Bladder Preservation Strategies for Muscle Invasive Bladder Cancer

Bladder Preservation Strategies for Muscle Invasive Bladder Cancer Jeff M. Michalski, MD, MBA, FACR, FASTRO The Carlos A. Perez Distinguished Professor of Radiation Oncology Department of Radiation Oncology Washington University School of Medicine St. Louis, Missouri USA

Organ conservation in contemporary oncology Anal carcinoma Rectal Cancer Breast carcinoma Esophageal carcinoma Laryngeal carcinoma Limb sarcomas Prostate carcinoma

Cystectomy versus ChemoRadiotherapy Comparing cure rates of modern selective bladder preserving approaches with salvage cystectomy to contemporary cystectomy series is difficult. Outcome results are confounded by discordance between clinical (TURBT) staging and pathologic (cystectomy) staging Best approach is to compare the results of prospective protocols in which the eligibility is based on clinical staging and all entered patients are reported for outcome

ACS / National Cancer Database (2004-2008): Stage Discrepancy Overall clinical-pathologic stage discrepancy rate was 47.8% and included: 41.9% upstaging at time of surgery 5.9% downstaging at time of surgery 5% of patients with MIBC were downstaged to non-invasive disease Gray et al. IJROBP 2014

Percent Discrepancy T-Stage Discrepancy 50 45,4 46,2 40 33,7 30 20 20,8 10 4,5 5,3 10,3 9,1 0 ct0/tis/ta ct1 ct2 ct3 ct4 Upstaged Downstaged Gray et al. IJROBP 2014

Study Population AJCC Clinical Stage AJCC Pathologic Stage III 15% IV 7% I 16% 0 4% IV 25% I 10% 0 4% II 58% III 30% II 31% Gray et al. IJROBP 2014

Survival by Stage Discrepancy 1.0 Clinical stage II 1.0 Clinical stage III 0.8 0.8 Surviving fraction 0.6 0.4 Surviving fraction 0.6 0.4 0.2 0.0 Downstaged Stage agreement Upstaged P <.001 0.2 0.0 Downstaged Stage agreement Upstaged P <.001 0 12 24 36 48 60 0 12 24 36 48 60 Time (months) Time (months) Gray et al. IJROBP 2014

Medically inoperable An Alternate Approach - Trimodality Therapy TURBT XRT (40Gy) + Concomitant Chemotherapy Cystoscopic response evaluation CR Non-CR Consolidation Chemo-radiation (64Gy) +/- adjuvant chemo Radical Cystectomy +/- adjuvant chemo

Long-term Results of TMT Are Excellent MGH Experience 1986-2013 (ct2-t4, n=475, f/u 7.2yrs) Giacalone et al. Eur Urol. 2017 n % Median Age 67 Sex Male 357 75% Female 118 25% Clinical T Stage ct2 317 67% ct3 134 28% ct4a 24 5% Hydronephrosis 57 12% Carcinoma in situ 116 24%

Long-term Results of TMT Are Excellent MGH Experience 1986-2013 (ct2-t4, n=475, f/u 7.2yrs) Neoadjuvant Chemotherapy TURBT Giacalone et al. Eur Urol. 2017 n % 118 25% Visibly complete 333 70% Visibly incomplete 142 30% Response to induction chemoradiation Complete 357 75% Incomplete 110 23% Unknown 8 2%

Bladder Sparing at MGH by Era Giacalone et al. Eur Urol. 2017

Disease-Specific Survival and Overall Survival DSS OS 5-year DSS: 66% 10-year DSS: 59% 15-year DSS: 56% 5-year OS: 57% 10-year OS: 39% 10-year OS: 25% Giacalone et al. Eur Urol. 2017

Cox Regression Analyses for Overall Survival European urology by EUROPEAN ASSOCIATION OF UROLOGY Reproduced with permission of ELSEVIER HEALTH SCIENCE JOURNALS in the format Post in a course management system via Copyright Clearance Center. Giacalone et al. Eur Urol. 2017

TURBT and Salvage Cystectomy Key to Success of TMT Maximal Complete TURBT Giacalone et al. Eur Urol. 2017

RTOG Experience 6 trials (5 phase II, 1 phase III) 468 Patients Median FU 4.3 years overall, 7.8 years for survivors

Disease-specific Survival(%) Does age matter? Pooled RTOG MIBC Studies DSS for Age < 75 vs. Age 75 100 75 50 71% 70% 65% 64% 25 Patients at Risk Age < 75 Age >=75 0 Age < 75 Age >=75 Failed 141 29 Total 403 84 p= 0.84(Gray) 0 1 2 3 4 5 6 7 8 9 10 Years after Randomization 387 80 340 71 284 55 239 43 207 35 176 29 156 23 145 16 106 10 77 7 53 4 Mak et al. J Clin Oncol 2014; 32: 3801-3809.

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

Survival After Curative Therapy Stein (2001) J Clin Oncol 2001. Dalbagni (2001) J Urol 2001 Grossman (2003) N Engl J Med 2003. Shipley (1998) J Clin Oncol1998. Rodel (2002) J Clin Oncol 2012. Giacalone Eur Urol 2017 James et al. N Engl J Med 2012. Mak et al. J Clin Oncol 2014

Selection is Key Tumor presentations with the highest success rates: Solitary T2 or early T3 tumors < 6 cm No tumor-associated hydronephrosis Tumors allowing a visibly complete TURBT Invasive tumors not associated with extensive carcinoma in situ Adequate renal function to allow cisplatin concurrent with radiation TCC histology

Propensity Score Analysis of Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in the Setting of a Multidisciplinary Bladder Cancer Clinic Kulkarni PMH JCO 2017

Propensity Score Analysis of Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in the Setting of a Multidisciplinary Bladder Cancer Clinic Kulkarni PMH JCO 2017

Propensity Score Analysis of Radical Cystectomy Versus Bladder-Sparing Trimodal Therapy in the Setting of a Multidisciplinary Bladder Cancer Clinic Kulkarni PMH JCO 2017

MRC SPARE Bladder Protocol TURBT Gemcitabine and Cisplatin 3 cycles Cystoscopic assessment of treatment response Incomplete response Complete response Definitive Radiation + Chemo Closed March 2010 with only 4% of cases Huddart et al BJU Int 2010

Which chemotherapy with radiation?

Role of Concurrent Chemotherapy The active radiosensitizing drugs include: Cisplatin, 5-FluoroUracil, Mitomycin C, Paclitaxel, Gemcitabine

University of Erlangen Experience n CR RT alone 98 57% RT + carboplatin 69 64% RT + cisplatin 115 81% RT + 5-FU/cis 45 87% Rodel et al. IJROBP 2002;52:1303-9

Concurrent Chemotherapy + Twice-Daily RT Protocol Induction treatment Patients Complete Response 95-06 TURBT, 5-FU plus 34 67% CP + BID RT 97-06 TURBT, CP + BID RT 52 74% adj MCV 99-06 TURBT, TAX plus 80 81% CP + BID RT adj CP + GEM

RTOG PROTOCOL 0233 (Randomized Phase II) (PI: AL Zietman, MD) Stage T2 T4a, No Hydronephrosis Candidate for cystectomy, if necessary TURBT randomization bid RT 5FU Cisplatin bid RT Paclitaxel Cisplatin Finished accrual 2008 93 patients

RTOG 0233 Bladder-intact survival by treatment arm Mitin T, Hunt, D, Zietman, A et al. Lancet Oncol 2013

RTOG PROTOCOL 0712 (Randomized Phase II) Stage T2 T4a, No Hydronephrosis Candidate for cystectomy, if necessary TURBT randomization RTOG (FCT): bid RT 5FU 400mg/m2 Cisplatin 15mg/m2 Michigan (GD): qd RT Gemcitabine 27mg/m2 Started accrual 2008, closed 2014

RTOG PROTOCOL 0712 (Randomized Phase II) Following ChemoRadiotherapy, patients received adjuvant Gem/Cis

NRG/RTOG 0712 70 patients enrolled, 66 eligible for analysis Regimen DM@3y BIDMF@3y CR Gr 3/4 tox FCT 22% 67% 88% 64% GD 16% 72% 78% 54% Once daily RT (GD) was as effective as BID Toxicity was less with GD Coen ASTRO 2017

Role of Neoadjuvant Chemotherapy No Level 1 (Phase III) data indicating cisplatin-based neoadjuvant chemotherapy given before definitive local treatment by RT or RT and concurrent chemotherapy significantly improves survival. RTOG 89-03 trial (n=123) negative (5 year survivals of 49% and 50%) Danish Cancer Group trial (n=113) negative (NCT had 5.6% lower survival) RT subgroup of MRC trial (n=413) trended insignificant in favor of NCT Meta-analysis negative (survival 30.4% vs 28.1%)

James NEJM 366: 1477-88, 2012

Phase III randomized trial of synchronous chemo-radiotherapy compared to radiotherapy alone 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 months James et al NEJM 2012

U. K. Chemotherapy regimen for MIBC MMC 12mg/m2 5FU 500mg/m2/d RT 55 Gy/20 f or 64 Gy/32 f Weeks 0 1 2 3 4 5 6 7 James et al NEJM 2012

LRDFS with & without chemotherapy 0.00 0.25 0.50 0.75 1.00 2-yr LRDFS 67% (95% CI: 59%, 74%) 54% (95% CI: 46%, 62%) HR = 0.66 (95% CI: 0.46, 0.95); p=0.02 CT = 52/182 No CT = 74/178 0 12 24 36 48 60 72 Months since randomisation N at risk (events) CT 182 (34) 106 (14) 71 (2) 51 (1) 41 (1) 23 (0) 11 No CT 178 (53) 94 (16) 62 (4) 48 (0) 25 (0) 18 (1) 9 James et al NEJM 2012

0.00 0.25 0.50 0.75 1.00 Invasive loco-regional disease free survival with and without concurrent chemotherapy 2-yr ILRDFS 82% (95% CI: 75%, 88%) CT=28/182 68% (95% CI: 59%, 75%) No CT=51/178 HR = 0.53 (95% CI: 0.33, 0.84); p=0.007 0 12 24 36 48 60 72 Months since randomisation N at risk (events) CT No CT 182 (20) 118 (6) 88 (2) 61 (0) 48 (0) 30 (0) 15 178 (35) 108 (13) 77 (2) 59 (1) 29 (0) 19 (0) 11 James et al NEJM 2012

0.00 0.25 0.50 0.75 1.00 OS in chemotherapy randomisation 2-yr OS 62% (95% CI: 54%, 68%) CT = 85/182 60% (95% CI: 52%, 67%) No CT = 98/178 HR = 0.81 (95% CI: 0.60, 1.09); p=0.16 0 12 24 36 48 60 72 Months since randomisation N at risk (events) CT 182 (35) 141 (33) 104 (10) 72 (4) 56 (1) 37 (1) 18 No CT 178 (35) 139 (34) 95 (14) 68 (12) 33 (3) 19 (0) 11 James et al NEJM 2012

Quality of life after chemo-radiation

Late Pelvic Toxicity: RTOG Results 157 patients with bladder preservation who survived 2 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 5 Efstathiou et al J Clin Oncol 2009

MGH Urodynamics and QOL Study 221 patients treated with TMT on protocols 1986-2000, median follow-up 6.3 years 78% have compliant bladders with normal capacity and flow parameters 85% have no or occasional urgency 25% have occasional to moderate bowel control symptoms 50% of men have normal erectile function Zietman AL, et al. J Urol 2003

GETUG 97-015 Prospective Phase II study of 51 MIBC patients treated with TMT 1999-2001, without disease relapse, median follow-up 8 years Mean global QOL, physical, emotional, personal, cognitive, and social function scores >70% 100% satisfactory bladder function 70% maintained bladder function scores 1 year after treatment 79% had sexual activity 18 months after treatment (vs. 56% pre-treatment) Lagrange JL, et al. IJROBP 2011

MGH/UNC: Long-Term QOL Cross-sectional study of 173 patients diagnosed in 1990-2011, disease-free for 2 years Treated at high-volume, academic medical centers with modern techniques Median follow-up: 5.6 years - 63% patients received cystectomy (n=109) - 82% ileal conduit and 18% neobladder diversions - 37% received TMT (n=64 ) - 9% required salvage cystectomy (n=6) Six validated QOL questionnaires, scored out of 100 Mak et al. IJROBP 2016

Validated Instruments General HRQOL: 1) EuroQOL EQ-5D: 3L and visual analog scale 2) European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) Symptom-specific HRQOL: 3) EORTC MIBC module (QLQ-BLM30) 4) Expanded Prostate Cancer Index Composite - Bowel Assessment (EPIC) Perception and Impact of Cancer: 5) Cancer and Treatment Perception Scale 6) Impact of Cancer Version 2 (IOCv2) Each instrument scaled to 0-100 score Mak et al. IJROBP 2016

MGH/UNC: Long-Term QOL Both cystectomy and TMT associated with good long-term QOL outcomes Compared to RC, TMT associated with: Modestly higher general QOL (by 7-10 points) Similar urinary scores Modestly higher bowel function (by 3-7 points) Markedly better sexual QOL (by 9-32 points) Better informed decision-making (by 14 points) Less concerns about appearance (by 14 points) Less life interference from cancer or cancer treatment (by 9 points) Mak et al. IJROBP 2016

Mak et al. IJROBP 52016

Mak et al. IJROBP 53 2016

ICUD-EAU Bladder Cancer Guidelines In selected patients with MIBC, bladder-preserving therapy with cystectomy reserved for tumor recurrence represents a safe and effective alternative to immediate RC Gakis et al. Eur Urol 2012

Acceptance of chemoradiation used in modern bladder-sparing therapy should not be limited by concerns of high rates of late pelvic toxicity

Closing Thoughts Combined modality therapy achieves a CR and preserves the native bladder in ~70% of patients, while offering long-term survival rates comparable to contemporary radical cystectomy series QOL studies have demonstrated that the retained native bladder functions well and long-term toxicity of chemort to pelvic organs is relatively low Incidence of cystectomy performed for palliation of treatment-related toxicity has been very low and the morbidity of salvage cystectomy appears comparable to primary cystectomy

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