Invasive Bladder Cancer Panel Discussion

Michael S. Cookson, MD, MMHC, FACSProfessor and Chair

Department of Urology, University of Oklahoma

Case Based Discussion

• Patient selection • Perioperative Management• Neoadjuvant Therapy• Surgical Approach• Role of Lymph Node Dissection• Adjuvant Treatment

History• 56 yo male seeks a second opinion regarding new

diagnosis of muscle-invasive bladder cancer• Presented with painless gross hematuria for 6weeks• ROS: 10 lbs. weight loss • PMH: HTN, Type2 DM, Hypercholesterolemia• SH: Nonsmoker, works in rubber tire manufacturing• AUASS 2, SHIM 21, ECOG 0

Clinical Information

• Physical Exam: Moderately obese (BMI 31)• CT Chest: No evidence of metastatic disease• CT Abdomen: Large tumor on the left lateral wall• Cysto/TURBT: Large sessile tumor on left lateral wall

mass; No other areas of concern– Path: High-grade (III/III) urothelial carcinoma invasive into

muscularis propria

• sCre 1.5 ng/dl (eGFR > 65), LFT’s within normal limits

Vale, et al Eur Urol 48:202, 2005

Neo-adjuvant Chemotherapy Meta Analysis5% Survival Advantage

• Individual patient data from 6 randomized trials• 9% survival benefit with platinum-based combinations

Cisplatin alone

Cisplatin combo

SWOG S1314

COXEN Validation Neoadjuvant

Chemotherapy Trial

Selection Criteria SWOG 8710

(T2-T4a N0M0, cisplatin eligible)

C

Y

S

T

E

C

T

O

M

Y

Randomize

to chemo

n=184

Gem-Cis

DD-MVAC

AssessmentTo characterize the

relationship of MVAC-

and GC-specific COXEN

scores in terms of pT0

rate

Biomarker validation and Biomarker discovery

Tumor

Sample

TURBT

CollectionTissue, blood, urine

Molecular AnalysisGene expression

Sequencing

microRNA

SNP

CollectionTissue (>P0), blood, urine

Molecular AnalysisGene expression

Sequencing

microRNA

SNP

Cystectomy

Pathology

Discovery

Activated July 1, 2014

Panel Discussion: Next Steps • Neoadjuvant chemotherapy (NAC) or upfront radical

cystectomy? –What factors influence NAC decision?• Radiographic T3/T4 disease• Variant histology• Hydronephrosis• Other?

–What if renal function is poor?– What is the role of repeat TUR prior to NAC?– Should complete TURBT be performed?

Assessment after NAC

• Patient received 3 cycles of Gemcitabine and Cisplatin which he tolerated well

• What is the role of restaging after NAC?– Imaging? –Repeat TUR-BT

• Does the absence of residual bladder cancer on repeat TUR-BT (cT0) influence decision making?

Preadmissioncounseling

No/selective bowel-prep

Fluid and carb loading/no prolonged fasting

No premed

No NG tubes

Mid-thoracic epidural anesthesia/analgesia

Short-acting Anesthetic agent

Avoidance ofSodium/fluid overload

No drains

Warm air bodyheating in surgery

Earlymobilization

Non-opioid oralanalgesia/NSAIDs

Prevention of nausea and vomiting

Stimulation of gut mobility

Early removal ofcatheters/drains

Earlyoral nutrition

Audit of compliance/outcomes

Core ERAS Protocol

ERAS

AntibioticprophylaxisThrombo-

prophylaxis

Avoidance of saltand water overload

PREOPERATIVE

INTRAOPERATIVEPOST

-OPE

RATIV

E

ERAS® Society. http://www.erassociety.org/index.php/eras-care-system/eras-protocol

Panel Discussion:Perioperative Interventions to Reduce

Morbidity of Radical Cystectomy• What is the role of Immunonutrition?– Pre-habilitation (exercise, shakes, smoking cessation) – How do you do it?

• Comment on enhanced recovery after surgery (ERAS) care pathways?– Bowel prep (ever vs. never vs. special circumstances)– Alvimopan (Entereg�)?– Epidural?– Duration of DVT prophylaxis– Discharge management

NCDB Data: Robotic RC

Bachman AG, et al, Urology, 2017

Almost 40% of cystectomies

are now performed by

minimally invasive

approach—and favored in

lower volume and non

academic centers

Comparison Points

Oncologic Outcomes Morbidity

Learning Curve Cost

Panel Discussion: Surgical Approach

• Robotic vs. open radical cystectomy?• If robotic, what about the diversion? –Intracorporeal vs. open diversion

Cancer-Specific Survival in Robotic vs Open: SEER-data

Hu JC et al, European Urology, 2016

NO DIFFERENCE IN CANCER-SPEC SURVIVAL: follow-up 44 mos

Xia L, Wang X, Xu T, Zhang X, Zhu Z, et al. (2015) Robotic versus Open Radical Cystectomy: An Updated Systematic Review and Meta-Analysis. PLoS ONE 10(3): e0121032. doi:10.1371/journal.pone.0121032

Meta Analysis: Outcomes that Favor the RobotBlood Loss Transfusion LOS

• First phase 3 multicenter randomized evidence comparing oncological outcomes of ORC to RARC

• Primary endpoint of 2-year progression free survival

• All surgeons fellowship trained or bladder cancer focused Parekh D et al. Lancet 2018; 391: 2525–36

RAZOR Trial

“robotic cystectomy was non-inferior to open cystectomy for 2-year progression-free survival.”

Parekh D et al. Lancet 2018; 391: 2525–36

0 5 10 150.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Prob

abili

ty o

f Not

Rec

urri

ng

P <0.001

Organ Confined (n=594)

Extraves ical (n=214)

Lymph Node (+) (n=246)

Recurrence-Free SurvivalUSC/Norris Cancer Center-Open

Stein JP et al: J Clin Oncol 19:666-75, 2001

Lymphadenectomy: Where�s the Line?

Iliac Artery Bifurcation

Common Iliac Artery

Aortic Bifurcation

Inferior Mesenteric Artery

Panel Discussion: Surgical Approach

• Extended lymph node dissection: Is it really necessary? If so, what are the boundaries?

• What to do with N+ disease post-cystectomy? • Should adjuvant treatment always be given,

and if so—what and when?

Fig. 2 Pooled hazard ratios across all nine studies by chemotherapy type CI = confidence interval; ES = effect size.

Adjuvant Chemotherapy for Invasive Bladder Cancer: A 2013 Updated Systematic Review and

Meta-Analysis of Randomized Trials

Leow, et al Eur Urol epub 8/2013

945 patients in 9 trialsHR 0.77 - 23% relative reduction in Death

• AUA/SUO: Patients with RC path pT3/T4and/or N+ who have not received cisplatin-based NAC should be offered adjuvant cisplatin- based chemotherapy. (Moderate Recommendation; Evidence Level: Grade C)

• EAU and ASCO: Data are not convincing enough to give an unequivocal recommendation for the use of immediate adjuvant chemotherapy as compared to chemotherapy at the time of relapse (1A)

• NCCN: Consider if pT3-4, any N+, if no NAC given (2B)

50

Adjuvant ChemotherapyGuidelines – AUA/SUO, EAU, ASCO