Zohar Levi, MD; Paul Rozen, MBBS; Rachel Hazazi, BSc; Alex Vilkin, MD; Amal Waked, BSc; Eran Maoz, MD; Shlomo Birkenfeld, MD; Moshe Leshno, MD, PhD; Yaron Niv, MD
Note: These results were presented, in part, at Digestive Diseases Week, Los Angeles, California, 20–25 May 2006.
Acknowledgments: The authors thank the medical and secretarial staff of the endoscopy units and the patients for their cooperation. They also thank Dr. Ester Shabtai and Doron Comaneshter for statistical analyses, Ms. Ziona Samuel for helping with patient enrollment, and Ms. Sally Zimmerman for secretarial assistance.
Grant Support: The Eiken Chemical Company, Alfa Wasserman, and Pharmatrade provided instruments and reagents. Research grants from the Eiken Chemical Company and the Katzman Family Foundation supported other costs.
Potential Financial Conflicts of Interest: Grants received: P. Rozen (Eiken Chemical Co.).
Requests for Single Reprints: Paul Rozen, MBBS, Department of Gastroenterology, Rabin Medical Center, Beilinson Hospital, 39 Jabotinsky Street, Petach Tikvah 49100, Israel; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Levi, Vilkin, and Niv; Ms. Hazazi; and Ms. Waked: Rabin Medical Center, Beilinson Campus, PO Box 85, Petach Tikva 49100, Israel.
Dr. Rozen: Department of Gastroenterology, Rabin Medical Center, Beilinson Hospital, 39 Jabotinsky Street, Petach Tikvah 49100, Israel.
Dr. Maoz: Clalit Health Services, Zamenhof Medical Center, 34 Zamenhof Street, Tel Aviv, Israel.
Dr. Birkenfeld: Clalit Health Services, Bat Yamon Medical Center, 33 Nusinson Street, Bat-Yam, Israel.
Dr. Leshno: Recanti Building, Tel Aviv University, Ramat Aviv, Israel.
Author Contributions: Conception and design: P. Rozen, Y. Niv.
Analysis and interpretation of the data: Z. Levi, P. Rozen, A. Waked, R. Hazazi, M. Leshno, Y. Niv.
Drafting of the article: P. Rozen, R. Hazazi, M. Leshno.
Critical revision of the article for important intellectual content: P. Rozen, M. Leshno, Y. Niv.
Final approval of the article: P. Rozen, R. Hazazi, A. Vilkin, S. Birkenfeld, Y. Niv.
Provision of study materials or patients: A. Vilkin, Z. Levi, E. Maoz, S. Birkenfeld, Y. Niv.
Statistical expertise: M. Leshno.
Obtaining of funding: P. Rozen, Y. Niv.
Administrative, technical, or logistic support: R. Hazazi, A. Vilkin, Z. Levi, A. Waked, Y. Niv.
Collection and assembly of data: Z. Levi, R. Hazazi, A. Vilkin, A. Waked.
Levi Z., Rozen P., Hazazi R., Vilkin A., Waked A., Maoz E., Birkenfeld S., Leshno M., Niv Y.; A Quantitative Immunochemical Fecal Occult Blood Test for Colorectal Neoplasia. Ann Intern Med. 2007;146:244-255. doi: 10.7326/0003-4819-146-4-200702200-00003
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Published: Ann Intern Med. 2007;146(4):244-255.
A colorectal cancer screening test should identify persons with early-stage cancer that is an immediate medical threat and persons with advanced adenomas that could be a future threat. As well as having high sensitivity, the screening test should have high specificity for detecting clinically significant neoplasia, cancer, and advanced adenomas to minimize follow-up colonoscopy examinations (1).
The commonly used guaiac-based fecal occult blood tests (FOBTs) have low specificity for detecting human hemoglobin and relatively low sensitivity for identifying clinically significant colorectal neoplasia (1–8). Office-developed qualitative immunochemical FOBTs are specific for detection of human hemoglobin and have improved test specificity (1, 4–6, 9–13). However, the manufacturers designed the test to have sensitivity for measuring hemoglobin similar to that of a sensitive guaiac-based FOBT, which is a limitation. Moreover, we found that doing the actual measuring in the office was not conducive to large-scale screening while maintaining quality control (1, 2, 6). We investigated a clinical laboratory–based immunochemical test that measures the hemoglobin content of a stool sample.
Jikei University School of Medicine
March 1, 2007
Immunochemical Fecal Occult Blood Test
TO THE EDITOR: In 1000 consecutive ambulatory patients at moderate to high risk for colorectal disease, Dr. Levi and colleagues showed that the quantitative immunochemical fecal occult blood test (FOBT) had good sensitivity and specificity to detect clinically significant neoplasia (1). The authors are to be congratulated on making the nomogram, by which we could estimate the posttest probability of clinically significant neoplasia not only in symptomatic patients but also in the general population.
A colonoscopy was completed in 93 % of their patients, but the rate of complication related to colonoscopy is not described in the article. Although colorectal cancer incidence rates increase with age and the diagnostic yield of colonoscopy is higher in the elderly group (2), the lifetime risk of colorectal cancer death actually decreases in persons with advancing age and increasing comorbidity (3). The risk of colonoscopy complications appears to increase with patient age and cormorbidity (4). Therefore, in elderly patients with poor health, the risks of invasive colorectal cancer screening may outweigh the benefits. I think the nomogram should not be used to determine whether to offer colonoscopy to these patients whose life expectancy is relatively limited.
Tetsuji Fujita, MD Jikei University School of Medicine Tokyo, Japan 105-8461
1. Levi Z, Rosen P, Hazazi R, Vilkin A, Waked A, Maoz E, et al. A quantitative immunochemical fecal occult blood test for colorectal neoplasia. Ann Intern Med. 2007; 146: 244-55.
2. Karajeh MA, Sanders DS, Hurlstone DP. Colonoscopy in elderly people is a safe procedure with a high diagnostic yield: a prospective comparative study of 2000 patients. Endoscopy. 2006; 38: 226-30.
3. Ko CW, Sonnenberg A. Comparing risks and benefits of colorectal cancer screening in elderly patients. Gastroenterology. 2005; 129: 1163-70.
4. Mandelblatt JS, Schechter CB, Yabroff KR, Lawrence W, Dignam J, Extermann M, et al. Toward optimal screening strategies for older women. J Gen Intern Med. 2005; 20: 487-96.
Yogesh M Shastri
Medizinische Klinik I-ZAFES, J. W. Goethe-University Hospital,
March 27, 2007
Quantitative Immunochemical Fecal occult blood test for diagnosing Colorectal neoplasia
We read with great interest the article by Levi et al(1) and must congratulate them for a nice piece of work. They have introduced really a unique concept of offering the possibility of having an option of different positivity thresholds for performing quantitative immunochemical fecal occult blood test (IFOBT). We have certain queries and comments to them. In the introduction section of their article they have mentioned that none of the English language publication study has systematically compared colonoscopy with the fecal immunochemical method for diagnosing CRN (colorectal neoplasia).We would like to bring to their attention that our group has published a study on the similar theme in 2006(2).
In our study 389 patients from 4 different centers in Germany, who were referred for colonoscopy, underwent 3 stool tests; a Guaiac based FOBT, a quantitative ELISA based IFOBT and a bedside qualitative Immunochemical strip test. The performance characteristics of the quantitative IFOBT in both these studies(1, 2) were quite similar, a sensitivity of 67% vs. 64% and specificity of 91% vs. 96% for diagnosing significant CRN in Levi's and our study respectively.
However there were some differences in both these studies (1, 2). Although in the quantitative ELISA based IFOBT in our study we did not evaluate the different range of cut offs threshold as evaluated by Levi. The fixed cut off threshold for positivity of ELISA in our study was 10 ng Hemoglobin/ml as against a range of cut-off 50 ng/ml to 150 ng/ml as that of in Levi's study. While the qualitative strip test evaluated by us was a manual bedside test(2, 3) with a fixed threshold of detection of up to 10ng/ml of Hemoglobin in stool.
Another apprehension about their study method(1) is the need for 3 stool sample collection. It's an accepted fact that increased number of stool sample will reduce the compliance of the screening as its cumbersome and may shy away many of the screenees. Also, it might pose the issue of acceptability for the patients and also might pose difficulties logistically at field level when this test is applied to the masses during CRC screening for average risk population.
As the cost of the test for performing CRC screening is also a very important factor. Some more elaboration on the costs incurred in performing this automated quantitative IFOBT would be appreciated. Does the $20 cost mentioned in the paper include the net charges to the patient? Does it also consider the other expenditure like the recurring cost of reagents, administrative costs and one time cost of the machine (analyzer) etc?
Sincerely - Yogesh Shastri, MD, DNB
- Jurgen Stein, MD, PhD
References: 1. Levi Z, Rozen P, Hazazi R, et al. A quantitative immunochemical fecal occult blood test for colorectal neoplasia. Ann Intern Med. 2007;146(4):244-55. 2. Hoepffner N, Shastri YM, Hanisch E, et al. Comparative evaluation of a new bedside faecal occult blood test in a prospective multicentre study. Aliment.Pharmacol.Ther. 2006;23(1):145-154. 3. Trojan J, Povse N, Schroder O, Stein J. A new immunological test strip device for the rapid, qualitative detection of faecal occult blood. Z.Gastroenterol. 2002;40(11):921-924.
Rabin Medical Center
April 18, 2007
April 17, 2007
IN RESPONSE: We thank Drs. Shastri and Stein for their comments and their very relevant questions which provide us with an opportunity to address several important clinical issues. Firstly, our comment on "systematic evaluation" refers to the automated developed and quantitative immunochemical FOBT (I-FOBT) (1). As they point out, they, we and others have evaluated the office-developed I-FOBT immunochemical test (2,3). However, this test uses a fixed threshold, set by the manufacturer, and the hand-development is not conducive for large scale population screening. Evaluating the I-FOBT as a laboratory test, with a quantified result, gives the treating physician the ability to use his clinical judgement as he would for any other laboratory test. Secondly, the number of requested stool samples definitely influences compliance. In our study population, who are used to collecting three guaiac FOBTs, this was not an issue. However, we are now completing a study on an average-risk population and this will allow us to evaluate compliance in that segment of the population who, to date, have not participated in FOBT screening. Thirdly, the maximum cost of FOBT screening is set by our Ministry of Health as this is a test available for the total population through their own HMO. The $20 cost is the total cost per patient that was estimated by the local agent for this I-FOBT. This will need to be budgeted by the HMO which is required to provide, at no cost, an annual FOBT to their average- risk members. References:
1. Levi Z, Rozen P, Hazazi R, Vilkin A, Waked A, Maoz E, Birkenfeld S, Leshno M, Niv Y. A quantitative immunochemical fecal occult blood test for colorectal neoplasia. Ann Intern Med. 2007;146:244-55. 2. Hoepffner N, Shastri YM, Hanisch E, Rosch W, Mossner J, Caspary WF, Stein J. Comparative evaluation of a new bedside faecal occult blood test in a prospective multicentre study. Aliment Pharmacol Ther 2006;23:145- 154. 3. Rozen P, Knaani J, Samuel Z., Comparative screening with a sensitive guaiac and specific immunochemical occult blood test within an endoscopy study. Cancer 2000;89:46-52. Paul Rozen, MB.BS Zohar Levi, MD Yaron Niv, MD, FACG, AGAF
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