the slides from this webinar. - Bladder Cancer Advocacy Network

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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