatment.

 

Table 1. Management of adenomas/CRC according the guidelines

NICE Guideline, 2011 {63}
	Stage I colorectal cancer
	Surgical resection,  with further treatment to patients whose tumour had involved resection margins (less than 1 mm)
	The colorectal multidisciplinary team (MDT) should consider further treatment for patients with locally excised, pathologically confirmed stage I cancer, taking into account pathological characteristics of the lesion, imaging results and previous treatments.
	Follow-up after curative resection
	Regular surveillance with: a minimum of two CTs of the chest, abdomen, and pelvis in the first 3 years and regular serum carcinoembryonic antigen tests (at least every 6 months in the first 3 years).
	Advanced and metastatic colorectal cancer
	FOLFOX (folinic acid plus fluorouracil plus oxaliplatin) as first-line treatment then single agent irinotecan as second-line treatment or
	FOLFOX as first-line treatment then FOLFIRI (folinic acid plus fluorouracil plus irinotecan) as second-line treatment or
	XELOX (capecitabine plus oxaliplatin) as first-line treatment then FOLFIRI (folinic acid plus fluorouracil plus irinotecan) as second-line treatment
SIGN Guideline,  2011 {64}
	Laparoscopic and open surgery can be offered for resection of colorectal cancer.
	All patients with Stage III colorectal cancer should be considered for adjuvant chemotherapy
	Combination treatment with 5-FU/leucovorin/oxaliplatin or capecitabine and oxaliplatin or 5-FU/leucovorin/irinotecan is the preferred options in patients with good performance status and adequate organ function.
	Consider raltitrexed for patients with metastatic colorectal cancer who are intolerant to 5-FU and leucovorin, or for whom these drugs are not suitable.
	Second line chemotherapy should be considered for patients with metastatic colorectal cancer with good performance status and adequate organ function.
	Irinotecan should be used as second line therapy following first line oxaliplatin (or vice versa).
	Cetuximab should be considered in combination with 5-FU/leucovorin/ oxaliplatin or 5-FU/leucovorin/irinotecan chemotherapy for patients with unresectable liver metastases if patients fulfil the SMC criteria.
	Rectal cancer
	Patients considered to have a moderate risk of local recurrence with total mesorectal excision surgery alone, and in whom the CRM is not threatened or breached on MRI, could be considered for preoperative radiotherapy (25 Gy in five fractions over one week) and immediate TME surgery.
	Patients who require down staging of the tumour because of encroachment on the mesorectal fascia should receive combination chemotherapy and radiotherapy, (BED >30 Gy) followed by surgery at an interval to allow cytoreduction.
EU Guideline, 2010 {2}
	General requirements for treatment of colorectal cancer and pre-malignant lesions Colorectal neoplasia should be managed by a multi-disciplinary team (VI - A).   The interval between the diagnosis of screen-detected disease and the start of definitive management should be minimised and in 95% of cases should be no more than 31 days (VI - B).   Colonoscopy should always be done with therapeutic intent i.e. the endoscopist carrying out screening or follow-up colonoscopy should have the necessary expertise to remove all but the most demanding superficial lesions (VI - A).   Management of pre-malignant colorectal lesions Pre-malignant lesions detected at screening endoscopy should be removed (III - A). Lesions that have been removed should be retrieved for histological examination (VI - A).   Colorectal lesions should only be removed by endoscopists with adequate training in techniques of polypectomy (V - A).   Large sessile lesions of the rectum should be considered for transanal surgical removal (II - B).   For large sessile rectal lesions, transanal endoscopic microsurgery (TEM) is the recommended method of local excision (II - B).   Consideration should be given to tertiary referral for patients with large sessile colorectal lesions (V - B).   Patients with large pre-malignant lesions not suitable for endoscopic resection should be referred for surgical resection (VI - A).   Appropriate precautions should be taken prior to endoscopic excision of colorectal lesions in patients on anticoagulants (V - C).   In patients with bare coronary stents, polypectomy should be delayed for at least one month from placement of the stents, when it is safe to discontinue clopidogrel temporarily (V - B).   In patients with drug-eluting coronary stents, polypectomy should be delayed for 12 months from placement of the stents, when it is safe to discontinue clopidogrel temporarily (V - B).   In patients with drug-eluting coronary stents, when early polypectomy is deemed essential, it can be delayed for only 6 months from placement of the stents, when it is probably safe to discontinue clopidogrel temporarily (VI - C).   Aspirin therapy can (IV – C) - and in patients with stents should - be continued prior to and during polypectomy (VI – B).   Management of pT1 colorectal cancer If there is clinical suspicion of a pT1 cancer, a site of excision should be marked with submucosal India ink (VI - C).   Where a pT1 cancer is considered high-risk for residual disease consideration should be given to completion colectomy along with radical lymphadenectomy, both for rectal cancer (II - A) and colon cancer (VI - A). If surgical resection is recommended, consideration should be given to obtaining an opinion from a second histopathologist as variation exists in evaluating high risk features (VI - B).   After excision of a pT1 cancer, a standardised follow-up regime should be instituted (VI - A). The surveillance policy employed for high-risk adenomas is appropriate for follow-up after removal of a low-risk pT1 cancer (III - B).   Management of colon cancer If a complete colonoscopy has not been performed either because the primary lesion precluded total colonoscopy, or for any other reason for failure to complete colonoscopy, the rest of the colon should be visualised radiologically before surgery if at all possible. This should be performed ideally by CT colography, or if this is not available, by high-quality double-contrast barium enema. If for any reason the colon is not visualised prior to surgery, complete colonoscopy should be carried out within 3 to 6 months of colectomy (VI - B).   Patients with a proven screen-detected cancer should undergo pre-operative staging by means of CT scanning of the abdomen and pelvis (V - B). Routine chest CT is not recommended (III - D).   Patients with screen-detected colon cancer that has not been adequately resected endoscopically should have surgical resection by an adequately trained surgeon (III - A).   Where appropriate, laparoscopic colorectal surgery should be considered (I - A).   Management of rectal cancer If a complete colonoscopy has not been performed either because the primary lesion precluded total colonoscopy, or any other reason for failure to complete colonoscopy, the rest of the colorectum should be visualised radiologically before surgery if at all possible. This should be performed ideally by CT colography, or if this is not available, by high-quality double-contrast barium enema. If for any reason the colon is not visualised prior to surgery, complete colonoscopy should be carried out within 6 months to 1 year of excision of the rectal cancer (VI - B).   Patients with a proven screen-detected rectal cancer should undergo pre-operative staging by means of CT scanning of the abdomen and pelvis (VI - B). Routine chest CT is not recommended (III - D).   Patients with a proven screen-detected rectal cancer should ideally undergo pre-operative local staging by means of MRI scanning of the pelvis in order to facilitate planning of pre-operative radiotherapy (III - B), although high-quality multi-slice CT scanning may provide adequate information (VI - C).   All patients undergoing radical surgery for rectal cancer should have mesorectal excision (II - A) by an adequately trained specialist surgeon (VI - A).   Patients undergoing surgery for rectal cancer may be considered for laparoscopic surgery (I - B).   All patients undergoing surgery for rectal cancer (and certainly those predicted on imaging to have T3/4 cancers and/or lymph node metastases) should be considered for pre-operative adjuvant radiotherapy with or without chemotherapy (I - A).   Local excision alone should only be performed for T1 sm1 rectal cancers, and if the patient is fit for radical surgery (III - B). In the patient in whom there is doubt about fitness for radical surgery, local excision of more advanced rectal cancer should be considered (III - B).   In patients in whom local excision for rectal cancer is planned, consideration should be given to pre-operative CRT (III - C).   If a local excision is carried out, and the pT stage is T1 sm3 or worse, then radical excision should be performed if the patient is fit for radical surgery (II- B).

Please see Results card, CUR 18.

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).  

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).

Same as Result card TEC 3 in the Domain Technical description and characteristics of the technology.

FITs (Faecal immunochemical tests), also known as Immunochemical faecal occult blood test (iFOBTs), are a newer  class of Faecal Occult Blood tests (the first FOBTs developed and marketed were gFOBTs). According the EU Guideline 2010 (2), iFOBT have improved test characteristics than gFOBT. iFOBTs have been used for population CRC screening in Japan since 1992. In the US, iFOBTs have been approved by FDA (Food and Drug Administration) since 2001 (OC-Sensor).

Today, a wide range of qualitative and quantitative tests is available worldwide. Overtime, manufacturers have developed new sampling methods (brush-sampling vs stick-sampling FIT) with the aim of increasing simplicity of use and acceptability of test by participants  {77}.

New generation DNA tests for CRC screening will combine genetic markers with an immunochemical assay for haemoglobin {62}. A multi-marker fecal DNA test plus FIT, Cologuard has been developed by Exact Sciences Corp. They announced results of preliminary analysis of recently completed DeeP-C pivotal clinical trial in April 2013 {78} registered in ClinicalTrial.gov (NCT01397747) {79}. No study results posted on ClinicalTrials.gov yet.  This study compared the performance of the Cologuard test to colonoscopy and fecal immunochemical testing or FIT (according the ClinicalTrial.gov, Primary outcome was Sensitivity and Specificity of the Exact CRC screening test with comparison to colonoscopy, both with respect to cancer; Secondary outcome was to compare the performance of the Exact CRC screening test to a commercially available FIT, both with respect to cancer and advanced adenoma). Exact Sciences planned to submit data from the DeeP-C study to the U.S. Food and Drug Administration as part of its pre-market approval (PMA) submission, and will submit the study's complete data set for publication in a peer-reviewed journal, presentation at a major medical meeting or both.

Data about market authorization status (CE mark) on FIT are provided by EUnetHTA Partners and Manufactures, and are presented below according answers from EUnetHTA Partners survey and EUnetHTA Manufacturers survey.

Data from EUnetHTA Partners Survey

Eight EUnetHTA Partner organisations provided information on market authorisation status of FIT (and/or FOBT) products and some of them provided information on their use in CRC screening programmes.

Croatia Product(s): Hemcare and Immocare-C, Care diagnostic Productions-und Vetriebsgssellschaft m.b.H, Austria Status: CE mark as in vitro diagnostic for occult blood testing in stool Use in CRC screening: not used in CRC screening programme (g-FOBT Hemognost test, BioGnost d.o.o., Zagreb is used in CRC screening)   Italy (Veneto Region) Product(s): OC SENSOR, EIKEN distributed by MEDICAL SYSTEM. Status: regular CE mark Use in CRC screening: Yes   Russia Product(s): FOB Gold Status: Russian registration certificate issued by Roszdravnadzor Use in CRC screening: Yes   Luxembourg FIT is currently not on the market   Lithuania Product(s): multiple registered FITs Status: Market authorization status here under Directive 98/79/EC of the European Parliament and the Council of European Union Use in CRC screening: information on the test specifically is used in CRC programme was not available   Spain Product(s): not specified Status: Approved Use in CRC screening: Yes   Slovenia Product(s): EIKEN, Japan Status: CE certificate Use in CRC screening: Yes   France Product(s): not specified Status: CE mark Use in CRC screening: used in CRC screening programmes in 7 regions

Data from Manufactures survey

 

Only one manufacturer provided information on their FITs (Sentinel Diagnostics). The following products have CE mark: FOB Gold^® NG, FOB Gold^® Tube Screen, SENTiFIT^®- FOB Gold^® latex, SENTiFIT^®mini - FOB Gold^® latex, SENTiFIT^® pierceTube.

The FOB Gold® is distributed in all EU countries and in non-EU countries such as Turkey, Russia, and Czech Republic.

 

 

Data about reimbursement status of CRC screening with FIT are provided by EUnetHTA Partners and Manufactures, and are presented below according answers from EUnetHTA Partners survey and EUnetHTA Manufacturers survey.

Data from EUnetHTA Partners Survey

Eleven EUnetHTA Partners provided data on FIT reimbursement for their respective countries; FIT is fully reimbursed in all cases where FIT is used as part of a CRC screening programme (5 countries, please see also Result card CUR12).

In specific, FIT is used in the Regions of Veneto and Lazio in Italy, Lithuania, Russia, Slovenia and Spain. FIT is also reimbursed in the Austrian province of Burgenland in the framework of the CRC FIT-based screening programme (no details for reimbursement are available).

 

 

Data from Manufactures Survey

 

Full reimbursement of the FIT test in the case of organised CRC screening activities by the National Public Health System was also reported by one Manufacturer that responded to the EUnetHTA survey (Sentinel Diagnostics, manufacturer of FOB Gold^®).

 

FIT (Faecal immunochemical test) is an alternative name for Immunochemical faecal occult blood test (iFOBT), a class of faecal occult blood tests. Faecal Occult Blood Tests (FOBTs) are tests for blood or blood products. They use blood as an indicator of the presence of tumour {1}.

A wide range of qualitative and quantitative iFOBT tests 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.

Similar to g FOBT, participants collect one or more stool samples. The sampling procedure varies: different sampling systems are available (wooden sticks, brushes) and samples may be applied either to a card (dry method) or to place into a vial (wet method). Samples can be analysed either using automated systems in the laboratory (for some manufacturers) or are read by the naked eye with a positive result indicated by a colour change on a strip {2}. The automated systems can be quantitative or qualitative. Qualitative tests produce a dichotomous result, with individuals categorized as either positive or negative if the amount of Hb in the faecal sample is above or below a specific analytical detection limit set by the manufacturers. In quantitative tests, specificity can be determined by the user {3}. The most frequently used values are 75 or 100 ng/mL. This is important due the fact that by increasing the positive cut-off limit, the test sensitivity and positivity rate decreases and specificity and positive predictive values for CRC detection increase. FIT kits with a visual result are designed as point-of-care devices and are qualitative. They can be adopted for use in clinical laboratories for population-based screening; however they retain a more manual approach than the automated systems.

In their report on the comparison of FITs vs. g FOBTs for population-based colorectal cancer screening in Ontario, CA {4} the FIT Guidelines Expert Panel has considered test processing in laboratories more suitable that point-of-care systems for a population-based screening program. Similarly, the NHS Centre for Evidence-based Purchasing in the UK adopted certain criteria that the iFOBTs had to meet in order to be evaluated for the CRC screening programme in the UK {5}. Only automated systems were included in the evaluation. Regarding staff requirements, more technical knowledge will be required than for gFOB tests. If the increased packing material is required to meet postal regulation, unpacking of iFOBT liquid sampling devices may take longer than for gFOBT.

Potential advantages and disadvantages of iFOBT are given in Table 1.

Table 1. Potential advantages and disadvantages of iFOBT (5)

 

Advantages of iFOBT

Disadvantages of iFOBT

 

Automated analysis	Sample instability in liquid collection devices
Specificity for human HB, reducing the number of false positive results	Possible additional requirements for packaging of the liquid sample collection devices to meet different MSs postal regulation
Increased sensitivity to human Hb	Cost of the test
Ability to adjust the cut-off Hb concentration in qualitative iFOBTs (except Hem-SP/MagStream HT method as qualitative method)

 

 

Three iFOBT are presented here, as three analytical platforms using the three sample collection devices: OC-Sensor/OC-Sensor Diana & OC-Sensor Micro, Hem-SP/MagStream HT, FOB Gold/SENTiFOB analyser.  In brief {6}:

•  OC-Sensor measures human Hb concentration in faeces samples by latex agglutination using polystyrene latex particles coated with polyclonal anti haemoglobin Ao antibodies. One sample only is recommended as number of separate samples used for assessment. The Diana has a memory capacity for 100 000 test results, with speed of 280 samples per hour analysis. Ten mg of faeces is recommended as quantity that should be collected by sampling device. Advantage is that this test is CE marked for a user defined cut-off (default setting 100 ng/mL), with 20 ng/mL in buffer as limit of detection. The faecal sample is collected into the OC-Auto sampling bottle 3. Analysis should be performed as soon as possible after sample collection; in case of any delay the sample collection bottles should be stored at 2-10C;
• Hem-SP/MagStream HT (MagStream Hem-Sp®) is based on magnetic particle agglutination (the magnetic particles are coated with rabbit anti-human Hb antibodies). Two samples are recommended as number of separate samples used for assessment. One disadvantage is that this method is qualitative, and has a non-adjustable cut-off at a Hb concentration equal to or greater than 20 ng/ml. In the presence of human haemoglobin, the particles remain aggregated in a spot with minimal change (positive result). In the absence of human haemoglobin, particles flow down the slope (negative result).  MagStream HT, an automated instrument which holds 400 samples has a memory capacity of 2 million test results, with speed of analysis of 960 tests per hour (MagStream HT). 0.3 mg of faeces is recommended as quantity should be collected by sampling device. The faecal sample is collected into the NEW HEMTUBE. Analysis should be performed as soon as possible after sample collection; in case of any delay the sample collection bottles should be stored at 2-10C. Freezing must be avoided;

The FOB Gold use an antigen-antibody agglutination reaction between human haemoglobin and polyclonal anti-human haemoglobin antibodies coated on polystyrene particles. The total reading time is 8 minutes, with speed of analyses of 75 tests/hr

• (SentiFOB). The FOB Gold reagents can be used on any suitable immunoassay automated analyser although the manufacturer provides the SENTiFOB analyser. Advantages of this test is that this test is CE marked for a user defined cut-off, with limit of detection of 14 ng/mL buffer, and measuring range of 15-1000 ng/ml. The faecal sample is collected into the FOB Gold tube. Analysis should be performed as soon as possible after sample collection; in case of any delay the sample tubes should be stored at 2-8 C.

 

Some of products characteristics are presented in Table 2.

 Table 2. Product characteristics of OC-Sensor/OC-Sensor Diana & OC-Sensor Micro, Hem-SP/MagStream HT, FOB Gold/SENTiFOB analyser {5-9}.

Product characteristics	OC-Sensor/OC-Sensor Diana & OC-Sensor Micro	Hem-SP/MagStream HT	FOB Gold/SENTiFOB analyser
Analyser name	OC-Sensor Diana OC-Sensor Micro	MagStream HT	SENTiFOB
Manufacturer	Eiken Chemical Co., Tokyo, Japan, www.eiken.co.jp/en/company/index.html	Fujirebio Inc. Japan, http://www.fujirebio.co.jp/english/index.html	Sentinel Diagnostics SpA, Milan, Italy, http://www.sentinel.it/uk/
Method	Latex agglutination	Magnetic particle agglutination	Latex agglutination (open method)
Sample collection system	OC-Auto sampling bottle 3	New HEMTUBE	FOB Gold tube
Measuring range	50-1050 ng/mL	>20 ng/mL	14-1000 ng/mL
Analyser sample volume	35 µL	25 µL	10 µL
Throughput (claimed/measured)	280 per hour/245 per hour	960 per hour/800 per hour	75 per hour/65 per hour
Usual threshold	175 ng Hb/ml in the buffer	211 pixels (MSR=1.0)	100 ng Hb/ml in the buffer
CE mark	Quantitative measurement	Qualitative measurement	Quantitative measurement
Use in population screening	The Netherlands, Northern Italy, US, Uruguay, France	Japan, France and Slovenia	Italy, France

 

Different authors {5-8} have compared the analytical performance of 3 iFOB tests: OC-Sensor/OC-Sensor Diana & OC-Sensor Micro, Hem-SP/MagStream HT, FOB Gold/SENTiFOB analyser. With regard to reproducibility and temperature stability, OC-Sensor performed better than Magstream and far better than FOB Gold. For all tests, variability was essentially related to sampling. Detected Hb levels were substantially lower for all tests at temperatures above 20 C. This loss is more important for FOB Gold than for other two tests. Some suggestion are made, like delay between sampling and test processing should be reduced to 3 days, or CRC screening programs should be stopped during the summer in countries with long period of very high temperatures >30 C. Patients should be advised to store faecal samples in the refrigerator at home before forwarding them by post.

Rossum et al. {10} reported that delay in sample return increased false negative iFOBT because of Hb degradation. Compared with no-delay, the adenoma detection rate was significantly decreased after >5 days delay (OR 0.6; 95% CI 0.4-0.9).

Sentinel Diagnostic Spa, manufacturer of FOB Gold NG test was only one who responded on our Survey for Manufacturer and sent documentation for their FIT products. The product leaflet of SENTiFIT pierce Tube (collection tube) writes that the human haemoglobin extracted from the feces sample and obtained according to the recommended collection procedure is stable for 14 days at 2-8 C or 7 days at 15-30 C protected from direct light.

The authors of the NHS Centre Evaluation report in 2009 {5}, concluded that the OC-Sensor/DIANA analyser was the most suitable system for the English CRC population-based screening programme. They reported that even when the faecal collection devices were used by experienced evaluation staff, none of the sampling devices gave reproducible results, contributing to the overall imprecision of the methods. Manufacturers claims for stability of the Hb in faecal samples added to the collection devices and stored at room temperature (23C-26C) prior the analysis were confirmed for the OC-Sensor/DIANA method only. Analytical methods comparisons are presented in Table 3.

Table 3. Analytical methods comparisons for 3 iFOB tests: OC-Sensor/OC-Sensor Diana & OC-Sensor Micro, Hem-SP/MagStream HT, FOB Gold/SENTiFOB analyser {5}

OC-Sensor/OC-Sensor Diana method (quantitative)	Hem-SP/MagStream HT method (qualitative)	FOB Gold/SENTiFOB analyser method (quantitative)
Good imprecision, results consistent with the manufacturers claims	Poor imprecision, results not consistent with the manufacturers claims at low Hb concentration	Poor imprecision, results not consistent with the manufacturers claims at low Hb concentration
Linear in the range 50-500 ng Hb/ml buffer	Not linear since the method is not designed to be linear accross a broad measuring range	Linear in the range 50-500 ng Hb/ml buffer
Identified a problem with samples with very high Hb concentration and did not produced a result		Identified a problem with samples with very high Hb concentration and did not produced a result

 

 

According the authors of this report {5}, all 3 analytical platforms are easy to operate and maintain once appropriate training has been received. For all three tests, the liquid samples stored at room temperature for more than three days are not suitable for analysis, due to deterioration of any Hb present. This should be taken in account when sending samples via different MSs postal systems (should be returned within this time). The OC-Sensor/DIANA analyser was the most suitable system for the UK bowl cancer screening programme, despite limited reagent, wash and waste capacity (regular attention will be required in a busy screening laboratory). The FOB Gold/SENTiFOB analyser has a very low sample throughput. The HemSp/MagStream HT has a non-adjustable cut-off, the method is not CE marked for quantitative measurement of human Hb. The system gave negative results for samples that were positive by other methods.

 

For all three tests sample collection devices should be stored between 2 and 10 C in case of any delay in analysis, so refrigerated storage space is required. The number of analysers required will depend on the laboratory workload; number required for a 5,000 sample per day workload will be 1 for HemSp/MagStream HT; 5 for OC-Sensor/DIANA, and 15 SentiFOB and 1 chemistry analyser for FOB Gold/SENTiFOB. Specialist training is provided by the manufacturers (instructions on routine use and maintance of the analyser). Staff will be required to authorise each batch of results generated from the iFOBT analysers and transfer the data to the bowel cancer screening programme database, if such exists {5}.

Results {5-8}

FITs /iFOBTs are a class of faecal occult blood tests and one out of few different screening options for colorectal cancer (CRC). The aim of population-based screening for CRC is to reduce mortality through both, prevention (by the removal of adenomas) and earlier diagnosis of CRC.

Overall, the advantages of FIT in contrast to gFOBT are: specificity for human Hb, reducing the number of false positive results and no dietetic restrictions are necessary; increased sensitivity to human Hb; automated analysis and the possibility to set cut-off limits (the latter applies only to quantitative FIT tests).

According to the EU Guidelines for quality assurance in CRC screening and diagnosis (2010) {6}:

-“iFOBT have improved test characteristics than gFOBT, and they are currently the test of choice for population CRC screening. In different settings, individual device characteristics like ease of use by participant and laboratory, suitability for transport, sampling reproducibility and sample stability are important and should be all taken into account when selecting the iFOBT most appropriate for CRC screening programme (Level of evidence II, Grade of recommendation A);

 

-Maximum period between collection and analysis is significantly shorter than for gFOBT (14-21 days), and screening programmes should adopt the conditions and period of storage described in manufacturers. Instructions for use should be appropriate for local conditions which might expose samples to high temperatures for long period of time (Level of evidence III, Grade of recommendation A);

 

-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)“.

 

FITs are a newer class of Faecal Occult Blood tests (the first FOBTs developed and marketed were gFOBTs). According the EU Guideline 2010(6), iFOBTs have improved test characteristics than gFOBT. iFOBTs have been used for population CRC screening in Japan since 1992. In the US, iFOBTs have been approved by the FDA (Food and Drug Administration) since 2001 (OC-Sensor).

Today, a wide range of qualitative and quantitative tests is available worldwide. Over time, manufacturers have developed new sampling methods (brush-sampling vs stick-sampling FIT) with the aim of increasing simplicity of use and acceptability of test by participants {11}.

According to Lin et al. {12}, a new generation DNA test for colorectal cancer screening will combine genetic markers with an immunochemical assay for haemoglobin. A multi-marker faecal DNA test plus FIT, Cologuard has been developed by Exact Sciences Corp.  They announced results of preliminary analysis of recently completed DeeP-C pivotal clinical trial in April 2013 (13), registered in ClinicalTrial.gov {14}. No study results posted on ClinicalTrials.gov yet. This study compared “the performance of the Cologuard test to colonoscopy and faecal immunochemical testing or FIT” (according the ClinicalTrial.gov, Primary outcome was Sensitivity and Specificity of the Exact CRC screening test with comparison to colonoscopy, both with respect to cancer; Secondary outcome was to compare the performance of the Exact CRC screening test to a commercially available FIT, both with respect to cancer and advanced adenoma). Exact Sciences planned to submit data from the DeeP-C study to the U.S. Food and Drug Administration as part of its pre-market approval (PMA) submission, and will submit the study's complete data set for publication in a peer-reviewed journal, presentation at a major medical meeting or both.

Apart of health professionals (primary care physicians and nurses, laboratory staff), people invited to screening will use this technology.

The EU guidelines for quality assurance in CRC screening and diagnosis {6} state that “people invited to screening need specific and clear instructions on how to use the kit. Factors that enhance accessibility and uptake are the design of a test kit, and simple and clear instructions which should be provided with the test kit. Effective sample collection is critical to the success of a screening programme with FOBT, so the process of collection should be as simple as possible. Physical and mental disabilities in the screened age group could be one of the reasons for non-participation.

Laboratory staff is necessary in settings where a screening programme is based on a FOBT. The training and skills required are dependent on the type of the test (gFOBT or iFOBT, qualitative or quantitative); staffs require supervision by appropriately qualified individual with expertise in clinical biochemistry, and the day-to-day running of the laboratory must be managed by an appropriate skilled scientific officer. Laboratory staff required training in good laboratory practice, training in the performance of the FOBT, and training in the use of the IT system used to record results, in addition to basic understanding of the CRC process. Laboratory Manager required training on managerial skills, internal quality control and external quality assurance; interactions between the laboratory process and the whole screening programme. Individual with expertise in clinical biochemistry which is responsible for the operation of laboratory required training  on in-depth understanding of CRC, screening process, performance characteristics of different type of FOBT; in-depth understanding of the technology required to perform the FOBT.

Primary care physicians and nurses in primary care should be informed about national CRC screening programme, to be able to help people invited to screening, if they asked for, in form of answering questions on screening and tests, but not to perform FOBT on an individual basis”.

FIT is used in population-based screening for CRC. Faecal occult blood testing for men and women in the range of 50-74 years is the only CRC screening method currently recommended by the EU {15}.

Results {5-9}

iFOBT have improved test characteristics than gFOBT. In different settings, individual device characteristics like ease of use by participant and laboratory, suitability for transport, sampling reproducibility and sample stability are important and should be all taken into account when selecting the iFOBT most appropriate for CRC screening programme.

In contrast to gFOBT, iFOBT requires shorter transportation time frame due instability on room temperature (this should be taken in account when sending samples via different MSs postal systems, should be returned within 3 days); new investments in laboratory; staff education (instructions on routine use and maintance of the analyser is provided by manufacturers);  all three tests sample collection devices should be stored between 2 and 10 C in case of any delay in analysis, so refrigerated storage space are required. The number of analysers required will depend on the laboratory workload. iFOBT sample collection tubes will require disposal in rigid bins to contain any liquid, which requires different procedure and more manual handling.

 

FIT is used in the population targeted for colorectal carcinoma screening (CRC). The target group is asymptomatic people at average risk, of both genders. Regarding the age-range, 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. According the Ontario HTA Report {16} 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 are other protocols for screening of individuals at higher risk for CRC.

In the European guidelines for quality assurance in CRC screening {6} it is suggested that “in the absence of additional evidence, the age range for a screening programme with iFOBT can be based on the limited evidence for the optimal age range in gFOBT trials. 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). “

This field of faecal tests for CRC screening is changing fast according literature data. In addition to faecal DNA tests, new area of research is use of RNA markers in stool, as well as the use of DNA or RNA in plasma, serum and urine. Much work is still ongoing on use of protein biomarkers in blood for CRC screening and early detection.

For phase of FIT please see Result card TEC 3.

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) the only commercially available test in the US, 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. Authors of the 2012 AHRQ HTA Report {12} 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. Existing evidence has little or no applicability to currently available faecal DNA testing.

At its website, Epigenomics stated that Septin9 test, the world's first blood-based IVD test for CRC screening, has been available as a CE-marked test kit in Europe and the Middle East since October 2009. For the improved Septin9 test, Epi proColon 2.0, according to the company’s press release {17}, the fourth module of the PMA was submitted to FDA, which contained the clinical data generated with the test, including the results of the recently reported head-to-head comparative study of the performance of the Epi proColon® to FIT(18) (with no study results posed yet), previously announced data from a clinical validation study in a cohort of prospectively collected samples and other clinical study results generated during the development of Epi proColon®. On 15 05 2013 they also announced that results of the head-to-head comparative study between its blood-based CRC detection test Epi proColon and FIT will be presented at the workshop of the WEO CRC Screening Committee during conference in Orlando, May 17, 2013 {19}.

Results {5-8,20}

Cut-off limits are important in CRC screening due the fact that, by increasing the positive cut-off limit, the test sensitivity and positivity rate decreases and specificity and positive predictive values for CRC detection increase.

European guidelines {6} state that “the choice of a cut-off concentration to be used in an immunochemical test to discriminate between a positive and negative result will depend on the test device chosen, the number of samples used and the algorithm adopted to integrate the individual test results. Whilst an increasing number of studies are reporting the experience of different algorithms, local conditions, including the effect on sample stability of transport conditions, preclude a simple prescribed algorithm at this time. Adoption 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 (VI - A)”.

Two out of three iFOBT are quantitative tests and have adjustable or user defined cut-off values (OC-Sensor and The FOB Gold); Hem-SP/MagStream HT is qualitative, and has a non-adjustable cut-off value:

• OC-Sensor is CE marked for a user defined cut-off (default setting 100 ng/mL), with 20 ng/mL in buffer as limit of detection.;
• Hem-SP/MagStream HT is qualitative, and has a non-adjustable cut-off at a Hb concentration equal to or greater than 20 ng/ml;
• The FOB Gold is CE marked for a user defined cut-off, with limit of detection of 14 ng/mL buffer, and measuring range of 15-1000 ng/ml.

 

Van Rossum at al. {20}, using OC-Sensor collection and OC-Micro analyser  concluded that cut-off of 75 ng/ml brought optimal results and may be recommended for population screening in Netherlands. They concluded also in settings where colonoscopy capacity is insufficient, a cut-off up to 200ng/ml would result in minimal false negative results for cancer although more for advance adenoma.

 

iFOBTs are around 10-fold more expensive than gFOBT. In an evaluation of three automated analytical iFOB methods in the UK {5}, investments made by a laboratory for use of FIT, include:

-Analytical platforms (automated analysers): The number of analysers required will depend on the laboratory workload; number required in the evaluation for a 5,000 sample per day workload will be 1 for HemSp/MagStream HT; 5 for OC-Sensor/DIANA, and 15 SentiFOB and 1 chemistry analyser for FOB Gold/SENTiFOB. All analysers required routine prentative maintance visits (part of the service contract, annualy, but depend on the workload). All analysers required a 13 amp power suplly and purified water to wash the cuvettes (OC-Sensor/DIANA) or for preparation of wash solutions (all three) and system solution (SentiFOB). All three have RS 232-C serial interface ports.

-Sample collection devices: for OC-Sensor the faecal sample was collected into the OC-Auto sampling bottle 3; for Hem-SP/MagStream HT (MagStream Hem-Sp®) the faecal sample was collected into the NEW HEMTUBE; for the FOB Gold the faecal sample was collected into the FOB Gold tube.

- Refrigerated storage space

- Clinical waste disposal.  iFOBT sample collection tubes required disposal in rigid bins to contain any liquid, which required different procedure and more manual handling.

- End of life disposal: end of life disposal of the products may have financial and/or environmental costs, depending on the regulations in place (e.g. Waste Electrical and Electronic Equipment regulation in the UK).

Please see Result card TEC 6.

Please see  Result card TEC 7.

The data and records needed that are described refer to the entire CRC screening process, not only for testing with iFOBT.

 

According the European guidelines (2010) {6}, relevant data on each individual and every screening test performed must be recorded, including the test results, the decision made as a consequence, diagnostic and treatment procedures and the subsequent outcome, including cause of death, should be ensured. The data must be linked at the individual level to several external data sources including population register, cancer or pathology registries, and registries of cause of death in the target population, to be able to evaluate the effectiveness of screening.

Legal authorisation should be put in place when the screening programme is introduced in order to be able to carry out programme evaluation by linking the above-mentioned data for follow-up (VI - A).

 

A database consisting of individual records (one record per person for each screening episode) is essential in order to produce results on screening performance (VI - A).

 

Quality control procedures for the database should be available and run regularly to check the quality of the data and to correct any data entry errors. (VI - A).

 

A table should be made to present the test results (positive, negative, or inadequate) by gender and age.

Following Process variables in screening with the faecal occult blood test (FOBT) and other in vitro tests should be applied: Screened/tested; Inadequate test; Positive test; Referral to follow-up colonoscopy.

Following Outcomes variables should be applied to CRC screening performed with any of the currently available primary screening tests; follow-up colonoscopy; lesions; adenomas; advanced adenoma; cancers; severe complications required hospitalizations; 30-day mortality.

Following data tables should be produced: target, eligible, invited, screened/tested at 1^st screening and at subsequent screening episodes; inadequate test; positive test or screening; follow-up colonoscopy examination attended; negative follow-up colonoscopy examination; positive follow-up colonoscopy examination; lesion detected; adenoma detected; non-advanced adenoma detected; advanced/high-risk adenoma detected; cancer detected by stage.

The registers needed are described in detail in the European guidelines for quality assurance in CRC screening {6}: “Relevant data on each individual and every screening test performed must be recorded, including the test results, the decision made as a consequence, diagnostic and treatment procedures and the subsequent outcome, including cause of death, should be ensured. The data must be linked at the individual level to several external data sources including population register, cancer or pathology registries, and registries of cause of death in the target population, to be able to evaluate the effectiveness of screening.

Legal authorisation should be put in place when the screening programme is introduced in order to be able to carry out programme evaluation by linking the above-mentioned data for follow-up.”

The qualification, training and quality assurance processes are described in detail in the respective European guidelines {6}:

“Laboratory staff is necessary in settings where a screening programme is based on a FOBT. The training and skills required are dependent on the type of the test (gFOBT or iFOBT, qualitative or quantitative); staffs require supervision by appropriately qualified individual with expertise in clinical biochemistry, and the day-to-day running of the laboratory must be managed by an appropriate skilled scientific officer.

Laboratory staff required training in good laboratory practice, training in the performance of the FOBT, and training in the use of the IT system used to record results, in addition to basic understanding of the CRC process.

Laboratory Manager required training on managerial skills, internal quality control and external quality assurance; interactions between the laboratory process and the whole screening programme.

Individual with expertise in clinical biochemistry which is responsible for the operation of laboratory required training  on in-depth understanding of CRC, screening process, performance characteristics of different type of FOBT; in-depth understanding of the technology required to perform the FOBT.

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).

 

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).

 

Quality assurance of iFOBT

Manufacturer’s Instructions for Use must be followed. Daily checks of analytical accuracy and precision across the measurement range with particular emphasis at the selected cut-off limit should be performed. Sufficient instrumentation should be available to avoid delays in analysis due to instrument failure or maintenance procedures. Performance data (both internal quality control and external quality assessment data) should be shared and reviewed by a Quality Assurance team working across the programme. (Level of evidence VI, Grade of recommendation B).

 

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).“

 

 

Please see Result card TEC 12.

According the Manufacturer of FOB Gold NG assay, simple training is required in order to inform the users about the use of the product and results interpretation. The typical professional laboratory operator is able to use the test in a very short time.

Information and education provided about CRC and CRC screening test and procedures is a key component of CRC screening programmes. Three phases in which information can be provided to participants are: Invitation phase (invitation for screening through invitation letters and leaflets); Reporting results page (screening test results are communicated to the participants), and Follow up phase (for people with positive FOBT results).

Personal invitation letters, preferably signed by the GP, should be used. Specific instructions on how to use FOBT kit or perform the bowel cleansing procedure need to be communicated to the patient. Patient should be able to understand written instructions how to perform these procedures. Written material should be clear, visually appealing and motivating.

 Recommendations from EU Guidelines {6} on different screening process steps are (see also TEC 14-Appendix 1):

“To communicate CRC screening information, including written instructions on how to use the FOBT kit or perform the bowel cleansing procedure, the language and text format used should be easy to understand and illustrations may be used. Ideally, written information (including written instructions) should not be the only source of information and should be complemented by visual communication instruments and/or oral interventions (VI - A).

 

Primary health care providers should be involved in the process of conveying information to people invited for screening (II - A).

 

In the context of an organised programme, personal invitation letters, preferably signed by the GP,

should be used. A reminder letter should be mailed to all non-attenders to the initial invitation (I - A).

 

Clear and simple instruction sheets should be provided with the kit (V - A).

 

Use of a non-tailored leaflet for the general population is advised; the leaflet should be included with the invitation letter. Information about CRC screening risks and benefits, CRC risks (incidence and risks factor), meaning of test results, potential diagnostic tests and potential treatment options should be included (VI - A).

 

Illustrations may be used, which would be particularly useful for minorities, the elderly or low-literacy participants (II - A).

 

Video/DVD may be a useful component in a multi-modal intervention in addition to written information, and would be particularly useful for the elderly, minorities and low literacy participants (I - B).

 

For the elderly, increasing the number of components of the multi-modal intervention and the period over which these components are provided may be more effective (I - B).

 

A computer-based decision aid could be used to help both the general population and specific groups to make informed decisions about CRC screening (I - B). The computer-based decision aid should be “user-friendly” and designed to fit with the computer abilities of the target population (general or specific groups).

 

If possible, all information provided by the screening programme should be available on a specific web site. This information should be regularly updated (VI - A).

 

Patient navigation could be used within CRC screening programmes, particularly to reach subgroups of the population such as the elderly, those with low literacy, and medically underserved patients. When used with minorities, the patient navigator should be from a similar ethnic background and/or live in the same community as the participant (I - B).

 

Verbal face-to-face interventions with a nurse or physician could be used to improve knowledge and participation. They would be useful to reach subgroups of the population such as the elderly, minorities and those with low literacy (I - A).

 

Nurses and primary care practitioners (GPs) should receive adequate training to be able to help people make informed decisions about CRC screening (VI - A).

 

CRC screening programmes should work closely with advocacy groups and the media and provide them with up-to-date, accurate and comprehensive information about CRC and CRC screening (VI - A).

 

A telephone or ideally a verbal face-to-face intervention, e.g. nurse or physician intervention, should be used to inform a patient of a positive screening test result, as obtaining such a result could be a source of psychological distress for the patient. A letter informing the patient should not be used as the only way of notifying a positive result (VI - A).

 

To increase endoscopy follow-up after a positive FOBT and facilitate communication, CRC

screening programmes should, where possible:

- Use a reminder-feedback and an educational outreach intervention targeted to the primary

care physician (II - A);

- Provide patients with a written copy of their screening report (II - A);

- Facilitate patient consultation with a gastroenterologist (V - B);

- Describe the follow-up procedure, make the follow-up testing more convenient and

accessible (VI - A); and

- Use direct contact intervention to address psychological distress and other specific barriers.

(V - B).

 

Each endoscopy service must have a policy for pre-assessment that includes a minimum data set relevant to the procedure. There should be documentation and processes in place to support and monitor the policy (III - B).

 

The endoscopy service must have policies that guide the consent process, including a policy on withdrawal of consent before or during the endoscopic procedure (VI - B).

 

Before leaving the endoscopy unit, patients should be informed about the outcome of their procedure and given written information that supports a verbal explanation (VI - A).

 

The outcome of screening examinations should be communicated to the primary care doctor (or equivalent) so that it becomes part of the core patient record (VI - B).

 

Ideally, the invitation letter and the letter used for notification of a positive result should be sent with a leaflet and should encourage participants to read it (VI - A).

 

Certain basic information, e.g. logistic/organisational information, description of the screening test, harms and benefits of screening, information about the FOBT kit and the bowel cleansing procedure, must be included in the invitation/result letter in case a person reads only the letter and not the leaflet (VI - A). ”

General information on CRC burden and CRC screening clinical importance and CRC screening methods available.

Domain research was used and completed with other studies used in HAS report dated 2008 and information from HAS recommendation dated 2013. Systematic reviews referenced in HAS report 2008 {3, 8} were used as a basis for this result card. 

The screening methods gFOBT and FIT are non-invasive procedures that are therefore not likely to cause any direct harm.

Indirect harm can be caused by a wrong or delayed diagnosis (see Q6) or by harms related to subsequent colonoscopy. Indeed, participants with a positive result of the screening test are referred for further diagnostic evaluation by invasive procedures which may be associated with various adverse events (see point 1 Harms from colonoscopy).

Furthermore, gFOBT and FIT may have a psychological impact related to the procedure itself and related to positive results (see point 2 Psychological harms).

The overall number of adverse events may be influenced by the number of colonoscopies that depends on sensitivity and specificity of the screening test {3}.           1) Harms from Colonoscopy

Summary of results:

The overall colonoscopy related morbidity is estimated to 5%. Minor complications such as bloating, abdominal pain or other complications related to bowel preparation have been reported. Major complications are rare and include perforation of the gut and haemorrhage. Complications related to sedation (hypoxia) or cardiovascular complications can be also observed. Infection risks are very rare. {4, 1}

One study also addressed the embarrassment experienced during endoscopy {5}. 

The frequency of colonoscopy complications varies from one study to another and results from the different trials are presented further below for completeness of information.

As for the duration of harms Senore et al. {5} found that in about 90% of the cases symptoms were of short duration (arose within two hours from screening and were resolved within four hours).

Summary table of selected references:Author, year	Type of reference	Title	Conclusions
HAS, 2013 {1}	National recommendation	HAS recommendation on colorectal screening and prevention	The overall morbidity related to colonoscopy is estimated to 5%. Major complications are rare.
Medical Services Advisory Committee, 2004 {4}	Assessment report	Faecal occult blood testing for population health screening	Occasional complications are associated with bowel preparation and sedation prior to colonoscopy.
Hewitson P, Glasziou P, Irwig L, Towler B, Watson E., 2007, update 2011 {3}	Cochrane systematic review	Screening for colorectal cancer using the faecal occult blood test, Hemoccult	The rate of perforation during colonoscopy is approximately 1 in 1,400.  Major bleedings occurred in 1 out of approximately 1100-1500 procedures.
Quintero et al., 2012 {6}	Article	Colonoscopy versus Fecal Immunochemical Testing in Colorectal-Cancer Screening	Among 24 subjects[1] in the colonoscopy group, 12 (50%) expereinced bleeding, 10 (42%) hypotension or bradycardia, 1 (4%) perforation, and 1 (4%) low blood saturation. Among 10 subjects[2] in the FIT group who had subsequent colonoscopy, 8 patients (80%) expereinced bleeding and 2 (20%) hypotension or bradycardia.
Guittet, L., et al., 2007 {7}	Article	Comparison of a guaiac based and an immunochemical faecal occult blood test in screening for colorectal cancer in a general average risk population	A perforation of the gut occurred in one out of 644 patients screened by colonoscopy (0,2%).
Senore, C., et al., 2011 {5}	Article	Acceptability and side-effects of colonoscopy and sigmoidoscopy in a screening setting	The burden of bowel preparation was associated with a nearly five-fold increase in the occurrence of serious disturbances among people undergoing TC, as compared with FS.

 

Results from different trials:

•   [Cochrane systematic review:  Screening for colorectal cancer using the faecal occult blood test, Hemoccult; 2007, update 2011] {3}

A systemic review of literature published up to June 2010 has been done with a primary objective to determine whether screening for colorectal cancer using the faecal occult blood test (guaiac or immunochemical) reduces colorectal cancer mortality. Secondary objective was to evaluate the range of benefits and harms of screening.

Four randomised controlled trials (Nottingham, Funen, Goteborg, Minnesota) involving about 327,000 participants have been included in the review, all of them using Hemoccult test as screening method. In all of the trials, participants with a positive Hemoccult test were referred for further diagnostic evaluation, performed by colonoscopy in all trials except one (Goteborg), in which participants received sigmoidoscopy and double-contrast barium enema.

Among three trials that used colonoscopy as the primary means of further investigation, two reported adverse outcomes in detail (Minnesota, Nottingham) and found that the rate of perforation during colonoscopy is approximately 1 in 1,400.  

In the Minnesota trial, of the 12,246 colonoscopies performed at the University of Minnesota hospital there were four perforations of the colon (all requiring surgery) and 11 serious bleeding complications (3 requiring surgery). The Nottingham randomised trial reported that there were seven complications (out of 1,474 procedures) associated with colonoscopy (five perforations, one major bleed, one snare entrapment). Six of these complications required surgery although none of these patients died from the colonoscopy complications.

Although participants from the Goteborg trial mainly received sigmoidoscopy and double-contrast barium enema in further investigation, colonoscopy has been also done in case of repeated failure of other diagnostic methods or for polypectomy. Therefore, adverse outcomes for both flexible sigmoidoscopy and colonoscopy are reported in this trial. One patient's large bowel was perforated during diagnostic endoscopy. Four perforations of the large bowel occurred during endoscopic polypectomy, and one case of bleeding occurred 12 days after polypectomy. No complications occurred in connection with the 1,987 double-contrast barium enemas.

•    Quintero et al, 2012: Colonoscopy versus Fecal Immunochemical Testing in Colorectal-Cancer Screening,] {6}

A randomized, controlled trial involving asymptomatic adults compared one-time colonoscopy with FIT every 2 years in a screening setting. Adults with positive result on FIT were further invited to undergo colonoscopy. The study design allowed for crossover between the two study groups. [3]

Major complications occurred in 24 subjects (0.5%)[4] in the colonoscopy group (12 subjects with bleeding, 10 subjects with hypotension or bradycardia, 1 subject with perforation, and 1 subject with low blood saturation) and in 10 subjects (0.1%)² in the FIT group in patients who had subsequent colonoscopy (8 subjects with bleeding and 2 subjects with hypotension or bradycardia.

•   Guittet, L., et al. (2007). "Comparison of a guaiac based and an immunochemical faecal occult blood test in screening for colorectal cancer in a general average risk population." {7}

This trial compared the screening performances of the gFOBT and the immunochemical faecal occult blood test (I-FOBT or FIT) in an average risk population sample of 10 673 patients who completed the two tests.

Patients with at least one positive test result were asked to undergo colonoscopy. One perforation was recorded in 644 colonoscopies. (0.2%)

•   Senore, C., et al. (2011). "Acceptability and side-effects of colonoscopy and sigmoidoscopy in a screening setting." {5}

The study compared subjects’ experiences of sigmoidoscopy and colonoscopy in a screening setting. They especially focused on side-effects other than perforation and bleeding risk, and provided an active follow-up beyond the period spent in the endoscopy unit with a prospective 30-day follow-up after discharge.

Adverse effects associated with the preparation were reported by 15.0%[5] of the interviewees examined with sigmoidoscopy and by 30.1%³ of those examined with colonoscopy (OR: 2.44; 95% CI: 2.01–2.95). The most common complaints in both groups were abdominal pain, bowel distension and anal irritation, mentioned by 10.1%, 7.7% and 3.2% of people in the sigmoidoscopy group and by 12.8%, 11.1%, and 7.3% of those in the colonoscopy group.

People experiencing more than mild embarrassment were 3.8% and 4.0% for sigmoidoscopy and colonoscopy respectively.

Immediately after the test, some patients reported severe pain (16.6% in the colonoscopy group and 9,5% in the sigmoidoscopy group).

Adverse physical reactions following discharge were reported by 521 (34.7%) people examined with sigmoidoscopy and by 448 (37.4%) of those examined with colonoscopy. In about 90% of the cases symptoms arose within two hours from screening and resolved within four hours.

Bowel distension and abdominal pain were the most common complaints, they were reported as the only symptom by 15.6% and 4.5% of interviewees examined with sigmoidoscopy and by 14.7% and 6.0% of those undergoing colonoscopy screening, and in association by 8.5% of people examined with sigmoidoscopy and by 8.8% of those undergoing colonoscopy.

Patients who underwent sedated colonoscopy were more likely to report feeling dizziness after discharge (3.4%) than those having an unsedated exam (0.8%).

The 30- day admission rate was 1.34% (16/1197), 1.13% (11/976) and 0.88% (12/1363) in the sigmoidoscopy, colonoscopy and FIT arms respectively. In addition, four people (2 in the sigmoidoscopy and 2 in the colonoscopy arm) reported at the phone interview having been referred to an emergency department following onset of abdominal pain (3 cases) or hypotension: they recovered and were discharged within a few hours.

 

2) Psychological harms

Summary of results:

The screening procedures gFOBT or FIT, eventually followed by a colonoscopy, may have a psychological impact related to the procedure itself and related to positive results. Impact of screening on daily life and levels of anxiety after a positive result of the screening test have been reported in several studies. Outcomes of these studies were psychiatric morbidity, anxiety, distress, worry and the effect on daily life {8}.

One study in particular {9} reported quality of life and level of anxiety of participants of a colorectal cancer screening programme that have been tested by FIT or by sigmoidoscopy, concluding that  the burden of participating in a CRC screening programme is limited.

•   Results from different trials:[NHS Centre for Reviews and Dissemination : Diagnostic Accuracy and Cost-Effectiveness of Faecal Occult Blood Tests Used in Screening for Colorectal Cancer: A Systematic Review, 2007] {8}

Three studies have been cited in the NHS systematic review: Parker et al (2002), Mant (1990) et al and Lindholm et al (1997).

In the trial by Parker et al., there was no significant difference in the proportion of participants with psychiatric morbidity, before and three months after FOBT was offered. For people with a false positive FOBT, the highest anxiety levels occurred after notification of a positive test and before colonoscopy. The lowest level of anxiety was experienced the day after colonoscopy and this remained low one month later.

In Mant’s paper 68% of people who had a false positive FOBT and filled the questionnaire reported experiencing distress, (62% of these slight distress, 24% moderate distress, and 14% very distressed). Sixty nine percent reported being worried that they may have cancer, and of these 68% reported experiencing slight distress, 24% moderate distress, and 8% were very distressed. Forty three percent of people found the dietary restrictions slightly disruptive, 6% moderately disruptive and 4% very disruptive. Delays in the process caused slight worry for 26% of people, moderate worry for 6%, and 4% were very worried.

In Lindholm’s paper 46% of addressed people were worried by the invitation, and refused to participate, and of these, 15% were ‘extremely’ worried. Sixteen percent of those who participated in the screening reported being ‘extremely’ worried. For people with a negative FOBT, 19% experienced severe worry, and of these 18% said that their daily life was negatively affected. For people with an initial positive FOBT, 60% experienced severe worry, and 38% said there daily life was negatively affected.

•   Kapidzic, A., et al. (2012). "Quality of life in participants of a CRC screening program."{9}

Quality of life and level of anxiety have been studied in Dutch participants of a colorectal cancer screening programme that have been tested by FIT or by sigmoidoscopy. Participants from CRC screening trials were sent a questionnaire, which included validated measures on generic health-related QOL, generic anxiety and screen-specific anxiety. The main research question of the study was whether QOL differed in participants with a positive test result compared with participants with a negative test result.

Thisretrospective questionnaire survey showed slightly worse QOL scores among positive FIT participants compared with FIT negative participants. Screen-specific anxiety was significantly higher among both positive FIT and sigmoidoscopy participants, indicating that a positive test result has a negative impact on participants’ emotional well-being, although differences were small and not clinically relevant. A prospective study needs to be conducted, where participants receive questionnaires at different time points during the entire screening process.

  [1] 0,5% of the screened population [2] 0.1% of the screened population [3] Among subjects who were assigned to undergo colonoscopy, 5649 subjects accepted the proposed strategy, whereas 1706 requested to be screened by means of FIT. Of the 5649 subjects who agreed to undergo colonoscopy, 4953 actually did so. Among subjects who were assigned to undergo FIT, 9353 subjects accepted the proposed strategy (and a total of 8983 subjects really underwent FIT) , whereas 117 asked to be screened by colonoscopy (and 106 really completed the test). This cross-over resulted in a total of 10611 patients receiving FIT and 5059 completing colonoscopy in a screening setting. Additionnaly, 663 FIT positive patients received colonoscopy. [4] As-screened population [5] Percentage calculated with regards to the total number of patients that completed the 30 days follow-up

•   There is no direct harm caused by either gFOBT or FIT. Indirect harm can be caused by a wrong or delayed diagnosis or by harms related to subsequent colonoscopy. Eventually, psychological impact of the screening can be observed.

•   The total number of adverse events may be different between gFOBT and FIT according to the number of colonoscopies which is related to the specificity and sensitivity of the test.

•   Population of some analysed studies {6, 5} slightly differs in age from the target population defined by the EU recommendations as they do not cover the entire age range 50-74 years.

•   All studies differed with respect to their approach to calculating the % of complications.

•   In Kapidzic’s study {9} of Quality of life, some patients filled-in the questionnaire up to 5 years after the screening took place, which could have influenced the QoL results. They also indicate having used a Dutch version of PCQ questionnaire for screen-specific anxiety. 

This result card is removed, because it is not relevant.

This result card is removed, because it is not relevant.

This result card is removed, because it is not relevant.

This result card is removed, because it is not relevant.

Domain research was used and completed with information from HAS report dated 2008 {2} and recommendation dated 2013{1}. Systematic reviews referenced in HAS report {8} were used as a basis for this result card.

Summary of results:

The screening methods gFOBT and FIT are non-invasive procedures that are therefore not likely to cause any direct harm to the participants. Harms can be observed on a psychological basis or can be due to subsequent colonoscopy examination, with different timing.

Summary table of selected references

Author, year	Type of reference	Title	Outcome
HAS, 2013 {1}	National guideline	HAS recommendation on colorectal screening and prevention	Perforation of colon or haemorrhage can be immediate or delayed (7-21 days after colonoscopy).
Senore, C., et al., 2011 {5}	Article	Acceptability and side-effects of colonoscopy and sigmoidoscopy in a screening setting	Bowel distension and abdominal pain were the most common complaints of late onset.
Parker, M. A. et al., 2002 Article referenced in {8}	Article	Psychiatric morbidity and screening for colorectal cancer	Psychological impact can be observed during the whole period of testing. In patients with false positive results, anxiety scores fell the day after colonoscopy and remained low 1 month later.

 

Results from different trials:1) Physical reactions to colonoscopy

Risks of severe complications such as gut perforation and hemorrhage can be immediate or delayed (7-21 days after colonoscopy). {1}

One study specifically examined the risk of immediate and late reactions other than gut perforation and hemorrhage after colonoscopy and sigmoidoscopy in a screening setting {5}.

Among immediate reactions, patients reported serious reactions following bowel preparation (mainly abdominal pain, bowel distension and anal irritation), severe pain immediately after the exam and embarrassment. {5}

The most common post-procedural complaints were abdominal distension and pain.

2) Psychological impact

Psychological impact can be observed as well during the whole period of testing, including time before testing and time after obtaining the results. In a clinical trial (Parker et al, 2002) a general health questionnaire was sent to 2184 subjects before the offer of screening, and 1541 (70.6%) were returned. Of the 1693 subjects offered the questionnaire 3 months after the offer of screening, 1303 (77%) returned it. Anxiety scores were measured in 100 test positive patients and were highest after notification of a positive test and before investigation by colonoscopy. In patients with false positive results, scores fell the day after colonoscopy and remained low 1 month later. No sustained anxiety has been seen in screening participants.

Harms can be observed on a psychological basis or can be due to subsequent colonoscopy examination, with different timing.

Domain research was used and completed with information from in HAS recommendation dated 2013 {1}. 

As the screening test is non-invasive procedure, no change in direct risk is expected over time. Risk of false negative results may be reduced by a better sensitivity of the test used for screening. Concerning false positive results, they may be reduced by better education and better compliance of the patient. As FIT is specific for human hemoglobine {1}, its use reduces the number of false positive results due to non-compliance of participants related to diet restriction.

Risk of complications of colonoscopy and sigmoidoscopy may be reduced by an experienced endoscopist. {1}

The reproducibility of the result and the consequent risk of false positive results may be influenced by patient’s non-compliance. However, no studies comparing the impact of patient’s compliance (diet, education) on the results of FIT and gFOBT are available.

Risk of complications of colonoscopy and sigmoidoscopy may be reduced by an experienced endoscopist. However, data on the reduction of the number of complications related to experience of endoscopist have not been found neither.

Domain literature search was used.

No susceptible patient goups are known, that would be more likely to be harmed through use of FIT or gFOBT. However there is one study addressing the risk of harm of colonoscopy in patients with co-morbidities.

 

• Hughes, K., B. Leggett, et al. (2005). "Guaic versus immunochemical tests: faecal occult blood test screening for colorectal cancer in a rural community." {13}

 

Complications related to colonoscopy are increased if participants with major co-morbidity are included in screening and referred for colonoscopy. One such patient of 92 patients, who underwent colonoscopy, developed heart failure during colonoscopy preparation.

No other susceptible patient groups were found from literature, that could be more likely to be harmed through use of FIT or gFOBT. One study suggests, that patients with co-morbidities can more likely to be harmed through use of colonoscopy.

The domain literature search and additional search was used.

False-positive test results may cause anxiety and stress to patients. Also there is the possibility of overdiagnosis (leading to unnecessary investigations or treatment) and the complications associated with treatment. However no studies were found to address the possibility of overdiagnosis. False-negative test results may delay the start of treatment. {8} 

False-positive and false-negative tests may cause anxiety, stress, overdiagnosis and delay in the start of treatment.

The domain literature search and additional search was used.

The risk of harmful events can be increased due to unexperienced laboratory personnel, who make mistakes, when reading test results{8}. There are many factors infuencing gFOBT test results – food, consumed medications, faecal hydration. FIT test, however does not have dietary or medications restrictions {13}.

• [NHS Centre for Reviews and Dissemination : Diagnostic Accuracy and Cost-Effectiveness of Faecal Occult Blood Tests Used in Screening for Colorectal Cancer: A Systematic Review, 2007] {8}

 

The accuracy of FOBTs depends upon appropriate performance and interpretation of the test(s). Interpretation of FOBTs may be problematic when they are done by inexperienced personnel. In a retrospective review of questionnaires applied to accredited laboratory personnel (in order to determine their ability to interpret FOBT results), 12% were unable to correctly interpret sample test cards (mainly false-positive results). This finding raised concerns that people with detectable colorectal cancers may be missed, solely because of errors in interpretation. One suggestion to improve test interpretation is the use of tests with automated reading. Alternatively a centralised location for the collection, processing, and interpretation of all tests would facilitate measures to improve consistency.

 

Guaiac tests are generally best at detecting large, more distal lesions. Because they depend upon peroxidase or pseudo-peroxidase activity in the faeces, and are not specific to the pseudoperoxidase activity of human haemoglobin, many variables are said to influence their results. These include dietary factors, for example animal haemoglobin/myoglobin in red meat, fruits and vegetables high in peroxidase activity (false-positive results), high doses of vitamin C (false-negative results), aspirin or other medication that may cause gastrointestinal bleeding (false-positive results) and faecal hydration. The drying out of the faecal specimen and exposure to high ambient temperature can also result in false negative findings. Conversely rehydration of the sample may deactivate the peroxidases from fruit and vegetables reducing the number of false positive results. A systematic review of five RCTs of CRC screening using a guaiac test (Haemoccult) suggested that dietary restriction during unrehydrated FOBT may not be necessary as it did not appear to affect positivity rates and completion rates. However, the review did not include evidence on the use of more recent guaiac tests such as Haemoccult Sensa, which are believed to be more susceptible to the effects of diet. It also failed to account for dietary differences between countries and ethnic groups

Complications from colonoscopy may depend on the education and experience of health professional {13}.

The risk of harmful events may be increased due to unexperienced laboratory personnel, dietary and medication restrictions (gFOBT) and education and experience of health professionals.

The additional literature search was used.

The alternative technologies used for the same purpose are – colonoscopy (not specifically addressed here as covered elsewhere in the document), flexible sigmoidoscopy, computer tomography (CT) and barium enema. As all of the three techniques are invasive, non-invasive FIT and gFOBT tests are safer in terms of colonic perforation, ionizing radiation or sedation performed.

Levin, et al. (2002). Complications of screening flexible sigmoidoscopy {16}

Flexible sigmoidoscopy (FS) is an invasive diagnostic test and can cause perforation in the lining of the bowel, bleeding and infection. Sedation can cause problems with breathing, heart rate and blood pressure. The principal finding of this study was that the rate of complications after FS is modest. Approximately 1 in 5000 screening subjects was hospitalized for a gastrointestinal complication, and 1 in 16,000 was hospitalized for a serious complication. Colonic perforations, serious bleeding, and diverticulitis leading to surgery each occurred in this population less often than in 1 of 50,000 examinations.

Broadstock, (2007). Computed tomographic (CT) colonography for the detection of colorectal cancer – a Technical Brief {17}

Computer tomography has following disadvantages: patients are exposed to ionizing radiation, although low-radiation dose protocols are under investigation. False positives can occur as a result of retained stool in the bowel, diverticular disease (which can produce poorly distensible areas of the colon), or thickened bowel folds. Patients are associated with a very small risk of colonic perforation in CT colonograpy. Both, computer tomography and barium enema, were said to expose patients to ionizing radiation and to be associated with a very small risk of colonic perforation.

The domain literature search was used.

Wong et al {15} evaluated the factors associated with choosing immunochemical faecal occult blood test (FIT) or colonoscopy for colorectal cancer (CRC) screening among 3430 Chinese participants taken from a community-based cancer screening programme in Hong Kong and determined that the choice of the colonoscopy test was significantly influenced by the perceived discomfort induced by screening (OR 1.36, 95% CI 1.15–1.59, P < 0.001) . The findings show that those who did not perceive that CRC screening would inflict physical discomfort preferred colonoscopy. The update of this preliminary study {14}which includes 7845 patients also finds that the perception of the cancer screening being uncomfortable or embarrassing were associated with lower odds of choosing colonoscopy over FIT (p<0,001). The perception of risk did not significantly affect the choice of the tests.

Hol et al {12}compared the perceived test burden and acceptability of guaiac-based faecal occult blood test (gFOBT), faecal immunochemical test (FIT) and flexible sigmoidoscopy in a representative sample of the Dutch population randomly invited for the two tests and showed that FIT was perceived as slightly less burdensome than gFOBT due to less reported discomfort during faecal collection and test performance. The vast majority of participants would encourage friends or relatives to undertake either gFOBT or FIT (gFOBT: 96%, 95.8%; p=0.76) and were willing to attend a successive screening round (gFOBT: 94.1%, 94%; p=0.76). A significantly smaller proportion of FS screenees were willing to attend another round (83.8%; p< 0,005). The perceived risk of colorectal screening did not significantly influence the recommendation to friends and/or relatives, or the willingness to return for a successive screening round.

The results of 4 focal groups (n=28) set up to explore the perceptions of colorectal cancer and fecal immunochemical testing among African Americans in a north Carolina Community {11} showed that negative attitudes about FIT were mostly due to embarrassment when returning samples. The multistep instructions were also acknowledged as a potential problem for uptake.

The comparison of the uptake of FIT and gFOBT in 5,464 and 10,668 randomized eligible participants in a screening programme in the Clalit Health Service (Israel) {10} showed that compliance in taking the kits was better (but not statistically significantly better) with gFOBT  (37.8% vs. 29.3%; OR 1.43 [95% CI 0.73–2.80]; P = 0.227). Independent factors associated with increased compliance were female gender, age ≥ 60 years and immigrant status.

The evidence is insufficient in quantity and quality to establish how the existence of perceived harms influences acceptability or tolerability. The findings suggest that the factor that influences acceptability is not so much risk perception but the discomfort of the test procedures {12, 14, 15}. The preference of FIT over colonoscopy can be influenced by the perceived discomfort and embarrassment associated with the latter but there seems to be many other factors involved, like age, educational level, occupational status or family history of colorectal cancer, that should be further explored {14}.

Even though the fewer number of faecal samples required for FIT with respect to gFOBT seems to lead to less discomfort during faecal collection, as the gFOBT has to be performed on three consecutive bowel movements and FIT is a one-sample test, evidence suggests that both tests are equally tolerable {12}. Both tests seem to be equally recommended to their family and/or friends by screening participants but it is not clear how this and other differences, like kit presentation, can influence the acceptance of both tests. Whilst some studies suggest that participation could be similar or even slightly higher with gFOBT {10}, others enhance that patients receiving immunochemical kits are approximately twice as likely to participate than those receiving the guaiac kit {13}. It would be reasonable to think that persons would prefer the user-friendly characteristics of the immunochemical test (more convenient, less messy, no dietary restrictions) but it must be acknowledged that these tests may be challenging to some people and thus acceptance could depend on the setting {11, 13}.

The domain literature search was used.

We found no studies that addressed occupational harms of FIT and gFOBT.

Universal precaution recommendations include the use of gowns to protect the skin and clothing from contamination with feces during procedures. Gloves should be worn during all procedures. Prolonged use of latex gloves may cause skin sensitivity, contact dermatitis or latex allergy. Both conjunctivitis and systemic infection can also occur from touching the eyes with contaminated fingers or others objects.

The domain literature search was used.

We found no studies meeting our inclusion criteria that addressed risks for public and environment of fecal immunochemical tests.

The domain literature search was used.

Only two organisational factors (dietary and medication restrictions, cooling measures) were considered to be potentially relevant, which could affect the harms. The accuracy of FOBTs depends upon appropriate performance and interpretation of the test and the interpretation of FOBTs may be problematic when they are done by inexperienced personnel (see SAF7).

In order to reduce the probability of a false positive result, dietary restrictions are usually recommended when guaiac-based tests are used. FIT tests have no dietary or medication restrictions {13}.

However, FIT test samples were requested in one study {10} to be kept in the refrigerator at home and brought back to clinic using cooling bags.

The domain literature search was used.

Safety risks for patients can be reduced by giving special attention to the management of patients with co-morbidities. Also the threshold of positivity of tests can influence the number of colonoscopies performed and thus safety.

Further education of GPs regarding the appropriateness of referrals for gFOBT in patients with major co-morbidities is important, because complications related to colonoscopy are increased in patients with major co-morbidites. {13}

 

• [NHS Centre for Reviews and Dissemination : Diagnostic Accuracy and Cost-Effectiveness of Faecal Occult Blood Tests Used in Screening for Colorectal Cancer: A Systematic Review, 2007] {8}

 

Changing the threshold for positivity (e.g. the number of windows required to show blue colouration on a Haemoccult slide) may change both the sensitivity and specificity of the test. Some studies stated that ‘any blue colour’ indicated a positive result, others specified that 2, 3 or more windows had to show a blue colouration to be positive, and some studies retested after what were considered ‘weak’ positive results. These differences in threshold will affect the observed positivity rate of the test, and as such, will impact on the proposed number of colonoscopies that would be required as a result of a screening programme with FOBT.

The domain literature search was used.

There were no safety risks for professionals found from literature.

 

Refer to domain search and domain methodology section.

 

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 {3} and four observational studies {4, 5, 6, 7} examined the effect of the use of FIT for colorectal cancer screening versus no screening on colorectal cancer mortality or incidence, but not on overall mortality. Tables 1 to 6 and Figure 1 {EFF Appendix 1} extract and evaluate the most important results of the five above mentioned studies. Because of the lack of direct evidence to answer the research question a GRADE profile has not been elaborated.

Refer to domain search and domain methodology section.

We have not identified any study that compares FIT vs gFOBT in terms of mortality. The identified studies that provide mortality information compared screening using FIT vs no screening. A controlled trial {3} and three observational studies {4, 6, 7} examined mortality effect of the use of FIT for colorectal cancer screening versus no screening. Therefore no direct evidence comparing FIT vs gFOBT in the context of a population based colorectal cancer screening program is available. Because of the lack of direct available evidence to answer the research question a GRADE profile has not been elaborated.

The tables 1 to 5 extract and evaluate the most important results of the four above mentioned studies. Only one of them is a randomised controlled trial{3}, two are case-control studies {6, 7} and one is an observational and comparative retrospective study{4}. The randomised controlled trial compares the use of one round Reverse Passive Hemagglutination (RPHA) immunochemical test along with an individual attribute degree value score versus no screening. This trial, which analyses the screening program conducted in Jiashan (China), presents several bias risks and it is no focused on our specific research question.

First at all, the index test differs from the test consider in our research question because the FIT was used together with a quantitative individual risk assessment method (Attributive Degree Value). On the other hand, the reference standard was initially sigmoidoscopy and colonoscopy only for positive sigmoidoscopies and for positive FIT for those who FIT was repeated. Individuals with a positive FOBT were asked to undergo flexible sigmoidoscopy (FS). If FS failed to detect colorectal lesions, the participants were asked to repeat the FOBT. Those without a lesion found by FS but with a positive repeated FOBT were re-examined by 150-cm colonoscopy to confirm the results. The no use of colonoscopy for all the positive FIT could lead to an underestimation of the colon cancer cases and may explain the better results for detection of rectal but no for colon cancer. Double reference standard can lead to a differential verification bias. That occurs when some of the index test results are verified by a different reference standard. This usually occurs when patients testing positive on the index test receive a more accurate, often invasive, reference standard than those with a negative test result. In this case, the results are overestimated.

The controlled trial is a cluster randomized trial based on townships allocation, with a high risk of bias in several key domains of the Cochrane risk of bias table (randomization, allocation concealment and blinding). Twenty one townships were matched by population size and age distribution into 10 pairs. In each pair, a table of random digits was used to allocate to the screening or to the control group. The unit of analysis was individuals, but there was no inter-cluster correction that would minimize the selection bias risk. On the other hand, there was no participant and personnel blinding, which implies a high risk of performance bias.

This trial obtained no significant differences for colorectal and colon, but significant for rectal cancer mortality, when compared those FIT based screened vs. those no screened. The 8 year cumulative colorectal cancer mortality rate per 1,000 was 2.08 for the FIT group (95% CI: 1.96-2.18) and 2.44 (95% CI: 2.33-2.55) for no screening (p=0.19). For the specific colon cancer mortality the 8 year cumulative mortality rate per 1,000 was 0.90 for the FIT group (95% CI: 0.83-0.97) and 0.83 for the no screening group (95% CI: 0.76-0.90) (p=0.222). The 8 year cumulative rectal cancer mortality rate per 1,000 was significantly different (p<0.05) for the FIT group (1.10; 95% CI: 1.02-1.18) vs the no screening group (1.61; 95% CI: 1.52-1.70).

The rest of the studies are observational retrospective studies with high risk of bias in most of the domains of the Cochrane risk of bias table. Two case-control studies compare, in the context of two different screening programs performed in two Japanese counties, the Odds Ratio of dying due to colorectal cancer for those screened within 1 to 5 years of case diagnosis vs. those no screened. The last one is a retrospective observational study that compares the five years survival rate of 194 screened detected colorectal cancer subjects versus 352 routinely detected (no screening) colorectal cancer at Hirosaki Hospital (Japan). Any of these observational studies provided high quality evidence of the effect of FIT versus gFOBT on the mortality caused by colorectal cancer in the context of a population based colorectal cancer screening program.

We have observed a similar reduction in CRC mortality in RCT of FIT versus no screening and in RCT of gFOBT vs no screening. If we compare the only one randomized clinical trial on CRC mortality in a population invited to FIT versus no screening {3} with the meta-analysis of four RCT on CRC mortality of gFOBT versus no screening {8}, we observe similar results but with a wide confidence interval. The meta-analysis used the Peto method and effect fixed modelization for obtaining an Odds Ratio of 0.84 (IC 95%: 0.78-0.9). Using the same method for estimating the effect of the unique RCT that compared FIT versus no screening the Odds Ratio would be 0.85 (CI 95%: 0.70-1.03). Table 7 {EFF Appendix 3}.

Refer to domain search and domain methodology section.

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 controlled trial {3} and three observational studies {4, 5, 7} examined the effect of the use of FIT for colorectal cancer screening versus no screening on colorectal cancer mortality but not on overall mortality. Tables 1 to 5 {EFF Appendix 3} extract and evaluate the most important results of the above mentioned studies. Because of the lack of direct evidence to answer the research question a GRADE profile has not been elaborated.

Refer to domain search and domain methodology section.

A recent Italian screening programme by biennial immunochemical FOBT reported a retrospective comparison of cancer rate and stages between average risk screening participants and those who did not participate in the screening programme. Although the overall cancer rate was similar in the two populations (1.23 versus 1.20 per 1000 person-years), there were significant differences in TNM stage distribution between the two groups (stage III–IV cancers 0.24 versus 0.74 per 1000 respectively, p = 0.009).

This large cross-sectional study reported that colorectal cancers detected by immunochemical FOBT screening are identified at an earlier pathological stage, with significant prognostic and economic advantages to the populations screened {9}.

Refer to domain search and domain methodology section.

Compared with standard gFOBT, current evidence from systematic reviews and clinical trials indicates a higher sensitivity for the detection of CRC and advanced adenomas, and higher rates of detection for CRC and advanced adenomas (refer to EFF 12, EFF 20, EFF 22) {10,15,16,17,18}. A superior sensitivity and detection rate of adenomas is a distinguishing performance characteristic of FIT compared with gFOBT, thus proving a greater preventive capacity. If all advanced adenomas and CRC detected are removed progression of lesions could be avoided. The endoscopic removal of pre-malignant lesions also reduces the incidence of CRC by stopping the progression to cancer.

TNM stage distribution of CRC detected in screening programmes using FIT shows an early detection, and early treatment of colorectal lesions before they become symptomatic can reduce morbidity and mortality associated to CRC. 

A recent Italian screening programme by biennial immunochemical FOBT reported a retrospective comparison of cancer rate and stages between average risk screening participants and those who did not participate in the screening programme. Although the overall cancer rate was similar in the two populations (1.23 versus 1.20 per 1000 person-years), there were significant differences in TNM stage distribution between the two groups (stage III–IV cancers 0.24 versus 0.74 per 1000 respectively, p = 0.009). This large cross-sectional study reported that colorectal cancers detected by immunochemical FOBT screening are identified at an earlier pathological stage, with significant prognostic and treatment cost advantages to the populations screened {9}. A major goal of a colorectal cancer mass screening programme is to diagnose cancer at an earlier stage, thus permitting curative treatment at lower cost, as the prognosis and cost of late-stage cancer at diagnosis are quite different. In this screening programme most of the screen-detected cancers were diagnosed at a very early stage; 81 per cent were TNM stage I or II and were therefore treated with curative intent, compared with only44·0 per cent of cancers detected within the same age range in the non-screened population.

It could be a case of lead time bias. Those participants who do not participate in the screening programme are diagnosed after they have signs and symptoms of cancer, so they are in advances TNM stages. If the screening program does not modify the progression, the increase in survival time makes it seem as though screened patients are living longer when that may not be happening (the date of diagnosis is earlier for screened patients).

Refer to domain search and domain methodology section.

We have not identified clinical trials or systematic reviews comparing FIT vs gFOBT in terms of the effectiveness of subsequent interventions (colonoscopy and surgery) in the context of population based colorectal cancer screening.  

 

Refer to domain search and domain methodology section.

A high-quality level systematic review studying differences in detection rates between FIT and gFOBT has been detected {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. The existence of heterogeneity (I2: 70.7%) led to use random effects model.

Refer to domain search and domain methodology section.

We have not identified clinical trials or systematic reviews comparing FIT vs gFOBT in terms of other health effects or clinical conditions not included in the project scope and requiring subsequent clinical management decisions. Therefore no direct evidence on other potential health conditions comparing FIT vs gFOBT in the context of a population based colorectal cancer screening program is available. 

Refer to domain search and domain methodology section.

All the systematic reviews and available RCTs included reported statistically significantly higher participation rates for FIT compared with gFOBT {10, 11, 15}. This means a higher charge of diagnostic colonoscopies in the population. With respect to FIT performance, compared with standard gFOBT, current evidence indicates a higher sensitivity for the detection of CRC and advanced adenomas, and higher rates of detection for CRC and advanced adenomas. These advantages of FIT are offset by a higher positivity rate (depending on the used cut-off level), which in turn may require a greater number of colonoscopies. A superior sensitivity and detection rate of adenomas is a distinguishing performance characteristic of FIT compared with gFOBT. These performance characteristics change when the cut-off level in hemoglobin concentration is changed, allowing a screening program to select the optimal cut-off for the program (more cancers and pre-malignant lesions detected with the minimum number of colonoscopies required).

Positive rates varies among randomized clinical trials from FIT 5.5% to gFOBT 3.2% {11}; FIT 4.8% to gFOBT 2.8%{12}; FIT 11.2% to gFOBT 7.9% {13} and FIT 3.2% to gFOBT 10.1%{14}. Differences in positive predictive values for CRC or advanced adenoma were no statistically significant.

The total number of colonoscopies needed to confirm positive test results is higher for FIT comparing to gFOBT. In one RCT{11} 20,623 individuals were invited; 10,301 received gFOBT and 10,322 FIT. Tests were returned by 10,993 individuals, 4836 (46.9%) in the gFOBT group and 6157 (59.6%) in the FIT group. To evaluate the outcome in the 456 positives results, a colonoscopy was performed in 383 (84%) patients. Total number of colonoscopies was 103 in the gFOBT group and 280 in the FIT group. Cancer was found in 11 of the G-FOBTs and in 24 of the FIT. Advanced adenomas were found in 46 of the gFOBT and in 121 of the FIT. The number of polyps found with gFOBT was 220 (of which 154 adenomas) and 679 with FIT (of which 470 adenomas). In this RCT the specificity of the FIT for advanced adenomas and cancer was lower compared with the gFOBT, but the detection rate for advanced adenomas and cancer with the FIT was significantly higher. Consequently, 3 times as many subjects tested with the FIT are referred for a negative colonoscopy. On the other hand, 3 times as many patients with advanced adenomas and 2 times more patients with cancer are left undetected in the gFOBT group compared with the FIT group, ultimately resulting in comparable Positive Predictive Values for both tests. 

We used both basic search done for the whole project and domain search (described in the Domain Methodology section). Furthermore test accuracy issues relative to Research Questions EFF 20, EFF 22, EFF 24, EFF 26, EFF 28, EFF 30 were selected from the above mentioned searches.

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. Two investigators independently reviewed the titles and abstract. Disagreement was resolved by discussion. See Table 8 {EFF Appendix 3} for included articles. These articles were used, where pertinent, to answer all the above-mentioned Research Questions.

The quality assessment criteria for studies we used for all above mentioned Research Questions are R-AMSTAR {2}  {EFF Appendix 2} for systematic reviews and Cochrane risk of bias for observational studies {1}. Two independent reviewers assessed quality and bias. Disagreement was resolved by discussion.

Extraction tables where tailored to research questions issues. Articles covered by systematic reviews that were in our included list were not extracted.

Data was synthesized in tables were possible and research questions were answered starting from the best quality of available evidence.

Very few good quality diagnostic studies comparing FIT versus gFOBT use as reference standard colonoscopy or flexible sigmoidoscopy for all positive or negative results in the index test {10,15}.

Allison et al. {14} and Park et al. {13} studied participants that would receive screening in practice. The reference standards used for each study were different, with Allison et al comparing FIT with gFOBT, and with Park et al comparing FIT with colonoscopy. In both studies, the reference standard and the index test were performed in a short time. In Allison et al, colonoscopy was not used as the comparator to FIT, although participants with a positive test were referred for colonoscopy, and those with a negative test were referred for FS. In Park et al, FIT results were compared directly with colonoscopy results. The index test was independent of the reference standard used.

In the study conducted by Park et al, positivity was slightly higher for FIT (11.2%) than for gFOBT (7.9%), but this difference was not statistically significant. The sensitivity for detecting CRC was statistically significantly increased when using FIT compared with gFOBT (FIT 92.3% versus gFOBT 30.8% [P<0.01]). The sensitivity of FIT (33.9%) compared with gFOBT (13.6%) for detecting advanced adenoma (AA) was significantly higher (P<0.05).

The difference in specificity for both CRC and AA was not statistically significant when comparing FIT (CRC 90.1%; AA 90.6%) with gFOBT (CRC 92.4%; AA 92.4%). The difference in PPV for both CRC and AA was not statistically significant when comparing FIT (CRC 12.8%; AA 23.3%) with gFOBT (CRC 6.7%; AA 13.1%).

In the study conducted by Allison et al, positivity was statistically significantly lower for FIT than the sensitive gFOBT used in the study (FIT 3.2% versus gFOBT 10.1% [P<0.01]). The difference in sensitivity for detecting CRC and AA was not statistically significant for FIT (CRC 81.8%; AA 29.5%) compared with gFOBT (CRC 64.3%; AA 41.3%).The specificity for both CRC and AA was statistically significantly higher for FIT than for gFOBT (CRC FIT 96.9% versus gFOBT 90.1% [P<0.01]; AA FIT 97.3% versus gFOBT 90.6% [P<0.01]). The PPV for both CRC and AA was also statistically significantly higher for FIT compared with gFOBT (CRC FIT 5.2% versus gFOBT 1.5% [P<0.01]; AA FIT 19.1% versus gFOBT 8.9% [P<0.01]). Positive likelihood ratio for distal cancer was 26.7 (95% CI 19.4-36.6) with FIT and 6.5 (4.3-9.6) with gFOBT. Positive likelihood ratio for distal adenomas ≥1 cm was 11.0 (7.9-15.3) with FIT and 4.4 (3.5-5.5) with gFOBT. This measure summarizes how many times more likely patients with the disease will test positive compared with patients without the disease.

In summary, the sensitivity and PPV of FIT for detecting CRC and AA compared with a standard gFOBT is superior. Differences on specificity are not so relevant. Positivity rates for FIT using the manufacturer’s standard cut-off level in hemoglobin concentration are higher than for gFOBT.

In a review and meta-analysis {10} seven diagnostic cohort studies in diagnostic patients scheduled for colonoscopy are included. The pooled PPV for detecting advanced colorectal neoplasm was significantly higher for FIT than for gFOBT (0.41 vs 0.29, P < 0.01). The sensitivity of FIT (0.67, 95% CI 0.61–0.73) was superior to that of gFOBT (0.54, 95% CI 0.48–0.60), as were the specificities (0.85, 95% CI 0.83–0.87 vs 0.80, 95% CI 0.78–0.82). Figure shows the SROC for FOBT in diagnosing advanced colorectal neoplasm of diagnosed patients, which indicates the mildly higher diagnostic accuracy of FIT.

Figure 1. Summary receiver operating characteristic curve (SROC) showing the diagnostic precision of guaiac-based fecal occult blood test (gFOBT) as Area Under the Curve (AUC) 0.7677, was lower than that of immunochemical fecal occult blood (iFOBT) as AUC 0.8241, for detecting advanced colorectal neoplasm in patients scheduled for colonoscopy.

From: Zhu MM, Xu XT, Nie F, Tong JL, Xiao SD, Ran ZH. Comparison of immunochemical and guaiac-based fecal occult blood test in screening and surveillance for advanced colorectal neoplasms: A meta-analysis.  Journal of Digestive Diseases, 2010; 11 (3): 148-60. 

Please refer to EFF 20

We identified 5 systematic reviews {10,15,16,17,18} and 3 additional diagnostic cohort trials {19,20,21} directly comparing FIT vs gFOBT and they are listed in table 9 with R-AMSTAR and risk of bias results. Data reported on accuracy measures are presented in the relative column of above mentioned table, starting from the more robust available evidence.

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 gBOBT. Please refer to Table 9 for values of accuracy measures.

 

Overall, FIT performance is superior to the standard gFOBT for the detection of CRC and adenomas. FIT has additional important advantages compared to gFOBT: higher screening participation rates, potential for automation in the laboratory and to select the cut-off level of hemoglobin concentration that defines a positive test. However, the following potential disadvantages are: greater specimen instability and possibly higher positivity rates.

No merging of available data has been performed do to the wide variability in settings and presented outcomes.

Need for further research:

• More well-designed randomized controlled studies directly comparing guaiac and FIT.
• 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 deciding if FIT is an appropriate CRC screening tool.

 

Please refer to EFF 20

The reference standard used in most reviews was colonoscopy {10,15,17,22}. Burch et al reported that one study was a diagnostic cohort study in which 3090 patients underwent colonoscopy and an unspecified immunochemical FOBT: for the detection of all neoplasms, sensitivity was 53% and specificity 99.6%; for the detection of CRC, sensitivity was 52.6% and specificity 87.2% {17}.

 

We found one systematic review reporting accuracy measures for colonoscopy among a total of five colorectal cancer screening methods {22}. It included 130 articles in total (of these 20 were relative to colonoscopy) and the reported mean ± standard deviation sensitivity of colonoscopy for cancer and for large polyps (≥10mm) was respectively 94.7 ± 4.6 % and 92.5± 6.2 % (compared to FOBTs 45.7 ± 26.5% and 18.5 ± 11.8%). Instead the overall specificity of colonoscopy for detecting CRC was 99.8 ± 0.2% (compared to FOBTs 87.6 ± 11.4%). Colonoscopy has the highest sensitivity and specificity of the selected screening methods.

 

In the remaining reviews the results were not clear. Nevertheless, one of them{15} reported results about one study also included in this review. Park 2010 et al{13} implemented a prospective study in a large population of average- risk people in which everyone underwent colonoscopy after having FIT and gFOBT: confirmed with better evidence the observations of others that FIT has a higher sensitivity for detecting advanced colorectal cancers than gFOBT, and has an acceptable specificity that significantly reduces the need for colonoscopic evaluation in the screened population. FIT results were compared directly with colonoscopy results: the positive rate of gFOBT in patients with adenomas did not differ from the patients with normal colonoscopies (8.0 % vs. 7.3 %); however, the positive rate of FIT at the 75 and 100 ng/ml thresholds was higher in patients with adenomas compared with that of patients with normal colonoscopies (16.9 % vs. 7.5 %, and 14.6 % vs. 7.3% ( P < 0.001 and P = 0.002), respectively.

Further literature research could be done on colonoscopy accuracy measures to gain a more comprehensive view, although most of the studies relative to accuracy measures of FOBTs refer to colonoscopy as the reference standard but do not report what these measures are for colonoscopy itself.

Please refer to EFF 20

We found a total of 7 studies relative to cut-off values for the amount of fecal blood that have attempted to define an optimal cut off value or have adopted producers indications and are here below described.

It is know that the positivity rate, specificity and the detection rate of advanced neoplasia varied with the cut-off level. A high-level quality review performed the analysis using different cut-off values in the meta analysis, and the superiority of FIT in the detection of advanced neoplasm was not significantly influenced. Ultimately, data extracted at a cut-off value of 75 ng/mL were considered as an acceptable trade-off between the detection rate and the number needed to scope {10}. Another review reported on 4 studies assessing FITs performances at multiple haemoglobin concentrations cut-off levels that differ from manufacture’s recommendations: in general, increasing the cut-off level of haemoglobin concentration the positivity rate decreased and the specificity and PPV increased {15}.

 

The faecal haemoglobin concentration at first screening predicts subsequent risk of incident colorectal neoplasia: the adjusted hazard ratios increased from 1.43 (95% CI 1.08–1.88) for baseline faecal haemoglobin concentration of 20–39 ng/mL, to 3.41 (2.02–5.75) for a baseline concentration of 80–99 ng/mL (trend test p<0·0001), relative to 1–19 ng/mL {23}. Nevertheless, findings needs to be validated for each kit separately, with a longer term follow-up, since colorectal neoplasia typically takes 10 years to develop, and using a large, population-based longitudinal follow-up study {23}.

 

Furthermore, f-Hb is related to severity of colorectal neoplastic disease: median f-Hb concentration was higher in those with cancer than those with no (p<0.002) or non-neoplastic (p<0.002) pathology, and those with LRA (p=0.0001); polyp cancers had lower concentrations than more advanced stage cancers (p<0.04). Higher f-Hb was also found in those with HRA than with LRA (p<0.006), large (>10 mm) compared with small adenoma (p<0.0001), and also an adenoma displaying high-grade dysplasia compared with low-grade dysplasia (p<0.009); f-Hb was significantly higher in those with a large compared with a small adenoma (p<0.0001){24}. Nevertheless, these results could be limited by the fact that false negative f-Hb were not taken into account and only participants with a positive result were referred for colonoscopy.

 

The cut-off level increases detection both for haemoglobin and haemoglobin-haptoglobin: when varying the cut-off level from 2 mcg/ g of stool (recommended by the manufacturer) to 14 mcg/g of stool, sensitivities for advanced adenomas and large adenomas ( ≥ 1 cm in diameter) ranged 40-24 % and 50-30 % for haemoglobin, and 33-12 % and 41-13 % for haemoglobin-haptoglobin, respectively, whereas specificities ranged 90–97 % for hemoglobin and 91–99 % for haemoglobin-haptoglobin; at cutoff values of 6 mcg/g of stool for hemoglobin and 4 mcg/g of stool for haemoglobin-haptoglobin, the specificity was ~ 95 % for both tests {25}.

 

A major advantage of FIT is recognized to be the automated and easier to interpret and furthermore, it measures the concentration of haemoglobin in the buffer, thus making it possible to choose the cut-off value. Nevertheless, the effect of different cut-off level in different FIT kit cannot be detected because manufacturers quote the concentration of haemoglobin not in the faeces, but in the buffer solution and this varies between different devices. Therefore, simple comparisons of cut-offs were not possible {19}.

 

Cut-off level detection is also linked to the colonoscopy capability: when colonoscopy capacity was unlimited, the optimal screening strategy was to administer an annual FIT with  a 50 ng/mL haemoglobin cut off level in individuals aged 45–80 years and to offer colonoscopy surveillance to all  individuals with adenomas. When colonoscopy capacity was decreasing, the optimal screening adaptation was to first increase the FIT haemoglobin cut-off value to 200 ng haemoglobin per mL and narrow the age range to 50–75 years, to restrict colonoscopy surveillance, and finally to further decrease the number of screening rounds {26}.

Please refer to EFF 20.

A high-quality review indicated that sensitivities were higher for the detection of CRC, and lower for adenomas, in both the diagnostic cohort and diagnostic case–control studies for both guaiac and immunochemical FOBTs {17}. Another review with lower quality due to unclear design and quality assessment of selected studies, compared sensitivity and specificity of the colorectal cancer mass screening methods: colonoscopy was reported as the one with best sensitivity and specificity while fecal occult blood test with the lowest. The mean ± standard deviation per patient sensitivities and specificity of colonoscopy respectively 94.7 ± 4.6 % and  99.8  ±  0.2% (compared to FOBTs 45.7 ± 26.5% 87.6 ± 11.4%) {22}.

 

A large population study found that the sensitivity of FIT for non-advanced adenomas, advanced adenomas, and cancer was 10.6%, 28.0%, and 78.6%, respectively. The sensitivity of FIT for advanced polypoid neoplasm (31.1%) was significantly higher than that of nonpolypoid ones (21.1%) (P <.001){27}. Furthermore, the sensitivity of FIT was in relation to neoplasm stage: FIT sensitivity showed stage-dependence and was 28.0% for advanced adenomas, 73.9% for invasive cancer, 66.7% for Tis plus T1 cancers, and 100% for T2 to T4 cancers (P for trend < .001){27}. The specificity was similar in relation with stage: 92.8% for invasive cancer, Tis plus T1 cancer and T2-T4 cancer.

 

Finally, the sensitivity of FIT for advanced neoplasms was in relation to location and morphology: the sensitivity was significantly lower for proximal polypoid advanced neoplasms compared with distal ones (27.7% vs 31.6%; P < .001) and proximal nonpolypoid advanced neoplasms compared with distal ones (16.2% vs 24.3%; P < .001) {27}. The trend was similar when proximal and distal, polypoid and nonpolypoid advanced adenomas were compared. For invasive cancers, although there was a trend toward lower sensitivity for proximal lesions, the result was not statistically significant {27}.

 

The I-FOBTs were significantly better than the G-FOBTs in detecting both cancers and advanced adenomas. The detection of cancers was at least twice as high with the I-FOBT as with the G-FOBT, and the number of advanced adenomas was about three to four times as high{19}. The same study also assessed detection according to stage of cancers at diagnosis: the proportion of Tis and stage 1 cancers was higher with I-FOBTs than with the G-FOBT. The differences between I-FOBTs and G-FOBTs, however, were not significant{19}. However, results need to be validated with cut off levels assessed in the faeces and not in the buffer solution {19}.

 

When applied on as second round test, the results reported here show that, despite a significant decrease in the PPV for CRC, a substantial number of significant lesions were detected; this applies more to advanced adenomas than to cancer cases and appears to be independent of the type of test used in the first round (guaiac FOBT or FIT) {28}.

 

FITs capability of reliably ruling in or out adenomas and CRC depends not only on its accuracy measures, but also on threshold and appropriate Mean Sejourn Time. Both of these issues need further research. Also refer to research question EFF15 for other factors influencing accuracy measures.

Please refer to EFF 20.

Many factors affecting the FITs accuracy have been studied. These are reported in the following table.

 

Effect of variations of different factors on fecal blood detection immunochemical screening 

 

Factor	Results	Conclusions	Reference
Round of detection	A significant decrease was observed in the PPV for advanced neoplasia between the first and second round, from 55% (132/239) to 44% (112/252; P=.017). The PPV for CRC was 8% (20/239) in the first round versus 4% (9/252) in the second round (P=.024). Ten interval cancers were diagnosed.	Despite a significant decrease in the PPV for CRC in a second round of screening, a substantial number of significant lesions are detected in a second screening round. This applies more to advanced adenomas than to cancer cases and appears to be independent of the type of test used in the first round (guaiac FOBT or FIT).	Denters 2012{28}
Temperature	The mean log10 Hb concentration in the low temperature group was significantly higher than those in the high temperature group (0.36 vs. 0.25 ng/ml, p=0.000). An increase in temperature of 1°C reduced the probability of a positive FIT by 3.1 %, but with no effect on  detection rate of colorectal neoplasms. High ambient temperature was not a significant risk factor for either the positive FIT result or the detection of colorectal neoplasms. Nevertheless, other Authors* reported   the FIT positive rate was significantly lower in summer than in winter, and explained these results as a decrease in fecal hemoglobin values in summer.	Potential instability of fecal hemoglobin at high ambient temperatures should be considered; however, its influence on performance of FIT may be attenuated by the short exposure time of fecal samples to high ambient temperature (i.e., rapid return system).	Cha 2012{29}
Delay between fecal sampling and delivery at the laboratory	Delay in sample return increased false negative immunochemical FOBT’s. Mainly precursor lesions, but also colorectal cancer, will be missed due to delayed sample return.  The decreased performance of the FIT due to delayed return of the sample was observed to be independent of the cut-off value for positivity of the FIT.	Although selection bias could in a certain measure result in a false negative result,  The evidence in this study shows how important it is to control all aspects and logistics of screening protocols. Subjects invited for screening should be adequately informed of the necessity of prompt return of the sample and reporting the date of taking the sample. However, more complicated information and effort, as well as the pressure of prompt return, might also result in decreased participation. The production of a less sensitive hemoglobin stabilizing buffer with improved stability is suggested. Until a less sensitive hemoglobin stabilizing buffer is produced, monitoring delay between fecal sampling and laboratory research should be part of quality control for screening with immunochemical FOBT. Inviting participants to perform a second test when delay is 5 days or more could be considered.	Van Rossum 2009{30}
Diet restrictions	The restricted diet subgroup and unrestricted diet subgroup had showed significant difference for advanced neoplasm detection rate and compliance rate	FIT removes the need for dietary restrictons.   However, some FIT advised alcohol and acetylsalicylic acid and similar restriction for 48 h before stool is collected (Rabeneck 2012).	Zhu 2010{10}
Type of care setting	Results demonstrated significant differences in the analytical performance among different FOBT methods.	Highly sensitive and specific FIT methods may be best suited for colorectal cancer screening programs where testing is performed in a central location. Guaiac-based methods are rapid and easy to perform and are suitable for bedside point-of-care testing albeit a high rate of false positive results should be expected.	Tannous 2009{31}
Sampling strategy used: multiple sample from consecutive stools or one sample	Number of samples for FIT: most kits require one sample, Hemoglobin NS-PLUS two samples over two days, HEMOCCULT ICT 3 samples/3days A one-day strategy resulted in an intermediate positive rate.	FIT is superior to gFOBT for participation rate (fewer samples, less stool handling).   However, another study in France reported a two day testing (choice based on the fact that CRC bleeding is often intermittent) not to be a barrier to compliance (Faivre 2012)	Rabeneck 2012{15}
Colonoscopy capacity and variation	For all levels of colonoscopy capacity, FIT screening was more effective clinically and in terms of cost compared with gFOBT screening.	FIT should be used at higher hemoglobin cutoff levels when colonoscopy capacity is limited compared with unlimited  and  is  more  effective  in  terms  of  health  outcomes  and  cost  compared  with  guaiac  FOBT at all colonoscopy capacity levels. Increasing the colonoscopy capacity substantially increases the health benefits of FIT screening	Wilschut 2011{26}
Sensitivity left vs right CRC	Sensitivities for subjects with left-vs right-sided advanced neoplasia were 33% (95% CI, 26 – 41%) and 20% (95% CI: 11 – 31%) at a specificity of 95% (overall sensitivity: 29%) and the areas under the receiver-operating characteristics curve were 0.71 (CI, 0.69 – 0.72) and 0.60 (CI, 0.58 – 0.63), respectively.	In conclusion, the immunochemical FOBT in our study was more sensitive for detecting subjects with left-vs right-sided advanced colorectal neoplasia. Our findings may stimulate further research in the field as well as modelling analyses to estimate the potential effect of site-specific test performance on the programmatic sensitivity and the effectiveness of annual or biennial FOBT based screening programmes, in particular with respect to protection from right-sided CRC.	Haug 2011{32}

* Grazzini G, Ventura L, Zappa M, et al. Influence of seasonal variation in ambient temperatures on performance of immunochemical faecal occult blood test for colorectal cancer screening: observational study from Florence district. Gut. 2010;59:1511– 1515.

Please refer to EFF 20.

The development of automated systems for the interpretation of the test has increased the advantage of FITs. Accurate interpretation of gFOBTs is not easy and requires well-run laboratories. An automated FIT is easier to interpret, and minimizes human error in test processing, thus making it a more objective laboratory test with excellent quality control. Furthermore, it measures the concentration of hemoglobin in the buffer, thus making it possible to choose the cutoff value. It is also possible to reinterpret the test in case of a technical problem {19}.

 

Direct comparison between quantitative and qualitative immunochemical fecal occult blood tests (FOBTs) has been studied. One cohort study reported that quantitative FITs offers advantages in terms of transparency and flexibility regarding the positivity threshold (e.g., specificity can be oriented toward available colonoscopy resources or personal risk profiles) and in terms of a higher level of standardization regarding test analysis and interpretation {25}.

 

These findings are also confirmed by another cohort study that reported a positivity rates of 8.1% for the qualitative and 2.5% for the quantitative FIT. The detection rate was 5.2% for the qualitative and 14.4% for the quantitative FIT. The odds ratio of a “suspicious cancer and cancer” versus a “normal” result was 2.73 (95% CI=2.22–3.35) for the quantitative compared to qualitative FIT {33}.

 

Another study about inter-observer variability in interpretation of 5 visually read FOBTs methods (standard guaiac-based method and four immunochemical methods)  reported  no cases of observer variability except for Hemoccult ITC test this was only minimal (on 1 sample 2 observers recorded a faint band at the cut off and one called the test negative){31}. 

Nine articles from the systematic review of the literature outlined in the domain methodology section were used to identify what types of resources are used when delivering FIT and its comparator gFOBT. The remaining seven included studies did not identify the exact types of resources needed for the two tests.

In general, articles and studies that mention the type of costs and resources, divide those into the screening costs (organization, invitation and procedure, including the material resources), diagnostic follow-up in case of positive results and costs of treatment and care (in case of detected disease). The results of each of the included studies are presented below:

 

Berchi et al. s’ (2010) {11} study of cost-effectiveness analysis of the optimal threshold of an automated immunochemical test for colorectal cancer screening (study looks at only 1 round of screening), conducted from June 2004 to December 2005 in Calvados (France), identified the following costs, related to cancer management: (a) the costs of organizing the campaign; (b) the costs of offering screening tests including the costs of purchasing, distributing, and interpreting the tests; (c) the costs of performing confirmatory colonoscopies; (d) the costs of treating screened tumors.

 

In an earlier study Berchi et al. (2004) {12} undertook a cost-effectiveness analysis of two strategies for the  screening of colorectal cancer in France (in a study taking a 20-yeartime-horizon) where resource use is presented from the perspective of the screening organizer, i.e., the Social Security Service. Therefore, the modeling of costs included all direct costs related to screening, diagnosis and management of cancer. This included the costs of organizing the screening campaign (public information, running costs), costs of purchasing, distributing and interpreting the tests, costs of explorations performed in individuals with a positive test, costs of diagnosing cancers in individuals with a negative test, the costs of treating cancers and the costs of follow-up.

 

A Canadian report from 2009 (Heitman et al., 2009) {14} tried to identify what was the cost-effectiveness of FIT in colorectal cancer screening of average risk individuals in comparison with FOBT and colonoscopy, and a strategy of no screening (report included a lifetime horizon). The investigators specified a cost-effectiveness study conducted from the perspective of the publicly funded health care system. The implementation of this perspective seems to be inconsistent, because relevant costs included were direct health care costs as well as patient time and transport costs according to recent guidelines (REF: Canadian Agency for Drugs and Technologies in Health (CADTH). Guidelines for the economic evaluation of health technologies: Canada). Societal costs (costs due to lost productivity) were excluded in the primary analysis. They assumed that gFOBT and FIT screening would be requested during a person’s annual visit to the general practitioner. As a result, they only considered the costs of the gFOBT and FIT kit and related laboratory and processing costs when estimating the direct cost of gFOBT and FIT. The total cost of gFOBT and FIT also included the relevant non-medical costs (patient, caregiver time and travel costs) according to CADTH guidelines. It is likely that higher costs would occur, particularly if a screening program is organized outside the regularly scheduled medical visits. They also mentioned the direct costs for colonoscopy, which includes: the non-physician costs (capital, nursing, drug, and cleaning costs) and the physician-related fees for the procedure.

 

In their study Heitman et al. (2010) {15} performed an incremental cost-utility analysis using a Markov model. Their study was based on an economic evaluation of CRC screening in average risk North American individuals, over a lifetime time-horizon. Heitman et al. included into an economic evaluation the non-physician costs (capital, nursing, drugs, and cleaning costs) and the physician fees for the procedure into the overall screening costs. Because they assumed that stool-based screening would be offered at a person’s annual visit to their general practitioner, they only considered the costs of the screening kit and related laboratory/processing costs. For all screening modalities, the authors included the relevant patient and caregiver time and travel costs (non-medical costs), on the basis of available surveys for flexible sigmoidoscopy, colonoscopy, both FOBTs, and computed tomographic colonography (CTC). The nonmedical costs of FIT and fecal DNA were assumed to be the same as gFOBT. In the base case, they did not consider the capital costs of initiating or administering a screening program and thus assumed that screening would be opportunistic in all strategies. They have also considered the costs of treatment.

 

Lejeune et al. (2010) {17} examined cost-effectiveness of screening for colorectal cancer in France (Burgundy) using gFOBT versus FIT (time-horizon: 20 years, or until age of 85, or until death) and divided the costs into:

1. the costs of organizing the screening program, including labor and equipment (similar for gFOBT and FIT screening programs).
2. the costs of informing and inviting the population (similar for gFOBT and FIT screening programs). This also includes the design and printing of the invitation letter and of the information leaflet sent at the beginning of each screening campaign, the manpower for preparing the mail and postage, the training cost of general practitioners (GPs), and the cost of informing the entire medical profession.
3. the distribution costs, including the costs for screening conducted during a regular consultation with a GP (taking into account the purchase price of the test kit and a special fee paid to GPs according to the number of tests received at the central analysis center, therefore, depending on participation in the screening program), the cost of the test sent by mail if the screening test was not performed during the medical phase (test kit, letter, envelope, instruction for use, stamp), and the cost of a reminder letter.
4. the cost of test revelation in a centralized analysis center included overhead costs, capital expenditure, running costs, and labor. The process cost also included the cost of sending test results to the participants and to their GPs.
5. the costs of a colonoscopy performed after a positive test.
6. the costs of the follow-up after large adenoma resection.
7. the costs of the follow-up of treated CRCs.
8. the average costs of treatment of CRC by stage.

 

Parekh et al. (2008) {18} in their study, which was modelled on a US population, examined in detail the potential impact of imperfect adherence on the effectiveness and cost-effectiveness of screening strategies (time horizon: until age 100 or death). They included the costs of screening, diagnostic testing, treatment of possible complications (e.g. ruptures from colonoscopies) and CRC care. If F-DNA, gFOBT or FIT test were positive, colonoscopy followed with polypectomy and biopsy as necessary. If colonoscopy was normal after a positive non-invasive test, the non-invasive test was assumed to be false positive and screening resumed in 10 years with the primary screening strategy.

 

A Dutch study that took a 10-years time-horizon and referred to a cost-effectiveness analysis and Colorectal cancer screening comparing no screening, immunochemical and guaiac fecal occult blood tests, carried out by van Rossum et al. (2011) {19} also considered only direct healthcare costs. The costs of the two FOBTs consisted of costs that were independent and dependent on the type of test. Ignoring the differences in participation between the FIT and gFOBT, costs independent of the type of test were costs related to the invitation for screening (e.g. letters and information brochures), basic administration of the tests, feedback of test results to the patient and postal charges. The costs which are directly dependent on the type of test were costs of the test itself and costs for laboratory analyses. To represent the costs of the actual test kits they used retail prices. The costs of the laboratory analysis of the FOBTs were based on costs for administration, laboratory work and correspondence of test results for returned tests only. Consequently, participation rates influenced the total costs of each screening strategy. A complete test kit of Hemoccult-II (gFOBT) includes a number of tests and the test developer solution. OC-Sensor testing materials (FIT) are made available separately and were, therefore, calculated for returned tests only. The costs of the automated analyzer OC-micro, used for the analysis of the OC-Sensor, were also included into the costs of a returned FIT given the assumption of 100,000 tests per year and depreciated over 3 years. All other clinical costs for the follow-up of positive FOBT results (e.g., CRC surgery) were given as charges and directly derived from the Dutch Health Care Authority database (NZA). The NZA is the supervisory body for all the healthcare markets in the Netherlands and supervises both healthcare providers and insurers in the curative markets and in the long-term care markets.

 

Sharp et al.’s (2012) {20} study is based on cost-effectiveness of population-based screening for colorectal cancer: a comparison gFOBT, FIT and flexible sigmoidoscopy (time-horizon: cohort entered simulation at age 30 until age 100 or death) and evaluated in Ireland. The study included direct costs, valued in 2008 Euros, associated with screening and cancer management. Costs of gFOBT and FIT kits and associated processing were estimated following discussion with the National Cancer Screening Service, test suppliers, and laboratory staff, and using Department of Health and Children salary scales. They do not specify the types of resources included in their study, only stating at the end that their model did not incorporate the costs of establishing the infrastructure to implement population-based screening for colorectal cancer. The model was developed from a third-party payer perspective, in this case a provincial organization that decides on funding for a provincial screening program for colorectal cancer. Therefore, lost productivity costs, which would be necessary to give a wider societal perspective, were not incorporated.

 

Wilschut et al. (2011) {24} undertook a cost-effectiveness analysis, comparing Fecal Occult Blood Testing (gFOBT and FIT) when colonoscopy capacity is limited, and depicted the different cost components in more detail. Their study is based on 30 years time-horizon. In their analysis they included (a) the screening costs for FOBT screening such as organizational costs, costs of test kits, costs of analysis of the tests (that includes material and personnel needed during the process of registration, analysis, and authorization of returned tests) and (b) the costs of CRC treatment divided into three clinically relevant phases of care: initial treatment, continuous care, and terminal care.

 

Zauber et al. (2010) {5} undertook research on the cost-effectiveness of colonoscopy and included several types of resources within their cost-effectiveness analysis: costs that occur during procedures, costs of tests associated with CRC screening, costs of complications of screening, and treatment costs. These costs included the facility charges (as applicable) and physician services charges. Thus beneficiaries’ copayments are not reflected in the analysis. They also conducted an analysis from a modified societal perspective, by including direct costs borne by beneficiaries as well as estimated patient time costs, but excluding costs caused by lost productivity caused by early death or disability.

 

From this literature it could be concluded that organized screening contains:

• the costs of screening (organization of screening, screening procedure etc.). However, some studies {11, 12, 14, 15} only considered the costs of FIT/gFOBT kits and related laboratory and processing costs, because they have assumed that gFOBT and FIT screening would be requested during a person’s annual visit to the general practitioner.
• the costs of diagnostic follow-up in case of positive results
• the costs of treatment in case of detected disease (the costs of all 4 stages: stage I, stage II, stage III and stage IV) (the treatment costs of possible complications (e.g. ruptures from colonoscopy) were also included)
• non-medical costs (patient/ caregiver time and travel costs)

 

In general, the types of resources used when undertaking FIT and gFOBT screening will be similar, due to the similarity of the alternative screening procedures. The resources used for screening include those necessary for the organization of screening (e.g., sending invitation, distributing the kits, sending re-invitation, and possibly collecting the samples), those for the screening procedure (e.g., laboratory analysis, sending information concerning results, and diagnostic follow-up in case of positive results), and those for treatment in case of detected disease. This results card (ECO 1) summarises the types of costs included in the literature. Attention should be drawn to fact that the majority of studies failed to mention costs associated with lost or re-gained productivity. Only six studies mentioned costs associated with lost productivity, but none of these included such costs into the analysis. The exclusion of productivity-related costs has both economic and ethical dimensions, and is a matter which is subject to much methodological debate. 

Eighteen different articles from the systematic review of the literature outlined in the domain methodology section were used to identify estimates of the amounts of resources that are used when delivering FIT and its comparators gFOBT and no-screening.

The term “resources” refers to the natural units of health care services used. After  reviewing the studies it can be concluded that majority of studies mainly focused on the estimation of financial resources {10-12, 16-19, 21, 22, 25}. Nevertheless, there are some studies which also mentioned other types of resources used, namely: the number of screening tests {13-15, 30}, colonoscopies (COL) {13-15, 20, 23, 24, 30}, computed tomographic colonographies (CTC) {30}, polypectomies {13, 14, 20}, number of ultrasounds (TUS), number of persons receiving PET scan, MRI scan, CT scan, pre-operative radiotherapy and undergoing colorectal resection {30}.

By comparing estimates of financial resources that would be used when delivering FIT and its comparator gFOBT, it can be summarized that the amount of resources used are approximately at the same level. Studies {11, 13, 17, 20-22, 25} have shown that the amounts of resources, when delivering FIT, can be slightly higher in comparison with gFOBT. Some other studies reported similar costs – depending also on specificity of the test or the different types of thresholds (i.e. positivity threshold to determine the optimal cut-off) {10, 11, 15}.

Van Ballegooijen et al. (2003) indicated that FIT at 95% specificity level (462,794,391 $) is more expensive than gFOBT Hemoccult II (205,556,566 $) but less expensive in comparison to gFOBT Hemoccult – SENSA (775,643,892 $). FIT at 98% specificity level is the least expensive strategy; total costs are estimated to 83,110,600 $ (results per 1 million individuals, age 65-79 at the beginning of the screening program) {10}.

Results of Berchi et al.’s study (2010) indicates that screening with FIT at a 20 ng/ml (1,555,041 €) and 55ng/ml cut-off level (1,119,406 €) is more expensive than gFOBT (907,805 €) – if comparing only total costs. However, FIT can be less expensive if using thresholds at 93ng/ml (713,764 €) and 148ng/ml (192,702 €) – if comparing only total costs. Berchi et al. concluded that at a threshold of 93 ng/ml screening with FIT would cost € 94,041 less than one round of screening with gFOBT and would allow the detection of four additional advanced tumors. At a threshold of 75 ng/ml one round of screening with FIT would cost €6,282 less than one round of screening with gFOBT and would allow the detection of forty-two additional advanced tumors. For both thresholds, the positivity rate of FIT was lower than that of gFOBT. Consequently, FIT enabled the detection of a higher number of tumors without substantially increasing the risk associated with confirmatory colonoscopy. The threshold at which FIT and gFOBT positivity rates were almost identical was 67 ng/ ml. Using this threshold, screening with FIT resulted in more advanced cancers screened than screening with gFOBT, but was also more costly (€863 per advanced tumor screened) {11}.

In one of the previous studies Berchi et al. (2004) mentioned that the total annual cost of organizing the campaign, which had been assessed by the Social Security Department, amounts to 63,256 €. They also conclude that FIT can be slightly more expensive in comparison to gFOBT. Five biennial screening campaigns cost 230 € per targeted individual (including refusals) with FIT and 177 € per targeted person with gFOBT. With ten biennial screening campaigns, the costs per targeted individual were 316 € for FIT and 234 € for gFOBT {12}.

Hassan et al. (2011) displayed the use of resources for a cohort of 100,000 subjects that were invited to screening. (In order to project the simulation outcomes on the French population; a steady state for population size and age distribution was assumed, as represented by the year 2010 French census data. The model outputs reflected all persons aged 50–100 years of age at a given point in time in the steady state, as opposed to a cohort aging from 50 to 100 years over 50 years.) Besides financial resources they presented also the number of colonoscopies, total number of screening tests and number of polypectomies. They indicated that the number of colonoscopies (COL), which were performed as a screening strategy every 10 years, amounted 153,862. COL performed after annual FIT screening were estimated to 89,265, after biennial FIT screening 56,827, after annual gFOBT screening 38,219 and after biennial gFOBT 21.160. The number of total screening tests after annual FIT screening was estimated to 615,237, after biennial FIT screening 346.930, after annual gFOBT screening 772,361 and after biennial gFOBT screening 425,987. They indicated that 22,168 polypectomies have been performed after the colonoscopy, 22,639 number of polypectomies after annual FIT screening, 14,683 number of polypectomies after biennial FIT screening, 10,833 after annual gFOBT screening and 6,005 after biennial gFOBT screening. They estimated that the amount of resources that is required for FIT is higher than the amount that is necessary when screening with gFOBT. The estimated costs for delivering FIT biennially are 90,851,477 € (909 € per individual) and increase to 108,657,236 € (1087 € per individual), when delivering the screening with FIT annually. The presented data stands for a cohort of 100,000 French subjects. If the gFOBT screening method is used, the necessary amount of resources for biennially screening amounts to 79,359,152 € (794 € per individual) and for annually screening – 88,132,104 € (881 € per individual) {13}.

 

A Canadian report from 2009 (Heitman et al.) {14}mentioned number of performed colonoscopies and polypectomies and also number of FIT and gFOBT screening tests (i.e., test kits, as well as colonoscopies, polypectomies performed after the results of primary screening test). The results are indicated in the table below:

 

Table 1: Results of Heitman et al. (2009) {14}

hey came to the conclusion that FIT tests differ in methods (type of assay and collection) and test performance. Given the heterogeneity of the available FIT tests, they modeled three independent scenarios: one representing studies reporting “lower” test performance (FIT-low), one representing studies with “mid-range” test performance (FIT-mid), and one representing studies with “high” test performance (FIT-high). Their use of FIT-low, FIT-mid, and FIT-high represents a spectrum of FIT sensitivity and specificity, which in their opinion may be the result of differences in the testing kits and collection methods. The results were based on 100,000 people screened and indicated that the amount of resources (i.e. the costs of screening and CRC management) are equal among gFOBT and FIT-low (1,820 CAN$ in average per patient). This could be due to the fact that approximately the same number of tests (FIT and FOBT) were used and similar number of cancer was detected. If screening is delivered with FIT-mid (1,730 CAN$ in average per patient) the costs are lower, while with FIT-high (1,920 CAN$ in average per patient) the costs are higher. This could be due to smaller number of FIT’s used and due to further treatment (higher number of colonoscopies, polypectomies and colonoscopy complications). The data seem to suggest a better detection of advanced adenomas and CRC with two or three days of fecal sampling compared with one day {14}.

Heitman’s et al. study, published one year later (2010), indicated the number of screening tests required (during the lifetimes for hypothetical cohort of 100.000 average risk patients), number of colonoscopies and base case costs of screening and managing CRC. The study compared FIT-low, FIT-mid and FIT-high with gFOBT-low and gFOBT-high. Using base case estimates, over the lifetimes of a 100,000 patient cohort, the estimations showed that in general the FIT screening option is less expensive in comparison to the gFOBT strategy. Screening with FIT-low amounts to 2,005 CAN$ (on average per patient), with FIT-mid to 1,833 CAN$ (on average per patient) and with FIT-high to 2,004 CAN$ (on average per patient). On the other hand screening with gFOBT-low amounts to 2,195 CAN$ (on average per patient) and with gFOBT-high 2,084 CAN$ (on average per patient). The data on the base case costs as well as on number of screening tests required, are presented also in the following table {15}:

Table 2: Results of Heitman et al. (2010) {15}

Heresbach et al. (2010) were the only ones (compared to other studies), who outlined the comparison between screening costs and overall costs. The results of the study were based on a cohort of 100,000 individuals from 50-74 years, observing a time horizon of 30 years. In the study by Heresbach et al. total costs of the strategy that uses FIT are higher in comparison to the overall/total costs of strategy that uses gFOBT. They estimated that invitations to FOBT screenings structurally cost much more than those for CTC screening, the latter induced a much higher expenditure associated with the cost of the screening procedure itself. However, FIT generated much more colonoscopy costs. The increase in the total cost of COL-P and COL-S relative to no screening was 48,951,079 € with FIT and 28,348,797 € with CTC. Fewer cancers were prevented by FIT than by CTC, which induced more costs of CRC treatments. On the whole, gFOBT was the least costly competing strategy (13,583,934 €) and FIT the most expensive one (28,560,396 €). When comparing only the amount of resources that are necessary for screening (invitation and the screening procedure) it can be seen that   the invitation to FIT screening and FIT procedure amounted slightly less in comparison to gFOBT’s invitation and procedure. Invitation to FIT screening amounted 1,717,911 €, in addition the FIT screening procedure amounted 3,037,266 €, while the invitation to gFOBT screening amounted 1,767,118 € and the gFOBT screening procedure – 3,880,590 € {16}.

Lejeune et al. (2010), similar to the studies mentioned above, concluded in their economic modeling study that costs for screening with FIT over a time period of 20 years (in a cohort of 100,000 persons over 50) are higher in comparison to gFOBT screening. The costs for FIT screening amounted to 78,579,147 € in comparison to gFOBT, which amounted to 74,608,067 € {17}.

Sharp et al. (2012) defined the use of resources on financial ones as well as on the screening-related endoscopic procedures. They indicated that FIT screening is a little bit more expensive than gFOBT screening. But the costs differ only slightly. Costs of FIT screening and CRC management per person was 1,114 € (age 55-74), in comparison to gFOBT, where the costs of screening and CRC management per person amounted to 1,107 € (age 55-74). They presented that in case of gFOBT at 55-74 years (over the entire lifetime of cohort, i.e. 10 screening rounds, rated per 100.000 population) 3.386 colonoscopies have been required, while for FIT screening 34.632 colonoscopies have been required. As regards polypectomy they have indicated that 1.215 polypectomies have been required after the gFOBT screening and 9.486 polypectomies after FIT screening {20}.

In one of the later studies Sharp et al. (2013) estimated the screening-related resource use for biennial gFOBT (at 55-74 years) and biennial FIT (at 55-74 years) as it is presented in the table below. They made a comparison between the first year of screening and the 10^th year of screening {30}.

Table 3: Results of Sharp et al. (2013) {30}

  It can be concluded from the table above that after FIT screening scenario higher number of colonoscopies and colonographies has been implemented. The numbers are higher for FIT screening also within CRC work-up and treatment. As regards the number of screening tests in year 1 the number of kits sent out and processed was the same for gFOBT and FIT screening scenario, while in year 10 the number of kits sent out and processed was a little lower within FIT screening scenario {30}.

Sobhani et al. (2011) indicated the expected costs for an individual at age 50, using FIT screening, as to 694 €, in comparison to gFOBT, where the expected costs are slightly lower – 584 € per individual. The expected costs for an individual at age 50 after 24 years (3-sample Oc-Sensor) for a cut-off level of 50ng/ml are 1,141 € and for a cut-off level of 100ng/ml 1,593 € gFOBT was estimated to be the cheapest screening test, with expected costs for an individual after 24 years of 1,120 € {21}.

Two US studies {22, 25} also indicated that the costs of FIT screening is comparable to gFOBT screening, but that FIT is still slightly more expensive. Telford et al. have estimated that the costs of FIT, performed annually (over the lifetime of 100,000 individuals, who commence screening at age 50 years) amount to 65,429,821 CAN$, whereas gFOBT, also performed annually (over the lifetime of 100,000 individuals, who commence screening at age 50 years) amounts 63,139,823 CAN$. They have estimated that the strategy of screening with FIT amounts to 1,437 CAN$ per person (in 2007) and with gFOBT to 1,415 CAN$ (in 2007) {22}.

Zauber et al. estimated that FIT screening costs 2,688,092 US$ (per 1,000 50 year olds), whereas gFOBT screening costs 2,369,426 US$ (per 1,000 50 year olds) if Hemoccult II is used and 2,615,292 US$ (per 1,000 50 year olds) if Hemoccult-SENSA is used {25}.

Wilschut et al. (2011) also presented the amount of screening resources, but only for FIT screening. Information on screening resources can be evident from the following table {24}:

Table 4: Results of Wilschut et al. (2011) {24}

Their results showed (as also indicated in the table) that FIT screening (cut-off at 50ng/ml) amounts to 493€ per 1,000 individuals aged 45–80 years during the year 2005. For an unlimited capacity, it was most beneficial to screen intensively with the lowest FIT hemoglobin cutoff level for referral to colonoscopy set at 50 ng hemoglobin per mL for those aged 45–80 years with an annual screening interval and offering colonoscopy surveillance to all individuals with adenomas. The colonoscopy demand with this strategy was 49 colonoscopies per 1000 individuals. To optimally adapt screening when capacity was limited to 40 colonoscopies per 1000 individuals, individuals with a FIT hemoglobin measurement between 50 and 75 ng hemoglobin per mL were no longer referred to colonoscopy and individuals between ages 45 and 50 years were no longer invited. This decreased the demand to 36 colonoscopies per 1000 individuals. If capacity was limited to 20 colonoscopies per 1000 individuals, the next step was to further increase the FIT hemoglobin cutoff to 200 ng/mL and to stop screening 5 years earlier at age 75. Also surveillance colonoscopies in individuals with only one or two non-advanced adenomas were cancelled. If colonoscopy demand had to decrease even further, it became efficient to greatly reduce the number of screening rounds by first narrowing the age range to 60–80 years and lengthening the screening interval to 2 years (11 rounds) to reach a demand of 10 colonoscopies per 1000 individuals, and then to narrow the age range to 60–69 years every 3 years (four rounds) for a final capacity of five colonoscopies per 1000 individuals {24}.

 

Parekh et al. (2008) estimated that the costs of FIT screening amounts to 2,428 US$, per person, whereas the costs of gFOBT screening amounts to 2,683 US$ per person. The results are presenting CRC cases and costs per 100,000 persons from age 50 – 100 years {18}.

 

Van Rossum et al. (2011) concluded that over a period of 10 years, an average person aged between 50 and 75 years would cost the healthcare system, €327 with G-FOBT and €301 with FIT screening. These costs included CRC-related costs {19}.

 

The last study, which found FIT screening to be less expensive than gFOBT screening, is the study of Whyte et al. (2012). They concluded that FIT screening amounts to 530 £ per person (age 60-74) over a lifetime, whereas gFOBT screening amounts to 558 £ per person. They also indicated the endoscopy resource use requirements for a cohort of 649,400 individuals – all 50 years-old, monitoring the data for year 2010. The results showed that after biennial gFOBT screening strategy (population of 60-74 year-olds) 38.242 screening colonoscopies and 21.030 surveillance colonoscopies have been performed. In case of FIT screening strategy (population of 60-74 year-olds) 117,681 screening colonoscopies and 43,254 surveillance colonoscopies have been performed {23}.

 

The review made on amount of resources revealed that the majority of studies mentioned mainly financial resources, although some studies specified also other types of resources used, namely: the number of screening tests, colonoscopies, colonographies, polypectomies, number of ultrasounds, number of receiving PET scan, MRI scan, CT scan, pre-operative radiotherapy and undergoing colorectal resection.

By comparing the amount of other (i.e. non-financial) types of resources it can be concluded that in studies that mentioned those type of resources the numbers of screening tests used were higher within gFOBT screening strategy in comparison to FIT screening strategy {13-15, 30}. In addition, all studies indicated that the number of colonoscopies and polypectomies performed after the primary screening test were higher after FIT screening strategy in comparison to gFOBT screening strategy {13-15, 20, 30}.

 

As regards the financial resources, the majority of studies revealed that FIT screening can be slightly more expensive than gFOBT screening {11-13, 17, 20-22, 25, 27; 10 and 14 – depends on the test performance and specificity). However, a few studies presented later revealed just the opposite {15, 16, 18, 19, 23}, thus that FIT screening is less expensive than gFOBT screening {15, 16}. The reason for this hasn’t been directly highlighted in the studies. Nevertheless it could be concluded that the costs vary according to the cut-off values and test sensitivities of FOBTs (i.e. FIT and gFOBT). Some studies, for example, indicated that FIT should be used at higher hemoglobin cut-off levels when colonoscopy capacity is limited. This means, if FIT is used at a low cut-off value, a higher number of colonoscopies will be required which consequently results in higher total costs of screening (and vice versa). Van Rossum et al. {19}, for example, indicated that colonoscopy costs have a relatively high impact on the total screening costs because the relative screening costs of gFOBT screening compared to FIT screening is lower in terms of the costs of follow-up colonoscopies.

 

Summary table of type of resources and estimated or assumed amounts of resources used when delivering FIT and its comparator gFOBT:

All costs presented in the results use a discount rate of 3% {10, 13, 16-19, 21, 24, 25}, 3.5% {23}, 4% {20} or 5% {12, 22} in their base case analysis; further details can be found under ECO 6. 

Thirteen different articles from the systematic review of the literature outlined in the domain methodology section were used to identify the unit costs (according to the standard definition used in health economic evaluation, a unit cost is the cost of natural resource unit, e.g. cost of test kit; in some situations, it can also be the cost of the medical resources required to treat a certain stage of disease, e.g. cost of the resources required to treat metastatic colon cancer) of the resources used when delivering FIT and its comparator gFOBT.

The unit costs of resources used were not presented in every study. The studies that did mention the unit costs are presented below. 

Heitman et al. (2010) in their study concludes that gFOBT screening, when comparing overall costs, is slightly more expensive in comparison to FIT screening. Nevertheless, when comparing unit costs in the study from 2010 and also in the report of 2009, it can be seen that the unit costs for FIT are slightly higher than the unit costs for gFOBT. Unit costs for FIT are 19 CAN$ (i.e. base case: direct health care costs including costs of the kit and the processing), whereas unit costs for gFOBT amount to 12 CAN$ (the test of the kit costs 5 CAN$ and processing costs 7 CAN$). They also specified non-medical costs, which included patients and caregivers time and travel costs, but excluded productivity losses, and in both cases amount to 36 CAN$. Heitman et al. indicated also the unit costs for diagnostic follow-up and further treatment. They estimated that diagnostic colonoscopy (includes physician costs of diagnostic colonoscopy – 327 CAN$ and nonphysician costs of colonoscopy – 530 CAN$) amounts 857 CAN$, while therapeutic colonoscopy (includes physician costs of therapeutic colonoscopy – 401 CAN$ and nonphysician costs of colonoscopy – 598 CAN$) amounts to 999 CAN$. The authors also presented the total cost of managing CRC, which amount for stage I on average to 25,049 CAN$, for stage II on average to 36,143 CAN$, for stage III on average to 96,768 CAN$ and for stage IV on average to 134,014 CAN$ {15}.

 

Van Ballegooijen et al. (2003) revealed that FIT has a unit cost of approximately 13 $ (i.e. when specificity is 98% and sensitivity 70%), whereas a gFOBT Hemoccult II has a unit cost of approximately 4.50 $ (i.e. when specificity is 98% and sensitivity 40%). But rather than providing an estimate of the unit cost of FIT, van Ballegooijen et al. used a threshold analysis to estimate the unit cost at which FIT could be considered to be as equally cost effective as gFOBT. Van Ballegooijen et al. also made estimations on the average number of colonoscopy, which follows a positive screening result. The estimated costs for colonoscopy were based on information provided by CMS (i.e. Centers for Medicare and Medicaid Services) on Medicare payment rates for 2002 for colonoscopy procedures and polypectomy procedures performed in free standing clinic settings, on outpatient hospital settings and ambulatory surgical settings. The weighted average payment across these settings was 646$ for diagnostic colonoscopy and 683 $ for diagnostic colonoscopy together with biopsy {10}.

 

Berchi et al. (2004) indicated the following annual cost per individual {12}:

• organization of screening campaign – 0.38 €;
• FIT test – 8.84 € (i.e. purchasing, distribution, revelation of the test);
• gFOBT test – 10.98 € (i.e. purchasing, distribution, revelation of the test);
• colonoscopy – 457.35 €;
• treatment⁽¹⁾ of stage A – 17,579 €;
• treatment of stage B – 21,858 €;
• treatment of stage C – 31,110 €;
• treatment of metastasized cancer – 17,384 € .

 

Heresbach et al. (2010) reported that the screening test proposal in both screening alternatives (FIT and gFOBT) costs 2.1 €. In addition to that, FIT costs 8.84 €, whereas the gFOBT is a little more expensive and it costs10.98 €. They have estimated that CTC (computed tomographic colonography) procedure costs 128.7 €, Colonoscopy without polypectomy costs 779 €, Colonoscopy with polypectomy of nonadenomatous polyps 1561 € and Colonoscopy with polypectomy of adenomatous polyps 3,610 € on average. They have calclated that the colorectal cancer treatment costs 17,000 € on average in stage I, 22.000 on average in stage II, 30,700 on average in stage III and 36,600 on average in stage IV {16}.

 

The results of the study by van Rossum et al. (2011) indicated that the participation-independent costs⁽²⁾ of the FOBTs were: €5.20 for gFOBT and €4.39 for FIT. Compared with the manually operated and evaluated gFOBT, the automated analyzer (OC-Sensor micro) reduced operation and evaluation time for the FIT with more than 90%. When assuming 100% participation of individuals in performing the test, one gFOBT overall cost €9.63 and one FIT cost €8.50. The actual participation was 47% for gFOBT and 60% for FIT. Therefore, the overall cost according to intention to screen for one gFOBT was €7.06 and for one FIT €6.22. Van Rossum et al. also presented the screening costs, which are independent of the type of test and the participation rate, as equal for FIT and gFOBT, i.e. 2.40 €. They presented equal screening costs also for screening that is independent on the type of test and depending on participation. Those costs amount to 3.04 € for both tests. The differences that they identified were only among the test specific invitation costs that are independent of participation (FIT costs 1.35 €; gFOBT costs 2.80 €) and among test specific costs that depend on participation (1.71 € for FIT and 1.39 € for gFOBT). Van Rossum et al. also presented colonoscopy and treatment costs. They have estimated that the average costs for colonoscopy (Including polypectomy and pathology) amounts 921 €. They divided the treatment base costs to a costs for surgery (12,366 €), chemotherapy (12,731 €), Surgery and chemotherapy metastasis (23,097 €) and Radiotherapy (5,710 €) {19}.

 

Lejeune et al. (2010) concluded that FIT is more expensive as gFOBT. Distribution costs per FIT test performed amount to 18 €, whereas for gFOBT these costs amount to 11.8 €. They also identified costs of revelation per test performed, which amounts 5 € for FIT and 4.5 € for gFOBT. They have also presented costs relative to positive tests and concluded that diagnostic colonoscopy on average costs 526 €, while colonoscopy together with polypectomy  costs 641 €. They have also indicated the treatment cost: 17,596 € for stage I, 20,472 € for stage II, 29,013 € for stage III and 35,059 € for stage IV {17}.

 

Some other studies came to similar conclusions (i.e. that FIT unit costs are higher than gFOBT’s). Parekh et al. (2008) assumed that the base case costs of FIT amount to 22 $ (for each cycle of FIT – i.e. per year), whereas for gFOBT they amount to15 $ (for each cycle – i.e. per year). Parekh et al. also indicated that the costs of colonoscopy costs on average 920 €. They concluded that the base case value for localized cancer stage amounts 51,000 €, base case value for regional cancer stage amounts 98,000 € and base case value for distant cancer stage amounts 200,000 € {18}.

 

Sharp et al. (2012) indicated that the costs for one FIT kit (i.e. cost per kit dispatched/per individual invited to participate in screening) amounts to 3.75 €, whereas a gFOBT kit costs less – 1.70 €. They claim that the costs of FIT processing/ analysis (i.e. costs per kit completed and returned/ cost per screening participant) amount to 11.60 €, in comparison to gFOBT, where the costs amount to 7.81 €. They indicated that cost of colonoscopy amounts 650 €, while cost of CTC amounts 550 €. They have calculated that the lifetime cost of stage I CRC-screen-detected amounts 22,885 €, of stage II 36,377 €, of stage III 48,032 € and of stage IV 35,799 € {20}.

 

Sobhani et al. (2011) compared FIT and gFOBT alternatives and concluded that the costs for the screening program, the invitation of the population and the distribution of the tests are the same for both tests. A screening program costs 1.26 € for both tests, inviting the population amounts to 0.65 € and the distribution amounts to 9.32 €. Sobhani et al. (2011) estimated that the gFOBT purchase costs 4 € and gFOBT analysis 3.2 €. He made the same assumption for FIT tests. They have calculated that the colonoscopy, performed in case of positive results, would cost 526 € on average, colonoscopy with polypectomy – 641 €. They have also made a calculation for the phase of treatment, where the stage I amounts 17,596 €, stage II 20,472 €, stage III 29,013 € and stage IV 35,059 € {21}.

 

Telford et al. (2010) concluded that the FIT test is more expensive than gFOBT test. The costs of the FIT kit ranges between 10 and 40 CAN$, whereas the gFOBT kit ranges between 5 and 20 CAN$ {22}.

 

Zauber (2010) identified the base case costs for FIT to be 22.22 US$ (payer is CMS - Center for Medicare and Medicaid Services) and modified societal costs to be 39.22 US$ (these costs include beneficiary costs (copayments) and time costs in addition to the payer costs). They identified the base case costs for gFOBT to be 4.54 US$ (payer is CMS) and modified societal costs to be 21.54 US$. Telford et a.l also made an estimation for colonoscopy and further treatment. They indicated that colonoscopy costs between 200 and 2000 €, cost of cancer care in year 1 for stage I ranges between 5,000 and 30,000 €, for stage II between 20,000 and 50,000 €, for stage III 30,000 – 100,000 € and for stage IV 50,000 – 500,000 € {22}.

 

Wilschut et al. (2011) also came to the conclusion that the unit costs of FIT are more expensive than of gFOBT. Costs for FIT invitation (organization and test kit), according to their data, amount to 14.85 €, whereas for gFOBT they amount to 14.05 €. They have also identified costs per attendee (personnel and material costs for analysis) to 4.37 € for FIT and 1.90 € for gFOBT. They have estimated that the colonoscopy costs are 303 € without polypectomy and 393 € with polypectomy. Initial treatment in stage I was estimated to be 12,500 € initial treatment in stage II was estimated to be 17,000 €, initial treatment in stage III was estimated to be 21,000 € and in stage IV to 25,000. All 4 treatment scenarios had also additional costs both for continuing treatment after the first year and in the event of terminal care due to either CRC or other causes. {24}.

 

From the studies that present the unit costs it could be summarized that the ratio of the price between FIT’s and gFOBT’s unit costs usually corresponds to the ratio of the overall amount of resources (i.e total strategy costs) between those two screening strategies. This means, if FIT unit costs are higher compared to the gFOBT unit costs, the total amount of resources for a FIT screening strategy are higher in comparison to a gFOBT screening strategy. Nevertheless, there are some exceptions (e.g. {15}) that are presented above. In addition, if FIT is used at a low cut-off value, a higher number of colonoscopies will be required which consequently results in higher total costs of screening (and vice versa). Van Rossum et al. {19}, for example, indicated that colonoscopy costs have a relatively high impact on the total costs of a screening strategy. The unit costs of colonoscopy and further treatment are comparable between studies. The colonoscopy costs on average amounts to 600 €, while further treatment costs increase with the cancer stages.

 

Author (year), Country	Study design	Included costs	FIT	FOBT	Colonoscopy	Treatment/management
van Ballegoijen et al. (2003), USA	Use of MISCAN-COLON micro-simulation model	Direct costs including a co-payment from the patient	$13	$4.50	$646   $683
			Hemocult II		*Diagnostic colonoscopy (weighted average payment) **Diagnostic colonoscopy together with biopsy (weighted average payment)
Berchi et al. (2004), France	State-transition model (Markov process)	Direct costs based on French health care insurance contracts	€8.84	€10.98	€457.35	€17,579* €21,858** €31,110*** €17,384****
						*Treatment of stage A **Treatment of stage B ***Treatment of stage C ****Treatment of metastasized cancer
Heitmann et al. (2010), Canada	Markov model, with calibration against the efficacy and effectiveness outcomes from the literature	Direct costs derived from the Canadian health care system, costs of patient time and transport costs	CAN$ 19	CAN$ 12	CAN$ 857*   CAN$ 999**	CAN$ 25,049* CAN$ 36,143** CAN$ 96,768*** CAN$ 134,014****
			including costs of the kit and processing	including costs of the kit and processing	*diagnostic colonoscopy **therapeutic colonoscopy	*Managing CRC at stage I **Managing CRC at stage II ***Managing CRC at stage III ****Managing CRC at stage IV
Heresbach et al. (2010), France	State-transition model (Markov process)	Direct costs obtained from French health care system	€ 8.84	€ 10.98	€ 128.7*   € 779**   € 1561***   € 3610****	€ 17,000* € 22,000** € 30,700*** € 36,600****
					*CTC (computed tomographic colonography) procedure (on average)   **Colonoscopy without polypectomy (on average)   ***Colonoscopy with polypectomy of nonadenomatous polyps (on average)   ****Colonoscopy with polypectomy adenomatous polyps (on average)	on average: *Treatment of CRC at stage I **Treatment of CRC at stage II ***Treatment of CRC at stage III ****Treatment of CRC at stage IV
Lejeune et al. (2010), France	State-transition model (Markov process)	Direct costs based on French health care insurance contracts	€ 23	€ 16,3	€ 526* € 641**	€ 17,596* € 20,472** € 29,013*** € 35,059****
					*diagnostic colonoscopy (on average) **colonoscopy together with polypectomy (on average)	*Treatment of CRC at stage I **Treatment of CRC at stage II ***Treatment of CRC at stage III ****Treatment of CRC at stage IV
Parekh et al. (2008), USA	State-transition model (Markov process)	Direct costs derived from Medicare fee schedule	€ 22	€ 15	€ 920	€ 51,000* € 98,000** € 200,000***
			per year	per year		*base case value for localized cancer stage **base case value for regional cancer stage ***base case value for distant cancer stage
van Rossum et al. (2011), Netherlands	State-transition model (Markov process)	Direct costs based on Dutch health care charges and retail prices)	€ 12,89	€ 14,63	€ 921	€ 12,366*   € 12,731**   €23,097***   € 5,710****
			dependent costs of the test, assuming 100 % participation (costs of the FOBT itself and costs for laboratory analyses	dependent costs of the test, assuming 100 % participation (costs of the FOBT itself and costs for laboratory analyses	including polypectomy and pathology) (on average	*costs for surgery   **costs for chemotheraphy   ***cost of surgery and chemotheraphy metastasis   ****radiotheraphy
Sharp et al. (2012), Ireland	State-transition model (Markov process), with calibration against the efficacy and effectiveness outcomes from the literature	Direct costs based on Health Service Executive	€ 3.75* € 11.60**	€ 7.81* € 1.70**	€ 650*   € 550**	€ 22,885* € 36,377** € 48,032*** € 35,799****
			*FIT kit  (costs per kit dispatched/ per individual invited to participate in screening) **FIT processing/analysis (costs per kit completed and returned/ costs per screening participant)	*gFOBT kit  (costs per kit dispatched/ per individual invited to participate in screening) **gFOBT processing/analysis (costs per kit completed and returned/ costs per screening participant)	*colonoscopy   **CTC	*Lifetime costs of stage I CRC-screen-detected *’Lifetime costs of stage II CRC-screen-detected ***Lifetime costs of stage III CRC-screen-detected ****Lifetime costs of stage IV CRC-screen-detected
Sobhani et al. (2011), France	State-transition model (Markov process)	Direct costs based on literature	€ 18.43	€ 18.43	€526* €641**	€ 17,596* € 20,472** € 29,013*** € 35,059***
			costs for the screening programme, the invitation of the population and the distribution of the tests are the same for FIT and gFOBT: Screening programme Inviting the population Distribution Purchase costs Analysis		*Colonoscopy in case of positive results (on average) **Colonoscopy with polypectomy (on average)	*Treatment of CRC at stage I **Treatment of CRC at stage II ***Treatment of CRC at stage III ****Treatment of CRC at stage IV
Telford et al. (2010), Canada	State-transition model (Markov process)	Direct costs based on data from the Provincial Ministry of Health	Between 10 and 40 CAN$	Between 5 and 20 CAN$
Wilschut et al. (2011) Netherlands	Use of MISCAN-COLON micro-simulation model	Direct costs derived from the Dutch health care system	€ 19.22	€ 15.95	€ 303*   € 393**	€ 12,500* € 17,000** € 21,000*** € 25,000****
			Costs per invitation (organizational costs and test kit) Costs per attendee (personnel and material costs for analysis)		*Colonoscopy   **Colonoscopy with polypectomy	*Treatment of CRC at stage I **Treatment of CRC at stage II ***Treatment of CRC at stage III ****Treatment of CRC at stage IV
Zauber (2010), USA	Use of MISCAN-COLON micro-simulation model	Direct costs derived from Medicare fee schedule excluding  co-payments borne by the patient	$ 22.22	$ 4.54	$ between 200 and 2,000	$ between 5,000 and 30,000* $ between 20,000 and 50,000** $ between 30,000 and 100,000*** $ between 50,000 and 500,000****
			base-case costs	base-case costs		*Treatment of CRC at stage I **Treatment of CRC at stage II ***Treatment of CRC at stage III ****Treatment of CRC at stage IV

 

  [1] Costs of treating cancers with regard to diagnostic stage (i.e. A, B, C and metastasized stage) were estimated using data from the Digestive Tumour Registry of Calvados and Social Security data on reimbursements for treating all CRCs incident in the Department of Calvados during the period 1st September 1997 to 31st August 1998. They were constituted of: hospital care (both public and private) and care given in the medical departments of retirement homes; outpatient care (specialised or non-specialised medical consultations, medical and paramedical acts); transportation for medical reasons; medical purchases such as pharmaceutical products and prosthesis (colostomy bags); and assistance provided to patients such as daily payments and other allowances (disability with or without recourse to a third person). [2] The costs of the FOBTs consist of costs that were independent and dependent on the type of test. Ignoring the differences in participation between the types of test, costs independent of the type of test were costs related to the invitation for screening as letters and information brochures, basic administration of tests, feedback of test results to the patient and postal charges. Costs dependent on the type of test were costs of the FOBT itself and costs for laboratory analyses.

The effectiveness of the screening methods for CRC is elaborated in the Clinical Effectiveness domain. The incremental effectiveness of FIT versus gFOBT presented here is based on the results of the systematic literature review of cost-effectiveness studies using decision analytic modelling. 

There are differences in the output measures used by the included cost-effectiveness studies. Eight studies are using life-years gained as the measure of effectiveness {10, 12, 13, 16-19, 25}, six are using Quality adjusted life years (QALY) {14, 15, 20-24} and one is using the intermediate outcome “detected advanced tumours” {11}. Since there are different study designs (type of model, perspective, time horizon, population, etc.) and input parameters (sensitivity, specificity, compliance rate, etc.) the results of the models are not necessarily comparable.

Life-years gained when using FIT instead of gFOBT:

 

• In general the results of the cost-effectiveness modelling show that using FIT instead of gFOBT increases the life-years per person. The incremental effects range from 0.041 life-years gained per person over a lifetime if annual screening is performed from age 65 – 79 {10}, to 0.003 life-years-gained after 10 years if only one round of screening is performed in a cohort of 50-75 year-olds {19}.
• There are two different types of guaiac-based tests, which are frequently used as comparators in cost-effectiveness studies: Hemoccult II and Hemoccult SENSA. The effect on life-years gained of the latter, Heoccult SENSA, is estimated to be similar to that of the immunochemical tests {10, 25}.
• Most studies using life-years gained as the measure for effectiveness are based on data from the USA and France {10, 12, 13, 16-18, 25}. Only one study is based on data from the Netherlands {19}.

 

Table 5: Incremental effects of FIT vs. gFOBT in life-years gained (LYG):

Author (year)	Life-years gained (1)	Comparators	Screening age	Participation rate	Discount rate	Country
van Ballegooijen et al. (2003) {10}	0.041	FIT 98%-specificity vs. gFOBT (Hemoccult II); annual	65-79	100%	3%	USA
	0.04	FIT 95% specificity vs. gFOBT (Hemoccult II); annual
	0.0008	FIT 98% specificity vs. gFOBT (Hemoccult Sensa); annual
	0.00003	FIT 95% specificity vs. gFOBT (Hemocult Sensa); annual
Berchi et al. (2004) {12}	0.0198	FIT vs. gFOBT; after 20 years; biennial	50-74	43.7%	5%	France
Hassan et al. (2011) {13}	0.01707	Annual FIT vs. biennial gFOBT	50-74	Adherence(2): 40%; compliance(3): 100%	3%	France
	0.01337	FIT vs. gFOBT; biennial
Heresbach et al. (2010) {16}	0.02744	FIT vs. gFOBT; after 30 years; biennial	50-74	42%	3%	France
Lejeune et al. (2010) {17}	0.01329	FIT vs. gFOBT; after 20 years; biennial	50-74	55%	3%	France
Parekh et al. (2008) {18}	0.00919	FIT vs. gFOBT; annual;	50-80	100%	3%	USA
van Rossum et al. (2011) {19}	0.003	FIT vs. gFOBT; after 10 years; 1 round of screening	50-75	gFOBT: 47% FIT: 60%	3%	Netherlands
Zauber (2010) {25}	0.0144	FIT vs. gFOBT (Hemoccult II); annual	50-80	100%	3%	USA
	-0.00005	FIT vs. gFOBt (Hemoccult Sensa); annual

 

⁽¹⁾ Per person when using FIT instead of gFOBT (over a lifetime if not stated otherwise)

⁽²⁾ Attending initial screening

⁽³⁾ Attending subsequent rescreening

QALYs gained when using FIT instead of gFOBT:

All included cost-effectiveness studies that used QALYs as effectiveness measure support the results of the studies using life-years gained as the endpoint. The results of the comparison between FIT and gFOBT range from 0.036 QALYs gained per person over a lifetime by screening a cohort of 50-75 year-olds annually with FIT instead of gFOBT {22}, to 0.01 QALYs gained over a lifetime when annually screening a population of the same age with a low performance FIT instead of a gFOBT {14}. The study with the highest QALY gain also assumes the highest compliance with the screening strategies (75%). The smallest differences between the effectiveness of FIT and gFOBT occur when the test performance (sensitivity) is assumed to be low. The studies using QALYs as effectiveness measure are based on data from Canada {14, 15, 22}, England {23}, France {21} and Ireland {20}. Wilschut et al. (2011) {24} does not give the estimated effects of FIT and gFOBT and hence does not allow an estimation of the incremental effects.

 

Table 6: Incremental effects of FIT vs. gFOBT in Quality Adjusted Life-years (QALYs):

Author (year)	QALYs gained (1)	Comparators	Screening age	Participation rate	Discount rate	Country
Heitman et al. (2009) (2) {14}	0.020	FITmid vs. gFOBT; annual;	50-74	adherence: 68%; compliance: 63%	5%	Canada
	0.020	FIThigh vs. gFOBT; annual;
	0.010	FITlow vs. gFOBT; annual;
Heitman et al. (2010) {15}	0.035	FIThigh vs. gFOBThigh; annual;	50-75	Adherence(3): 68%; compliance(4): 63%	5%	Canada
	0.011	FITlow vs. gFOBTlow; annual;
Sharp et al. (2012) {20}	0.016	FIT vs. gFOBT; biennial;	55-74	53%	4%	Ireland
Sobhani et al. (2011) {21}	0.013	FIT vs. gFOBT; biennial;	50-75	57.3%	3%	France
Telford et al. (2010) {22}	0.036	FIT vs. gFOBT; annual;	50-75	73%	5%	Canada
Whyte et al. (2012) {23}	0.016	FIT vs. gFOBT; biennial;	60-74	adherence: 54%; compliance: 85%	3.5%	England

 

⁽¹⁾ Per person when using FIT instead of gFOBT (over a lifetime).

⁽²⁾ The time horizon is not clearly stated in the published article but it seems likely to be over a lifetime.

⁽³⁾ Attending initial screening

⁽⁴⁾ Attending subsequent rescreening

 

Increase in detected advanced tumours when using FIT instead of gFOBT:

 

One cost-effectiveness study uses detected advanced tumours as effectiveness measure {11}. This is an intermediate outcome that is used in clinical studies, and can only be assumed to be correlated with the final outcomes, life-years and QALYs gained. The results of this study show that the higher the cut-off level of the FIT (ranging from 20 – 148 ng/ml) the less effective FIT becomes compared to gFOBT (incremental effects ranging from 188 more detected tumours by FIT compared to gFOBT to 99 less detected by FIT). The reason for this is that the positive predictive value increases with the cut-off level, which means that a higher cut-off level reduces unnecessary follow-up colonoscopies but it also reduces the chance that a tumour is found if the level of blood in the stools is low (e.g. 20ng/ml).

 

Overall, the FIT seems to be more effective than gFOBT irrespective of the outcome measure used. The only exception is Zauber (2010) who compared FIT with a specific gFOBT (Hemoccult SENSA) and estimated that this specific gFOBT is marginally more effective (at the 5^th decimal place) than FIT {25}. 

The transferability of a model´s results depends on similarities and dissimilarities of the relevant settings. Important model parameters that should be comparable are the age range, the rate of compliance and the discount rate. Furthermore, the basic demography of the model country and the country-specific epidemiology should be considered when transferring results from one setting to another. 

The incremental cost-effectiveness ratio (ICER) of FIT versus gFOBT is based on the studies identified through the systematic literature search described above. In most of these studies the incremental cost-effectiveness ratio (ICER) was already calculated and explicitly given. For the remaining studies the incremental costs and effects of FIT versus gFOBT was calculated and divided to obtain the ICER:

ICER= DCosts/D Effects

For the estimation of the overall costs of the different screening technologies most of the cost-effectiveness models adopted a payer’s perspective and hence only included the direct costs of the screening programme, the follow-up tests and the treatment of a detected adenoma or cancer. Heitman et al. (2009 and 2010) {14, 15} also added indirect costs of the patient time and of the transport. 

The 16 identified studies all contained an estimation of either cost-effectiveness (effects are measured in life-years gained) {10, 12, 13, 16-19, 25} or cost-utility (effects are measured in QALYs) {14, 15, 20-24}, based on health-economic models.

The calculated ICERs varied across the studies as was expected due to the different modelling structures and parameter assumptions. However, given that the studies were undertaken in different settings (countries and health-care systems) and used data from different points in time the result that FIT was estimated to be ‘dominant’ or have a relatively low incremental cost-effectiveness ratio (ICER), is consistent across almost all the studies.

The consequences of screening for colorectal cancer can potentially occur throughout the participants’ remaining lifetime. Hence, the time horizon for a study modelling the costs and effects of different screening strategies for CRC should be over a lifetime, if sufficient information is available to support such an approach. If a life-time horizon is not taken or not possible, then there is a potential that important costs and/or effects will be ignored. For the reason being that costs of a screening occur immediately, whereas the effects (life years / QALYs gained) usually occur later in life, a shorter time horizon might underestimate the cost-effectiveness of a technology. There are three studies included in this review that use shorter than lifetime time horizons (10 {19}, 20 {11, 12, 17} and 30 years {16, 24}).

Costs per life-year gained when using FIT instead of gFOBT:

In one third of the reported ICERs (four of 12) FIT dominates gFOBT, meaning that FIT is associated with lower costs and higher effects than gFOBT (see table below). However, most of these studies were based on US-data {10, 18}. One model estimated that FIT was dominated by gFOBT if used in a screening population of 50-80-year-olds {25}; this is the study were Hemeoccult SENSA was used, which is assumed to have effects similar to those of FIT, and to cost less than FIT. The remaining estimates of the ICER are ranging between around 3,000 € and 17,500 € per life-year gained {10, 12, 13, 16, 17, 25}. The publication date of the studies does not seem to play a significant role in the differences between the ICERs.

Table 7: Incremental Cost Effectiveness Ratios (ICERs) using life years gained

Author (year)	ICER[1] (=ΔCosts/ Δlife-year gained)	Comparators	Screening age	Costs included	Discount rate	Country
van Ballegooijen et al. (2003) {10}	FIT dominates gFOBT	FIT 98% specificity vs. gFOBT (Hemoccult II and Hemoccult Sensa); annual	56-79	Direct costs derived from Medicare fee schedule including co-payments born by the patient (in 2002 US Dollars)	3%	USA
	FIT dominates gFOBT	FIT 95% specificity vs. gFOBT (Hemoccult Sensa); annual
	6,400 US$ per LYG (~ 4,700 €)	FIT 95% specificity vs. gFOBT (Hemoccult II)
Berchi et al. (2004) {12}	3,000€ per LYG	FIT vs. gFOBT; after 20 years; biennial	50-74	Direct costs based on French health care insurance contracts (in 2003(b) Euros)	5%	France
Hassan et al. (2011) {13}	8,600 € per LYG	FIT vs. gFOBT; biennial	50-74	Direct costs based on French health care insurance contracts (in 2010(b) Euros)	3%	France
	17,600 € per LYG	Annual FIT vs. biennial gFOBT
Heresbach et al. (2010) {16}	5,500 € per LYG	FIT vs. gFOBT; after 30 years; biennial	50-74	Direct costs obtained from French health care system (in 2005/07(a) Euros)	3%	France
Lejeune et al. (2010) {17}	3,000 € per LYG	FIT vs. gFOBT; after 20 years; biennial	50-74	Direct costs based on French health care insurance contracts (in 2006 Euros)	3%	France
Parekh et al. (2008) {18}	FIT dominates gFOBT	FIT vs. gFOBT; annual;	50-80	Direct costs derived from Medicare fee schedule (in 2006 US Dollars)	3%	USA
van Rossum et al. (2011) {19}	FIT dominates gFOBT	FIT vs. gFOBT; after 10 years; 1 round of screening	50-75	Direct costs based on Dutch health care charges and retail prices (in 2009(a) Euros)	3%	Netherlands
Zauber (2010) {25}	22,100 US$ per LYG (~ 16,400 € )	FIT vs. gFOBT (Hemoccult II)	50-80	Direct costs derived from Medicare fee schedule excluding co-payments borne by the patient (in 2007 US Dollars)	3%	USA
	FIT is dominated by gFOBT	FIT vs. gFOBT (Hemoccult SENSA); annual

 

1. year of price based on referenced literature
2. year of price not given, and assumed to correspond to year prior to publication

 

Costs per QALY gained when using FIT instead of gFOBT:

All of the studies that used QALYs as a measure of effectiveness were conducted recently, i.e., between 2009 {14} and 2012 {20} (see table below).

Half of the estimated ICERs based on the included models show that FIT dominates gFOBT {14, 15, 23, 24}. The settings (Canada, England and the Netherlands), the screening age (50-74, 60-74 and 45-80) and the assumed base-case discount rates (3%, 3.5% and 5%) vary across these studies. Two of the ICERs where FIT dominated gFOBT were estimated from a model that included costs for patient time and transport to the screening {14}. The ICERs of the remaining four studies {14, 20-22} range between around 400 € and almost 9,000 € per QALY which is well below one often-suggested ICER threshold of 50,000 US $ (around 36,960 €).

Table 7: Incremental Cost Effectiveness Ratios (ICERs) using QALYs

Author (year)	ICER (1) (= ΔCosts/ ΔQALY gained)	Comparators	Screening age	Costs-included	Discount rate	Country
Heitman et al. (2009) (2) {14}	FIT dominates gFOBT	FIT-low vs. gFOBT; annual	50-74	Direct costs derived from the Canadian health care system, costs of patient time and transport costs (in 2007 CAN Dollars)	5%	Canada
	FIT dominates gFOBT	FIT-mid vs. gFOBT; annual
	5,000 CAN$ per QALY (~ 3,600 €)	FIThigh vs. gFOBT; annual
Heitman et al. (2010) {15}	FIT dominates gFOBT	FIT-mid, -low and -high vs. gFOBT low and high	50-75	Direct costs derived from the Canadian health care system, costs of patient time and transport costs (in 2007 CAN Dollars)	5%	Canada
Sharp et al. (2012) {20}	400 € per QALY	FIT vs. gFOBT; biennial;	55-74	Direct costs based on Health Service Executive (in 2008 Euros)	4%	Ireland
Sobhani et al. (2011) {21}	8,800 € per QALY	FIT vs. gFOBT; biennial	50-75	Direct costs based on literature (in 2010 Euros)	3%	France
Telford et al. (2010) {22}	600 CAN$ per QALY (~ 400 €)	FIT vs. gFOBT; annual	50-75	Direct costs based on data from the Provicial Ministry of Health (in 2007 CAN Dollars)	5%	Canada
Whyte et al. (2012) {23}	FIT dominates gFOBT	FIT vs. gFOBT; biennial;	60-74	Direct costs based on data from the National Health Service	3.5%	England
Wilschut et al. (2011) {24}	FIT dominates gFOBT	FIT (at all cut-off levels) vs. gFOBT; after 30 years; annual	45-80	Direct costs derived from the Dutch health care system (in 2010(a) Euros)	3%	Netherlands

1. year of price not given, and assumed to correspond to year prior to publication

 

⁽¹⁾ Numbers are rounded to full hundreds (exact estimates can be found in the Appendix “Study Designs and Results”

⁽²⁾ The time horizon is not clearly stated in the published article but it seems likely to be over a lifetime.

 

[1] Numbers are rounded to full hundreds (exact estimates can be found in the Appendix “Study Designs and Results”

Adjustment of price levels:

 

The results of the cost-effectiveness models were not adjusted to one price level or one point in time. Since most studies (12 of 16) were conducted in or after 2008 this might cause non-significant changes to the ranking of the ICERs in the tables but is unlikely to change the overall order dramatically.

 

Sensitivity analyses:

An analysis of the robustness of the results was not given by all studies, especially not on the gFOBT-vs.-FIT ICER since the primary aim of some studies was to compare not only FIT and gFOBT but also other screening strategies, or no screening at all.

 

1. Studies life years gained as the outcome measure:

 

The result of the study of van Ballegooijen et al. (2003) revealed that FIT with a 98% specificity dominates gFBOT (Hemeoccult II) and that this holds even if the compliance rate decreases from 100% to 60% for gFOBT and 90% for FIT {10}.

In a Monte Carlo simulation Parekh et al. (2008) shows that FIT dominates a no screening strategy in 100% of the simulations whereas gFOBT dominates a no-screening strategy in only around 95% of the simulations {18}. A direct comparison of FIT and gFOBT using a Monte Carlo simulation was not conducted.

Van Rossum et al. (2011) present the results of a deterministic sensitivity analysis, with the result that only very low CRC incidence and very high estimated costs of colonoscopy have a negative impact on the cost-effectiveness of FIT {19}.

Another deterministic sensitivity analysis was conducted by Berchi et al. (2004) using different assumptions about the participation rate, the costs of gFOBT, costs of colonoscopy, costs of CRC treatment, quality of FIT and natural history of disease {12}. The results suggest a robustness of the finding that FIT is more effective but also more costly than gFOBT.

Lejeune et al.’s (2010) sensitivity analysis also shows that FIT remained more effective and more costly for all parameter variations, but that the ICER increases if the price for gFOBT is decreased by 50% or if the sensitivity of FIT decreases. The ICER decreases if the price for FIT decreases by 50%, if the participation rate of FIT is increased by 10%, if the lead time associated with FIT increases or if FIT`s sensitivity increases {17}.

A probabilistic sensitivity analysis of the model designed by Heresbach et al. (2010) shows that FIT is more effective than gFOBT in 97.8% and dominant in 8.9% of the simulations {16}.

Hassan et al. (2011) also conducted a probabilistic sensitivity analysis with the result that annual FIT had the highest net-benefit in 20% of the simulations, compared to other strategies such as sigmoidoscopy every five years, of colonoscopy every 10 years which had the highest net-benefit in 40% and 26% of the simulations respectively {13}.

In the publication of Zauber (2010) no sensitivity analysis is reported {25}.

 

1. Studies using QALYs gained as the outcome measure:

 

The univariate sensitivity analysis of Heitman et al. (2009) showed that changing the costs or the screening interval (biennial instead of annual) did not change the dominance of FIT-mid (representing studies with “mid-range” test performance) over gFOBT {14}.

In the study published by Heitman et al. one year later (2010) no sensitivity analysis of the direct comparison of FIT versus gFOBT was published, but the probabilistic analysis shows that in nearly 100% of the simulations FITmid was cost saving and more effective compared to no screening, but no direct comparison of {15}.

The results of the model presented by Whyte et al (2012) are highly sensitive to several model parameters such as uptake, endoscopy costs and FIT thresholds. In the probabilistic sensitivity analysis FIT remains cost-effective compared to gFOBT at an assumed willingness-to-pay threshold of 20,000 £ {23}.

Wilschut et al. (2011) conducted a deterministic sensitivity analysis on different parameters. FIT (50ng/ml) for the age group 45-80 years remained most cost-effective when attendance rate increased to 100%, quality of life loss was taken into account, fatal complications decreased, FOBT costs and colonoscopy costs were halved, and when complication and treatment costs were halved or doubled. FIT (50ng/ml) for the age group 50-80 years became more cost-effective for all other parameter changes {24}.

In the one-way sensitivity analysis of Sharp et al. (2012) the most influential parameters were the discount rate, the costs of the tests and the costs of managing CRC. The ICERs for FIT and gFOBT compared to no screening always remained below the chosen notional cost-effectiveness threshold (45,000 € per QALY). The probabilistic sensitivity analysis showed that uncertainty was greatest for FIT, but all cost-effectiveness ratios remained below the notional threshold and the incremental QALY gains for FIT exceeded those for gFOBT in most simulations {20}.

The model of Telford et al. (2010) was sensitive to variations in the sensitivity of the tests to detect advanced adenoma, the costs of the test, the compliance with screening and the costs of cancer care. The probabilistic sensitivity showed that the ranking of strategies did not change and that no strategy was dominant {22}.

In the model of Sobhani et al. (2011) the participation rate seems to have a very high impact on the results, whereas changing the compliance rate for colonoscopy did not change the results much. Throughout the one-way sensitivity analyses the 3-sample FIT with a cut-off level of 50ng/ml was consistently the most cost-effective choice {21}.

 

It is difficult to provide an overall statement on the robustness of the ICER estimations because neither the methods of sensitivity analysis nor the reporting of the results are standardised. The matter is further complicated by that fact that in some of the studies FIT is not directly compared to gFOBT but both are compared to no screening. As a consequence, the sensitivity analyses focus on the robustness of the cost-effectiveness compared to no screening.

 

In conclusion, the deterministic sensitivity analyses of the studies using life years gained as the outcome measure show that the model results are quite robust, especially to changes in compliance and participation rate, but might be sensitive to other assumptions, such as that the CRC incidence is very low, the costs of a colonoscopy or a gFOBT is very high or that the sensitivity of FIT decreases. The probabilistic sensitivity analyses suggest that the results are rather robust.

The sensitivity analyses of the studies using QALYs gained as the outcome measure show no common pattern and therefore no qualified statement about influential parameters can be given.

 

Six studies reported the result of a deterministic sensitivity analysis {10, 12, 17, 19, 21, 24}, four used a probabilistic method {13, 15, 16, 18}and four studies used both, a deterministic and a probabilistic analysis {14, 20, 22, 23}. Only one study did not report a sensitivity analysis {25}. 

The systematic review of the literature, outlined in the domain methodology –section, was used to form the description of the time horizons used in the studies found (see table “Study designs and results” in Appendix). The appropriateness of the time horizon relates to three main considerations:

1. the extent to which a study can be considered comparable to other studies on the same topic
2. data availability and decision-making context
3. the discount rate

In studies of technologies with a potential for life-long consequences, the time horizon of cost-effectiveness analysis would ideally be over the remaining lifetime. However, the relevant time horizon will also depend on the availability of appropriate data, as well as on the availability of appropriate statistical or mathematical models, in order to estimate costs and outcomes. In the cost-effectiveness studies located, the majority use a time period over which most of the significant economic and health consequences of the intervention could become apparent. In order to do this, they invariably link intermediate endpoints to final endpoints and/or extrapolate evidence on effectiveness. One approach when undertaking an economic evaluation with a time horizon of the remaining lifetime of the modelled cohort, is that costs and effects can be measured alongside a trial and then, when appropriate, be extrapolated using modelling (e.g., by synthesizing trial-based information with information on costs and effects from other studies).

 

Although some of these models may not describe reality with full face validity, they may be able to offer a useful method of making relative cost-effectiveness comparisons between different screening modalities.

The main differences and similarities between the studies with respect to the stated time horizons and discount rate(s) can be found from the Appendix (see table “Study designs and results”). 

The systematic review of the literature outlined in the domain methodology section and many of the details concerning the method of analysis can be found from the other results cards within this domain. In this result card we will focus on the types of modelling used, the two broad categories can be classed as modelling on the basis of a single study, such as in {11, 12} and those using a stage-based or natural history modelling approach using multiple sources of evidence (i.e., most others). We also draw on one overview of the cost-effectiveness literature {6} and on one earlier HTA {5}.

Single-study-based economic evaluations have the potential advantage of the internal validity of the trial design and the advantage of joint collection of data on both resource use and effectiveness. However, the aims of the underlying trials and economic evaluations, may differ in significant respects, which can lead to problems concerning the suitability or comparability of trial-based economic analyses. Despite the aims of single-study-based economic evaluations generally being somewhat different than model-based economic evaluation, trial-based economic analyses may provide individual-level analysis of the impact of the screening technology and its comparator(s). On the other hand, it should be kept in mind that in many instances modelling is needed, e.g., to estimate final outcomes from the intermediate outcomes measured during a trial, or to extrapolate to the envisaged population. As an alternative to single-study-based economic evaluations, ‘stage-shift models’ or ‘natural-history models’ can be used to synthesise information from numerous studies and sources.

Stage-shift models (sometimes referred to as ‘shallow’ models) generally compare the distribution of disease stages associated with screening (e.g., observed in screening trials) with the distribution of disease stages at diagnosis (at a later point in time) seen in the absence of a screening programme (e.g., observations from cancer registers or screening-trial comparator arms) {39}. In the case of CRC, relevant stages could include absence of disease, pre-cancerous lesions, different stages of cancer. In stage-shift models the effect of screening is modelled by shifts to less severe stages, e.g., using information that, given systematic screening, proportionally more people will be diagnosed with pre-cancerous lesions or at an early stage of cancer that may be more operable or still curable. One common feature is that modelling starts at the time of the first screening and models estimate costs and effects as a function of disease stage at screening or diagnosis.

An alternative to stage-shift models is to use ‘natural-history models’ to estimate the development of cancer and its precursor stages in a population that is followed from an early age onwards (e.g., starting in young adulthood or at birth). For each member of the modelled cohort, the development of disease is tracked, i.e., the model determines at each point in time whether the person remains disease free, has a precursor lesion, or has developed a certain stage of cancer. Such epidemiological models of the natural history of the disease, sometimes referred to as ‘deep models’, have the advantage of serving as a basis for ‘applying’ or ‘plugging-in’ a diverse range of screening strategies, diagnostic procedures, treatments, and associated costs and effects. One limitation is that extensive epidemiological data of high quality are required. Natural-history models also usually cover the early stages of the disease process and there are often gaps in knowledge that hinder modelling. On the other hand, lead-time and length-time issues (e.g., the question whether screening participants may encounter a net survival benefit or beneficial treatment, or whether he/she is only diagnosed earlier), may be efficiently addressed using natural-history models, if suitable input data are available.

The differences and similarities between the studies with respect to the type of model used can be found from the Appendix (see table “Study designs”).