the slides from this webinar. - Bladder Cancer Advocacy Network

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the slides from this webinar. - Bladder Cancer Advocacy Network

Muscle-Invasive Bladder Cancer:Bladder-Sparing TherapyJason A. Efstathiou, MD, DPhilAssistant Professor of Radiation OncologyMassachusetts General HospitalHarvard Medical SchoolBladder Cancer Advocacy NetworkPatient Insight WebinarApril 11, 2013


Organ conservation incontemporary oncology• Anal carcinoma• Breast carcinoma• Esophageal carcinoma• Laryngeal carcinoma• Limb sarcomas• Prostate carcinoma


Breast CancerPatient Power (Advocacy)• Many high profile women activists beginning in 1980• Mary Lasker, Rose Kushner (NCAB), and the KomenFoundationRose Kushner’s quotes*:“You mean I had a mastectomy for nothing”“Happily for women, surgical custom is changing”* S. Mukharjee, The Emperor of all Maladies


Muscle-invading TCC bladderCystectomyCystectomyalternativesBladder removaland reconstructionBladderconservationGoals:• cure patient and optimize survival• prevention of pelvic failure and distant metastasis• functional urinary reservoir and high QOL


So what’s the modern alternative tocystectomy?Trimodality therapy• Maximal TURBT• Radiation therapy• Chemotherapy


TURBTXRT (40Gy)+Concomitant ChemotherapyCystoscopic responseevaluationCRConsolidationChemo-radiation (64Gy)+/- adjuvant chemoNon-CRRadicalCystectomy+/- adjuvant chemo


Bladder Conservation: Evolution of theMGH and RTOG approach1986-93NeoadjuvantchemoResponseevaluationMCVx2RT + C1994-98AcceleratedradiationAdjuvantchemotherapybidRT+C/5FuMCV x 31999-2012EnhancedRadiationsensitizationAdjuvantchemotherapybidRT+C/TaxqdRT+GemG + C x 4


Long-term MGH Experience 1986-2006• N = 348• Clinical stages T2-T4a• Treated on protocols 1986-2006• Median age 66.3 years (range 27.3–88.6)• Median FU for those alive 7.7 years• Actuarial endpoints included: OS, DSSEfstathiou et al Eur Urol 2012


Long-term MGH Experience 1986-2006Background Characteristics (n=348)GenderMale 74%Female 26%Clinical StageT2 54%T3 38%T4a 8%Visibly complete TURBTYes 65%No 33%HydronephrosisYes 17%No 83%Efstathiou et al Eur Urol 2012


Long-term MGH Experience 1986-2006OutcomesCR rate 72%Overall Survival5 yrs 52%10 yrs 35%15 yrs 22%Disease Specific Survival5 yrs 64%10 yrs 59%15 yrs 57%% undergoing Cystectomy* 29%Immediate (non-CR) 17%Salvage 12%*No patient required cystectomy due to treatment-related toxicityEfstathiou et al Eur Urol 2012


Long-term MGH Experience 1986-200664%59%57%80% of those alive at 5 years still havenative bladder


Long-term Cystectomy & PLND Results• USC & U. Bern ; 1985-2005 ; 959 patients• pT2-3, cN0, cM0, median F/U 10 yrs(10 yrs. 60%)Zehnder, Studer, Skinner et al. J Urol 2011


Long-term MGH Experience 1986-2006Importance of Clinical Stage74%67%63%53%49%49%Efstathiou et al Eur Urol 2012


Long-term MGH Experience 1986-2006Importance of a Complete ResponseEfstathiou et al Eur Urol 2012


All TURBT TURBTpatients complete not complete p valueNumber 343 227 116CR rate 72% 79% 57%


What is the importance of an aggressiveTURBTfor“Cystectomy Avoidance”?“The TURBT must be done with thedetermination to resect all visibletumor. Nothing less will suffice.”NM Heney et al NATURE Rev Clin Oncol 2009


Selection is KeyTumor presentations with the highestsuccess rates:• Solitary T2 or early T3 tumors < 6 cm• No tumor-associated hydronephrosis• Tumors allowing a visibly completeTURBT• Invasive tumors not associated withextensive carcinoma in situ• Adequate renal function to allow cisplatinconcurrent with radiation• TCC histology


Long-term MGH Experience 1986-2006Influence of AgeEfstathiou et al Eur Urol 2012


ACS / National Cancer Database (2004-2008)Gray et al., European Urology 2012


ACS / National Cancer Database (2004-2008)Gray et al., European Urology 2012


ACS / National Cancer Database (2004-2008)Gray et al., European Urology 2012


Which chemotherapy with radiation?


Role of Concurrent ChemotherapyThe active radiosensitizing drugs include:• Cisplatin, Paclitaxel, 5-FU, Mitomycin C,Gemcitabine and tumor hypoxia-reducingdrugs


Phase III randomized trial of synchronouschemo-radiotherapy compared to radiotherapyalone in muscle invasive bladder cancer(BC2001 CRUK/01/004)• 360 patients 2001 – 2008• clinical stage T2-4aNx bladder cancer• XRT 55 Gy/20 or 64 Gy/32• RT + MMC & 5-FU• GFR > 25 ml/min• Median follow-up 49 monthsJames et al NEJM 2012


0.00 0.25 0.50 0.75 1.00Invasive loco-regional disease free survival with and withoutconcurrent chemotherapy2-yr ILRDFS82% (95% CI: 75%, 88%)CT=28/18268% (95% CI: 59%, 75%)No CT=51/178HR = 0.53 (95% CI: 0.33, 0.84); p=0.0070 12 24 36 48 60 72Months since randomisationN at risk (events)CT 182 (20) 118 (6) 88 (2) 61 (0) 48 (0) 30 (0) 15No CT 178 (35) 108 (13) 77 (2) 59 (1) 29 (0) 19 (0) 11James et al NEJM 2012


RTOG PROTOCOL 07-12 (Randomized Phase II)Stage T2 – T4a, No HydronephrosisCandidate for cystectomy, if necessaryTURBTrandomizationRTOG:bid RT5FUCisplatinMichigan:qd RTGemcitabineStarted accrual 2008


RTOG PROTOCOL 09-26 (Phase II)Stage T1 G2 or G3, Failed intravesicaltherapy, Cystectomy next stepTURBTFull dose RTConcurrent cisplatinCystoscopicsurveillanceStarted accrual 2010


Personalized Care in the Era of Biomarkers andMolecular Targeted AgentsCan biomakers be used to predict outcomes andeven select an optimal treatment for subsets ofmuscle-invading bladder cancer patients, thusbenefiting individuals?


RTOG 05-24: Phase I-II study of treatmentfor non-cystectomy candidatesTURBT---------> Her-2 stain < 3+ --------> XRT + weekly taxolTURBT---------> Her-2 stain 3+ ----------> XRT + weekly taxol+ HERCEPTIN


MRE11 Predictive of CSS Following Radical Radiotherapyfor Muscle Invasive Bladder CancerRadiation cohortCystectomy cohortP


Validation of predictive markers in Danish group• TIP60 predictivemarker for DSScystectomycohorts, and MRE11in radiotherapycohort• p16 also correlatedwith DSS, but notpredictive• Ki67, p53, andpATM notcorrelated in DSS inany of the cohortsLaurberg et al., BJU Int. 2012


Stratification based on combination ofMRE11 and TIP60 markersLaurberg et al., BJU Int. 2012


Quality of life after chemo-radiation


MGH Quality of Life Study221 patients, T2-4NX-0M0 bladder cancer,Treated on protocols 1986-2000, median f/u 6.3 years,Urodynamics study, QOL questionnaire• 78% have compliant bladders with normal capacityand flow parameters• 85% have no urgency or occasional urgency• 25% have occasional to moderate bowel controlsymptoms• 50% of men have normal erectile functionZietman, Talcott, Krane et al J Urol 2003


Late Pelvic Toxicity: RTOG Results157 patients with bladder preservation who survived2 to 13 years (median follow-up 5.2 years)• 22% Grade 1• 10% Grade 2• 7% Grade 3 (5.7% GU, 1.9% GI)• 0% Grade 4• 0% Grade 5Efstathiou et al J Clin Oncol 2009


Quality of life after treatment of invasive bladder cancer:Cystectomy or organ-conserving therapy2 comparative cross-sectional studies available:Trento, Italy 1996Incontinent diversion vs chemo-RTKarolinska, Sweden 2002Incont. and cont. diversions vs RT vs controls


Quality of life after treatment of invasive bladder cancer:Cystectomy or organ-conserving therapyQOL advantage to chemo-RT:psychologic adjustmentphysical well-beingenergysexual functionurinary functionQOL equivalence chemo-RT vs surgery:Social functioningBowel function


QoL due to urinary symptoms after TURBT and chemoRTIf you were to spend the rest of your life with your urinarycondition the way it is now, how would you feel about that?mixed–delightedpleasedmostlysatisfiedaboutequallysatisfiedanddissatis-mostlydissatisfiedunhappy terriblefied18.5% 51.7% 17.2% 9.1 % 0.8% 2 % 0.7%Weiss et al 2005


“The best bladder you will everhave is the one you are born with”(even if it has had an aggressiveTURBT and some radiation)Anthony Zietman


Acceptance of chemoradiationused in modern bladder-sparingtherapy should not be limited byconcerns of high rates of latepelvic toxicity


Morbidity of primary radical cystectomyDonat et al 20091142 RCs at MSKCC 1995-2005Prospectively captured morbidity dataReported complications within 90 daysGraded 0-5 on modified Clavien Scale


Morbidity of primary radical cystectomyDonat et al 200964% More than 1 complication13% Grade 3-526% Readmissions2% 90 day mortalityDonat et al Eur Urol 2009


Morbidity of salvage radical cystectomyat the MGHGrade Total


ICUD-EAU Bladder Cancer2012 Guidelines“In selected patients with MIBC, bladder-preservingtherapy with cystectomy reserved for tumorrecurrence represents a safe and effectivealternative to immediate RC”Gakis, Efstathiou, Lerner et al Eur Urol 2012


Closing Thoughts• Combined modality therapy achieves a CR and preservesthe native bladder in ~70% of patients, while offeringlong-term survival rates comparable to contemporaryradical cystectomy series• QOL studies have demonstrated that the retained nativebladder functions well and long-term toxicity ofchemoRT to pelvic organs is relatively low• Incidence of cystectomy performed for palliation oftreatment-related toxicity has been very low and themorbidity of salvage cystectomy appears comparableto primary cystectomy


Closing Thoughts• These results support the acceptance of modernbladder-sparing trimodality therapy for selectedpatients as a proven alternative to cystectomy• The optimal regimen of combined chemoRT, as well asthe addition of rational molecular targeted therapyand personalized treatment selection, continues tobe investigated


Closing Thoughts• The contribution of selective bladder sparingtherapy to the quality of life of patientsrepresents a unique opportunity for patients,urologic surgeons, radiation oncologists,and medical oncologists to work hand inhand in a truly multidisciplinary effort

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