A higher detection rate for colorectal cancer and advanced adenomatous polyp for screening with immunochemical fecal occult blood test than guaiac fecal occult blood test, despite

A higher detection rate for colorectal cancer and advancedadenomatous polyp for screening with immunochemical fecaloccult blood test than guaiac fecal occult blood test, despitelower compliance rate. a prospective, controlled, feasibility study

Zohar Levi1*, Shlomo Birkenfeld2*, Alex Vilkin1, Micha Bar-Chana3, Irena Lifshitz3, Miri Chared2, Eran Maoz2

and Yaron Niv1

1 Gastroenterology Department, Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel2 Gastroenterology Units, Clalit Health Services, Tel Aviv University, Tel Aviv, Israel3 Ministry of Health, National Cancer Registry, Israel

Immunochemical fecal occult blood test (FIT) is a new colorectal cancer (CRC) screening method already recommended by the

American screening guidelines. We aimed to test the feasibility of FIT as compared to guaiac fecal occult blood test (G-FOBT)

in a large urban population of Tel Aviv. Average-risk persons, aged 50–75 years, were offered FIT or G-FOBT after

randomization according to the socioeconomic status of their clinics. Participants with positive tests underwent colonoscopy.

Participants were followed through the Cancer Registry 2 years after the study. Hemoccult SENSATM and OC-MICROTM (three

samples, 70 ng/ml threshold) were used. FIT was offered to 4,657 persons (Group A) and G-FOBT to 7,880 persons (Group B).

Participation rate was 25.9% and 28.8% in Group A and B, respectively (p < 0.001). Positivity rate in Group A and B was

12.7% and 3.9%, respectively (p < 0.001). Cancer found in six (0.49%) and eight (0.35%) patients of Group A and B,

respectively (NS). Cancer registry follow-up found missed cancer in five (0.22%) cases of Group B and none in Group A (NS).

The sensitivity, specificity, negative and positive predictive value for cancer in Group A and B were 100%, 85.9%, 100%, 3.9%

and 61.5%, 96.4%, 99.8%, 9.1%, respectively. There was increased detection of advanced adenomatous polyp (AAP) by FIT,

irrespective of age, gender, and socioeconomic status (Per Protocol: odds ratio 2.69, 95% confidence interval 1.6–4.5;

Intention to Screen: odds ratio 3.16, 95% confidence interval 1.8–5.4). FIT is feasible in urban, average-risk population, which

significantly improved performance for detection of AAP and CRC, despite reduced participation.

Annual or biennial guaiac fecal occult blood test (G-FOBT)screening reduces colorectal cancer (CRC) mortality by 16–33%1–3 or even more.4 The advantages of G-FOBT include pri-vacy, noninvasiveness and cost-effectiveness. However, thestandard G-FOBT is faulted for its low sensitivity for CRC andadvanced adenomatous polyp (AAP), low specificity due to non-specificity for human hemoglobin, the need for periodic testing,low patient adherence and the possibility of inaccurate develop-ment and evaluation.5–7

Recently, the FIT was developed to improve specificityand eliminate the need for dietary restriction. Laboratory-

based, automated, immunochemical measurement of fecalhuman hemoglobin allows clinicians to choose a fecal hemo-globin threshold level to perform colonoscopy and can adjustthis threshold to take account of the patient’s risk foradvanced neoplasia. FIT was first approved by the U.S. Foodand Drug Administration as a qualitative test and then wasrecommended by the American Cancer Society.8 Recently, itwas added to the recommendation of the American TaskForce.9 The American College of Gastroenterology recom-mends colonoscopy for screening CRC of the average-riskpopulation and FIT (instead of G-FOBT) as a second option.10

Key words: colorectal cancer, screening, sensitivity, specificity, fecal occult blood test, guaiac, immunochemical test, FIT, G-FOBT

Abbreviations: AAP: advanced adenomatous polyp; CRC: colorectal cancer; FIT: immunochemical fecal occult blood test; G-FOBT: guaiac

fecal occult blood test; Hb: hemoglobin; HGD: high-grade dysplasia; ITS: intention to screen; LGD: low-grade dysplasia; NNS: number

needed to scope; NPV: negative predictive value; PP: per protocol; PPV: positive predictive value; SA: serrated adenoma; SES: socioeconomic

status; TA: tubular adenoma; TVA: tubovillous adenoma; VA: villous adenoma

*Z.L. and S.B. contributed equally to this work.

DOI: 10.1002/ijc.25574

History: Received 18 Mar 2010; Accepted 8 Jul 2010; Online 23 Jul 2010

Correspondence to: Yaron Niv, Gastroenterology Department, Rabin Medical Center, Tel Aviv University, Tel Aviv, Israel,

Tel.: 972-50-4065401, E-mail: [email protected]

Epidemiology

Int. J. Cancer: 128, 2415–2424 (2011) VC 2010 UICC

International Journal of Cancer

IJC

In a series of recent articles, we found FIT equal or betterthan G-FOBT in detecting CRC and AAP in symptomatic orasymptomatic high-risk patients.11–17 At the manufacturer-recommended threshold of 100 ng/ml, the three-sample testsensitivity and specificity for detecting cancer were 88% and90%, respectively, and for detecting significant neoplasia(CRC and AAP) were 62% and 93%, respectively.15 van Rossumet al. conducted a population-based study on a random sampleof 20,623 individuals aged 50–75 years randomized to eitherG-FOBT (Hemoccult II) or FIT (OC-Sensor).18 The number-to-scope to find one cancer was comparable between the tests.However, participation and detection rates for advanced adeno-mas and cancer were significantly higher for FIT.

The aim of this study is to compare FIT with G-FOBT inscreening the average-risk people in a prospective, controlledstudy. Because FIT is more demanding procedure, and asso-ciated with complex logistics, we aimed to assess the feasibil-ity of this approach in the urban population in Israel, withspecial relation to different socioeconomic classes.

Material and MethodsThe study was designed as a population based study where av-erage-risk persons aged 50–75 years were offered either FIT(OC-MICROTM, Eiken Chemical Co., Tokyo, Japan) or G-FOBT (Hemoccult SENSATM, Beckman Coulter, Fullerton,CA) according to a randomization program based on the soci-oeconomic status (SES) of the primary care clinic. Patientsfrom nine primary care clinics of Clalit Health Services (CHS)in Tel Aviv were included. Only screenees with positive testswere referred to colonoscopy. All the participants who per-formed the test were followed though the Israel National Can-cer Registry from the end of the study (Fig. 1).

Inclusion criteria

Asymptomatic people aged 50–75 years who belonged to theselected nine clinics were included in the study.

Exclusions criteria

(i) Patients who underwent colonoscopy or sigmoidoscopy inthe last 5 years. (ii) Patients who participated in the G-FOBTgeneral screening program in the last 2 years. (iii) Patients whohad an established CRC or inflammatory bowel disease (IBD).The information about previous colonoscopies, G-FOBT routinescreening program and IBD were extracted from the computer-ized CHS database. Patients with visible rectal bleeding, hema-turia, menstruation or with symptoms related to the gastrointes-tinal tract were instructed not to perform FOBT.

Randomization by the socioeconomic status of the

clinic. Every patient of CHS belongs to a primary care clinicthat are categorized according to the number of insured patientsand the SES of the area. In Israel, every citizen is entitled forcomprehensive medical insurance by law. People with lowincome are free of paying National Security tax. The authoritiesreport CHS patients who are free of paying National Securitytaxes on a regular basis. The percentage of patients who are free

of paying tax serves as a marker for the SES level of the clinic.According to CHS strategy, a clinic with up to 15% patients whoare free of paying tax is leveled as high SES, between 16–30%leveled as medium SES, and above 30% as low SES.

Primary care clinics participating in the study

Nine medium-sized primary care clinics (1,000–2,000patients) were included, three clinics from each SES. BecauseFIT is more expensive and needs more complex strategy(cooling bags and specific transportation), we divided clinicsinto 1/3 using FIT (one clinic from each SES) and 2/3 usingG-FOBT (two clinics from each SES).

Design

All included people received an invitation letter to participate inthe study. Asymptomatic people willing to participate wereinstructed to go to the primary care clinic and ask for the FOBTkits. Those willing to participate were instructed how to preparethe FOBTs and were asked to bring it back to the clinic. Thekits were then transported to a central laboratory. The patientswith positive tests were referred to a consultant gastroenterologistwith a recommendation to perform colonoscopy (Fig. 1).

Hemoccult SENSATM (HOS). Cards were provided at the pri-mary care clinic. Patients willing to participate in the studyreceived an oral explanation and written instructions about testpreparation. Patients were requested to follow the manufac-turer’s instructions on diet and use of medications before andduring the preparation for G-FOBT. They applied stool on sixwindows of three cards and brought them back to the clinicwhere they were provided. Then, the cards were collected andchecked at the central laboratory of the CHS. Test result wassent to the patient and appeared online in his electronic file.The test is positive if any one of the six windows is positive.

OC-MICRO (FIT)

This FIT has been described by us and by others.14 Patientswilling to participate in the study received an oral explanationand written instructions about the test preparation. They weregiven the kit for fecal sampling and requested to prepare threeconsecutive daily samples without any limitation of diet ormedication. The patients were instructed to keep the samplesin the refrigerator and bring the samples back to the clinicusing a cooling bag provided with the kits. Samples were refri-gerated at 4�C until developed within 2 weeks of preparation.The samples were analyzed by the OC-MICROTM instrument,hemoglobin amount was measured and the results were givenautomatically as ng/ml of buffer. We referred to 70 ng/mlthreshold as a positive test (the highest of three tubes).

Colonoscopy

Colonoscopy was to the cecum or to an obstructing carci-noma if present. Otherwise, an incomplete examination wasrepeated or the patient excluded from the analysis. All lesionswere noted, biopsied or removed and the number of polyps

Epidemiology

2416 Comparison of FIT and G-FOBT


was noted, as were their size and sites. Polyps were classifiedas nonadenomas or adenomas. Adenomas were grouped bysize: �5, 6–9 and �10 mm; by their histology: tubular, tu-bulo-villous and villous; and dysplasia: low-grade (LGD) orhigh-grade (HGD). The term ‘‘significant’’ neoplasms

included CRC or AAP; this latter category included adeno-mas �10 mm in diameter or having �20% villous histologyor having any amount of HGD independent of size. AllAAPs <10 mm were reexamined to confirm their size andhistology diagnosis.

Figure 1. Flow chart of the study.

Epidemiology

Levi et al. 2417


Cancer registry follow-up

Using recode linkage analysis techniques and personal identi-fication number given to all Israeli citizens on birth or immi-gration, as well as other demographic data, we identified can-cer in the cohort of CHS members. The Israel NationalCancer Registry (INCR) is a population-based national cancerregistry in operation since 1960. Reporting is mandatorysince 1982, and the registry meets all internationally acceptedrequirements for coding system and completeness of data. Allthe participants completed at least 2 years of follow-up beforethe transaction day.

Analysis and statistical methods

The study was designed as a population-based study where onlypatients with positive FOBT were sent to colonoscopy, therefore,the sensitivity of AAP could not be calculated. Detection rate wasdefined as the percentage of patients with lesions among thecompliant population (performed FOBT, per protocol) or theinvited population (intention to screen). Positivity rate wasdefined as the percentage of positive tests among the compliantpopulation. Positive predictive value (PPV) was defined as thepercentage of patients with lesions among the patients whounderwent colonoscopy. Number needed to scope (NNS) wasdefined as the number of colonoscopies needed to perform todetect one AAP/CRC (the value is the reciprocal of PPV).Because fecal hemoglobin had no normal distribution, we usedthe median rather the mean for description of hemoglobin leveland used nonparametric tests. We used the v2 test or Fisher exacttest for the comparison of different rates. Binary logistic regres-sion analysis (forward, conditional) for the detection of cancer orcancer and advanced adenoma was performed including all cova-riates tested by univariate [age (<60 years, �60 years), gender(male, female), SES (low, medium, high) and National SecurityTax Free (yes, no)] in both per protocol and intention to screenanalysis. All p values appear in the tables, p<0.05 was consideredas significant. Statistical analysis was performed with SPSS sys-tem for windows, software version 15.

Ethics

Rabin Medical Center Institutional Review Board authorizedthe study in 2008. The patients were informed and askedwhether they wanted to participate in the study but did nothave to sign an informed consent. The analysis performedand the decision to publish the results were the responsibilityof the authors.

ResultsExcluded patients

A total of 3,822 of 16,359 patients were excluded (23.3%). Ofthe excluded patients, 2,367 underwent colonoscopy or sig-moidoscopy in the last 5 years, 1,694 participated in the on-going national G-FOBT screening program in the last 2years, 180 patients had a diagnosis of CRC and 49 patientshad a diagnosis of IBD.

Included patients (Table 1)

A total of 12,539 patients were included in the study: 4,657patients of Group A had FIT and 7,880 patients of Group Bhad G-FOBT. In Group A, the patients were younger (the dif-ference in the proportion of patients younger than 60 years was4.2%, p < 0.001) and the proportion of women was lower (thedifference in the proportion was �2.8%, p ¼ 0.002). The pro-portion of patients who were free of paying tax was not differ-ent among the two groups (difference of �0.6%, p ¼ 0.44) andthe percentage of patients who belonged to low SES primarycare clinic was also similar (difference of 0.2%, p ¼ 0.87).

Compliance with performing FOBT (Table 2, Fig. 1)

The compliance to take the FOBT kits from the clinic (kitdispension) was lower in Group A as compared to Group B(33.0% vs. 45.9%, p < 0.001). However, once dispensed, theproportion of patients who performed the test was higher inGroup A than Group B (78.4% vs. 62.7%, p < 0.001). Theoverall compliance (test performed per invited population)was 25.9% and 28.8% in Group A and B, respectively (p <

0.001). Regression analysis model yielded that older age[odds ratio (OR) 1.025, p < 0.001] and female gender (OR1.29, p < 0.001) were associated with test compliance. Thiswas correct when calculated for both groups.

Test results and positivity rate (Table 2, Fig. 2)

The test was positive in 153 (12.7%) and 88 (3.9%) patients ofGroup A and B, respectively (p < 0.001). The range of FITresults was 0–3007 ng/ml. Because the distribution of FIT resultsis skewed, we used the median in describing the results and non-parametric tests for difference between the groups. Median FITlevels for normal or nonadvanced adenoma (n ¼ 73), advancedadenoma (n ¼ 29) and cancer (n ¼ 6) were 170, 506 and 1828ng/ml, respectively (p ¼ 0.003 by Kruskal Wallis). Technicalperformance problem happened in 13 patients of Group A.Seven patients prepared only two tubes and two patients pre-pared one tube. These patients were included in the intension toscreen (ITS) but not in the per protocol (PP) analysis.

Follow-up colonoscopy (Tables 2 and 3)

Colonoscopy followed positive FOBT in 108 (70.6%) and 63(71.6%) patients of Group A and B, respectively (p ¼ 0.86).The colonoscopy was complete in all cases (up to the cecumor an obstructing tumor). In Group A, colonoscopy detectedsix cancers and 29 AAPs. In Group B, colonoscopy detectedeight cancers and 14 AAPs. Polyp and cancer characteristicsare presented in Table 3.

Cancer registry follow-up

The transaction was performed 2 years after the last FOBTwas performed. The registry detected five cancers missed byG-FOBT (had a negative G-FOBT). Two cancers were locatedin the sigmoid colon, one in the descending colon, one in theascending colon and one in the cecum. All missed cancers

Epidemiology



occurred in persons older than 60 years and three were men.The registry did not detect missed cancer in patients with anegative FIT. One patient of each group, with a positiveFOBT, had CRC that was not detected by referral colono-scopy (detected later by the registry). These cases were ‘‘colo-noscopy noncompliant’’ patients but, for the purpose ofFOBT performance analysis, they were regarded as ‘‘true pos-itive.’’ The registry did not identify any case of gastric oresophageal cancer with positive FOBT.

Cancer detection rates and performance characteristics

(Table 2, Fig. 3)

Detection rate was defined as the percentage of patients withlesion detected among the population that performed FOBT

(per protocol) or invited to participate in the study (intentionto screen). Cancer occurred in six patients in Group A andin 13 patients in Group B, the calculated rates per 10,000persons performing the test is 49 and 57 cases, respectively(p ¼ 0.74). However, FOBT detected all cases of cancer inGroup A but only 8/13 cancers in Group B (these false-nega-tive cases were detected later by the INCR). Therefore, thecancer detection rate was 49/10,000 in Group A and 35/10,000 in Group B (p ¼ 0.50). Sensitivity of FIT was betterthan G-FOBT (the same for three tubes or first tube, thresh-old 70 ng/ml) (p < 0.001). Raising the threshold to 200 ng/ml and testing only the first tube would have result in thesame sensitivity in both methods. Univariate analysis for thedetection of cancer reveals an increased detection rate among

Table 1. Characteristics of invited persons to participate in the study according to test type

Parameter FIT (n 5 4,657) G-FOBT (n 5 7,880) Difference1 (%) p2

Gender

Men (n) 2113 3354 0.002

% 45.4% 42.6% 2.8

Women (n) 2544 4526

% 54.6% 57.4% �2.8

Age 0.001

Mean 6 SD (years) 60.4 6 7.6 61.3 6 7.6 �0.83

<60 years (n) 2342 3633 <0.001

% 50.3% 46.1% 4.2

�60 years (n) 2315 4247

% 49.7% 53.9% �4.2

Primary care clinic SES3

High

FPT (n) 185 380

% 13.6% 15.3% �1.7 0.13

Pays tax (n) 1178 2096

% 86.4% 84.7% 1.7

Medium

FPT (n) 340 837

% 22.1% 26.9% �4.8 <0.001

Pays tax (n) 1201 2276

% 77.9% 73.1% 4.8

Low

FPT (n) 707 918

% 40.3% 40.1% 0.20 0.87

Pays tax (n) 1046 1373

% 59.7% 59.9% �0.2

Free of paying Tax (FPT) (n) 1232 2135

% 26.5% 27.1% �0.6 0.44

1Difference in the proportions between FIT and G-FOBT arms. 2p for proportions between FIT and G-FOBTarms. 3Data obtained from the National Social Security Institute. Primary care clinic socioeconomic(SES) classification made according to percentage of insured patients who are Free of Paying nationalinsurance Tax (FPT): low (<16% FPT), medium (17–32% FPT), high (�33% FPT).

Epidemiology

Levi et al. 2419


patients older than 60 years (74 cases/10,000 and 51 cases/10,000 in Group A and B, respectively, p < 0.001) andpatients from low SES clinics (75 cases/10,000 and 13 cases/10,000 in Group A and B, respectively, p < 0.001). However,logistic regression analysis, adjusting for age, gender, and SESof the clinic, reveals that test type was not a significantdeterminant.

Advanced adenomatous polyp detection rates

(Table 2, Fig. 3)

AAP was detected in 29 patients in Group A and 14 patients inGroup B. The calculated detection rate among patients perform-ing the tests was 241 cases/10,000 and 62 cases/10,000, respec-tively (p < 0.001). The detection rate with FIT was better alsowhen raising the threshold to 200 ng/ml and using only the first

Table 2. Test performance of G-GOBT versus FIT (�70 ng/ml, highest of three tubes)

Parameter FIT (n 5 4,657) G-FOBT (n 5 7,880) Difference1 (%) p2

Kit dispensed 1536 3616

Compliance to take the kit (%/invited) 33.0% 45.9% �13.9 <0.001

Test performed (n) 1204 2266

Participation rate (%/kit dispensed) 78.4% 62.7% 15.7 <0.001

Participation rate (%/invited) 25.9% 28.8% �2.9 <0.001

Positive FOBT (n) 153 88

Positivity rate (% of performed FOBT) 12.7% 3.9% 8.8 <0.001

Follow-up colonoscopy (n) 108 63

Follow-up colonoscopy rate (% of positive FOBT) 70.6% 71.6% 1.0 0.86

Colonoscopy rate

PP 9.0% 2.8% 6.2 <0.001

ITS 2.3% 0.80% 1.5 <0.001

Detection of CRC and AAP (n) 35 22

Detection rate

PP 2.9% 1% 1.9 <0.001

ITS 0.8% 0.3% 0.5 <0.001

PPV (95% CI)

PP 22.9% (16.2–29.5) 25.0% (16.6–34.0) �2.1 0.70

Detection of AAP (n) 29 14

Detection rate

PP 2.41% 0.62% 1.79 <0.001

ITS 0.62% 0.18% 0.45 <0.001

PPV (95% CI)

PP 19% (12.7–25.2) 15.9% (8.3–23.6) 3.1 0.55

Detection of cancer (n) 6 8

Detection rate

PP 0.49% 0.35% 0.14 0.50

ITS 0.13% 0.10% 0.03 0.65

PPV (95% CI)

PP 3.9% (0.8–7.0) 9.1% (3.1–15.1) �5.2 0.09

Missed cancer (n) (cancer registry follow-up) 0 5

Missing rate

PP 0 0.22% �0.22 0.12

Overall cancer (detected and missed) 6 13

Overall cancer rate

PP 0.49% 0.57% �0.08 0.78

1The arithmetic difference between FIT and G-FOBT. 2The difference in proportions between FIT and G-FOBT.Abbreviations: AAP, advancedadenomatous polyp; ITS, intention to screen; PP, per protocol; PPV, positive predictive value.

Epidemiology



tube (p ¼ 0.003). By univariate analysis, the AAP detection ratewas significantly higher irrespective of age group, gender, SESclass clinic and tax paying status. Adjusting for age, gender, SESand tax paying status reveals that FIT detected significant neo-plasia (cancer and AAP) better than G-FOBT by both ITS andPP analysis [ITS: OR 2.69, 95% confidence interval (CI) 1.59–4.57, p ¼ 0.001; PP: OR 3.16, 95% CI 1.8–5.4, p < 0.001].

DiscussionFollowing the recent recommendations to use FIT instead ofG-FOBT,10 we looked at the feasibility of performing FIT ina large-scale urban population where G-FOBT served as theusual CRC screening modality for the last 10 years. Wefound that the procedure was feasible and convenient, eventhough the study results should be taken with caution; notalways logistic efforts associated with a study may be trans-lated with the same success to daily practice.

Several studies compared the performance of FIT toG-FOBT in the average-risk population using different kits,randomization methods and design (see tables). Other studiescompared FIT to G-FOBT in symptomatic patients referredto colonoscopy.11–17 In this population-based study, we com-pared the performance of FIT and G-FOBT in a large urbanpopulation. The strength of our study is in using the mostsensitive representatives of each method, OC-SENSA and theOC-MICRO at a low threshold, using three samples; in hav-ing two arms, each for one procedure (performing both testsby the same person does not allow true comparison, biasingtoward the more compliant participants) and including theSES in the randomization process, we could investigate itspossible effect on compliance. In addition, we had a follow-up of 2 years after the end of the study through the INCR.

The sensitivity of FIT for the detection of cancer was sig-nificantly higher. FIT detected 49 cases of cancer/10,000 per-sons who performed the test, 14 cases/10,000 more than thatdetected by G-FOBT (p < 0.001). The cancer registry follow-up detected five missed cancers in the G-FOBT group (trans-lated to 22 cases/10,000 more cases) and no missed case inthe FIT group.

The WHO defined that the objective of mass screening forCRC is to detect 50 prevalent cases among 10,000 subjectsolder than 50 years.19 It seems that the FIT group has reachedthis goal. The sensitivity of FIT remains significantly higherthan of G-FOBT even using 100 ng/ml, three tubes, as a thresh-old (p ¼ 0.008). The increased sensitivity has opposite relation-ship with the number needed to scope to detect one cancer.

Table 3. Colonoscopy results with subdivisions according tohistology and size of polyps (per patient analysis, according to mostsevere pathology)

FIT (n 5 108) G-FOBT (n 5 61)

Normal (N) 42 31

Non-AAP (N) 31 8

Histology

Hyperplastic 7 2

TA (LGD) 24 6

Size

�5 mm 18 6

6–9 mm 13 2

AAP (N) 29 14

Histology

TA 12 5

TVA/VA 17 7

SA 0 2

Size

6–9 mm 2 0

�10 mm 27 14

Dysplasia

LGD 21 11

HGD 8 3

CRC (N) 6 8

Location (ICD Code)

Rectum (C20.9) 0 1

Recto-sigma (C19.9) 0 3

Sigmoid colon (C18.7) 3 1

Transverse colon (C18.4) 1 1

Ascending colon (C18.2) 2 0

Cecum (C18.0) 0 2

Abbreviations: AAP, advanced adenomatous polyp; CRC, colorectalcancer; HGD, high-grade dysplasia; ICD, International ClassificationDisease; LGD, low-grade dysplasia; SA, serrated adenoma; TA, tubularadenoma; TVA, tubulovilllous adenoma; VA, villous adenoma.

Figure 2. Mean fecal Hb (ng/ml) according to colonoscopy results

(maximum of three tubes). AAP, advanced adenomatous polyp;

CRC, colorectal cancer.

Epidemiology

Levi et al. 2421


Interestingly, using only one tube with a threshold of 70 ng/mlresults in improved sensitivity but equal NNS as G-FOBT.

Data are accumulating about the improved cancer detec-tion rate by FIT. van Rossum et al.18 performed a similarcomparative study of FIT and G-FOBT. They did not followthe patients with ‘‘negative test’’ and used the less sensitiveHemoccult II test. They also reported an increased cancerdetection rate using FIT with a cutoff of 100 ng/ml (threetubes). In their study, the positivity rate and the PPV werecomparable between the two methods.

Guittet et al.20 investigated variation in sensitivity of FITand G-FOBT in a sample of 20,322 subjects. The gain in sen-sitivity by using FIT increased from invasive cancers (ratio ofsensitivities ¼ 1.48) to high-risk adenomas (3.32) and wasinversely related to the amount of bleeding. In a large retro-spective Japanese study of nearly 22,000 asymptomatic, aver-age-risk participants, the sensitivity and specificity of one dayFIT for detecting invasive cancer was 65.8% and 94.6%,respectively, similar to our results, using only the first fecalsample and a 100 ng/ml hemoglobin threshold.21

We could not demonstrate higher participation rate forthe FIT than G-FOBT calculated by intention to screen anal-ysis, because more kits were dispersed in Group B, theG-FOBT arm. We believe that the reasons for this differenceare the familiarity of the population with G-FOBT and thelogistic efforts needed for keeping the FIT in the refrigeratorand bring the samples to the clinic in a cooling bag. Theoverall participation rate with the FIT was 3.2% lower thanthat with G-FOBT. However, once the kit was dispensed, thecompliance was 15.8% higher in the FIT arm.

Of the three samples, the study was designed with 70 ng/mlFIT cutoff. Patients with results �70 ng/ml were diagnosed

positive and referred to colonoscopy. Testing the first tubeonly at the threshold of 100 ng/ml, as sometimes practiced,would have result at in a poorer performance. Similar findingwas found by van Rossum et al.,22 as described in their sec-ond article, and Grazzini et al.23,24

The main limitation of our study is the randomization byclinic site, with only nine clinics studied, and not by patients.We demonstrated a small advantage for G-FOBT in kit dis-pensing; however, once dispensed, the proportion of patientswho performed the test was higher with FIT. Our data supportusing FIT in the population level, giving important data aboutnumber of tests and cutoff level for determination of a positiveresult but could not demonstrate a higher compliance rate ofFIT than for G-FOBT as demonstrated by others.18,20,25–34

In summary, we demonstrated a successful screening pro-ject using FIT. This strategy is feasible in a large-scale urbanpopulation. Using FIT instead of G-FOBT resulted in anincreased CRC and AAP detection rate, irrespective of age,gender and income. Further studies are needed to optimizeFIT threshold, using three tubes, for prevention of cancer bythe early detection of AAPs.

AcknowledgementsEiken Japan provided the OC-MICROTM instrument, reagents and partialfinancial support for administration. Author roles: Zohar Levi: Acquisitionof data, analysis and interpretation of data, drafting of the manuscript, statis-tical analysis. Shlomo Birkenfeld: Acquisition of data, analysis and interpre-tation of data, drafting of the manuscript. Alex Vilkin: Acquisition of data,analysis and interpretation of data. Micha Bar-Chana: Cancer registry fol-low-up. Irena Lifshitz: Cancer registry follow-up. Miri Chared: Acquisitionof data, coordination of the trial. Eran Maoz: Acquisition of data. Yaron Niv:Study concept and design, acquisition of data, analysis and interpretation ofdata, drafting of the manuscript, study supervision

Figure 3. Estimated number of CRC and AAP cases detected for 10,000 candidates (intention to screen) according to test type, threshold

and number of tubes used. AAP, advanced adenomatous polyp; CRC, colorectal cancer.

Epidemiology



References

1. Hardcastle JD, Chamberlain JO, RobinsonMH, Moss SM, Amar SS, Balfour TW,James PD, Mangham CM. Randomisedcontrolled trial of faecal-occult-bloodscreening for colorectal cancer. Lancet1996;348:1472–7.

2. Kronborg O, Fenger C, Olsen J, JørgensenOD, Søndergaard O. Randomised study ofscreening for colorectal cancer with faecal-occult-blood test. Lancet 1996;348:1467–71.

3. Mandel JS, Bond JH, Church TR, SnoverDC, Bradley GM, Schuman LM, Ederer F.Reducing mortality from colorectal cancerby screening for fecal occult blood.Minnesota Colon Cancer Control Study. NEngl J Med 1993;328:1365–71.

4. Niv Y, Lev-El M, Fraser G, Abuksis G,Tamir A. Protective effect of faecal occultblood test screening for colorectal cancer:worse prognosis for screening refusers. Gut2002;50:33–7.

5. Niv Y. Fecal occult blood test—theimportance of proper processing. J ClinGastroenterol 1990;12:393–5.

6. Young GP, Rozen P, Levin B. How shouldwe screen for early colorectal neoplasia. In:Rozen P, Young GP, Levin B, Spann SJ,eds. Colorectal cancer in clinical practice.London: Martin Dunitz, 2002. 77–99.

7. Selinger RR, Nolman S, Dominitz JA.Failure of health care professionals tointerpret fecal occult blood tests accurately.Am J Med 2003;114:64–7.

8. Smith RA, Cokkinides V, Eyre HJ.American Cancer Society guidelines for theearly detection of cancer, 2003. CA CancerJ Clin 2003;53:27–43.

9. Levin B, Lieberman DA, McFarland B,Andrews KS, Brooks D, Bond J, Dash C,Giardiello FM, Glick S, Johnson D,Johnson CD, Levin TR, et al. Screeningand surveillance for the early detection ofcolorectal cancer and adenomatous polyps,2008: a joint guideline from the AmericanCancer Society, the US Multi-Society TaskForce on colorectal cancer, and theAmerican College of Radiology.Gastroenterology 2008;134:1570–95.

10. Rex DK, Johnson DA, Anderson JC,Schoenfeld PS, Burke CA, InadomiJM;American College of Gastroenterology.American College of Gastroenterologyguidelines for colorectal cancer screening2009. Am J Gastroenterol 2009;104:739–50.

11. Vilkin A, Rozen P, Levi Z, Waked A, MaozE, Birkenfeld S, Niv Y. Performancecharacteristics and evaluation of anautomated developed and quantitative,immunochemical, fecal occult bloodscreening test. Am J Gastroenterol 2005;100:2519–2.

12. Levi Z, Hazazi R, Rozen P, Vilkin A,Waked A, Niv Y. A quantitative

immunochemical fecal occult blood test ismore efficient for detecting significantcolorectal neoplasia than is a sensitiveguaiac test. Aliment Pharmacol Ther 2006;23:1359–64.

13. Levi Z, Rozen P, Hazazi R, Vilkin A, MaozE, Birkenfeld S, Niv Y. Can quantificationof feacal occult blood predetermine theneed for colonoscopy in patients at risk fornon-syndromic familial colorectal cancer?Aliment Pharmacol Ther 2006;24:1475–81.

14. Rozen P, Waked A, Vilkin A, Levi Z, NivY. Evaluation of a desk top instrument forthe automated development andimmunochemical quantification of fecaloccult blood. Med Sci Monit 2006;12:MT27–MT32 (www.MedSciMonit.com).

15. Levi Z, Rozen P, Hazazi R, Vilkin A,Waked A, Maoz E, Birkenfeld S, LeshnoM, Niv Y. A quantitative immunochemicalfecal occult blood screening test forcolorectal neoplasia. Ann Intern Med 2007;146:244–55.

16. Rozen P, Levi Z, Hazazi R, Waked A,Vilkin A, Maoz E, Birkenfeld S, Niv Y.Quantitative colonoscopic evaluation ofrelative efficiencies of an immunochemicalfecal occult blood test and a sensitiveguaiac test for detecting significantcolorectal neoplasms. Aliment PharmacolTher 2009;29:450–7.

17. Rozen P, Levi Z, Hazazi R, Waked A,Vilkin A, Maoz E, Birkenfeld S, Leshno M,Niv Y. Identification of colorectaladenomas by a quantitativeimmunochemical faecal occult bloodscreening test depends on adenomacharacteristics, development threshold usedand number of tests performed. AlimentPharmacol Ther 2009;29:906–17.

18. van Rossum LG, van Rijn AF, Laheij RJ,van Oijen MG, Fockens P, van KriekenHH, Verbeek AL, Jansen JB, Dekker E.Random comparison of guaiac andimmunochemical fecal occult blood testsfor colorectal cancer in a screeningpopulation. Gastroenterology 2008;135:82–90.

19. Wilson J, Junger Y. Principles and practiceof mass screening for disease. PublicHealth Paper No. 34. Geneva: WHO, 1968.

20. Guittet L, Bouvier V, Mariotte N, ValleeJP, Levillain R, Tichet J, Launoy G.Comparison of a guaiac and animmunochemical faecal occult blood testfor the detection of colonic lesionsaccording to lesion type and location. Br JCancer 2009;100:1230–5.

21. Morikawa T, Kato J, Yamaji Y, Wada R,Mitsushima T, Shiratori Y. A comparisonof the immunochemical fecal occult bloodtest and total colonoscopy in the

asymptomatic population. Gastroenterology2005;129:422–8.

22. van Rossum LG, van Rijn AF, Laheij RJ,van Oijen MG, Fockens P, Jansen JB,Verbeek AL, Dekker E. Cutoff valuedetermines the performance of a semi-quantitative immunochemical faecal occultblood test in a colorectal cancer screeningprogramme. Br J Cancer 2009;101:1274–81.

23. Grazzini G, Visioli CB, Zorzi M, Ciatto S,Banovich F, Bonanomi AG, Bortoli A,Castiglione G, Cazzola L, Confortini M,Mantellini P, Rubeca T, et al.Immunochemical faecal occult blood test:number of samples and positivity cutoff.What is the best strategy for colorectalcancer screening? Br J Cancer 2009;100:259–65.

24. Grazzini G, Ciatto S, Cislaghi C,Castiglione G, Falcone M, Mantellini P,Zappa M; Working Group of RegionalReference Centre for Oncological Screeningof Tuscany. Cost evaluation in a colorectalcancer screening programme by faecaloccult blood test in the District ofFlorence. J Med Screen 2008;15:175–81.

25. Hol L, van Leerdam ME, van BallegooijenM, van Vuuren AJ, van Dekken H,Reijerink JCIY, van der Togt ACM,Habbema JDF, Kuipers EJ. Screening forcolorectal cancer: randomised trialcomparing guaiac-based andimmunochemical faecal occult bloodtesting and flexible sigmoidoscopy. Gut2010;59:62–8.

26. Hughes K, Leggett B, Del Mar C, Croese J,Fairley S, Masson J, Aitken J, Clavarino A,Janda M, Stanton WR, Tong S, NewmanB. Guaiac versus immunochemical tests:faecal occult blood test screening forcolorectal cancer in a rural community.Aust N Z J Public Health 2005;29:358–64.

27. Federici A. Rossi PG, Borgia P, BartolozziF, Farchi S, Gasuticchi G. Theimmunochemical faecal occult blood testleads to higher compliance than the guaiacfor colorectal cancer screening programes:a claster randomized controlled trial. J MedScreen 2005;12:83–8.

28. Ko CW, Dominitz JA, Nguyen TD. Fecaloccult blood testing in a general medicalclinic: comparison between guaiac-basedand immunochemical-based tests. Am JMed 2003;115:111–4.

29. Hundt S, Haug H, Brenner H.Comparative evaluation ofimmunochemical fecal occult blood testsfor colorectal adenoma detection. AnnIntern Med 2009;150:162–9.

30. Dancourt V, Lejeune C, Lepage C,Gailliard MC, Meny B, Faivre J.Immunochemical faecal occult blood tests

Epidemiology

Levi et al. 2423


are superior to guaiac-based tests for thedetection of colorectal neoplasms. Eur JCancer 2008;44:2254–8.

31. Allison JE, Sakoda LC, Levin TR, TuckerJP, Tekawa IS, Cuff T, Pauly MP, ShlagerL, Palitz AM, Zhao WK, Schwartz JS,Ransohoff DF. Screening for colorectalneoplasms with new fecal occult bloodtests: update on performance

characteristics. J Natl Cancer Inst 2007;99:1462–70.

32. Allison JE, Tekawa IS, Ransom LJ, AdrainAL. A comparison of fecal occult-bloodtests for colorectal-cancer screening. N EnglJ Med 1996;334:155–9.

33. Castiglione G, Zappa M, Grazzini G,Mazzotta A, Biagini M, Salvadori P, CiattoS. Immunochemical vs guaiac faecal occult

blood tests in a population-based screeningprogramme for colorectal cancer. Br JCancer 1996;74:141–4.

34. Robinson MH, Marks CG, Farrands PA,Thomas WM, Hardcastle JD. Populationscreening for colorectal cancer: comparisonbetween guaiac and immunological faecaloccult blood tests. Br J Surg 1994;81:448–51.

Epidemiology



A higher detection rate for colorectal cancer and advanced adenomatous polyp for screening with immunochemical fecal occult blood test than guaiac fecal occult blood test, despite

Documents