Multi-disciplinary Team (MDT) Guidance for Managing Bladder Cancer

Transcription

1 Multi-disciplinary Team (MDT) Guidance fr Managing Bladder Cancer 2nd Editin (January 2013) Prduced by: British Ur-nclgy Grup (BUG) British Assciatin f Urlgical Surgens (BAUS) Sectin f Onclgy Actin n Bladder Cancer (ABC) This guidance has been supprted by unrestricted educatinal grants frm: Cambridge Labratries (A Divisin f Alliance Pharmaceuticals Ltd) PrStrakan Limited (part f the Kywa Kirin grup) Pierre Fabre Ltd The develpment and cntent f this guidance has nt been influenced in any way by the supprting cmpanies. Date f preparatin: January 2013

2 This guidance has been develped fr healthcare prfessinals and multi-disciplinary teams with the fllwing aims: T prvide evidence-based guidance n the management ptins fr superficial, muscle-invasive and advanced bladder cancer T ensure clarity n the rle f the MDT n the management f superficial, muscle-invasive and advanced bladder cancer Acknwledgements: The Guidance has been cmpiled and edited frm a multi-disciplinary panel with extensive experience in the management f patients with bladder cancer. Particular recgnitin fr wrk n this Guidance ges t: Dr Alisn Birtle, Cnsultant Clinical Onclgist, Prestn; Mr Leyshn Griffiths, Cnsultant Urlgist, Leicester 2

3 Cntents Abbreviatins...4 Integrated care and the Multi-disciplinary team (MDT)...5 Apprach within the MDT...7 Key questins fr the MDT...7 Apprach t the patient...9 Key pints fr discussin with the patient...9 Patient expectatins...9 Assessment and diagnsis...11 Primary diagnsis...11 Determinatin f disease spread/staging...15 Nn-muscle invasive bladder cancer: Management ptins...17 Transurethral resectin first resectin...18 Transurethral resectin secnd resectin...19 Immediate, single instillatin f adjuvant intravesical chemtherapy...20 Fllw-up f patients with lw-risk NMIBC (lw risk f recurrence and prgressin)...22 Additinal intravesical chemtherapy r BCG fr patients with intermediate-risk NMIBC (intermediate r high risk f recurrence and intermediate risk f prgressin)...23 Fllw-up f patients with intermediate-risk NMIBC...25 Adjuvant BCG fr high-risk NMIBC (high risk f recurrence r prgressin)...25 Fllw-up f patients with high-risk NMIBC...30 Primary radical cystectmy fr patients with high-risk NMIBC...30 Patients failing t respnd t adjuvant BCG therapy...31 Muscle invasive bladder cancer: Management ptins...33 Radical treatments...34 Radical cystectmy...37 Synchrnus chemradiatin/selective bladder preservatin...41 Radical raditherapy...46 Neadjuvant chemtherapy prir t definitive lcal treatment...48 Neadjuvant raditherapy prir t radical cystectmy r radical raditherapy...50 Adjuvant chemtherapy...50 Advanced (metastatic) bladder cancer: Management ptins...51 First-line systemic chemtherapy...51 Secnd-line systemic therapy in metastatic disease...54 Symptmatic/palliative treatments patients unfit fr chemtherapy...56 Onging supprt...57 References

4 Abbreviatins 5-ALA: 5-aminlevulinic acid BCG: bacillus Calmette-Guérin BPT: bladder-preserving therapy BSC: best supprtive care CI: cnfidence interval CIS: carcinma in situ CR: cmplete respnse CRT: chemraditherapy CT: cmputed tmgraphy DC: dcetaxel + cisplatin DFS: disease-free survival DRE: digital rectal examinatin DSS: disease-specific survival EAU: Eurpean Assciatin f Urlgy ECOG: Eastern C-perative Onclgy Grup EORTC: Eurpean Organizatin fr the Research and Treatment f Cancer GC: gemcitabine + cisplatin GCb: gemcitabine + carbplatin GCSF: granulcyte clny stimulating factr GFR: glmerular filtratin rate HAL: hexaminlevulinic acid HR: hazard rati IFN: interfern NBI: narrw-band imaging NMIBC: nn-muscle invasive bladder cancer OR: dds rati ORR: verall respnse rate OS: verall survival PDD: phtdynamic diagnsis PFS: prgressin-free survival PR: partial respnse PS: perfrmance status PSA: prstate-specific antigen RCON: raditherapy + carbgen + nictinamide RCP: Ryal Cllege f Pathlgists RCT: randmised cntrlled trial RFS: recurrence-free survival RR: relative risk SD: stable disease TB: tuberculsis TCC: transitinal cell carcinma TNM: tumur-nde-metastasis TTP: time t prgressin TUR: transurethral resectin US: ultrasund WHO: Wrld Health Organizatin LUTS: lwer urinary tract symptms MDT: multi-disciplinary team MMC: mitmycin C MRC: Medical Research Cuncil MRI: magnetic resnance imaging M-CAVI: methtrexate + vinblastine + carbplatin M-VAC: methtrexate + vinblastine + cisplatin 4

5 Integrated Care and the Multi-disciplinary Team (MDT) The prvisin f a cnsistent treatment strategy acrss a multi-disciplinary team (MDT), as well as the mdel f integrated care is increasingly being adapted as a valuable apprach t vercme the fragmentatin f patient management. In additin, an MDT prvides an ideal framewrk t cnduct audits and facilitate peer review. The management strategies prpsed fr patients with nn-muscle invasive bladder cancer (NMIBC), muscle invasive and advanced bladder cancer within the MDT can be successfully driven when the members f the MDT wrk tgether with nging supprt prvided by the wider team (Table 1). The MDT can prvide patients with treatment ptins that are specifically tailred t address their individual needs, such as disease state, c-mrbid cnditins and lifestyle. T ensure the success f the MDT apprach, familiarity with the entire spectrum f management strategies is recmmended. Table 1: Prpsed cmpsitin f the MDT in the nn-muscle invasive, muscle invasive and advanced bladder cancer setting Urlgical surgens Clinical and medical nclgists* MDT c-rdinatr and administrative supprt Pathlgists Urlgy and nclgy nurse specialists Palliative care specialists Radilgists *Medical nclgist attendance is nt necessary fr lw-risk superficial disease The purpse f the treatment algrithms presented in this dcument is t prvide a unique framewrk that can be adapted fr the management f the three main types f bladder cancer: nn-muscle invasive, muscle invasive and advanced transitinal cell carcinma (TCC) (Figure 1). 1 Management f the less cmmn tumurs such as squamus cell carcinmas r adencarcinmas are nt addressed within this dcument. 5

6 Figure 1: Summary f the definitin f urinary bladder cancer stages (adapted frm the American Jint Cmmittee n Cancer staging manual 2010) 1 NON-MUSCLE INVASIVE TCC MUSCLE INVASIVE TCC ADVANCED TCC (METASTATIC) pta/ptis/t1 N0 M0 T2/T3/T4 Nx/N0/N1 M0 Any T N2/N3 M1 T Primary tumur TX T0 T1 T2 T3 T4 pta ptis pt2a pt2b pt3a pt3b pt4a pt4b Primary tumur cannt be assessed N evidence f primary tumur Nn-invasive papillary carcinma Carcinma in situ: flat tumur Tumur invades subepithelial cnnective tissue Tumur invades muscle Tumur invades superficial muscle (inner half) Tumur invades deep muscle (uter half) Tumur invades perivesical tissue Micrscpically Macrscpically (extravesical mass) Tumur invades any f the fllwing: prstate (direct strmal invasin), uterus, vagina, pelvic wall, abdminal wall Tumur invades prstate, uterus r vagina Tumur invades pelvic wall r abdminal wall N Reginal lymph ndes NX Reginal lymph ndes cannt be assessed N0 N reginal lymph nde metastasis N1 Single psitive nde in primary drainage regins N2 Multiple psitive mdes in primary drainage regins N3 Cmmn iliac nde invlvement M Distant metastasis MX Distant metastasis cannt be assessed M0 N distant metastasis M1 Distant metastasis is: in situ; M: metastases; N; nde; p: pathlgical; TCC: transitinal cell carcinma 6

7 Apprach within the MDT Key questins fr the MDT Grade (Wrld Health Organizatin [WHO]) Tumur size Tumur Nde Metastasis (TMN) stage New/recurrent Single/multiple Risk grup if NMIBC Previus tumurs Previus respnse t intravesical therapy Bladder symptms/functin Bladder diverticula diagnsis Bwel symptms Bilateral hip prsthesis Hydrnephrsis Renal functin Age C-mrbidities Life expectancy Availability f apprpriate clinical trials The MDT plays an essential rle in nn-muscle invasive, muscle invasive and advanced bladder cancer management. Hwever, it is ften difficult t knw which patients warrant discussin; thus it is essential t ensure that individual patients details tgether with their diagnsis are available, as well as a recrd f any decisins that may have resulted frm meetings. It is crucial that in rder t fully discuss a particular patients treatment plan, a member f the MDT team shuld have already seen the patient. As the majrity f patients are surced thrugh pathlgy, relapses are mre difficult t identify and as such patient identificatin cntinues t be a prblem. T ensure that all prfessinal grups and apprpriate disciplines cntribute t, and participate in, decisins n the clinical management f patients, MDTs have repeatedly been endrsed as the principal way t d this. One f the key cncepts f integrated care is t supprt the rle f the MDT (wrking as a single unit) but it shuld nt be frgtten that the MDT has the freedm t clinically tailr management strategies fr the specific needs f an individual patient. 7

8 Treatment strategies are influenced by the fllwing: The stage f the bladder cancer, as well as the risk f disease prgressin, survival and patient characteristics, such as age and general fitness, influence the treatment strategy emplyed by the MDT. All these factrs shuld be discussed t determine the mst apprpriate treatment mdality fr an individual patient. Fr example, age may be a restrictive factr in pting fr surgery fr sme patients with bladder cancer. Patient preference shuld be discussed within the MDT and the MDT shuld ensure the invlvement f the patient in determining the mst apprpriate treatment strategy. Patient case ntes, pathlgy reprts, labratry test results and radilgy data shuld be made available fr discussin at the meeting. The inclusin f a patient in an apprpriate clinical trial shuld als be cnsidered. 8

9 Apprach t the patient Key pints fr discussin with the patient Likelihd f recurrence Likelihd f disease prgressin Treatment ptins Ability t tlerate general anaesthetic Fitness fr radical raditherapy Fitness fr cystectmy Fitness fr chemtherapy Patient preference Lcal disease cntrl Majr symptms Life expectancy Palliative care Treatment side-effects Impact f treatment n quality f life Occupatinal expsure and advice Smking histry and cessatin advice Diabetes and piglitazne treatment Clinical trials Patient expectatins The patient has the right t discuss their treatment strategy with apprpriately trained members f the MDT The ccurrence f any ptential side-effects assciated with each treatment mdality and the implicatins fr future lifestyle changes shuld be discussed with the patient by the healthcare prfessinal when determining an apprpriate management ptin. T ensure the patient and his/her partner, family and/r carers can make an infrmed decisin, based upn the treatment ptins that are ffered, all the pints detailed abve shuld be addressed. Fr example, the chice between radical raditherapy and radical cystectmy may be influenced by a patient s anticipated effect f treatment n quality f life. The available treatment mdalities and the ptential adverse effects they may have n lifestyle and quality f life shuld be discussed with all patients. The lack f guidance fr hw healthcare prfessinals shuld effectively exchange clinical evidence supprting varius treatment ptins t patients facing decisins is acknwledged. Hwever, if recmmendatins are largely based n apprpriate clinical studies and expert pinin, it is pssible t achieve the five cmmunicatin tasks when framing and cmmunicating clinical evidence (Table 2). 9

10 Table 2: Exchange f clinical evidence with patients 1. Understand the patient s experience, expectatins and preferences 2. Build partnerships between the patient and carer 3. Prvide evidence, including uncertainties, and discuss adverse events 4. Prvide and present recmmendatins 5. Check fr understanding and agreement 10

11 Assessment and Diagnsis Primary diagnsis Symptms Asymptmatic nn-visible haematuria is generally the first sign f bladder cancer and is the mst cmmn finding in NMIBC. 2,3 It is micrscpically present in almst all patients with cystscpically detectable tumurs. 4 Hwever, it is an intermittent finding upn repeat testing. 5 Lwer urinary tract symptms (LUTS) such as urgency, increased urinary frequency and bladder pain may be assciated with the presence f carcinma in situ (CIS). 2,3 A key issue is the wrkup fllwing presentatin f haematuria r LUTS. Screening There is currently n evidence t supprt pprtunistic screening fr bladder cancer withut a clinical reasn. 6 Urine cytlgy The diagnsis f a high-grade tumur r CIS can be made fllwing cytlgical analysis f vided urine. 3 Urine cytlgy is highly specific (>90%) and has a reasnable sensitivity fr detecting high-grade lesins /CIS (>60%). Hwever, the sensitivity f urine cytlgy in detecting bladder cancers (especially lw-grade NMIBC) in patients presenting with nn-visible haematuria may be subptimal; a negative test des nt rule ut malignancy. Urine cytlgy shuld therefre nt be used as a diagnstic test in islatin

12 Urinary mlecular bimarker tests Rutine applicatin f these tests has nt been established t date. 3 Currently available mlecular urinary bimarkers apprved by the US Fd and Drug Administratin are the qualitative pint-f-care tests (NMP22 Bladder Chek; bladder tumur antigen stat) and the labratry-based tests (BTA TRAK; ImmunCyt ; UrVysin). The sensitivities f NMP22, ImmunCyt and UrVysin are significantly higher than that f urine cytlgy. Hwever, the higher sensitivity cmes at a price f reduced specificity. All three nvel bimarkers and cytlgy were better at detecting mre aggressive higher-risk tumurs than less aggressive lwer-risk tumurs. 10 The clinical value f a nvel urinary bimarker depends nt nly n its perfrmance metrics but als the clinical cntext in which it is t be used. As an adjunct in the primary detectin f bladder cancer, such as in the haematuria clinic envirnment, the cncern is that the lwer specificity (higher false psitive rate) f currently available urinary bimarkers wuld lead t unnecessary anxiety, further cstly and invasive investigatins and the ptential dilemma f discharging a patient with a psitive urinary bimarker test but negative diagnstic investigatins. The mst prmising arena fr the use f nvel cntemprary bimarkers is likely t be as part f surveillance prtcls in patients with a previus histry f lw- r intermediaterisk NMIBC. Hwever, surveillance prtcls utilising nvel urinary bimarkers have nt been validated in large prspective studies. Mrever, the cst-effectiveness and patient acceptability f such appraches needs further study. White light cystscpy Cystscpy, guided by white light, has been the gld standard technique fr the detectin and fllw-up f bladder cancer. Hwever, the use f white light can lead t missing lesins that are nt visible. 3 Phtdynamic diagnsis-assisted cystscpy Phtdynamic (flurescence) diagnsis-assisted (PDD) cystscpy with 5-aminlevulinic acid (5-ALA) r hexaminlevulinic acid (HAL) imprves the detectin f bladder tumurs cmpared with cnventinal white-light cystscpy (WLC), especially with respect t CIS and results in mre cmplete resectins. HAL is an ester-derivative f 5-ALA with better biavailability and a shrter instillatin time. Only HAL is currently registered fr PDD in bladder cancer patients. There are cnflicting data n the effects f PDD n lnger term utcmes. The true added value f PDD in reducing tumur recurrence in rutine practice is difficult t assess as studies vary in the use f immediate single- dse intravesical chemtherapy psttransurethral resectin (TUR) and chice f phtsensitiser (5-ALA r HAL). The effects f PDD n time t prgressin (TTP) r survival remain t be demnstrated. PDD is mst useful fr detectin f CIS and guiding bipsies in patients with psitive cytlgy r a histry f high-grade NMIBC. 3 PDD may als have a rle t play in patients wh have psitive urine cytlgy, but negative WLC and negative upper urinary tract imaging. 12

13 Clinical evidence A systematic review and meta-analysis assessed the perfrmance f PDD in 27 studies. 11 Mst used 5-ALA (n=18) as the nly phtsensitising agent. The median sensitivity fr PDD was 92% (95% cnfidence interval [CI], ) versus 71% (95% CI, 49 93) fr WLC. Fr higher-risk tumurs, the median sensitivity f PDD was 89% (95% CI, 6 100) whereas fr WLC it was 56% (95% CI, 0 100). Fr lwer-risk tumurs, the median sensitivity f PDD and WLC were bradly similar; 92% (95% CI, 20 95) versus 95% (95% CI, 8 100), respectively. Hwever, the verall median specificity was less fr PDD than fr WLC; 57% (95% CI, 36 79) versus 72% (95% CI, 47 96). In patient-based detectin f bladder cancer acrss 4 studies using 5-ALA and 3 using HAL, the median (range) sensitivity and specificity fr 5-ALA was 96% (64 100) and 52% (33 67) respectively, cmpared with 90% (53 96) sensitivity and 81% (43 100) specificity fr HAL. Fur randmised cntrlled trials (RCTs) using 5-ALA reprted clinical effectiveness. PDD at TUR resulted in fewer residual tumurs at first check cystscpy (relative risk [RR], 0.37; 95% CI, ] and lnger recurrence-free survival (RFS) (RR, 1.37; 95% CI, ] than WLC. A meta-analysis f clinical studies has shwn that an additinal 20% f NMIBC (95% CI, 8 35) was detected using PDD cmpared with WLC, and an additinal 39% f CIS cases (95% CI, 23 57). 12 In additin, this analysis demnstrated imprved RFS rates with PDD versus WLC (16 27% higher at 12 mnths and 12 15% higher at 24 mnths). Mre recently, 3 RCTs f PDD versus WLC have been published shwing cnflicting data n the clinical effectiveness f PDD N benefit f PDD with 5-ALA was demnstrated fr the detectin f bladder tumurs, recurrence rates r prgressin rates. 13 Imprved detectin rates with 5-ALA assisted PDD did nt translate int reduced recurrence rates at 12 mnths. 14 PDD with HAL resulted in imprved RFS at shrt-term fllw-up (9 mnths) cmpared with WLC. 15 This was a large trial (766 patients) in 28 centres in the USA, Canada and Eurpe. In this study, 16% f Ta and T1 tumurs were detected slely with HAL-PDD. Narrw-band imaging cystscpy Narrw-band imaging (NBI) cystscpy has been develped fr use in bth flexible and rigid cystscpies. It increases cntrast between nrmal and hypervascularised structures by filtering white light t 2 narrw bandwidths that are absrbed by haemglbin. Several small nn-randmised studies have shwn prmising results in terms f imprved bladder tumur detectin cmpared with WLC. Mre recently, NBI-assisted TUR was shwn t reduce the residual tumur rate cmpared t a matched chrt. 16 Hwever, the rle f NBI cystscpy as an aid t TUR and in surveillance needs further evaluatin in RCTs. 13

14 Bipsy Eurpean Assciatin f Urlgy (EAU) guidance recmmends that n visualisatin f the urthelium, abnrmal areas shuld be bipsied, using either cld-cup r resectin lp methds. 3 In patients with psitive urine cytlgy but n visible tumur r nn-papillary tumur, bipsies frm the trigne, bladder dme and bladder walls shuld be perfrmed. 3 In this scenari, PDD imprves detectin f bladder tumur and culd facilitate mre targeted bipsies. Histpathlgy Sufficient muscle tissue frm bipsies is required fr crrect assignment f a T categry. 3 In rder t limit the variability in classifying and grading Ta and T1 tumurs, it is recmmended that the pathlgist review the histlgical findings tgether with the urlgist, in rder t prvide a clinical cntext Histpathlgists in the UK are currently recmmended t cntinue reprting the 1973 Wrld Health rganizatin (WHO) classificatin alngside the 2004 WHO classificatin and that results are cmpared thrugh prspective audit f patient utcmes. Further details can be btained in the standards and databases fr reprting cancers prepared by the Ryal Cllege f Pathlgists (RCP) and a published cmment. 20,21 Ultrasngraphy Transabdminal ultrasund (US) is a useful tl fr investigatin f haematuria. It permits detectin f renal masses, intraluminal bladder masses and hydrnephrsis. 3 14

15 Cmputed tmgraphy urgraphy and Intravenus urgraphy In many centres, cmputed tmgraphy (CT) urgraphy is nw the investigatin f chice cmpared with intravenus (IV) urgraphy. Hwever, the use f CT requires the expsure f the patient t an increased dse f radiatin. Urgraphy is generally used t detect filling defects within the kidneys and ureters, which may indicate the presence f a tumur within the ureter. 22 CT urgraphy can als prvide mre cmprehensive infrmatin including lcal tumur stage, the status f lymph ndes and neighburing rgans. The diagnstic accuracy f CT urgraphy has been estimated at arund 90%; therefre, it shuld nly be used in cnjunctin with cystscpy and histlgy fr the diagnsis f urinary tract cancers. 23,24 Rutine urgraphy is nt advised in all patients at the time a primary bladder tumur has been detected Urgraphy shuld, hwever, be cnsidered in selected cases where the incidence f upper tract findings is higher, such as patients with trignal tumurs and thse with high-risk r multifcal NMIBC. The incidence f cncmitant upper urinary tract TCC is lw (1.8%), but in patients with trignal tumurs, the incidence is 7.5%. 30 The risk f upper urinary tract TCC recurrence during fllw-up is mre likely in patients with high-grade and multifcal NMIBC. 31 In such patients, urgraphy is als recmmended during surveillance. 26,29,32,33 Fllw-up urgraphy shuld nly be cnsidered in patients wh are fit fr upper tract interventin. In such patients, the frequency f upper tract imaging surveillance has nt been validated. There is n evidence t supprt annual imaging f the upper tract. Upper urinary tract CT r IV urgraphy shuld be used as a surveillance tl in patients with high-risk NMIBC wh have received bacillus Calmette Guérin (BCG), but the ptimal frequency is unknwn. Functinal tests and bichemistry The fllwing tests may be useful in the detectin f advanced bladder cancer: Renal functin test (glmerular filtratin rate [GFR]) Liver functin test Full bld cunt Bne bichemistry Determinatin f disease spread/staging Imaging mdalities (CT and magnetic resnance imaging [MRI]) shuld be used fr the staging f suspected muscle invasive bladder tumurs, where this will influence treatment decisins. 24,34 15

16 Lcal staging f invasive bladder cancer Bth CT and MRI may be used fr lcal staging f bladder cancer, but neither technique can detect tumurs that have micrscpically invaded perivesicular fat, i.e. Stage T3a. 35 Therefre they are used t detect T3b and mre advanced tumurs. MRI is superir t CT in evaluating the T stage f suspected muscle invasive bladder cancer Ndal invlvement The sensitivities f bth CT and MRI in the detectin f lymph nde metastases are lw. 24,35 Distant metastases CT and MRI can be used t detect distant metastases within the lungs and liver. 34 Rutine scanning f bne and brain is nt recmmended unless specific symptms indicative f bne r brain metastases are present. 24 The use f US is nt recmmended in patients fr whm a diagnsis f bladder cancer has already been established. US may be used fr the evaluatin f metastases, in patients with cntraindicatins t CT and/ r MRI. Hwever, its sensitivity cmpared with these ther mdalities is lw

17 Nn-muscle invasive bladder cancer: Management ptins Figure 2: Algrithm fr the primary management f nn-muscle invasive bladder cancer (adapted frm Griffiths et al., 2012) 40 Suspected NMIBC TUR Bipsy & histpathlgical analysis Cnsider immediate single instillatin f adjuvant intravesical chemtherapy Repeat TUR If incmplete first resectin NMIBC (TCC) Lw risk Intermediate risk High risk Cnsider re-resectin and CT urgram 5 year fllw-up nly (if n recurrence) Surveillance cystscpies +/- urine cytlgy Very high risk &/r lng life-expectancy N further intravesical chemtherapy Cnsider further intravesical chemtherapy (maximum 1 year) r BCG + maintenance (1 3 years) Intravesical BCG + maintenance (1 3 years) Cnsider immediate radical cystectmy + pelvic lymphadenectmy BCG: bacillus Calmette Guérin; NMIBC: nn-muscle invasive bladder cancer; TCC: transitinal cell carcinma; TUR: transurethral resectin The Eurpean Organizatin fr the Research and Treatment f Cancer Geniturinary (EORTC GU) Grup has carried ut a large number f randmised trials in NMIBC patients, which has allwed the develpment f a risk assessment tl fr recurrence and prgressin. 41 The annual risk f and cumulative risk f tumur recurrence and prgressin can be made using the EORTC scring system, which cmbines data n previus tumur recurrence rate, number f tumurs, tumur diameter, T stage, WHO grade and presence r absence f cncmitant CIS. The web-based EORTC risk calculatr can be dwnladed frm: bladdercalculatr/default.htm. It is recgnised that the EORTC risk calculatr may verestimate the risk f recurrence and prgressin in patients with high-risk NMIBC because in histrical trials, re-resectin was nt standard practice, nly 171 patients verall were treated with BCG and mst f these patients had inductin BCG withut maintenance. The Spanish Urlgical Club fr Onclgical Treatment (CUETO) has prpsed a scring mdel t stratify the risk f recurrence and prgressin in patients treated with BCG

18 Transurethral resectin first resectin Overview Transurethral resectin (TUR) is the gld standard fr the initial diagnsis and treatment f newlydiagnsed, apparently NMIBC. The adequacy f the initial TUR and the skills and experience f the surgen may have a substantial impact n the recurrence rate at the first fllw-up cystscpy. Small tumurs (<1 cm) can be resected en blc. Larger tumurs (>1 cm) shuld be resected s that at least exphytic tumur and deep (tumur base) bipsies are submitted in separate fractins. Patient selectin Newly-diagnsed NMIBC Adverse effects f treatment Bleeding Infectin Perfratin f the bladder wall Clt retentin Clinical evidence The basic technique fr TUR is illustrated in Wiesner et al., It can be accessed at: TUR is used t remve the tumur and t btain a bipsy specimen, which is subject t histpathlgical analysis t determine the tumur type, stage and grade. The pathlgical reprt shuld cntain infrmatin n the type f specimen, tumur histlgy, grwth pattern, grade and depth f invasin and the invlvement f adjacent urthelium. Further details can be btained in the standards and databases fr reprting cancers prepared by the RCP. 21 Brausi et al. highlighted that the quality f the initial TUR perfrmed by the individual surgen may have a substantial impact n the lcal recurrence rate at the first fllw-up cystscpy. An verall evaluatin f 2410 patients wh participated in 7 studies revealed that 316 (13.1%) patients had a recurrence at the first fllw-up cystscpy. When the data were analysed by the number f institutins wh enrlled a median f 30 patients with a single tumur, lcal recurrence rates at the first cystscpy check-up ranged frm 3.5% t 20.6%, which suggested that the quality f the initial TUR was highly variable. 44 Remval f adequate detrusr muscle tissue is assciated with a reduced risk f disease recurrence after the first TUR. 45 In a study f 356 patients, the absence f detrusr muscle in tumurs fllwing first TUR was assciated with an RR f recurrence at first fllw-up cystscpy (at 3 mnths) f 44% cmpared with 22% fr tumurs including detrusr muscle (dds rati [OR], 2.9; 95% CI, ; p=0.002). 45 The presence f negative muscle tissue indicates a cmplete resectin

19 Transurethral resectin secnd resectin Overview In many patients underging initial TUR, a subsequent secnd TUR perfrmed 2 6 weeks later has demnstrated a high incidence f residual tumur. 46 Multiple tumurs, prly-defined tumurs and CIS may cntribute t an incmplete first resectin. 46 Repeat TUR imprves staging accuracy and can enhance treatment utcmes in NMIBC if all visible residual and suspected tumur is remved. 46 A secnd TUR shuld be perfrmed when bipsies cntain insufficient r n muscle tissue and/r inadequate separate exphytic tumur and tumur base fractins. Fr patients with pta disease, if adequate bipsy samples have been btained (i.e. muscle included) and macrscpic tumur clearance cnfirmed, a secnd TUR is generally unnecessary. Fr patients with pt1 disease, repeat TUR shuld als be cnsidered, especially fr high-grade tumurs. Adverse effects f treatment As per the first TUR. Clinical evidence A prspective study randmised 210 patients with newly-diagnsed T1 bladder cancer t repeat TUR within 2 6 weeks f first TUR, r n repeat TUR. All patients received instillatin f mitmycin C (MMC) within 24 hurs f the first TUR. 47 Secnd TUR resulted in a change f treatment strategy in 8 patients underging this prcedure, due t changes in staging. Presence f CIS r T2 tumur at secnd TUR was crrelated with grade, size and numbers f the initial tumur. Tumur-free status was cnfirmed histlgically in 67% f this grup f patients. RFS was significantly higher in patients underging secnd TUR than in thse nt underging this prcedure (5-year RFS, 59% versus 32%; p=0.0001). In an analysis f 1312 patients underging repeat TUR, arund 50% f patients with lw-grade tumurs demnstrated residual disease % f patients with T1 tumurs fllwing first TUR had residual disease n repeat TUR. Anther analysis f 523 patients initially staged as T1, after repeat TUR 106 (20%) were upstaged t muscle invasive disease (T2). 48 In a separate study, 110 patients with newly-diagnsed NMIBC underwent repeat TUR. 49 Cystscpy prir t the secnd TUR was negative in 79 (78%) patients, but 14 f these were subsequently fund t have residual disease. Of the ttal 40 patients with residual disease at the secnd TUR, 22 had an identical stage t the first TUR, 9 had a lwer stage and 9 had a higher stage f bladder tumur. Of 76 patients with stage T1 cancer after the first TUR, 25 (33%) demnstrated residual disease at secnd TUR. 19

20 Immediate, single instillatin f adjuvant intravesical chemtherapy Overview Based n clinical evidence, a single instillatin f adjuvant intravesical chemtherapy after the first TUR shuld be cnsidered the standard f care fr all NMIBC patients. There is strng evidence fr the use f single-dse intravesical chemtherapy at first TUR, with the greatest benefit bserved with lw-grade, lw-risk tumurs. A meta-analysis cnducted by the EORTC demnstrated that a single instillatin f adjuvant intravesical chemtherapy immediately after TUR reduces the RR f lcal recurrence by 39% in all risk grups. 50 The single instillatin f chemtherapy is thught t eradicate any tumur left behind after an incmplete first TUR and t destry any circulating tumur cells that culd implant at the resectin site t prevent recurrence. Evidence suggests that the first instillatin f adjuvant intravesical chemtherapy shuld be administered n the same day as the TUR, and ideally within 6 hurs f the prcedure. 50 The chemtherapeutic agents MMC, epirubicin and dxrubicin are all cnsidered t have similar efficacy. 50 An immediate single instillatin f adjuvant intravesical chemtherapy shuld be avided when it is bvius r even suspected that the bladder wall is perfrated. 51 Patient selectin First r repeat TUR after diagnsis f any NMIBC, if clinically safe t d s and the bladder is clear f any macrscpic disease. Adverse effects f treatment Irritative bladder symptms, including dysuria and frequency Haematuria Allergic skin reactins with MMC 52 Irritative bladder symptms with epirubicin 20

21 Clinical evidence A meta-analysis f 7 RCTs (n=1476) cmpared ne immediate pst-perative instillatin f adjuvant chemtherapy using MMC, epirubicin, dxrubicin r thitepa, with TUR alne, t determine whether adjuvant chemtherapy decreased the risk f recurrence in patients with single and multiple Ta/T1 tumurs. 50 Recurrence data were available fr 1476 patients at a median fllw-up f 3.4 years. Recurrence ccurred in 48.4% f patients wh had TUR alne and in 36.7% f patients receiving ne pst-perative instillatin f chemtherapy. This was assciated with a decreased risk f recurrence by 39% (OR, 0.61; 95% CI, ; p<0.0001) versus TUR alne. Patients with a single tumur (recurrence rate, 35.8%; OR, 0.61; 95% CI, ; p= ) r multiple tumurs benefited (recurrence rate, 65.2%; OR 0.44; 95% CI, ; p=0.06) frm ne immediate instillatin f adjuvant chemtherapy cmpared with TUR alne. Hwever, in patients with multiple tumurs, ne instillatin may be subptimal and additinal adjuvant treatment is necessary (discussed in mre detail belw). Fr every 100 patients treated with a single instillatin f adjuvant chemtherapy, 12 repeat TURs were avided. Thus, 9 patients must be treated with a single instillatin f adjuvant chemtherapy t prevent a recurrence. The cst f a TUR, anaesthesia and hspitalisatin is prbably mre than 9 times that f ne instillatin f adjuvant chemtherapy. Kaasinen et al. fund that the risk f recurrence dubled if the first instillatin f MMC was nt administered within 24 hurs f TUR. 53 Buffiux et al. demnstrated that when the first instillatin f adjuvant chemtherapy was given within 24 hurs after TUR with lng-term maintenance chemtherapy, patients tended t have fewer recurrences than thse wh received treatment later than 24 hurs

22 Fllw-up f patients with lw-risk NMIBC (lw risk f recurrence and prgressin) Overview In patients at lw risk f recurrence and prgressin (EORTC recurrence and prgressin scres = 0), the prbability f recurrence and prgressin at 1 year is 15% and 0.2%, respectively. 41 Data n the ptimal fllw-up regimen fr patients with lw-risk NMIBC is limited. EAU guidelines recmmend that all patients with lw-risk TaT1 tumurs shuld have a fllw-up cystscpy at 3 mnths after the first resectin. If recurrence-free at 3 mnths, the next cystscpy is advised at 9 mnths, and then yearly fr 5 years. 3 Clinical evidence Oge et al. retrspectively evaluated the recurrence and prgressin rates f 120 patients with ptag1/g2 and small (<4 cm) TCC. 55 The recurrence rate was 6.5% at 3 mnths, and 6.7% and 3.6% at 6 and 9 mnths, respectively. When the first 3-mnth fllw-up cystscpy was clear, the 6-, 9- and 12-mnth cystscpy recurrence rates were 4.3%, 2.7% and 8%, respectively. The prgressin rate was <1% fr the first year. In a Scttish study utilising a prspective database, patients with TaG1 were fllwed fr up t 20 years after TUR. 56 The authrs cncluded that tumur status at 3 mnths was the strngest predictr f recurrence. Of patients wh had nt experienced recurrence at 5 years, 98.3% remained tumur-free fr 20 years. 22

23 Additinal intravesical chemtherapy r BCG fr patients with intermediate-risk NMIBC (intermediate r high risk f recurrence and intermediate risk f prgressin) Overview The main pririty in these patients is t reduce the risk f recurrence, althugh the risk f prgressin is nt negligible. Accrding t an analysis f 7 EORTC trials using the EORTC risk tables, the prbability f recurrence at 1 and 5 years in patients with intermediate-risk TaT1 bladder cancer is 24 38% and 46 62%, respectively; the risk f prgressin t muscle invasive disease is estimated at 1 5% at 1 year and 6 17% at 5 years. 41 The prphylactic effect f a single instillatin f chemtherapy after TUR lasts fr 1 2 years. 52,57 The results f an EORTC and Medical Research Cuncil (MRC) meta-analysis shwed that adjuvant chemtherapy after TUR prevents disease recurrence; hwever, it has n apparent effect n disease prgressin. 58 The ptimal duratin and intensity f intravesical chemtherapy schedule is currently undefined. Hwever, the available evidence des nt supprt intravesical chemtherapy fr mre than 1 year. Fr preventin f recurrence, maintenance BCG is required t demnstrate superirity t MMC. 59 Current EAU guidelines recmmend either a maximum f 1 year f intravesical chemtherapy r a minimum f 1 year f intravesical BCG. 3 The superir efficacy f BCG needs t be balanced against its increased txicity. Patient selectin Recurrent ptag1 TCC 2. ptag1/g2 TCC and either >3 cm tumur diameter r multiple tumurs. pt1g2 TCC and <3 cm tumur diameter and single tumur. Adverse effects f treatment Irritative bladder symptms. e.g. dysuria, urgency Haematuria Infectin 23

24 Clinical evidence A meta-analysis f 5 studies cnducted by the Japanese Urlgical Cancer Research Grup, which included 1732 patients with NMIBC, revealed that the prphylactic effect f a single instillatin f intravesical chemtherapy after TUR cntinued fr a perid f 500 days. 57 Tw parallel randmised studies cnducted by the EORTC highlighted that 1-year f mnthly (15 instillatins) maintenance chemtherapy was n mre effective than 6 mnths (9 instillatins) f treatment in reducing the recurrence rate when the first instillatin was given immediately after TUR. 54 Mre recently, a Japanese randmised study f 150 patients with TaT1 bladder cancer demnstrated that lng-term epirubicin therapy was mre effective than shrt-term treatment after TUR in preventing recurrence. 60 At 3 years, the recurrence rate was 14.8% in the grup wh received 1 year f epirubicin (19 instillatins) cmpared with 36.1% in thse wh received 3 mnths f epirubicin (9 instillatins) after TUR. The MRC has shwn that five dses f adjuvant MMC is nt superir t a single dse and that the treatment effect f a single dse lasts fr at least 7 years. 61 In a prspective randmised study, Serretta et al. demnstrated that 10 mnthly instillatins f chemtherapy fllwing a 6-week inductin cycle f treatment (a ttal f 16 instillatins) was nt superir t the 6-week chemtherapy cycle (6 instillatins) alne in terms f the recurrence-free rate, in 482 patients with Ta/T1 tumurs (single, multiple r recurrent). 62 At a median fllw-up f 48 mnths (range, 3 78), recurrence rates were 29.6% fr 6 instillatins f chemtherapy versus 29.2% fr 16 instillatins f chemtherapy (p=0.43). In an earlier study, 495 patients with intermediate- t high-risk primary r recurrent bladder cancer (ptag1/2, pt1g1 3) were randmised t 6 weekly instillatins f MMC, 6 weekly instillatins f BCG, r 6 weekly instillatins fllwed fr mnthly instillatins f MMC fr 3 years. 63 At a median fllw-up f 2.9 years (range: 0 6.6), recurrence rates were 10.4% in the lngterm MMC arm, 25.1% fr BCG and 25.7% fr 6 weekly instillatins f MMC. Three-year recurrence rates were 65.5%, 68.6% and 86.1% fr BCG (p= versus lngterm MMC), 6 weekly instillatins f MMC (p= versus lng-term MMC) and lng-term MMC, respectively. In an individual patient data meta-analysis cmparing BCG with MMC (n=2820), maintenance BCG resulted in a significant (32%) reductin in the risk f recurrence cmpared with MMC. In cntrast, in studies where maintenance BCG was nt given, there was a significant (28%) increase in risk f recurrence. 59 In a large RCT, BCG with maintenance significantly reduced the risk f prgressin/distant metastases (hazard rati [HR], 0.63), verall survival (OS) (HR, 0.76) and disease-specific survival (DSS) (HR, 0.47) cmpared with intravesical epirubicin. 64 The bserved treatment benefit was at least as large, if nt larger, in the intermediate-risk patients as cmpared with the high-risk patients. In this trial, high-risk patients did nt underg re-resectin. 24

25 Fllw-up f patients with intermediate-risk NMIBC Overview Data n the ptimal fllw-up regimen fr patients with intermediate-risk NMIBC is limited. EAU guidelines recmmend that patients with TaT1 tumurs at intermediate-risk f prgressin shuld have a fllw-up schedule using cystscpy and urinary cytlgy, which is dependent n the individual patient. 3 Adjuvant BCG fr high-risk NMIBC (high risk f recurrence r prgressin) Overview The risk fr tumur recurrence and prgressin t muscle invasive disease is high within this grup f patients with NMIBC. Accrding t an analysis f 7 EORTC trials using the EORTC risk tables, the prbability f recurrence at 1 and 5 years in patients with high-risk TaT1 bladder cancer is 61% and 78%, respectively; the risk f prgressin t muscle invasive disease is estimated at 5 17% at 1 year and 17 45% at 5 years. 41 Patients wh have multiple tumurs at presentatin and recurrence at 3 mnths have a 1-year risk f further recurrence f 90%. 65 Clinical evidence frm a meta-analysis shws that when BCG is cmpared with a variety f strategies, the risk f prgressin frm TaT1/CIS t muscle invasive disease is reduced prvided maintenance instillatins are given. 66 Similar findings were demnstrated fr the subgrups f patients with CIS r papillary tumurs. In studies and meta-analyses cmparing BCG with intravesical chemtherapy in a cmbinatin f high-risk and intermediate-risk patients, cntradictry results have been btained with respect t the relative benefit f BCG n prgressin. 59,64,67 The ptimum BCG maintenance regimen is nt yet knwn. A cmmnly used schedule is that described by Lamm et al., wh recmmended 27 instillatins ver a 3-year perid, i.e. administratin nce every 6 weeks. 68 Current EAU Guidelines fr high-risk TaT1 TCC and als fr CIS recmmend at least 1 year f intravesical BCG. 3 The results f the Phase III trial EORTC 30962, which included intermediate-risk and selected highrisk (slitary tumur withut CIS) patients, failed t demnstrate that 1 year f intravesical BCG was inferir t 3 years f intravesical BCG, r that 3 years f BCG was superir t 1 year f BCG. 69 The best DFS was demnstrated in thse patients wh had received 3 years f BCG but this was nt statistically significant. A pragmatic apprach shuld be therefre cnsidered in these patients after 1 year f BCG, based n risk f prgressin and side-effects. 25

26 Patient selectin pt1g2 and either >3 cm tumur diameter r multiple tumurs. pta/t1g3. CIS. Immuncmpetent (avid patients with leukaemia/lymphma, Human Immundeficiency Virus infectin, rgan transplant, and active and previus GU tuberculsis [TB]). Cautin if previus pelvic raditherapy >40 Gy. Adverse effects f treatment Haematuria has been reprted in 31 35% f patients. 70,71 BCG-induced cystitis has been reprted in 3 54% f patients. 67,70 72 Systemic side-effects such as fever, general malaise and skin rash have been reprted in 15 39% f patients. 70,73 BCG therapy may prvke bth lcal and systemic side-effects and these can be serius in apprximately 5% f treated patients. Only the systemic side-effects can be serius and lifethreatening and require early systemic therapy. It is therefre imprtant t prevent cmplicatins and BCG instillatin shuld be avided after traumatic catheterisatin, when frank haematuria persists after bladder bipsy, during the first 14 days after TUR and when irritative viding symptms r systemic upset persist after previus instillatins f BCG. It is expected that with repeated instillatin, patients will develp shrt-lived bladder irritative symptms lasting hurs, assciated with mild fever, arthralgia and even frank haematuria. Persistence f these symptms is a warning t defer the next instillatin until they have settled. Reductin t ne-third f the dse culd als be cnsidered. Granulmatus prstatitis ccurs in the majrity f treated men, but it is usually asymptmatic and requires n treatment. In the small percentage f patients where this is symptmatic, high-dse flurquinlne antibitics are recmmended, alng with suspensin f intravesical therapy. 74 Epididymitis can be due t either BCG infectin r mre usual urpathgens. Therefre initial treatment with a quinlne antibitic is apprpriate. Isniazid 300 mg daily fr 6 weeks shuld be cnsidered. Generalised plyarthritis, ften assciated with cnjunctivitis, des ccur and there is an assciatin with the HLA-B27 gentype. As it is generally an allergic reactin, treatment with systemic sterids and/r isniazid may be required and n further BCG therapy shuld be given. Referral t an apprpriate physician shuld be cnsidered. Miliary BCG infectin affecting lungs, liver, kidneys and brain may rarely ccur as may BCG septicaemia. If clinically suspected then there shuld nt be a delay befre the administratin f triple anti-tb chemtherapy and high-dse systemic sterids. Bld testing fr TB can help with mre rapid diagnsis. The recmmended treatment regimen is isniazid 300 mg daily fr 3 mnths, rifampicin 600 mg daily and ethambutl 1200 mg daily fr 6 weeks and prednislne 40 mg daily r greater IV during the acute stages. 67,75 26

27 Clinical evidence A meta-analysis f 24 clinical trials with data relating t prgressin n 4863 patients was cnducted by the EORTC. TUR + BCG was cmpared with either TUR alne r TUR + nn-bcg treatment (cntrl). 66 At a median fllw-up f 2.5 years (maximum f 15 years), 9.8% f patients receiving TUR + BCG prgressed cmpared with 13.8% f cntrl patients. Overall, treatment with BCG was assciated with a 27% reductin in tumur prgressin (OR, 0.73; 95% CI, ; p=0.001). Similar treatment effects were reprted in the 2880 patients with nly papillary tumurs (OR, 0.68; 95% CI, ; p=0.001) and in the 403 patients with CIS (OR, 0.65; 95% CI, ; p=0.001). Patients receiving maintenance BCG demnstrated a 37% reductin in tumur prgressin (OR, 0.63; 95% CI, ; p= ). N reductin in tumur prgressin was reprted in the 4 trials where maintenance BCG was nt administered. The Phase III EORTC trial randmised 1355 patients t 1 year f full-dse BCG (1YFD), 3 years f full-dse BCG (3YFD), 1 year f ne-third dse BCG (1Y3D) r 3 years f third-dse BCG (3Y3D). 69 At a median fllw-up f 7.1 years, 5-year DFS was 58.8% (1YFD), 54.5% (1Y3D), 64.2% (3YFD), and 62.6% (3Y3D). The inferirity f the disease-free interval fr 1Y3D versus 1YFD was nt demnstrated. FD BCG was nt superir t ne-third BCG (p=0.092). 3 years f BCG was nt superir t 1 year f BCG (p=0.059). There were n differences between treatment grups fr TTP r duratin f survival. The Suth West Onclgy Grup 8507 study randmised 550 patients with recurrent Ta/T1 disease r CIS t inductin + maintenance BCG therapy fr 3 years (ttal 27 dses) r n maintenance (i.e. inductin BCG therapy nly). 68 Median RFS was 76.8 mnths (95% CI, ) with maintenance BCG versus 35.7 mnths (95% CI, ) with n maintenance BCG (p<0.0001). 5-year OS was 83% in the maintenance grup cmpared with 78% in the n maintenance grup. A meta-analysis f data frm 9 trials invlving 700 patients with CIS has demnstrated that BCG is assciated with a superir respnse rate and reductin in disease recurrence when cmpared with chemtherapy (MMC, epirubicin, adriamycin). 76 Cmplete respnse (CR) was achieved by 68.1% f patients receiving BCG versus 51.5% f patients receiving chemtherapy (OR, 0.53; p=0.0002). Based n a median fllw-up f 3.6 years, 161 f 345 patients receiving BCG (46.7%) had n evidence f disease cmpared with 93 f 355 patients n chemtherapy (26.2%), a reductin f 59% in the dds f treatment failure n BCG (OR, 0.41; p <0.0001). 27

28 BCG versus mitmycin C In an individual patient data meta-analysis f data frm 9 clinical trials invlving 2820 intermediate- and high-risk patients with Ta, T1 r CIS, TUR + BCG was cmpared with TUR + MMC. Median fllw-up was 4.4 years (maximum 17.7 years). 59 In the studies with BCG maintenance therapy (n=1324), a 32% reductin in the risk f recurrence was determined versus MMC (43.2% versus 57.9%; p<0.0001). Ntably, withut maintenance BCG (n=1496), the risk f recurrence was increased versus MMC, by 28% (42.6% versus 31.8%; p=0.006). There were n significant differences in prgressin, OS r DSS, irrespective if patients receiving BCG with maintenance were subanalysed. In a meta-analysis f data frm 9 trials perfrmed by Bhle & Bck (n=2410), median fllw-up was 26 mnths (range, ). 67 When cnsidering all treatment regimens, there was n significant difference between BCG and MMC in tumur prgressin (7.7% versus 9.4%; OR, 0.77; 95% CI, ; p=0.081). In the subgrup f patients receiving maintenance BCG therapy fr at least 1 year, the risk f prgressin was significantly reduced cmpared with MMC (OR, 0.66; 95% CI, ; p=0.02). In patients nt receiving maintenance BCG therapy, there were n differences between treatments in terms f disease prgressin (OR, 1.16; 95% CI, ; p=0.61). In a meta-analysis invlving 700 patients with CIS and where the verall median fllw-up was 3.4 years, a reductin f 43% in the dds f treatment failure n BCG was shwn prvided BCG maintenance was given (OR, 0.57; p=0.04)

29 BCG versus epirubicin In a large prspective RCT (837 eligible patients), intravesical epirubicin was cmpared with BCG alne and BCG + isniazid in patients with intermediate- and high-risk Ta/T1 bladder cancer, fllwing TUR. Patients received instillatins f drug therapy immediately fllwing TUR and 6 weekly dses, fllwed by 3 weekly instillatins at mnths 3, 6, 12, 18, 24, 30 and 36 (27 in ttal). Median fllw-up was 9.2 years. 64 There were n differences between the tw BCG grups fr any utcme, s these data were cmbined. BCG with maintenance significantly reduced the risk f prgressin/distant metastases (HR, 0.63), OS (HR, 0.76) and DSS (HR, 0.47) cmpared with intravesical epirubicin. 77 In all patients the risk f recurrence was significantly reduced with BCG versus epirubicin (HR, 0.62; 95% CI, ; p<0.001); similar results were achieved in intermediate-risk patients (n=497; HR, 0.59; 95% CI, ; p<0.001). Hwever, this was nt true fr the subgrup f high-risk patients (n=323; HR, 0.69; 95% CI, ; p=0.09). In all, intermediate- and high-risk patients, there were n significant differences between BCG and epirubicin fr disease prgressin. Disease-specific mrtality was significantly reduced in intermediate-risk patients with BCG versus epirubicin (HR, 0.35; 95% CI, ; p=0.02) but nt in high-risk patients (HR, 0.60; 95% CI, ; p=0.39). In a meta-analysis by the Cchrane Grup, BCG was cmpared with epirubicin, using data frm 5 clinical trials invlving 1111 patients with TaT1 bladder cancer. 71 The meta-analysis did nt include the large RCT described abve. 64 The incidence f recurrence was 35.5% with BCG versus 51.4% with epirubicin (RR, 0.69; 95% CI, ; p<0.05) There was n significant difference between treatments fr the risk f disease prgressin. Prgressin t T2 r greater stage ccurred in 8.02% f patients receiving BCG and 10.32% f patients receiving epirubicin (RR, 0.78; 95% CI, ; p=0.19). Results frm nly tw trials were analysed fr mrtality data. There was n significant difference between BCG and epirubicin fr verall mrtality (RR, 0.86; 95% CI, ), r fr disease-specific mrtality (RR, 0.94; 95% CI, ). 29