Physical activity and risk of cancers of the colon and rectum: an Italian case-control study

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1 British Journl of Cncer (1999) 79(11/12), Cncer Reserch Cmpign Article no. bjoc Physicl ctivity nd risk of cncers of the colon nd rectum: n Itlin cse-control study A Tvni 1, C Brg 1, C L Vecchi 1,2, E Conti 3, R Filiberti 4, M Montell 5, D Amdori 6, A Russo 7 nd S Frnceschi 7 1 Istituto di Ricerche Frmcologiche Mrio Negri, Vi Eritre 62, Miln, Itly; 2 Istituto di Sttistic Medic e Biometri, Università degli Studi di Milno, Vi Venezin 1, Miln, Itly; 3 Istituto Regin Elen per lo Studio e l Cur dei Tumori, Vi Regin Elen 299, Rom, Itly; 4 Istituto Nzionle per l Ricerc sul Cncro, Vile Benedetto XV 10, Genov, Itly; 5 Istituto per lo Studio e l Cur dei Tumori Sentore Pscle, Npoli, Itly; 6 Istituto Oncologico Romgnolo, Ospedle Pierntoni, Vi Forlnini, Forlì, Itly; nd 7 Centro di Riferimento Oncologico, Vi Pedemontn Occ.le, Avino (Pordenone), Itly Summry We investigted the reltionships between risk of colon nd rectl cncers nd physicl ctivity in both sexes t different ges by cse-control study conducted between 1991 nd 1996 in six Itlin centres. Cses were 1225 ptients (688 men, 537 women) below the ge of 75 with colon cncer nd the controls included 4154 ptients (2073 men, 2081 women) dmitted to hospitl for cute, non-neoplstic conditions. We lso nlysed 722 cses of rectl cncer. Compred with the lowest level of occuptionl physicl ctivity t yers old the odds rtios (OR) for the highest level were 0.64 (95% confidence intervl, CI ) in men nd 0.49 (95% CI ) in women. The inverse ssocition in both sexes ws similr t nd yers old. No ssocition ws found in either sex for leisure-time physicl ctivity. For both sexes the inverse reltionship between occuptionl physicl ctivity t yers old nd colon cncer risk ws not significntly heterogeneous cross strt of selected covrites, nd for scending, trnsverse, descending nd sigmoid colon. Rectl cncer risk ws not ssocited with ny mesure of physicl ctivity (OR = 1.32 for men nd 0.88 for women for the highest level of occuptionl physicl ctivity t yers old compred with the lowest). This study confirms tht occuptionl physicl ctivity is protective ginst colon, but not ginst rectl cncer. Keywords: cse-control study; colon cncer; epidemiology; physicl ctivity; rectl cncer Most cohort nd cse-control studies hve found n inverse ssocition between physicl ctivity nd colon cncer risk usully similr in either sex nd ny colon ntomicl subsite (Mcfrlne nd Lowenfels, 1994; Longnecker et l, 1995; Colditz et l, 1997; Slttery et l, 1997). There is lso generl greement on substntil lck of ssocition between physicl ctivity nd risk of rectl cncer both in prospective nd cse-control studies (Mcfrlne nd Lowenfels, 1994; Colditz et l, 1997). Scnty dt re vilble on the ge t which physicl ctivity effects the gretest benefit. Most studies on physicl ctivity t work considered the usul lifetime occuption, while other studies hve exmined specific times prior to dignosis. A prospective study of Wisconsin women (Mrcus et l, 1994) found tht those who reported strenuous physicl ctivity from 14 to 22 yers old were t similr risk of colon cncer to those reporting no ctivity. Another prospective study on Hrvrd lumni (Lee et l, 1991) showed tht those with high levels of ctivity throughout their lives were t the lowest risk of developing colon cncer. Similrly, cse-control study from North Americ showed tht high level of vigorous leisure time physicl ctivity during the pst 20 yers ws protective ginst colon cncer in both men nd women (Slttery et l, 1997). However, s most findings relte to men nd to North Americn nd North Europen popultions, further studies re needed in Received 24 June 1998 Revised 9 October 1998 Accepted 13 October 1998 Correspondence to: A Tvni other popultions, especilly in women, to estblish the ges t which physicl ctivity hs most impct, nd to ssess whether the protection is restricted to ny specific ntomicl subsites of the lrge bowel. To exmine these issues we nlysed dt from lrge cse-control study conducted in Itlin res between 1991 nd SUBJECTS AND METHODS The dt were derived from cse-control study of colorectl cncer conducted between June 1991 nd 1996 (L Vecchi et l, 1997) in six Itlin res: greter Miln; the provinces of Pordenone nd Gorizi; the urbn re of Geno; the province of Forli (northern Itly); the province of Ltin (centrl Itly) nd the urbn re of Nples (southern Itly). The interviewers were centrlly trined nd the structured questionnires were tested for relibility nd reproducibility of dietry vribles (Frnceschi et l, 1993; Decrli et l, 1996). Less thn 4% of cses nd controls pproched for interview refused to prticipte nd the response rtes did not vry cross hospitls nd geogrphicl res. Cses of colon cncer comprised 688 men (medin ge, 62; rnge, 19 to 74 yers) nd 537 women (medin ge, 61; rnge, 24 to 74 yers) with incident, i.e. dignosed within the yer before interview, histologiclly confirmed cncer, nd ll hd been dmitted to the mjor teching nd generl hospitls in the res under surveillnce. Cses of rectl cncer comprised 435 men nd 286 women (medin ge, 62; rnge, 24 to 74 yers) with incident, histologiclly confirmed cncer. Cncers of the colon nd rectum nd their ntomicl subsites were defined ccording to the 1912

2 Physicl ctivity nd colorectl cncer 1913 Tble 1 Distribution of 1225 colon cncer cses nd 4154 controls ccording to selected covrites, Itly, Colon cncer Controls Women Women Age (yers) < Eduction (yers) < Totl lcohol intke (g ethnol dy 1 ) < Totl energy intke (kclories dy 1 ) < to < Approximte tertiles. Interntionl Clssifiction of Diseses, 9th Edition (ICD-9). Colon cncer corresponded to ICD-9 153; scending colon included ICD , 153.4, nd 153.6; trnsverse nd descending colon ICD , nd 153.7; nd sigmoid colon to ICD Rectl cncer included ICD ; rectosigmoid junction corresponded to ICD ; nd rectum to ICD Controls comprised 2073 men (medin ge, 59; rnge, 19 to 74 yers) nd 2081 women (medin ge, 56; rnge, 20 to 74 yers), residing in the sme geogrphicl res nd dmitted to the sme network of hospitls where the cses hd been identified, for wide spectrum of cute conditions unrelted to known or potentil risk fctors for colorectl cncer. Of these, 23% hd trumtic conditions (mostly frctures nd sprins), 28% non-trumtic orthopedic disorders (mostly low bck pin nd disc disorders), 20% cute surgicl conditions (mostly bdominl, such s cute ppendicitis or strngulted herni), nd 29% miscellneous other illnesses (such s eye, er, nose, throt nd dentl disorders). All interviews were conducted in hospitl using structured questionnire which included informtion on personl chrcteristics nd hbits, nthropometric vribles, eduction nd other socio-economic fctors, generl lifestyle hbits, such s smoking, lcohol, coffee consumption, medicl history nd dietry hbits. The section on physicl ctivity included questions on selfreported intensity of ctivity t work nd in leisure time seprtely. Physicl ctivity ws elicited for four specific periods of life: t the ges of 12, 15 to 19, 30 to 39 nd 50 to 59 yers. For occuptionl physicl ctivity, ptients were sked bout their jobs, which were clssified into five ctegories (scores between 1 nd 5) corresponding to very hevy, hevy, verge, stnding nd minly sitting. Physicl ctivity in leisure time ws defined on the bsis of the number of hours per week of sport or ctivity such s wlking, grdening, cycling, etc. The scores rnged Tble 2 Distribution of colon cncer cses nd controls, nd corresponding odds rtios (OR) with 95% confidence intervls (CI), ccording to the level of occuptionl physicl ctivity t vrious ges, Itly, Women Cses Controls OR (95% CI) b Cses Controls OR (95% CI) b At yers old 1 (lowest) c c ( ) ( ) ( ) ( ) ( ) ( ) 5 (highest) ( ) Unknown 2 2 χ 2 trend 21.84** 3.89* At yers old 1 (lowest) c c ( ) ( ) ( ) ( ) ( ) ( ) 5 (highest) ( ) Unknown χ 2 trend 9.81** 12.56** At yers old 1 (lowest) c c ( ) ( ) ( ) ( ) ( ) ( ) 5 (highest) ( ) Unknown χ 2 trend 8.59** 1.02 The two ctegories with the highest level of physicl ctivity were combined. b Estimtes from multiple logistic regression equtions, including terms for centre, ge, intke of totl lcohol nd energy, nd eduction. c Reference ctegory: *P < 0.05, **P < Cncer Reserch Cmpign 1999 British Journl of Cncer (1999) 79(11/12),

3 1914 A Tvni et l Tble 3 Distribution of colon cncer cses in ntomicl subsites nd corresponding odds rtios (OR) with 95% confidence intervls (CI), ccording to the level of occuptionl physicl ctivity t yers old, Itly Women No. OR (95% CI) b No. OR (95% CI) b Ascending colon 1 (lowest) 16 1 c 13 1 c ( ) ( ) ( ) ( ) 4 (highest) ( ) ( ) χ 2 trend Trnsverse nd descending colon 1 (lowest) 23 1 c 13 1 c ( ) ( ) ( ) ( ) 4 (highest) ( ) ( ) χ 2 trend 6.54* 7.42** Sigmoid colon 1 (lowest) 45 1 c 29 1 c ( ) ( ) ( ) ( ) 4 (highest) ( ) ( ) χ 2 trend 9.50** 1.91 The sum does not dd up to the totl becuse of some missing vlues. The two ctegories of the highest level of physicl ctivity were combined. b Estimtes from multiple logistic regression equtions, including terms for centre, ge, eduction nd intke of totl lcohol nd energy. c Reference ctegory: *P < 0.05, **P < Tble 4 Distribution of rectl cncer cses nd corresponding odds rtios (OR) with 95% confidence intervls (CI), ccording to level of occuptionl physicl ctivity t yers old, Itly Women No. OR (95% CI) b No. OR (95% CI) b Rectosigmoid junction 1 (lowest) 15 1 c 13 1 c ( ) ( ) ( ) ( ) 4 (highest) ( ) ( ) χ 2 trend Rectum 1 (lowest) 39 1 c 22 1 c ( ) ( ) ( ) ( ) 4 (highest) ( ) ( ) χ 2 trend The sum does not dd up to the totl becuse of some missing vlues. The two ctegories of highest physicl ctivity were combined. b Estimtes from multiple logistic regression equtions, including terms for centre, ge, eduction nd intke of totl lcohol nd energy. c Reference ctegory. between 1 nd 4, corresponding to < 2, 2 4, 5 7 nd > 7 h of physicl ctivity per week. No informtion ws vilble on intensity or mount of ctivity. For women, the scores of the two highest levels of either occuptionl or leisure-time physicl ctivity were combined, s there were too few women in the ctegories with the highest ctivity. unconditionl multiple logistic regression, fitted by the method of mximum likelihood (Breslow nd Dy, 1980) in men nd women seprtely. Two models were considered: the first (Model A) including terms for geogrphicl re, quinquenni of ge nd totl intke of lcohol nd energy (not shown); nd the second (Model B) with further terms for eduction. Dt nlysis Odds rtios (OR) of colon cncer, nd the corresponding 95% confidence intervls (CI) for incresing levels of occuptionl nd leisure-time physicl ctivity t vrious ges were derived using RESULTS Tble 1 gives the distribution of colon cncer cses nd the comprison group ccording to ge, eduction nd lcohol nd energy intke in men nd women. The cncer ptients were more British Journl of Cncer (1999) 79(11/12), Cncer Reserch Cmpign 1999

4 Physicl ctivity nd colorectl cncer 1915 educted nd reported higher energy intkes thn the controls. Tble 2 shows the distribution of colon cncer cses nd controls with corresponding multivrite ORs (estimted by Model B) for men nd women, in reltion to their occuptionl levels of physicl ctivity t different ges. Compred with men in the lowest level of occuptionl physicl ctivity, the ORs (Model A) of colon cncer for men in the highest level were 0.39, 0.51 nd 0.57 (sttisticlly significnt), respectively, t 15 19, nd yers old, with significnt trends in risk. Similrly, in women, the corresponding ORs were 0.54, 0.44 nd The inverse ssocition ws weker, but still significnt fter further llownce for eduction, nd the ORs for the highest level of ctivity compred with the lowest in subsequent ge groups were 0.47, 0.64 nd 0.69 in men, nd 0.62, 0.49 nd 0.75 in women, with significnt trends in risk except for women t yers old. No consistent ssocition ws found between leisure-time physicl ctivity nd colon cncer risk for either sex t the sme ges (not shown). A lifelong index of occuptionl physicl ctivity ws lso computed, combining the informtion from vrious ges considered in subjects ged 50 yers or older. For mles, the multivrite ORs (Model B) for incresing quintiles of ctivity compred with the lowest were 0.95, 0.71, 0.83 nd 0.39 (χ 2 trend = 18.68, P < 0.01); the corresponding vlues in women were 0.77, 0.73, 0.82 nd 0.52 (χ 2 trend = 6.14, P < 0.05). The risk of colon cncer for ech level of occuptionl physicl ctivity t ge 30 to 39 yers old in seprte strt of selected covrites ws not significntly heterogeneous cross strt for ge t dignosis, eduction, body mss index nd intke of lcohol, totl energy, vegetbles, fibre or strch. Tble 3 shows the risk of cncer in ntomicl subsites of the colon for levels of occuptionl physicl ctivity t 30 to 39 yers old. The protection ppered consistent in the colon subsites considered; the ORs for the highest level of ctivity for men nd women were, respectively, 0.79 nd 0.43 for the scending colon, 0.46 nd 0.29 for the trnsverse nd descending colon, nd 0.54 nd 0.58 for the sigmoid colon. The reltion between risk of rectl cncer nd occuptionl physicl ctivity t 30 to 39 yers old is reported in Tble 4. There ws no consistent ssocition between physicl ctivity nd cncers of the rectosigmoid junction or rectum in either sex. The ORs were somewht below unity for the rectosigmoid junction, which presents problems of misclssifiction of the sigm (Doll, 1980). Similrly, no ssocition ws found with physicl ctivity t work nd in leisure time t the ges of 12, 15 to 19 nd 50 to 59 yers old for either sex (not shown). DISCUSSION Severl biologicl mechnisms hve been proposed to explin the influence of exercise on colon crcinogenesis, possibly involving multiple but, in some cses, overlpping pthwys (Mcfrlne nd Lowenfels, 1994; Potter, 1995; Colditz et l, 1997). Physicl ctivity my increse colonic motility, which in turn is ssocited with reduced colon cncer risk (Cummings et l, 1992; Potter, 1995), possibly becuse of the shorter contct between the colonic mucos nd possible crcinogens. This theory, however, lcks rel experimentl or epidemiologicl evidence (Mcfrlne nd Lowenfels, 1994). However, physicl ctivity lso reduces insulin resistnce, thus voiding colon cncer stimultion possibly linked to hyperglycemi nd hyperinsulinemi (Mcfrlne nd Lowenfels, 1994; Colditz et Cncer Reserch Cmpign 1999 l, 1997), s supported by the finding tht people with high level of physicl ctivity hve lower incidence of non-insulin-dependent dibetes mellitus (Helmirich et l, 1991). Other possible mechnisms include the interction with body mss nd body ft composition, chnges in serum cholesterol nd bile cid metbolism, or, in women, chnges in levels nd vilbility of sex hormones (Mcfrlne nd Lowenfels, 1994; Potter, 1995). Exercise cn lso rise the production of some prostglndins tht, in turn, my influence colon cncer risk (Demers et l, 1981; Colditz, et l, 1997), nd the ctivtion of the immune system response hs lso been postulted (Simon, 1984). The lck of ssocition between colon cncer risk nd leisuretime physicl ctivity might depend on its low level nd frequency mong Itlin men nd prticulrly mong women. Moreover, it is usully shorter lsting, more often restricted to younger people, is more difficult to define nd quntify ccurtely thn occuptionl ctivity, nd, in Itly, mostly involves people in the highest socil clsses, which is correlte of colon cncer (Potter et l, 1993). Some of the ssocitions with low occuptionl physicl ctivity might lso be explined in terms of socil clss correltes. Allownce for eductionl level somewht ttenuted the inverse reltionship of occuptionl physicl ctivity with colon cncer risk, but the generl pttern of protection clerly persisted. Adjustment for eduction my, however, constitute n overdjustment, becuse eductionl level is lrgely relted to physicl ctivity t work. The potentil confounding effect of severl other covrites ws llowed for in the nlysis, but there ws no mteril modifiction in the pttern of risk estimtes. There re problems of relibility nd vlidity in the ssessment of physicl ctivity becuse we used subjective score with no quntifiction of totl energy expenditure. However, the similr interview settings provide ressurnce ginst potentil informtion bis (D Avnzo et l, 1997) nd there is no reson to ssume different recll on the bsis of the disese sttus, s the inverse ssocition between colon cncer risk nd physicl ctivity is not mtter of public knowledge in Itly. This study ws not popultion-bsed, but cses were identified in the mjor teching nd generl hospitls of the study re, the prticiption of cses nd controls ws lmost complete, nd we excluded from the control group ptients dmitted to hospitl for chronic conditions or digestive trct diseses. Exclusion of controls with orthopedic (including trumtic conditions) from the nlysis did not modify the risk estimtes. Further ressurnce tht the medicl conditions of controls did not influence the results comes from the consistency of the protective effect of physicl ctivity cross different ges, even from long before the dignosis tht led to hospitl dmission. The ttributble risk of colon cncer in this popultion, under the ssumption tht the physicl ctivity of the entire popultion could be incresed to the two highest levels, ws 15% (95% CI, 4 26%) in men nd 17% (95% CI, 1 36%) in women (Mezzetti et l, 1996), which ws similr to tht reported in North Americn study (Slttery et l, 1997). The finding tht high level of occuptionl physicl ctivity cross ges confers some protection ginst colon cncer is prticulrly importnt in view of the benefits of physicl ctivity on other chronic diseses too, such s cncer t certin other sites nd crdiovsculr diseses (L Vecchi nd Negri, 1992). ACKNOWLEDGEMENTS This work ws conducted with the contribution of the Itlin Assocition for Cncer Reserch, Miln, nd of the Europe British Journl of Cncer (1999) 79(11/12),

5 1916 A Tvni et l ginst Cncer Progrmme of the Commission of the Europen Communities. The uthors thnk Mrs J Bggott, MP Bonifcino nd the GA Pfeiffer Memoril Librry stff for editoril ssistnce. REFERENCES Breslow NE nd Dy NE (1980) Sttisticl Methods in Cncer Reserch, Vol. 1, The nlysis of cse-control studies. IARC Scientific Publictions, 32 Colditz GA, Cnnuscio CC nd Frzier AL (1997) Physicl ctivity nd reduced risk of colon cncer: implictions for prevention. Cncer Cuses Control 8: Cummings JH, Binghm SA, Heton KW nd Estwood MA (1992) Fecl weight, colon cncer risk, nd dietry intke of nonstrch polyscchrides (dietry fiber). Gstroenterology 103: D Avnzo B, L Vecchi C, Ktsouynni K, Negri E nd Trichopoulos D (1997) Hospitl nd popultion controls: n ssessment of nd reproducibility of food frequency dt. Eur J Cncer Prevention 6: Decrli A, Frnceschi S, Ferrroni M, Gngnrell P, Prpinel MT, L Vecchi C, Negri E, Slvini S, Flcini F nd Gicos A (1996) Vlidtion of food frequency questionnire to ssess dietry intkes in cncer studies in Itly: results for specific nutrients. Ann Epidemiol 6: Demers LM, Hrrison TS, Hlbert DR nd Snten RJ (1981) Effect of prolonged exercise on plsm prostglndin levels. Prostglndins Med 6: Doll R (1980) Generl epidemiologic considertions in etiology of colorectl cncer. In Colorectl Cncer: Prevention, Epidemiology nd Screening. Progress in Cncer Reserch nd Therpy, Vol. 3. Winwer S, Schottenfeld D, Sherlock P (eds), pp Rven Press: New York Frnceschi S, Negri E, Slvini S, Decrli A, Ferrroni M, Filiberti R, Gicos A, Tlmini R, Nnni O, Pnrello G nd L Vecchi C (1993) Reproducibility of n Itlin food frequency questionnire for cncer studies: results for specific food items. Eur J Cncer 29A: Helmrich SP, Rglnd DR, Leung RW nd Pffenbrger RS Jr (1991) Physicl ctivity nd reduced occurrence of non-insulin-dependent dibetes mellitus. N Engl J Med 325: L Vecchi C nd Negri E (1992) Public eduction on diet nd cncer: clories, weight nd exercise. In Public Eduction on Diet nd Cncer. Benito E, Gicos A, Hill MJ (eds), pp Kluwer: Dordrecht L Vecchi C, Negri E, Frnceschi S, Conti E, Montell M, Decrli A nd Filiberti R (1997) Aspirin nd colorectl cncer. Br J Cncer 76: Lee I-M, Pffenbrger RS Jr nd Hsieh C-C (1991) Physicl ctivity nd risk of developing colorectl cncer mong college lumni. J Ntl Cncer Inst 83: Longnecker MP, Gerhrdsson de Verdier M, Frumkin H nd Crpenter C (1995) A cse-control study of physicl ctivity in reltion to risk of cncer of the right colon nd rectum in men. Int J Epidemiol 24: Mcfrlne GJ nd Lowenfels AB (1994) Physicl ctivity nd colon cncer. Eur J Cncer Prev 3: Mrcus PM, Newcomb PA nd Storer BA (1994) Erly dulthood physicl ctivity nd colon cncer risk mong Wisconsin women. Cncer Epidemiol Biomrkers Prev 3: Mezzetti M, Ferrroni M, Decrli A, L Vecchi C nd Benichou J (1996) Softwre for ttributble risk nd confidence intervl estimtion in cse-control studies. Comput Biomed Res 29: Potter JD (1995) Risk fctors for colon neoplsi. Epidemiology nd biology. Eur J Cncer 31A: Potter JD, Slttery ML, Bostick RM nd Gpstur SM (1993) Colon cncer: review of the epidemiology. Epidemiol Rev 15: Simon HB (1984) The immunology of exercise. A brief review. JAMA 252: Slttery ML, Edwrds SL, M K-N, Friedmn GD nd Potter JD (1997) Physicl ctivity nd colon cncer: public helth perspective. Ann Epidemiol 7: British Journl of Cncer (1999) 79(11/12), Cncer Reserch Cmpign 1999