J Clin Oncol 29: by American Society of Clinical Oncology INTRODUCTION

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1 VOLUME 29 NUMBER 16 JUNE JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T From the Iteratioal Collaboratio of Trialists o behalf of the Medical Research Coucil Advaced Bladder Cacer Workig Party (ow the Natioal Cacer Research Istitute Bladder Cacer Cliical Studies Group), the Europea Orgaisatio for Research ad Treatmet of Cacer Geito- Uriary Tract Cacer Group, the Australia Bladder Cacer Study Group, the Natioal Cacer Istitute of Caada Cliical Trials Group, Fibladder, Norwegia Bladder Cacer Study Group, ad Club Urologico Espaol de Tratamieto Ocologico Group. The members ad affiliatios of the writig committee are listed i the olie-oly Appedix. Submitted August 26, 21; accepted December 21, 21; published olie ahead of prit at o April 18, 211. The Medical Research Coucil (MRC) Cliical Trials uit was supported by a grat from the MRC, Uited Kigdom, ad the Europea Orgaisatio for Research ad Treatmet of Cacer Data Cetre was supported by Grats No. 2U1 CA through 5U1 CA from the Natioal Cacer Istitute (Bethesda, MD). The cotets of this article are solely the resposibility of the authors ad do ot ecessarily represet the official views of the Natioal Cacer Istitute. Authors disclosures of potetial coflicts of iterest ad author cotributios are foud at the ed of this article. Cliical Trials repository lik available o JCO.org. Correspodig author: Gareth Griffiths, CSTAT, Wales Cacer Trials Uit, School of Medicie, Cardiff Uiversity, 6th Floor, Neuadd Meirioydd, Heath Park, Cardiff CF14 4YS, Uited Kigdom; griffithsg@cf.ac.uk. 211 by America Society of Cliical Ocology X/11/ /$2. DOI: 1.12/JCO Iteratioal Phase III Trial Assessig Neoadjuvat Cisplati, Methotrexate, ad Viblastie Chemotherapy for Muscle-Ivasive Bladder Cacer: Log-Term Results of the BA Trial Iteratioal Collaboratio of Trialists o behalf of the Medical Research Coucil Advaced Bladder Cacer Workig Party (ow the Natioal Cacer Research Istitute Bladder Cacer Cliical Studies Group), the Europea Orgaisatio for Research ad Treatmet of Cacer Geito-Uriary Tract Cacer Group, the Australia Bladder Cacer Study Group, the Natioal Cacer Istitute of Caada Cliical Trials Group, Fibladder, Norwegia Bladder Cacer Study Group, ad Club Urologico Espaol de Tratamieto Ocologico Group See accompayig editorial o page 2135 A B S T R A C T Purpose This article presets the log-term results of the iteratioal multiceter radomized trial that ivestigated the use of eoadjuvat cisplati, methotrexate, ad viblastie () chemotherapy i patiets with muscle-ivasive urothelial cacer of the bladder treated by cystectomy ad/or radiotherapy. Nie hudred sevety-six patiets were recruited betwee 1989 ad 1995, ad media follow-up is ow 8. years. Patiets ad Methods This was a radomized phase III trial of either o eoadjuvat chemotherapy or three cycles of. Results The previously reported possible survival advatage of is ow statistically sigificat at the 5% level. Results show a statistically sigificat 16% reductio i the risk of death (hazard ratio,.84; 95% CI,.72 to.99; P.37, correspodig to a icrease i 1-year survival from 3% to 36%) after. Coclusio We coclude that chemotherapy improves outcome as first-lie adjuctive treatmet for ivasive bladder cacer. Two large radomized trials (by the Medical Research Coucil/Europea Orgaisatio for Research ad Treatmet of Cacer ad Southwest Ocology Group) have cofirmed a statistically sigificat ad cliically relevat survival beefit, ad eoadjuvat chemotherapy followed by defiitive local therapy should be viewed as state of the art, as compared with cystectomy or radiotherapy aloe, for deeply ivasive bladder cacer. J Cli Ocol 29: by America Society of Cliical Ocology INTRODUCTION I 1999, we published the first results of the largest ever radomized trial of eoadjuvat chemotherapy i muscle-ivasive bladder cacer. 1 This was a iteratioal multiceter study comparig local radical treatmet aloe with local radical treatmet preceded by three cycles of eoadjuvat cisplati, methotrexate, ad viblastie () chemotherapy. The trial was ope to patiet etry betwee 1989 ad 1995 ad recruited 976 patiets. The first aalysis showed a covetioally osigificat 15% reductio i the risk of death after eoadjuvat chemotherapy (hazard ratio [HR],.85; 95% CI,.71 to 1.2; P.75), which traslated ito a absolute differece i 3-year survival of 5.5% (95% CI,.5% to 11%), with 3-year survival rates of 5% i patiets who did ot receive ad 55.5% i patiets who did receive. At that time, the media legth of follow-up for those patiets still alive was 4 years. Also at that time, the survival beefit from eoadjuvat chemotherapy did ot meet our prespecified cliical trial goal, ad the study was reported as such. The study has ow further matured, with a media legth of follow-up for patiets still alive of more tha 8 years. Data for this aalysis were locked i 25. For a umber of practical ad istitutioal reasos (eg, ceters closig dow the trial to further follow-up), oly a small amout of more recet data has bee 211 by America Society of Cliical Ocology 2171 Dowloaded from ascopubs.org by o November 26, 218 from Copyright 218 America Society of Cliical Ocology. All rights reserved.

2 Griffiths et al Radomly Allocated (N = 976) Allocated to o ( = ) Allocated to ( = ) Received allocated itervetio of 3 cycles Did ot receive allocated itervetio Received 2 cycles Received 1 cycle Received 4 cycles Received cycles Reasos Real toxicity effect/impaired fuctio Other toxicity effects of chemotherapy Disease progressio or early death Refusal to cotiue treatmet Protocol errors/uspecified reaso ( = 392) ( = 99) ( = 37) ( = 33) ( = 1) ( = 28) ( = 23) ( = 18) ( = 14) ( = 21) ( = 23) Fig 1. CONSORT diagram., cisplati, methotrexate, ad viblastie. Lost to follow-up Still o therapy ( = 2) ( = ) Lost to follow-up Still o therapy ( = 4) ( = ) Aalyzed ( = ) Aalyzed ( = ) forthcomig, ad further aalysis with loger follow-up is cosidered impracticable. The followig updated results are preseted as the defiitive ad fial outcome of this importat study. PATIENTS AND METHODS Full details of the trial desig, patiet eligibility, ad treatmet were published previously. 1 I summary, eligible patiets had to have histologically prove muscle-ivasive urothelial cell carcioma of the bladder (T2 grade 3, T3, or T4a ad N/X, M) ad be cosidered suitable for curative treatmet. Glomerular filtratio rate had to be more tha 5 ml/mi, ad iformed coset of the patiet eeded to have bee obtaied. Figure 1 shows the trial desig. Chemotherapy The regime used i this trial was as follows: day 1: methotrexate 3 mg/m 2 itraveous (IV) bolus ad viblastie 4 mg/m 2 IV bolus; day 2 before hydratio: cisplati 1 mg/m 2 IV ifusio; day 2 after hydratio: foliic acid 15 mg (oral or IV) every 6 hours for four doses commecig 24 hours after methotrexate o day 1; day 8: methotrexate 3 mg/m 2 IV bolus ad viblastie 4 mg/m 2 IV bolus; ad day 9: foliic acid 15 mg (oral) every 6 hours for four doses after methotrexate o day 8. This schedule was repeated every 21 days for a total of three cycles. The protocol cotaied detailed dose reductio schedules, available o request. Study Desig, Outcome Measures, ad Statistical Aalysis Radom assigmet was performed by a telephoe call, facsimile, or computer coectio to the Medical Research Coucil (MRC) Cacer Trials Office (ow the MRC Cliical Trials Uit), Europea Orgaisatio for Research ad Treatmet of Cacer Headquarters, Natioal Cacer Istitute of Caada Cliical Trials Group Cetral Office, or Australia Natioal Health ad Medical Research Coucil Cliical Trials Cetre. A miimizatio method for radomly assigig patiets was used, ad patiets were stratified by istitutio, choice of defiitive treatmet (cystectomy, radiotherapy, or radiotherapy plus cystectomy) ad tumor stage. Each istitutio selected its preferred local treatmet optio (radiotherapy/cystectomy) to reduce idividual bias i selectio of treatmets for specific patiets. Kapla-Meier curves of overall ad disease-specific survival, metastases-free survival, locoregioal disease-free survival, overall diseasefree survival, ad locoregioal cotrol were compared usig the two-sided log-rak test. All aalyses were by itetio to treat. To calculate the absolute differece i survival time ad the other outcome measures betwee ad o at fixed time poits, the HR was applied to the evet rate for the o group. 2 Overall survival was defied as the time from radom assigmet to death from ay cause. Patiets still alive were cesored at the time of last follow-up. For disease-specific survival, oly deaths caused by bladder cacer where cosidered evets. Metastasis-free survival was defied as the Table 1. Ed Poits 3-Year Rate (%) 5-Year Rate (%) 1-Year Rate (%) Ed Poit No Differece 95% CI No No HR 95% CI P Overall survival to to Metastasis-free survival to to.9.1 Locoregioal disease-free survival to to Disease-free survival to to.95.8 Locoregioal cotrol to to Abbreviatios:, cisplati, methotrexate, ad viblastie; HR, hazard ratio by America Society of Cliical Ocology JOURNAL OF CLINICAL ONCOLOGY Dowloaded from ascopubs.org by o November 26, 218 from Copyright 218 America Society of Cliical Ocology. All rights reserved.

3 Phase III Trial of Neoadjuvat Chemotherapy i Bladder Cacer time from radom assigmet to first recogitio of metastases or death. Patiets who were alive ad free from metastases were cesored at the time of last follow-up. Locoregioal disease-free survival was defied as the time from radom assigmet to reappearace of locoregioal disease (ivasive tumor withi the bladder or pelvis) or death. Patiets who were alive ad free from locoregioal disease were cesored at the time of last follow-up. Disease-free survival was defied as the time from radom assigmet to reappearace of locoregioal disease, metastases, or death. Patiets who were alive ad disease free were cesored at the time of last follow-up. Locoregioal cotrol was defied as the time from radom assigmet to reappearace of locoregioal disease (ivasive tumor withi the bladder or pelvis). Patiets who were free from locoregioal disease were cesored at the time of last follow-up. Exploratory iteractio aalyses were plaed to assess whether was more effective or less effective over o (i terms of overall survival) i subgroups defied by all iitial patiet characteristics collected at radom assigmet ad the chose defiitive treatmet. To test for cosistecies i the size of ay effect of, a 2 test for iteractio was performed, or whe appropriate, a 2 test for tred was performed. Kapla-Meier curves of overall survival ad locoregioal disease-free survival were produced i subgroups of patiets who actually received cystectomy oly ad patiets who actually received radiotherapy oly, ad the differece betwee ad o i each subgroup was compared usig the two-sided log-rak test. The trial was origially powered to detect a absolute improvemet i 2-year survival of 1% (5% icreased to 6%; with a power approachig 9%, a two-sided sigificace level of 5% required 374 evets). There was o correctio of the P value to adjust for the previous aalysis. RESULTS Betwee November 1989 ad July 1995, 976 patiets were recruited from 16 istitutios i 2 coutries by seve differet atioal or iteratioal cliical groups; patiets were radomly assiged to receive, ad patiets were assiged to ot receive. The iitial patiet characteristics ad choice of local radical treatmet have bee published previously 1 ad were balaced betwee arms. I summary, 34% ( 334), 58% ( 567), ad 8% ( 75) of patiets had T2, T3, ad T4a disease, respectively; 88% ( 854) had A 1. B 1. Overall Survival No Metastasis-Free Survival No No Time (moths) No Time (moths) C 1. D 1. Locoregioal Disease-Free Survival No Disease-Free Survival No No Time (moths) No Time (moths) Fig 2. Kapla-Meier curves for (A) overall survival, (B) metastasis-free survival, (C) locoregioal disease-free survival, ad (D) disease-free survival., cisplati, methotrexate, ad viblastie by America Society of Cliical Ocology 2173 Dowloaded from ascopubs.org by o November 26, 218 from Copyright 218 America Society of Cliical Ocology. All rights reserved.

4 Griffiths et al grade 3 disease; ad 65% ( 634) had N. The media age was 64 years; 88% of patiets ( 863) were male; ad 43% ( 415), 5% ( ), ad 8% ( 76) of patiets chose the local radical treatmet of radiotherapy, cystectomy, ad a combiatio of radiotherapy ad cystectomy, respectively. I this updated aalysis, the media follow-up time for patiets still alive is 8. years (iterquartile rage, 5.7 to 1.2 years), ad the maximum follow-up time is 13.9 years. Primary Ed Poits The updated results for overall survival, metastases-free survival, locoregioal disease-free survival, disease-free survival, ad locoregioal cotrol are listed i Table 1 ad show i Figure 2. The results show a covetioally statistically sigificat 16% reductio i the risk of death (HR,.84; 95% CI,.72 to.99; P.37), 23% reductio i the risk of metastases or death (HR,.77; 95% CI,.66 to.9; P.1), 13% reductio i the risk of local disease or death (HR,.87; 95% CI,.75 to 1.1; P.67), 18% reductio i the risk of disease or death (HR,.82; 95% CI,.7 to.95; P.8), ad 4% reductio i the risk of locoregioal relapse (HR,.96; 95% CI,.8 to 1.15; P.632) after. Cause of Death A total of 591 patiets have died (Table 2). The mai cause of death was bladder cacer, which was attributed to 72% of deaths (223 of 39 deaths) i patiets who did ot receive ad 7% of deaths (198 of 282 deaths) i patiet who received. A exploratory aalysis of disease-specific survival resulted i a HR of.83 (95% CI,.68 to 1.; P.5). Table 2 shows cause of death accordig to the type of defiitive treatmet actually received. The additio of to stadard treatmet resulted i a 16% reductio i the overall risk of death from all causes. Ievitably, the potetial beefit of chemotherapy will have bee compromised by ay treatmet-related deaths. Chemotherapy-related mortality was 1%, operative mortality after cystectomy was 3.7%, ad oe death was attributed to radiotherapy. Treatmet-Related Mortality Trialists were cocered from the outset that the operative risks of cystectomy might be magified by preoperative chemotherapy or that itself might cause treatmet-related deaths, icludig more cardiovascular toxicity. Table 2 shows that either treatmet was risk free, but chemotherapy-related mortality was low (1%) ad less tha half that reported for methotrexate, viblastie, doxorubici, ad cisplati (MVAC) i a subsequet iteratioal trial of MVAC versus gemcitabie plus cisplati. 3 Salvage Chemotherapy Twety-ie patiets i the arm ad 84 patiets i the o arm received some form of salvage chemotherapy. Give the efficacy of chemotherapy observed i this trial ad other studies, salvage chemotherapy is ulikely to have iflueced overall survival, although it is recogized that the true impact of salvage chemotherapy give i this situatio caot be determied with certaity. Iteractio Aalyses As reported previously, there is a suggestio (for overall survival) that eoadjuvat may have had a greater effect i the followig three subgroups: patiets with better real fuctio, larger tumor size, or poorly differetiated tumors (data ot show). There was o evidece that eoadjuvat had a greater or lesser effect i subgroups of choice of defiitive treatmet (radiotherapy, cystectomy, or radiotherapy plus cystectomy; test of iteractio 2 value [df].112 [2]; P.946). Radiotherapy Versus Cystectomy The choice of defiitive treatmet used i this trial was based o patiet or physicia choice ad was ot radomly assiged, ad the trial was desiged explicitly ot to compare various defiitive local treatmets. Thus, o coclusios should be draw from the data preseted cocerig the relative merit of cystectomy compared with radiotherapy. I Norway, preoperative radiotherapy was carried out, but there were isufficiet umbers to aalyze separately. The importace of this cautio is edorsed by the fidig that although some patiet ad tumor characteristics were well balaced i the two groups (Table 3), fewer patiets receivig radiotherapy, compared with patiets who uderwet cystectomy, had a WHO performace status of (55% [223 of 43 patiets] v 82% [353 of 428 patiets], respectively), fewer patiets had T2 tumors (31% [124 of 43 patiets] v 38% [162 of 428 patiets], respectively), fewer patiets were N (62% [248 of 43 patiets] v 75% [319 of 428 patiets], Table 2. Cause of Death Accordig to the Type of Defiitive Treatmet Actually Received No (No. of patiets) (No. of patiets) Defiitive Treatmet Received Defiitive Treatmet Received Total Preoperative Preoperative Patiets Cause of Death RT RT Cystectomy Cystectomy Missig Total RT RT Cystectomy Cystectomy Missig Total No. % Total patiets Patiets who died Cause of death Disease related (TCC) Treatmet related Other maligacy Cardiovascular Other cause Missig Abbreviatios:, cisplati, methotrexate, ad viblastie; RT, radiotherapy; TCC, trasitioal cell carcioma by America Society of Cliical Ocology JOURNAL OF CLINICAL ONCOLOGY Dowloaded from ascopubs.org by o November 26, 218 from Copyright 218 America Society of Cliical Ocology. All rights reserved.

5 Phase III Trial of Neoadjuvat Chemotherapy i Bladder Cacer Table 3. Patiet Demographics ad Cliical Characteristics by Radiotherapy ad Cystectomy Groups RT ( 43) Preoperative RT Cystectomy ( 66) Cystectomy ( 428) Characteristic No. of Patiets % No. of Patiets % No. of Patiets % Tumor stage T T T4a Histologic grade (local pathologist) 1/ Missig 1 Nodal status N NX Age, years Sex Male Female WHO performace status / Tumor size, cm Missig 4 5 Calculated GFR, ml/mi Missig 1 4 Abbreviatios: RT, radiotherapy; GFR, glomerular filtratio rate. respectively), ad more patiets were older tha age 65 years (49% [197 of 43 patiets] v 34% [146 of 428 patiets], respectively). It seems that there was a elemet of selectio whe choosig defiitive treatmet so that survival after these two differet forms of treatmet should ot be compared. The iteractio aalysis (previous sectio) ad Figures 3A ad 3B show a importat fidig, amely, that for overall survival, there was o evidece that eoadjuvat was more or less effective whe combied with either radiotherapy or cystectomy. A total of 43 patiets received radiotherapy aloe, ad 428 patiets received cystectomy aloe. The reductios i the risk of death with were 2% ad 26% for the radiotherapy aloe ad cystectomy aloe groups, respectively (radiotherapy aloe: HR,.8; 95% CI,.63 to 1.2; P.7; cystectomy aloe: HR,.74; 95% CI,.57 to.96; P.22). For locoregioal disease-free survival (Figs 3C ad 3D), there was some evidece of a greater impact with over o give before cystectomy (a 26% reductio i risk; HR,.74; 95% CI,.58 to.95; P.19) tha the same chemotherapy give before radiotherapy (a 9% reductio i risk; HR,.91; 95% CI,.73 to 1.14; P.417). However, this may be explaied by the differet patiet ad tumor characteristics discussed earlier. DISCUSSION This aalysis of mature data shows that the previously reported possible survival advatage of observed i the first aalysis is ow statistically sigificat at the 5% level ad, although the estimates of HRs have remaied relatively uchaged, the icrease i the umber of evets has resulted i a arrowig of the 95% CIs. Three cycles of before cystectomy or radiotherapy results i a 16% reductio i the risk of death, correspodig to a icrease i 3-year survival from 5% to 56%, 1-year survival from 3% to 36%, ad media survival time of 7 moths (from 37 to 44 moths). did ot result i more cardiovascular deaths. Some might cosider the umber of cystectomy-related deaths (3.7%) to be high, 4 but this operative mortality rate was lower tha that reported i oe of the largest reviews of cystectomies performed i the Uited States 5 durig the years covered by the trial. Thus, there is o evidece to suggest that the additio of eoadjuvat made cystectomy (or radiotherapy) more dagerous i this trial. At both the outset (1989) ad the coclusio (1995) of the trial, more tha 7% of participatig cliicias were of the opiio that a by America Society of Cliical Ocology 2175 Dowloaded from ascopubs.org by o November 26, 218 from Copyright 218 America Society of Cliical Ocology. All rights reserved.

6 Griffiths et al A 1. B Overall Survival Overall Survival No No No Time (moths) No Time (moths) C 1. D 1. Locoregioal Disease-Free Survival No Locoregioal Disease-Free Survival No No Time (moths) No Time (moths) Fig 3. Overall survival i patiets who received (A) radiotherapy oly ad (B) cystectomy oly. Locoregioal disease-free survival i patiets who received (C) radiotherapy oly ad (D) cystectomy oly., cisplati, methotrexate, ad viblastie. improvemet i survival of 1% would be eeded to justify the use of eoadjuvat i routie practice. This magitude of beefit has ot bee achieved with this trial, which shows, alog with the metaaalysis published i 25 by the Advaced Bladder Cacer Collaboratio, 6,7 a clear beefit i overall survival of oly 5% to 6% at 3 years. As is commo practice, the ed poit of locoregioal disease-free survival has bee defied to iclude the presece of tumor i the pelvis, distatmetastases, addeath. Thisisothelpfulfromthecliicalperspective because the iclusio of distat metastases ad death i the defiitio may overshadow the serious cliical problem of bladder cacer persistig orrecurrigithepelvisaftercompletioofdefiitivetreatmet. Thus, i Table 2, we have added data for locoregioal cotrol (HR,.96; 95% CI,.8 to 11.5; P.632). These show o sigificat beefit from the additio of to either radiotherapy or cystectomy, a fidig that may be surprisigbutisimportatgivethehighlocalrelapserateithissituatio ad its symptomatic cosequeces for the patiet. Aother measure of local cotrol is the umber of patiets who uderwet salvage cystectomy for tumor relapse i the bladder after radiotherapy. It was hoped that the additio of to radiotherapy would improve eradicatio of primary tumor, but we observed o evidece to support ay beefit. Overall, 49% of patiets (24 of patiets) who received were reported to have developed locoregioal relapse compared with 48% of patiets (231 of patiets) who did ot receive. I patiets who received radiotherapy as defiite treatmet, 57% of patiets (12 of 21 patiets) who received were reported to have developed locoregioal relapse compared with 62% of patiets (12 of 193 patiets) whodidotreceive. Ipatietswhoreceivedcystectomyasdefiite treatmet, 4% of patiets (84 of 212 patiets) who received were reported to have developed locoregioal relapse compared with 39% of patiets (84 of 216 patiets) who did ot receive. The Southwest Ocology Group (SWOG) study published i 23 8 erolled 317 patiets oto a study of eoadjuvat MVAC before cystectomy versus cystectomy aloe ad showed a 25% reductio i the risk of death with the additio of MVAC (HR,.75; 95% CI,.57 to 1.; P.6). I our study, although we have observed a smaller by America Society of Cliical Ocology JOURNAL OF CLINICAL ONCOLOGY Dowloaded from ascopubs.org by o November 26, 218 from Copyright 218 America Society of Cliical Ocology. All rights reserved.

7 Phase III Trial of Neoadjuvat Chemotherapy i Bladder Cacer reductio i risk of death with (ie, 16%), this was statistically sigificat at the 5% level ad icluded both cystectomy ad radiotherapy patiets. Whe aalyzig patiets i our trial who oly had cystectomy ( 428), a similar populatio to that of the SWOG study, we foud a similar effect size (HR,.74; 95% CI,.57 to.96; P.22), although these results should be iterpreted with cautio because i our trial the choice of whether to give patiets cystectomy or radiotherapy was based o patiet or physicia choice ad was ot radomly assiged ad there is some evidece to suggest there was a elemet of patiet selectio. I the SWOG trial, 33% of evaluable patiets ( 5) had grade 4 (severe) graulocytopeia, with 17% of patiets ( 26) experiecig grade 3 GI toxicity (ausea, vomitig, stomatitis, diarrhea, or costipatio). I our study, as reported i the iitial aalysis, 1 although serious adverse effects from chemotherapy were ot commo, five patiets assiged to chemotherapy died from toxic effects durig treatmet (mortality rate, 1%). Data o ausea ad vomitig were ot collected, but aecdotal reports suggest that they were commo despite the recommeded use of atiemetics accordig to istitutioal practice. WHO grade 3 or 4 leukopeia, thrombocytopeia, ad eutropeic fever occurred i 16%, 6.5%, ad 1% of patiets, respectively. No grade 3 or 4 real toxic effects occurred, but 26% of patiets required dose decreases or delay (accordig to protocol) because of impaired real fuctio. How patiets ad cliicias apply the fidigs from this trial will vary, ad although improvemets of this magitude have resulted i the wide use of adjuvat treatmet i a umber of other cacers (icludig breast, colo, ovary, ad stomach), the icrease i survival will eed to be balaced agaist the toxicity ad other disadvatages of chemotherapy (eg, the cost to the patiet i terms of treatmet time ad impact o quality of life). This is a decisio each doctor has to make with each patiet. Although the combiatio of gemcitabie with cisplati has show comparable efficacy ad lesser toxicity whe compared with MVAC, 3 o ew aget or combiatio has yet show ay evidece of beig more active or effective tha or MVAC. Although reduced morbidity is welcome, it is sigificatly icreased efficacy that is required. Also of importace, o radomized trial has show that gemcitabie plus cisplaticofersaequivaletsurvivalbeefititheeoadjuvatcotext. Sice completio of the trial i 1995, other chemotherapy regimes have bee itroduced for advaced urothelial cacer, 9-11 ad some authors have suggested that they should be tested i ew trials of adjuvat or eoadjuvat therapy. It would seem that although overall respose rates of 5% to 6% ad complete respose rates of 2% may be ecouragig idicators of activity i phase II studies, they may ot predict a major icremet i cure rate i phase III studies i the (eo)adjuvat settig, ad it is likely that oly modest improvemets will be achieved. Therefore, to ultimately get cosiderable improvemets for both idividuals ad populatios, a series of modest improvemets to be added together may be required, as opposed to oe breakthrough treatmet. We believe that future trials should cosider ew strategies for treatmet developmet such as the developmet of ew surrogate ed poits/biomarkers ad targeted agets that may provide better evidece of treatmet activity ad idividualized treatmet strategies that may result i larger improvemets i specific subpopulatios. We coclude that chemotherapy improves outcome as firstlie adjuctive treatmet for ivasive bladder cacer. Neoadjuvat or MVAC chemotherapy followed by defiitive local therapy should costitute the state of the art for fit patiets with deeply ivasive bladder cacer, as compared with cystectomy or radiotherapy aloe. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) idicated o potetial coflicts of iterest. AUTHOR CONTRIBUTIONS Coceptio ad desig: Regiald Hall, Richard Sylvester, Derek Raghava, Mahesh K.B. Parmar Provisio of study materials or patiets: Regiald Hall Collectio ad assembly of data: Richard Sylvester, Derek Raghava, Mahesh K.B. Parmar Data aalysis ad iterpretatio: Gareth Griffiths, Richard Sylvester, Derek Raghava, Mahesh K.B. Parmar Mauscript writig: All authors Fial approval of mauscript: All authors REFERENCES 1. Iteratioal Collaboratio of Trialists: Neoadjuvat cisplati, methotrexate ad viblastie chemotherapy for muscle-ivasive bladder cacer: A radomised cotrolled trial. Lacet 354:533-54, Parmar MKB, Machi D: Survival Aalysis: A Practical Approach. Chichester, Uited Kigdom, Joh Wiley & Sos, vo der Maase H, Segelov L, Roberts JT, et al: Log-term survival results of a radomized trial comparig gemcitabie plus cisplati, with methotrexate, viblastie, doxorubici, plus cisplati i patiets with bladder cacer. J Cli Ocol 23: , Rosario DJ, Becker M, Aderso JB: The chagig patter of mortality ad morbidity from radical cystectomy. BJU It 85:427-43, 2 5. Hollebeck BK, Wei Y, Birkmeyer JD: Volume, process of care, ad operative mortality for cystectomy for bladder cacer. 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Urol Ocol [epub ahead of prit o September 21, 21] by America Society of Cliical Ocology 2177 Dowloaded from ascopubs.org by o November 26, 218 from Copyright 218 America Society of Cliical Ocology. All rights reserved.