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Colonoscopy versus barium enema: A reappraisal of the facts and issues
GASTROENTEROLOGY 1997;113:1048–1053
CORRESPONDENCE Readers are encouraged to write letters to the editor concerning articles that have been published in GASTROENTEROLOGY. Short, general comments are also considered, but use of the Correspondence section for publication of original data in preliminary form is not encouraged. Letters should be typewritten, double-spaced, and submitted in triplicate.
Colonoscopy Versus Barium Enema: A Reappraisal of the Facts and Issues Dear Sir: After reading the article ‘‘Relative Sensitivity of Colonoscopy and Barium Enema for Detection of Colorectal Cancer in Clinical Practice’’ by Rex et al.,1 I believe there are a number of issues that need to be clarified. These pertain to the information presented in the actual study as well as the ensuing discussion and interpretation of the data. Much emphasis is placed on the distribution of cancers by stage, particularly for early lesions. An unfortunate omission is the failure to define the specific staging classification used. It is unclear whether carcinoma in situ is included in the Dukes’ A cancers or whether lesions extending into the muscularis are in the Dukes’ A or B groups. Nevertheless, if one combines the A and B groups (both of which have an excellent prognosis), the relative frequencies were comparable (62% colonoscopy vs. 54% barium enema [BE]). Another piece of missing information is a discriminatory analysis of cancer stage by the type of BE performed. Although the overall sensitivity of doublecontrast BE (DCBE) and single-contrast BE was not significantly different, it is generally accepted that the former is superior for the smaller (and probably earlier) lesions. It is possible that an analysis of cancers detected by DCBE would have shown higher percentage of Dukes’ A lesions. The review of the literature on performance of BE is troublesome because much is made of the ‘‘bias’’ incorporated in previous studies, yet a critique of the references cited indicates a selection bias as well as imprecision in their interpretation. Six studies using methodology similar to the present one are described.2 – 7 The range of sensitivities is correctly stated as 71%–95%. What is not mentioned is that 4 of the 6 had sensitivities of ú90%.3 – 5,7 In addition, there are at least 3 similar studies not included that reported sensitivity of ú90%.8 – 10 Furthermore, in 5 of those 9 studies (including the 2 with sensitivities between 70% and 80%), 75%–95% of the missed cancers were perceptive errors and could be identified on retrospective review.2,3,6,8,9 Thus, a simple modification such as double readings could readily overcome many of the possible shortcomings. Indeed, the BE does not miss the lesions, but, rather, the neoplasms are overlooked. Three better designed prospective studies are described as reporting sensitivities of 65%–75% for cancer and large polyps in symptomatic patients.11 – 13 However, it is inaccurate to combine these studies under one general category. In 1 of them,11 sensitivity for cancer was 100% (21 of 21) and adequate information on large polyps was not presented. In the second study,12 only 66 patients were studied and only two cancers were present. Once again, the data on large polyps are limited. The third study13 involved an asymptomatic surveillance population. The polyp threshold evaluated was ú7 mm, rather than the usual 1 cm. Nevertheless, despite these limitations, sensitivity of BE was 71%, and only 1 of 3 of the missed polyps were ú1 cm. Rex et al. refer to 3 biased studies14 – 16 in which follow-up was limited to patients with positive radiographic findings. Actually, 1 of these studies14 did not follow such a design and is probably the best controlled study. From a consecutive group of patients who had previously undergone a DCBE, 190 patients were randomly selected for a subsequent colonoscopy. Sensitivity for cancer was 100% (6 of 6) and for polyps ú 1 cm 81% (17 of 21).
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Sensitivity for cancer in studies in which DCBE was performed after a positive fecal occult blood test (FOBT) is quoted as ranging from 50% to 75%.17 – 20 A careful review of the data from 1 of the studies reveals the actual sensitivity, when considering the entire colon, to be 80%.20 The only other study with more than 80 cases showed a sensitivity of 75%.17 Two other studies had a small number of cancer cases, and the results were 50% (n Å 8)18 and 75% (n Å 12).19 In the former study, one of the missed lesions was carcinoma in situ; in the latter study, 4 patients with cancer on DCBE refused colonoscopy but were not included in the sensitivity analysis. If these cases are incorporated, the sensitivity becomes 81%. Even if one accepts that colonoscopy is more sensitive than DCBE, the relevant considerations are: what is the magnitude of this difference, what is the clinical significance of this variance, and what is the incremental cost of this benefit? Many studies have shown that only approximately 5% of symptomatic patients undergoing colonoscopy will have cancer.21–23 Even the highest predictive indication, positive FOBT, only has a 10% yield. This figure is probably an overestimate because it is derived from randomized controlled trials with unhydrated samples. In mass population evaluations or studies with rehydrated samples, the figure is 2%–5%. When one considers that, with colonoscopy, the risk of perforation is 25 times that of DCBE24,25 and 3–4 times more expensive, this could be considered a pretty steep price for the 10% gain (over DCBE) in the detection of cancer. The clinical significance in terms of outcome of this additional 10% warrants discussion. Delay in diagnosis is not always associated with a worsened prognosis. The average delay in the present study was approximately 10 months. Given the typical slow progression of this neoplasm, a number of these cases may not have advanced from a curable to incurable status. On the other hand, some may have been incurable when originally overlooked. It would have been interesting to know the ultimate Dukes’ stage of the cancers missed by BE in the present study. Although it is impossible to determine whether the C and D lesions were less advanced at presentation, lesions subsequently detected at a favorable stage were far less likely to have suffered from the initial failure. I would also contend the generalized recommendation that patients with persistent symptoms require a colonoscopy after a negative BE. Given that there is a low probability of colon cancer and that the sensitivity of the radiographic procedure is relatively high, DCBE has a high negative predictive value. Because many patients have persistent symptoms (even after colonoscopy) due to the high prevalence of irritable bowel disease, this would be an extremely unproductive policy. In summary, the interpretation and clinical application of the study by Rex et al. should not be based on a comparison of sensitivity data. The information needs to be integrated into a more complex decision process in which many factors are considered in an environment where the prioritization of fiscal concerns has increased. SETH N. GLICK, M.D.
Department of Radiology Medical College of Pennsylvania and Hahnemann University Philadelphia, Pennsylvania 1. Rex DK, Rahmani EY, Haseman JH, Lemmel GT, Kaster S, Buckley JS. Relative sensitivity of colonoscopy and barium enema for
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detection of colorectal cancer in clinical practice. Gastroenterology 1997;112:17–23. Brady AP, Stevenson GW, Stevenson I. Colorectal cancer overlooked at barium enema examination and colonoscopy: a continuing perception problem. Radiology 1994;192:373–378. Bolin S, Franzen L, Nilsson E, Sjo¨dahl R. Carcinoma of the colon and rectum. Tumors missed by radiologic examination in 61 patients. Cancer 1988;61:1999–2008. Evers K, Laufer I, Gordon RL, Kressel HY, Herlinger H, Gohel VK. Double-contrast enema examination for detection of rectal carcinoma. Radiology 1981;140:635–639. Beggs J, Thomas BM. Diagnosis of carcinoma of the colon by barium enema. Clin Radiol 1983;140:1143–1149. Anderson N, Cook HB, Coates R. Colonoscopically detected colorectal cancer missed on barium enema. Gastrointest Radiol 1991;16:123–127. Johnson CD, Carlson HC, Taylor WF, Weiland LP. Barium enemas of carcinoma of the colon: sensitivity of double and single contrast studies. Am J Radiol 1983;140:1143–1149. Fork FT. Radiographic findings in overlooked colon carcinomas. A retrospective analysis. Acta Radiol 1988;29:331–336. Kelvin FM, Gardiner R, Vas W, Stevenson GW. Colorectal cancers missed on double contrast barium enema study: a problem in perception. AJR 1981;131:307–313. Bloomfield JA. Reliability of barium enema in detecting colonic neoplasia. Med J Aust 1981;1:631–633. Brewster NT, Grieve DC. Double-contrast barium enema and flexible sigmoidoscopy for routine colonic investigation. Br J Surg 1994;81:445–447. Durdey P, Weston PM, Williams NS. Colonoscopy or barium enema as initial investigation of colonic disease. Lancet 1987;2: 549–551. Williams CB, Macrae FA, Bartram CI. A prospective study of diagnostic methods in adenoma follow-up. Endoscopy 1982;14:74– 78. Steine S, Strodahl A, Lunde O, Loken K, Laerum E. Double-contrast barium enema versus colonoscopy in the diagnosis of neoplastic disorders: aspects of decision making in the general practice. Fam Pract 1993;10:288–291. Ott DJ, Scharling ES, Chen YM, Wu WC, Gelfand DW. Barium enema examination: sensitivity in detecting colonic polyps and carcinomas. South Med J 1989;82:197–200. de Roos, Hermans J, Shaw PC, Kroon H. Colon polyps and carcinomas: prospective comparision of a single and double-contrast examination in the same patients. Radiology 1989;154:11–13. Winawer SJ, Flechinger BJ, Schottenfeld D, Miller DG. Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 1991;85:1311–1318. Sontag SJ, Druczak C, Aranha GV, Chejfee G, Frederick W, Greenlee HB. Fecal occult blood testing for colorectal cancer in Veteran’s Administration Hospital. Am J Surg 1983;145:89–93. Eliott MS, Levenstein JH, Wright JP. Faecal occult blood testing in the detection of colorectal cancer. Br J Surg 1984;71:785– 786. Kewenter J, Brevinge H, Engara˚s B, Haglind E. The yield of flexible sigmoidoscopy and double-contrast barium enema in the diagnosis of neoplasms in the large bowel in patients with a positive hemoccult: Endoscopy 1995;27:159–163. Rex DK. Colonoscopy: a review of its yield for cancer and adenomas by indication. Am J Gastroenterol 1995;90:353–365. Chak A, Post AB, Cooper GS. Clinical variables associated with colorectal cancer on colonoscopy: a prediction model. Am J Gastroenterol 1996;91:2483–2488. Neugut AI, Garbowski GC, Waye JD, Forde KA, Treat MR, Tsai JL, Lee WC. Diagnostic yield of colorectal neoplasia with colonoscopy for abdominal pain, change in bowel habits and rectal bleeding. Am J Gastroenterol 1993;88:1179–1183.
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24. Blakeborough A, Sheridan MB, Chapman AH. Complications of barium enema examination: a survey of UK consultant radiologists 1992 to 1994. Clin Radiol (in press). 25. Waye JD, Kahn O, Auerbach ME. Complications of colonoscopy and flexible sigmoidoscopy. Gastrointest Endosc Clin North Am 1996;6:343–377.
Reply. Every patient in the study had cancer, defined as malignant cells below the muscularis mucosa. Patients with severe dysplasia (carcinoma-in-situ) were excluded. For tumors invading the muscularis propria, we used the local pathologist’s classification, which was primarily the Astler–Coller modification. The distribution of classes in cases detected by DCBE was A, 45 (11.3%); B, 181 (45.4%); C, 113 (28.3%); and D, 60 (15.0%). Contrary to Dr. Glick’s assessment, there is a clear reduction in survival with A compared with B cancers regardless of classification. As discussed in the paper, the data suggest that BE (including DCBE) missed a significant number of Dukes’ A cancers that did not present clinically within the 3-year period evaluated in the study. Dr. Glick disagrees with our interpretation of BE sensitivity reported in previous literature. I was aware of many studies of BE sensitivity, many of which I considered flawed and/or from centers of extreme excellence. Recognizing that radiologists and endoscopists have never agreed on the interpretation of BE studies or which studies deserve emphasis, I chose to base our comments on the review by the Office of Technology Assessment.1 Based on their review of the literature, this independent panel estimated the sensitivity of DCBE for cancer and large polyps in a screening population at 70%. That they were generous to BE in their estimate is supported by the National Polyp Study finding that blinded, prospective DCBE by experts missed half of polyps ¢1 cm in size (Ann Zauber, personal communication presented orally at Digestive Disease Week 1994) in a surveillance population with a disease spectrum similar to that of a screening population, and also by the Mayo Clinic reporting last year of the first cross-sectional prevalence study of screening BE (performed using single-contrast BE). In 738 asymptomatic average-risk persons, polyps were identified in 32 persons (4%), adenomas in 16 (2%), and cancer in none.2 This result is remarkable when recalling that colonoscopy has identified adenomas in 24%–41% and cancer in 1% of screenees in similar populations.3 – 6 Our discussion regarding overall BE sensitivity reflects the ranges of sensitivity, assessment of bias in specific studies, and conclusions of this independent panel.1 In the only other study of relative sensitivity of BE and colonoscopy for cancer with design like ours, the calculated sensitivity of BE in symptomatic patients was 76%.7 With regard to asymptomatic patients with positive FOBT, it is true that in the largest study the total reported sensitivity of BE for cancer in the colon was 80%. However, DCBE missed 25% of cancers and 26% of polyps ¢1 cm in the rectosigmoid, the only portion of the colon evaluated endoscopically in all patients.8 Thus, as we stated in the manuscript, the 6 studies of BE (5 of DCBE) evaluating all patients with positive FOBT by both BE and endoscopy show a range of BE sensitivity for cancer of 50%–75%. My point in reviewing this literature was to show that our calculated sensitivity of BE in clinical practice (83%) was well within the expected range of sensitivity. Dr. Glick’s selection and interpretation of studies does not diminish that assertion. It is no consolation to patients if radiologists miss their cancers because of perceptive vs. technical errors. Until radiologists enforce the practice of double reading (how will they do this in small hospitals with one radiologist?), this distinction is irrelevant. Dr. Glick does not like our recommendation to perform colonoscopy in patients with ‘‘persistent’’ symptoms. However, in 4 studies
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GASTROENTEROLOGY Vol. 113, No. 3
of persistent rectal bleeding after negative BE, colonoscopy detected cancer in 6%–10% of patients.9 – 12 In the only study of colonoscopy for persistent nonbleeding symptoms, cancer was detected in 6%.13 Clinicians have to be trusted to differentiate significant persistent symptoms from irritable bowel syndrome, which in young people often does not require any colon imaging for diagnosis. Based on the reported sensitivities of BE for cancer in many of the hospitals we studied and the above cited reports, we continue to recommend colonoscopy after negative BE when symptoms compatible with cancer persist. The current perforation rate of colonoscopy is unknown, but is surely less than the 1:500 determined in older studies. In the University of Minnesota FOBT trial, there were only 4 perforations in more than 12,000 colonoscopies.14 In a prospective study by Waye et al., there were no diagnostic perforations in 2097 colonoscopies.15 In skilled hands, the complications of colonoscopy are now largely related to polypectomy. To the extent that BE identifies polyps, it leads to colonoscopy and polypectomy. Thus, to contend that the strategy of initial BE results in ‘‘25 times’’ less perforation is misleading. The growth rates of colorectal tumors are not well understood. We do not have survival data on our patients, but certainly in some the failure to diagnose did not influence the ultimate outcome. However, there is no basis to contend that a delay of 10.9 months or longer does not produce some reduction in a patient’s chance of survival. From a patient satisfaction perspective, patients with colorectal cancer who experience diagnostic delays of this length are often not convinced that the delay is insignificant. Clinicians responsible for delays of this length can find themselves trying to convince juries that the delay is not significant. Dr. Glick’s comments regarding negative predictive value are misplaced. High negative predictive value is an expected consequence in a low-prevalence disease. However, in this situation, relatively high negative predictive value can still be associated with important deficiencies in sensitivity. Colorectal cancer is a serious disease, and its early and reliable diagnosis is an issue that informed patients and the clinicians charged with their care take very seriously. Relatively high negative predictive value does not justify poor sensitivity in a disease causing 55,000 deaths per year in the United States alone. The actual gain in sensitivity of colonoscopy vs. BE in our study was not 10% but 12% for DCBE vs. colonoscopy by gastroenterologists, 15% for single-contrast vs. colonoscopy by gastroenterologists, and up to 31% in individual hospitals. Would an informed patient choose to undergo full bowel preparation and then have a test with a 10%–30% chance of missing cancer if they have it, when an alternative safe and comfortable test with a 5% or much lower chance of missing cancer is available? Our recommendation, as in our paper, is to review the relative sensitivity and other quality aspects of the two tests at a local level. Then informed physicians and patients can decide for themselves. DOUGLAS K. REX, M.D.
Division of Gastroenterology/Hepatology Department of Medicine Indiana University School of Medicine Indianapolis, Indiana
1. Office of Technology Assessment: Cost-effectiveness of colorectal cancer screening in average-risk adults: background paper for the 104th Congress. 2. Johnson DC, Ilstrup DM, Fish NM, et al. Barium enema: detection
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of colonic lesions in a community population. AJR 1996;167: 49–43. Johnson DA, Gurney MS, Volpe RJ, et al. A prospective study of the prevalence of colonic neoplasms in asymptomatic patients with age-related risk. Am J Gastroenterol 1990;85:969–974. Foutch PC, Mai H, Pardy K, et al. Flexible sigmoidoscopy may be ineffective for secondary prevention of colorectal cancer in asymptomatic, average-risk men. Dig Dis Sci 1991;36:924– 928. Lieberman DA, Smith FW. Screening for colon malignancy with colonoscopy. Am J Gastroenterol 1991;86:946–951. Rex DK, Lehman GA, Ulbright TM, et al. Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family history. Am J Gastroenterol 1993;88:825–831. Brady AP, Stevenson GW, Stevenson I. Colorectal cancer overlooked at barium enema examination and colonoscopy: a continuing perceptual problem. Radiology 1994;192:373–378. Kewenter J, Breginge H, Engara¨s B, et al. The value of flexible sigmoidoscopy and double-contrast barium enema in the diagnosis of neoplasms in the rectum and colon in subjects with a positive hemoccult: result of 1831 rectosigmoidoscopies and double-contrast barium enemas. Endoscopy 1995;27:159– 163. Brand EJ, Sullivan BH, Sivak MV, et al. Colonoscopy in the diagnosis of unexplained rectal bleeding. Ann Surg 1980;192:111– 113. Guillem JG, Forde KA, Treat MR, et al. The impact of colonoscopy on the early detection of colonic neoplasms in patients with rectal bleeding. Ann Surg 1987;206:606–611. Swarbrick ET, Fevre DI, Hunt RH, et al. Colonoscopy for unexplained rectal bleeding. Br Med J 1978;1:1685–1687. Teague RH, Manning AP, Thornton RJ, et al. Colonoscopy for investigation of unexplained rectal bleeding. Lancet 1978:1350– 1352. Neugut AI, Garbowski GC, Waye JD, et al. Diagnostic yield of colorectal neoplasia with the use of colonoscopy for abdominal pain, change in bowel habits, and rectal bleeding. Am J Gastroenterol 1993;88:1179–1184. 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. Waye JD, Lewis BS, Yessayan S. Colonoscopy: a prospective report of complications. J Clin Gastroenterol 1992;15:347–351.
Bystander T-Cell Clones in Chronic Hepatitis C Dear Sir: Bertoletti et al. addressed the issue of cytokine secretion of bystander T-cell clones, derived from liver tissue, in chronic hepatitis B and chronic hepatitis C.1 They reported that T helper (Th) 1 cells prevailed in chronic hepatitis C, whereas Th0 and Th2 clones were predominant in chronic hepatitis B. A total of 291 clones were derived from patients with chronic hepatitis B, and 260 clones were from patients with chronic hepatitis C. Because these clones did not react specifically to hepatitis B or hepatitis C viral antigens, and the majority was reported to express several activation markers (major histocompatability complex class II and CD69), it would be of considerable interest to know to which extent these T-cell clones also expressed the CD30 antigen, an activation marker of the tumor necrosis factor/ nerve growth factor receptor superfamily.2 Reiser et al. failed to find significant amounts of CD30-positive T lymphocytes in liver specimens of patients with chronic hepatitis C.3 However, we noted in a recent study that, in patients with chronic hepatitis C, peripheral CD30-positive lymphocytes are readily expanded in vitro after stimu-
WBS-Gastro
CORRESPONDENCE Readers are encouraged to write letters to the editor concerning articles that have been published in GASTROENTEROLOGY. Short, general comments are also considered, but use of the Correspondence section for publication of original data in preliminary form is not encouraged. Letters should be typewritten, double-spaced, and submitted in triplicate.
Colonoscopy Versus Barium Enema: A Reappraisal of the Facts and Issues Dear Sir: After reading the article ‘‘Relative Sensitivity of Colonoscopy and Barium Enema for Detection of Colorectal Cancer in Clinical Practice’’ by Rex et al.,1 I believe there are a number of issues that need to be clarified. These pertain to the information presented in the actual study as well as the ensuing discussion and interpretation of the data. Much emphasis is placed on the distribution of cancers by stage, particularly for early lesions. An unfortunate omission is the failure to define the specific staging classification used. It is unclear whether carcinoma in situ is included in the Dukes’ A cancers or whether lesions extending into the muscularis are in the Dukes’ A or B groups. Nevertheless, if one combines the A and B groups (both of which have an excellent prognosis), the relative frequencies were comparable (62% colonoscopy vs. 54% barium enema [BE]). Another piece of missing information is a discriminatory analysis of cancer stage by the type of BE performed. Although the overall sensitivity of doublecontrast BE (DCBE) and single-contrast BE was not significantly different, it is generally accepted that the former is superior for the smaller (and probably earlier) lesions. It is possible that an analysis of cancers detected by DCBE would have shown higher percentage of Dukes’ A lesions. The review of the literature on performance of BE is troublesome because much is made of the ‘‘bias’’ incorporated in previous studies, yet a critique of the references cited indicates a selection bias as well as imprecision in their interpretation. Six studies using methodology similar to the present one are described.2 – 7 The range of sensitivities is correctly stated as 71%–95%. What is not mentioned is that 4 of the 6 had sensitivities of ú90%.3 – 5,7 In addition, there are at least 3 similar studies not included that reported sensitivity of ú90%.8 – 10 Furthermore, in 5 of those 9 studies (including the 2 with sensitivities between 70% and 80%), 75%–95% of the missed cancers were perceptive errors and could be identified on retrospective review.2,3,6,8,9 Thus, a simple modification such as double readings could readily overcome many of the possible shortcomings. Indeed, the BE does not miss the lesions, but, rather, the neoplasms are overlooked. Three better designed prospective studies are described as reporting sensitivities of 65%–75% for cancer and large polyps in symptomatic patients.11 – 13 However, it is inaccurate to combine these studies under one general category. In 1 of them,11 sensitivity for cancer was 100% (21 of 21) and adequate information on large polyps was not presented. In the second study,12 only 66 patients were studied and only two cancers were present. Once again, the data on large polyps are limited. The third study13 involved an asymptomatic surveillance population. The polyp threshold evaluated was ú7 mm, rather than the usual 1 cm. Nevertheless, despite these limitations, sensitivity of BE was 71%, and only 1 of 3 of the missed polyps were ú1 cm. Rex et al. refer to 3 biased studies14 – 16 in which follow-up was limited to patients with positive radiographic findings. Actually, 1 of these studies14 did not follow such a design and is probably the best controlled study. From a consecutive group of patients who had previously undergone a DCBE, 190 patients were randomly selected for a subsequent colonoscopy. Sensitivity for cancer was 100% (6 of 6) and for polyps ú 1 cm 81% (17 of 21).
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Sensitivity for cancer in studies in which DCBE was performed after a positive fecal occult blood test (FOBT) is quoted as ranging from 50% to 75%.17 – 20 A careful review of the data from 1 of the studies reveals the actual sensitivity, when considering the entire colon, to be 80%.20 The only other study with more than 80 cases showed a sensitivity of 75%.17 Two other studies had a small number of cancer cases, and the results were 50% (n Å 8)18 and 75% (n Å 12).19 In the former study, one of the missed lesions was carcinoma in situ; in the latter study, 4 patients with cancer on DCBE refused colonoscopy but were not included in the sensitivity analysis. If these cases are incorporated, the sensitivity becomes 81%. Even if one accepts that colonoscopy is more sensitive than DCBE, the relevant considerations are: what is the magnitude of this difference, what is the clinical significance of this variance, and what is the incremental cost of this benefit? Many studies have shown that only approximately 5% of symptomatic patients undergoing colonoscopy will have cancer.21–23 Even the highest predictive indication, positive FOBT, only has a 10% yield. This figure is probably an overestimate because it is derived from randomized controlled trials with unhydrated samples. In mass population evaluations or studies with rehydrated samples, the figure is 2%–5%. When one considers that, with colonoscopy, the risk of perforation is 25 times that of DCBE24,25 and 3–4 times more expensive, this could be considered a pretty steep price for the 10% gain (over DCBE) in the detection of cancer. The clinical significance in terms of outcome of this additional 10% warrants discussion. Delay in diagnosis is not always associated with a worsened prognosis. The average delay in the present study was approximately 10 months. Given the typical slow progression of this neoplasm, a number of these cases may not have advanced from a curable to incurable status. On the other hand, some may have been incurable when originally overlooked. It would have been interesting to know the ultimate Dukes’ stage of the cancers missed by BE in the present study. Although it is impossible to determine whether the C and D lesions were less advanced at presentation, lesions subsequently detected at a favorable stage were far less likely to have suffered from the initial failure. I would also contend the generalized recommendation that patients with persistent symptoms require a colonoscopy after a negative BE. Given that there is a low probability of colon cancer and that the sensitivity of the radiographic procedure is relatively high, DCBE has a high negative predictive value. Because many patients have persistent symptoms (even after colonoscopy) due to the high prevalence of irritable bowel disease, this would be an extremely unproductive policy. In summary, the interpretation and clinical application of the study by Rex et al. should not be based on a comparison of sensitivity data. The information needs to be integrated into a more complex decision process in which many factors are considered in an environment where the prioritization of fiscal concerns has increased. SETH N. GLICK, M.D.
Department of Radiology Medical College of Pennsylvania and Hahnemann University Philadelphia, Pennsylvania 1. Rex DK, Rahmani EY, Haseman JH, Lemmel GT, Kaster S, Buckley JS. Relative sensitivity of colonoscopy and barium enema for
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detection of colorectal cancer in clinical practice. Gastroenterology 1997;112:17–23. Brady AP, Stevenson GW, Stevenson I. Colorectal cancer overlooked at barium enema examination and colonoscopy: a continuing perception problem. Radiology 1994;192:373–378. Bolin S, Franzen L, Nilsson E, Sjo¨dahl R. Carcinoma of the colon and rectum. Tumors missed by radiologic examination in 61 patients. Cancer 1988;61:1999–2008. Evers K, Laufer I, Gordon RL, Kressel HY, Herlinger H, Gohel VK. Double-contrast enema examination for detection of rectal carcinoma. Radiology 1981;140:635–639. Beggs J, Thomas BM. Diagnosis of carcinoma of the colon by barium enema. Clin Radiol 1983;140:1143–1149. Anderson N, Cook HB, Coates R. Colonoscopically detected colorectal cancer missed on barium enema. Gastrointest Radiol 1991;16:123–127. Johnson CD, Carlson HC, Taylor WF, Weiland LP. Barium enemas of carcinoma of the colon: sensitivity of double and single contrast studies. Am J Radiol 1983;140:1143–1149. Fork FT. Radiographic findings in overlooked colon carcinomas. A retrospective analysis. Acta Radiol 1988;29:331–336. Kelvin FM, Gardiner R, Vas W, Stevenson GW. Colorectal cancers missed on double contrast barium enema study: a problem in perception. AJR 1981;131:307–313. Bloomfield JA. Reliability of barium enema in detecting colonic neoplasia. Med J Aust 1981;1:631–633. Brewster NT, Grieve DC. Double-contrast barium enema and flexible sigmoidoscopy for routine colonic investigation. Br J Surg 1994;81:445–447. Durdey P, Weston PM, Williams NS. Colonoscopy or barium enema as initial investigation of colonic disease. Lancet 1987;2: 549–551. Williams CB, Macrae FA, Bartram CI. A prospective study of diagnostic methods in adenoma follow-up. Endoscopy 1982;14:74– 78. Steine S, Strodahl A, Lunde O, Loken K, Laerum E. Double-contrast barium enema versus colonoscopy in the diagnosis of neoplastic disorders: aspects of decision making in the general practice. Fam Pract 1993;10:288–291. Ott DJ, Scharling ES, Chen YM, Wu WC, Gelfand DW. Barium enema examination: sensitivity in detecting colonic polyps and carcinomas. South Med J 1989;82:197–200. de Roos, Hermans J, Shaw PC, Kroon H. Colon polyps and carcinomas: prospective comparision of a single and double-contrast examination in the same patients. Radiology 1989;154:11–13. Winawer SJ, Flechinger BJ, Schottenfeld D, Miller DG. Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 1991;85:1311–1318. Sontag SJ, Druczak C, Aranha GV, Chejfee G, Frederick W, Greenlee HB. Fecal occult blood testing for colorectal cancer in Veteran’s Administration Hospital. Am J Surg 1983;145:89–93. Eliott MS, Levenstein JH, Wright JP. Faecal occult blood testing in the detection of colorectal cancer. Br J Surg 1984;71:785– 786. Kewenter J, Brevinge H, Engara˚s B, Haglind E. The yield of flexible sigmoidoscopy and double-contrast barium enema in the diagnosis of neoplasms in the large bowel in patients with a positive hemoccult: Endoscopy 1995;27:159–163. Rex DK. Colonoscopy: a review of its yield for cancer and adenomas by indication. Am J Gastroenterol 1995;90:353–365. Chak A, Post AB, Cooper GS. Clinical variables associated with colorectal cancer on colonoscopy: a prediction model. Am J Gastroenterol 1996;91:2483–2488. Neugut AI, Garbowski GC, Waye JD, Forde KA, Treat MR, Tsai JL, Lee WC. Diagnostic yield of colorectal neoplasia with colonoscopy for abdominal pain, change in bowel habits and rectal bleeding. Am J Gastroenterol 1993;88:1179–1183.
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24. Blakeborough A, Sheridan MB, Chapman AH. Complications of barium enema examination: a survey of UK consultant radiologists 1992 to 1994. Clin Radiol (in press). 25. Waye JD, Kahn O, Auerbach ME. Complications of colonoscopy and flexible sigmoidoscopy. Gastrointest Endosc Clin North Am 1996;6:343–377.
Reply. Every patient in the study had cancer, defined as malignant cells below the muscularis mucosa. Patients with severe dysplasia (carcinoma-in-situ) were excluded. For tumors invading the muscularis propria, we used the local pathologist’s classification, which was primarily the Astler–Coller modification. The distribution of classes in cases detected by DCBE was A, 45 (11.3%); B, 181 (45.4%); C, 113 (28.3%); and D, 60 (15.0%). Contrary to Dr. Glick’s assessment, there is a clear reduction in survival with A compared with B cancers regardless of classification. As discussed in the paper, the data suggest that BE (including DCBE) missed a significant number of Dukes’ A cancers that did not present clinically within the 3-year period evaluated in the study. Dr. Glick disagrees with our interpretation of BE sensitivity reported in previous literature. I was aware of many studies of BE sensitivity, many of which I considered flawed and/or from centers of extreme excellence. Recognizing that radiologists and endoscopists have never agreed on the interpretation of BE studies or which studies deserve emphasis, I chose to base our comments on the review by the Office of Technology Assessment.1 Based on their review of the literature, this independent panel estimated the sensitivity of DCBE for cancer and large polyps in a screening population at 70%. That they were generous to BE in their estimate is supported by the National Polyp Study finding that blinded, prospective DCBE by experts missed half of polyps ¢1 cm in size (Ann Zauber, personal communication presented orally at Digestive Disease Week 1994) in a surveillance population with a disease spectrum similar to that of a screening population, and also by the Mayo Clinic reporting last year of the first cross-sectional prevalence study of screening BE (performed using single-contrast BE). In 738 asymptomatic average-risk persons, polyps were identified in 32 persons (4%), adenomas in 16 (2%), and cancer in none.2 This result is remarkable when recalling that colonoscopy has identified adenomas in 24%–41% and cancer in 1% of screenees in similar populations.3 – 6 Our discussion regarding overall BE sensitivity reflects the ranges of sensitivity, assessment of bias in specific studies, and conclusions of this independent panel.1 In the only other study of relative sensitivity of BE and colonoscopy for cancer with design like ours, the calculated sensitivity of BE in symptomatic patients was 76%.7 With regard to asymptomatic patients with positive FOBT, it is true that in the largest study the total reported sensitivity of BE for cancer in the colon was 80%. However, DCBE missed 25% of cancers and 26% of polyps ¢1 cm in the rectosigmoid, the only portion of the colon evaluated endoscopically in all patients.8 Thus, as we stated in the manuscript, the 6 studies of BE (5 of DCBE) evaluating all patients with positive FOBT by both BE and endoscopy show a range of BE sensitivity for cancer of 50%–75%. My point in reviewing this literature was to show that our calculated sensitivity of BE in clinical practice (83%) was well within the expected range of sensitivity. Dr. Glick’s selection and interpretation of studies does not diminish that assertion. It is no consolation to patients if radiologists miss their cancers because of perceptive vs. technical errors. Until radiologists enforce the practice of double reading (how will they do this in small hospitals with one radiologist?), this distinction is irrelevant. Dr. Glick does not like our recommendation to perform colonoscopy in patients with ‘‘persistent’’ symptoms. However, in 4 studies
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of persistent rectal bleeding after negative BE, colonoscopy detected cancer in 6%–10% of patients.9 – 12 In the only study of colonoscopy for persistent nonbleeding symptoms, cancer was detected in 6%.13 Clinicians have to be trusted to differentiate significant persistent symptoms from irritable bowel syndrome, which in young people often does not require any colon imaging for diagnosis. Based on the reported sensitivities of BE for cancer in many of the hospitals we studied and the above cited reports, we continue to recommend colonoscopy after negative BE when symptoms compatible with cancer persist. The current perforation rate of colonoscopy is unknown, but is surely less than the 1:500 determined in older studies. In the University of Minnesota FOBT trial, there were only 4 perforations in more than 12,000 colonoscopies.14 In a prospective study by Waye et al., there were no diagnostic perforations in 2097 colonoscopies.15 In skilled hands, the complications of colonoscopy are now largely related to polypectomy. To the extent that BE identifies polyps, it leads to colonoscopy and polypectomy. Thus, to contend that the strategy of initial BE results in ‘‘25 times’’ less perforation is misleading. The growth rates of colorectal tumors are not well understood. We do not have survival data on our patients, but certainly in some the failure to diagnose did not influence the ultimate outcome. However, there is no basis to contend that a delay of 10.9 months or longer does not produce some reduction in a patient’s chance of survival. From a patient satisfaction perspective, patients with colorectal cancer who experience diagnostic delays of this length are often not convinced that the delay is insignificant. Clinicians responsible for delays of this length can find themselves trying to convince juries that the delay is not significant. Dr. Glick’s comments regarding negative predictive value are misplaced. High negative predictive value is an expected consequence in a low-prevalence disease. However, in this situation, relatively high negative predictive value can still be associated with important deficiencies in sensitivity. Colorectal cancer is a serious disease, and its early and reliable diagnosis is an issue that informed patients and the clinicians charged with their care take very seriously. Relatively high negative predictive value does not justify poor sensitivity in a disease causing 55,000 deaths per year in the United States alone. The actual gain in sensitivity of colonoscopy vs. BE in our study was not 10% but 12% for DCBE vs. colonoscopy by gastroenterologists, 15% for single-contrast vs. colonoscopy by gastroenterologists, and up to 31% in individual hospitals. Would an informed patient choose to undergo full bowel preparation and then have a test with a 10%–30% chance of missing cancer if they have it, when an alternative safe and comfortable test with a 5% or much lower chance of missing cancer is available? Our recommendation, as in our paper, is to review the relative sensitivity and other quality aspects of the two tests at a local level. Then informed physicians and patients can decide for themselves. DOUGLAS K. REX, M.D.
Division of Gastroenterology/Hepatology Department of Medicine Indiana University School of Medicine Indianapolis, Indiana
1. Office of Technology Assessment: Cost-effectiveness of colorectal cancer screening in average-risk adults: background paper for the 104th Congress. 2. Johnson DC, Ilstrup DM, Fish NM, et al. Barium enema: detection
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of colonic lesions in a community population. AJR 1996;167: 49–43. Johnson DA, Gurney MS, Volpe RJ, et al. A prospective study of the prevalence of colonic neoplasms in asymptomatic patients with age-related risk. Am J Gastroenterol 1990;85:969–974. Foutch PC, Mai H, Pardy K, et al. Flexible sigmoidoscopy may be ineffective for secondary prevention of colorectal cancer in asymptomatic, average-risk men. Dig Dis Sci 1991;36:924– 928. Lieberman DA, Smith FW. Screening for colon malignancy with colonoscopy. Am J Gastroenterol 1991;86:946–951. Rex DK, Lehman GA, Ulbright TM, et al. Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family history. Am J Gastroenterol 1993;88:825–831. Brady AP, Stevenson GW, Stevenson I. Colorectal cancer overlooked at barium enema examination and colonoscopy: a continuing perceptual problem. Radiology 1994;192:373–378. Kewenter J, Breginge H, Engara¨s B, et al. The value of flexible sigmoidoscopy and double-contrast barium enema in the diagnosis of neoplasms in the rectum and colon in subjects with a positive hemoccult: result of 1831 rectosigmoidoscopies and double-contrast barium enemas. Endoscopy 1995;27:159– 163. Brand EJ, Sullivan BH, Sivak MV, et al. Colonoscopy in the diagnosis of unexplained rectal bleeding. Ann Surg 1980;192:111– 113. Guillem JG, Forde KA, Treat MR, et al. The impact of colonoscopy on the early detection of colonic neoplasms in patients with rectal bleeding. Ann Surg 1987;206:606–611. Swarbrick ET, Fevre DI, Hunt RH, et al. Colonoscopy for unexplained rectal bleeding. Br Med J 1978;1:1685–1687. Teague RH, Manning AP, Thornton RJ, et al. Colonoscopy for investigation of unexplained rectal bleeding. Lancet 1978:1350– 1352. Neugut AI, Garbowski GC, Waye JD, et al. Diagnostic yield of colorectal neoplasia with the use of colonoscopy for abdominal pain, change in bowel habits, and rectal bleeding. Am J Gastroenterol 1993;88:1179–1184. 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. Waye JD, Lewis BS, Yessayan S. Colonoscopy: a prospective report of complications. J Clin Gastroenterol 1992;15:347–351.
Bystander T-Cell Clones in Chronic Hepatitis C Dear Sir: Bertoletti et al. addressed the issue of cytokine secretion of bystander T-cell clones, derived from liver tissue, in chronic hepatitis B and chronic hepatitis C.1 They reported that T helper (Th) 1 cells prevailed in chronic hepatitis C, whereas Th0 and Th2 clones were predominant in chronic hepatitis B. A total of 291 clones were derived from patients with chronic hepatitis B, and 260 clones were from patients with chronic hepatitis C. Because these clones did not react specifically to hepatitis B or hepatitis C viral antigens, and the majority was reported to express several activation markers (major histocompatability complex class II and CD69), it would be of considerable interest to know to which extent these T-cell clones also expressed the CD30 antigen, an activation marker of the tumor necrosis factor/ nerve growth factor receptor superfamily.2 Reiser et al. failed to find significant amounts of CD30-positive T lymphocytes in liver specimens of patients with chronic hepatitis C.3 However, we noted in a recent study that, in patients with chronic hepatitis C, peripheral CD30-positive lymphocytes are readily expanded in vitro after stimu-
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