Adjuvant chemotherapy for colon carcinoma with positive lymph nodes: use and benefit in routine health care practice

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1 doi: / bjoc , vilble online t on Adjuvnt chemotherpy for colon crcinom with positive lymph nodes: use nd benefit in routine helth cre prctice C Bouchrdy 1, P-E Queneu 2, G Fiorett 1, M Usel 1, M Zellweger 3, I Neyroud 1, L Rymond 1, C de Wolf 1 nd AP Sppino 4 1 Genev Cncer Registry, Institute for Socil nd Preventive Medicine, 55 boulevrd de l Cluse, 1205 Genev, Switzerlnd; 2 Deprtment of Gstroenterology nd Heptology, University Hospitl, Genev, Switzerlnd; 3 Deprtment of Internl Medicine, University Hospitl, Genev, Switzerlnd; 4 Division of Oncology, University Hospitl, Genev, Switzerlnd Summry In 1990, n interntionl consensus ws reched on the efficcy of djuvnt chemotherpy for lymph node positive (stge III) colon crcinom (CC). This study evlutes the use nd benefit of such therpy in routine helth cre prctice. The study includes ll ptients with stge III CC treted by puttive curtive surgery (n = 182) recorded t the Genev cncer registry between 1990 nd Fctors modifying chemotherpy use were determined by logistic regression, considering ptients with chemotherpy s cses (n = 55) nd others s controls (n = 127). The effect of chemotherpy on the 5-yer survivl ws evluted by the Cox model. Anlyses were djusted for possible confounders. The use of chemotherpy incresed over the period (P trend < 0.001). Age strongly modulted chemotherpy use. In 1996, 54% of eligible ptients received chemotherpy, this proportion fell to 13% fter ge 70. Decisions to use chemotherpy significntly depended on stge, grde nd cncer site. The chnce to be treted ws non-significntly lower mong individuls of low socil clss, widowed nd foreigners. Chemotherpy significntly decresed mortlity rtes (Hzrd rtio: 0.35, 95%CI: ), independently of the prognostic fctors nd with similr benefit regrdless of stge nd ge group. Strong beneficil effect of djuvnt chemotherpy on stge III CC cn be chieved in routine prctice. However, this study shows tht it is probbly not optimlly utilised in Switzerlnd, prticulrly mong the elderly. Keywords: colon crcinom; djuvnt chemotherpy; survivl; good prctices; ptterns of cre; cncer registry Colon crcinom is one of the most frequent mlignncies nd one of the min cuses of cncer deths in industrilised countries. In Switzerlnd, it is estimted tht ech yer pproximtely 1100 men nd 1050 women re dignosed with colon crcinom (Levi et l, 1998). Despite the rther fvourble prognosis, only hlf of the ptients survive 5 yers fter dignosis (Gtt et l, 1996; Berrino et l, 1999). The only curtive option for ptients with colon crcinom is surgery (Cohen et l, 1997). For stge I disese (Dukes stge A nd B-1 (Astler nd Coller, 1954) invsion to the musculris propri without nodl involvement) there is more thn 90% probbility of cure. This probbility drops to pproximtely 75% for the stge II disese (Dukes stge B-2, invsion into or through the seros, without nodl involvement), nd reches only pproximtely 35% for the stge III disese (Dukes stge C, metstsis to regionl lymph nodes). The poor prognosis of nonmetsttic dvnced disese is due to residul cncer in occult or microscopic form, for which chemotherpy or immunotherpy is most effective (Cohen et l, 1997). At the end of the 1980s, rndomised clinicl trils provided evidence tht djuvnt postopertive chemotherpy in colon crcinom ptients with regionl lymph node metstsis increses the Received 2 Februry 2001 Revised 11 June 2001 Accepted 4 July 2001 Correspondence to: C Bouchrdy survivl rtes by pproximtely 30% (Lurie et l, 1989; Moertel et l, 1990; IMPACT, 1995). Dt were less convincing for ptients without positive lymph nodes. Bsed on these evidences nd given the infrequent toxic side effects, therpeutic guidelines were estblished in 1990, recommending systemtic djuvnt chemotherpy fter surgery for stge III colon crcinom (NIH consensus conference, 1990). Recommendtions re not lwys followed, nd therefore gret disprities my exist between guidelines nd prctice. There re nerly no dt on the generlistion of such prctice mong the popultion nd on the observed benefits outside clinicl trils. This study evlutes the use nd benefit of such therpy in routine helth cre prctice in the Swiss cnton of Genev. MATERIALS AND METHODS The dt were derived from the Genev cncer registry dt set, which includes informtion on ll incident cses of mlignnt neoplsms occurring in the popultion of the cnton, pproximtely inhbitnts. The registrtion collects informtion from vrious sources nd is considered ccurte. This cn be ttested in prticulr by the very low percentge (< 2%) of cses recorded from deth certifictes only (Bouchrdy, 1997). Notifiction is bsed on voluntry greement between the recording medicl institutions of the cnton nd the registry. All hospitls, pthologicl lbortories nd prctitioners re requested to report ll current nd pst cncer cses. Dt re systemticlly bstrcted from hospitl nd lbortory records by trined tumour 1251

2 1252 C Bouchrdy et l registrrs. Privte prctitioners regulrly receive inquiry forms to secure missing clinicl nd therpeutic dt. Deth certifictes re consulted systemticlly. Recorded dt include sociodemogrphic informtion (ge, gender, ntionlity, plce of birth, mritl sttus nd occuption), dignostic circumstnces (origin of dignosis, presence of symptoms nd methods of ssessment), tumour chrcteristics (primry site, histologic type nd differentition coded ccording to the Interntionl Clssifiction of Diseses for Oncology (ICD-O) ) (World Helth Orgniztion, 1976), stge of disese t dignosis, tretment during the first 6 months fter dignosis (surgery, rdiotherpy or chemotherpy), finlity of tretment (curtive, pllitive or not specified), survivl sttus nd cuse of deth. The Genev cncer registry previously published description of the survivl ssessment (Rymond et l, 1996). In brief, the index dte for incidence refers to the confirmtion dte of dignosis, or to the dte of hospitlistion if it precedes the dignosis nd is relted to the disese. The registry performs 2 types of follow-up. In ddition to pssive follow-up (routine exmintion of deth certifictes nd hospitl records), n ctive follow up is crried out routinely ech yer using the files of the Cntonl Popultion Office. For decesed ptients, the cuse of deth is determined from clinicl records nd recorded systemticlly ccording to the World Helth Orgniztion clssifiction (World Helth Orgniztion, 1967). Ptient selection The study ws limited to colon crcinom (ICD-O code 153). Cncers of the rectum nd rectosigmoid junction (ICD-O codes nd 154.1) were not considered. Between 1990 nd 1996, 930 ptients with histologiclly confirmed first primry invsive colon crcinom (excluding 4 mlignnt tumours other thn crcinom) were recorded in the resident popultion of the Swiss cnton of Genev. The study concerned only stge III colon cncer ptients (Dukes stge C, metstsis to regionl lymph nodes) treted with puttive curtive surgery, i.e. surgery with totl mcroscopic nd microscopic removl (n = 182). We excluded ptients who were not operted (n = 3), or who hd pllitive surgery only (n = 4) or surgery with no specifiction of being curtive or not (n = 9). Vribles considered The size of the tumour fter resection (in cm) ws clssified in five ctegories ( 3, 4, 5, > 5 nd unknown), nd the T clssifiction of the pthologicl p (Interntionl Union ginst Cncer, 1992; 1987) in 4 groups: pt1 (submucos) or pt2 (musculris propri), pt3 (subseros, nonperitonelized pericolic tissues), pt4 (viscerl peritoneum/other orgns structures) nd ptx (unknown/unclssifible). The level of lymph node invsion ws studied using the pn clssifiction in four groups: pn1 ( 3 pericolic), pn2 (> 3 pericolic), nd pn3 (nodes on nmed vsculr trunk). The tumour clssifiction ws coded ccording to the ICD-O code for histologic grding nd differentition: grde I (well differentited, differentited), grde II (modertely differentited, modertely well differentited), grde III (poorly differentited), grde IV (undifferentited, nplstic) nd unknown. Antomicl sites considered were: trnsverse colon (ICD-O 153.1), descending colon (ICD-O 153.2), sigmoid colon (ICD-O 153.3), cecum (ICD-O 153.4), scending colon nd ppendix (ICD-O ) nd not specified (ICD-O 153.9). 4 levels of socil clss (bsed on the ptient s lst occuption or, for unemployed women, tht of the spouse) were considered: low (mnul employees, skilled nd unskilled workers), middle (nonmnul employees nd dministrtive stff), high (professionls, executives, dministrtors) nd unknown. The helth cre sector in chrge of the colon crcinom surgery ws of privte (initil tretment in the privte sector) or public nture (initil tretment in the public sector). The methods of discovery (consulttion following symptoms, screening or check-up exmintion, fortuitous discovery during consulttion, unknown) were regrouped in 2 ctegories (screening, other). Screening procedures for colon crcinom minly referred to routine fecl occult blood testing or endoscopic exmintion. Additionl dt on the type of chemotherpy mong treted ptients nd on the presence of co-morbid conditions mong untreted ptients were collected from clinicl files. Sttisticl nlysis Determinnts of chemotherpy use Dt were nlysed through unconditionl multivrite logistic regression, considering ptients with djuvnt chemotherpy s cses nd ptients with no djuvnt chemotherpy s controls (Breslow nd Dy, 1980). All models were log-liner fitted using the generlised liner interction modelling sttisticl pckge (Frncis et l, 1993). The identified fctors therefore concerned the modifiers of chemotherpy use. Fctors of interest were lterntively ge t dignosis, gender, period of dignosis, ntionlity, mritl sttus, socil clss, method of discovery, helth cre sector, ntomicl site, tumour differentition, tumour size, T stge nd N stge t dignosis. The models contined the fctor of interest nd ge (continuous) for estimtion of the crude effect. For estimtion of the djusted effect, we priori decided to djust for ll other vribles linked to chemotherpy use. The significnce of ech vrible of interest ws ssessed by compring the goodness of fit mesure (devince ccording to degree of freedom) of the model with nd without the vribles of interest. Results re presented s reltive risk estimtes of being treted vs. untreted. Estimtion of the effect of djuvnt chemotherpy The 5-yer survivl ws estimted by the cturil method (intervls in months nd stndrd error ccording to Greenwood). The effect of djuvnt chemotherpy on 5-yer specific mortlity rtes ws evluted by Cox proportionl hzrds model ccounting only for ge (in continuous), or lso for fctors linked to both chemotherpy use nd prognosis, such s tumour chrcteristics nd stge (djusted effect). Anlyses were performed using both observed survivl (totl number of deths) nd specific survivl (deth from colon crcinom only). In order to evlute the potentil vrition of the effect of chemotherpy with individul or tumour chrcteristics, n interction term involving chemotherpy use nd ge or T nd N clssifictions, or tumour differentition ws introduced in the Cox model (Hill et l, 1990). RESULTS Among the 182 colon crcinom ptients with positive lymph nodes who hd curtive surgery, 55 (30%) received djuvnt chemotherpy (the cses) nd 127 did not (the controls). 89% of the treted group

3 Adjuvnt chemotherpy fter colon crcinom 1253 received the Europen stndrd therpy, i.e. 5-Fluorourcil plus Leucovorin (folinic cid). Determinnts of djuvnt chemotherpy use Tble 1 shows the ptient distribution ccording to sociodemogrphic chrcteristics nd chemotherpy use. Chemotherpy use strongly diminished fter the ge of 70: pproximtely 50% of ptients ge 70 yers received chemotherpy, compred with < 10% of ptients ge 70 yers. After djusting for confounders, the chnce of being treted ws more thn 15-fold lower for ptients 70 compred with those < 60 yers (djusted OR: 0.06, 95% CI: ). For 69 of the 85 ptients ged 70 yers who did not receive chemotherpy, clinicl informtion on the existence or bsence of co-morbid conditions ws vilble. Of those 69 ptients, 22 hd co-morbid conditions (6 lcoholic, psychitric or nervous system disorders; 5 pulmonry or crdic disorders, 3 post-surgicl complictions; 8 other unfvourble generl conditions such s cchexi, dibetes mellitus). For 47 ptients no relevnt co-morbid conditions were reported, nd their generl sttus ws described s good. Among them, 2 ptients refused tretment. For the others, ge ws mentioned to be the min reson for the clinicl decision not to tret with chemotherpy. A typicl sentence in the medicl records ws Due to the ge of the ptient, no djuvnt therpy ws proposed. The proportion of treted ptients incresed over time. In 1992, less thn 20% of the ptients were treted with chemotherpy. This proportion incresed to 54% in The probbility of being treted ws bout 8-fold higher in compred with the period (djusted OR: 7.74, 95% CI: ). With respect to other sociodemogrphic fctors, widowed hd pproximtely 3-fold lesser chnce of being treted compred with mrried individuls (djusted OR: 0.34, 95% CI: ). The chnce to be treted ws lso lower for foreigners thn for Swiss ntionls (djusted OR: 0.65, 95% CI: ), nd pproximtely 2-fold higher mong individuls belonging to middle or high socil clss (djusted OR: 2.42, 95% CI: nd OR: 1.84, 95% CI: , respectively). However, the effects of these fctors were not significnt. No gender difference ws seen. In the current series, 6% of the stge III colon crcinom were dignosed by screening (Tble 2). There ws significnt link between method of discovery nd chemotherpy use only in non-djusted nlyses (Tble 2). Approximtely one third of the ptients hd surgery in privte institutions. The proportion of ptients with djuvnt chemotherpy ws 41% in the privte sector compred with 24% in the public sector. This reflected the differences in ge (men ge of the Tble 1 Distribution of stge III colon crcinom ptients nd estimtion of the effect of sociodemogrphic chrcteristics on djuvnt chemotherpy use Adjuvnt chemotherpy Crude effect Adjusted effect Yes No OR (95%CI) OR b (95%CI) (cses) (controls) n = 55 n = 127 Age group (yers) < c 1 c ( ) 0.72 ( ) *** ( ) 0.06*** ( ) Gender Mle c 1 c Femle ( ) 0.62 ( ) Period of dignosis c 1 c ( ) 2.28 ( ) *** ( ) 7.74*** ( ) Civil sttus Mrried c 1 c Widowed ( ) 0.34 ( ) Single ( ) 0.68 ( ) Other ( ) 1.69 ( ) Ntionlity Swiss c 1 c Other ( ) 0.65 ( ) Socil clss Low c 1 c Middle ( ) 2.42 ( ) High ( ) 1.84 ( ) Unknown 1 9 Excluded Excluded Odds rtio djusted for ge (continuous); b Odds rtio djusted for ge (continuous), period (continuous), cncer sub-site (cecum, other), differentition (well, other), lymph node clssifiction (N1, N2, other) nd tumour clssifiction (T1 nd T2, T3, other); c Reference ctegory; *P < 0.05, **P < 0.01, *** P <

4 1254 C Bouchrdy et l Tble 2 Distribution of stge III colon crcinom ptients nd estimtion of the effect of method of discovery, nd helth cre sector on djuvnt chemotherpy use Adjuvnt chemotherpy Crude effect Adjusted effect Yes No OR (95%CI) OR b (95%CI) (cses) (controls) n = 55 n = 127 Method of discovery Other c 1 c Screening * ( ) 5.23 ( ) Unknown 0 5 Excluded Excluded Helth cre sector d Public c 1 c Privte ( ) 1.16 ( ) Odds rtio djusted for ge (continuous); b Odds rtio djusted for ge (continuous), period (continuous), cncer sub-site (cecum, other), differentition (well, other), lymph node clssifiction (N1, N2, other) nd tumour clssifiction (T1 nd T2, T3, other); c Reference ctegory; d First tretment; P < 0.05, ** P < 0.01, ***P < ptients privtely treted ws 64 yers vs. 73 yers for the public sector) nd the chnce of being treted ws similr in both privte nd public prctice fter ccounting for ge (Tble 2). Tble 3 presents the ptient distribution by site nd stge of the primry tumour. Cecum cncer ws less frequently treted by chemotherpy thn cncers of other sites (21% vs. 32%, P = 0.20) (Tble 3). Cecum crcinom ws treted bout 5 times less compred with trnsverse colon crcinom (djusted OR: 0.23, 95% CI: ) (Tble 3). The proportion of treted ptients incresed ccording to the level of tumour differentition, with n lmost 12-fold increse in use of chemotherpy for poorly differentited tumours compred with well differentited tumours (djusted OR: 12.55, 95% CI: ). In the current series, 69% of the ptients hd less thn 3 pericolic nodes invsion (N1), while 9% hd nodl invsion on nmed vsculr trunk (N3). The probbility of being treted ws not significntly higher for N3 compred with N1 stges (djusted OR: 2.37, 95% CI: ). However, it ws significntly lower when the tumour invded through the musculris propri into subseros, or into pericolic tissues (T3 or T4), compred with lesser locl invsion (T1 nd T2), even fter ccounting for the severity of nodl invsion (OR: 0.16, 95% CI: nd OR: 0.10, 95% CI: for T4 nd T3, respectively). The tumour size hd no influence on chemotherpy use. Effect of djuvnt chemotherpy After 5 yers, 85 ptients were still live, 74 ptients died of colon crcinom nd 21 died of other cuses. 2 ptients were lost to follow-up becuse they left the cnton. The men follow-up ws 1138 dys (stndrd devition: 644). The 5-yer survivl of colon crcinom ptients with positive lymph nodes nd curtive surgery ws 45% (stndrd error: 4%) for crude survivl nd 54% (stndrd error 4%) for specific survivl. Since results on crude nd specific survivl were very similr, we decided to present only the observed survivl dt. Tble 4 shows the effect of potentil prognostic fctors on instntneous deth rtes. Results were djusted for ge, or for ge plus period, T nd N clssifictions nd tumour site. Age hd no effect on prognosis when ccounting for other prognostic fctors, while the effect of period nd N stge remined significnt. Survivl 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 0 Figure 1 Crude survivl Specific survivl djuvnt chemotherpy, n = 55 no djuvnt chemotherpy, n = Yers fter dignosis Survivl fter curtive surgery for stge III colon crcinom Regrdless of ge, period, site, T nd N clssifictions, the ptients who received chemotherpy hd n lmost 3-fold (Hzrd rtio: 0.35, 95% CI: ) significntly decresed mortlity rte. Adjustment for dditionl fctors, such s socil clss nd method of discovery, did not modify the results. None of the interction nlyses ws significnt, i.e. the effect of chemotherpy ws similr regrdless of ge-group, stge or tumour differentition. As observed in Figure 1, the 5-yer survivl ws higher in the groups treted vs. untreted with djuvnt chemotherpy, for both observed survivl (70%, stndrd error: 5% vs. 34%, stndrd error 3%), nd specific survivl (75%, stndrd error: 7% vs. 44%, stndrd error 5%). Only ptients who survived long enough could undergo chemotherpy tretment, so dditionl nlyses were performed on the sme series, excluding 18 ptients who died during the first 6 months fter dignosis. As expected, ll these ptients belonged to the untreted group. Nevertheless, these new nlyses provided similr results for both determinnts of chemotherpy use nd efficcy of chemotherpy. The hzrd rtio ssocited with the use of chemotherpy in multi-djusted Cox model ws 0.37 (95% CI: ), i.e. very close to the results presented in Tble 4.

5 Adjuvnt chemotherpy fter colon crcinom 1255 Tble 3 use Distribution of stge III colon crcinom ptients nd estimtion of the effect of tumour chrcteristics on djuvnt chemotherpy Adjuvnt chemotherpy Crude effect Adjusted effect Yes No OR (95%CI) OR b (95%CI) (cses) (controls) n = 55 n = 127 Antomicl site Trnsverse colon c 1 c Descending colon ( ) 0.53 ( ) Sigmoid colon ( ) 1.38 ( ) Cecum ( ) 0.23* ( ) Ascending colon d ( ) 0.53 ( ) Not specified 0 9 Excluded Excluded Tumour differentition Well c 1 c Modertely ( ) 2.37 ( ) Poorly ** ( ) 12.55** ( ) Unknown 2 8 Excluded Excluded Size of tumour (cm) c 1 c ( ) 0.46 ( ) ( ) 0.95 ( ) ( ) 0.60 ( ) Unknown 2 2 Excluded Excluded T1 1 1 T2 7 6 ] 1 ] c 1 c T ( ) 0.10** ( ) T ( ) 0.16* ( ) Unknown 0 2 Excluded Excluded N c 1 c N ( ) 1.03 ( ) N ( ) 2.37 ( ) Unknown 0 3 Excluded Excluded Odds rtio djusted for ge (continuous); b Odds rtio djusted for ge (continuous), period (continuous), cncer sub-site (cecum, other), differentition (well, other), lymph node clssifiction (N1, N2, other), nd tumour clssifiction (T1 nd T2, T3, other); c Reference ctegory; d Appendix included; * P < 0.05, **P < 0.01, ***P < DISCUSSION This study shows tht in dily prctice the probbility of receiving djuvnt chemotherpy fter surgery for stge III colon crcinom remins low, despite estblished recommendtions. According to the literture, the expected proportion of ineligible ptients should be round 5% (Moertel et l, 1990; NIH Consensus conference 1990; IMPACT, 1995), wheres we observed tht still in 1996 prcticlly 50% of the ptients were not treted. We found very few studies providing popultion dt on djuvnt chemotherpy use for stge III colon crcinom in generl prctice fter the publiction of the therpeutic guidelines in the 1990s (NIH consensus conference, 1990). The proportion of treted ptients ws 35% in French study in (Jouve et l, 1998) nd 51% in New Jersey study in (Mhoney et l, 2000). Adjuvnt chemotherpy dministrtion strongly decreses with ge. In 1996, < 13% of ptients ge 70 yers received djuvnt chemotherpy. This could reflect the decline of the generl condition due to old ge nd higher prevlence of co-morbid conditions, or ptient s refusl. But lso it could be the consequence of generl unwillingness to tret the elderly, possibly due to the limited dt on chemotherpy efficcy mong ptients ge 70 yers (Trimble et l, 1994). Co-morbidity ws bsent in bout 2/3 of the ptients ged 70 who did not receive chemotherpy. In this study, the informtion collected on co-morbid conditions ws done retrospectively nd is probbly not complete. However, the results re comptible with those previously reported (Jouve et l, 1998; Mhoney et l, 2000), nd strongly suggest tht the ge fctor per se is limiting chemotherpy prescription. Recent dt provided ressuring evidence on the tolernce, s well s on the efficcy of chemotherpy mong elderly ptients with colon crcinom (Ross et l, 1998; Popescu et l, 1999). Arbitrry ge cut-off ppers therefore unjustified. The current study does not show ny significnt differences in chemotherpy efficcy between ge-groups (χ 2 interction test between ge nd chemotherpy = 5.6, P = 0.13). In prticulr, mong the 9 ptients ge 70 yers who received chemotherpy, ll except 1 were live fter 5 yers. Becuse cncer occurs more often in the elderly (in this study, one fourth of stge III colon cncer concerned ptients ge 70 yers), the indiction for chemotherpy mong this group is public helth mtter tht should not be neglected. The djuvnt

6 1256 C Bouchrdy et l Tble 4 Effect of djuvnt chemotherpy nd prognostic fctors on instntneous mortlity rtes fter surgery for stge III colon crcinom Cox proportionl hzrds model ccounting for ge only Cox proportionl hzrds model ccounting for other prognostic fctors Cses Deths Hzrd rtio (95% CI) Hzrd rtio b (95%CI) n = 182 n = 95 Chemotherpy No c 1 c Yes ** ( ) 0.35** ( ) Age-group (yers) < c 1 c ( ) 1.54 ( ) ** ( ) 1.68 ( ) Period of dignosis c 1 c ( ) 0.77 ( ) * ( ) 0.51 ( ) Antomicl site Trnsverse colon c 1 c Descending colon ( ) 0.68 ( ) Sigmoid colon ( ) 1.55 ( ) Cecum ( ) 1.52 ( ) Ascending colon ( ) 1.70 ( ) Not specified 9 5 Excluded Excluded T1, T c 1 c T ( ) 0.98 ( ) T ( ) 1.43 ( ) Unknown 2 Excluded Excluded N c 1 c N ** ( ) 2.51*** ( ) N ( ) 2.50** ( ) Unknown 3 Excluded Excluded Hzrd rtio djusted for ge (continuous); b Hzrd rtio djusted for ge (continuous), chemotherpy (no, yes), period (continuous), site of the tumour (cecum, other), T clssifiction (T1 nd T2, T3, T4, unknown), N clssifiction (N1, N2, N3, unknown); c Reference ctegory; *P < 0.05, **P < 0.01, ***P < chemotherpy use ws higher mong ptients with poorly differentited tumours, indicting prescription trgeting ptients presenting crcinogenic criteri ssocited with worse prognosis. However, there re no rel indictions ginst treting ptients with well or modertely differentited tumours. With regrd to locl invsion, there ws lesser propensity to tret tumours invding through the musculris propri when compred with more fvourble stges. This ws lso observed for cecl cncer, which is often dignosed t more dvnced stge, probbly due to its possibility to extend before occurrence of symptoms such s occlusion (Cohen et l, 1997). The worse generl condition nd the obstructive presenttion (Wolmrk et l, 1983) re likely to explin the lesser probbility of being treted when the locl invsion increses. There ws generl tendency of reduced chemotherpy use mong widowed, foreigners nd ptients belonging to lower socioeconomic clss, demonstrting once more tht the disfvoured hve lower ccess to optiml tretment (Polednk, 1989). These lst results were not significnt, probbly becuse of the low power of the study. Ressuringly, the propensity of being treted ws similr in privte institutions nd the university hospitl sector, even fter n dditionl djustment for socioeconomic sttus (OR: 1.1; 95%CI: ). Beyond clinicl trils, we hve hrdly ny informtion on the effect of djuvnt chemotherpy in routine helth cre prctice. With regrd to dt vilble in current prctice derived from the US ntionl cncer dt bse, ptients with stge III crcinom dignosed between were found to hve n increse of 3% of the 3-yer reltive survivl (Jessup et l, 1996). Tht study, however, involves prescriptions before 1990, period when vrious drugs were used without proven effectiveness. In other studies, effectiveness of chemotherpy in stge III crcinom ws not reported (Bert et l, 1995; Jouve et l, 1998). We observed reltive reduction in deth rtes of 65% mong treted ptients (95% CI: 32 82%), i.e. pproximtely twice tht expected from clinicl trils (Moertel et l, 1990; Wolmrk et l, 1993; Frncini et l, 1994; IMPACT, 1995; O Connell et l, 1997; Mmouns et l, 1999). This importnt difference in survivl is not generted from rndomised study, nd prtly reflects the lower propensity to give chemotherpy to ptients with puttive poorer prognosis. In current prctice the choice, whether to tret or not, is bsed on the presence of co-morbid conditions: the observed 5- yer survivl in untreted ptients ws 34% compred to pproximtely 43% in control groups in clinicl trils (Lurie et l, 1989; Frncini et l, 1994). The 5-yer survivl in treted ptients (70%)

7 Adjuvnt chemotherpy fter colon crcinom 1257 is very close to tht observed in the treted group in clinicl trils (pproximtely 70%) (Lurie et l, 1989; Frncini et l, 1994). To minimise the effect of ptient selection we excluded ll ptients who died within 6 months of dignosis, nd obtined very similr result of chemotherpy effectiveness. CONCLUSION Adjuvnt chemotherpy hs proved its effectiveness for stge III colon crcinom ptients, however, it hs not reched its full potentil in dily prctice. The probbility of being treted remins low, prticulrly mong the elderly. This non-rndomised study bsed on reltively smll group of ptients confirms the beneficil effect of djuvnt chemotherpy use in routine prctice. ACKNOWLEDGEMENTS The uthors thnk Prof J Torhorst nd Prof U Lffer for inititing this study nd Mrs Stin Blgojevic for her expert technicl help nd editoril ssistnce. REFERENCES Astler VB nd Coller FA (1954) The prognostic significnce of direct extension of crcinom of the colon nd rectum. 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