Incidence and Recurrence Rates of Colorectal Adenomas: A Prospective Study

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1 GASTROENTEROLOGY 1995;108: Incidence and Recurrence Rates of Colorectal : A Prospective Study ALFRED I. NEUGUT,*'* JUDITH S. JACOBSON,* HABIBUL AHSAN,* JASON SANTOS,* GAlL C. GARBOWSKI,* KENNETH A. FORDE, MICHAEL R. TREAT, ~ and JEROME WAYE Departments of *Medicine and Surgery and ~School of Public Health, College of Physicians and Surgeons, Columbia University, New York; and lidepartment of Medicine, Mount Sinai School of Medicine, New York, New York Background/Aims: The frequency of colorectal adenomas, the precursor lesions for most cases of colorectal carcinoma, has been generally measured as prevalence rates of adenomas at autopsy or colonoscopy. The aim of this study was to estimate the incidence rate of adenomas and compare it with the adenoma recurrence rate. Methods: Data on colonoscopies performed in three New York City practices were collected prospectively. The cumulative rate of adenoma diagnosis on repeat colonoscopy was calculated for patients with no abnormalities on index colonoscopy ("incidence" rate) and for patients with adenomas on the index co- Ionoscopy ("recurrence" rate). Results: The cumulative incidence rate of adenomas at 36 months was 16%, and the cumulative recurrence rate at 36 months was 42% (P < 0.004). The recurrence rate was higher in patients with multiple adenomas than in those with a single adenoma on index colonoscopy, although the increase was not statistically significant. Conclusions: Although the recurrence rate has always been assumed to be elevated, this study is the first to compare the recurrence rate of adenomas with the incidence rate directly and to show that the recurrence rate is indeed elevated. A denomatous polyps (adenomas) are benign tumors that are widely recognized as precursor lesions for the vast majority of colorectal cancers. 1'2 Because they are generally asymptomatic, their frequency in different populations has generally been described in terms of prevalence rates rather than incidence rates. Before the mid-1980s, studies of adenoma prevalence were based on consecutive autopsies in which the entire large bowel was examined More recently, adenoma prevalence rates have been derived from colonoscopy studies of symptomatic or high-risk individuals. 2'16-25 Most recently, several colonoscopy screening studies have been performed among asymptomatic average-risk individuals Since the 1970s, it has been known that patients who have had an adenoma are likely to have another. Patients whose adenomas were removed have been found to have a 15%-60% risk for a new, metachronous, or recurrent adenoma within 3-4 years after the previous polypectomy. 2'29-37 In particular, the National Polyp Study showed a recurrence rate of 32% at 3 years9 The recurrence rate has generally been assumed to be higher than the incidence rate in those without prior colorectal neoplasia. Indeed, because recurrence is so common, it has been used as a surrogate end point for invasive colorectal cancer in randomized chemoprevention trials Actual adenoma incidence rates can be determined only by serial examinations of the colon in a population without a history of colorectal neoplasia. In a recent study, Rex et al. 43 did this using sigmoidoscopy and found a 6% incidence of left-sided adenomas after 3 years. No prior study has reported the results of serial colonoscopies in a population where the initial colonoscopy result was negative. Between 1986 and 1988, we collected data on patients undergoing colonoscopy in three colonoscopy practices in New York City. Some of the patients who had negative results on colonoscopies and no prior colorectal neoplasia underwent repeat colonoscopy. In this paper, we report the results of these reexaminations as actual adenoma incidence rates. In addition, we calculated the incidence of metachronous adenomas (the recurrence rate) for patients who initially had adenomas and who subsequently underwent colonoscopy. As a result, we are able to compare the adenoma recurrence rate with the adenoma incidence rate. Materials and Methods As part of a study of risk factors for colorectal adenomatous polyps, we collected clinical and demographic data on all patients undergoing colonoscopy in three colonoscopy practices in New York City between April 1986 and March The total number of patients who underwent colonoscopy was Of them, 2443 (81.8%) were eligible for our study. To 1995 by the American Gastroenterological Association /95/$3.00

2 February 1995 COLORECTAL ADENOMA INCIDENCE AND RECURRENCE 403 be eligible, patients had to be between the ages of 35 and 84 years; had to reside in New York, New Jersey, or Connecticut; had to be English or Spanish speaking; and had to undergo colonoscopy that extended at ieast to the splenic flexure (in fact, more than 90% of study participants underwent colonoscopy extending to the cecum). Data sheets indicating the reasons for colonoscopy and the clinical findings were completed by the colonoscopist at the time of colonoscopy. Pathology slides on all suspected neoplastic lesions were reviewed by the study pathologist (Dr. Cecilia Fenoglio-Preiser of the University of Cincinnati Medical School). The details of this study are described elsewhere All eligible subjects were contacted by letter and telephone regarding interview. Ultimately, 2001 were successfully interviewed. Of these 2001 patients, 299 were found to have one or more pathologically defined adenomas with no prior history of colon carcinoma, adenomatous polyps, or inflammatory bowel disease. They formed the case group for our case-control study and were compared with the control group, which consisted of 508 individuals who had no colorectal neoplasia on the index colonoscopy and no history of colorectal neoplasia or inflammatory bowel disease. Subsequent to this case-control study, we continued to collect clinical data sheets documenting the findings at colonoscopy for these patients. Data collection and data entry were complete through the end of We used Cox proportional hazards modeling using the BMDP Statistical Software Package (BMDP Statistical Software, University of California Press, Los Angeles, CA) to compare the recurrence rates of adenomas with the incidence rates of adenomas, controlling for age, sex, and education. Cumula- tive incidence and recurrence rates were estimated from the curves generated as above. Results Of the 508 patients who had no abnormalities on their index colonoscopy, 99 (19.4%) underwent a repeat colonoscopy within the follow-up period. Of the 299 patients with an adenoma on their index colonoscopy, 178 (59.5%) underwent repeat colo,loscopy. The time intervals between colonoscopies varied. Table 1 shows demographic data on patients who underwent repeat colonoscopy and those who did not in the initial normal and initial adenoma groups. The patients with no abnormalities on initial colonoscopy who underwent followup were comparable with those who did not undergo repeat colonoscopy in sex and age distribution (Table 1). However, those who underwent repeat colonoscopy were more educated (P = 0.008) and more likely to be white (P = 0.005). Patients who had an adenoma on initial colonoscopy and underwent repeat colonoscopy also were similar in sex distribution but slightly younger than those who did not undergo follow-up colonoscopy. Their educational level was somewhat higher than that of patients who did not undergo repeat colonoscopy (P = 0.12), but the difference was not as great as for the initially normal group. Race distribution was similar for both adenoma groups. Table 2 shows data on clinical variables in the study population, including indications for initial and Table 1. Demographic Characteristics of Patients Who Underwent Repeat Colonoscopy and Those Who Did Not Index colonoscopy Normal results With follow-up Without follow-up With follow-up Without follow-up Sex (%) Male 46 (46.5) 179 (43.8) 102 (57.3) 71 (58,7) Female 53 (53.5) 230 (56.2) 76 (47.2) 50 (41.3) Age (yr [%]) (38.4) 149 (36.4) 38 (21.3) 18 (14.9) (33,3) 124 (30.3) 56 (31.5) 42 (34.7) (28.3) 136 (33.3) 84 (47.2) 61 (50.4) Median age Education (%) High school graduate or less 16 (16.2) 138 (33.8) 55 (30.0) 44 (36.4) Some college 19 (19.2) 69 (16.9) 20 (11.2) 22 (18.2) College graduate 21 (21.2) 52 (12.7) 42 (23.6) 21 (17.4) Postgraduate training 43 (43.4) 149 (36.5) 61 (34.3) 34 (28.1) Race (%) Black 2 (2.0) 41 (10.1) 9 (5.1) 10 (8.3) Hispanic 3 (3.0) 29 (7.1) 6 (3.4) 2 (1.6) White 92 (92.9) 333 (81.6) 159 (90.3) 108 (89.2) Asian 2 (2.0) 4 (1.0) Other -- 1 (0.2) 2 (1.1) 1 (0.8)

3 404 NEUGUT ET AL. GASTROENTEROLOGY Vol. 108, No. 2 follow-up colonoscopy. Among patients who underwent follow-up colonoscopy, rectal bleeding or other gastrointestinal symptoms were indications for the initial procedure in 44.4% of patients with no abnormalities initially and 43.8% of those with an adenoma on index colonoscopy. For the follow-up procedure, the main indications for the group with no abnormalities initially were rectal bleeding or other gastrointestinal symptoms (38.8%) and family history (32.6%). Among patients with adenomas on index colonoscopy, 94.9% underwent follow-up colonoscopy for surveillance. The percentage of patients with multiple adenomas on the index colonoscopy and the degree of dysplasia on the index colonoscopy for those who did and did not have follow-up were comparable (Table 2). The main results of the study are shown in Figure 1 and Table 3. The recurrence rate was significantly higher than the incidence rate. By the end of the follow-up period (mean, 34 months), 24% of patients with negative colonoscopy results initially (24 of 99) had developed a new adenoma and 46% of patients with adenoma initially (81 of 178) had had a recurrent adenoma. Figure 2 divides the initial adenoma group into those with a single adenoma on the index colonoscopy and those with multiple adenomas on the index colonoscopy. Unsurprisingly, risk of a new adenoma was highest in 100 A o~ 80 Q) U r, w 60 "0 "6 F-,>w 40 E u 2o lie E* E E X BE X EB X i l l l l l X X X x X X X **** I I I I I I I Time (Months) Figure 1. Cumulative incidence rates of adenomatous polyps by time interval after initial colonoscopy. I, polyps; x, normal. *P = the group that had multiple adenomas initially; risk in those with a single initial adenoma was lower but higher than that in patients who had no abnormalities on the index colonoscopy. Those with three or more adenomas had a higher recurrence rate, but the numbers were too small for statistical significance. When stratified by indication for follow-up colonoscopy, the recurrence rate remained higher than the incidence rate in every category *E Table 2. Clinical Characteristics of Patients Who Underwent Repeat Colonoscopy and Those Who Did Not Index colonoscopy Normal results With follow-up Without follow-up With follow-up Without follow-up Indications for index colonoscopy (%) Surveillance, screening Rectal bleeding Other gastrointestinal symptoms Family history Other indications Indications for first follow-up colonoscopy (%) Surveillance, screening Rectal bleeding Other gastrointestinal symptoms Family history Other indications No. of adenomas on index colonoscopy (%) >3 Degree of dysplasia on index colonoscopy (%) None or mild Moderate Severe Carcinoma in situ Intramucosal cancer 3 (3.0) 31 (31.3) 13 (13.1) 37 (37.4) 15 (15.2) 18 (18.4) 28 (28.6) 10 (10.2) 32 (32.6) 10 (10.2) 1 (0.2) 153 (37.6) 72 (17.7) 76 (18.7) 105 (25.8) 11 (6.2) 61 (34.3) 17 (9.5) 19 (10.7) 70 (39.3) 169 (94.9) 5 (2.8) 2 (1.1) 0 (0.0) 2 (1.1) 105 (66.5) 33 (20.9) 20 (12.6) 148 (93.7) 5 (3.2) 2 (1.3) 2 (1.3) 1 (o.5) 2 (1.6) 38 (31.4) 7 (5.8) 9 (7.4) 65 (53.7) 80 (66.1) 31 (25.6) 10 (&3) 114 (94.2) 6 (5.0) 1 (0.8) 0 (0.0) 0 (0.0)

4 February 1995 COLORECTAL ADENOMA INCIDENCE AND RECURRENCE 405 Table 3. Cumulative Incidence of No abnormalities on index colonoscopy on index colonoscopy Total Total no. of patients followed up 99 Men 46 Women 53 No. of adenomas on index colonoscopy >3 Indications for first follow-up colonoscopy Surveillance, screening 18 Rectal bleeding and/or other gastrointestinal symptoms 38 Family history 32 Other indications 10 on follow-up (%) Total on follow-up (%) 24 (24.0) (45.5) 9 (19.6) (48.0) 15 (28.3) (42.2) (41.9) (48.5) (65.O) 4 (22.2) (45.0) 4 (10.5) 7 3 (42.9) 11 (34.4) 0 0 (0.0) 5 (50.0) 2 2 (100.0) except family history. Recurrence rates were higher than incidence rates in all age groups in men and in women aged years (Table 4). Table 5 shows the index incidence rate and recurrence rate for adenomas by time interval after the index colonoscopy. As can be seen, the incidence rate up to 53 months is in the 17.5%-30% range, and the recurrence rate ranges from 28.6% to 39.5%. Among the 10 study participants who had follow-up after 53 months, only 1 had previously had an adenoma. Of the 9 who had not, 4 had an adenoma at months. Discussion Because of the difficulty in diagnosing adenomatous polyps and the general absence of symptoms associ- A,0 m ',~,_c m > 0 E O 4o 2O AA xx: AA X AA AA AA AA X Hi AAA X Ill A~X MI ** IlilliI *Alll 0 ---* ** *nil i I I I I I I Time (Months) Figure 2. Cumulative incidence rates of adenomatous polyps by time interval after initial colonoscopy, x, 1 adenomatous polyp; A, >1 adenomatous polyp; I, no adenomatous polyps. *P = *I IX *x 72 ated with them, true incidence rates have not previously been available. Results of repeated colonoscopy in individuals with normal results on initial examinations have not been reported. In this study, we present, to our knowledge, the first published data on incidence rates for colorectal adenomas. Rates of recurrence (or incidence of metachronous adenomas) have been reported in the past, but no prior study has directly compared the recurrence rate with the incidence rate in previously neoplasia-free individuals. This study shows that recurrence rates are indeed elevated compared with the incidence rate in normal individuals. This finding is reassuring inasmuch as it is known that postpolypectomy patients are known to have an elevated risk for colorectal cancer 2'33'47-52 and should therefore have an increased risk for metachronous adenomas as well. Our finding strengthens support for use of the adenoma recurrence rate as a surrogate end point in colon cancer chemoprevention trials The recurrence rate shown in this study is comparable with the rate previously described by our group in a similar population 34 as well as with the general range of recurrence rates in the literature However, the study has several limitations. The most obvious and important is the selection of the patients who underwent repeat colonoscopy. Less than one-fifth of the patients with initially normal results on colonoscopy underwent repeat colonoscopy. These patients probably are not representative of the entire cohort with initially normal results. They may have had persistent, recurrent, or new symptoms or a particularly high level of anxiety. The subgroup who underwent repeat colonoscopy had a higher educational level than those who did not have

5 406 NEUGUT ET AL. GASTROENTEROLOGY Vol. 108, No. 2 repeat colonoscopy. This sort of selection bias would probably be present in any study in which the incidence rate was generated from a screening program. Colorectal cancer has been associated with markers of high socioeconomic status in most populations, 53 but socioeconomic status is difficult to assess as a risk factor for adenomas because patients who undergo colonoscopy without having cancer are likely to be relatively well educated and insured. Another important limitation of this study is that the patients undergoing colonoscopy are not, for the most part, asymptomatic average-risk individuals. Most had an indication for the index colonoscopy: rectal bleeding, either occult or overt, other symptoms, or family history. Our prior study of this population did not show a significant variation in the prevalence of adenomas on index colonoscopy by symptom, nor was the prevalence of adenomas significantly higher in symptomatic than asymptomatic individuals. 46 Apparently, most adenomas diagnosed at colonoscopy are an incidental finding and not the cause of the symptoms that led to the colonoscopy. Thus, the prevalence or incidence rate of adenomas in this population undergoing colonoscopy may not be significantly different from what one might expect in the general population. The prevalence rate of adenomas in asymptomatic average-risk subjects in our population 25 was comparable with prevalence rates previously described in colonoscopy screening studies of asymptomatic average-risk individuals In the present study, patients with and without adenomas on index colonoscopy differed in the distribution of indications for follow-up. However, for each indication except family history, which is not an indication for colonoscopy in patients with a personal history of neoplasia, the recurrence rate was higher than the incidence rate. The patients with no abnormalities initially underwent recolonoscopy primarily because of symptoms, whereas the patients with adenomas underwent recolonoscopy for surveillance purposes (Table 2). Thus the difference between these two groups in follow-up yield is a conservative finding. Table 4. Cumulative Incidence and Recurrence Rates of by Sex and Age at Index Colonoscopy Men Women Age (yr) Adenoma (%) Normal (%) Adenoma (%) Normal (%) <55 9/25 (36.0) 4/18 (22.2) 2/13 (15.4) 4/20 (20.0) /29 (31.0) 2/15 (13.3) 14/27 (51.9) 4/18 (22.2) -->65 31/48 (64.6) 3/13 (23.1) 16/36 (44.4) 7/15 (46.7) Table 5. Incidence Rate and Recurrence Rate of by Time Interval Following Index Colonoscopy Index colonoscopy Normal results Adenoma Time interval No. No. (mo) scoped Recurrences scoped Recurrences The relatively high (34.4%) adenoma incidence rate in patients with no previous abnormalities who had a family history of colorectal cancer may have implications for screening intervals in this subgroup of patients. Other findings in this study are consistent with those of past studies. For example, the recurrence rate was higher among patients with multiple adenomas at index colonoscopy than for those with a single adenoma at index colonoscopy. It is estimated that up to 10% of adenomas are missed on a single colonoscopy. 54 Thus, some of the incidence rate may represent missed adenomas; however, we are unable to quantify this error. In summary, our study gives the first estimates of incidence rates for colorectal adenomatous polyps, with a cumulative incidence of approximately 16% after 3 years. The incidence rate of metachronous adenomas, or recurrence rate, was significantly higher than the initial adenoma incidence rate and was higher for those with multiple adenomas at initial polypectomy than for those with a single adenoma. Despite the selection factors in the overall patient population and the selection biases among patients undergoing repeat colonoscopy, these incidence and recurrence estimates appear to be consistent with prior studies and the understanding of the natural history of colorectal neoplasia. This information should be useful in the design of future chemoprevention trials and in the development recommendations for colorectal cancer screening. References 1. Jackman R J, Mayo CW. The adenoma-carcinoma sequence and cancer of the colon. Surg Gynecol Obstet 1951; 93: Neugut AI, Jacobson JS, DeVivo I. Epidemiology of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prey 1993; 2: Williams AR, Balasoorrya BAW, Day DW. Polyps and cancer of the large bowel: a necropsy study in Liverpool. Gut 1982;23:

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7 408 NEUGUT ET AL. GASTROENTEROLOGY Vol. 108, No. 2 as risk factors for colorectal adenomatous polyps. Ann Epidemiol 1993; 3: Neugut AI, Garbowski GC, Waye JD, Forde KA, Treat MR, Tsai JL, Lee WC. 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: , Brahme F, Ekelund GR, Norden JG, Wenckert A. Metachronous colorectal polyps: comparison of development of colorectal polyps and carcinomas in persons with and without histories of polyps. Dis Colon Rectum 1974; 17: , Rider JA, Kirsner JB, Moeller HC, Palmer WL. Polyps of the colon and rectum: their incidence and relationship to carcinoma. Am J Med 1954; , Weakley FL, Swinton NW. Follow-up study of patients with benign mucosal polyps of the rectum. Dis Colon Rectum 1962;5: , Koppel M, Bailar JC, Weakley FL, Shimkin MB. Incidence of cancer in the colon and rectum among polyp free patients. Dis Colon Rectum 1962;5: Lotfi AM, Spencer R J, Ilstrup DM, Melton J. Colorectal polyps and the risk of subsequent carcinoma. Mayo Clin Proc 1986; 61: Olsen HW, Lawrence WA, Snook CW, Mutch WM. Review of recurrent polyps and cancer in 500 patients with initial colonoscopy for polyps. Dis Colon Rectum 1988;31: Schottenfeld D, Winawer SJ. Large intestine, In: Schottenfeld D, Fraumeni JF, eds. Cancer epidemiology and prevention, Philadelphia: Saunders, 1982: Hixson L J, Fennerty MB, Sampliner RE, Garewal HS. Prospective blinded trial of the colonoscopic miss rate of large colorectal polyps. Gastrointest Endosc 1991;37: Received April 22, Accepted September 13, Address requests for reprints to: Alfred I. Neugut, M.D., Ph.D., Division of Oncology, Columbia-Presbyterian Medical Center, 630 West 168th Street, New York, New York