Colorectal can cer (CRC) is amongst the lead ing

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1 /STRU^NI RAD UDK / :614.22(569.4)"1989/2002" DOI: /ACI R Gen der dif fer ences in colorectal can cer pre sen ta tion and... out come at a sin gle Is raeli in sti tu tion: Edward Ram 1,7, An drew Zbar 2,7,8, Gil Bachar 3,7, Haim Krissi 4,7, Samia Joubran 5, Lea Rath-Wolfson 6,7 1 Di vi sion of Sur gery, Hasharon Hos pi tal, Rabin Med i cal Cen ter, Petach Tikva Is rael 2 De part ment of Sur gery and Trans plan ta tion, Chaim Sheba Med i cal Cen ter, Ramat Gan Is rael 3 De part ment of Ra di ol ogy, Hasharon Hos pi tal, Rabin Med i cal Cen ter, Petach Tikva Is rael 4 Urogynecology Unit, De part ment of Ob stet rics and Gy ne col ogy, Rabin Med i cal Cen ter, Helen Schnei der Hos pi tal for Women, Petach Tikva, Is rael 5 The Bruce Rappaport Fac ulty of Med i cine Technion-In sti tute of Tech nol ogy and the Ha Emek Med i cal Cen ter Is rael 6 De part ment of Pa thol ogy, Hasharon Hos pi tal, Rabin Med i cal Cen ter, Petach Tikva Is rael 7 Tel-Aviv Uni ver sity, Sackler School of Med i cine, Is rael Back ground: The data for gen der dif fer ences in colorectal can cer (CRC) pre sen ta tion and survival are con flict ing, most likely re flect ing the Na - tional ap proach to CRC screen ing. Pa tients and Meth ods: Anal y sis was per formed on 431 pa tients pre sent ing with CRC to a sin gle ter tiary in sti tu - tion be tween 1989 and 2002, as sess ing gen der dif - fer ences in clin i cal pre sen ta tion and can cer-spe - cific sur vival. Re sults: Males pre sented more commonly with rec tal bleed ing, weak ness/leth argy and oc cult blood positivity with women more com monly presenting with constipation, abdominal pain and ane mia. Women pre sented with a more ad vanced AJCC stage (III or IV) than men (P<0.0001) and with a higher Dukes stage (P<0.001), with no gen der dif - fer ences in histologic grade of CRC. The pos i tive histologic nodal bur den was greater in women than in men (P <0.0001). There was no dif fer ence be tween the sexes in stage for right-sided co lonic tu mors and a barely sig nif i cant trend in left-sided co lonic and rec tal tumors towards more advanced stage presentation in fe males. The over all 5-year and 10-year sur vival rates were higher in males when com pared with fe males (91.8%vs.72.2% 5-year OS re spec tively, P< and 40.6% vs. 23.9% 10-year OS re spec tively, P<0.0001). A worse sur vival was ev i dent in women > 65 years, for all sites of can cer and for all can cer stages ex ceed ing Dukes stage A. Dis cus sion: There are in her ent sex differences in the clinical presentation, pathologic fea - tures, pri mary site and sur vival in CRC. An im proved understanding of gender-related differences in CRC could in flu ence the qual ity pro vi sion of care in women, par tic u larly re gard ing screen ing and the more reg u lated use of adjuvant ther a pies with proven ben e - fit. Key Words: gen der, colorectal can cer, can cer-spe cific sur vival rezime INTRODUCTION: Colorectal can cer (CRC) is amongst the lead ing causes of can cer-re lated mor tal ity in the United States and Eu rope, with an es ti mated new cases and an nual deaths from the dis ease in the United States alone 1. Re cent data shows a de cline in the over all CRC in ci dence in the United States by about 3% per an - num in men and by 2.2% in women with a con com i tant re duc tion in can cer-spe cific mor tal ity in the two groups of 3.9% and 3.4%, re spec tively 2. There has been a re - ported grad ual mi gra tion in the site of CRC to wards a more prox i mal co lonic lo ca tion, 3 ac com pa nied by a worse over all prog no sis for right-sided le sions; 4 find ings which have screen ing im pli ca tions and which di rectly af - fect re sec tion rates for prox i mal and dis tal can cers 5. Stud - ies of gen der dif fer ences have shown de vel op ing tem po ral shifts in the site dis tri bu tion and in ci dence of CRC, with higher fre quen cies of rec tal and left-sided co - lonic can cers in older males and of right-sided can cers in older fe males 6,7. The data con cern ing gen der dif fer ences in can cer-spe cific sur vival for CRC are con flict ing, with some sys tem atic stud ies show ing no dif fer ence 8 whereas oth ers have shown fe male sur vival ad van tage 9. Vari a - tions in re ports re flect the trend for women to pres ent more fre quently with lo cally ad vanced prox i mal can cers and as emer gen cies; 10 effects which may off set their in - her ent sur vival ad van tage. In Is rael, the Na tional CRC site mi gra tion trends have been sim i lar to those re ported else where, with less ad - vanced dis ease in el derly co horts 11. By con trast, the lo cal Arab pop u la tion ap pears to be ex press ing the trends of the Is raeli Jew ish pop u la tion de tected over the pre vi ous de cade show ing an in crease in left-sided and rec tal le - sions, most likely con se quent upon eth nic dif fer ences in screen ing im ple men ta tion and par tic i pa tion 12. The aim of this study was to as sess gen der dif fer ences in pre sen ta -

2 16 E. Ram et al. ACI Vol. LX males females Percent rectal bleeding constipation abdominal pain anemia weakness occult blood Symptoms FIG URE 1. GEN DER DIF FER ENCES IN PRE SENT ING SYMP TOMS FOR PA TIENTS WITH PROVEN CRC tion, pa thol ogy and out come in patients pre sent ing to a sin gle in sti tu tion over a 14-year pe riod. PA TIENTS AND METH ODS: In sti tu tional Re view Board ap proval was ob tained for the con duct of this chart re view in cor po rat ing only those pa tients who un der went colorectal re sec tion at Hasharon Hos pi tal, Petach Tikvah, (a ter tiary colorectal re fer ral cen ter in Is rael), be tween Jan u ary 1989 un til De cem ber Pa tients were in cluded for anal y sis with histological con fir ma tion of in va sive car ci noma us ing the cri te ria of Wu et al. 13 by search ing for ad mis sion ICD-10 codes which showed equiv a lency to the ICD-O-3 on col - ogy codes (C , C19.9, C20.9 and C26.0). Can - cers were di vided into right-sided co lon (ce cum, C18.0, as cend ing co lon C18.2, hepatic flex ure C18.3, trans verse co lon C18.4 and splenic flex ure C18.5), left-sided co lon (de scend ing co lon C18.6 and sig moid co lon C18.7) and rec tal (rectosigmoid junc tion C19.9 and the rec tum not oth er wise spec i fied - NOS C20.9). We did not in clude in the anal y sis sep a rate clas si fi ca tions such as can cers of the ap pen dix (C18.1), co lon can cers NOS (C18.9), over lap - ping sub-sites (C18.8) and other can cers of the in tes ti nal tract NOS (C26.0). Ba sic pa tient de mo graph ics (age, gen der), patho logic data (grade and lymph node har vest), can cer stage (AJCC and Dukes stag ing) and sur vival out come were re corded. Sta tis ti cal anal y sis was per - formed with the SPSS 16.0 (Chi cago, IL) soft ware us ing the Chi-squared or Fisher s ex act test where ap pro pri ate for group com par i son and the Kaplan-Meier anal y sis for cen sored data in the as sess ment of sur vival. The log-rank test was used for sur vival com par i sons with two-tailed P val ues < 0.05 be ing con sid ered sig nif i cant. FIG URE 2. 5-YEAR CU MU LA TIVE SUR VIVAL OF CRC PA TIENTS WITH GENDER SEPARATION RE SULTS Over the time pe riod of anal y sis there were 431 op er - ated pa tients with colorectal can cer (mean age years, range years over all). These in cluded 233 (54%) males (mean age years) and 198 (46%) fe males (mean age years) with 29.7% of cases be ing aged 75 years or older. Four pa tients were lost to fol low-up with a me dian fol low-up of 99.4 months (range months). Ta ble 1 shows the data for gen der, age, site, Dukes and AJCC stag ing and histologic grade for the en tire group. The mean num ber of lymph nodes re trieved from sur gi cal spec i mens in the groups over all was per case with 74.4% re corded as N0 sta - tus. Fig ure 1 shows the gen der sep a ra tion of pre sent ing

3 Br. 4 Gen der dif fer ences in colorectal can cer pre sen ta tion and out come at a sin gle Is raeli institution 17 TABLE 1 DEMOGRAPHIC DATA FOR ALL PATIENTS (n=431) Gen der Kaplan-Meier Survival Curve Males 233 (54%) Females 198 (46%) Cum Survival.8.6 Age (years) Women < (31.3%).4 Men (39%) > (29.7%) Site Right colon 110 (25.5%) Left colon 237 (55%) Rectum 84 (19.5%) Dukes' stage A 25 (5.8%) C 102 (23.7%) B 282 (65.4%) D 22 (5.1%) AJCC Stage (25.5%) (49%) 3 93 (21.6%) 4 17 (3.9%) Histologic grade G1 96 (22.3%) G2 327 (75.9%) G3 8 (1.9%) symptoms, with sig nif i cant dif fer ences noted be tween the sexes for rec tal bleed ing (30.1% males vs. 19.4% fe - males, re spec tively), weak ness/leth argy (5.8% males vs. 3.1% fe males, re spec tively) and oc cult blood positivity (4.4% males vs. 1% fe males, re spec tively). Con sti pa tion as a pre sent ing symp tom was more com mon in women Time (Months) FIGURE YEAR CU MU LA TIVE SUR VIVAL OF CRC PA TIENTS WITH GENDER SEPARATION (21.9% fe males vs. 17.3% males, re spec tively) as was ab dom i nal pain (20.9% fe males vs. 14.6% males, re spec - tively) and ane mia (18.4% fe males vs.12.4% males, re - spec tively) with no dif fer ences be tween the groups in the re port ing of a change in bowel habit over the pre vi ous 3 months (15.5% males vs 15.3% fe males, re spec tively). Ta ble 2 shows the gen der sep a ra tion of the main pa - ram e ters re corded in Ta ble 1 dem on strat ing that more males pre sented with rec tal can cer and more fe males pre - sented with right-sided co lonic can cer (P < ). As a con se quence, more males than fe males un der went an te - rior re sec tion (47 /20.5%/ vs. 21/10.6%/, re spec tively) and low an te rior re sec tion (17 /7.4%/ vs. 0 /0%/, re spec - tively) with women more fre quently un der go ing a left colectomy when com pared with males (57 /28.8%/ vs. 37 /16.2%/, re spec tively) or a right colectomy (58 [29.3%] vs. 52 /22.7%/, re spec tively). There were no dif fer ences in the des ig nated sigmoidectomy rates be tween gen ders (76 /33.2%/ males vs. 62 /31.3%/ fe males, re spec tively). Women pre sented with a more ad vanced AJCC stage (III or IV) than men (P<0.0001) and with a higher Dukes stage (P<0.001), with no dif fer ence be tween the sexes in histologic grade al though the num bers of un dif fer en ti ated tu mors in each group was small (over all 1.9%). The pos i - tive histologic nodal bur den was greater in women than in men (207/1751; vs. 113/2049; , re spec tively: P <0.0001). Ta ble 3 shows the broad gen der dif fer ences in stage for the dif fer ent sites of CRC (right co lon, left co lon and rec - tum). There was no dif fer ence be tween the sexes in stage for right-sided co lonic tu mors and a barely sig nif i - cant trend in left-sided co lonic and rec tal tu mors to wards more ad vanced stage pre sen ta tion in fe males, where the num bers in some cat e go ries were very small. Af ter 5 years of fol low-up there were 74 deaths (19 males, 55

4 18 E. Ram et al. ACI Vol. LX females) re sult ing in an over all 5-year sur vival rate of 82.8% (males 91.8% vs. fe males 72.2%, re spec tively: P <0.0001) with a 10-year can cer-spe cific sur vival of 40.6% in males and 23.9% in fe males, P<0.0001). These dif fer ences are shown graph i cally in Fig ures 2 and 3. Ta - ble 4 shows gen der-re lated dif fer ences for can cer-spe cific sur vival, with women show ing a worse sur vival in age groups > 65 years, in all sites of can cer and in all can cer stages (ex cept Dukes A). DIS CUS SION: This sin gle-in sti tu tion study over a 14-year pe riod showed sig nif i cant gen der dif fer ences in the symptomatology of colorectal can cer (CRC) and the CRC tu mor site, with women pre sent ing with more ad vanced tu mors and with a greater lymph node bur den over all. There were no stage dif fer ences be tween the sexes for right-sided colonic tu mors with a barely sig nif i cant trend to wards more a dvanced left-sided and rec tal tu mors in women. Women over the age of 65 years, (re gard less of can cer site or sta- ge), showed worse can cer-spe cific sur vival rates when com pared with men. The main lim i ta tion of the study is the small num bers in some sub group anal y ses with the ad van tage that very few pa tients were lost to fol - low-up in sur vival anal y sis. The data con cern ing a gen der ef fect on can cer-spe cific survim 14-20, many show ing a better prog no sis for women 8-10, and a few sug gest ing that fe males have a worse 27, out come 28. Dif fer ences in out come may in part be ex - plained by idiosyncracies within the data col lec tion sys - tems where in for ma tion has been based on can cer reg is - try data and where fre quently there has been no separation ei ther of case mix or be tween over all and caner-spe - cific causes of death. In ter pre ta tion of prog nos tic outcomes de rived from pre dom i nantly Eu ro pean data should also be tem pered with the knowl edge that CRC-spe cific sur vival is con sis tently lower in Eu rope than in the United States 29. Gen der-re lated dif fer ences in CRC sur vival are com - plex and vary for spe cific sub groups. In a Scot tish study by McArdle et al., women had sur vival ad van tage un der the age of 75 years for co lonic can cer but only pro vided that these re sec tions were per formed with cu ra tive in tent in an elec tive set ting 9. In this study, gen der-re lated sur - vival ad van tage be came over whelmed if there was an emer gency pre sen ta tion, ad vanced dis ease or if a re sec - tion was per formed for pal lia tive pur poses. More over, this group found that the ex cess mor tal ity rates in case-mix-ad justed anal y ses were due to inter-cur rent non-can cer-re lated deaths, most of which were car dio vas - cu lar in or i gin. These find ings are in keep ing with those re ported by Koo et al. who showed an op pos ing ef fect of gen der on can cer-spe cific sur vival at ei ther side of the age of 50 years, 10 a study which is in agree ment with ours and oth ers where older women in par tic u lar tend to pres ent more emergently with prox i mally lo cated can - cers 30. TABLE 2 GENDER SEPARATION OF DEMOGRAPHIC FEATURES IN PATIENTS PRESENTING W Age (Years) Males (n=233) Females (n=198) P value 68.95± ± N.S. <65 64 (27.5) 71 (35.8) (40.5) 74 (37.3) >75 75 (32.2) 53 (26.7) Site < Right colon 52 (22.3) 58 (29.2) Left colon 118 (50.6) 119 (60.1) Rectum 63 (27.0) 21 (10.6) Dukes Stage A 13 (5.6) 12 (6.1) B 171 (73) 11 (5.6) C 41 (17.6) 61 (31) D 8 (3.4) 14 (7.1) AJCC Stage 1 69 (30.1) 41 (20.7) (52.4) 87 (43.9) 3 33 (14.4) 60 (30.3) 4 7 (3.1) 10 (5.1) Grade G1 48 (20.6) 48 (24.2) G2 179 (76.8) 148 (74.7) G3 6 (2.6) 2 (1.0) <0.001 < P=0.348 Our study showed gen der dif fer ences for pre sent ing symp toms in the di ag no sis of CRC, where men pre sented more com monly with bleed ing and women pre sented more of ten with ab dom i nal pain and con sti pa tion. These dif fer ences in age and type of pre sen ta tion be tween the

5 Br. 4 Gen der dif fer ences in colorectal can cer pre sen ta tion and out come at a sin gle Is raeli institution 19 TABLE 3 GENDER DIFFERENCES IN STAGE FOR DIFFERENT CRC SITES. Right colon Men (n=233) Women (n=198) P value Dukes stage 0.57 Left Colon A 2 (3.8) 1 (1.7) B 41 (80.7) 41 (70.7) C 6 (11.5) 11 (19.0) D 3 (5.8) 5 (8.6) Dukes stage A 9 (7.6) 11 (9.2) B 79 (67) 58 (48.7) C 27(22.9) 45 (37.8) D 3 (2.5) 5 (4.2) Rectum Dukes stage A 2 (3.1) 0 B 51 (81.0) 12(57.1) C 8 (12.7) 5 (23.8) D 2(3.1) 4(19) sexes for symp tom atic CRC have im por tant im pli ca - tions for en do scopic screen ing pol icy where anal y sis of health re source use gen er ally shows a lower take-up rate of colonoscopic screen ing amongst women 31. In this re - spect, spe cific bar ri ers to colonoscopic screen ing vary in the sexes where women view bowel prep a ra tion and con - cerns re gard ing bodily ex po sure dur ing colonoscopy as pro ce dural im ped i ments in con trast to men who re port phys i cal invasiveness as more of a con cern 32. The higher pro por tion of older women with prox i mal can cers would sug gest that screen ing pro grams only uti liz ing flex i ble sigmoidoscopy would be in ef fec tive. Tra di tion ally, better rec tal can cer sur vival in women has been at trib uted to an a tom i cal dif fer ences in the pel vis which fa vors rec tal re sec tion, al though this is de bat able where Jeyarajah et al. have shown better to tal mesorectal ex ci sion (TME) scores in spec i mens de rived from male pa tients 33 Al though these an a tom i cal con sid er ations would not ac count for dif fer ences in co lon can cer sur - vival rates be tween the sexes, any po ten tial an a tom i cal ad van tage would ap pear to be squan dered by a later fe - male dis ease pre sen ta tion and ev i dence to sug gest less re - cruit ment of older women for nec es sary adjuvant treat - ments which have proven sur vival ben e fit 34. Im pact on can cer-spe cific sur vival may also re flect a higher in ter - rup tion and ces sa tion rate of adjuvant treat ment in women who have been shown to ex pe ri ence more fluorouracil-re lated tox ic ity than men 35. Al though most stud ies have not dem on strated sex dif - fer ences in CRC stage at pre sen ta tion, 9, 16 two ret ro spec - tive stud ies from the same group us ing both lo cal and State data showed women as hav ing more ad vanced stage can cers than men, a find ing sim i lar to our study 36,37. Other stud ies have also shown a higher pro por tion of ad - vanced (Dukes C and D) can cers in men in the prox i mal co lon with out such site-spe cific dif fer ences in women, where it has been pos tu lated that MSI-high can cers lo - cated in the prox i mal co lon in fe males have a de creased propensity to metastasize when com pared with stage-matched pa tients with MSI-sta ble can cers 7. Our study also showed a higher nodal bur den in women with node-positive dis ease. This is in keep ing with data re - ported by Paulson et al. who showed that women with co lon can cer had greater nodal har vests than agematched men 38 In this re spect, gen der-re lated dif fer ences in lymph node har vest ing will af fect stag ing and pro vide a more con sis tent use of adjuvant ther apy with more ac - cu rate stage-ad justed sur vival anal y ses. The un der ly ing rea sons for the in her ent vari a tions in gen der-re lated CRC sur vival which have fa vored women are spec u la tive, with the sug ges tion that hor monal dif fer - ences could ac count for dis par i ties amongst the sexes in im mune re sponse to CRC. In this re spect, there are sev - eral pieces of ev i dence fa vor ing an hor monal ef fect where cir cu lat ing es tro gen lev els are thought to be immuno-pro tec tive, 39 where hor mone re place ment ther - apy has been linked to CRC sur vival 40 and where es tro - gen ad min is tra tion has been shown to lead to un reg u lated CRC cell growth in vi tro 41 as well as to mea sur able microsatellite in sta bil ity in CRC tu mors 42. Out comes may also be af fected by gen der dif fer ences in the mo lec u lar bi ol ogy of right- and left-sided CRC. In this re spect, prox i mal tu mors tend to show more microsatellite in sta - bil ity, mis match re pair gene ex pres sion and CpG methylation in con trast to dis tal can cers where chro mo - somal in sta bil ity is more com mon as is tu mor sup pres sor gene (p53 and APC) down-reg u la tion and onco gene (k-ras) up-regulation 43. The im pact of anastomotic leak - age, (which ap pears to be more com mon in men), will also af fect re ported data con cern ing early over all sur vival in the groups 44. In sum mary, there are in her ent sex dif fer ences in the clin i cal pre sen ta tion, patho logic fea tures, pri mary site and sur vival in CRC which have im pli ca tions for en do - scopic screen ing. The data is con flicted where can -

6 20 E. Ram et al. ACI Vol. LX cer-spe cific sur vival is a more per ti nent end-point than over all sur vival. A better un der stand ing of gen der-re lated dif fer ences in CRC out come may pro vide av e nues for qual ity im prove ment by broad en ing ac cess to screen ing in ves ti ga tions and life-ex tend ing adjuvant treat ments par - tic u larly in older women. SUMARY RAZLIKE U LOKALIZACIJI, SIMPTOMATOLOGIJI, I PRE@IVLJAVANJU OD KOLOREKTALNOG KARCINOMA U ZAVISNOSTI OD POLA BOLESNIKA U ZDRAVSTVENOJ USTANOVI U IZRAELU: Uvod: Podaci o simptomatologiji, lokalizaciji i pre`ivlajanju od kolorektalnog karcinoma u zavisnosti od pola bolesnika su kontradiktorni. Materijal i metode: Prikupljeni su podaci od 431 bolesnika le~èenih od kolorektalnog karcinoma u tercijarnoj zdravstvenoj ustanovi periodu Analizirane su razlike u na~èinu prezentacije odnosno simptomatrologiji i kancer specifiènom pre`ivlajavnju u zavisnosti od pola bolesnika. Rezultati: Kod muškaraca su se ~èeš}e javljali rektalno krvavljenje, slabost/letargija i okultno krvavljenje dok su se kod `ena ~èeš}æe javljali opstipacija, bol u trbuhu imalokrvnost. Kod `ena je ~èeš}e registrovana bolest u uznapredovalom stadijumu (AJCC stadijum III ili IV P<0.0001; Dukes stadijum, P<0.001), pri è~emu nije bilo zna~ajnih razlika u stepenu diferencijacije tumora. Kod `ena su è~eš}e registrovane metastaze u limfnim è~vorovima (P <0.0001). Nije bilo razlike u stadijumu bolesti medju polovima za tumore desnog kolona, za razliku od tumora levog kolona i rektuma gde je registrovan trend è~eš}eg dijagnostikovanja uznapredovale bolesti kod `ena. Ukupno petogodišnje i desetogodišnje pre`ivljavanje je bilo ve}e kod muškaraca (petogodišnje 91.8% vs.72.2%, P< i desetogodišnje, 40.6% vs.23.9%, P<0.0001). Lošije pre- `ivljavanje je registrovano kod `ena starijih od 65 godina za sve lokalizacije karcinoma i za sve stadijume bolesti ve}e od Dukes A stadijuma. Diskusija Postoje zna~ajne razlike medju polovima u klinièkoj prezentaciji, patološkim karakteristikama, lokalizaciji i pre`ivljavanju od kolorektalnog karcinoma. Bolje shvatanje ovih razlika mo`e poboljšati kvalitet leè~enja i uticati na naè~in skrininga i ordiniranja postoperativne adjuvantne terapije, pre svega kod `ena. REF ER ENCES: 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al. Can - cer sta tis tics CA Can cer J Clin 2009; 59: Gib bons L, Wa ters C, Mao Y et al. Trends in colorectal can cer in ci dence and mor tal ity. Health Rep 2001; 12: Meza R, Jeon J, Renehan AG, Luebeck EG. Colorectal can cer in ci dence trends in the United States and United King dom: ev i dence of right- to left-sided bi o - log i cal gra di ents with im pli ca tions for screen ing. Can cer Res 2010; 70: TABLE 4 GENDER DIFFERENCES IN CRC-SPECIFIC SURVIVAL.5-YEAR SURVIVAL (%) Age (Years) Men (n=233) Women (n=198) P value < > < Site Right colon Left colon Rectum Dukes stage A B < C D All patients Cumulative 5-year survival < Meguid RA, Slidell MB, Wolfgang CL, Chang DC, Ahuja N. Is there a dif fer ence in sur vival be tween rightver sus left-sided co lon can cers? Ann Surg Oncol 2008; 15: Myer PA, Mannalithara A, Singh G, Ladabaum U. Prox i mal and dis tal colorectal can cer re sec tion rates in the United States since wide spread screen ing by colonoscopy. Gastroenterology 2012; 143: Efremidou EI, Laratzopoulos N, Papgeorgiu SM, Romanidis K, Tourlis T, Kouklakis G, Manolas KJ. Colorectal car ci noma: cor re la tion be tween age, gen der and subsite dis tri bu tion. Chirurgia (Bucur)2008;103: Koo JH, Leong RWL. Sex dif fer ences in ep i de mi o - log i cal, clin i cal and patho log i cal char ac ter is tics of colorec tal can cer. J Gastroenterol Hepatol 2010; 25: Ratto C, Sofo L, Ippoliti M, Merico M, Doglietto GB, Crucitti F. Prog nos tic fac tors in colorectal can cer. Lit er a ture re view for clin i cal ap pli ca tion- Dis Co lon Rec - tum 1998;4l:

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