- Email: [email protected]
The role of colonoscopy for screening of colorectal cancer
The Role of Colonoscopy for Screening of Colorectal Cancer Nuzhat A. Ahmad and "timothy C. Hoops OLORECTAL C A N C E R (CRC) is the third most commonly diagnosed cancer in the United States, with approximately 135,000 new cases expected each year, and the second most common cause of death from cancer, with about 55,000 deaths annually. ~ There is evidence that detection of CRC at an early stage by screening can improve survival (secondary prevention)? -4 There is a significant difference in survival between those diagnosed at an early stage compared with those diagnosed at a later stage as demonstrated by estimated 5-year survival rates of 90% for those with localized disease, 60% for those with regional disease, and 5% for those with distant metastases. 5 Screening identifies individuals with CRC or adenomatous polyps from among those without signs and symptoms of the disease. Screening is effective in the primary prevention of cancer through removal of adenomatous polyps that are precursors of most c a n c e r s . 6'7
C
SCREENING FOR COLORECTAL CANCER About 75% of CRCs occur in individuals at average risk, that is with no known risk factor other than age. Screening is advocated for those aged 50 years and older because the incidence of CRC begins to rise significantly between 40 and 50 years of age. 8 The recommended options for CRC screening in asymptomatic individuals at average risk are shown in Figure 1. Although the various recommendations differ in their specifics, the essentials are to recommend periodic fecal occult blood testing or sigmoidoscopy, or both in those age 50 years and older. Barium enema can be an additional screening modality. The role of colonoscopy as a screening test for CRC is rapidly evolving. The role of fecal occult blood testing (FOBT) and flexible sigmoidoscopy is discussed briefly before the discussion of the role of colonoscopy in the screening of CRC.
From Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia, PA. Address reprint requests to Timothy C. Hoops, MD, Presbyterian Medical Center, 218 Wright Saunders, 39th and Market Sts, Philadelphia, PA 19104. Copyright 9 2000 by W.B. Saunders Company 0037 198X/00/3504-0010510.00/0 doi :10.1053/sroe.2000.17758 404
FECAL OCCULT BLOOD TESTING FOBT is performed by using standard hemoccult cards that detect the peroxidase activity of hemoglobin from erythrocytes. The rationale for this examination is based on the observation that two thirds of all CRCs will bleed intermittently in the course of a week. FOBT can also detect polyps, as they may bleed, particularly if large, although this application is controversial as is discussed later. The best evidence that screening reduces mortality from CRC comes from three randomized controlled trials. 2-4 In the Minnesota trial, mortality was reduced by 33% in those who were screened annually with FOBT. 2 Some of the slides were rehydrated before testing, which increased sensitivity but decreased specificity. All patients with positive test results were evaluated with colonoscopy. It has been argued that a portion of the benefit in this study was from the high percentage of persons who received colonoscopy, in effect making it a test of colonoscopy rather than FOBT. In two European population=based studies, where FOBT was performed biennially without rehydration, the mortality rates were reduced 15% to 18% as a result of screening for 10 years. 3,4 A metaanalysis of these randomized, controlled trials concluded that mortality from CRC was reduced by 16% in those randomized to screening. 9 All three trials demonstrated that screening with FOBT reduced mortality by detecting cancers at an earlier stage. However, there are several limitations of FOBT as a screening test for CRC. The sensitivity for detection of cancer is only 33% to 50% for one-time testingY ~ but it improves if testing is repeated every 1 to 2 years. This obviously requires strict compliance. Furthermore, most patients with adenomas have a negative FOBT, thus making it a less reliable screening test. H,12 The American College of Gastroenterology endorses annual FOBT and recommends that rehydration be performed at the discretion of the physician.13 Patients with positive FOBT should undergo colonoscopy. 2-4 Double-contrast barium enema to evaluate a positive FOBT has been associated with a miss rate for cancer of up to 25%, 14-17 although this figure may vary with the expertise of the radiologist. Development of symptoms after a negative FOBT should lead to re-evaluation of the patient.
Seminars in Roentgenology, Vol XXXV, No 4 (October), 2000: pp 404-408
ROLE OF COLONOSCOPY FOR CRC SCREENING
405
I
I
I verage I I
I
I FOBT q 1 yr Flex sig q 5yr D C B E q 5-10 yr Colonoscopy q 10 yr
Fig 1. Colorectal cancer screening algorithm. (Modified and reprinted with permission. 8)
FLEXIBLE SIGMOIDOSCOPY
Most CRCs arise from preexisting adenomatous tissue. This occurs usually, but not always, in a polypoid lesion. In most cases, this malignant transformation occurs over 10 to 35 years.18-2~This long interval for the development of cancer provides an opportunity to prevent cancer by removal of precursor adenomas detected at screening. With flexible sigmoidoscopy, it is possible to not only detect early stage cancers but also to remove premalignant lesions and interrupt the neoplastic progression early in its long, natural history. There is strong and compelling evidence for a protective effect of sigmoidoscopy with the removal of adenomas. About 50% to 60% of polyps and CRCs are found within reach of the 60-cm flexible sigmoidoscope. 11'21"26 In a randomized controlled trial, the sensitivity of flexible sigmoidoscopy for detection of adenomas or colorectal cancers in the rectosigmoid region has been estimated to be 87% and 85%, respectivelyY Patients with polyps less than 0.5 cm should undergo biopsy, and if adenomatous epithelium or cancer is found, the patient should be offered a full colonoscopy. If large (-->1 cm) polyps are found, colonoscopy should be recommended directly. 8 Hyperplastic polyps do not have any malignant potential, whereas small tubular adenomas less than 1 cm in size are considered to have a low malignant potential. 28-3~ Three case-control studies suggest that sigmoidoscopy screening can reduce mortality from cancer of the distal colon and rectum. In a study from the Kaiser-Permanente program, Selby et al 6 examined the use of screening rigid sigmoidoscopy in 261
Increased
I
t
Age <501 [Age_> 501 No screening
] Personal history colon cancer or polyps
I Colonoscopy Flex s i g / D C B E
Family history colon cancer or polyps
I Flex sig +/- DCBE Colonoscopy Begin at age 40
patients who died of cancer of the distal colon or rectum, compared with case-matched controls. Only 8.8% of the patients with cancer had undergone screening sigmoidoscopy, compared with 24.2% of the controls. The authors estimated that screened subjects had only 30% of the risk for fatal cancers of the rectum and distal colon, compared with the unscreened cohort. Furthermore, they demonstrated that the benefit of screening sigmoidoscopy may extend over 10 years. This observation was confirmed by another study by Newcomb et al, 31 which suggested that the risk of death from cancer in the distal colon or rectum was reduced by 79% after a single sigmoidoscopic examination. These studies were performed with rigid sigmoidoscopy. Nonetheless, the results have been extrapolated to establish the effectiveness of flexible sigmoidoscopy. Muller and Sonnenberg 32 demonstrated in a large case-control study that patients with colon and rectal cancer were about half as likely to have undergone a flexible sigmoidoscopy or colonoscopy in the previous 10 years compared with control patients without cancer. Atkin et a133 conducted a long-term study in patients who had adenomas removed by sigmoidoscopy up to 30 years previously and estimated that 80% of rectal cancers had been prevented by adenoma removal. Flexible sigmoidoscopy is a safe procedure with the principle complication being perforation, which occurs at a rate of 1 to 2 per 10,000. 8'32 The compliance rates for screening sigmoidoscopy range from 30% to 50%. 34 Reasons given for the low compliance include cost, discomfort, fear, low reimbursement, and lack of training and equipment. 35,36
406
AHMAD AND HOOPS
Whether patients with diminutive ( < 5 mm) adenomas found at sigmoidoscopy warrant a subsequent colonoscopy is controversial. Several investigators have found that patients with a distal tubular adenoma smaller than 1 cm are not at greater risk of having synchronous advanced proximal colonic lesions 3~ or subsequent CRC. 33 This issue was recently examined in a study by Schoen et al,38 which examined 981 patients with distal adenomas found on initial colonoscopy. The finding of an advanced proximal adenoma (greater than 1 cm size, villous architecture, or high-grade dysplasia) was twice as likely for patients with distal advanced adenomas compared with those with distal nonadvanced adenomas (5.9% vs 2.9%). However, not performing a colonoscopy in patients with a nonadvanced distal adenoma would have led to missing 36% of the advanced proximal adenomas. Another recent study found that the prevalence of advanced proximal neoplasia was similar among patients with no tubular adenomas at sigmoidoscopy, those with tubular adenomas less than 1 cm in diameter, and those with tubular adenomas 1 cm in diameter or larger. 39 These data support performance of a colonoscopy in patients with nonadvanced distal adenomas. 38 However, even this approach may fall short in those patients who have proximal adenomas in the absence of distal adenomas. One study estimated that about 30% of CRCs would be missed with a negative screening sigmoidoscopy or a sigmoidoscopy that did not detect a distal adenoma. 4~ The results of a recent prospective study further support this data. 41 In a study of 116 patients with cancer proximal to the splenic flexure, only 16% were discovered to have distal adenomas with a size equal to or greater than 1 cm. Thus, the authors concluded that most patients with cancer proximal to the splenic flexure will have a normal screening flexible sigmoidoscopy. At this point the National Health Services Task Force and the American Gastroenterotogical Association guidelines for colorectal screening recommend FOBT testing annually with flexible sigmoidoscopy every 5 years. A positive test should lead to a full evaluation of the colon preferably with colonoscopy. SCREENING COLONOSCOPY Recently published guidelines have suggested that colonoscopy may be a reasonable screening
option for CRC. 8 Even though there are no randomized controlled trials or case-control studies to demonstrate that screening colonoscopy reduces CRC mortality, there is indirect evidence for its efficacy as a screening tool. A cohort of patients who underwent colonoscopy and removal of colon adenomas by polypectomy experienced a 76% to 90% decrease in CRC incidence compared with a reference population. 7 Furthermore, there were no deaths from CRC in this cohort of patients. Not only does this study prove that identification and removal of adenomas is the central element in prevention of CRC, but it also underscores the potential effectiveness of screening colonoscopy and polypectomy as a CRC prevention strategy. Other evidence that suggests colonoscopy may be a more effective screening tool includes prospective 41 and retrospective 4~ studies of colonoscopy findings in patients with colon cancer proximal to the splenic flexure. These have consistently found that at least two thirds of these patients have no neoplasm distal to the splenic flexure. Thus, a flexible sigmoidoscopy would be normal in a substantial number of these patients. Two prospective studies examined the yield of screening colonoscopy in average risk patients.11.45 Lieberman and Smith 1~ found that 28% of patients with no distal polyps had adenomas in the proximal colon. Among 23 patients with advanced adenomas, 9 had no adenomas in the distal 60 cm of the colon. Moreover, 40% of subjects with adenomatous polyps had no index lesions in the distal colon. Rex et al, 45 in their study of 210 asymptomatic average risk patients, found that 11% of patients with no distal lesions had proximal adenomas. Furthermore, 36% of patients with adenomas and one individual with cancer had no neoplasms distal to the splenic flexure. Based on these findings, the authors recommended a single screening colonoscopy on persons in their early 60s. In addition, some studies have suggested that CRCs have shifted toward the proximal colon in the past 30 years. 4648 Many patients with serious proximal neoplasia may go undetected with only a distal colon examination. There are currently no observational studies to determine the optimum interval for screening colonoscopy in average-risk persons. The longest reported interval at which asymptomatic average-risk persons age -->50 years with an initial normal
ROLE OF COLONOSCOPY FOR CRC SCREENING
407
c o l o n o s c o p y have u n d e r g o n e a second colonoscopy is 5.5 years. 49 N o cancer was detected at 5.5 years, and the incidence o f adenomas with advanced pathology was less than 1%. Given these data as well as information on the growth rate o f a d e n o m a s 5~ and the time sequence o f the a d e n o m a c a r c i n o m a sequence, 51 screening c o l o n o s c o p y at 10-year intervals seems reasonable pending the availability o f observational studies. T h e A m e r i c a n C o l l e g e o f G a s t r o e n t e r o l o g y currently r e c o m m e n d s c o l o n o s c o p y e v e r y 10 years beginning at age 50 years. 13 The risks o f c o l o n o s c o p y include perforation and bleeding related to polypectomy. The current rate o f perforation from diagnostic colonoscopy is uncertain, but m a y be on the order o f one in several thousand colonoscopies. 2,52-54 Other potential arguments against screening c o l o n o s c o p i e s include the cost o f the procedure, the need for sedation, the loss o f a workday for the procedure, and the need for a full colon preparation. H o w e v e r , any procedure that e x a m i n e s the entire colon requires a similar preparation. The r e i m b u r s e m e n t for colonoscopies has decreased such that this should no longer be m u c h o f an issue. Sedation is also a positive aspect o f colonoscopies, a l l o w i n g significant patient c o m fort during the examination.
Theoretically, c o l o n o s c o p y should be more acceptable to patients than flexible sigmoidoscopy. Unfortunately, there are very little data on the c o m p l i a n c e that could be e x p e c t e d if c o l o n o s c o p y were adopted for screening. Indirect e v i d e n c e for c o m p l i a n c e with screening c o l o n o s c o p y may be deduced f r o m a study by Rex et aP 2 in which less than 15% o f medical personnel invited by mail to undergo free screening c o l o n o s c o p y accepted the offer. H o w e v e r , there are several advantages o f c o l o n o s c o p y o v e r flexible s i g m o i d o s c o p i c screening: increased c o n v e n i e n c e for the patient secondary to diagnosis and treatment in a single session, decreased risk of patients being lost to f o l l o w - u p after detection o f polyps by tests with o n l y diagnostic capability, and i m p r o v e d patient satisfaction secondary to the use of sedation. 55 The arguments in f a v o r o f screening colonoscopy are compelling, and we foresee a progressive shift towards the adoption o f c o l o n o s c o p y as the screening tool of choice o v e r the next several years. A l t h o u g h m a n y details remain to be explored, such as age o f first screening and intervals between examinations, the availability o f a single test that is both diagnostic and therapeutic m a k e s this an excellent instrument to reduce the morbidity and mortality o f C R C .
REFERENCES 1. Parker SL, Tong T, Bolden S, et al: Cancer Statistics, 1996. CA Cancer J Clin 65:5-27, 1996 2. Mandel JS, Bond JH, Church TR, et al: Reducing mortality from colorectal cancer by screening for fecal occult blood: Minnesota colon cancer control study. N Engl J Med 328:13651371, 1993 3. Hardcastle JD, Chamberlain JO, Robinson MHE, et al: Randomized controlled trial of fecal-occult-blood screening for colorectal cancer. Lancet 348:1472-1477, 1996 4. Kronborg O, Fenger C, Olsen J, et al: Randomized study of screening for colorectal cancer with fecal-occult-blood test. Lancet 348:1467-1471, 1996 5. Ries LAG, Miller BA, Hankey BE et al (eds): SEER cancer statistics Review, 1973-1991: Tables and Graphs, National Cancer Institute. NIH Pub. No. 94-2789, Bethesda, MD, National Cancer Institute, 1994, p 51 6. Selby JV, Friedman GD, Quesenberry CP Jr, et al: A case-control study of screening simodoscopy and mortality from colorectal cancer. N Engl J Med 326:653-657, 1992 7. Winawer SJ, Zauber AG, Ho MN, et al: Prevention of colorectal cancer by colonoseopic polypectomy: The National Polyp Study Workgroup. N Engl J Med 329:1977-1981, 1993 8. Winawer SJ, Fletcher RH, Miller L, et al: Colorectal cancer screening: Clinical guidelines and rationale. Gastroenterology 112:594-642, 1997 9. Towler B, Irwig L, Glasziou P, et al: A systematic review
of the effects of screening for colorectal cancer using the fecal-occult-blood test, Hemoccult. Lancet 317:559-565, 1998 10. 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 269:1262-1267, 1993 11. Lieberman DA, Smith FW: Screening for colon malignancy with colonoscopy. Am J Gastroenterol 86:946-951, 1991 12, 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 88:825-831, 1995 13. Rex DK, Johnson DA, Lieberman DA, et al: Colorectal cancer prevention 2000: Screening recommendations of the American College of Gastroenterology. Am J Gastroenterol 95:868-877, 2000 14. Kewenter J, Breringe H, Engras B, et al: 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 test. Endoscopy 27:159-163, 1995 15. Elliot MS, Levenstein JH, Wright JP: Fecal occult blood testing in the detection of colorectal cancer. Br J Surg 71:785786, 1984 16. Winawer SJ, Flechinger BJ, Schottenfeld D, et al: Screening for a colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 85:1311-1318, 1991
408
17. Sontag SJ, Durczak C, Aranha GV, et al: Fecal occult blood testing for colorectal cancer in Veteran's Administration Hospital. Am J Surg 145:89-93, 1983 18. Atkin WS, Cuzick J, Northover JMA, et al: Prevention of colorectal cancer by once-only sigmoidoscopy. Lancet 341:736740, 1993 19. Morson BC: The polyp-cancer sequence in the large bowel. Proc R Soc Med 67:451-457, 1974 20. Stryker SJ, Wolff BG, Culp CE, et al: Natural history of untreated colon polyps. Gastroenterology 93:1009-1013, 1987 21. Johnson DA, Gurney MS, Volpe RJ, et al: A prospective study of the prevalence of colonic neoplasms in asymptomatic patients with an age-related risk. Am J Gastroenterol 85:969974, 1990 22. Lieberman D: Mass screening: A North American perspective, in Young GP, Rozen P, Levin B (eds): Prevention and Early Detection of Colorectal Cancer. Philadelphia, PA, WB Saunders, 1996, pp 289-300 23. Neugut AI, Pita S: Role of sigmoidoscopy in screening for colorectal cancer: A critical review. Gastroenterology 95:492499, 1988 24. Shinya H, Wolff WI: Morphology, anatomic distribution and cancer potential of colonic polyps: An analysis of 7,000 polyps endoscopically removed. Ann Surg 190:679-683, 1979 25. Tedesco FJ, Waye JD, AveUa JR, et al: Diagnostic implications of the spatial distribution of colonic mass lesions (polyps and cancers): A prospective colonoscopic study. Gastrointest Endosc 26:95-97, 1980 26. Wmawer SJ, Gottlieb LS, Stewart ET, et al: First progress report of the National Polyp Study. Gastroenterology 84:1352, 1983 27. Jensen J, Kewenter J, Asztely M, et al: Double contrast barium enema and flexible rectosigmoidoscopy: A reliable diagnostic combination for detection of colorectal neoplasm. Br J Surg 77:270-272, 1990 28. Glick SN, Teplick SK, Balfe DM, et al: Large colonic neoplasm missed by endoscopy. Am J Radio1152:513-517, 1989 29. Spencer RJ, Melton LJ llI, Ready RL, et al: Treatment of small colorectal polyps: A population based study of the risk of subsequent carcinoma. Mayo Clin Proc 59:305-310, 1984 30. Zarchy TM, Ershoff D: Do characteristics of adenomas on flexible sigmoidoscopy predict advanced lesions on baseline colonoscopy? Gastroenterology 106:1501-1504, 1994 31. Newcomb PA, Norfleet RG, Storer BE, et al: Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 84:1572-1575, 1992 32. Muller AD, Sonnenberg A: Prevention of colorectal cancer by flexible endoscopy and polypectomy: A case-control study of 32,702 veterans. Ann Intern Med 123:904-910, 1995 33. Atkin WS, Morson BC, Cuzick J: Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med 326:658-662, 1992 34. Vernon SW: Adherence to colorectal cancer screening: A brief overview. Ann NY Acad Sci 768:292-295, 1995 35. Petravage J, Swedberg J: Patent response to sigmoidoscopy recommendations via mailed reminders. J Fam Pract 27:387-389, 1988 36. Holt WS: Factors affecting compliance with screening sigmoidoscopy. J Fam Pract 32:585-589, 1991
AHMAD AND HOOPS
37. Grossman S, Milos ML, Tekawa IS, et al: Colonoscopic screening of persons with suspected risk factors for colon cancer, II: past history colorectal neoplams. Gastroenterology 96:299-306, 1989 38. Schoen RE, Corle D, Cranston L, et al: Is colonoscopy needed for the nonadvanced adenoma found on sigmoidoscopy? Gastroenterology 115:533-541, 1998 39. Levin T, PalitzA, Grossman S, et al: Predicting advanced proximal colonic neoplasia with screening sigmoidoscopy. JAMA 281:1611-1617, 1999 40. Lemmel GT, Haseman JH, Rex DK, et al: Neoplasia distal to the splenic flexure in patients with proximal colon cancer. Gastrointest Endosc 44:109-111, 1996 41. Rex DK, Chak A, Vasudeva R, et al: Prospective determination of distal colon findings in average-risk patients with proximal colon cancer. Gastrointest Endosc 49:727-730, 1999 42. Dinning JP, Hixon LJ, Clark LC: Prevalence of distal colonic neoplasia associated with proximal colon cancer. Ann Intern Med 154:854-856, 1994 43. Buffett C, Laurent-Puig P, Hagege H, et al: Occurrence of synchronous and metachronous polyps associated with colon cancer: Differences between proximal and distal colorectal cancer. Gastroenterology 102:A347, 1992 (abstr) 44. Castiglione G, Ciatto S, Mazzotta A, et al: Sensitivity of screening sigmoidoscopy for proximal colorectal tumors. Lancet 345:726-727, 1995 45. Rex DK, Lehman GA, Hawes RH, et al: Screening colonoscopy in asymptomatic average risk persons with negative fecal occult blood tests. Gastroenterology 100:64-67, 1991 46. Nelson RL, Persky V, Turyk M, et al: Tune trends in distal colorectal cancer subsite location related to age and how it affects choice of screening modality. J Surg Onco169:235-238, 1998 47. Kee K Wison RH, Gilliland R, et al: Changing site distribution of colorectal cancer. BMJ 305:158, 1992 48. Mamazza J, Gordon PH: The changing distribution of large intestine cancer. Dis Colon Rectum 25:558-562, 1982 49. Rex DK, Cummings OW, Helper DJ, et al: Five-year incidence of adenomas after negative colonoscopy in asymptomatic average-risk persons. Gastroenterology 1 l 1:1178-1181, 1996 50. Hofstad B, Vatn MH, Andersen SN, et al: Growth of colorectal polyps: Redetection and evaluation of unresected polyps for a period of three years. Gut 39:449-456, 1996 51. Zanber AG, Winawer SJ: Initial management and follow-up surveillance of patients with colorectal adenomas. Gastroenterol Clin North Am 26:85-101, 1997 52. Waye JD, Lewis BS, Yessayan S: Colonoscopy: A prospective report of comphcations. J Clin Gastroentero115:347-351, 1992 53. Basson MD, Etter L, Panzini LA: Rates of colonoscopic perforation in current practice. Gastroenterology 114:1115, 1998 (letter) 54. Zubarik R, Fleischer DE, Mastropietro C, et al: Prospective analysis of complications 30 days after outpatient colonoscopy. Gastrointest Endosc 50:322-328, 1999 55. Van Ness MM, Chobanian SJ, Winters C Jr, et al: A study of patient acceptance of double-contrast barium enema and colonoscopy: Which procedure is preferred by patients.'? Arch Intern Med 147:2175-2176, 1987
C
SCREENING FOR COLORECTAL CANCER About 75% of CRCs occur in individuals at average risk, that is with no known risk factor other than age. Screening is advocated for those aged 50 years and older because the incidence of CRC begins to rise significantly between 40 and 50 years of age. 8 The recommended options for CRC screening in asymptomatic individuals at average risk are shown in Figure 1. Although the various recommendations differ in their specifics, the essentials are to recommend periodic fecal occult blood testing or sigmoidoscopy, or both in those age 50 years and older. Barium enema can be an additional screening modality. The role of colonoscopy as a screening test for CRC is rapidly evolving. The role of fecal occult blood testing (FOBT) and flexible sigmoidoscopy is discussed briefly before the discussion of the role of colonoscopy in the screening of CRC.
From Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia, PA. Address reprint requests to Timothy C. Hoops, MD, Presbyterian Medical Center, 218 Wright Saunders, 39th and Market Sts, Philadelphia, PA 19104. Copyright 9 2000 by W.B. Saunders Company 0037 198X/00/3504-0010510.00/0 doi :10.1053/sroe.2000.17758 404
FECAL OCCULT BLOOD TESTING FOBT is performed by using standard hemoccult cards that detect the peroxidase activity of hemoglobin from erythrocytes. The rationale for this examination is based on the observation that two thirds of all CRCs will bleed intermittently in the course of a week. FOBT can also detect polyps, as they may bleed, particularly if large, although this application is controversial as is discussed later. The best evidence that screening reduces mortality from CRC comes from three randomized controlled trials. 2-4 In the Minnesota trial, mortality was reduced by 33% in those who were screened annually with FOBT. 2 Some of the slides were rehydrated before testing, which increased sensitivity but decreased specificity. All patients with positive test results were evaluated with colonoscopy. It has been argued that a portion of the benefit in this study was from the high percentage of persons who received colonoscopy, in effect making it a test of colonoscopy rather than FOBT. In two European population=based studies, where FOBT was performed biennially without rehydration, the mortality rates were reduced 15% to 18% as a result of screening for 10 years. 3,4 A metaanalysis of these randomized, controlled trials concluded that mortality from CRC was reduced by 16% in those randomized to screening. 9 All three trials demonstrated that screening with FOBT reduced mortality by detecting cancers at an earlier stage. However, there are several limitations of FOBT as a screening test for CRC. The sensitivity for detection of cancer is only 33% to 50% for one-time testingY ~ but it improves if testing is repeated every 1 to 2 years. This obviously requires strict compliance. Furthermore, most patients with adenomas have a negative FOBT, thus making it a less reliable screening test. H,12 The American College of Gastroenterology endorses annual FOBT and recommends that rehydration be performed at the discretion of the physician.13 Patients with positive FOBT should undergo colonoscopy. 2-4 Double-contrast barium enema to evaluate a positive FOBT has been associated with a miss rate for cancer of up to 25%, 14-17 although this figure may vary with the expertise of the radiologist. Development of symptoms after a negative FOBT should lead to re-evaluation of the patient.
Seminars in Roentgenology, Vol XXXV, No 4 (October), 2000: pp 404-408
ROLE OF COLONOSCOPY FOR CRC SCREENING
405
I
I
I verage I I
I
I FOBT q 1 yr Flex sig q 5yr D C B E q 5-10 yr Colonoscopy q 10 yr
Fig 1. Colorectal cancer screening algorithm. (Modified and reprinted with permission. 8)
FLEXIBLE SIGMOIDOSCOPY
Most CRCs arise from preexisting adenomatous tissue. This occurs usually, but not always, in a polypoid lesion. In most cases, this malignant transformation occurs over 10 to 35 years.18-2~This long interval for the development of cancer provides an opportunity to prevent cancer by removal of precursor adenomas detected at screening. With flexible sigmoidoscopy, it is possible to not only detect early stage cancers but also to remove premalignant lesions and interrupt the neoplastic progression early in its long, natural history. There is strong and compelling evidence for a protective effect of sigmoidoscopy with the removal of adenomas. About 50% to 60% of polyps and CRCs are found within reach of the 60-cm flexible sigmoidoscope. 11'21"26 In a randomized controlled trial, the sensitivity of flexible sigmoidoscopy for detection of adenomas or colorectal cancers in the rectosigmoid region has been estimated to be 87% and 85%, respectivelyY Patients with polyps less than 0.5 cm should undergo biopsy, and if adenomatous epithelium or cancer is found, the patient should be offered a full colonoscopy. If large (-->1 cm) polyps are found, colonoscopy should be recommended directly. 8 Hyperplastic polyps do not have any malignant potential, whereas small tubular adenomas less than 1 cm in size are considered to have a low malignant potential. 28-3~ Three case-control studies suggest that sigmoidoscopy screening can reduce mortality from cancer of the distal colon and rectum. In a study from the Kaiser-Permanente program, Selby et al 6 examined the use of screening rigid sigmoidoscopy in 261
Increased
I
t
Age <501 [Age_> 501 No screening
] Personal history colon cancer or polyps
I Colonoscopy Flex s i g / D C B E
Family history colon cancer or polyps
I Flex sig +/- DCBE Colonoscopy Begin at age 40
patients who died of cancer of the distal colon or rectum, compared with case-matched controls. Only 8.8% of the patients with cancer had undergone screening sigmoidoscopy, compared with 24.2% of the controls. The authors estimated that screened subjects had only 30% of the risk for fatal cancers of the rectum and distal colon, compared with the unscreened cohort. Furthermore, they demonstrated that the benefit of screening sigmoidoscopy may extend over 10 years. This observation was confirmed by another study by Newcomb et al, 31 which suggested that the risk of death from cancer in the distal colon or rectum was reduced by 79% after a single sigmoidoscopic examination. These studies were performed with rigid sigmoidoscopy. Nonetheless, the results have been extrapolated to establish the effectiveness of flexible sigmoidoscopy. Muller and Sonnenberg 32 demonstrated in a large case-control study that patients with colon and rectal cancer were about half as likely to have undergone a flexible sigmoidoscopy or colonoscopy in the previous 10 years compared with control patients without cancer. Atkin et a133 conducted a long-term study in patients who had adenomas removed by sigmoidoscopy up to 30 years previously and estimated that 80% of rectal cancers had been prevented by adenoma removal. Flexible sigmoidoscopy is a safe procedure with the principle complication being perforation, which occurs at a rate of 1 to 2 per 10,000. 8'32 The compliance rates for screening sigmoidoscopy range from 30% to 50%. 34 Reasons given for the low compliance include cost, discomfort, fear, low reimbursement, and lack of training and equipment. 35,36
406
AHMAD AND HOOPS
Whether patients with diminutive ( < 5 mm) adenomas found at sigmoidoscopy warrant a subsequent colonoscopy is controversial. Several investigators have found that patients with a distal tubular adenoma smaller than 1 cm are not at greater risk of having synchronous advanced proximal colonic lesions 3~ or subsequent CRC. 33 This issue was recently examined in a study by Schoen et al,38 which examined 981 patients with distal adenomas found on initial colonoscopy. The finding of an advanced proximal adenoma (greater than 1 cm size, villous architecture, or high-grade dysplasia) was twice as likely for patients with distal advanced adenomas compared with those with distal nonadvanced adenomas (5.9% vs 2.9%). However, not performing a colonoscopy in patients with a nonadvanced distal adenoma would have led to missing 36% of the advanced proximal adenomas. Another recent study found that the prevalence of advanced proximal neoplasia was similar among patients with no tubular adenomas at sigmoidoscopy, those with tubular adenomas less than 1 cm in diameter, and those with tubular adenomas 1 cm in diameter or larger. 39 These data support performance of a colonoscopy in patients with nonadvanced distal adenomas. 38 However, even this approach may fall short in those patients who have proximal adenomas in the absence of distal adenomas. One study estimated that about 30% of CRCs would be missed with a negative screening sigmoidoscopy or a sigmoidoscopy that did not detect a distal adenoma. 4~ The results of a recent prospective study further support this data. 41 In a study of 116 patients with cancer proximal to the splenic flexure, only 16% were discovered to have distal adenomas with a size equal to or greater than 1 cm. Thus, the authors concluded that most patients with cancer proximal to the splenic flexure will have a normal screening flexible sigmoidoscopy. At this point the National Health Services Task Force and the American Gastroenterotogical Association guidelines for colorectal screening recommend FOBT testing annually with flexible sigmoidoscopy every 5 years. A positive test should lead to a full evaluation of the colon preferably with colonoscopy. SCREENING COLONOSCOPY Recently published guidelines have suggested that colonoscopy may be a reasonable screening
option for CRC. 8 Even though there are no randomized controlled trials or case-control studies to demonstrate that screening colonoscopy reduces CRC mortality, there is indirect evidence for its efficacy as a screening tool. A cohort of patients who underwent colonoscopy and removal of colon adenomas by polypectomy experienced a 76% to 90% decrease in CRC incidence compared with a reference population. 7 Furthermore, there were no deaths from CRC in this cohort of patients. Not only does this study prove that identification and removal of adenomas is the central element in prevention of CRC, but it also underscores the potential effectiveness of screening colonoscopy and polypectomy as a CRC prevention strategy. Other evidence that suggests colonoscopy may be a more effective screening tool includes prospective 41 and retrospective 4~ studies of colonoscopy findings in patients with colon cancer proximal to the splenic flexure. These have consistently found that at least two thirds of these patients have no neoplasm distal to the splenic flexure. Thus, a flexible sigmoidoscopy would be normal in a substantial number of these patients. Two prospective studies examined the yield of screening colonoscopy in average risk patients.11.45 Lieberman and Smith 1~ found that 28% of patients with no distal polyps had adenomas in the proximal colon. Among 23 patients with advanced adenomas, 9 had no adenomas in the distal 60 cm of the colon. Moreover, 40% of subjects with adenomatous polyps had no index lesions in the distal colon. Rex et al, 45 in their study of 210 asymptomatic average risk patients, found that 11% of patients with no distal lesions had proximal adenomas. Furthermore, 36% of patients with adenomas and one individual with cancer had no neoplasms distal to the splenic flexure. Based on these findings, the authors recommended a single screening colonoscopy on persons in their early 60s. In addition, some studies have suggested that CRCs have shifted toward the proximal colon in the past 30 years. 4648 Many patients with serious proximal neoplasia may go undetected with only a distal colon examination. There are currently no observational studies to determine the optimum interval for screening colonoscopy in average-risk persons. The longest reported interval at which asymptomatic average-risk persons age -->50 years with an initial normal
ROLE OF COLONOSCOPY FOR CRC SCREENING
407
c o l o n o s c o p y have u n d e r g o n e a second colonoscopy is 5.5 years. 49 N o cancer was detected at 5.5 years, and the incidence o f adenomas with advanced pathology was less than 1%. Given these data as well as information on the growth rate o f a d e n o m a s 5~ and the time sequence o f the a d e n o m a c a r c i n o m a sequence, 51 screening c o l o n o s c o p y at 10-year intervals seems reasonable pending the availability o f observational studies. T h e A m e r i c a n C o l l e g e o f G a s t r o e n t e r o l o g y currently r e c o m m e n d s c o l o n o s c o p y e v e r y 10 years beginning at age 50 years. 13 The risks o f c o l o n o s c o p y include perforation and bleeding related to polypectomy. The current rate o f perforation from diagnostic colonoscopy is uncertain, but m a y be on the order o f one in several thousand colonoscopies. 2,52-54 Other potential arguments against screening c o l o n o s c o p i e s include the cost o f the procedure, the need for sedation, the loss o f a workday for the procedure, and the need for a full colon preparation. H o w e v e r , any procedure that e x a m i n e s the entire colon requires a similar preparation. The r e i m b u r s e m e n t for colonoscopies has decreased such that this should no longer be m u c h o f an issue. Sedation is also a positive aspect o f colonoscopies, a l l o w i n g significant patient c o m fort during the examination.
Theoretically, c o l o n o s c o p y should be more acceptable to patients than flexible sigmoidoscopy. Unfortunately, there are very little data on the c o m p l i a n c e that could be e x p e c t e d if c o l o n o s c o p y were adopted for screening. Indirect e v i d e n c e for c o m p l i a n c e with screening c o l o n o s c o p y may be deduced f r o m a study by Rex et aP 2 in which less than 15% o f medical personnel invited by mail to undergo free screening c o l o n o s c o p y accepted the offer. H o w e v e r , there are several advantages o f c o l o n o s c o p y o v e r flexible s i g m o i d o s c o p i c screening: increased c o n v e n i e n c e for the patient secondary to diagnosis and treatment in a single session, decreased risk of patients being lost to f o l l o w - u p after detection o f polyps by tests with o n l y diagnostic capability, and i m p r o v e d patient satisfaction secondary to the use of sedation. 55 The arguments in f a v o r o f screening colonoscopy are compelling, and we foresee a progressive shift towards the adoption o f c o l o n o s c o p y as the screening tool of choice o v e r the next several years. A l t h o u g h m a n y details remain to be explored, such as age o f first screening and intervals between examinations, the availability o f a single test that is both diagnostic and therapeutic m a k e s this an excellent instrument to reduce the morbidity and mortality o f C R C .
REFERENCES 1. Parker SL, Tong T, Bolden S, et al: Cancer Statistics, 1996. CA Cancer J Clin 65:5-27, 1996 2. Mandel JS, Bond JH, Church TR, et al: Reducing mortality from colorectal cancer by screening for fecal occult blood: Minnesota colon cancer control study. N Engl J Med 328:13651371, 1993 3. Hardcastle JD, Chamberlain JO, Robinson MHE, et al: Randomized controlled trial of fecal-occult-blood screening for colorectal cancer. Lancet 348:1472-1477, 1996 4. Kronborg O, Fenger C, Olsen J, et al: Randomized study of screening for colorectal cancer with fecal-occult-blood test. Lancet 348:1467-1471, 1996 5. Ries LAG, Miller BA, Hankey BE et al (eds): SEER cancer statistics Review, 1973-1991: Tables and Graphs, National Cancer Institute. NIH Pub. No. 94-2789, Bethesda, MD, National Cancer Institute, 1994, p 51 6. Selby JV, Friedman GD, Quesenberry CP Jr, et al: A case-control study of screening simodoscopy and mortality from colorectal cancer. N Engl J Med 326:653-657, 1992 7. Winawer SJ, Zauber AG, Ho MN, et al: Prevention of colorectal cancer by colonoseopic polypectomy: The National Polyp Study Workgroup. N Engl J Med 329:1977-1981, 1993 8. Winawer SJ, Fletcher RH, Miller L, et al: Colorectal cancer screening: Clinical guidelines and rationale. Gastroenterology 112:594-642, 1997 9. Towler B, Irwig L, Glasziou P, et al: A systematic review
of the effects of screening for colorectal cancer using the fecal-occult-blood test, Hemoccult. Lancet 317:559-565, 1998 10. 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 269:1262-1267, 1993 11. Lieberman DA, Smith FW: Screening for colon malignancy with colonoscopy. Am J Gastroenterol 86:946-951, 1991 12, 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 88:825-831, 1995 13. Rex DK, Johnson DA, Lieberman DA, et al: Colorectal cancer prevention 2000: Screening recommendations of the American College of Gastroenterology. Am J Gastroenterol 95:868-877, 2000 14. Kewenter J, Breringe H, Engras B, et al: 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 test. Endoscopy 27:159-163, 1995 15. Elliot MS, Levenstein JH, Wright JP: Fecal occult blood testing in the detection of colorectal cancer. Br J Surg 71:785786, 1984 16. Winawer SJ, Flechinger BJ, Schottenfeld D, et al: Screening for a colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 85:1311-1318, 1991
408
17. Sontag SJ, Durczak C, Aranha GV, et al: Fecal occult blood testing for colorectal cancer in Veteran's Administration Hospital. Am J Surg 145:89-93, 1983 18. Atkin WS, Cuzick J, Northover JMA, et al: Prevention of colorectal cancer by once-only sigmoidoscopy. Lancet 341:736740, 1993 19. Morson BC: The polyp-cancer sequence in the large bowel. Proc R Soc Med 67:451-457, 1974 20. Stryker SJ, Wolff BG, Culp CE, et al: Natural history of untreated colon polyps. Gastroenterology 93:1009-1013, 1987 21. Johnson DA, Gurney MS, Volpe RJ, et al: A prospective study of the prevalence of colonic neoplasms in asymptomatic patients with an age-related risk. Am J Gastroenterol 85:969974, 1990 22. Lieberman D: Mass screening: A North American perspective, in Young GP, Rozen P, Levin B (eds): Prevention and Early Detection of Colorectal Cancer. Philadelphia, PA, WB Saunders, 1996, pp 289-300 23. Neugut AI, Pita S: Role of sigmoidoscopy in screening for colorectal cancer: A critical review. Gastroenterology 95:492499, 1988 24. Shinya H, Wolff WI: Morphology, anatomic distribution and cancer potential of colonic polyps: An analysis of 7,000 polyps endoscopically removed. Ann Surg 190:679-683, 1979 25. Tedesco FJ, Waye JD, AveUa JR, et al: Diagnostic implications of the spatial distribution of colonic mass lesions (polyps and cancers): A prospective colonoscopic study. Gastrointest Endosc 26:95-97, 1980 26. Wmawer SJ, Gottlieb LS, Stewart ET, et al: First progress report of the National Polyp Study. Gastroenterology 84:1352, 1983 27. Jensen J, Kewenter J, Asztely M, et al: Double contrast barium enema and flexible rectosigmoidoscopy: A reliable diagnostic combination for detection of colorectal neoplasm. Br J Surg 77:270-272, 1990 28. Glick SN, Teplick SK, Balfe DM, et al: Large colonic neoplasm missed by endoscopy. Am J Radio1152:513-517, 1989 29. Spencer RJ, Melton LJ llI, Ready RL, et al: Treatment of small colorectal polyps: A population based study of the risk of subsequent carcinoma. Mayo Clin Proc 59:305-310, 1984 30. Zarchy TM, Ershoff D: Do characteristics of adenomas on flexible sigmoidoscopy predict advanced lesions on baseline colonoscopy? Gastroenterology 106:1501-1504, 1994 31. Newcomb PA, Norfleet RG, Storer BE, et al: Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 84:1572-1575, 1992 32. Muller AD, Sonnenberg A: Prevention of colorectal cancer by flexible endoscopy and polypectomy: A case-control study of 32,702 veterans. Ann Intern Med 123:904-910, 1995 33. Atkin WS, Morson BC, Cuzick J: Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med 326:658-662, 1992 34. Vernon SW: Adherence to colorectal cancer screening: A brief overview. Ann NY Acad Sci 768:292-295, 1995 35. Petravage J, Swedberg J: Patent response to sigmoidoscopy recommendations via mailed reminders. J Fam Pract 27:387-389, 1988 36. Holt WS: Factors affecting compliance with screening sigmoidoscopy. J Fam Pract 32:585-589, 1991
AHMAD AND HOOPS
37. Grossman S, Milos ML, Tekawa IS, et al: Colonoscopic screening of persons with suspected risk factors for colon cancer, II: past history colorectal neoplams. Gastroenterology 96:299-306, 1989 38. Schoen RE, Corle D, Cranston L, et al: Is colonoscopy needed for the nonadvanced adenoma found on sigmoidoscopy? Gastroenterology 115:533-541, 1998 39. Levin T, PalitzA, Grossman S, et al: Predicting advanced proximal colonic neoplasia with screening sigmoidoscopy. JAMA 281:1611-1617, 1999 40. Lemmel GT, Haseman JH, Rex DK, et al: Neoplasia distal to the splenic flexure in patients with proximal colon cancer. Gastrointest Endosc 44:109-111, 1996 41. Rex DK, Chak A, Vasudeva R, et al: Prospective determination of distal colon findings in average-risk patients with proximal colon cancer. Gastrointest Endosc 49:727-730, 1999 42. Dinning JP, Hixon LJ, Clark LC: Prevalence of distal colonic neoplasia associated with proximal colon cancer. Ann Intern Med 154:854-856, 1994 43. Buffett C, Laurent-Puig P, Hagege H, et al: Occurrence of synchronous and metachronous polyps associated with colon cancer: Differences between proximal and distal colorectal cancer. Gastroenterology 102:A347, 1992 (abstr) 44. Castiglione G, Ciatto S, Mazzotta A, et al: Sensitivity of screening sigmoidoscopy for proximal colorectal tumors. Lancet 345:726-727, 1995 45. Rex DK, Lehman GA, Hawes RH, et al: Screening colonoscopy in asymptomatic average risk persons with negative fecal occult blood tests. Gastroenterology 100:64-67, 1991 46. Nelson RL, Persky V, Turyk M, et al: Tune trends in distal colorectal cancer subsite location related to age and how it affects choice of screening modality. J Surg Onco169:235-238, 1998 47. Kee K Wison RH, Gilliland R, et al: Changing site distribution of colorectal cancer. BMJ 305:158, 1992 48. Mamazza J, Gordon PH: The changing distribution of large intestine cancer. Dis Colon Rectum 25:558-562, 1982 49. Rex DK, Cummings OW, Helper DJ, et al: Five-year incidence of adenomas after negative colonoscopy in asymptomatic average-risk persons. Gastroenterology 1 l 1:1178-1181, 1996 50. Hofstad B, Vatn MH, Andersen SN, et al: Growth of colorectal polyps: Redetection and evaluation of unresected polyps for a period of three years. Gut 39:449-456, 1996 51. Zanber AG, Winawer SJ: Initial management and follow-up surveillance of patients with colorectal adenomas. Gastroenterol Clin North Am 26:85-101, 1997 52. Waye JD, Lewis BS, Yessayan S: Colonoscopy: A prospective report of comphcations. J Clin Gastroentero115:347-351, 1992 53. Basson MD, Etter L, Panzini LA: Rates of colonoscopic perforation in current practice. Gastroenterology 114:1115, 1998 (letter) 54. Zubarik R, Fleischer DE, Mastropietro C, et al: Prospective analysis of complications 30 days after outpatient colonoscopy. Gastrointest Endosc 50:322-328, 1999 55. Van Ness MM, Chobanian SJ, Winters C Jr, et al: A study of patient acceptance of double-contrast barium enema and colonoscopy: Which procedure is preferred by patients.'? Arch Intern Med 147:2175-2176, 1987