Registre des Tumeurs Digestives du Calvados, CJF INSERM 96-03, Faculté de Médecine, Avenue de Côte de nacre, Caen cedex, France;

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1 British Journl of Cncer (1999) 81(2), 5 9 Article no. bjoc Colorectl cncer fter negtive Hemoccult II test nd progrmme sensitivity fter first round of screening: the experience of the Deprtment of Clvdos (Frnce) V Bouvier 1, G Lunoy 1, C Herbert 1, H Lefevre 1, J Murel 1,2 nd M Gignoux 1,2 1 Registre des Tumeurs Digestives du Clvdos, CJF INSERM 96-03, Fculté de Médecine, Avenue de Côte de ncre, 132 Cen cedex, Frnce; 2 Service de Chirurgie Digestive, CHU, Avenue de Côte de ncre, 133 Cen cedex, Frnce Summry Colorectl cncers emerging fter negtive Hemoccult II re described in the context of first round of mss screening in the Deprtment of Clvdos (Frnce), from April 1991 to the end of December People with cncer occurring fter negtive test until 31 December 1995 were identified by locl cncer registry. Incidence ws clculted nd the progrmme sensitivity ws estimted. The incidence of cncer emerging fter negtive test ws 57.7 per 000, i.e. hlf of the clculted incidence in the reference group (141.6 per 000). These cncers did not differ from those of either the non-responder or reference groups, in prticulr for the stge of extension. The progrmme sensitivity ws globlly higher thn tht estimted in Europen trils: 77.2, 66.3 nd 55.9%, 1, 2 nd 3 yers fter the test respectively. Progrmme sensitivity ws higher for distl colon cncer 1 yer fter the test, which is probbly due to the reltively slow growth of this subsite. Keywords: colorectl cncer; screening; flse-negtive test; Hemoccult II ; progrmme sensitivity Colorectl cncer is frequent in Western countries. In Frnce, with 33 0 cses per yer (Benhmiche et l, 1997), it is the most frequent cncer for both sexes nd represents bout 15% of ll mlignnt tumours (Fivre et l, 1997). Severl mss-screening trils took plce in the 19s, essentilly in Anglo-Sxon countries. Hemoccult II, the most frequently used fecl occult blood test until now, hs hd its efficcy proven in three controlled trils (Mndel et l, 1993; Hrdcstle et l, 1996; Kronborg et l, 1996), with significnt reduction of colorectl-specific mortlity between the screened groups nd the control groups. Unfortuntely, the benefit obtined is low nd the extension of screening to the generl popultion in Frnce must overcome two problems: the poor prticiption rte nd the reltively low sensitivity of the test. In the literture the definition of sensitivity is vrible. In fct, it is importnt to distinguish test sensitivity nd progrmme sensitivity. The ltter, which is the most frequently used, corresponds to the bility of screening progrmme to detect cncer, nd cn be directly estimted with the rtio / + c where is the number of cncers detected by screening nd c the number of cncers emerging fter negtive test. The former is the bility of test to detect cncer nd cnnot be directly estimted since c includes not only cncers missed by the test but lso rpidly growing cncers not yet existing t the time of the test. Its estimtion thus requires either modelling of the test rection s function of the presence of occult blood in the feces, s clculted with the dt of the Minnesot tril using rehydrted test (Church et l, 1997), or modelling the MST (men sojourn time) of the Received 7 July 1998 Revised 25 Mrch 1999 Accepted 12 April 1999 Correspondence to: V Bouvier tumour s recently clculted with French dt (Lunoy et l, 1997). Due to this reltively low sensitivity of the test, the emergence of cncer mong subjects with negtive test could become one of the problems physicins my fce in mss screening. At present, dt bout such cncers is sprse. The present study describes cncers emerging fter negtive Hemoccult II (without rehydrtion) from the dt of the first round of screening in the Deprtment of Clvdos, nd determines their incidence ccording to clinicl prmeters (sex, ge, subsite nd stge) nd the time since the test. Using this incidence, the progrmme sensitivity, defined s the probbility for n individul with detectble colorectl cncer to be detected by this progrmme, ws estimted ccording to the sme prmeters. POPULATION AND METHODS Between April 1991 nd the end of December 1994, first round of screening for colorectl cncer with Hemoccult II ws progressively done in the six res of the Deprtment of Clvdos (Frnce). The popultion invited for screening comprised people ged yers. The six res were progressively included in the screening progrmme over 18 months. The tests were first proposed by generl prctitioners nd occuptionl doctors. Letters were then sent out inviting people to obtin the test free of chrge from their generl prctitioner or phrmcist. No dietry or drug restrictions were required. All tests were miled to single centre nd were processed without rehydrtion. A test ws considered positive when blue colour ppered in the centre or diffused from the centre to the edges of the slide within s fter plcing drop of hydrogen peroxide in the centre. It ws considered borderline when the blue stin ws confined to the edges. If the result ws positive or borderline, subjects were 5

2 6 V Bouvier et l Tble 1 Chrcteristics of colorectl cncer in Deprtment of Clvdos between 1991 nd 1995 for people ged 45 to 74 Positive test Negtive test Non-responders Reference Totl Sex Mle 94 (61.8) 52 (52.0) 7 (59.8) 7 (58.1) 5 Femle 58 (36.2) 48 (48.0) 139 (.2) 149 (41.9) 394 Stge I 69 (45.4) 28 (28.0) 85 (24.6) 84 (23.6) 266 II 83 (54.6) 72 (72.0) 265 (75.4) 272 (76.4) 692 Age (8.5) (.0) 35 (.1) 35 (9.8) (31.0) 35 (35.0) 112 (32.4) 1 (33.7) (.5) 55 (55.0) 199 (57.5) 1 (56.5) 547 Subsite Proximl 26 (17.1) 25 (25.0) 78 (22.5) 74 (.8) 3 Distl 98 (64.5) 42 (42.0) 155 (44.8) 176 (49.4) 471 Rectum 26 (17.1) 33 (33.0) 1 (31.8) 6 (29.8) 275 Unknown 2 (1.3) 0 3 (0.9) 0 5 Totl Stge I: Dukes A; Stge II: ll the others. Tble 2 Distribution of sex, ge, stge nd subsite of cncer occurring fter negtive test ccording to the time since test First yer Second yer Third yer Totl Sex Mle 23 (51.1) 16 (51.6) 13 (54.2) 52 Femle 22 (48.9) 15 (48.4) 11 (45.8) 48 Stge I 14 (31.1) (32.3) 4 (16.7) 28 II 31 (68.9) 21 (67.7) (83.3) 72 Age (8.9) 4 (12.9) 2 (8.3) (37.8) (32.3) 8 (33.3) (53.3) 17 (54.8) 14 (58.4) 55 Subsite Proximl 8 (17.8) 11 (35.5) 6 (25.0) 25 Distl 24 (53.3) 9 (29.0) 9 (37.5) 42 Rectum 13 (28.9) 11 (35.5) 9 (37.5) 33 Totl Stge I: Dukes A; Stge II: ll the others. Figure 1 Progrmme sensitivity ccording to time since test invited by their prctitioner to undergo colonoscopy. Screening orgniztion nd the test modlity hve been described in previous ppers (Lunoy et l, 1995, 1996). Of those invited for this first round of screening, 71 7 subjects completed the test (rte prticiption: 43.4%). The positivity rte ws 2.8% ( positive tests). Among this popultion, 13 (79.4%) were fully investigted (colonoscopy ± DCBE), nd 1277 (63.2%) hd complete colonoscopy. Thus 152 cncers were dignosed nd the predictive positive vlue for cncer ws 9.5%. All the cncers dignosed between 1991 nd 1995 in people living in the deprtment were recorded by the locl digestive cncer registry, whether they occurred in subject prticipting in the screening or not. In this wy, four different groups were constituted: 1. Cncers occurring fter positive test in prticipting individuls (positive-test group) 2. cncers occurring fter negtive test in prticipting individuls (negtive-test group) 3. cncers occurring in people refusing to prticipte (refusers group) British Journl of Cncer (1999) 81(2), 5 9

3 Sensitivity of colorectl cncer screening 7 Tble 3 Incidence of colorectl cncer per 000 fter negtive test ccording to time nd clinicl prmeters Time People t Cumulted Cumulted Cumulted incidence Cumulted incidence Cumulted the beginning incidence incidence ccording to ge ccording to subsite incidence of the period ccording to ccording sex to stge Mle Femle Proximl Distl Rectl I II ( ) ( ) ( ) ( ) ( ) ( ) Stge I: Dukes A; Stge II: ll the others. 4. cncers occurring before the offer of screening (reference group). The follow-up ws t lest 12 months for ll the negtive test group, 24 months for.5% nd 36 months only for 38.5% of it. These vlues were tken into ccount for the clcultion of colorectl cncer incidence fter negtive test. For exmple, people who completed the test in My 1994, with n 18-month follow-up, were considered s censored dt over this period for the determintion of incidence. The progrmme sensitivity ws estimted by Se p = / + c, being the number of cncers detected with positive test nd c the number of cncers occurring fter negtive test. After 12 months, cncers emerging fter negtive test were known only for people who hd long enough follow-up period. So fter 12 months, c in the formul Se p = / + c ws estimted by pplying n incidence clculted s bove to the totl number of negtive tests. Extension of cncers ws clssified ccording to two stges: stge I (Dukes A: crcinom not yet extended through the musculris propri nd no regionl lymph node metstsis (Dukes, 1932)) nd stge II for ll the others. Subsite ws clssified ccording to three segments: the proximl colon including cecum, scending colon, heptic flexure nd trnsverse colon; the distl colon with splenic flexure, descending colon, sigmoid colon nd rectosigmoid, nd the rectum. The incidence nd the progrmme sensitivity were clculted with Microsoft Excel 5.0 softwre nd for sttisticl nlysis, SAS System for Windows, Relese 6. softwre ws used. RESULTS Cncers occurring fter negtive test From 1 Jnury 1991 to 31 December 1995, 988 cncers were dignosed in Clvdos: 152 (16.0%) fter positive test (positivetest group), (.5%) fter negtive test (negtive-test group), 346 (36.3%) in the non-responder subjects (refusers group) nd 356 (37.3%) before screening invittion (reference group). Thirtyfour cncers were excluded: 22 (2.2%) for incomplete dt nd 12 (1.2%) cses dignosed more thn 36 months fter negtive test. Tble 1 shows the distribution of clinicl chrcteristics of cncer ccording to group. Cncers in the negtive-test group were significntly different from those of the positive-test group, regrding stge (P < 0.05) nd subsite (P < 0.05), but not from the refusers group or the reference group. Figure 2 Men Women Progrmme sensitivity ccording to sex. Tble 2 shows clinicl chrcteristics (sex, ge, stge, subsite) of cncers occurring fter negtive test ccording to the time since test. No significnt difference ws found in distribution of sex, ge, stge nd subsite ccording to the time since test. Tble 3 shows the evolution of incidence of cncer mong people with negtive test ccording to the clinicl prmeters. Men incidence during this period ws 57.7 per 000. In comprison, clculted incidence in the reference group for the sme period ws per 000, more thn twice the men incidence in the negtive-test group. Progrmme sensitivity fter first round Figures 1 nd 2 show the evolution of sensitivity of the progrmme estimted s described bove. Globlly, progrmme sensitivity ws 77.2% t 1 yer, 66.3% t 2 yers nd 55.9% t 3 yers. Progrmme sensitivity followed the sme evolution in time (Figure 2) for men nd women. One yer fter the test it ws respectively.3% nd 72.5%;.3% nd.7% fter 2 yers; nd.5% nd.1% 3 yers fter the test. The sensitivity rtio ws quite stble with time for these 3 yers (1., 1.15 nd 1.). British Journl of Cncer (1999) 81(2), 5 9

4 8 V Bouvier et l Stge I Stge II Figure 3 Progrmme sensitivity ccording to ge Figure 5 Progrmme sensitivity ccording to stge Figure 4 Proximl colon Distl colon Rectum Sensitivity of the progrmme ccording to the cncer subsite Progrmme sensitivity ws constntly better for people ged yers thn for the others (Figure 3): 1 yer fter the test, the sensitivity ws 79.3% (65 74 yers) versus 73.4% (55 64 yers) nd 76.5% (45 54 yers); the corresponding figures fter 2 yers were 68.9%, 63.1% nd 61.3%, nd fter 3 yers were 57.7%, 53.0% nd 54.7%. Figure 4 shows the evolution of progrmme sensitivity ccording to subsite. One yer fter the test, sensitivity ws.3% for distl cncer, 77.4% for proximl cncer nd 66.7% for rectl cncer. During the following period, sensitivity for distl colon ws mrkedly different from the other two subsites. Two yers fter, progrmme sensitivity ws 73.3% for distl cncer, 55.4% for proximl cncer nd 51.4% for rectl cncer. Three yers fter, the corresponding figures were, respectively, 64.9, 45.0 nd.7%. The rtio between distl cncer nd other subsites British Journl of Cncer (1999) 81(2), 5 9 incresed in time: 1.15 fter 1 yers, 1.37 fter 2 yers nd 1.51 fter 3 yers. Progrmme sensitivity ws better for less dvnced cncer. One yer fter the test, it ws 81.1% for stge I nd 72.2% for stge II. The corresponding figures fter 2 yers were, respectively, 72.9% nd 59.9%, nd fter 3 yers, 68.7% nd 47.3% (Figure 5). DISCUSSION According to our results, cncers emerging fter negtive test do not differ from those of the reference nd non-responder groups, in prticulr for stge of extension. In the two Europen prospective trils, cncers emerging fter negtive test were dignosed with better stge thn those occurring in the control group (Hrdcstle et l, 1996; Kronborg et l, 1996). This conflict could be due to higher rte of Dukes A stge mong reference or non-responder subjects in our study (respectively 23.6% nd 24.6%) thn corresponding rtes observed mong the control groups in Fünen or Nottinghm (11.0%), which reveled difference in the helth cre systems of two Europen countries. The use of colonoscopy hs been widespred in Frnce since the 19s, so ccess to colonoscopy is certinly esier in Frnce. In fct, the percentge of stge I (Dukes A) in our reference group is similr to tht of the control group from Minnesot, where subjects were volunteers from cncer society. In no study do cncers fter negtive test present worse extension thn those of the reference group. Therefore, whtever the country, ptients nd physicins do not seem to be flsely ressured by negtive Hemoccult II nd re wtchful of symptoms. In our study, the incidence in the negtivetest group ws bout hlf tht of the reference group, in ccordnce with the results of Allison showing tht negtive subjects hd only hlf the likelihood of developing colorectl cncer thn the generl popultion (Allison et l, 19). From public helth point of view, progrmme sensitivity is of greter importnce thn test sensitivity, becuse it reflects progrmme efficcy fter integrting severl determinnts such s test sensitivity nd nturl history of cncer. The best wy to estimte progrmme sensitivity is to obtin vilble dt from severl

5 Sensitivity of colorectl cncer screening 9 rounds of screening. In our study, we estimted progrmme sensitivity fter only one round. In this condition, our progrmme sensitivity ws globlly higher thn tht estimted in the other Europen trils. The generl progrmme sensitivity ws 77.2% 1 yer fter the test, while it ws % in the study of Allison et l, nd 89.3% in the Minnesot tril tht used rehydrted test. Two yers fter the test, it ws 68.5%, which is higher thn the clculted sensitivity from the Fünen ( %) nd Nottinghm ( %) trils. This difference my be due to the fct tht our study focused only on the first round of screening, prevlent cncers detected with the test being more numerous for the first round thn for the others. For exmple, using the dt from Fünen, the sensitivity fter the first round ws.0% (37 detected cncers nd nine intervl cncers), wheres fter two rounds the sensitivity fell to 55.0% ( screendetected cncers nd intervl cncers) (Kronborg et l, 1989, 1996). It could lso result from the difference in the positive rte of Hemoccult II : 1 1.2% in Nottinghm, % in Fünen, 1.4% in the Allison study nd 2.8% in the Clvdos progrmme. This vrition of positive rtes could be due to the dietry restriction 3 dys before tking the test in Fünen, the repetition of testing fter first positive test with one to four positive slides in Nottinghm nd the considertion of borderline test s positive in Clvdos (Kronborg et l, 1987; Lunoy et l, 1995; Robinson et l, 1995). Progrmme sensitivity ws better for mles nd for subjects ged yers, in ccordnce with the results from the Minnesot nd Fünen studies. Progrmme sensitivity ws lso different ccording to the subsite, nd higher for the distl colon 1 yer fter the test, despite higher incidence of distl cncer mong the negtive-test group in comprison with other subsites. This surfce discrepncy my hve two cuses. First, distl cncers re the most frequent in the generl popultion. For instnce, between 1978 nd 19, crude incidence in Clvdos ws 35.9/ 000 for distl cncer, 26.2/ 000 for rectl cncer nd 17.8/ 000 for proximl cncer (unpublished dt). Secondly, regrding the nturl history of colorectl cncer, the MST for distl cncer hs been estimted to be bout twice s long s the other two subsites: 6.44 yers versus 3.49 yers for proximl cncer nd 2.61 yers for rectl cncer (Lunoy et l, 1997). It seems resonble to think tht the cncers emerging in the first yer fter negtive test re minly missed cncers, nd tht the longer the time since the test, the higher the proportion of rel surfcing cncers. Thus, since test sensitivity is similr for the vrious subsites (Lunoy et l, 1997), progrmme sensitivity during the first yer fter the test is lso similr. Moreover, since distl cncer grows more slowly thn the others, progrmme sensitivity tends to be better for this locliztion in subsequent yers. The finding tht cncers dignosed fter negtive Hemoccult II do not hve worse stge of extension thn those dignosed mong generl popultion is n encourging result, since it reduces the expected negtive effect due to the low sensitivity of the test. ACKNOWLEDGEMENTS We would like to thnk Mrs Odile Gignoux Duron for her contribution to the editing of the finl version. REFERENCES Allison JE, Feldmn R nd Tekw IS (19) Hemoccult screening in detecting colorectl neoplsm: sensitivity, specificity nd predicting vlue. Ann Intern Med 112: Benhmiche AM, Fivre J, Menegoz F nd Grosclude P (1997) Les cncers digestifs en Frnce à l ube de l n 00. Hepto-Gstro 4: 8 12 Church TR, Ederer F nd Mndel JS (1997) Fecl occult blood screening in the Minnesot study: sensitivity of the screening test. J Ntl Cncer Inst 89: Dukes CE (1932) The clssifiction of cncer of the rectum. 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