A comparative study of faecal occult blood kits in a colorectal cancer screening program in a cohort of healthy construction workers

Ir J Med Sci (2011) 180:103–108 DOI 10.1007/s11845-010-0605-0 ORIGINAL ARTICLE A comparative study of faecal occult blood kits in a colorectal cancer screening program in a cohort of healthy construction workers M. Shuhaibar • C. Walsh • F. Lindsay • N. Lee • P. Walsh • P. O’Gorman • G. Boran R. McLoughlin • A. Qasim • N. Breslin • B. Ryan • H. O’Connor • C. O’Morain • Received: 12 April 2010 / Accepted: 30 September 2010 / Published online: 17 October 2010 Ó Royal Academy of Medicine in Ireland 2010 Abstract Background The incidence of colorectal cancer (CRC) has been increasing. We evaluated uptake rates and outcomes of faecal immunochemical test (FIT) and Guaiac test (gFOBT) kits as part of a two-step CRC screening. Methods A 3-year CRC screening program for a defined population of construction workers was conducted. Those satisfying the inclusion criteria were provided with gFOBT or FIT kits. Individuals testing positive were invited for a colonoscopy. Results A total of 909 faecal testing kits were distributed. Age range was 53–60 years. Compliance rate was higher for FIT (58.3%) as compared to gFOBT (46.7%) (p = 0.0006). FIT detected adenomatous polyps and CRC in 37.5 and 25%, respectively, whereas; gFOBT detected 23.5 and 18%. Colonoscopies were normal in 53 and 25% tested positive by gFOBT and FIT, respectively (p = 0.016). M. Shuhaibar (&)
F. Lindsay
N. Lee
R. McLoughlin
A. Qasim
N. Breslin
B. Ryan
H. O’Connor
C. O’Morain Department of Gastroenterology/Clinical Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, The Adelaide and Meath Hospital, Dublin Incorporating The National Children’s Hospital, Tallaght, Dublin, Ireland e-mail: shuhaibm@tcd.ie C. Walsh Department of Statistics, Trinity College Dublin, The Adelaide and Meath Hospital, Dublin Incorporating The National Children’s Hospital, Tallaght, Dublin, Ireland P. Walsh
P. O’Gorman
G. Boran Department of Clinical Chemistry, Trinity College Dublin, The Adelaide and Meath Hospital, Dublin Incorporating The National Children’s Hospital, Tallaght, Dublin, Ireland Conclusion The FIT was more cost-effective when compared with gFOBT with higher return rate, sensitivity and specificity. A comparative study of faecal occult blood kits in a CRC screening program in a healthy cohort of construction workers. Keywords Colorectal cancer (CRC)
Screening
FIT (faecal immunochemical testing)
gFOBT (gauaic faecal occult blood test)
Adenomas
Uptake rates
Outcomes Introduction/background Colorectal cancer (CRC) is the third most common cancer worldwide, with nearly one million new cases and 492,000 related deaths annually [1]. In Europe, there are 3.2 million cancer cases diagnosed per year and colorectal cancer (CRC) is the second most common malignancy with an incidence of 400,000 and greater than 200,000 annual deaths [2]. Death from CRC can be prevented with early detection through screening of asymptomatic individuals, and providing early curative treatment. Five-year survival can be achieved in 90% of early diagnosed cases in comparison to 65% in advanced cases [3]. CRC is ideal for screening as it takes years to progress from a benign to a malignant stage [4]. A multistep sequence of genetic alterations usually results in the transformation of normal mucosa to a precursor adenoma and ultimately carcinoma [5]. Greater than 95% of CRC arise from colorectal adenomas [6, 7], which in the majority of cases originates from a detectable polyp. Despite the availability of screening tools, including faecal occult blood testing (FOBT), flexible sigmoidoscopy and colonoscopy, there is no agreed gold standard method for 123 104 CRC screening. Some programs apply a two-step approach starting with non-invasive FOBT that is followed by colonoscopy while direct colonoscopy can be the gold standard in other centres. Screening for CRC using guaiac FOBT has been shown to reduce mortality by 15% (the Nottingham study) [8], and by 33% in the Minnesota study [9, 10]. In addition, an 18-year follow-up data from the Minnesota trial demonstrated that annual and biennial serial FOBT screening reduces CRC incidence by 17–20%, respectively [11]. In the past few years, a faecal immunochemical test (FIT) was developed with higher specificity and at least comparable sensitivity to gFOBT. It utilises antibodies specific to the globin portion of human haemoglobin. As globin is quickly degraded in the upper intestine, the FIT is specific for lower gastrointestinal bleeding. It requires no dietary restrictions, is simple to use, and sample testing is automated. This quantitative test limits human error in analysis and allows precise, adjustable, pre-defined cut-off points for an abnormal result, based on the population characteristics and risks. In this study, we evaluated the uptake rate and outcomes of two different FOBTs, followed by a colonoscopy for those testing positive in a defined cohort of Irish construction workers. Patients and methods Study subjects/construction workers Study population comprised a well-defined cohort of male construction workers, aged 50 years and over. These workers were members of the Irish Construction Worker Health Trust (CWHT) which was established in 1994, to promote better health and lifestyle. Screening was provided for diabetes, hypertension, ischaemic heart disease, hypercholesterolaemia and prostate cancer. In June 2006, screening for CRC started through the distribution of free FOBT kits from a university teaching hospital to construction workers. Occupational nurses, in at least eight-health screening mobile clinics around Ireland, provided information about CRC and screening using FOBT kits; gFOBT in the initial phase and subsequently FIT kits. Participants included for screening had no symptoms suggestive of bowel cancer or inflammatory bowel disease; no history of melena or rectal bleeding and were on no medication that may give false-positive FOBT results. Individuals who had a normal colonoscopy for any reason, over the previous 5 years were excluded from the study. Workers who fulfilled the inclusion criteria were instructed by the occupational nurses about using the 123 FOBT test kits, with specific guide on sample collection. In the case of gFOBT, they were asked to apply two samples to each card from three-separate bowel motions, whereas in the case of FIT, to apply a sample to the buffer solution in the two- specific containers, on two consecutive days. Participants were required to pack the kits in the provided biohazard sealed envelope and post them within a day to be analysed at the hospital laboratories. There were 473 gFOBT (Hemoccult II SENSA) kits and 436 FIT (sample containers for Eiken OC-Sensor) kits issued during the 36 months study period. Laboratory analysis The gFOBT test detects pseudo-peroxidase activity in haemoglobin when it interacts with a guaiac-impregnated (gFOBT) card in the presence of a hydrogen peroxide developer. The reaction produces a compound with a quinine structure that produces an unstable blue bis-methylene quinine dye within 30–60 s. A positive result is indicated by the immediate appearance of a blue colour on the addition of the hydrogen peroxide developer. Because the blue dye is unstable, delayed reading may result in falsenegative results. The analytical sensitivity of this gFOBT is between 0.3 and 1 mg Hb/g of faeces; however, this can be improved (0.15 mg Hb/g) by hydrating the sample on the kit prior to applying hydrogen peroxide as recommended by Haemoccult Sensa, Beckman Coulter Inc. Fullerton, CA. The haemoglobin content of the received FIT sample kits was analysed using an occult censor (OC-Sensor l from Eiken, Japan). This is a semi-automated analyser with quantitative output. In this study, a cut-off point of 100 ng/ml was employed to define a positive sample corresponding to ±20 lg haemoglobin/g of stool. This cut-off was based on the previous published experiences [12, 13]. The samples were loaded in a sample rack, automatically punctured, and one drop of buffer was extracted and dripped into the reaction tube. The reaction tube contained latex antibody particles and buffer. The reading is set between 10 and 400 lg Hb/g faeces and 50 specimens can be processed per hour. The analyser gives a print out with haemoglobin measurement and reports any encountered errors. The results of the stool analysis were then matched with the patient’s demographic details. Subjects who tested positive for FOB were counselled by the colon cancer screening nurse coordinator at the Gastroenterology department and invited to have a full colonoscopy. Subjects who tested negative were reassured and advised to have the test repeated in 2 years time (Fig. 1). 105 Fig. 1 Study design and summary of results n=909 FOBT kits distributed 473 G-FOBT 436 FIT 221 Returned (48%) 254 Returned (58%) 17 positive 16 positive CRC - 2 Dukes B -1 Dukes C and 2 precancerous lesions (Tubular Adenomas) and 2 hyperplastic polyps, 1 diverticular disease & haemorrhoids 9 No Abnormality Detected Statistical analysis Statistical analysis for this study was carried out in R version 2.9.0 [14]. Test for proportions and Chi squared tests were carried out as appropriate. Results A total of 909 FOBT kits were distributed over 36 months of the study period to construction workers throughout the Republic of Ireland. Of the 909 kits, 473 were gFOBT kits (52%) and 436 were FIT (48%). The return rate for the gFOBT was 46.7% (221/473), and statistically significantly lower compared with FIT kits 58.3% (254/436) (p = 0.0006). Of the 221 returned gFOBT kits, 17 (7.6%) tested positive and these subjects were contacted to attend for colonoscopy. There was 3 CRCs (17.6%) diagnosed, 2 Dukes stage B and 1 Dukes stage C that required surgery 4 No Abnormality Detected P=0.035 4 CRC cancerous - 1 Dukes A -2 Dukes B - 1 TVA with HGD Dysplasia and 6 pre cancerous adenomatous lesions and follow-up therapy. The gFOBT-positive-predictive value for CRC was 18% (5–44%). 4 patients had polyps (23.5%), 2 were tubular adenomas and the other 2 were benign hyperplastic polyps. 1 patient had haemorrhoids and diverticulosis. The remaining 9 subjects had no abnormality detected on colonoscopy. Of the returned 254 FIT kits, 16 (6.3%) tested positive. There were 4 CRC cases (25%) including, 2 Dukes B, 1 Dukes A, and 1 had tubulo-villous adenoma with highgrade dysplasia. The FIT-positive-predictive value for CRC was 25% (8–53%). All participants were asymptomatic and received curative surgery; left hemicolectomy, right hemicolectomy and local excision. The age range for this cohort was 53–60 (Table 1) with a median age of 56.4 years at diagnosis. The mean FIT was 230, 174 ng/ml for the first and second reading, respectively. There was one tubulo-villous adenoma in a 65-year-old patient which was fully excised at colonoscopy. Two patients had tubular adenomas with low-grade dysplasia (LGD) and three others had tubular 123 106 Table 1 Construction workers general characteristics Age range (years) 53–60 Gender Males 99% Smoking (%) 42% BMI (body mass index) 25–30 in 43% (over weight), [30 but \40 in 12% (obese) Socioeconomic class Mid-low in 65% adenoma. The remaining 4 positive FIT patients (18.7%) had normal colonoscopies. Their mean age was 59.3 years, with a mean FIT of 89.6 for the first and 89 ng/ml for the second FIT reading. Details of the FIT readings for the cases are provided in Table 2. The overall observed positive-predictive value for gFOBT and FIT was 53% (95% CI 29–76%) and 75% (95% CI 47–92%) for cancer and adenoma respectively (p = 0.15). This supports the cost-effectiveness of FIT kits over gFOBT. Discussion In this study, we compared the outcomes of two different FOBT kits; the Guaiac (gFOBT) and Immunochemical tests (FIT), in a defined cohort of construction workers. This cohort has an increased risk of CRC as was outlined in a recent report [15]. Table 2 Details of the I-FOBT test readings for all those classified as positive (positive [100 ng/ml) Histology 1st I-FOBT (ng/ml) 2nd I-FOBT (ng/ml) Age Malignancy Dukes A 375 269 60 Dukes B (N = 2) 259 190 244 72 56 53 95 110 57 TVA w HGD Pre-malignancy stage TVA 1 355 135 65 TA w LGD (N = 2) 347 125 55 150 [1,000 52 39 140 61 188 74 58 198 80 58 84 108 60 160 0 52 25 159 66 77 40 65 TA (N = 3) No lesion detected 123 Despite the limitation of our study in view of small numbers, the compliance rate, the high return rate of the provided kits added to its power in addition to the numbers of new cases diagnosed with CRC in otherwise asymptomatic individuals. There was a higher compliance rate in the FIT group at 58.3% as compared to 46.7% in the gFOBT group. The combination of reduced dietary restrictions, simplified stool sampling is thought to contribute to the 11% improved uptake in FIT. This finding is in agreement with Van Rossum’s study, which showed a higher compliance rate of 60% in the FIT group when compared with 47% (p \ 0.01) for gFOBT [16]. This was confirmed in three other randomised controlled trials [17– 19]. Population-based programmes also showed a high FIT uptake rate ranging from 17 to 90.1% [20–22], whereas gFOBT uptake rate was in the region of 17.2 to 70.8% [23– 26]. In our cohort, there were 3 (17.6%) CRC and 2 adenomatous polyps detected using gFOBT, as compared to 4 (25%) CRC (95% CI 8–53%) and 6 adenomas 37.5% (95% CI 18–62%) in FIT group. Our observed positive-predictive value for cancer or adenoma was 53% (95% CI 29–76%) with the gFOBT and 75% with FIT (95% CI 47–92%). FIT also facilitated the early identification of precancerous adenomatous lesions. FIT has a higher specificity when compared with gFOBT. Another screening study using this quantitative immunochemical stool test, with 100 ng/mL as the cut-off point, found an overall positivity of 3.7% and a positive-predictive value for colon cancer and adenoma of 41.6% [27, 28]. Population-based studies [20–22] showed that FIT-positive rates can range from 4 to 11% which is comparable to our cohort at 6.3%. As part of evaluating the cost-effectiveness for a national CRC screening programme in Ireland, the Health Information and Quality Authority in its recently published report confirmed that FIT at 55–74 years was associated with the maximum health gain [13]. Furthermore, FIT was associated with reduced CRC incidence and mortality by 14.7 and 36%, respectively [13]. A variety of FOBTs are available [11, 29]; however, our choice for the initial phase of this study was Hemoccult II SENSA which has been most widely used and thought to reduce mortality [8, 9, 32, 33]. The gFOBT has formed the basis of many regional and national CRC screening programmes [23, 25, 28, 30, 31]. This test is not specific for human haemoglobin and the results may vary with diet, stool sample volume, application, hydration [8], patient compliance, and operator analysis. Furthermore, Guaiac continued to be manufactured from tree resin extraction and therefore would be susceptible to batch variation, resulting in changing analytical sensitivity. All this in turn will have an implication on the 107 follow-up on the correctly indicated colonoscopy to facilitate early CRC diagnosis. gFOBT and FIT are non-invasive methods of screening, and were evaluated for the primary step in developing a cohesive national screening programme for CRC. A recent, randomised population-based trial by Van Rossum et al. [16] became a milestone in comparing gFOBT directly with FIT in a large cohort of 20,623 patients aged between 50 and 75 years. The positivity rate was significantly higher with FIT when compared with gFOBT (5 vs. 2.4%, respectively, p \ 0.01). The cancer detection rate per 1,000 colonoscopies was 71% higher with FIT group [16]. A French study confirmed FIT superiority to gFOBT for the detecting CRC and advanced adenomas [34]. Another study by Van Rossum et al. [35] showed that CRC was detected at a significantly earlier stage with OC-Sensor (p \ 0.0001), as compared to Hemoccult II (p = 0.29). This helped achieving earlier local excision and better survival. Despite the available evidence, FIT has been incorporated in very few populations screening programmes [21, 36, 37]. There is supporting evidence that high participation rates are not required for CRC screening cost-effectiveness [38]. We believe that despite our study numeric limitations, it has added and correlated well with the mounting European evidence for FIT as the preferred primary non-invasive tool for CRC population screening programme. 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