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2420 Evaluation of an Automated Immunochemical Fecal Occult Blood Test for Colorectal Neoplasia Detection in a Chinese Population Wai Man Wong, M.D.1 Shiu Kum Lam, M.D.1 Kwan Lok Cheung, B.Sc1 Teresa Sze Man Tong, B.Sc1 Paul Rozen, MBBS2 Graeme P. Young, M.D.3 Kin Wah Chu4 Judy Ho4 Wai Lun Law, M.S4 Hiu Ming Tung4 Hok Kwok Choi4 Yee Man Lee4 Kam Chuen Lai1 Wayne H. C. Hu1 Chi Kuen Chan1 Man Fung Yuen, M.D.1 Benjamin Chun-Yu Wong, M.D.1 1 Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong. 2 Department of Gastroenterology, Tel Aviv Medical Center, Tel Aviv University, Tel Aviv, Israel. 3 Department of Gastroenterology and Hepatology, Flinders Medical Centre, Flinders University of South Australia, Adelaide, Australia. 4 Department of Surgery, University of Hong Kong, Queen Mary Hospital, Hong Kong. Supported by the Simon K. Y. Lee Gastroenterology Research Fund, University of Hong Kong, Queen Mary Hospital, Hong Kong. The authors thank members of the World Organization for Digestive Endoscopy/World Health Organization/American Society for Gastrointestinal Endoscopy Outreach Program for the International Promotion of Colorectal Cancer Screening for their advice on the development of the study protocol and its evaluation; Fujirebio, Inc. (Tokyo, Japan) for providing the Magstream 1000 machine and test kits; Seekers Biochemical Ltd. (Hong Kong) for technical support and facilitation; and Ms. Fiona M. Y. Fung, Ms. Vicky Y. K. Ho, and the endoscopy nurses from the Departments of Medicine and Surgery, Queen Mary Hospital, Hong Kong, for their © 2003 American Cancer Society BACKGROUND. Most commercial fecal occult blood tests (FOBT) used for colorectal carcinoma screening of Western populations are guaiac-based, manually developed, subjective, and sensitive to dietary components. Preliminary studies demonstrated the unsuitability of these tests for screening a Chinese population. The goal of the current study was to evaluate the performance characteristics of a human hemoglobin–specific automated immunochemical FOBT, the Magstream 1000/Hem SP (Fujirebio, Inc., Tokyo, Japan), in a Chinese population referred for colonoscopy. METHODS. Two hundred fifty consecutive patients who were referred for colonoscopy and met the study inclusion criteria provided samples for the immunochemical FOBT (without dietary restrictions) from two successive stool specimens. Tests were developed with an automated instrument that had an adjustable sensitivity threshold. The sensitivity, specificity, and positive predictive value for detecting colorectal adenomas and carcinomas were calculated according to the manufacturer’s instructions over a range of sensitivity levels. RESULTS. At the optimal threshold level, the sensitivity, specificity, and positive predictive value for detection of significant colorectal neoplasia (adenomas ⱖ 1.0 cm and carcinomas) were 62%, 93%, and 44%, respectively. The test was easy to use, and results did not depend on operator experience. CONCLUSIONS. The automated immunochemical FOBT used in the current study was a robust, convenient, and useful tool for colorectal carcinoma screening in the study population. Cancer 2003;97:2420 – 4. © 2003 American Cancer Society. DOI 10.1002/cncr.11369 KEYWORDS: colon carcinoma, adenoma, colorectal neoplasia, screening. C olorectal carcinoma (CRC) is a leading cause of cancer mortality in the United States, Europe, and Westernized Asian cities such as Hong Kong.1 As a result, CRC is becoming a major medical and economic burden for China. It is believed that most cases of sporadic colorectal carcinoma arise from preexisting adenomatous polyps. By screening asymptomatic, average-risk individuals, curable carcinomas and removable adenomatous polyps can be detected; detection can lead to interruption of the natural history of the disease or an increased chance of curing it.2 Three large-scale randomized trials (1 each in the United States, the United Kingdom, and Denmark) using a guaiac-based fecal occult assistance and for providing care to the patients in the study. Hospital, Pokfulam Road, Hong Kong; Fax: (011)-8522872-5828; E-mail: [email protected] Address for reprints: Dr. Benjamin C.-Y. Wong, Department of Medicine, University of Hong Kong, Queen Mary Received December 10, 2002; revision received January 8, 2003; accepted January 28, 2003. Automated Immunochemical FOBT/Wong et al. blood test (FOBT) reported a reduction in CRC mortality of 15–33% on an intent-to-screen basis.3–5 These trials also demonstrated that when screening was repeated annually or biennially, an even higher level of sensitivity was achieved (i.e., program sensitivity in detecting colorectal neoplasia at a treatable stage improved with each screening cycle). In addition, screening can reduce the incidence of CRC by identifying large adenomatous polyps so that they can be removed.2,6 In Hong Kong, the incidence of CRC has increased significantly over the past decade, and CRC currently is the second most common carcinoma (after lung carcinoma) in Hong Kong. In 1999, the age-standardized rates of CRC per 100,000 males and females were 37.8 and 28.2, respectively.7 These rates are comparable to the age-standardized rates per 100,000 persons for white males in the United States (43.9) and for the populations of Japan (39.5) and Australia and New Zealand combined (45.8).8,9 CRC is a growing medical problem in Hong Kong and in sectors of the Chinese population that are becoming Westernized.10 The FOBT is the simplest, cheapest noninvasive and effective CRC screening method available. There are 2 types of commercially available FOBTs: 1) guaiac tests that detect the pseudoperoxidase activity of heme; and 2) immunochemical tests that detect either the globin protein of human hemoglobin or other blood products. Guaiac-based FOBTs are used more frequently and have been validated extensively for screening in North America and most of Europe. However, the guaiac tests are not human hemoglobin– specific and therefore require the patient to avoid red meat, certain uncooked vegetables, vitamin C, and nonsteroidal anti-inflammatory drugs (NSAIDs) before and during the fecal sample collection period. These restrictions can affect patient compliance as well as the accuracy of the tests. Extensive screening experiences in Japan suggested that a two-day immunochemical FOBT that did not require dietary restriction was more suitable for the study populations than was the guaiac test.11,12 Most commercial or in-house guaiac-based and immunochemical FOBTs are interpreted by the visual determination of color changes after manual addition of reagent solutions to the stool samples. In research settings, methods of test interpretation may be well standardized; however, if an FOBT is to be widely used, a more objective method is essential for avoiding interobserver variation. The Magstream 1000/Hem SP automated system (Fujirebio, Inc., Tokyo, Japan) is an immunologic FOBT that is easy to use and well suited to centralized management of a high test volume, because it elimi- 2421 nates human bias in the interpretation of results. The assay evolved from the Immudia-Hem SP test (Fujirebio, Inc.). The hemagglutination technique using chicken red cells in the Immudia-Hem SP test was replaced by magnetically induced agglutination, which was made possible by the attachment of rabbit antibodies against human hemoglobin to particles of gelatin containing ferrite and gum arabic.13 This modification led to faster agglutination and produced a more stable agglutinate, which allowed automated result interpretation by the Magstream 1000 instrument.14 The assay is suitable for high-volume testing and general population screening. After our initial experience with a sensitive guaiac FOBT, in which we found the test unsuitable for our Chinese study population because of its low specificity for significant neoplasia, we performed the current study to evaluate the Magstream 1000/Hem SP system. MATERIALS AND METHODS Patient Population From May 2001 to June 2002, 250 consecutive patients at Queen Mary Hospital (Hong Kong) who required colonoscopy for the investigation of gastrointestinal symptoms or colonic polyp surveillance were recruited for study. Patients with a previously positive FOBT, history of overt gastrointestinal bleeding, active rectal bleeding, menstruation, hematuria, and known ulcerative colitis were excluded. Patients were asked to begin fecal sampling for the FOBT at least five days before hospital admission to ensure that two samples were collected before bowel preparation commenced. No dietary restriction was required. Medications such as aspirin and NSAIDs were withdrawn one week before preparation of the stool tests. The study was approved by a local ethics committee, and all examinees provided written informed consent. Patients were asked to prepare fecal samples from two consecutive stool specimens using the collection kit provided by the manufacturer (Fujirebio, Inc.). Each collection kit contained two collection tubes, two sample collection probes, identification labels, a patient instruction sheet, and stool collection papers in a resealable plastic bag. The collection tube consisted of a translucent tube and a push-fit lid, which was held in place by a small adhesive label. The outer edge of the lid was hollow, and the internal diameter of the lid decreased in steps until it reached a soft septum seal. Stool specimens were collected with a sample probe by repeated scraping until the specimen collection line was stained. The probe then was pushed through the septum seal, and the tip of the probe was immersed in buffered saline solution, which contained 2422 CANCER May 15, 2003 / Volume 97 / Number 10 rabbit serum and sodium azide (a preservative). Collection tubes were returned to the hospital on the day of colonoscopy. Samples were collected with dropper tips that were provided by the manufacturer. Each tip had a shielded point to pierce through the bottom of the collection tube. Sample aliquots (25 L) were transferred to microtiter plates, which then were placed in a rack on the side of the Magstream 1000 and automatically carried into the machine. The Magstream 1000/Hem SP immunoassay system is a microprocessor-controlled analytic system for automatic processing of the Hem SP magnetic particle immunoassay. The system used an immunologic indirect agglutination method to detect fecal occult blood with rabbit anti– human hemoglobin, which was attached to magnetic gelatin particles. Agglutination of the magnetic gelatin particles was accelerated by the use of magnetic force to draw particles together at the bottom of a V-shaped well. The plate then was tilted to 60° from horizontal to allow free magnetic particles to run down the slope of the well and form a measurable line. In the presence of human hemoglobin, particles remained in the shape of a tight button or a short line during tilting. The length of the line was determined optically using reflected 690-nm light and was measured in standard units (SU) (1 SU ⫽ 0.03 mm). The cutoff recommended by the manufacturer was 100 SU, but the cutoff level was adjustable. Samples with values ⬎ 100 SU were deemed negative, whereas samples with values ⱕ 100 SU were deemed positive. The system had a sensitivity of 20 mg hemoglobin per liter or 0.1– 0.2 mg hemoglobin per gram of feces. The positive and negative controls (25 L each) were purified human hemoglobin and buffer diluent containing azide, respectively. Correlation with Clinical Findings Colonoscopy was performed without knowledge of FOBT results. All participating endoscopists had at least six years of experience in colonoscopy. If colorectal polyps were detected, the polyp site was recorded and polypectomy performed. Polyps were examined histologically, and the size and histologic type of each polyp were recorded. The locations and histologies of carcinomas also were recorded. Colonoscopy was incomplete in 2 patients (1%) due to obstructing tumors of the sigmoid colon. Statistical Analysis The presence of an adenomatous polyp of any size or a carcinoma was considered a positive finding on colonoscopy. Patients were classified by largest detected adenoma or by the presence of carcinoma. Findings were analyzed based on the number of de- TABLE 1 Patient Demographic Data, Indications for Endoscopy, and Endoscopy Findings (Classified by Worst Neoplasia) Demographic data M/F (%) Mean age ⫾ SD (range) (years) Indication for colonoscopy (%) History of colonic polypsa History of cured colorectal carcinomaa Family history of colorectal neoplasiaa Abdominal pain Anemia Alteration of bowel habits Other Findings at colonoscopy (%) Normal Inflammatory polyps Hyperplastic polyps Adenoma Cecum and ascending colon Transverse colon Descending and sigmoid colon Rectum Carcinoma Cecum and ascending colon Transverse colon Descending and sigmoid colon Rectum 134/116 (54/46) 59.5 ⫾ 9.5 (40–81) 68 (27) 38 (15) 28 (11) 16 (6) 28 (11) 51 (20) 21 (8) 165 (66) 2 (1) 12 (5) 14 (6) 12 (5) 29 (12) 7 (3) 4 (2) 0 (0) 2 (1) 1 (1) SD: standard deviation. a Patients were asymptomatic. tected neoplasms (adenomas or carcinomas), adenomas only, and clinically significant neoplasms (adenomas ⱖ 1.0 cm in diameter or carcinomas). The sensitivity, specificity, and positive predictive values of the Magstream 1000/Hem SP system were calculated using the cutoff provided by the manufacturer as well as other cutoff values. To evaluate the effect of time to development on sensitivity, we arbitrarily divided the study population into two halves according to time to development. The statistical methods used included the Student t test, chi-square test, and Fisher exact test; differences were estimated by comparing confidence intervals from paired tests. P ⬍ 0.05 was considered statistically significant. All P values were twosided. RESULTS Demographic and clinical data for the 250 patients were tabulated (Table 1). The mean patient age was 59.5 years. Fifty-four percent of patients were male, and all were ethnically Chinese. Seventy-three (54%) patients were asymptomatic (personal history of colonic polyps, personal history of cured colorectal carcinoma, and family history of colorectal neoplasia). Sixty-three patients were found to have adenomatous Automated Immunochemical FOBT/Wong et al. 2423 TABLE 2 Positivity Rate (at Various Cutoff Values) of Magstream 1000/Hem SP for Detection of Colorectal Carcinoma, Adenoma, and Significant Colorectal Neoplasiaa in 250 Chinese Patients Who Underwent Colonoscopy Cutoff (SUb) Endpoint (%) 50 60 70 80 90 100 Overall positivity (n ⫽ 250) Positivity in normal colon (n ⫽ 165) Carcinomas (n ⫽ 7) detected Large adenomas (n ⫽ 19) detected Significant neoplasms (n ⫽ 26) detectedc All adenomas (n ⫽ 63) detected Specificity of significant neoplasia (n ⫽ 165) PPV for carcinoma PPV for significant neoplasia 15 (6) 2 (1) 4 (57) 4 (21) 8 (31) 8 (13) 163 (99) 4/15 (27) 8/15 (53) 29 (12) 8 (5) 7 (100) 6 (32) 13 (50) 13 (21) 157 (95) 7/29 (24) 13/29 (45) 36 (14) 12 (7) 7 (100) 9 (47) 16 (62) 16 (25) 153 (93) 7/36 (19) 16/36 (44) 43 (17) 17 (10) 7 (100) 9 (53) 16 (65) 16 (29) 148 (90) 7/43 (16) 16/43 (37) 44 (18) 18 (11) 7 (100) 9 (53) 16 (65) 16 (29) 147 (89) 7/44 (16) 16/44 (36) 51 (20) 22 (13) 7 (100) 10 (53) 17 (65) 18 (29) 143 (87) 7/51 (14) 17/51 (33) SU: standard units; PPV: positive predictive value. a Includes adenomas ⱖ 10 mm and carcinomas. b 1 SU ⫽ 0.03 mm. c Equivalent to overall detection sensitivity. polyps (19 had adenomas ⱖ 1.0 cm), and 7 had CRC. Colonoscopies were normal for 165 patients. Two of the seven patients with CRC had obstructing lesions that prevented a complete colonoscopic examination. The test had a mean time to development of 5.9 days (median, 3 days; range, 0 –33 days) from the first day of sample collection. Mean time to development was similar for FOBTs with positive results and FOBTs with negative results. All patients returned their samples; none defaulted. The collection kit was easy to use, and there was no leakage during delivery. Test Sensitivity in Detection of Colorectal Carcinoma and Significant Colorectal Neoplasia All cases of CRC were detected by the Magstream 1000. At the standard cutoff (100 SU), the sensitivity, specificity, and positive predictive value of the Magstream 1000 for detection of CRC were 100%, 87%, and 14%, respectively. For significant colorectal neoplasms (adenomas ⱖ 1.0 cm in diameter or carcinomas), the detection rate was 65% at the standard cutoff. There was no difference in the sensitivity of significant neoplasia detection between the early and late stool specimen development groups (P ⫽ not significant) (Table 2). Test Sensitivity in Detection of Adenomas The mean adenoma size for all patients was 0.7 cm (range, 0.2–3.0 cm). Mean adenoma size was significantly larger for patients with positive Magstream 1000 results compared with patients with negative results (1.2 cm vs. 0.58 cm, P ⬍ 0.001). The sensitivity of the Magstream 1000 for detection of all adenomas was 29% using the standard cutoff of 100 SU (Table 2). Effect of Cutoff Value Sensitivities, specificities, and positive predictive values were calculated for different cutoffs. The detection rate of CRC remained at 100% even when the cutoff was decreased to 60 SU. At a cutoff of 70 SU, the sensitivity, specificity, and positive predictive value for detection of significant colorectal neoplasia were 62%, 93%, and 44%, respectively; however, the detection rate for large adenomas (size, ⱖ 1 cm) decreased from 53% to 47% (Table 2). DISCUSSION In the current study, a one-time FOBT had a positive predictive value, sensitivity, and specificity of 33– 44%, 62– 65%, and 87–93%, respectively, for the detection of significant colorectal neoplasia in a mixed group of symptomatic and asymptomatic individuals; results depended on the development threshold chosen. These results are suitable for screening and are consistent with results from other studies that used immunochemical tests to screen larger populations.15–18 The test used in the current study is easy to perform, and results are independent of operator experience. Although the number of patients was small and all patients were recruited after the decision to perform colonoscopy had been made, we were able to obtain useful information regarding the accuracy of the Magstream 1000/Hem SP FOBT in a group of Chinese patients. One of the main advantages of using an immuno- 2424 CANCER May 15, 2003 / Volume 97 / Number 10 chemical FOBT was that the test lacked a dietary restriction requirement, which would not have been widely acceptable to the local population. In general, the Chinese eat a variety of food items and consume a large amount of fruits and vegetables every day; such a diet produced a high false positive rate for the guaiac test, despite the adoption of a three-day delayed development period (Wong et al. 2003, unpublished data). In addition, extensive screening experience in Japan suggested that a two-day immunochemical FOBT was more suitable for that population than was the guaiac test.11,12 At the standard cutoff, the positivity rate for samples from patients with “normal” colonoscopy findings was 13%; this rate is quite high and would lead to an excessive colonoscopy rate. However, the population that we studied was not a true screening population, and 46% of examinees had abdominal symptoms. Lowering the cutoff value to 70 SU decreased the false positive rate to 7%, but this improvement was offset slightly by decreased sensitivity in the detection of large adenomas (down from 53% to 47%). We believe that these undetected lesions eventually would be identified with annual retesting. A large pilot study of truly asymptomatic patients could help to determine the optimal cutoff value in the study population. The current study provides useful data regarding the potential application of an automated immunochemical FOBT in screening the Chinese population for CRC. We have demonstrated that the Magstream 1000/Hem SP assay is a robust, specific, and accurate tool for the detection of significant colorectal neoplasia and provides the basis for a large-scale screening program in the Chinese population. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. REFERENCES 1. 2. 3. Rozen P. Colorectal cancer: does early detection matter? Postgrad Med J. 2001;77:289 –291. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med. 1993;329:1977–1981. Mandel JS, Bond JH, Church TR, et al. Reducing mortality 18. from colorectal cancer by screening for fecal occult blood. N Engl J Med. 1993;328:1365–1371. Hardcastle JD, Chamberlain JO, Robinson MH, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. 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