Correspondence
Screening for Colorectal Cancer
N Engl J Med 1993; 329:1351-1354October 28, 1993
- Article
To the Editor:
We have three questions about the important fecal occult-blood screening study by Mandel et al. (May 13 issue)1. First, although mortality from colorectal cancer was significantly reduced in the annually screened group, it is not clear whether this gain can be attributed to the selective detection of cancer by screening or to an artifact of the very high rate of false positive results (occurring in 10 percent of those screened each year) and consequent numerous colonoscopies. According to the authors' data, about 10,000 colonoscopies or colorectal examinations were performed in this group of about 15,000 to evaluate positive fecal occult-blood tests. Perhaps the random performance of 10,000 colonoscopies in this group, irrespective of the test results, would have yielded a similar outcome.
Second, we question the estimate of the sensitivity of the fecal occult-blood test for colorectal cancer, which appears to be based on data from an earlier report by the authors2. Participants who tested negative were not evaluated, but were followed for only one year to confirm this result. The authors' exceedingly high sensitivity estimate of 92 percent seems to be contradicted by their own observations that as few as 38 percent of cancers diagnosed in those who underwent screening were preceded by a positive fecal occult-blood test. In addition, if the sensitivity of the test exceeded 90 percent, it is surprising that mortality from colorectal cancer was not influenced in the biennially screened group. More rigorous estimates, based on comparisons with the results of colonoscopy or colonic roentgenography -- the gold standards -- in asymptomatic, nonreferred patients, suggest a much lower sensitivity of 30 percent or less3,4.
Third, mass screening with rehydrated paper slides (Hemoccult) would be prohibitively expensive. With the use of this technique, 10 percent of those who are screened will undergo colonoscopy each year, but 98 of every 100 patients with a positive fecal occult-blood test will not have cancer. The national cost of screening the 60 million Americans between the ages of 50 and 80 years, assuming an average fee of $1,000 for colonoscopy and related consultations, would exceed $6 billion annually. In view of the many unmet health care needs and limited health care dollars, we seriously question such an expenditure. This is particularly true when the patients identified are an average of 70 years old, when there are other strong potential causes of death, and when the data of Mandel and associates show no effect on overall mortality.
We challenge the conclusion of the editorial5 accompanying the article by Mandel et al. that fecal occult-blood screening has come of age. National health care programs should not be pressured to bear the costs of such screening. Our resources could be much better spent by seeking out more sensitive and specific screening tools that could be applied to the population at risk in a cost-effective manner.
5 ReferencesDavid A. Ahlquist, M.D.
Charles G. Moertel, M.D.
Douglas B. McGill, M.D.
Mayo Clinic, Rochester, MN 559051
Mandel JS ,Bond JH ,Church TR , et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993;328:1365-1371
Full Text | Web of Science | Medline2
Mandel JS ,Bond JH ,Bradley M , et al. Sensitivity, specificity, and positive predictivity of the Hemoccult test in screening for colorectal cancers. Gastroenterology 1989;97:597-600
Web of Science | Medline3
Ahlquist DA ,Wieand HS ,Moertel CG , et al. Accuracy of fecal occult blood screening for colorectal neoplasia: a prospective study using Hemoccult and HemoQuant tests. JAMA 1993;269:1262-1267
CrossRef | Web of Science | Medline4
Rozen P . Screening for colorectal neoplasia in the Tel Aviv area: cumulative data 1979-89 and initial conclusions. Isr J Med Sci 1992;28:Suppl:8-20
Medline5
Winawer SJ . Colorectal cancer screening comes of age. N Engl J Med 1993;328:1416-1417
Full Text | Web of Science | Medline
To the Editor:
Mandel et al. demonstrate a decided advantage in favor of annual fecal occult-blood screening and extend earlier studies showing, for example, the influence of sigmoidoscopy on reducing mortality from rectal cancer1 and of periodic colonoscopy on reducing the incidence of colorectal cancer in patients with previous polyps2.
Technological capabilities have come a long way since this study was initiated in the 1970s. The data show that, at best, fecal occult-blood screening would decrease deaths from colon cancer by 19,000 per year. It is likely that much greater decreases can be effected by techniques such as colonoscopy, which allows the removal of precancerous lesions (polyps), whether or not they are bleeding. As the authors point out, fecal occult-blood screening by itself did not identify or cure cancer but was a stimulus for a definitive study, usually colonoscopy.
Two thirds of deaths from cancer will occur despite repeatedly negative annual fecal occult-blood tests. The cost of colonoscopy has been the main impediment to its more widespread use for screening. The cumulative costs of medical expenses and lost wages must be attributed to screening programs that have lower direct costs but that allow preventable diseases and deaths to occur. The safety profile of colonoscopy demonstrated by Mandel et al. and the declining costs (there has been a 54 percent reduction in reimbursement under Medicare, with plans for further reductions) will make this the screening test of choice in the 21st century.
2 ReferencesWilliam D. Carey, M.D.
American College of Gastroenterology, Arlington, VA 22206Edgar Achkar, M.D.
Cleveland Clinic Foundation, Cleveland, OH 441951
Selby JV ,Friedman GD ,Quesenberry CP Jr ,Weiss NS . A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992;326:653-657
Full Text | Web of Science | Medline2
Winawer SJ ,Zauber AG ,Gerdes H , et al. Reduction in colorectal cancer incidence following colonoscopic polypectomy: report from the National Polyp Study (NPS). Gastroenterology 1991;100:Suppl:A410-A410 abstract.
To the Editor:
In the study by Mandel et al., cumulative mortality rates from all causes in the screened and control groups were identical. As expected, ischemic heart disease was a much more common cause of death than colorectal cancer. A small increase in the rate of mortality from ischemic heart disease in the screened group more than offset the decreased rate of mortality from colorectal cancer in this group. Is it possible that this increased rate of mortality from ischemic heart disease was related to the stress associated with screening and follow-up?
Robert Perlman, M.D., Ph.D.
University of Chicago, Chicago, IL 60637To the Editor:
. . . What benefit do physicians offer patients by suggesting fecal occult-blood screening? We offer to reduce their risk of death from colorectal cancer by less than 0.3 percent and their overall risk of death not at all, and we subject them to a nearly 10 percent risk of colonoscopy (with its attendant 1 in 3000 risk of perforation or serious bleeding requiring emergency surgery). This is not to mention the enormous costs incurred to achieve such minimal (or nonexistent) benefits. The use of screening in routine clinical care is most unlikely to achieve the efficacy reported in the well-conducted trial by Mandel et al. The case for recommending routine annual fecal occult-blood screening is very weak indeed.
Brian Budenholzer, M.D.
Group Health Northwest, Spokane, WA 99206To the Editor:
The report by Mandel et al. did not include data on the distribution of the cancers detected. If proximal tumors are more likely to bleed than distal ones, fecal occult-blood screening may be a useful adjunct to flexible sigmoidoscopy, which has been shown in case-control studies to reduce mortality from left-sided colorectal cancer1,2. Can the authors provide information on the distribution of cancers in the three groups of participants?
2 ReferencesAlfred I. Neugut, M.D., Ph.D.
Judith S. Jacobson, M.P.H.
Columbia University School of Public Health, New York, NY 100321
Selby JV ,Friedman GD ,Quesenberry CP Jr ,Weiss NS . A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992;326:653-657
Full Text | Web of Science | Medline2
Newcomb PA ,Norfleet RG ,Storer BE ,Surawicz TS ,Marcus PM . Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 1992;84:1572-1575
CrossRef | Web of Science | Medline
To the Editor:
. . . Mandel and associates have shown that fecal occult-blood screening can decrease mortality from colorectal cancer in average-risk patients but at substantial cost when the screening test involves the use of a rehydrated paper slide (Hemoccult II). In 1992, we presented data from a colorectal-cancer screening program for more than 8000 patients at average risk.1 Our study showed that a two-tiered test using a card combining both Hemoccult II Sensa, a more sensitive guaiac test similar in performance characteristics to the rehydrated Hemoccult II, and HemeSelect, a specific test for human hemoglobin, detected 1.5 times as many clinically important colorectal neoplasms (including polyps ≥ 1 cm in diameter) as Hemoccult II, without a notable decrease in specificity.1 The use of two-tiered fecal occult-blood screening could be more cost effective than the use of Hemoccult II Sensa or a rehydrated Hemoccult II alone.
1 ReferencesJames E. Allison, M.D.
Kaiser Permanente Medical Center, Oakland, CA 94611To the Editor:
In their report on the efficacy of fecal occult-blood testing in reducing mortality from colorectal cancer, Mandel et al. state that the “increase in cost [resulting from rehydration of the slides] is substantial and will have to be weighed against the estimated benefit.” Using a computer program (CAN*TROL1) designed to project the potential effects of cancer-control interventions to the U.S. population, we have constructed preliminary estimates of the net costs and the number of years of life saved by the use of a fecal occult-blood screening program in the U.S. population 50 to 80 years of age. We incorporated the reduction in mortality rates, the rates of compliance, and the costs of colonoscopies engendered by false positive tests and the discovery of benign polyps reported by Mandel et al. Assuming a cost of $5 for the test and a cost of $500 for colonoscopy (consistent with 1988 charges allowed by Medicare2), we estimate that a program of annual screening in which 40 percent of the population 50 to 80 years of age participated (similar to current levels of participation in mammography screening programs) would result in an estimated annual net expenditure to health care consumers of $2 billion in 1994 and $2.5 billion by 2000. The cost effectiveness is estimated to be about $25,000 per year of life saved (or about $30,000 when both costs and the number of years of life are discounted at 5 percent). This level of cost effectiveness compares favorably with estimates of cost effectiveness for programs of breast-cancer screening for women over the age of 503.
Ninety-five percent of the net costs are attributable to the colonoscopies. This cost component dwarfs the cost of fecal occult-blood testing and other downstream costs and savings. If colonoscopy is assumed to cost $1,500, then the cost effectiveness of this program is estimated to be about $70,000 per year of life saved (or more than $80,000 in discounted terms), a value that is at the higher end of the spectrum of health interventions that have been evaluated. Tripling the cost of fecal occult-blood testing results in only an 8 percent increase in the cost per year of life saved.
3 ReferencesMartin L. Brown, Ph.D.
National Cancer Institute, Bethesda, MD 208921
Eddy DM. A computer-based model for designing cancer control strategies. In: Greenwald P, Sondik EJ, eds. Cancer control objectives for the nation: 1985-2000. NCI monographs. No. 2. Washington, D.C.: Government Printing Office, 1986:75-82. (NIH publication no. 86-2880.)
2
Office of Technology Assessment. Costs and effectiveness of colorectal cancer screening in the elderly -- background paper. Washington, D.C.: Government Printing Office, 1990. (OTA-BH-H-74.)
3
Brown ML . Economic considerations in breast cancer screening of older women. J Gerontol 1992;47:51-58
Medline
Author/Editor Response
The authors reply:
To the Editor: Ahlquist et al. erroneously conclude that 10,000 of the 15,000 annually screened participants had a colonoscopy. In fact, during the 13 years of the study only about 4500 did. As we stated, the performance of a large number of colonoscopies might increase the likelihood of detecting nonbleeding cancers by chance,1 but bleeding rather than nonbleeding cancers were the chief contributor. The predictive value of the fecal occult-blood test increases as the number of positive slides increases (Figure 1Figure 1
Positive Predictive Value of Fecal Occult-Blood Testing for Colorectal Cancer, According to the Number of Positive Slides in the Annually and Biennially Screened Groups through 13 Years of Follow-up.); this was a five-fold greater cumulative 13-year incidence of colorectal cancer after the first screening among those who tested positive than among those who tested negative (Figure 2Figure 2
Cumulative Incidence of Colorectal Cancer in the Annually and Biennially Screened Groups as a Whole, According to the Time since Randomization and the Results of the First Fecal Occult-Blood Test.), and the test had a high sensitivity (92 percent) for detecting colorectal cancer. The apparent discrepancy between the 92 percent sensitivity and the proportion of cancers detected by screening in the annually screened group (50 percent, not 38 percent) can be explained by noncompliance (only 46 percent completed all the screenings) and the three-year hiatus (1983 through 1985) in screening.Ahlquist et al. also question the absence of a reduction in mortality in the biennially screened group in view of the high sensitivity of the test, but less of a reduction in mortality was to be expected, given the less frequent screening, lower sensitivity, smaller shifts in cancer stage, and poorer survival in this group. Additional follow-up is necessary.
We did not perform colonoscopy in patients with negative screening tests. We considered a result to be falsely negative if colorectal cancer was diagnosed within 12 months after a negative test result.
Ahlquist et al. indicate that their use of colonoscopy as a gold standard for the identification of false negative results in asymptomatic nonreferred patients greatly lowered sensitivity2. This is misleading, for only about 50 percent of their patients who had undergone resection (who would not normally undergo screening) and none of the patients' relatives with negative test results underwent colonoscopy. They conducted telephone interviews of a small sample of patients with negative test results to identify “missed” cases and estimated sensitivity in this group from one case diagnosed within one year after a negative screening result. We had a larger sample and more rigorous follow-up.
The difference in mortality from ischemic heart disease noted by Perlman is not statistically significant. The absence of an observed difference in overall mortality in such a small study, noted by Ahlquist et al. and Budenholzer, does not prove this was not a true effect.
We do not agree that the sensitivity of fecal occult-blood testing must be higher in the proximal colon than in the distal colon to augment flexible sigmoidoscopy. Sensitivity in the right and left colon is similar (Table 1Table 1
Cancers Detected by Screening and in the Interval between Tests in the Annually Screened Group through Study Year 13.).We believe that the efficacy of flexible sigmoidoscopy for screening must be demonstrated by randomized trials, because the problem of correction for self-selection bias in case-control studies of screening remains unresolved3.
Allison's argument that two-tiered screening could be more cost-effective is premature. The two-tiered test has not been shown to reduce mortality.
3 ReferencesJack S. Mandel, Ph.D.
Timothy R. Church, Ph.D.
Fred Ederer, M.A.
School of Public Health, University of Minnesota, Minneapolis, MN 554551
Mandel JS ,Bond JH ,Church TR , et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993;328:1365-1371
Full Text | Web of Science | Medline2
Ahlquist DA ,Wieand HS ,Moertel CG , et al. Accuracy of fecal occult blood screening for colorectal neoplasia: a prospective study using Hemoccult and HemoQuant tests. JAMA 1993;269:1262-1267
CrossRef | Web of Science | Medline3
Connor RJ ,Prorok PC ,Weed DL . The case-control design and the assessment of the efficacy of cancer screening. J Clin Epidemiol 1991;44:1215-1221
CrossRef | Web of Science | Medline
Author/Editor Response
We need to have a clear perspective on the current status of screening for colorectal cancer. During the past 20 years a considerable number of studies worldwide have rigorously tested the feasibility and effectiveness of screening for colorectal cancer by testing for blood in stool, including five controlled trials with an enrollment of 309,000 people1. Early worries that the apparent benefits of early-stage cancer detection and improved survival were entirely due to screening bias are no longer tenable, given recent reports of a reduction in mortality from colorectal cancer as a result of screening2,3. There is also recent evidence of the effectiveness of screening sigmoidoscopy,1 as well as data on colonoscopic polypectomy and follow-up after polyps have been detected as a result of screening4. These developments, along with advances in medical and surgical treatment, fulfill the criteria of the World Health Organization for screening. I believe, in contrast to Ahlquist and colleagues, that as a result of this progress, colorectal-cancer screening has come of age. However, as I suggested in my editorial, this is only one step in the process -- a very large step indeed -- from which point further maturation can proceed.
Challenges remain. There is general agreement that a better test that retains the high sensitivity of the rehydrated slide without loss of specificity is a desirable next step.
In the future, fecal occult-blood tests will probably advance from being guaiac-based tests to using genetic techniques. The ultimate goal is for genetic testing of peripheral blood to identify persons at risk for polyps and cancer. In addition, major efforts are needed to increase awareness of the risk and the methods available for prevention and treatment, to understand the reasons for noncompliance with preventive strategies, and to deal with the cost issues raised by Ahlquist and colleagues. When effective methods of controlling cancer are available, should we dismiss these strategies as being too costly, or should we ask how we can make these lifesaving benefits cost effective and therefore affordable to all? Reports have indicated that screening for colorectal cancer with fecal occult-blood tests and sigmoidoscopy in people over the age of 65 can be as cost effective as mammography5. I believe that screening has come of age. We now need to address the next set of important issues so that we can translate research progress into clinical benefit. I am certain that we all share this goal.
5 ReferencesSidney J. Winawer, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 100211
Winawer SJ . Colorectal cancer screening comes of age. N Engl J Med 1993;328:1416-1417
Full Text | Web of Science | Medline2
Mandel JS ,Bond JH ,Church TR , et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993;328:1365-1371
Full Text | Web of Science | Medline3
Winawer SJ, Flehinger BJ, Schottenfeld D, Miller DG. Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst (in press).
4
Winawer SJ ,Zauber AG ,O'Brien MJ , et al. Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. N Engl J Med 1993;328:901-906
Full Text | Web of Science | Medline5
Office of Technology Assessment. Costs and effectiveness of colorectal cancer screening in the elderly. Washington, D.C.: Government Printing Office, 1990. (OTA-BH-H-74.)
- Citing Articles (4)
Citing Articles
1
Amnon Sonnenberg. (2002) Cost-effectiveness in the prevention of colorectal cancer. Gastroenterology Clinics of North America 31:4, 1069-1091
CrossRef2
Richard L. Nelson. (1997) Screening for colorectal cancer. Journal of Surgical Oncology 64:3, 249-258
CrossRef3
Hiroshi Saito. (1996) Screening for Colorectal Cancer by Immunochemical Fecal Occult Blood Testing. Cancer Science 87:10, 1011-1024
CrossRef4
Hiroshi Saito, Yasushi Soma, Junichi Koeda, Toyohito Wada, Hitoshi Kawaguchi, Tomotaka Sobue, Tadashi Aisawa, Yutaka Yoshida. (1995) Reduction in risk of mortality from colorectal cancer by fecal occult blood screening with immunochemical hemagglutination test. A case-control study. International Journal of Cancer 61:4, 465-469
CrossRef
