Oral UFT (uracil plus futrafur) for neoadjuvant chemotherapy of gastric cancer

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1 64 Gstric Cncer (1999) 2: Y. Nio et l.: Neodjuvnt UFT for gstric cncer 1999 by Interntionl nd Jpnese Gstric Cncer Associtions Originl rticle Orl UFT (urcil plus futrfur) for neodjuvnt chemotherpy of gstric cncer Yoshinori Nio, Chikge Iguchi, Kunihiro Ymsw, Msyuki Itkur, Hiroshi Omori, Koji Hshimoto, Seiji Yno, Shoichiro Sumi, nd Ktsuhiro Tmur First Deprtment of Surgery, Shimne Medicl University, 89-1, Eny-cho, Izumo Shimne , Jpn Abstrct: Bckground. Neodjuvnt chemotherpy hs become one of the topics of interest in chemotherpy of gstric cncer; the present study ssessed the clinicl benefits of neodjuvnt chemotherpy with orl urcil nd futrfur (UFT) for gstric cncer. Methods. Between 1991 nd 1997, 82 ptients with gstric cncer (36 with erly nd 46 with dvnced cncers) received UFT t mg/dy orlly for 1 6 weeks before surgery. Objective responses, histologicl effects, nd postsurgicl survivl rtes were ssessed. Results. In 69 of the 82 ptients, the objective responses of the primry lesions were ssessed by endoscopy or upper gstrointestinl series exmintion, nd 2 complete responses (CR)s, 25 prtil responses (PRs), nd 42 no chnges (NCs) were seen (39.1% response). Histologicl effects were evluted in 82 ptients, nd 2 grde 3, 11 grde 2, 11 grde 1b, 27 grde 1, nd 31 grde 0 effects were seen. A longer period of UFT dministrtion ws ssocited with CR or PR. However, the objective responses did not correlte with the histologicl effects. All the ptients underwent gstrectomy, nd during the medin follow-up period of 41 months, 3-yer survivl rtes were 97.1% for ptnm stge 1, 75% for stge 2, 86.7% for stge 3, nd 41.6% for stge 4. The survivl rtes of stge 3 nd stge 4 ptients were higher thn those of the historicl controls in our deprtment. However, CR or PR did not correlte with the improvement in survivl. Side effects before surgery were not serious; they included slight myelotoxicity, liver dysfunction, nd norexi; however, 3 ptients (3.7%) hd suture insufficiency, 3 ptients (3.7%) hd methicillin-resistnt Stphylococcus ureus (MRSA) enteritis, nd 7 ptients (8.5%) hd liver dysfunction. Conclusions. Preopertive chemotherpy for gstric cncer with orl UFT ws sfe nd resulted in good locl response (mcro- nd microscopiclly) which my indicte the possibility of improved survivl with neodjuvnt chemotherpy with UFT. Furthermore, preopertive chemotherpy with orl UFT is esy nd ptients cn receive this tretment on n outptient bsis. Offprint requests to: Y. Nio Received for publiction on Feb. 5, 1999; ccepted on Mrch 15, 1999 Key words: gstric cncer, neodjuvnt chemotherpy, UFT Introduction Although the results of tretment for gstric cncer in Jpn hve been improving over the pst two decdes, gstric cncer is still one of the leding cuses of cncer deth in Jpn. The 5-yer survivl rtes of gstric cncer ptients fter gstrectomy hve reched more thn 90% for stge 1 nd 70% 80% for stge 2. However, the prognosis of ptients with stge 3 or 4 gstric cncer is still poor, nd 5-yer survivl rtes re bout 40% for stge 3 nd 5% 10% for stge 4. In order to improve the tretment results for gstric cncer, vriety of therpies hve been employed, nd chemotherpy hs plyed the most importnt role. However, it is still uncler whether postopertive djuvnt chemotherpy improves survivl, lthough gstric cncer is now considered to be reltively sensitive to chemotherpy compred with cncers of other digestive orgns. Since the introduction of cispltin (CDDP), vriety of combintion chemotherpies, including etoposide 5-fluorourcil (5FU) CDDP (EAP) nd 5FU Adrimycin CDDP (FAP) regimens hve been employed for the tretment of gstric cncer [1 4]. After the report by Wilke nd collegues (5), neodjuvnt chemotherpy hs become one of the topics of interest in chemotherpy of gstric cncer [5 7]. The first reports on neodjuvnt chemotherpy of gstric cncer were published in Jpn, in the 1960s [8,9], nd since these reports, mny Jpnese reserchers hve employed vrious neodjuvnt chemotherpies [10 17]. The mjor purpose of neodjuvnt chemotherpy is preopertive downstging, to enble more curtive surgery. Previous neodjuvnt chemotherpies employed intensive chemotherpies such s EAP or FAP, nd we

2 Y. Nio et l.: Neodjuvnt UFT for gstric cncer 65 hve lso employed n intensive 5FU CDDP 4 epirubicin (FPEPIR) regimen ( modified version of the FAP regimen) [18,19]; however, these therpies frequently cuse serious side effects nd result in the interruption or postponement of surgery; their true effects re still uncler. In Jpn, neodjuvnt chemotherpy regimens hve been different from those used in Western countries, becuse mny neodjuvnt regimens hve included orl 5-FU or mixture of urcil nd futrfur t 4 :1 (UFT) [12,13,16,17]. In generl, the choice of djuvnt chemotherpy for gstric cncer in Jpn hs differed from tht in the United Sttes nd Europen countries; in Jpn, orl chemotherpy with fluoropyrimidines hs been the stndrd regimen for gstric cncer. Among these orl fluoropyrimidines, UFT is the most populr gent in Jpn. The side effects of orl UFT re not serious; ccordingly, UFT is used especilly for djuvnt chemotherpy fter surgery on n outptient bsis in Jpn [20 22]. The response rtes of digestive orgn cncers to UFT lone in Jpn were reported to be: gstric cncer, 27.7%; colorectl cncer, 25.0%; liver cncer, 19.2%; pncretic cncer, 25.0%; nd gllbldder or bile duct cncer, 25.0% [23]. These results re similr to those of intensive intrvenous chemotherpies. Accordingly, UFT cn be employed for neodjuvnt chemotherpy insted of these intensive chemotherpies, nd neodjuvnt chemotherpy with orl UFT my hve mjor dvntge, in tht UFT cn be dministered on n outptient bsis. To chieve downstging during the witing period for surgery, we hve employed preopertive chemotherpy with orl UFT from 1991, nd totl of 82 ptients hve received this therpy. In the present study, the clinicl benefits of preopertive chemotherpy with orl UFT for gstric cncer during the witing period for surgery were ssessed with regrd to the objective response nd the benefits in terms of postsurgicl survivl. Tble 1. Ptient profile Number of ptients 82 Age (yers) (verge, ) Sex Mle:femle 56 : 26 Mcroscopic dignosis before surgery 1. Erly cncer: n 32 Type I n 4 II n 4 IIb n 0 IIc n 23 II IIc n 2 III n 2 2. Advnced cncer: n 50 Borrmnn I n 4 II n 8 III n 30 IV n 8 Postopertive ptnm stge clssifiction (UICC, 1987) b Stge 1 n 40 2 n 6 3 n 19 4 n 17 Including one recurrent cncer of the remnnt stomch b Excluding one recurrent cncer of the remnnt stomch nine 2.0 mg/dl), or liver dysfunction (GOT, GPT, nd lkline phosphtse four fold norml limits), (5) severe hert disese or concomitnt mlignnt disese, nd (6) pregnncy. All ptients nd their fmilies were fully informed with regrd to the tretment progrm, nd informed consent ws obtined. Between 1991 nd 1997, totl of 82 ptients with gstric cncer were included in the present study: 36 with erly (pt1) gstric cncers nd 46 with (pt2 4) dvnced gstric cncer ccording to the postopertive Interntionl Union ginst Cncer clssifiction. After surgery, the stge of gstric cncer ws clssified ccording to the (UICC) TNM stge clssifiction (1987). The ptient profile is summrized in Tble 1. Ptients nd methods Ptients Two bsic criteri for preopertive chemotherpy with UFT hd to be met before dministrtion: (1) histologicl or cytologicl proof of gstric cncer, nd (2) performnce sttus 3 on the Europen Coopertive Oncology Group (ECOG) scle. Contrindictions included: (1) totl disbility (performnce sttus [PS] 4, ECOG score), (2) prior chemotherpy, rdiotherpy, or immunotherpy within 4 weeks, (3) ctive infectious disese, (4) severe nemi (hemoglobin 9.0 g/dl), leukopeni ( 3000 white blood cells/mm 3 ), thrombocytopeni ( pltelets/mm 3 ), zotemi (creti- Tretment protocol for neodjuvnt chemotherpy with UFT The ptients were dministered UFT orlly fter mels during the witing period for surgery. The dministrtion usully strted from the first visiting dy to the outptient wrd nd the ptients were given the lst UFT t 6 p.m. on the dy before surgery. One cpsule of UFT includes 100 mg of futrfur (FT), nd the dose of UFT is usully expressed s the does of FT. Three different doses (300, 400, nd 600 mg/dy) were used, nd the dose of UFT for ech ptient ws determined ccording to the ptients condition (PS, body weight, ge, hemtology, nd serum biochemistry), becuse UFT sometimes cuses serious myelotoxicity or heptotoxicity.

3 66 Y. Nio et l.: Neodjuvnt UFT for gstric cncer Exmintions of hemtology, serum biochemistry, nd serum tumor mrkers, nd evlutions of the symptomtic sttus nd performnce sttus were routinely performed t weekly or biweekly intervls, sometimes more frequently. The size of the primry lesion ws usully ssessed before UFT dministrtion nd 1 or 2 dys before surgery by endoscopy nd/or upper gstrointestinl series exmintion, sometimes more frequently. If the disese ppered to progress or serious side effects were seen, the ptients were either mnged symptomticlly nd supportively or offered lterntive experimentl regimens if their generl condition seemed to be pproprite. Postsurgicl djuvnt chemotherpy The ptients were treted with djuvnt chemotherpy ccording to their postsurgicl stge clssifiction. Stge 1 3 ptients received djuvnt chemotherpy with UFT for 1 3 yers nd stge 4 ptients received intensive chemotherpy with one to four courses of CDDP, 5-FU, nd epirubicin (FPEPIR regimen) [19] ccording to their condition nd then received orl UFT dily for s long s possible. Evlution of objective response nd histopthologicl effects The objective response ws evluted s complete response (CR), prtil response (PR), no chnge (NC), or progressive disese (PD) by endoscopy, upper gstrointestinl series exmintion, nd computed tomogrphy (CT) scn, nd the histopthologicl effect ws evluted bsed on the grde (0 3), ccording to the criteri of the Jpnese Reserch Society for Gstric Cncer (1995, First English Edition). The durtion of the response ws not included in the evlution of the objective response, becuse ll ptients underwent surgery. Evlution of side effects The WHO stndrd criteri for toxicity [24] were used. Follow-up of ptients All ptients were followed-up by physicl exmintion, generl X-ry exmintion, ultrsonogrphy (US), CT, routine hemtologic nd biochemicl exmintions, nd serum tumor mrker ssys. Assy of drug concentrtions The concentrtion of FT ws mesured by highpressure liquid chromtogrphy, nd tht of 5-FU ws mesured by gs-mss chromtogrphy ccording to the method described by Mrunk et l. [25]. Sttisticl evlution The response rte of the primry lesion, the histologicl effects, nd the survivl rte fter surgery were evluted to judge the effects of the therpies. χ 2 nd Mnn-Whittney U-tests were used to compre ptient bckgrounds mong the three dosge groups. Overll survivl ws clculted by the Kpln-Meier method. A P vlue of less thn 0.05 ws considered to be significnt. Sttisticl nlysis ws crried out using SAS computer softwre SAS Institute Inc., Cry, NC, USA. Results Dose nd period of drug dministrtion (Tble 2) UFT ws dministered t three doses (300, 400, nd 600 mg/body per dy). The dministrtion period rnged Tble 2. Preopertive dose of UFT Erly cncer Advnced cncer Overll (pt1, n 36) (pt2 4, n 46) (n 82) Dose (mg/body per dy) Period (dys) Totl dose (g) UFT, Urcil plus futrfur 4 : 1 According to postopertive pthology

4 Y. Nio et l.: Neodjuvnt UFT for gstric cncer 67 between 7 nd 40 dys, nd the totl dose rnged between 2.4 nd 21.6 g. Side effects (Tble 3) Side effects were not serious before surgery: norexi in 11 ptients (13.4%), leukopeni in 3 ptients (3.7%), thrombocytopeni in 2 ptients (2.4%), nd slight liver dysfunction in 2 ptients (2.4%). Postopertive complictions were seen in 13 ptients: 3 ptients (3.7%) with Tble 3. Side effects (evluted in 82 ptients) I. Preopertive side effects Anorexi 11 (13.4%) Mssive bleeding from gstric cncer 2 (2.4%) Leukopeni ( 300 WBC/mm 3 3 (3.7%) Thrombocytoperi ( pltelets/mm 3 ) 2 (2.4%) GOT ( 100 IU/l) 2 (2.4%) II. Postopertive complictions Suture insufficiency 3 (3.7%) MRSA enteritis 3 (3.7%) GOT ( 100 IU/l) 7 (8.5%) b MRSA, Methicillin-resistnt Stphylococcus ureus One ptient hd pnperitonitis due to colonic perfortion nd two ptients hd enteritis b Two ptients hd high-level elevtion of GOT, of more thn 500 IU/l suture insufficiency, 1 with perfortive peritonitis, nd 2 with enteritis due to methicillin-resistnt stphylococcus ureus (MRSA); ll of these ptients were cured by conservtive therpy or re-opertion. Liver dysfunction (serum GOT level 100 IU/l) ws seen in 7 ptients (8.5%) nd serum GOT levels incresed to more thn 500 IU/l in 2 ptients. It seemed tht ptients who received UFT for long period suffered more often from postopertive complictions. Objective nd histologicl responses In 69 of the 82 ptients, the sizes of primry tumors before nd fter UFT dministrtion were compred by endoscopy or upper gstrointestinl series exmintion, nd 2 CRs, 25 PRs, nd 42 NCs were seen (27/69, 39.1% response). The involved nodes becme smller in 2 ptients, nd single lesion of liver metstsis disppered in 1 ptient. Findings for 4 representtive ptients who responded to the neodjuvnt UFT tretment re shown in Figs. 1, 2. There ws no reltionship between the response nd the clinicl stge (Tble 4). Tble 5 summrizes the reltionship between the response nd the dose nd dministrtion period. The results lso suggest tht the dose my not be very importnt fctor, but longer periods of UFT dministrtion, espe- c b d Fig. 1 d. Representtive ptient with complete response (CR). The ptient, 70-yer-old womn, received urcil futrfur, 4 : 1 (UFT) t 300 mg/dy for 16 dys. Before UFT: IIc-like dvnced gstric cncer t lesser curvture of the prepyloric region. b After UFT: scr formtion of ulcertive lesion; objective response ws evluted s CR. c Resected specimen: no mcreoscopic lesion ws seen. d Pthology: miniml lesion of well differentited denocrcinom; the histologicl response ws evluted s grde 2. The postopertive stge clssifiction ws stge 1: pt1 (m), pn0, M0

5 68 Y. Nio et l.: Neodjuvnt UFT for gstric cncer Tble 4. Mcroscopic nd histologicl response fter preopertive UFT Postopertive stge Effect Stge (1 n 40) Stge 2 4 (n 42) Overll (n 82) Mcroscopic response CR 2 (5.6%) 0 2 (2.9%) PR 14 (38.9%) 11 (33.3%) 25 (36.2%) NC 20 (55.5%) 22 (66.7%) 42 (60.9%) PD Unevluble Histologicl effect Grde 3 1 (2.5%) 1 (2.4%) 2 (2.5%) Grde 2 5 (12.5%) 6 (14.3%) 11 (13.4%) Grde 1b 3 (7.5%) 8 (19.0%) 11 (13.4%) Grde 1 13 (32.5%) 14 (33.3%) 27 (32.9%) Grde 0 18 (45.0%) 13 (31.0%) 31 (37.8%) CR, Complete response; PR, prtil response; NC, no chnge; PD, progressive disese ptnm, (UICC 1987) Tble 5. Administered dose nd mcroscopic response fter preopertive UFT (evluted in 69 of 82 ptients) CR PR NC PD Unevluble Overll (n 82) 2 (2.9%) 25 (36.2%) 42 (60.9%) 0 13 I. Dose (mg/body) 300 mg (n 38) 1 (3.0%) 14 (42.4%) 18 (54.5%) mg (n 30) 0 7 (16.7%) 17 (70.8%) mg (n 14) 1 (8.3%) 4 (33.3%) 7 (58.3%) 0 2 II. Dose (mg/kg per dy) 6.0 (n 33) 0 12 (41.4%) 17 (58.6%) (n 32) 1 (3.7%) 10 (37.0%) 16 (59.3%) (n 17) 1 (7.7%) 3 (23.1%) 9 (69.2%) 0 4 III. Totl dose (g/kg) 0.1 (n 24) 0 9 (45%) 11 (55%) (n 40) 1 (3.0%) 11 (33.3%) 21 (36.7%) (n 18) 1 (6.3%) 5 (31.2%) 10 (62.5%) 0 2 IV. Administrtion period (dys) 14 (n 23) 0 5 (29.4%) 12 (70.6%) (n 26) 1 (4.4%) 7 (30.4%) 15 (65.2%) (n 33) 1 (3.5%) 13 (44.8%) 15 (51.7%) 0 4 cilly for more thn 3 weeks, my be ssocited with good objective responses. The histologicl effect ws evluted in 82 ptients nd the following clssifictions were mde: grde 3 (complete disppernce or necrosis of tumor cells), 2; grde 2 (necrotic chnges 2/3 re), 11; grde 1b ( 1/ 3 re), 11; grde 1 ( 1/3 re), 27; nd grde 0 (no histologicl chnges), 31 (Tble 4). There ws correltion between the histologicl effect nd depth of the primry tumor, nd the frequences of grde 2 3 responses were significntly higher (P 0.05) in pt4 tumors thn in pt1 3 tumors (Tble 4). There ws no reltionship between the histologicl response nd the histology (dt not shown). Correltion between the mcroscopic nd pthologicl responses is summrized in Tble 6, which indictes no correltion between them. In the present study, 2 ptients with CRs were observed. One ws 77 yer-old mn who hd smll Borrmn type II dvnced gstric cncer t the pyloric ring, nd biopsy demonstrted poorly differentited denocrcinom. After dministrtion of UFT t 300 mg/dy for 23 dys, endoscopic exmintion reveled complete disppernce of the ulcertive lesion, nd the objective response ws evluted s CR. No ulcertive lesion ws found mcroscopiclly in the resected specimen; however, postopertive pthology demonstrted cncer cells infiltrting to the musculris propri, nd the histologicl response ws evluted s grde 1b. The postopertive stge clssifiction ws stge 1b: pt2 (pm), pn0, M0. He died of liver metstsis 46 months fter the surgery. The second ptient with CR ws 70 yer-old women (Fig. 1), who hd lrge IIc-like dvnced gstric cncer, nd biopsy

6 Y. Nio et l.: Neodjuvnt UFT for gstric cncer b1 c1 b2 c2 Fig. 2 c. Representtive ptients responding to tretment. A 66-yerold womn dignosed s Bor III (complete pyloric stenosis). 1 Before nd 2 fter UFT 300 mg/dy for 12 dys. There ws prtil response (size reduction) but stenosis ws llevited. b A 79-yer-old mn dignosed s Bor I. b1 Before nd b2 fter UFT 300 mg/dy for 25 dys. There ws prtil response (size reduction). c A 50-yer-old mn dignosed with liver metstsis. c1 Before nd c2 fter UFT 600 mg/dy for 35 dys. There ws prtil response in the primry lesion but the liver metstsis disppered (rrows) Tble 6. Correltion between mcroscopic nd pthologicl responses Grde of pthologicl response Objective response Totl 3 2 1b 1 0 CR PR NC PD Unevluble Totl demonstrted well-differentited denocrcinom. After dministrtion of UFT t 300 mg/dy for 16 dys, endoscopic exmintion demonstrted the scr of the ulcertive lesion, nd the objective response ws evluted s CR, nd no ulcertive lesion ws found mcroscopiclly. At first, the pthologists dignosed no cncer cells remining in the resected specimens; however, in joint meeting of surgeons nd pthologists, miniml lesion ws discovered in the submucosl lyer, nd the histologicl response ws evluted s grde 2. Her postopertive stge clssifiction ws stge 1: pt1 (m), pn0, M0. Six yers hve pssed since the surgery nd

7 70 Y. Nio et l.: Neodjuvnt UFT for gstric cncer Tble 7. Drug concentrtion in tissues (29 ptients) Dose (/dy) 600 mg (n 6) 400 mg (n 13) 300 mg (n 10) Durtion (dys) Primry lesion FT µg/g tissue (n 5) (n 9) (n 5) 5-FU µg/g tissue (n 5) (n 9) (n 6) Norml mucos FT (n 6) (n 11) (n 8) 5-FU (n 6) (n 11) (n 8) Metsttic node FT (n 3) (n 4) 0.0 (n 2) 5-FU (n 3) (n 4) 0.0 (n 2) Norml node FT (n 3) (n 12) (n 8) 5-FU (n 3) (n 12) (n 8) FT, Futrfur; 5-FU, 5-fluorourcil Tble 8. Comprison of survivl rtes fter surgery in ptients who received neodjuvnt UFT nd historicl controls 3-yer survivl rtes ptnm stge Control Neodjuvnt UFT Stge % (n 306) 97.1% (n 40) Stge % (n 38) 75.0% (n 6) Stge % (n 78) 86.7% (n 19) Stge % (n 117) 41.6% (n 17) Historicl controls in our deprtment, she is now hospitlized for rheumtoid rthritis, with no signs of recurrence. Drug concentrtion in tumor tissue (Tble 7) All ptients were given UFT t 6:00 p.m. on the dy before surgery, nd underwent surgery from 9:00.m. Blood ws drwn t 9:00.m. nd the tissues were tken between 11:00.m. nd 3:00 p.m. in the operting room. Tble 7 shows the drug concentrtions in the cncerous nd norml tissues, indicting tht lrger doses my be ssocited with higher concentrtion of FT in the tissues. However, there were only slight differences in 5-FU concentrtions mong the three dosge groups. Survivl fter surgery All the ptients underwent gstrectomy, nd the survivl curves fter gstrectomy re shown in Fig. 3. During the follow-up period of months (medin period, 41 months), 16 ptients died: 12 due to recurrence of the cncer nd 4 of other diseses, including cerebrl poplexy, dibetes mellitus, sepsis cused by pneumoni, nd myelodysplsi. Comprtive survivl rtes for ptients in this series t our deprtment, nd Fig. 3. Postopertive survivl curves of ptients who received neodjuvnt UFT. During the medin follow-up period of 41 months, the 3-yer survivl rtes were 97.1% for ptients in stge 1 (n 40), 75% for those in stge 2 (n 6), 86.7% for those in stge 3 (n 19), nd 41.6% for those in stge 4 (n 17) historicl controls t the Jpn Cncer Institute Hospitl were clculted. The 3-yer survivl rtes were 97.1% for stge 1 (n 40), 75% for stge 2 (n 6), 86.7% for stge 3 (n 19), nd 41.6% for stge 4 (n 17). These survivl rtes were higher thn those of the historicl controls in our deprtment (3-yer survivl rtes: 94% for stge 1, 78% for stge 2, 61% for stge 3 nd 15% for stge 4) (Tble 8). The correltion between postopertive survivl nd the objective response is summrized in Fig. 4, indicting no difference in the survivl curves between the NC group nd the CR or PR groups. Discussion Since the reports of Wilke nd collegues [5], neodjuvnt chemotherpy of gstric cncer hs

8 Y. Nio et l.: Neodjuvnt UFT for gstric cncer 71 Fig. 4. Objective responses nd postopertive survivl curves fter neodjuvnt UFT. Dotted lines, No chnge (NC) (n 42); continuous lines, CR or prtil response (PR) (n 27) ttrcted the interest of clinicl oncologists, nd neodjuvnt chemotherpy hs been employed for the tretment of vrious mlignncies, such s esophgel, brest, nd gstric cncers. The mjor im of neodjuvnt chemotherpy is downstging for resectble cncer nd improving the resectbility of currently inoperble cncer. In the present study, neodjuvnt chemotherpy with UFT for gstric cncer chieved n objective response of 39%, which is comprble to the responses produced by intensive chemotherpies, nd comptible with previous reports on the clinicl effects of orl UFT [23]. UFT is widely used for chemotherpy of digestive orgn cncers in Jpn, nd response rtes of vrious cncers to orl UFT re reported to be comprble to those of intensive i.v. chemotherpies, including CDDP, which usully chieve 20% 40% response rte for gstric cncer. In ddition, the side effects of UFT re not so severe [23]. Recently, it hs lso been reported tht combintion regimen with UFT nd leucovorin chieved high response rte in colorectl cncer nd ws well tolerted [26,27]. These results suggest tht UFT my be employed for neodjuvnt chemotherpy insted of intensive i.v. chemotherpy. In the present study, endoscopic exmintion showed tht dvnced gstric cncer becme similr to erly gstric cncer in severl ptients, nd CT exmintion demonstrted the obvious shrinkge of metsttic nodes nd disppernce of liver metstsis in two ptients. These responses do not lwys suggest preopertive downstging, but preopertive downsizing of the primry nd metsttic lesions ws chieved in severl ptients by UFT. It is uncler whether neodjuvnt therpy contributes to improved survivl fter surgery. There hve been no reports on this subject, becuse it is difficult to define the effect of neodjuvnt therpy in the phse II setting. Six yers hve pssed since the strt of the present study, but the medin follow-up durtion is only 41 months. As shown in Tble 8, the survivl rtes of stge 3 nd 4 ptients were higher thn those of the historicl controls in our deprtment, lthough the number of the ptients ws not sufficient for conclusive results to be drwn. Furthermore, comprisons with historicl controls cn be severely flwed. In ddition, the present study demonstrted tht there ws no correltion between the objective response nd the postopertive survivl. Accordingly, if neodjuvnt UFT is truly beneficl to improve survivl, the mcroscopic downsizing of primry tumors my not ply n importnt role. In our previous report, n nlysis using Akike s informtion criteri demonstrted tht the N-fctor s well s the T-fctor were significnt fctors ffecting the postopertive survivl of gstric cncer ptients [28]. Accordingly, one possible mechnism for the beneficl effect of neodjuvnt chemotherpy on survivl my be medited by its effect on nodl involvment. Since the present study ws not rndomized controlled study, such tril with lrger smple size is necessry to clrify the true effects of neodjuvnt chemotherpy with UFT for gstric cncer. Orl UFT lso hs much milder side effects thn intensive i.v. chemotherpies. Previous reports showed tht 41.4% of ptients receiving orl UFT experienced side effects, but tht the mjor side effects were norexi (24.3%), nuse nd vomiting (12.5%), nd dirrhe (11.1%); hemtologicl toxicity ws noted in only 6.9% of ptients [23]. These results suggest n dvntge of orl UFT in tht ptients cn receive mbultory chemotherpy without serious side effects. By contrst, intensive chemotherpy usully requires hospitl cre, due to its serious side effects, resulting in n impired qulity of life (QOL) nd high cost. Accordingly, orl UFT my contribute to improving ptient s QOL nd my lso reduce tretment costs, mking in much more suitble for neodjuvnt chemotherpy of gstric cncer thn other intensive i.v. chemotherpies. However, in the present study, three ptients becme infected with MRSA nd seven hd moderte liver dysfunction fter surgery. While ll of these ptients recovered, these complictions seemed to be ssocited with the long period of dministrtion ( 4 weeks). Accordingly, it is recommended tht the dose of orl UFT should be reduced fter 2 weeks of dministrtion. Becuse the frequency of liver dysfunction with UFT therpy is reported to be 0.6% [23], the incidence of postopertive liver dysfunction in the present study seems to be high. The mechnisms responsible for postopertive liver dysfunction re uncler. Fluoropyrimidines, in generl, sometimes cuse serious liver dysfunction, nd vrious medictions fter surgery, including drugs used for nesthesi nd ntibiotics in

9 72 Y. Nio et l.: Neodjuvnt UFT for gstric cncer the present study, my work synergisticlly to cuse liver dysfunction. In the present study, UFT ws dministered t three different doses. Becuse UFT is n orl gent nd one cpsule includes 100mg of FT or one pckge includes 150mg of grnules, it is difficult to dminister certin does per kg or per m 2, nd n obvious dose-dependency hs not been seen [23]. The drug concentrtions in the tissues my reflect this sitution, becuse the FT concentrtion in cncer tissue ws correlted with the dose dministered, but the 5-FU concentrtion ws not (Tble 7). The reson for the lck of obvious dosedependency in chemotherpy with UFT is not cler. After orl dministrtion, UFT my be prtly degrded by stomch cid, bsorbed by the gut, metbolized into 5-FU by the liver, nd then ccumulte in tumor tissues. Accordingly, differences mong ptients in stomch cid ctivity, gut bsorption rtes, nd metbolizing enzyme ctivity in the liver my be involved. While no dose-dependent effects were noted in the present study, higher response rte ws seen in ptients who received UFT for more thn 3 weeks (Tble 5). This result seems resonble becuse the effect of 5-FU is timedependent. The results lso suggests tht 400 mg/body for 3 weeks my be enough to chieve n objective response. In ddition, in the present study, postopertive complictions, especilly MRSA enteritis nd suture insufficiency, were seen in ptients who received UFT t 400 or 600mg/body for more thn 4 weeks. Accordingly, we recommend neodjuvnt chemotherpy with UFT t mg/body for the first 2 weeks nd then t 300 mg/body in order to reduce side effects nd chieve high response rte. In conclusion, the present study indictes tht preopertive chemotherpy for gstric cncer with orl UFT my result in clinicl downsizing of primry tumors, s well s the prevention of tumor growth before surgery. 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