National Polyp Study data: evidence for regression of adenomas

Transcription

1 5 Natonal Polyp Study data: evdence for regresson of adenomas

2 78 Chapter 5 Abstract Objectves The data of the Natonal Polyp Study, a large longtudnal study on survellance of adenoma patents, s used for testng assumptons on the adenoma-carcnoma sequence. Methods The observed adenoma and colorectal cancer ncdence n the Natonal Polyp Study were compared wth the smulated outcomes of the MISCAN-COLON model of epdemology and control of colorectal cancer for the Unted States populaton based on expert opnon. Varants of ths model were explored n order to dentfy assumptons on the adenomacarcnoma sequence that are consstent wth the study observatons. Results The hgh observed adenoma detecton rates at survellance and low observed colorectal cancer ncdence n the Natonal Polyp Study could only be explaned by assumng a hgh ncdence rate of adenomas accompaned by regresson of adenomas. Conclusons The Natonal Polyp Study data suggest that adenoma prevalence results from a dynamc process of both formaton as well as regresson of adenomas. Ths lowers the expectatons for the effects of colorectal cancer screenng strateges that focus on adenoma detecton.

3 Natonal Polyp Study data: evdence for regresson of adenomas 79 Introducton The evoluton of colorectal cancer from a precursor leson, the adenoma, was frst reported n studes from St. Mark s Hosptal n London and later desgnated by Morson and coworkers as the adenoma-carcnoma sequence [Morson 1976, Morson 1984]. Morson stated that the evoluton of cancer from adenomas takes at least fve years and may be more than 20 years [Morson 1976]. Introducton of colonoscopy provded an opportunty for clarfyng ths sequence because of ts ablty to examne the entre colon and remove polyps for pathologcal examnaton. These pathology studes have n recent years been correlated wth molecular genetc studes [Vogelsten 1988]. The adenoma-carcnoma sequence s now well establshed as the major pathway for the development of colorectal cancer n the general populaton and n hgh rsk patents n famles wth Famlal Adenomatous Polyposs (FAP) and Heredtary Non-Polyposs Colorectal Cancer (HNPCC) [Muto 1975, Morson 1984]. The epdemology and natural hstory of adenomas are not only mportant for choosng the optmal follow-up polcy after polypectomy, but also for evaluatng endoscopc screenng for colorectal adenomas and cancer. A better understandng of the dynamcs of the adenoma-carcnoma progresson would further clarfy what can be expected of varous colorectal cancer screenng strateges that nvolve adenoma detecton. The Natonal Polyp Study was a longtudnal study that provded prospectve data on the adenoma-carcnoma sequence and the effect of colonoscopc polypectomy. It was organzed n 1978 and began to accrue patents n Its purpose was to evaluate more frequent and less frequent follow-up survellance ntervals n patents n whom newly dagnosed adenomas were removed. Removal of these adenomas resulted n a colorectal cancer ncdence that was markedly lower than expected wthout polypectomy. In ths report we present a study of the natural hstory of the adenoma-carcnoma sequence, applyng a mcro-smulaton model for colorectal cancer epdemology and control (MISCAN-COLON) [Loeve 1999] to the data of the Natonal Polyp Study. Materal and methods The Natonal Polyp Study data The Natonal Polyp Study was a randomzed controlled tral of colonoscopc survellance n patents who have had at least one adenoma removed [Wnawer 1993b]. All patents referred for colonoscopy or polypectomy between November 1980 and February 1990 n seven partcpatng centers who dd not have a famly or personal hstory of famlal polyposs, nflammatory bowel dsease, or a personal hstory of polypectomy or colorectal cancer were elgble for enrollment n the study. A total of 9112 subjects referred for colonoscopy were canddates for the study. Of these, 4763 were excluded because no polyps were found. Other excluded subjects were 776 wth non-adenomatous polyps only, 549 wth colorectal cancer, 149 wth nflammatory bowel dsease or other condtons, and

4 80 Chapter 5 35 wth a sessle adenoma wth a base larger than 3cm. Patents wth ncomplete ntal examnatons were also excluded (n=208). The colon had to be cleared wth 3 examnatons or wthn 3 months for the patent to be part of the study. Of the 2632 elgble patents, 1418 patents consented to partcpate and were randomzed to one of two arms. All detected polyps were removed and a survellance colonoscopy was offered n Arm A at 1, 3 and 6 years after ntal colonoscopy and n Arm B at 3 and 6 years after ntal colonoscopy. If the colon was not cleared wth hgh confdence at survellance colonoscopy, the patent was scheduled for repeat colonoscopy. Mean follow-up tme was 5.9 years. Fve cancers were found durng the tral (C. I ) (2 n arm A and 3 n arm B), whle 21 were expected based on the U.S. populaton wth the same age and sex dstrbuton [Wnawer 1993a], and 43 to 48 were expected based on a comparson wth two polyp bearng cohorts wthout nterventon [Stryker 1987, Atkn 1992]. All fve cancers were asymptomatc malgnant adenomas detected at survellance colonoscopy. The model The results of the MISCAN-COLON model are generated by mcro-smulaton of ndvduals n whom adenomas and subsequent colorectal cancer may develop. Although the MISCAN-COLON model s orgnally desgned for evaluaton of populaton based screenng n an asymptomatc populaton, t can also be used to smulate survellance after polypectomy. The output of the model conssts of the adenoma and cancer detecton rates at ntal and survellance colonoscopy and the effect of ntal and survellance colonoscopy on cancer ncdence and mortalty. Parameter values n the expert-opnon-based model (expert MISCAN-COLON model) as presented n Table 5.1 have been establshed durng two meetngs at the Unted States Natonal Cancer Insttute [Loeve 1998, Loeve 1999, Loeve 2000]. In ths expert model, t s assumed that adenomas are ether non-progressve and wll never develop nto cancer n a lfetme or progressve and are destned to develop nto colorectal cancer. The average duraton between ncdence of a progressve adenoma and clncal dagnoss of cancer s assumed to be 20 years. The duraton between adenoma ncdence and preclncal colorectal cancer s assumed exponentally dstrbuted wth a mean of 16.4 years, whle the duraton of preclncal cancer s exponentally dstrbuted wth a mean of 3.6 years. It s assumed that polypectomy completely prevents growth of the polyp nto cancer. If all ndvduals have equal rsk for adenomas,.e., adenomas are randomly dstrbuted over the populaton, the resultng adenoma multplcty s Posson dstrbuted. However, autopsy studes show a larger than Posson varaton [Koretz 1993], probably because of varaton n genetc and envronmental factors. The model accounts for the heterogenety n adenoma multplcty by drawng a rsk ndex for each ndvdual. The ndvdual adenoma ncdence rate s equal to the ndvdual rsk ndex multpled by the age-specfc adenoma ncdence rate. Ths rsk ndex s drawn from a gamma dstrbuton wth mean 1 and a varance of 2, whch s chosen to ft the multplcty dstrbuton of adenomas n autopsy studes [Dggle 1994]. The probablty that a new adenoma s progressve s age-dependent but does not depend on the ndvdual rsk ndex. The agespecfc adenoma ncdence and the probablty that an adenoma s progressve s chosen to ft observed US cancer ncdence n 1978 before the ntroducton of screenng [Natonal

5 Natonal Polyp Study data: evdence for regresson of adenomas 81 Table 5.1 Man assumptons n the expert MISCAN-COLON model, establshed n expert meetngs at the Natonal Cancer Insttute n 1996 and Parameter Value Based on Adenoma ncdence Age dependent: yrs: 0.9% per yr yrs: 1.9% per yr yrs: 3.3% per yr yrs: 2.6% per yr Adenoma prevalence n autopsy and colonoscopy studes of 15% n age group to 33% n age group 70+ [Johnson 1990, DSaro 1991, Leberman 1991b, Rex 1991, Koretz 1993], cancer ncdence n SEER regstry n 1978 [Natonal Cancer Insttute 2001] Dstrbuton of rsk for adenomas over the general populaton Duraton dstrbutons n preclncal stages Mean duraton of nonprogressve adenomas Mean duraton of progressve adenomas Mean duraton of preclncal cancer Probablty to develop cancer from removed adenoma Senstvty of dagnostc and survellance colonoscopy for adenomas Senstvty of dagnostc and survellance colonoscopy for cancer Gamma dstrbuted, mean 1, varance 2 Exponental Lfelong 16.4 yrs Expert opnon Multplcty dstrbuton of adenomas n autopsy studes [Koretz 1993] Expert opnon, other cancer models [Walter 1983, Gyrd- Hansen 1997, Launoy 1997] Expert opnon 3.6 yrs Cancer detecton rate at frst screenng and background cancer ncdence n FOBT trals [Hardcastle 1989, Kronborg 1989] 0% Expert opnon 5mm: 80% 6-9mm: 85% 10+mm: 95% Back-to-back colonoscopy studes [Hxson 1991, Rex 1997b, Rex 1997c] 95% Back-to-back colonoscopy studes [Hxson 1991, Rex 1997b, Rex 1997c] Cancer Insttute 2001] and prevalence of adenomas n autopsy and colonoscopy studes [Johnson 1990, DSaro 1991, Leberman 1991b, Rex 1991, Koretz 1993]. The partcpants n the Natonal Polyp Study had adenomas dagnosed and removed. The MISCAN-COLON model s adapted to ths stuaton by applyng a

6 82 Chapter 5 fcttous screenng test to the general populaton to select ndvduals wth adenomas detected at dagnostc colonoscopy. These ndvduals consttuted the smulated tral populaton. Lke n the Natonal Polyp Study, smulated ndvduals wth colorectal cancer dagnosed at the dagnostc colonoscopy were excluded from the tral populaton. The senstvty of the fcttous screenng test was adjusted to reproduce the age dstrbuton, the dstrbuton of adenomas over the dstal and proxmal colon, and the sze and multplcty-dstrbuton of adenomas at ntal polypectomy n the Natonal Polyp Study. In the Natonal Polyp Study, ncomplete survellance colonoscopes (%) were followed by repeat colonoscopy. Therefore, we defne a survellance examnaton as a seres of one or more colonoscopes n a short tme perod of whch at least one reaches the cecum and the examnaton s consdered to be of hgh confdence. The reach of a survellance examnaton s assumed to be 100%,.e., the complete bowel s vsualzed. The reach of the ntal colonoscopy s also assumed to be 100% because patents wth ncomplete ntal colonoscopes were excluded from the study. Senstvty of the ntal colonoscopy and the survellance examnatons s based on tandem studes of colonoscopy and ncreases from 80% for adenomas 5mm to 95% for preclncal cancer [Hxson 1991, Rex 1997b, Rex 1997c]. The smulated populaton of 5 ndependent smulatons of 30,000 each (5*30,000=150,000) was desgned to be approxmately 100 tmes as large as the observed Natonal Polyp Study cohort of 1,418 patents n mnmze chance varaton n the smulaton results. The Natonal Polyp Study survellance schema and the observed complance rates per arm and round are appled to the smulated tral populaton. Analyss Outcomes of the model are the smulated number of cancers durng the tral and the smulated number of survellance examnatons at whch adenomas are detected. The model further dfferentates between cancers that are detected by a survellance examnaton and those that are nterval detected. These cancers are further subdvded nto those orgnatng from adenomas or preclncal cancers mssed at ntal colonoscopy, and those n newly developed, fast-progressng lesons. The observed cancer and adenoma ncdence rates n the tral were compared wth the rates as smulated by the MISCAN-COLON model based on expert opnon. In case of dscrepances between observed and smulated results, we vared a few pvotal assumptons n order to search for models that are consstent wth observed results. Parameters that were vared are the adenoma ncdence n the tral populaton, the duraton dstrbuton of progressve adenomas, the spontaneous regresson rates of non-progressve adenomas, and the senstvty of colonoscopy. The goodness of ft of each set of model assumptons s evaluated by the devance, whch compares fve outcomes of the model wth the observed Natonal Polyp Study results. The results that are ncluded n the devance are the number of survellance detected (asymptomatc) cancers (observed n the Natonal Polyp Study: 5), the number of nterval cancers (observed: 0), the number of survellance examnatons wth adenomas n Arm A at the frst survellance examnaton (observed: 150 n 545 examnatons), n Arm A at the 2nd survellance examnaton (observed: 73 n 338 examnatons) and n Arm B at

7 Natonal Polyp Study data: evdence for regresson of adenomas 83 the frst survellance examnaton (observed: 137 n 428 examnatons). The devance s defned as 5 = 1 2 ( k (log p log λ ) + ( n k ) (log(1 p ) log(1 λ ))) where k s the observed number of occurrences for outcome, n s the observed number of partcpants for the cancer results and the number of examnatons for the adenoma results, p =k /n s the observed rate, and λ s the smulated rate. A low devance ndcates a good ft wth the Natonal Polyp Study data. If the devance s hgher than 11.07, the smulated results are sgnfcantly dfferent from the observed results n the Natonal Polyp Study. Results MISCAN-COLON model based on expert opnon Table 5.2 shows that the MISCAN-COLON model based on expert opnon smulated a Table 5.2 Characterstcs at ntal polypectomy of all patents and ther adenomatous polyps ncluded n the Natonal Polyp Study, as observed n the Natonal Polyp Study and as smulated n the expert MISCAN-COLON model (n=1418). Characterstc Observed Smulated Age <50 13% 11% % 27% % 40% % 20% 80+ 2% 3% Adenoma sze* 5mm 27% 27% 6-9mm 18% 17% 10mm 55% 56% No. of adenomas* 1 57% 61% 2 22% 23% 3 20% 16% Ste of largest adenoma* Dstal colon 64% 61% Proxmal colon 36% 39% * Forty-four patents wth polyps classfed as adenomas by the local pathologst were classfed as non-adenomas by the revew pathologsts and were excluded from the Natonal Polyp Study cohort smulated n ths modelng study (n=1374).

8 84 Chapter 5 cohort that successfully reproduced the characterstcs at ntal polypectomy of the Natonal Polyp Study populaton. However, ths expert MISCAN-COLON model smulates a cancer ncdence durng the survellance perod of 1.5 per 1000 person-years whch s more than twce as hgh as the observed 0.6 (95% confdence nterval ), whle t smulates a 18% adenoma detecton rate at survellance examnatons whch s consderably lower than the observed 27% (95% confdence nterval, 25%-30%), see model A n Table 5.3. Of the smulated cancer ncdence n the frst sx years after ntal polypectomy, 61% s caused by cancers developed from new progressve adenomas, 22% s caused by mssed adenomas that progressed nto cancer and 18% s from preclncal cancers mssed at ntal colonoscopy. Of the smulated cancers, 40% s found at survellance colonoscopy, and 60% are dagnosed because of symptoms, whle n the Natonal Polyp Study all 5 ncdent cancers were detected at survellance. The overall goodness of ft of the expert model s poor, manly caused by the poor ft of adenoma detecton rates. Natural hstory assumptons to better explan the observed rates Hgher model-smulated adenoma detecton rates than n the expert MISCAN-COLON model can be acheved wth a lower senstvty of colonoscopy for adenomas or a hgher adenoma ncdence. Low senstvty for adenomas. The senstvty for adenomas has to be extremely low n order to smulate the observed adenoma detecton rates n the Natonal Polyp Study, whch conflcts wth the low observed cancer ncdence (model B n Table 5.3). Hgher adenoma ncdence. The smulated adenoma detecton rates are more n agreement wth the observatons when the adenoma ncdence rate n the patents referred for colonoscopy s doubled (model C n Table 5.3). The resultng adenoma prevalence s not n agreement anymore wth the adenoma prevalence n the unscreened general populaton whch s about 33% n the 70+ age category [Johnson 1990, DSaro 1991, Leberman 1991b, Rex 1991, Koretz 1993, Levn 1999]. However, the Natonal Polyp Study cohort s a selected populaton wth an adenoma ncdence that may be hgher than n the general populaton. A serous problem s that ncreasng the adenoma ncdence also ncreases the rsk for cancers, thus further ncreasng the already too hgh smulated cancer ncdence (from 1.5 to 2.4 per 1000 person years compared to 0.6 observed). Ths could theoretcally be resolved by restrctng the ncrease n ncdence to non-progressve adenomas. However, ths would make the cancer rsk n patents wth multple adenomas smlar to the cancer rsk n patents wth only one adenoma, whch s not consstent wth publshed data that show that adenoma multplcty s a rsk factor for colorectal cancer [Lotf 1986, Bertaro 1999]. Therefore, assumng a hgher adenoma ncdence that s assocated wth a hgher adenoma prevalence has to be rejected. Hgher adenoma ncdence combned wth regresson. The hgh adenoma detecton rates n the Natonal Polyp Study can also be explaned by assumng hgh adenoma ncdence compensated by spontaneous regresson of (non-progressve) adenomas. If spontaneous regresson occurs regularly, adenoma ncdence can be hgh whle adenoma prevalence agrees wth observed prevalence, even n older age groups where adenoma prevalence and multplcty hardly ncrease accordng to autopsy and colonoscopy studes.

9 Natonal Polyp Study data: evdence for regresson of adenomas 85 Table 5.3 Cancer ncdence rate and proporton of survellance examnatons wth adenomas as observed n the Natonal Polyp Study populaton and as smulated wth the expert MISCAN-COLON model and several model varants. Cancer rate per 1000 person years Proporton of survellance examnatons wth adenomas Survellance detected Interval detected Observed * ** A. Expert MISCAN-COLON assumptons Assumptons ntended to rase the adenoma detecton rate B. Low adenoma senstvty (60%) C. Hgh adenoma ncdence D. Hgh adenoma ncdence and spontaneous regresson Assumptons ntended to reduce the cancer ncdence rate E. No fast-growng adenomas (constant duraton of 20 yr) F. Hgh cancer senstvty (100%) Assumptons ntended to ft both the cancer ncdence and adenoma detecton rate G. No fast-growng adenomas, hgh adenoma ncdence and spontaneous regresson H. Hgh cancer senstvty, hgh adenoma ncdence and spontaneous regresson * 95% Confdence nterval ** 95% Confdence nterval Although t s generally assumed that adenomas grow nto cancer or reman n the colon untl death, spontaneous regresson or washout of adenomas has been reported [Cole 1961, Knoernschld 1963, Hoff 1986, Gardello 1993]. In the observatonal study of Knoernschld, the mucosa near asymptomatc bengn polyps was tattooed n 257 patents. After follow-up of 3 to 5 years, the polyp had completely dsappeared n 18% of the patents. Table 5.3 shows the results of model D n whch non-progressve adenomas dsappear on average after 5 years wth an exponentally dstrbuted duraton. The adenoma ncdence s three to fve tmes hgher than n the expert MISCAN-COLON model. Between the ages 55 years and 84 years the ncdence s approxmately 10% per All Arm A, year 1 Arm A, year 3 Arm B, year 3 All Devance

10 86 Chapter 5 year wth a peak n age group years of 16% per year. Ths model varant results n adenoma detecton rates that are more n agreement wth the Natonal Polyp Study observatons. Because n ths model most ndvduals wll develop adenomas at some tme durng ther lfe, the colorectal cancer rsk n ndvduals wth adenomas s less ncreased than n the expert MISCAN-COLON model. Ths explans why the smulated colorectal cancer ncdence s lower than n the expert MISCAN-COLON and not sgnfcantly dfferent from the observed colorectal cancer ncdence (model D n Table 5.3). In summary, a hgh adenoma ncdence combned wth spontaneous regresson of adenomas s the only explanaton of the observed adenoma detecton rate that does not ncrease smulated cancer ncdence and even decreases the smulated cancer ncdence. The devances of models B, C, and D are all lower than the devance of the expert MISCAN-COLON model, whch ndcates that models B, C, and D are more n agreement wth the Natonal Polyp Study results. The smulated results of model B and C are stll sgnfcantly dfferent from the observed results (P<0.05), manly due to the dfference n nterval-detected cancers. The smulated results of model D are sgnfcantly dfferent from the observed results (P<0.05), due to the dfference n nterval-detected cancers and the smulated adenoma detecton rate n Arm A, year 1. To decrease the smulated cancer ncdence further, we explored two possbltes for lowerng the cancer ncdence: no fast-growng progressve adenomas, and a hgh senstvty of colonoscopy for cancer. No fast-growng adenomas. In the expert MISCAN-COLON model, approxmately 30% of the progressve adenomas wll develop nto cancer wthn sx years, due to the exponentally dstrbuted duraton of 20 years on average. Wth fewer fast-growng progressve adenomas than assumed n the expert MISCAN-COLON model, cancers from new polyps wll not surface n the frst years after polypectomy and thus the ncdence wll reman low. As an example, model E n Table 5.3 s a model n whch adenomas do not develop nto cancer wthn the tral perod,.e., there are no fast-growng (wthn sx years) progressve adenomas. Under these assumptons, none of the ncdent cancers n the frst sx years after polypectomy are newly developed, 74% develop from cancers mssed at ntal colonoscopy and 26% develop from adenomas mssed at ntal colonoscopy. The percentage of cancers developng from mssed adenomas s small, because most mssed adenomas are small and take more than sx years to develop. In ths smulaton, 51% of the cancers are dagnosed at survellance examnatons, compared to 39% n the expert model. The smulated cancer ncdence rate decreases from 1.5 to 0.6 per 1000 years, whch s equal to the observed rate. Hgher senstvty for cancer. The assumed senstvty of colonoscopy for cancer s 95% n the expert model, based on a retrospectve study of colonoscopc senstvty for cancer [Rex 1997c]. However, n the NPS study sgmodoscopy or barum enema was performed as the reason for referral for colonoscopy n 25% and 44% of the patents respectvely [Wnawer 1992] and often addtonal colonoscopes were performed to "resolve" cases, whch gves extra opportuntes to detect cancer n these patents. Rasng the senstvty for preclncal cancer n the MISCAN-COLON model from 95% to 100%

11 Natonal Polyp Study data: evdence for regresson of adenomas 87 reduces the ncdence from mssed cancers. But because mssed cancers cause only 18% of the cancer cases n the expert model, the decrease n cancer ncdence s modest, from 1.5 to 1.2 per 1000 years (model F n Table 5.3). Nether of these two assumptons that ncrease the cancer ncdence n the study perod affect the smulated adenoma detecton rates, whch remans too low. Because the devance largely depends on the adenoma detecton rates, the devances of model E and F are comparable or hgher than the expert MISCAN-COLON model (model A). Table 5.3 shows the results of the MISCAN-COLON model wth hgh adenoma ncdence and spontaneous adenoma regresson, combned wth no fast-growng progressve adenomas (model G), and combned wth 100% colonoscopc senstvty for cancer (model H). The smulated cancer ncdence n model G s more than 60% reduced compared to model F, whle the smulated cancer ncdence n model H s only slghtly reduced compared to model F. In Model D the smulated cancer ncdence s hgher than observed, but not sgnfcantly dfferent. If that model s modfed wth the assumpton of no fast growng adenomas (model G), the smulated cancer ncdence s lower than observed, but agan not sgnfcantly dfferent. Thus, models that nclude the assumpton of development and regresson of adenomas and n whch the percentage of the progressve adenomas that wll develop nto cancer wthn sx years s between 0% and 30% are consstent wth the observed cancer ncdence. The devances of model G and H are comparable wth the devance of model D. Dscusson The assumptons of the expert MISCAN-COLON model were developed n collaboraton wth the Natonal Cancer Insttute, Unted States, n meetngs of a group of colorectal cancer experts [Loeve 1999]. In order to clarfy the natural hstory of the adenomacarcnoma sequence, a few pvotal natural hstory assumptons made by ths group were modfed to determne whch natural hstory assumptons best ft the Natonal Polyp Study observed data. The expert MISCAN-COLON model predcted a hgher cancer ncdence and lower adenoma detecton rates than observed n the Natonal Polyp Study. In order to have the hghest concordance between the model results and the Natonal Polyp Study results, a new factor had to be ntroduced,.e., adenoma regresson. Hgh adenoma ncdence combned wth regresson accounted for the hgh percentage of patents wth adenomas at survellance, wthout losng ts consstency wth adenoma prevalence data from autopsy studes and wthout ncreasng the colorectal cancer ncdence durng the study. The hgh ncdence s supported by a study of repeat colonoscopy that estmated that the 1-year adenoma ncdence rate s 11% [Bensen 1999]. The assumpton that adenomas spontaneously regress s supported by prevous fndngs n short-term studes that adenomas may regress n sze [Hoff 1986, Hofstad 1996]. A recent study of celecoxb n patents wth famlal adenomatous polyposs reported adenoma regresson n the control group. In ths study, a tattoo was placed at baselne endoscopy near a small area wth a hgh densty of polyps. Repeat endoscopy was performed sx months later and the number of polyps at the tattooed area n the placebo group was 4.5%

12 88 Chapter 5 less than at baselne endoscopy [Stenbach 2000]. The Telemark study recently reported that adenoma prevalence n patents who had undergone sgmodoscopy 13 years before was not sgnfcantly lower than n the patent wthout prevous sgmodoscopy. The authors menton adenoma regresson as one of the possble explanatons [Ths-Evensen 2001]. The cost-effectveness of repeat sgmodoscopy or colonoscopy colorectal cancer screenng n the general populaton has been studed usng models [Frazer 2000, Khandker 2000, Sonnenberg 2000]. None of these ncluded the assumpton that adenomas regress and adenoma ncdence s accordngly hgh. Hgh adenoma ncdence combned wth regresson makes adenoma detecton as a strategy for colorectal cancer preventon less favorable, because more adenomas wll develop n the populaton after polypectomy. Furthermore, t s lkely that more ndvduals wll develop at least one adenoma. Thus, n repeat screenng rounds, many adenomas wll be detected n those wthout prevous adenomas. There s less dfference n rsk level between ndvduals wth and wthout adenomas, makng survellance of adenoma patents less effectve. Also, many adenomas wll be detected at survellance n ndvduals wth adenomas detected, as observed n the Natonal Polyp Study. Ths ncreases the fnancal and qualty of lfe costs expected of frequent survellance and (endoscopc) screenng. The Natonal Polyp Study provded the opportunty to examne the dynamcs of the natural hstory of the adenoma-carcnoma sequence. The outcome suggests that the adenoma-carcnoma sequence s a dynamc process of formaton and regresson of adenomas. Ths has negatve consequences for the effects and costs expected from endoscopc colorectal cancer screenng and survellance of adenoma patents. Acknowledgement Work was partally supported by Research Contract NO1-CN wth the Natonal Cancer Insttute n Bethesda, Maryland. Support was also gven by the Tavel-Reznk Fund. The authors thank Martn Brown, Project Offcer of the Natonal Cancer Insttute.