’Original article Colorectal cancer in a second round after a negative faecal immunochemical test Luis Bujandaa, Cristina Sarasquetab, Antoni Castellsc, María Pelliséc, Joaquín Cubiellad, Inés Gila, Angel Cosmea, Eunate Arana-Arrie, Izaskun Mara, Isabel Idigorasf and Isabel Portillof; on behalf of the EUSCOLON study investigators Objective The faecal immunochemical test is one of the tests recommended by scientific societies for colorectal cancer (CRC) screening in average-risk populations. Our aim was to evaluate the characteristics of CRC detected in a second round of screening after negative results in a first round. Methods We studied patients in whom CRC was detected in a screening programme. This programme included asymptomatic individuals between 50 and 69 years old and offered tests every 2 years. A total of 363 792 individuals were invited to participate in the first round of faecal immunochemical test screening and 100 135 individuals in the second round after a first negative result. The screening strategy consisted of faecal testing of a single sample using an automated semiquantitative kit, with a cut-off of 20 μg haemoglobin (Hb)/g faeces. Results The rate of positive results was 6.9% (16 467/238 647) in the first round and 4.8% (3359/69 193) in the second round (P < 0.0005). Overall, 860 (0.36%) cases of CRC were detected in the first round and 100 (0.14%) in the second round (P < 0.005). The location of the cancer was proximal in 12.5 and 24% of cases detected in the first and second rounds, respectively (P = 0.008). Hb concentrations were higher in the first round (211 vs. 109 μg Hb/g faeces in the second round; P = 0.002). Multivariate analysis confirmed that, in the second round, CRC diagnosed was more often proximal (hazard ratio vs. first round, 2.4; 95% confidence interval, 1.3–4.4; P = 0.003) and the concentration of Hb/g faeces was lower (hazard ratio vs. first round, 2.1; 95% confidence interval, 1.3–3.5; P = 0.003). Conclusion The CRC detection rate is lower in the second round of screening. Further, in the second round, CRC detected is more often in a proximal location and Hb concentrations are lower. Eur J Gastroenterol Hepatol 27:813–818 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Introduction
Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth leading cause of cancer-related death [1]. Evidence from several studies has shown that CRC screening is effective and cost-effective in averagerisk populations [2–6]. Specifically, randomized-controlled trials have shown that population-based screening for CRC with faecal occult blood tests reduces CRC mortality by 15–33% [7–10]. The faecal immunochemical test (FIT) is one of the tests recommended by scientific societies for CRC screening in average-risk populations [2]. In a recently published European Journal of Gastroenterology & Hepatology 2015, 27:813–818 Keywords: colorectal cancer screening, faecal immunochemical test, first round, negative faecal immunochemical test a Department of Gastroenterology, Hospital Donostia, Instituto Biodonostia, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco (UPV/EHU), bHospital Universitario Donostia, Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), San Sebastián, cDepartment of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), IDIBAPS, University of Barcelona, Barcelona, dServicio de Aparato Digestivo, Complexo Hospitalario Universitario de Ourense, Ourense, e Hospital Universitario de Cruces, Baracaldo and fPrograma de Cribado de Cáncer Colorrectal, Servicio Vasco de Salud, País Vasco, Spain
Correspondence to Luis Bujanda, MD, PhD, Department of Gastroenterology, Hospital Donostia, Avda Paseo Beguiristain s/n, 20014 San Sebastián, Spain Tel: + 34 943 007 173; fax: + 34 943 007 065; e-mail: [email protected] Received 8 December 2014 Accepted 6 March 2015
population-based randomized trial, FITs detected as many cases of CRC as colonoscopy in the first screening round, and the two techniques detected CRC at a similar stage [11]. Moreover, the FIT was associated with a higher participation rate than colonoscopy or the guaiac faecal occult blood test [12]. However, the sensitivity and specificity of FIT have been found to be 27–31% and 95–97%, respectively, for advanced neoplasia and 65.8–75% and 94.6–95% for CRC [13,14]. Because of this variability in the detection of advanced neoplasia, FIT screening is usually performed every 1–2 years after 50 years of age. Denters et al. [15] describe the characteristics of four cases of CRC detected (0.19%) in a second round after a negative FIT result in the first round of screening. They observed that the distribution of the location of the cancer in the colon (proximal/distal) was similar to that in the first round. However, there is a lack of data on the detection rate of CRC with FITs, and the staging and characteristics of these tumours in a second round compared with the first round. The aim of this study was to evaluate the characteristics of CRC detected in a second round of screening after negative results in a first round. Methods Study population and data collection
Individuals with CRC detected in the CRC screening programme in the Basque country between April 2009 and
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DOI: 10.1097/MEG.0000000000000366
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April 2013 were eligible for inclusion in the study [16]. This screening programme includes asymptomatic individuals between 50 and 69 years old and tests are performed every 2 years. Eligible individuals were invited to participate in the screening, and 2 weeks later, an FIT kit was sent to his/her home. The kit contained a plastic container for the stools, a probe and a collection tube together with a plastic bag in which to seal them, and written instructions on how to collect the sample for the test. Specifically, after one bowel movement, they were instructed to sweep the tip of the probe through the stool several times and then insert the probe into the collection tube. Participants then handed the sample in at their health centre the following day. During the study period, 363 792 individuals were invited to participate in the first round of FIT screening (first round) and 100 135 individuals in the second round after a first negative result (second round). The eligible population was contacted progressively from April 2009. In April 2011, the second round was started in individuals who had obtained a negative FIT result. Individuals were excluded from the study if they had any of the following: a personal history of CRC, adenoma or inflammatory bowel disease; a family history of hereditary or familial CRC (defined as ≥ 2 first-degree relatives with CRC or 1 diagnosed before the age of 60); or any severe comorbidities; as well as if they had undergone a previous colectomy; a previous CRC screening test in which faecal occult blood was detected in the last 2 years; or a sigmoidoscopy/colonoscopy in the last 5 years. Those who tested positive in the first round, were at least 70 years of age, had moved out of the region or had died were not invited to participate in the second round. The screening strategy consisted of an FIT of a single sample using the automated semiquantitative OC-Sensor kit (Eiken Chemical Co., Tokyo, Japan) without any specific diet or medication limitations. Samples were processed as described previously [11]. Individuals with at least 100 ng haemoglobin (Hb) per ml of buffer solution (corresponding to 20 μg Hb/g faeces) were invited for a colonoscopy. In those undergoing colonoscopy, bowel cleansing and sedation was performed as described previously [17]. All colonoscopies were performed by experienced endoscopists (each performing > 200 colonoscopies per year) [18]. Tumours were staged according to the American Joint Committee on Cancer classification and stages III and IV were considered advanced [19]. The location was classified as proximal or distal, proximal indicating that the tumour lay between the cecum and the splenic flexure, and distal indicating that it lay between the splenic flexure and the anus. In addition to the FIT result, stage and location, we analysed histological findings, the degree of differentiation of the tumour and patient age and sex. Statistical analysis
χ2 and/or Fisher’s tests were used to compare categorical variables, and t-tests were used to compare continuous variables between the groups (first round and second round). Faecal Hb concentrations are presented as medians and were compared using nonparametric Mann–Whitney U tests. Logistic regression was used to analyse the independent effect of each variable on the probability of identifying
CRC in the second round. All analyses were carried out using SPSS 17.0 (SPSS, Inc., Chicago, Illinois, USA). Results
A total of 363 792 individuals were invited to the first round and 100 135 individuals to the second round after a negative FIT result (Fig. 1). Of these, 238 647 individuals (65%) participated in the first round and 69 193 individuals (69%) participated in the second round (P < 0.0005). Of the patients who completed the FIT, 47% (112 164) in the first round and 45% (31 136) in the second round were men (P < 0.0005). The FIT positivity rate was 6.9% (16 467) in the first round and 4.8% (3359) in the second round (P < 0.0005). Of those with positive results, 62% in the first round and 58% in the second round were men (P < 0.0005). We found CRC in 860 (0.36%) individuals in the first round and in 100 individuals (0.14%) in the second round (P < 0.005). The location of the CRC was proximal in 12.5% of cases in the first round and 24% in the second round (P = 0.008) (Table 1). There were no significant differences in terms of age, sex, stage, histological findings or degree of differentiation. Quantification of faecal Hb showed that Hb concentrations were higher in those with higher stage CRC, with values of 167, 283, 260 and 212 μg Hb/g faeces for stages I, II, III and IV, respectively (P < 0.005). Significantly higher concentrations were found in the first round than the second round overall (211 vs. 109 μg Hb/g faeces, respectively), and in the case of stage I cancer for both distal and proximal locations (Table 2). However, in the case of stage IV CRC in a proximal location, Hb concentrations were actually higher in the second round, although the difference did not reach significance. Variables that showed an independent effect on the likelihood of detecting CRC in the second round were proximal location [hazard ratio in the second vs. first round, 2.4; 95% confidence interval (CI), 1.3–4.4; P = 0.003] and bleeding (hazard ratio, 2.1; 95% CI, 1.3–3.5; P = 0.003). The probability of diagnosing CRC in individuals with Hb concentrations lower than 145 μg Hb/ g faeces was twice as high in the second round as the first (hazard ratio, 2.1; 95% CI, 1.3–3.5; P = 0.003). Endoscopic treatment was more common in cases detected in the first round than the second (30 vs. 18%; P < 0.05). There was no significant difference in stage between the first and the second round by location (proximal or distal) of the tumours. First-round Hb concentrations among patients with CRC diagnosed in the second round were as follows: below 5 μg Hb/g faeces in 58 individuals (58%); between 5 and 9.9 μg Hb/g faeces in 18 individuals (18%); between 10 and 14.9 μg Hb/g faeces in 10 individuals (10%); and between 15 and 19.9 μg Hb/g faeces in 10 individuals (10%), whereas data was missing for four cases (4%) as errors were made during the collection of the sample and the test was not repeated. The mean Hb concentrations in the second round were 297, 248, 492, 865 and 651 μg Hb/ g faeces for cut-off points of less than 5, 5–9.9, 10–14.9 and 15–19.9 μg Hb/g faeces and cases with missing firstround data (because of errors) in the first round, respectively. The Hb concentrations in the second round were
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Colorectal cancer in second round Bujanda et al.
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815
2 172 175 individuals in the Basque country
583 706 between 50−69 years of age 284 427 (49%) men
363 792 invited to participate in the first round 177 866 (49%) men
238 647 participated in the first round (65%) 112 164 (47%) men
16 467 FIT positive (6.9%) 10 209 men (62%)
860 CRC (5.9%) 571 men (66%)
100 135 with negative first round invited to second round 48 966 (45%) men
69 193 participated in the second round (69%) 31 136 (45%) men 3 359 FIT positive (4.8%) 1 952 men (58%)
100 CRC (2.9%) 66 men (66%)
Fig. 1. Study recruitment and participant flow. CRC, colorectal cancer.
significantly lower in individuals with less than 10 μg Hb/g faeces than those with between 10 and 19.9 μg Hb/g faeces in the first round (285 vs. 674 μg Hb/g faeces; P < 0.05). Discussion
In our study, fewer cases of CRC were diagnosed in second-round FIT screening than in baseline screening (CRC being found in 0.36% of participants in the first round vs. 0.14% in the second round). Van Roon et al. [20] found CRC in 0.36% (22/7229) and 0.3% (4/1280) of participants in the first and second rounds, respectively, and Denters et al. [15] found rates of 0.41% (12/2871) and 0.19% (4/2022), respectively, in these rounds, whereas Morikawa et al. [14] detected CRC in 0.36% (79/21 805) of participants in a first round. Large polyps and colorectal tumours are more frequently ulcerated and bleed more than smaller polyps and small flat colorectal tumours. Hence, the diagnosis of the latter by FIT screening is more difficult. In our study, we observed that the Hb concentration detected in FITs increases with the CRC stage. Similar findings have been reported by other authors. For example, Morikawa et al. [14] obtained a mean sensitivity of 65.8% for invasive cancer, with sensitivities by Dukes’ stage of 50.0% for stage A, 70.0% for stage B and 78.3% for stage C or D [14].
The location of the CRC was proximal in 12.5% of cases detected in our first-round FITs. Previous studies on consecutive series of patients with CRC found proximal CRC in 25% of cases [11,21,22]. These data suggest that around 12.5% of proximal CRCs are not detected in the first round of screening with a FIT. Similar figures have been reported for advanced neoplasia. Studies published by both Morikawa et al. [14] and Haug et al. [23] concluded that FIT screening has lower sensitivity for the detection of proximal than distal advanced neoplasia (16–20 vs. 31–33%, respectively). Similar results were found when FIT screening sensitivity was analysed for proximal versus distal CRC (56.5 vs. 69.6%, respectively) [14]. By contrast, other research has shown that this screening has a similar sensitivity for detecting proximal and distal neoplasia (38 and 37%, respectively) [13]. Several factors could explain more cases of proximal CRC being found in the second round than the first. First, cancer in the right colon is more likely to be sessile or flat than that in the left colon and rectum and may bleed less [24]. Second, some rapidly progressing cancers, such as those because of hereditary syndromes, may not have been present at the time of the first FIT [25]. Third, nonbleeding cancer remains in a nonbleeding state for a long time in the right colon and CRC may have an intermittent bleeding pattern. Fourth, Hb from proximal CRC may degrade before reaching the anus, which could affect the accuracy of FITs [26]. Fifth, because of differences in stool
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Table 1. Characteristics of patients with CRC in the first round of FIT screening and second round after a first negative result
Sex (men) [n (%)] Age (years) Location [n (%)] Proximal Stage [n (%)] I II III IV Haemoglobin concentration (μg Hb/g faeces) [median (IQR)]b Histological findings Adenocarcinoma [n (%)] Mucinous or signet-ring cell Carcinoid Differentiation [n (%)] Well-to-moderately Poorly Haemoglobin concentration distribution (μg Hb/g faeces) [n (%)] < 58 58–144 145–311 312–786 > 786 < 145d > 145 Treatment [n (%)] Only endoscopy Surgery ± chemotherapy ± radiotherapy
First round (n = 860)
Second round (n = 100)
571 (66) 61.5 ± 5.3
66 (66) 61.4 ± 4.9
108/860 (12.5) 428 160 201 71 211
(50) (19) (23) (8) (78–604)
24/76 (24) 45 20 26 9 109
(45) (20) (26) (9) (47–497)
P 0.5 0.7 0.008 0.5a
0.002c
842 (98) 14 4
97 (97) 2 1
0.6
826 (96) 34 (4)
97 (97) 3 (3)
1.0
164 164 180 181 171 328 532
27 24 13 15 21 56 44
0.04
(19) (19) (21) (21) (20) (38) (62)
258 (30) 602 (70)
(27) (24) (13) (15) (21) (56) (44)
18 (18) 82 (82)
0.001
0.08
CRC, colorectal cancer; FIT, faecal immunochemical test; Hb, haemoglobin. Linear trend. Interquartile range. c Mann–Whitney U-test. d Grouped according to the cut-off point for which there were the greatest differences between quartiles. a
b
Table 2. Median haemoglobin concentration (μg Hb/g faeces) in the first and second rounds of FIT screening by stage and location Proximal
Stage Stage Stage Stage
I II III IV
Distal
First round
Second round
214 186 194 110
46 69 168 570
P
First round
Second round
P
0.01 0.2 0.9 0.1
176 303 277 271
88 693 63 165
0.02 0.7 0.2 0.6
FIT, faecal immunochemical test; Hb, haemoglobin.
consistency, blood may be more homogeneously distributed when originating from the right side and dominantly on the surface when originating from the left side, and this would also favour the detection of left-sided neoplasia [23]. In our study, the concentration of Hb in faeces was lower in patients with CRC diagnosed in the second round than the first (overall and in those with distal or proximal stage I cancer). Surprisingly, however, faecal Hb concentrations tended to be higher in the second round than the first round in the subset of patients diagnosed with stage IV proximal, although the difference did not reach significance. There are many potential strategies to improve the diagnosis of proximal CRC. First, we could increase the frequency of screening to every year; however, a recent study, examining intervals of 1, 2 and 3 years, showed that the yield at the second screening round was not influenced by the interval length within this 1- to 3-year range [20]. Second, the number of tests per round could be increased,
but data on the effect of this are conflicting. Analysing FIT results, one study showed that the sensitivity increased from 33 to 47% on testing three samples instead of one [27], and another showed that the positivity rate increased from 8 to 13% on adding a second sample [28], whereas the sensitivity for detecting colorectal neoplasia was reported to be 56% with the 1-day method, 83% with the 2-day method and 89% with the 3-day method [29]. By contrast, other studies examining the ability to detect CRC after two or three samples indicated no improvement in sensitivity or specificity. In addition, the requirement to take several faecal samples decreases participation in screening, whereas, conversely, the 1-day method may increase the acceptability of screening. Third, a lower cutoff could be used for Hb concentration. Cost-effectiveness analysis of different cut-offs concluded that the best cut-off point was 27.5 μg Hb/g faeces (115 ng/ml) [30]. A lower cut-off (10 μg Hb/g faeces) would increase the number of positive screenings and require more colonoscopies and more unnecessary colonoscopies. Fourth, different cut-offs could be used at different stages and under different circumstances, for example the cut-off could be set at 20 μg Hb/g faeces in the first round and 15 or even 10 μg Hb/g faeces in the second round, or the cut-off could be lower in the first round (15 or 10 μg Hb/g faeces) depending on colonoscopy capacity and costs. In our study, with a cutoff of 20 μg Hb/g faeces, the positivity rate was 6.9% in the first round and 4.8% in the second round. Applying a lower cut-off of 10 μg Hb/g faeces in the first round would have yielded a positive result for 20% of the individuals found to have CRC detected in the second round. Fifth, qualitative FITs could be used; however, when compared
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Colorectal cancer in second round Bujanda et al.
with other FITs, the sensitivity and specificity are similar [31]. Finally, we should consider using new methods of stool analysis or combining the FIT with other tests, such as faecal DNA or combined faeces and blood tests, to improve the detection of proximal CRC [32,33]. This study has several strengths. All participants in this accuracy study were screening naive. They were consecutively invited to participate in the FIT screening. All FIT samples were collected, delivered, processed and analysed in accordance with the protocol, minimizing the risk of Hb degradation. To our knowledge, this is the first study to examine the characteristics of a large number of individuals with CRC who obtained negative results in a first-round FIT in a population screening programme. In other studies [15,20,34], the number of CRC cases analysed after a negative first-round FIT result was very small, ranging between three and seven cases. Some limitations should also be recognized. First, it is unknown whether advanced CRCs were false negatives in the first round of FIT screening. Second, we have not determined the molecular characteristics of proximal tumours, and therefore, do not know whether they were present previously. Third, colonoscopy was not performed in participants with negative FIT results. Fourth, we cannot be sure whether all participants were completely asymptomatic. In conclusion, our study indicates that the detection rate of CRC in a second round of FIT screening is lower than that in a first round. For CRC diagnosed in the second round after a negative FIT result in the first round, Hb concentrations in faeces were lower and the tumour was more likely to be proximal.
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9
10
11
12
13
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15
Acknowledgements
Author contributions: L.B., A. Castells and M.P. developed the study concept and design and drafted the manuscript. J.C., I.G., A. Cosme, E.A., I.M., I.I. and I.P. obtained the clinical data, designed and analysed the database and interpreted the data. L.B. and C.S. carried out the statistical analysis of data and contributed toward the interpretation of data. All authors read and approved the final version of the manuscript.
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Conflicts of interest
There are no conflicts of interest.
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Appendix Investigators of the EUSCOLON study: Fidencio Bao (Organización Sanitaria Integrada Barakaldo-San Eloy, Baracaldo); Juan Carrascosa (Organización Sanitaria Integrada Goierri-Alto Urola, Zumarraga); José M. EnriquezNavascués (Hospital Universitario Donostia, San Sebastián); Carlos Enciso and Maite Escalante (Hospital Universitario de Álava, Vitoria); Javier Fernández and Alain Huerta (Organización Sanitaria Integrada BarrualdeGaldakao, Galdakao); Luisa Goyeneche (Organización Integrada Sanitaria
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detection of colorectal neoplasia. Hepatogastroenterology 1999; 46:228–231. Hernandez V, Cubiella J, Gonzalez-Mao C, Iglesias F, Rivera C, Iglesias B, et al. Fecal immunochemical test accuracy for colorectal cancer and advanced neoplasia in average-risk population screening. World J Gastroenterol 2014; 20:1038–1047. Hundt S, Haug U, Brenner H. Comparative evaluation of immunochemical fecal occult blood tests for colorectal adenoma detection. Ann Intern Med 2009; 150:162–169. Giráldez MD, Lozano JJ, Ramírez G, Hijona E, Bujanda L, Castells A, Gironella M. Circulating microRNAs as biomarkers of colorectal cancer: results from a genome-wide profiling and validation study. Clin Gastroenterol Hepatol 2013; 11:681.e3–688.e3. Ahlquist DA. Molecular detection of colorectal neoplasia. Gastroenterology 2010; 138:2127–2139. Crotta S, Segnan N, Paganin S, Dagnes B, Rosset R, Senore C. High rate of advanced adenoma detection in 4 rounds of colorectal cancer screening with the fecal immunochemical test. Clin Gastroenterol Hepatol 2012; 10:633–638.
Bidasoa, Irún); Eduardo Millán (Subdirección Asistencia Sanitaria, Servicio Vasco de Salud); Enrique Ojembarrena, José I. Pijoan and Haritz Cortés (Hospital Universitario de Cruces, Baracaldo); Pedro Otazua (Organización Sanitaria Integrada al Alto Deba, Mondragón); Francisco Polo (Hospital Universitario de Basurto, Bilbao); Leire Zubiaurre and Eva Zapata (Organización Integrada Sanitaria Bajo Deba, Mendaro), Jose Luis Hurtado (Comarca Atención Primaria Araba, Vitoria).
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Introduction
Colorectal cancer (CRC) is the third most common cancer worldwide and the fourth leading cause of cancer-related death [1]. Evidence from several studies has shown that CRC screening is effective and cost-effective in averagerisk populations [2–6]. Specifically, randomized-controlled trials have shown that population-based screening for CRC with faecal occult blood tests reduces CRC mortality by 15–33% [7–10]. The faecal immunochemical test (FIT) is one of the tests recommended by scientific societies for CRC screening in average-risk populations [2]. In a recently published European Journal of Gastroenterology & Hepatology 2015, 27:813–818 Keywords: colorectal cancer screening, faecal immunochemical test, first round, negative faecal immunochemical test a Department of Gastroenterology, Hospital Donostia, Instituto Biodonostia, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco (UPV/EHU), bHospital Universitario Donostia, Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), San Sebastián, cDepartment of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), IDIBAPS, University of Barcelona, Barcelona, dServicio de Aparato Digestivo, Complexo Hospitalario Universitario de Ourense, Ourense, e Hospital Universitario de Cruces, Baracaldo and fPrograma de Cribado de Cáncer Colorrectal, Servicio Vasco de Salud, País Vasco, Spain
Correspondence to Luis Bujanda, MD, PhD, Department of Gastroenterology, Hospital Donostia, Avda Paseo Beguiristain s/n, 20014 San Sebastián, Spain Tel: + 34 943 007 173; fax: + 34 943 007 065; e-mail: [email protected] Received 8 December 2014 Accepted 6 March 2015
population-based randomized trial, FITs detected as many cases of CRC as colonoscopy in the first screening round, and the two techniques detected CRC at a similar stage [11]. Moreover, the FIT was associated with a higher participation rate than colonoscopy or the guaiac faecal occult blood test [12]. However, the sensitivity and specificity of FIT have been found to be 27–31% and 95–97%, respectively, for advanced neoplasia and 65.8–75% and 94.6–95% for CRC [13,14]. Because of this variability in the detection of advanced neoplasia, FIT screening is usually performed every 1–2 years after 50 years of age. Denters et al. [15] describe the characteristics of four cases of CRC detected (0.19%) in a second round after a negative FIT result in the first round of screening. They observed that the distribution of the location of the cancer in the colon (proximal/distal) was similar to that in the first round. However, there is a lack of data on the detection rate of CRC with FITs, and the staging and characteristics of these tumours in a second round compared with the first round. The aim of this study was to evaluate the characteristics of CRC detected in a second round of screening after negative results in a first round. Methods Study population and data collection
Individuals with CRC detected in the CRC screening programme in the Basque country between April 2009 and
0954-691X Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/MEG.0000000000000366
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April 2013 were eligible for inclusion in the study [16]. This screening programme includes asymptomatic individuals between 50 and 69 years old and tests are performed every 2 years. Eligible individuals were invited to participate in the screening, and 2 weeks later, an FIT kit was sent to his/her home. The kit contained a plastic container for the stools, a probe and a collection tube together with a plastic bag in which to seal them, and written instructions on how to collect the sample for the test. Specifically, after one bowel movement, they were instructed to sweep the tip of the probe through the stool several times and then insert the probe into the collection tube. Participants then handed the sample in at their health centre the following day. During the study period, 363 792 individuals were invited to participate in the first round of FIT screening (first round) and 100 135 individuals in the second round after a first negative result (second round). The eligible population was contacted progressively from April 2009. In April 2011, the second round was started in individuals who had obtained a negative FIT result. Individuals were excluded from the study if they had any of the following: a personal history of CRC, adenoma or inflammatory bowel disease; a family history of hereditary or familial CRC (defined as ≥ 2 first-degree relatives with CRC or 1 diagnosed before the age of 60); or any severe comorbidities; as well as if they had undergone a previous colectomy; a previous CRC screening test in which faecal occult blood was detected in the last 2 years; or a sigmoidoscopy/colonoscopy in the last 5 years. Those who tested positive in the first round, were at least 70 years of age, had moved out of the region or had died were not invited to participate in the second round. The screening strategy consisted of an FIT of a single sample using the automated semiquantitative OC-Sensor kit (Eiken Chemical Co., Tokyo, Japan) without any specific diet or medication limitations. Samples were processed as described previously [11]. Individuals with at least 100 ng haemoglobin (Hb) per ml of buffer solution (corresponding to 20 μg Hb/g faeces) were invited for a colonoscopy. In those undergoing colonoscopy, bowel cleansing and sedation was performed as described previously [17]. All colonoscopies were performed by experienced endoscopists (each performing > 200 colonoscopies per year) [18]. Tumours were staged according to the American Joint Committee on Cancer classification and stages III and IV were considered advanced [19]. The location was classified as proximal or distal, proximal indicating that the tumour lay between the cecum and the splenic flexure, and distal indicating that it lay between the splenic flexure and the anus. In addition to the FIT result, stage and location, we analysed histological findings, the degree of differentiation of the tumour and patient age and sex. Statistical analysis
χ2 and/or Fisher’s tests were used to compare categorical variables, and t-tests were used to compare continuous variables between the groups (first round and second round). Faecal Hb concentrations are presented as medians and were compared using nonparametric Mann–Whitney U tests. Logistic regression was used to analyse the independent effect of each variable on the probability of identifying
CRC in the second round. All analyses were carried out using SPSS 17.0 (SPSS, Inc., Chicago, Illinois, USA). Results
A total of 363 792 individuals were invited to the first round and 100 135 individuals to the second round after a negative FIT result (Fig. 1). Of these, 238 647 individuals (65%) participated in the first round and 69 193 individuals (69%) participated in the second round (P < 0.0005). Of the patients who completed the FIT, 47% (112 164) in the first round and 45% (31 136) in the second round were men (P < 0.0005). The FIT positivity rate was 6.9% (16 467) in the first round and 4.8% (3359) in the second round (P < 0.0005). Of those with positive results, 62% in the first round and 58% in the second round were men (P < 0.0005). We found CRC in 860 (0.36%) individuals in the first round and in 100 individuals (0.14%) in the second round (P < 0.005). The location of the CRC was proximal in 12.5% of cases in the first round and 24% in the second round (P = 0.008) (Table 1). There were no significant differences in terms of age, sex, stage, histological findings or degree of differentiation. Quantification of faecal Hb showed that Hb concentrations were higher in those with higher stage CRC, with values of 167, 283, 260 and 212 μg Hb/g faeces for stages I, II, III and IV, respectively (P < 0.005). Significantly higher concentrations were found in the first round than the second round overall (211 vs. 109 μg Hb/g faeces, respectively), and in the case of stage I cancer for both distal and proximal locations (Table 2). However, in the case of stage IV CRC in a proximal location, Hb concentrations were actually higher in the second round, although the difference did not reach significance. Variables that showed an independent effect on the likelihood of detecting CRC in the second round were proximal location [hazard ratio in the second vs. first round, 2.4; 95% confidence interval (CI), 1.3–4.4; P = 0.003] and bleeding (hazard ratio, 2.1; 95% CI, 1.3–3.5; P = 0.003). The probability of diagnosing CRC in individuals with Hb concentrations lower than 145 μg Hb/ g faeces was twice as high in the second round as the first (hazard ratio, 2.1; 95% CI, 1.3–3.5; P = 0.003). Endoscopic treatment was more common in cases detected in the first round than the second (30 vs. 18%; P < 0.05). There was no significant difference in stage between the first and the second round by location (proximal or distal) of the tumours. First-round Hb concentrations among patients with CRC diagnosed in the second round were as follows: below 5 μg Hb/g faeces in 58 individuals (58%); between 5 and 9.9 μg Hb/g faeces in 18 individuals (18%); between 10 and 14.9 μg Hb/g faeces in 10 individuals (10%); and between 15 and 19.9 μg Hb/g faeces in 10 individuals (10%), whereas data was missing for four cases (4%) as errors were made during the collection of the sample and the test was not repeated. The mean Hb concentrations in the second round were 297, 248, 492, 865 and 651 μg Hb/ g faeces for cut-off points of less than 5, 5–9.9, 10–14.9 and 15–19.9 μg Hb/g faeces and cases with missing firstround data (because of errors) in the first round, respectively. The Hb concentrations in the second round were
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Colorectal cancer in second round Bujanda et al.
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815
2 172 175 individuals in the Basque country
583 706 between 50−69 years of age 284 427 (49%) men
363 792 invited to participate in the first round 177 866 (49%) men
238 647 participated in the first round (65%) 112 164 (47%) men
16 467 FIT positive (6.9%) 10 209 men (62%)
860 CRC (5.9%) 571 men (66%)
100 135 with negative first round invited to second round 48 966 (45%) men
69 193 participated in the second round (69%) 31 136 (45%) men 3 359 FIT positive (4.8%) 1 952 men (58%)
100 CRC (2.9%) 66 men (66%)
Fig. 1. Study recruitment and participant flow. CRC, colorectal cancer.
significantly lower in individuals with less than 10 μg Hb/g faeces than those with between 10 and 19.9 μg Hb/g faeces in the first round (285 vs. 674 μg Hb/g faeces; P < 0.05). Discussion
In our study, fewer cases of CRC were diagnosed in second-round FIT screening than in baseline screening (CRC being found in 0.36% of participants in the first round vs. 0.14% in the second round). Van Roon et al. [20] found CRC in 0.36% (22/7229) and 0.3% (4/1280) of participants in the first and second rounds, respectively, and Denters et al. [15] found rates of 0.41% (12/2871) and 0.19% (4/2022), respectively, in these rounds, whereas Morikawa et al. [14] detected CRC in 0.36% (79/21 805) of participants in a first round. Large polyps and colorectal tumours are more frequently ulcerated and bleed more than smaller polyps and small flat colorectal tumours. Hence, the diagnosis of the latter by FIT screening is more difficult. In our study, we observed that the Hb concentration detected in FITs increases with the CRC stage. Similar findings have been reported by other authors. For example, Morikawa et al. [14] obtained a mean sensitivity of 65.8% for invasive cancer, with sensitivities by Dukes’ stage of 50.0% for stage A, 70.0% for stage B and 78.3% for stage C or D [14].
The location of the CRC was proximal in 12.5% of cases detected in our first-round FITs. Previous studies on consecutive series of patients with CRC found proximal CRC in 25% of cases [11,21,22]. These data suggest that around 12.5% of proximal CRCs are not detected in the first round of screening with a FIT. Similar figures have been reported for advanced neoplasia. Studies published by both Morikawa et al. [14] and Haug et al. [23] concluded that FIT screening has lower sensitivity for the detection of proximal than distal advanced neoplasia (16–20 vs. 31–33%, respectively). Similar results were found when FIT screening sensitivity was analysed for proximal versus distal CRC (56.5 vs. 69.6%, respectively) [14]. By contrast, other research has shown that this screening has a similar sensitivity for detecting proximal and distal neoplasia (38 and 37%, respectively) [13]. Several factors could explain more cases of proximal CRC being found in the second round than the first. First, cancer in the right colon is more likely to be sessile or flat than that in the left colon and rectum and may bleed less [24]. Second, some rapidly progressing cancers, such as those because of hereditary syndromes, may not have been present at the time of the first FIT [25]. Third, nonbleeding cancer remains in a nonbleeding state for a long time in the right colon and CRC may have an intermittent bleeding pattern. Fourth, Hb from proximal CRC may degrade before reaching the anus, which could affect the accuracy of FITs [26]. Fifth, because of differences in stool
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Table 1. Characteristics of patients with CRC in the first round of FIT screening and second round after a first negative result
Sex (men) [n (%)] Age (years) Location [n (%)] Proximal Stage [n (%)] I II III IV Haemoglobin concentration (μg Hb/g faeces) [median (IQR)]b Histological findings Adenocarcinoma [n (%)] Mucinous or signet-ring cell Carcinoid Differentiation [n (%)] Well-to-moderately Poorly Haemoglobin concentration distribution (μg Hb/g faeces) [n (%)] < 58 58–144 145–311 312–786 > 786 < 145d > 145 Treatment [n (%)] Only endoscopy Surgery ± chemotherapy ± radiotherapy
First round (n = 860)
Second round (n = 100)
571 (66) 61.5 ± 5.3
66 (66) 61.4 ± 4.9
108/860 (12.5) 428 160 201 71 211
(50) (19) (23) (8) (78–604)
24/76 (24) 45 20 26 9 109
(45) (20) (26) (9) (47–497)
P 0.5 0.7 0.008 0.5a
0.002c
842 (98) 14 4
97 (97) 2 1
0.6
826 (96) 34 (4)
97 (97) 3 (3)
1.0
164 164 180 181 171 328 532
27 24 13 15 21 56 44
0.04
(19) (19) (21) (21) (20) (38) (62)
258 (30) 602 (70)
(27) (24) (13) (15) (21) (56) (44)
18 (18) 82 (82)
0.001
0.08
CRC, colorectal cancer; FIT, faecal immunochemical test; Hb, haemoglobin. Linear trend. Interquartile range. c Mann–Whitney U-test. d Grouped according to the cut-off point for which there were the greatest differences between quartiles. a
b
Table 2. Median haemoglobin concentration (μg Hb/g faeces) in the first and second rounds of FIT screening by stage and location Proximal
Stage Stage Stage Stage
I II III IV
Distal
First round
Second round
214 186 194 110
46 69 168 570
P
First round
Second round
P
0.01 0.2 0.9 0.1
176 303 277 271
88 693 63 165
0.02 0.7 0.2 0.6
FIT, faecal immunochemical test; Hb, haemoglobin.
consistency, blood may be more homogeneously distributed when originating from the right side and dominantly on the surface when originating from the left side, and this would also favour the detection of left-sided neoplasia [23]. In our study, the concentration of Hb in faeces was lower in patients with CRC diagnosed in the second round than the first (overall and in those with distal or proximal stage I cancer). Surprisingly, however, faecal Hb concentrations tended to be higher in the second round than the first round in the subset of patients diagnosed with stage IV proximal, although the difference did not reach significance. There are many potential strategies to improve the diagnosis of proximal CRC. First, we could increase the frequency of screening to every year; however, a recent study, examining intervals of 1, 2 and 3 years, showed that the yield at the second screening round was not influenced by the interval length within this 1- to 3-year range [20]. Second, the number of tests per round could be increased,
but data on the effect of this are conflicting. Analysing FIT results, one study showed that the sensitivity increased from 33 to 47% on testing three samples instead of one [27], and another showed that the positivity rate increased from 8 to 13% on adding a second sample [28], whereas the sensitivity for detecting colorectal neoplasia was reported to be 56% with the 1-day method, 83% with the 2-day method and 89% with the 3-day method [29]. By contrast, other studies examining the ability to detect CRC after two or three samples indicated no improvement in sensitivity or specificity. In addition, the requirement to take several faecal samples decreases participation in screening, whereas, conversely, the 1-day method may increase the acceptability of screening. Third, a lower cutoff could be used for Hb concentration. Cost-effectiveness analysis of different cut-offs concluded that the best cut-off point was 27.5 μg Hb/g faeces (115 ng/ml) [30]. A lower cut-off (10 μg Hb/g faeces) would increase the number of positive screenings and require more colonoscopies and more unnecessary colonoscopies. Fourth, different cut-offs could be used at different stages and under different circumstances, for example the cut-off could be set at 20 μg Hb/g faeces in the first round and 15 or even 10 μg Hb/g faeces in the second round, or the cut-off could be lower in the first round (15 or 10 μg Hb/g faeces) depending on colonoscopy capacity and costs. In our study, with a cutoff of 20 μg Hb/g faeces, the positivity rate was 6.9% in the first round and 4.8% in the second round. Applying a lower cut-off of 10 μg Hb/g faeces in the first round would have yielded a positive result for 20% of the individuals found to have CRC detected in the second round. Fifth, qualitative FITs could be used; however, when compared
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Colorectal cancer in second round Bujanda et al.
with other FITs, the sensitivity and specificity are similar [31]. Finally, we should consider using new methods of stool analysis or combining the FIT with other tests, such as faecal DNA or combined faeces and blood tests, to improve the detection of proximal CRC [32,33]. This study has several strengths. All participants in this accuracy study were screening naive. They were consecutively invited to participate in the FIT screening. All FIT samples were collected, delivered, processed and analysed in accordance with the protocol, minimizing the risk of Hb degradation. To our knowledge, this is the first study to examine the characteristics of a large number of individuals with CRC who obtained negative results in a first-round FIT in a population screening programme. In other studies [15,20,34], the number of CRC cases analysed after a negative first-round FIT result was very small, ranging between three and seven cases. Some limitations should also be recognized. First, it is unknown whether advanced CRCs were false negatives in the first round of FIT screening. Second, we have not determined the molecular characteristics of proximal tumours, and therefore, do not know whether they were present previously. Third, colonoscopy was not performed in participants with negative FIT results. Fourth, we cannot be sure whether all participants were completely asymptomatic. In conclusion, our study indicates that the detection rate of CRC in a second round of FIT screening is lower than that in a first round. For CRC diagnosed in the second round after a negative FIT result in the first round, Hb concentrations in faeces were lower and the tumour was more likely to be proximal.
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7
8
9
10
11
12
13
14
15
Acknowledgements
Author contributions: L.B., A. Castells and M.P. developed the study concept and design and drafted the manuscript. J.C., I.G., A. Cosme, E.A., I.M., I.I. and I.P. obtained the clinical data, designed and analysed the database and interpreted the data. L.B. and C.S. carried out the statistical analysis of data and contributed toward the interpretation of data. All authors read and approved the final version of the manuscript.
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Conflicts of interest
There are no conflicts of interest.
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Appendix Investigators of the EUSCOLON study: Fidencio Bao (Organización Sanitaria Integrada Barakaldo-San Eloy, Baracaldo); Juan Carrascosa (Organización Sanitaria Integrada Goierri-Alto Urola, Zumarraga); José M. EnriquezNavascués (Hospital Universitario Donostia, San Sebastián); Carlos Enciso and Maite Escalante (Hospital Universitario de Álava, Vitoria); Javier Fernández and Alain Huerta (Organización Sanitaria Integrada BarrualdeGaldakao, Galdakao); Luisa Goyeneche (Organización Integrada Sanitaria
30
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detection of colorectal neoplasia. Hepatogastroenterology 1999; 46:228–231. Hernandez V, Cubiella J, Gonzalez-Mao C, Iglesias F, Rivera C, Iglesias B, et al. Fecal immunochemical test accuracy for colorectal cancer and advanced neoplasia in average-risk population screening. World J Gastroenterol 2014; 20:1038–1047. Hundt S, Haug U, Brenner H. Comparative evaluation of immunochemical fecal occult blood tests for colorectal adenoma detection. Ann Intern Med 2009; 150:162–169. Giráldez MD, Lozano JJ, Ramírez G, Hijona E, Bujanda L, Castells A, Gironella M. Circulating microRNAs as biomarkers of colorectal cancer: results from a genome-wide profiling and validation study. Clin Gastroenterol Hepatol 2013; 11:681.e3–688.e3. Ahlquist DA. Molecular detection of colorectal neoplasia. Gastroenterology 2010; 138:2127–2139. Crotta S, Segnan N, Paganin S, Dagnes B, Rosset R, Senore C. High rate of advanced adenoma detection in 4 rounds of colorectal cancer screening with the fecal immunochemical test. Clin Gastroenterol Hepatol 2012; 10:633–638.
Bidasoa, Irún); Eduardo Millán (Subdirección Asistencia Sanitaria, Servicio Vasco de Salud); Enrique Ojembarrena, José I. Pijoan and Haritz Cortés (Hospital Universitario de Cruces, Baracaldo); Pedro Otazua (Organización Sanitaria Integrada al Alto Deba, Mondragón); Francisco Polo (Hospital Universitario de Basurto, Bilbao); Leire Zubiaurre and Eva Zapata (Organización Integrada Sanitaria Bajo Deba, Mendaro), Jose Luis Hurtado (Comarca Atención Primaria Araba, Vitoria).
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