Neoadjuvant and Adjuvant Chemotherapy Approaches for Invasive Bladder Cancer

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Neoadjuvant and Adjuvant ChemotherapyApproaches for Invasive Bladder Cancer

Derek Raghavan, Earle Burgess, Kris E. Gaston, Michael R. Haake, and Steven B. Riggs

Deeply invasive bladder cancer, representing approximately 20% of incident cases, is cured byradical cystectomy or radiotherapy in less than 50% of cases. In an effort to improve cure rates,based on objective response rates in metastatic disease of 40%–70% from combination chemother-apy regimens, systemic chemotherapy has been incorporated into programs of definitive treatmentfor this disease. Several randomized trials and a meta-analysis have confirmed a survival benefit fromneoadjuvant chemotherapy followed by definitive local treatment, reflecting both median survivalfigures and cure rates. Despite several promising phase II trials, no randomized trial of classicaladjuvant chemotherapy for bladder cancer has demonstrated an overall survival benefit, despiteincrements in disease-free survival. Molecular prognostication has been studied in an effort toimprove the utility of systemic therapy for invasive non-metastatic bladder cancer, but randomizedtrials have not shown associated survival benefit. Despite level 1 evidence of a survival benefit fromneoadjuvant MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], cisplatin) or cisplatin,methotrexate, and vinblastine (CMV) chemotherapy, more than 50% of incident cases do notreceive such treatment.Semin Oncol 39:588-597 © 2012 Elsevier Inc. All rights reserved.

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In the United States, the incidence of bladder cancer
with muscle invasion is about 3–4 new cases per100,000 males and 0.5–1 new case per 100,000

females per year, representing about 20% of incidencecases of this malignancy.1,2 In addition, 20%–50% of

on-invasive disease eventually changes its characternd becomes invasive. As in other sites, the majority ofnvasive disease is urothelial cancer (UC), formerlyermed transitional cell carcinoma, with around 15% ofases being squamous cell carcinoma, adenocarci-oma, or other less common variants.3

In the United States, the usual treatment of choicefor muscle-invasive bladder cancer is radical cystec-tomy with bilateral pelvic lymph node dissection,4,5

based on the ability to achieve local control and theprognostic information available from the specimen ofthe primary cancer and lymph nodes.6 More recently itppears that innovations in technology, such as the usef robotic assistance, can maintain the efficacy of rad-

Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC.Conflicts of interest: D.R. is on the President’s Advisory Board, Sanofi

Aventis, and consults for Gerson Lehrman intermittently. The otherauthors have no conflicts.

Address correspondence to Derek Raghavan, MD, PO Box 32861, Char-lotte, NC, 28232-2861. E-mail: [email protected].

0270-9295/ - see front matter© 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1053/j.seminoncol.2012.08.003
Semin588

cal cystectomy while reducing the morbidity of therocedure.7

However, organ-sparing approaches provide a viablealternative, especially for frail and very elderly patients,those with significant intercurrent medical disorders,or for patients who will not accept the side effects andrisks associated with surgery.8,9

Despite potentially curative surgery, approximately50% of patients with deeply muscle-invasive UC (stagesT3–4) develop metastases within 2 years, and most ofthem die of their disease.2

The most important prognostic factor for survival ispathologic (p) stage, but grade, presence of hydrone-phrosis, nature and extent of prior treatment, and per-haps patterns of gene expression also may affect out-come. Five-year overall survival (OS) rates for pT2, pT3,and pT4 tumors are 60%–80%, 30%–50%, and �20%,respectively.2,5 Extravesical extension and/or extensivelymph node metastases correlate with a higher risk ofpostsurgical recurrence.5,10 Despite these adverse find-ings, it is important to understand, when designingstrategies for improving outcome, that patients withlymph node involvement from bladder cancer, or withextravesical extension, can be cured by surgeryalone.5,10

THERAPEUTIC STRATEGY

In 1981, hypothesizing that preemptive (neoadju-
vant) systemic chemotherapy might improve survival
ars in Oncology, Vol 39, No 5, October 2012, pp 588-597

mailto:[email protected]

http://dx.doi.org/10.1053/j.seminoncol.2012.08.003

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Chemotherapy approaches for invasive bladder cancer 589

for patients with muscle-invasive UC, we designed aphase II trial to assess tumor downstaging and toxic-ity.11 At that time, single-agent chemotherapy was thetandard of care, and it was known that cisplatin, meth-trexate, the vinca alkaloids, and doxorubicin had sig-ificant anti-cancer efficacy for metastatic UC. Threeenters demonstrated that this approach was associ-ted with tumor downstaging and an apparent increasen survival, based on historical comparison,12–14 not-withstanding the inherent flaws in such comparisons,including the risks of case selection bias, stage, andtreatment migration.15

However, when considering the potential use ofneoadjuvant chemotherapy, some drawbacks requiredconsideration. One potential disadvantage of this ap-proach was the potential for delaying definitive treat-ment, given that up to 40% of UC are not responsive tochemotherapy.2 Another concern was the discordancebetween clinical and pathologic staging in the assess-ment of chemotherapy response, such that endoscopycould suggest a complete response (CR) when, in real-ity, only a partial response (PR) or less was present.There was also concern that, after chemotherapy, lessrobust patients may not be sufficiently well to toleratedefinitive local treatment.

In one report, a clinical CR (T0 tumor by transure-thral resection) was obtained after treatment with thecombination MVAC regimen (methotrexate, vinblas-tine, doxorubicin [Adriamycin], cisplatin) in 57%; how-ever, only 30% had pathologic T0 (pT0) disease (ie, apathologic CR [pCR]) defined at subsequent cystec-tomy.16 Pathologic response rates are related to thestage, grade, and size of the primary tumor. In a laterseries from Memorial Sloan-Kettering Cancer Center(MSKCC), the pCR rates after neoadjuvant MVAC inpatients with T2/T3a and T3b/T4 tumors were approx-imately 43% and 9%, respectively.17

Thus it seemed essential to validate the early phaseII trials with a definitive, randomized clinical trial. Fur-thermore, as computed tomography scanning was in-troduced into routine management at that time, there

Table 1. Randomized Clinical Trials of Neoadjuv

SeriesNeoadjuvant

RegimenDefinitiveTherapy Ne

Shipley CMV RT/CMRC-EORTC CMV RT/cystectomyIntergroup MVAC CystectomyNordic 1 AC CystectomyNordic 2 CM CystectomyAbbreviations: C, cisplatin; A, doxorubicin; M, methotrexate; Cy

Organization for Research and Treatment of Cancer; RT, radio

was the potential that this step introduced stage migra-tion. Although we demonstrated tumor downstaging,the randomized comparison of single-agent cisplatin,followed by definitive radiotherapy (RT), versus RTalone failed to reveal a survival benefit.18 Similarly,single-agent cisplatin did not confer a survival benefitwhen used as neoadjuvant therapy prior to cystec-tomy.19

Soon afterwards, combination regimens for UC weredeveloped, incorporating cisplatin, methotrexate, vin-blastine, and doxorubicin,20 and randomized trials dem-

nstrated their superiority over single-agent therapy foretastatic disease.21 Accordingly, these regimens, in-

cluding cisplatin, methotrexate, and vinblastine (CMV)and MVAC, were tested as neoadjuvant therapy forUC.16,22 Consequent upon the demonstration of higheresponse rates and apparently greater increases in sur-ival in phase II trials, a series of phase III trials werenitiated to test the hypothesis further (Table 1).

RANDOMIZED TRIALSOF MULTI-AGENT CHEMOTHERAPY

Several multicenter, randomized, controlled trialshave now been completed, with the majority indicat-ing a small, but consistent survival benefit from neoad-juvant combination chemotherapy for deeply invasivebladder cancer.

MRC/EORTC Trial

The largest published trial was performed jointly bythe Medical Research Council (MRC), the EuropeanOrganization for Research and Treatment of Cancer(EORTC), National Cancer Institute (NCI) Canada, andthe Australasian Bladder Cancer Group, and includedmore than 900 patients with high-grade T2–T4a, N0–NX, M0 bladder UC.23 They were randomly assigned tohree cycles of neoadjuvant CMV (n � 491) or nohemotherapy (n � 485), followed by each institu-ion’s selection of local standard management (ie, rad-

emotherapy for Invasive Bladder Cancer

dian Survivalith/Withoutant Therapy (mo)

Actuarial Long-TermSurvival With/WithoutNeoadjuvant Therapy

36/36 48%/49% at 5 yr44/37.5 50%/40% at 8 yr72/45 55%/45% at 6 yr

t reached/72 59%/51% at 5 yrt listed 51%/42% at 7 yrhosphamide; MRC-EORTC, Medical Research Council/European; V, vinblastine.

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590 D. Raghavan et al

ical cystectomy or RT). Our first review of the datashowed the absolute OS benefit from chemotherapy at3 years to be 5.5% (55.5% v 50%), which was less thanhe predefined difference that was sought, and weeported this initially as a negative trial.23 A later anal-sis with 7 years of follow-up showed a 15% OS benefitith neoadjuvant CMV, with a 7% increment in long-

erm survival.24 In this study, a greater survival benefitas seen in patients undergoing surgery as definitive

reatment, although the study was not designed forormal comparison between the modalities of localreatment.

INT 0080 Trial

The US Intergroup trial randomly assigned 317 pa-tients with T2–4a, N0M0 bladder UC to cystectomywith or without three preoperative courses of MVAC.25

Of importance, it required 13 years for this trial tocomplete accrual, which may have contributed to adilution of the results. In the final report with a medianfollow-up of 8.7 years, patients treated with MVACwere significantly more likely to have a pCR (38% v5%) and the improvements in median OS (77 v 46onths, P � .06), and 5-year OS (57% v 43%, P � .06)ere of borderline statistical significance upon two-

ailed statistical analysis. One third of the patients re-eiving neoadjuvant chemotherapy had grade �3 he-atologic or gastrointestinal adverse effects, although

here were no treatment-related deaths. It was ourelief that this publication defined a new standard forhe management of invasive bladder cancer in other-ise healthy patients.25

Subsequent reports by uninvolved investigators, us-ing the Southwestern Oncology Group (SWOG) data-base retrospectively assessed whether surgical factors,in addition to neoadjuvant chemotherapy, had prog-nostic significance for survival.26 An optimal cystec-tomy and thorough pelvic lymph node dissection (de-fined as negative resection margins and at least 10lymph nodes in the surgical specimen) were reportedlyassociated with the longest survival, although it shouldbe emphasized that the Intergroup trial was not de-signed to answer this question, and thus confoundingvariables, unrelated to the quality of surgery or experi-ence of the surgeons, could have contributed to thisoutcome.

Of importance, a secondary analysis of SWOG 87–10compared outcomes of neoadjuvant MVAC for 236cases of pure UC, versus 59 mixed tumors (with ele-ments of squamous or glandular differentiation).27 Thisstudy indicated a survival benefit from MVAC chemo-therapy for patients with mixed tumors (P � .02), witha trend suggesting a greater benefit among mixed tu-mors than for pure UC. Whether that observation isreal, given the relatively uneven size distributions, this
report does suggest that mixed tumors should not be
precluded from neoadjuvant protocols. However, thisobservation is not informative for patients with puresquamous carcinoma or adenocarcinoma of the blad-der.

Nordic 1 Trial

The Nordic Cooperative Bladder Cancer Study Group(Nordic-1) randomly assigned 325 patients with high-grade T1, or stages T2T4a, NX, M0 bladder UC toshort-term RT followed by cystectomy with or withouttwo cycles of pre-irradiation cisplatin plus doxorubi-cin.28 At 5 years, neoadjuvant chemotherapy was asso-ciated with a trend towards better OS (59% v 51%), andcancer-specific survival (64% and 54%, respectively) inthe entire group, but in subset analysis, there was astatistically significant 15% absolute OS benefit and a20% cancer-specific survival benefit in patients withT3/T4 disease.

Nordic 2

The subsequent Nordic-2 trial compared cisplatinplus methotrexate followed by cystectomy with cystec-tomy alone in 317 patients with T2–4a, NxM0 bladdercancer.29 The 7% difference in 5-year OS (53% v 46%)did not reach the level of statistical significance, al-though this also may have reflected the regimen usedor modest number of cases randomized.

Meta-analyses

When we conducted a meta-analysis that includedindividual patient data from 3,005 individuals enrolledin 11 randomized trials, comparing neoadjuvant che-motherapy with local therapy alone, we were able todemonstrate that neoadjuvant therapy resulted in astatistically significant 14% reduction in the risk ofdeath, which translated into a 5% absolute improve-ment in 5-year OS (from 45% to 50%).30 Although over-all published data from the INT 0080 trial were in-cluded, we were unable to secure original individualdata from SWOG for this meta-analysis, and thus ex-trapolated from the published report.25 A survival ben-efit was seen, irrespective of whether data from theINT 0080 trial were included.

NEOADJUVANT CHEMOTHERAPYAND BLADDER PRESERVATION

Neoadjuvant chemotherapy also has been incorpo-rated into programs of bladder preservation by increas-ing the proportion of patients whose disease can becontrolled surgically by repeated, aggressive transure-thral resections (with or without RT) or by a partialcystectomy. Our studies from more than 25 years agodemonstrated that this approach was feasible, where
we combined RT and single-agent cisplatin,11,12 and

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many patients with cT2–T4 disease secured remissionsthat were sustained for 10� years.

Shipley and colleagues at Massachusetts GeneralHospital31,32 and the Radiation Therapy OncologyGroup (RTOG)33 developed an algorithm to identifypatients who would require early cystectomy when theattempt at organ preservation was failing: endscopicassessment at around 40–50 Gy, which will identifyfailure of response sufficiently early that the patientscan still be referred for radical cystectomy withoutundue surgical morbidity. The RTOG randomized trialof neoadjuvant CMV chemotherapy followed bychemoradiation versus chemoradiation alone failed toidentify a survival benefit, which may have been due tothe failure of the strategy, the impact of chemotherapyin both arms, patient numbers, case selection bias, orearly closure.33 Sandler and Mirhadi9 have covered theopic of chemoradiation in an accompanying paper inhis series.

Bladder adenocarcinomas are generally resistant tohemotherapy, and these patients should not be con-idered for a neoadjuvant bladder-sparing approachutside of a structured clinical trial. Less clear cut is theorrect approach for squamous carcinomas, as there isow evidence that regimens based on platinum com-lexes and taxanes, with or without gemcitabine, haveignificant anti-cancer efficacy. Despite that, we knowf no published series providing clear evidence thateoadjuvant therapy should be used routinely for thisype of bladder cancer.

ADJUVANT THERAPY

The quality of information available to guide ourdecisions in the use of adjuvant therapy for bladdercancer is inferior to the extensive level 1 data support-ing the use of neoadjuvant MVAC chemotherapy. Thereis simply no completed randomized, clinical trial thathas shown an overall survival benefit in favor of adju-vant therapy of any type for invasive bladder cancer.

Three randomized clinical trials have been com-pleted,34 –36 each of which have shown disease-freeurvival benefits, but none of which have demonstratedtatistically significant improvements in overall sur-ival, the sine qua non of a successful adjuvant trial.

The trial conducted at the University of Southernalifornia, which attempted to assess the utility ofycles of adjuvant cisplatin-doxorubicin-cyclophosph-mide after radical cystectomy, was confounded byeveral flaws of execution, including non-random usef predictive cytotoxic assays to modify chemotherapyegimens.34 Although a disease-free survival benefit was

seen, the adjuvant regimen did not confer an overallsurvival benefit, which was hardly surprising in view ofthe failure of randomized trials to demonstrate a statis-tically significant difference between this triplet and
single-agent cisplatin.
The trial reported by Stockle et al was fundamentallyflawed in design—specifically, based on the belief thatsystemic chemotherapy was ineffective in the setting ofrelapsed cancer, these investigators randomized theirseries of patients to receive adjuvant chemotherapyafter radical cystectomy versus cystectomy alone.35 Inhis study, when patients in the cystectomy arm re-apsed, they were not routinely treated by systemichemotherapy, and thus the study actually only testedhe role of chemotherapy at some time versus nohemotherapy at any time for many of the patients.oday, this study would perhaps be viewed as unethi-al. This error was further compounded in a subse-uent publication in which patients from non-random-

zed studies were added to the original series in anll-conceived attempt to improve statistical power,

hile inadvertently violating principles of sound statis-ical design.36

The Stanford University trial, assessing adjuvantCMV chemotherapy, was closed prematurely by itsData Safety Monitoring Committee because its pre-specified goal of improved disease-free survival hadbeen met37; however, the total number of cases wasmall, and there was not a statistically significant differ-nce between the two arms with respect to OS.

The EORTC attempted to test the utility of adjuvantVAC chemotherapy for patients after radical cystec-

omy for deeply invasive bladder cancer, but regretta-ly the study closed prematurely because of poor ac-rual. Unfortunately, many collaborating cliniciansrroneously believed that the role of chemotherapyad already been proven, and thus were reluctant tonter cases. As a result, no level 1 evidence has beenublished to support this strategy, and the many non-andomized phase II adjuvant trials simply show mod-st efficacy in highly selected populations but do notrove the utility of the strategy.

A recent report from the Spanish Urological Group,sing the combination of paclitaxel-gemcitabine-cispla-in as adjuvant chemotherapy, provided provocativend impressive survival data38; however, it should beecalled that the phase II data with surprising medianurvival figures from this group, using this regimen foretastatic disease, did not translate into sustained long-

erm results in our more strongly powered randomizedlinical trial.39

As discussed below, the recent publication of theso-called p53 trial, testing the utility of adjuvant MVACchemotherapy in patients with p53 mutation, failed toconfirm its original hypothesis, and provided no sug-gestion of a survival benefit for this group of patientswho received adjuvant MVAC chemotherapy.40

Finally, consistent with an unfortunate recent trendin medicine that considers numbers to be more impor-tant than trial design, Svatek et al published an analysisof 3,947 patients with bladder cancer from 11 centers,
of whom 932 received chemotherapy after definitive

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local therapy.41 Despite the many flaws of analysis,ncluding heterogeneity of patients and treatment, se-ere risks of case selection, and treatment selectionias, the authors concluded that adjuvant chemother-py was associated with significant improvement inurvival. This was a particularly puzzling conclusion,iven that the treated patients had an estimated 32.8%robability of 5-year survival, with a 6-week increment

n median survival in the highest risk cohort—hardly auantum leap forward.

NEOADJUVANT VERSUS ADJUVANT THERAPY

No well-designed, published trials have directlycompared neoadjuvant versus adjuvant chemotherapyin patients undergoing cystectomy. Investigators at theM.D. Anderson Cancer Center attempted to address theoptimal timing of perioperative chemotherapy by ran-domly assigning 140 patients with locally advanced UCto two preoperative plus three postoperative coursesof the MVAC regimen versus five postoperative coursesfollowing cystectomy and pelvic lymph node dissec-tion.42

At an average follow-up of nearly 7 years, the mediansurvival for the entire group was 4 years, and patientsundergoing postoperative chemotherapy alone hadsimilar disease-free survival to those receiving neoadju-vant plus adjuvant chemotherapy. The patterns of cy-totoxic and perioperative morbidity did not differ sig-nificantly between the two groups. Patients whounderwent neoadjuvant chemotherapy had a lowerpositive surgical margin rate than those who receivedonly adjuvant treatment, and a lower incidence of pel-vic lymph node metastasis at exploration.42

Forty percent of patients with node-positive diseasewere reportedly cured at the time of reporting, a figurethat is higher than reported from MSKCC and Ger-many43,44 but comparable to the University of SouthernCalifornia series.5

Pertinent to this issue, a retrospective, non-random-ized study was reported from Columbia University, inwhich outcomes of neoadjuvant and adjuvant chemo-therapy were compared in a small series of 146 cases.Although there was no obvious difference between theneoadjuvant and adjuvant groups, the study was heav-ily confounded by heterogeneity of chemotherapy reg-imens and patient populations, and perhaps by heavycase selection bias.45 Interestingly, there was a statisti-ally significant difference in disease-specific survivalavoring neoadjuvant gemcitabine-cisplatin versus adju-ant gemcitabine-cisplatin but no overall difference inurvival. Multivariable analysis showed no specificrends, although the series was actually underpoweredor a significant analysis of this type.

In the absence of a specific randomized trial com-aring optimal neoadjuvant and adjuvant chemother-
py regimens in association with cystectomy, it is not
ossible to make a definitive recommendation abouthe utility of adjuvant chemotherapy as compared toeoadjuvant treatment. However, it is important toote that level 1 data and a meta-analysis support theoutine use of neoadjuvant MVAC chemotherapy foreeply invasive, clinically non-metastatic UC, whereashe extant data in support of adjuvant approaches areuch weaker.

FUTURE DIRECTIONS

It appears that, at least for the next few years, themajor developments in the treatment of invasive blad-der cancer are likely to evolve in the field of molecularprediction and prognostication, given the lack of obvi-ous progress in systemic therapy, and the relativelyconstant state of surgery and RT. The new surgical andRT technologies enumerated by Stamatakis et al6 andSandler and Mirhadi9 will likely affect morbidity morethan mortality, a highly desirable aim but not a gamechanger.

Molecular Prognostication by p53 Status

Mutations in the p53 tumor-suppressor gene are themost extensively characterized putative new prognos-tic determinants for invasive bladder cancer. A signifi-cant correlation between p53 nuclear staining by im-munohistochemistry (IHC) (termed overexpressionbecause the protein product of the wild-type gene isnot normally expressed) and the presence of p53 gene

utations facilitates the assessment of mutant versusild-type p53 status in the primary tumor.40,46

p53 mutations, as inferred by IHC overexpression,have been reported to confer a poor prognosis inmuscle-invasive bladder UC,47,48 although others have

ot been able to separate the influence of p53 overex-ression from tumor stage.49,50 In one analysis of 243

patients undergoing cystectomy for pTa–pT4B disease,the risk of both disease recurrence and death wassignificantly higher in patients whose tumors containedmutant as compared to wild-type p53.47 Recurrenceates for tumors with and without detectable p53 im-unoreactivity were 62% versus 7% for pT1 tumors,

6% versus 12% for pT2 tumors, and 80% versus 11%or pT3 tumors.

p53 status also may influence outcome from bladderreservation therapies, for example, among 90 patientsndergoing neoadjuvant MVAC chemotherapy, pa-ients with mutant p53 were three times more likely to

die from their disease than those with wild-type p53.48

The impact of p53 overexpression on survival waspredominantly in T2 and T3a tumors.

These data have led to prospective risk-directed tri-als using the p53 status of the primary muscle-invasivetumor to determine treatment. For example, at MSKCC,
aggressive TURBT and neoadjuvant chemotherapy was

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used to facilitate bladder preservation in patients withboth favorable biological features (wild-type p53 in-erred from IHC staining) and clinical features (muscle-nvasive, organ-confined disease without hydronephro-is).51 Their initial results suggested that the bladderould be preserved for up to ten years in patients withild-type p53 tumors that are confined to the bladder

wall (stage T2).At the University of Southern California, it was hy-

pothesized that adjuvant chemotherapy enhances sur-vival in patients with p53 mutant tumors40,46,52 basedon retrospective analysis of an adjuvant trial testing theutility of cisplatin-doxorubicin-cyclophosphamide.34

This was further tested, in collaboration with SWOG, ina recently published trial, in which patients with tu-mors expressing mutant but not wild-type p53 wererandomly assigned to a different adjuvant regimen(MVAC chemotherapy) or to observation after cystec-tomy.40 The study was confounded by procedural prob-lems, including a lower than predicted event rate andhigh refusal rate by patients, but was closed prema-turely by the Data and Safety Monitoring Committeewhen a futility analysis indicated that completion of thetrial would not confirm the prognostic significance ofmutant p53, nor the utility of adjuvant MVAC.40

Although the prognostic role of mutant p53 expres-sion by IHC has been well characterized in UC, thesestudies did not explore the interrelationship of p53homologues p63 and p73. Recent data suggest thataltered expression of the p53 family members also mayhave prognostic significance in bladder UC53,54 and may

otentially mediate chemosensitivity to platinum-basedherapy.55 Future studies will be needed to definehether altered co-expression of all p53 family mem-ers in bladder UC has improved prognostic and pre-ictive value over mutant p53 expression alone.

Other Applications of MolecularTechnology to Neoadjuvant Chemotherapy

Although the most robust studies to date have fo-cused on p53 prediction of outcome, several otherapproaches have been explored, at least at a prelimi-nary level. Font et al reported that expression ofBRCA1 mRNA in paraffin-embedded biopsy tissues pre-dicts for response to neoadjuvant cisplatin-based che-motherapy.56 In their study, pT0–1 status was attainedn 24 of 39 cases with low/intermediate BRCA1 levels,ompared with 22% (4 of 18) patients with highRCA1 expression (P � .01). In this study, medianurvival was 168 months versus 34 months, respec-ively (P � .002).

Excision repair cross-complementing 1 (ERCC1) isn enzyme involved in repair of cisplatin-DNA adductsnd contributes to cisplatin resistance.57 Reduced ex-

pression of ERCC1 is associated with a benefit from
cisplatin-based adjuvant chemotherapy in lung can-
cer.58 Hoffman et al analyzed ERCC1 RNA levels from108 patients included in the German Urological Coop-erative Group AUO-AB 05/95 trial, which comparedadjuvant MVEC (methotrexate, vinblastine, epirubicin,cisplatin) to cisplatin/methotrexate in patients withpT3/4 or node-positive bladder cancer.59 This analysisidentified an association between ERCC1 gene expres-sion and progression-free survival (relative risk � 2.24;P � .01). Median OS for the low ERCC1 expressiongroup (�75th percentile) was 72.4 months comparedwith 33.1 months for the high-ERCC1 expression group(P � .19). Although the Kaplan-Meier analysis for OSailed to reach statistical significance in this series,hese data suggest that structured, prospective analysisf ERCC1 expression and response to cisplatin-basedeoadjuvant or adjuvant therapy in bladder UC may beseful.

Additional data that suggest ERCC1 expression inC may predict therapeutic response to platinum-ased therapy can be found in a small series of patientsith muscle-invasive bladder cancer who received

hemoradiation.60 Twelve of 14 patients withoutERCC1 expression by IHC achieved a CR to treatment,in contrast to only two of the eight patients withERCC1 expression, suggesting that ERCC1 expression

ay predict outcome to chemoradiation in muscle-nvasive bladder cancer.60

Takata et al61 assessed the utility of gene expressionrofiling as a predictive index for response to chemo-herapy. In another program design, Smith et al62 de-

veloped a 20-gene expression model that predictedlymph node involvement, with a view to improvingselection of patients for neoadjuvant chemotherapy.

Newer Chemotherapy Approaches

Despite the superiority of MVAC over other regi-mens in the setting of metastatic disease, the mediansurvival is still only 1–2 years, depending on the inclusioncriteria of treated patients, and toxicity is substantial. Theresults obtained with gemcitabine and cisplatin in pa-tients with metastatic disease,63 with approximatelyequivalent anticancer effect and a reduction in toxicity,have led to their investigation in the neoadjuvant andadjuvant setting. As an example, the ”conventionalarm” in the ongoing Cancer and Leukemia Group B(CALGB) 90104 trial consists of cisplatin plus gemcit-abine, chosen instead of MVAC because of its improvedtoxicity profile. However, it is important to note thatthere is no well-powered, level 1 evidence that provesequivalence of the neoadjuvant use of the MVAC regi-men compared to gemcitabine-cisplatin.

It is possible that the previously noted combinationof gemcitabine-cisplatin-paclitaxel, with significant ac-tivity in advanced disease,39 could have more utility inthe neoadjuvant setting, but this would require formal
testing.

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Although there have been provocative data suggest-ing the utility of targeted therapies in the managementof metastatic bladder cancer,64 it is not yet clear

hether they have useful application for invasive, clin-cally non-metastatic disease, despite preliminary re-orts from phase II trials. Thus the demonstration of ofT0 status at cystectomy after treatment with neoadju-ant use of the epidermal growth factor receptorEGFR) inhibitor erlotinib,65 while promising and pro-ocative, needs to be assessed in a randomized clinicalrial.

At present, there is no defined standard beyondVAC in the neoadjuvant setting. For the patient with

ntercurrent illnesses that preclude the use of theVAC regimen, or who refuses the aggressive ap-roach with MVAC, gemcitabine-cisplatin constitutes aeasonable alternative, provided that the patient under-tands the limitations of available data.

Another possible option for patients unable to tol-rate cisplatin-based chemotherapy regimens may beffered by a regimen recently tested in the Unitedingdom. James et al completed a randomized trial ofhemoradiation, in which chemotherapy was givenynchronously with the RT, versus RT alone.66 Their

study was unusual, in a contemporary context, in thatthey employed a regimen predicated on infusional5-fluoruracil and mitomycin-C, and recorded impres-sive OS from the combination of this regimen and RT.While the series was clearly dominated by patients withclinical stage T2 disease, there was a surprisingly im-pressive long-term survival in the patients treated by anon–platinum-containing chemoradiation regimen, andthis may require further consideration in the design ofnon–cross-resistant regimens in the future for use in aneoadjuvant setting.

PATTERNS OF ACTUAL USE OFPERIOPERATIVE CHEMOTHERAPYFOR INVASIVE BLADDER CANCER

Despite the extensive evidence that there is a clini-cally relevant and statistically significant improvementin survival for patients who receive neoadjuvant MVACchemotherapy plus definitive local treatment for inva-sive bladder cancer, compared to local treatment alone,surveys of clinical practice consistently indicate thatthe medical community has been cautious in adoptingthis approach in routine practice. For example, Porteret al, in a study of the Surveillance, Epidemiology andEnd Results (SEER)-Medicare database for 1992–2002,assessed the use of perioperative chemotherapy forinvasive bladder cancer and reported its use to beuncommon.67 Similarly David et al,68 reporting from theNational Cancer Data Base, drew very similar conclu-sions for the period 1998–2003. This seems reason-able, given that the positive randomized trial data were
first published in peer-reviewed form in 2003.
However, Miles et al reported a study comparing useof neoadjuvant chemotherapy before and after publica-tion of the randomized trial data, and showed that therewas an increment of use from 0.8% to 14.0% of patients(P �.01), still showing that much less than 50% ofpatients were routinely treated with this well-validatedapproach to care.69

Similarly, Raj et al, in a retrospective single-institu-tion survey of 238 patients who underwent radicalcystectomy for bladder cancer between 2003 and2008, noted that only 17% (25 of 145 patients withclinical stage �T2) received cisplatin-based neoadju-vant chemotherapy.70

SUMMARY

On the basis of the two most recent intergroup trials(INT 0080 in the United States and the MRC/EORTCinternational trial) and the 2003 meta-analysis, the treat-ment paradigm for muscle invasive bladder UC hasshifted away from cystectomy alone towards the use ofperioperative chemotherapy. The reduction in cancer-based mortality that follows the use of neoadjuvantchemotherapy is 13%–24%, a similar figure to the ben-efit of adjuvant chemotherapy in women with early-stage breast cancer. The absolute improvement in curerate from neoadjuvant chemotherapy is 7%–8%.

A discussion regarding neoadjuvant chemotherapyshould be considered for all patients with muscle-inva-sive and locally advanced bladder cancer who couldpotentially tolerate cisplatin-based chemotherapy. Atpresent, the only regimen that can be recommendedon the basis of level I evidence is the MVAC regimen.The meta-analysis also suggests that other cisplatin-based regimens may have similar utility. Despite thesedata, it is clear that neoadjuvant chemotherapy is stillused in this setting in less than 50% of patients, forreasons that are unclear. It also appears that classicaladjuvant therapy is frequently administered after cys-tectomy for deeply invasive, high-grade bladder cancer,despite the absence of definitive data proving an OSbenefit from this approach.

Every effort should be made to ensure optimal sur-gery at the time of radical cystectomy, particularlyensuring negative resection margins and a thoroughbilateral pelvic lymph node dissection (defined as 10 ormore lymph nodes in the pathology specimen).

For patients who are not protocol-eligible and whohave undergone radical cystectomy but have not re-ceived neoadjuvant chemotherapy, it is reasonable toconsider adjuvant cisplatin-based chemotherapy if ex-travesical extension or node-positive disease is evidentfollowing cystectomy, in the hope of improving dis-ease-free survival or OS. Of importance, this concepthas never been validated by a well-powered random-
ized clinical trial. Eligible patients should be encour-

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aged to enroll on clinical trials testing different strate-gies in the adjuvant setting.

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Neoadjuvant and Adjuvant Chemotherapy Approaches for Invasive Bladder Cancer