Surgical Management of Bladder Cancer

Dr. Hemant B. Tongaonkar

Professor & Head, Genitourinary & Gynecologic Oncology Tata Memorial Hospital, Mumbai

Bladder Cancer Epidemiology

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1.5-2% of all malignant neoplasms in males in India Second commonest urologic malignancy after prostate cancer More common in industrialised than in developed countries More common in urban than rural areas

Bladder Cancer Investigations

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Urine Cytology Excretory Urography Cystoscopy & Biopsy of tumour Bimanual Examination Ultrasonography CT Scan Abdomen & Pelvis Metastatic Work-up

Bladder Cancer

Staging Bladder Cancer

Superficial Locally Invasive Metastatic

Superficial Bladder Cancer Treatment Transurethral resection of bladder tumours + Multiple random punch biopsies from bladder & prostatic urethra To identify high risk factors

Superficial Bladder Cancer Aim of Treatment Identify risk factors to predict natural history Low risk High risk Observe Aggressive treatment Prophylactic therapy Close monitoring

Random Mucosal Biopsies In Superficial Bladder Cancer

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Rationale: To detect abnormalities (CIS, dysplasia or Ca) in normal looking areas in bladder & prostatic urethra (Althausen) Abnormal biopsy predictive of recurrence &/or progression Indication for intravesical therapy Low risk 4-6% High risk 11.6% (EORTC 99) Random biopsies often useless & add nothing to prognosis or treatment decision Tumour implantation a possibility (Clemeny 2003) Only indication: +ve cytology in presence of papillary tumours

Sites for selected mucosal biopsies in TUR

Superficial Bladder Cancer Problems in Management

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Local relapse after adequate TUR 70-80%

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Progression to muscle invasion 20%

Superficial Bladder Cancer Factors Affecting Natural History

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Tumour grade Multiplicity & Tumour size Condition of adjacent epithelium Depth of invasion Tumour configuration DNA ploidy Vascular & Lymphatic emboli Biologic & Genetic factors

SBC: Natural History Impact of Tumour Grade

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Strong correlation bet tumour grade & tumour stage: Low grade Superficial High grade Invasive Grade I Grade III <5% invasive at diagnosis 50% invasive within 2 yrs Strong predictor of survival Grade I 95% survive 5 years Grade III 40% survive 5 years

SBC: Natural History Impact of Lamina Propria Invasion

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Marked diff in biologic behaviour of stage Ta & T1 tumours T1: High risk of recurrence & progression Worst with T1G3 Progression rate % Ta T1 NBCCG-A Study British Study 4% 0% 24% 46%

Muscularis Mucosae

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Often confused with muscularis propria Proper labeling of tissue imp Need for interpretation of the whole picture Prognostic impact demonstrated T1a : Between epithelium & muscularis mucosae T1b : Level of muscularis mucosae T1c : Between muscularis mucosae & submucosa

SBC: Natural History Impact of T Size & Multiplicity

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Larger or multiple tumours: Worse prognosis With multiple tumours: Increased risk of recurrence Reduced interval to recurrence With increasing tumour size: Increased risk of recurrence & progression < 5 cm 9% > 5 cm 35% progression rate

SBC: Natural History Impact of Mucosal Changes Strong predictor of local recurrence & stage progression Althausen Heney Rec rate % Normal 3.8% 8.0% Abnormal 78% 33%

Superficial Bladder Cancer Risk Grouping

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Low risk : Ta G1 Single <3 cm tumour with rec rate <1/ year Single post-op instillation of chemo High risk : T1 G3 Multifocal Large Highly recurrent & Tis Intermediate : All others TaT1 G1-2 >3 cm Single post-op instillation of chemo & to continue intravesical therapy in high & intermediate risk

Superficial Bladder Cancer Intravesical Therapy High risk of recurrence High risk of progression Chemotherapy Immunotherapy Thiotepa Doxorubicin Epirubicin Mitomycin Ethoglucid BCG Interferon Interleukin-2 KLH

Superficial Bladder Cancer Intravesical Chemo on Recurrence Thiotepa N 1130 Control Treated Benefit P 61% 49% 12% 5/9 Mito Doxo Etho Epirubi Total 1157 1389 209 399 3899 53% 53% 59% 41% 54% 44% 38% 28% 29% 40% 9% 15% 31% 12% 14% 2/6 3/5 S S -

Superficial Bladder Cancer Intravesical BCG on recurrence Lamm Herr N Control Treated Benefit P 57 86 52% 95% 20% 42% 32% 53% S S Herr Pagano Melkos 49 133 94 Ruben 77 Cumulative 496 100% 83% 59% 42% 73% 35% 26% 32% 35% 31% 65% 57% 27% 7% 42% S S S NS S

Superficial Bladder Cancer Intravesical Chemo on Progression Thiotepa Mitomycin Doxorubicin Epirubicin Cumulative N Treated % Control % 513 4.5 6.0 527 572 399 2011 3.9 15.2 3.6 7.5 7.3 12.6 2.4 6.9 P NS NS NS NS NS

Superficial Bladder Cancer Intravesical BCG on Progression

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Reduces stage progression rate Reduces progression to muscle invasion Increases progression-free interval Reduces no of patients requiring cystectomy Increases period of bladder preservation Reduces no of deaths from disease Increases disease specific survival

Superficial Bladder Cancer Indications of Intravesical Therapy

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Multiple or multicentric tumours Rapidly recurrent tumours Lamina propria invasion (T1) Poorly differentiated tumours Dysplasia or CIS in random biopsies

Intravesical BCG vs Control TMH TRIAL

DFS

Multivariate Analysis of Prognostic Variables Variable Age Sex No of tumours Tumour grade Tumour stage Treatment P value 0.61

0.82

0.59

0.45

0.12

0.0006

Carcinoma-in-situ of Bladder

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Flat intraepithelial neoplasm of high histologic grade (Melicow 1952) Exists in 2 forms Aggressive: Can dev into solid muscle invasive tumour Non-aggressive (Ca paradoxicum): Lacks capacity of invasion & mets (Weinstein) Occurs rarely with low grade SBC 25% patients with high grade SBC 20-75% of high grade muscle-invasive Ca 20% pts undergoing cystectomy for CIS have microscopic muscle invasive cancer

CIS Bladder: Natural History

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Not clearly understood Some have protracted course > 10 yrs without muscle invasion Others progress rapidly to muscle invasion & has poor prognosis despite definitive Rx Symptomatic patients have shorter interval preceding muscle invasion Diffuse vs. Focal: Prognostically diff entities Risk of progression to muscle invasion: Focal CIS Diffuse CIS 8% 78% High rec & progression rate despite standard definitive therapy: Poor prognosis

Carcinoma-in-situ of Bladder Treatment Options

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Transurethral resection Immediate cystectomy Intravesical chemotherapy Intravesical immunotherapy

CIS Bladder: Management

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TUR: High rec rate (80-100%), progression rate (50-80%) & mortality (30-40%) since: Lesion not visible endoscopically Ill-defined margins Too extensive to treat Ass with muscle invasion in many Immediate cystectomy: Advocated since CIS ass with invasive tumour in majority 65-80% survival Results not diff if cystectomy done after failure of intravesical therapy

CIS Bladder: Management

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Intravesical chemo: CR rates 20-46% only irrespective of agent used: Suboptimal Intravesical BCG immunotherapy: - Most appropriate first line therapy - Excellent results: 70-82% CR - BCG vs. Cystectomy: No difference - CIS after BCG failure: Ominous but cystectomy still possible - Long-term results unclear: Lifelong follow up essential

Cystectomy for superficial disease 1. Low- to moderate-grade polychronotropic disease that renders the bladder nonfunctional 2. High-risk superficial disease that has not responded to early intravesical therapy.

3.Immediate cystectomy is an option in high grade T1 disease, especially if the presentation is multifocal, but it is generally considered as a treatment option after assessing the response to a course intravesical therapy

Muscle Invasive Bladder Cancer Options of Management

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Radical Cystectomy Radical Radiation Therapy Chemotherapy Combined Chemo + Radiation therapy in selected patients Pre-op Radiotherapy + Surgery Neoadjuvant Chemotherapy + Surgery

Invasive Bladder Cancer Radical Cystectomy

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Treatment of choice : Gold Standard Local control 90-95% Survival 30-60% 50% die of metastatic disease : Related to nodal mets & depth of invasion : Need for adjuvant / neoadjuvant therapy Operative mortality low Nerve sparing technique preserves potency Requires urinary diversion in majority

Muscle Invasive Bladder Cancer

Radical Cystectomy : Results

Path Stage 5 Year Survival Median Range T2 T3a T3b T4 63 57 31 18 53-75 39-74 15-48 0-29 ( Herr, Urol Oncol 2, 92, 1996)

Radical Cystectomy DFS vs pStage & LN status

Author Mathur Montie Guiliani Skinner Malkowitz Wishnow Waehre Schoenberg Ghoneim Bassi N 58 99 202 197 160 71 227 101 1026 369 P2 72 62 75 64 76 80 79 84 66 63 P3 40 57 19 44 NA NA 36 56 31 33 P4a 29 75 0 36 NA NA 29 NA 19 28 N+ NA NA NA 44 NA NA 22 48 23 15

Partial Cystectomy

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Urachal adenocarcinoma at the dome

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TCC bladder if: Solitary muscle invasive tumour Location at dome Preferably no extravesical spread Random mucosal biopsies negative Need to perform ureteric reimplantation not an absolute contraindication Intra-op F.S. for –ve surgical margins mandatory

Extraperitoneal Radical cystectomy

Open Vs Laparoscopic approach Hand assisted approach

Robotic Radical Cystectomy Da Vinci

Prostate & SV sparing cystectomy

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Rad cystectomy adversely affects male sexuality & QOL (Potency rates 13-25%) Nerve sparing technique, 50% still lose potency (Walsh) Prostate & SV sparing cystectomy developed Functional results better but oncological outcome needs to be evaluated over a longer follow up

Invasive Bladder Cancer Impact of Lymphadenectomy

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Valuable staging manouevre Identifies high risk group requiring adjuvant therapy Prognostication Therapeutic in presence of micromets: Curative potential & survival benefit (Stein 2003, Skinner 1982, Madersbacher 2003, /vieweg 1999) Optimal boundaries need to be defined to accurately diagnose mets & to improve therapeutic benefit without increasing morbidity

Muscle Invasive Bladder Cancer Prognostic Factors

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Tumour stage & LN status independent prognostic factors for DFS & OAS Among node +ve patients, OC disease better survival than EV (Stein 2003, Herr 2002, Mills 2001, Vieweg 1999) Substratification of nodal status imp for prognostication

Bladder Cancer New insights into LN drainage

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290 patients RC+ Extended LND: LN +ve 27.9% 15.8% located lat to ext iliac vessels Isolated LN involvement in presacral or common iliac regions in 25% Among pelvic LN +ve, 57% also had +ve nodes in common iliac & 31% above aortic bifurcation With standard LND, 74.1% +ve nodes would have been left behind & 6.8% mis-classified at LN -ve Leissner 2003

Bladder Cancer New insights into LN drainage

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Tumours localised to one half: 30% +ve nodes located on contralateral side (Leissner 2004) Crossing lymphatic drainage in 41% of node +ve (Mills 2001)

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Unpredictable, crossing drainage & skip lesions support more comprehensive LND

Which aspects of LND contribute to improved results?

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No of lymph nodes dissected, independent of no of +ve nodes Extent of dissection: Standard vs Extended (Paulson 1998) Node -ve: Extended 90% vs 71% Standard Benefit regardless of the T stage (OC 85% vs 64%) Node +ve: 24% vs 7% Herr (2003): RCT No LND (33%) vs Obturator (46%) vs Standard (60%)

Non-invasive staging alternatives Identification & localisation of nodes

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Occult mets in grossly normal nodes common (approx 40%) Despite modern imaging, incidence of occult mets 14-27% CT /MRI fail to predict occult LN mets in 21 15% PET scan: False –ve: 33% Sentinel LN biopsy: Low accuracy Surgical excision with path evaluation only reliable method of staging bladder cancer

Invasive Bladder Cancer Pre-op Radiation Therapy

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Moderate dose 20 Gy / 5 Fr or 40-50 Gy / 20 25 Fr Eradication of primary & nodal disease in few patients after pre-op RT alone No survival benefit in randomised trials Meta-analysis : 10% survival advantage MD Anderson Trial : Reduces pelvic relapses in T3b patients (28% vs 9%) No survival benefit

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Invasive Bladder Cancer Radical Radiation Therapy Indications : Patients unfit / unwilling for surgery Rarely, selective modality Bladder conservation protocols

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55-65 Gy : Target volume definition & adequate margins important

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Initial CR (T0) 40-52% Bladder DF 35-45% for T2-4 at 5 years

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Overall survival 25-40% Excellent local control means good survival Salvage cystectomy for residual / rec disease Cystitis, proctitis, sexual dysfn common

Invasive Bladder Cancer Salvage Cystectomy

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Cystectomy following definitive radiation therapy Planned procedure or for progressive, residual or recurrent disease after RT or for RT related complications Survivals comparable to radical cystectomy in 4 randomised trials Technical challenge: Devascularisation & fibrosis Acceptable mortality & morbidity

Invasive Bladder Cancer Ext Radiotherapy + Salvage Cystectomy Deferring cystectomy until local progression occurs does not adversely affect rate of metastases or compromise survival Imp implications for design of trials aimed at bladder conservation (4 randomised trials)

High Risk Factors After Cystectomy

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Deep muscle invasion or extravesical spread Prostate or adjacent organ involvement High grade or undiff histology Lymphatic or vascular emboli Lymph node metastases +ve surgical cut margins (Residual) Adjuvant therapy indicated

Prostatic Involvement

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Primary adenoca of prostate 25% in Western literature <3% in India Secondary involvement of prostate by TCC: Prostatic urethra or stroma or glandular: Prognostic imp Imp to plan diversion & adjuvant therapy

Invasive Bladder Cancer Adjuvant Chemotherapy

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Basis : 50% develop distant mets despite adequate local therapy within 2 years Indications : Stage pT3-T4 / N+ tumours Poorly diff tumours Regimen : M-VAC, CMV, CISCA Survival advantage in subgroup of locally advanced disease & limited nodal mets disease (Skinner 1991, Stockle 1992) Gives accurate staging Does not delay local treatment

Invasive Bladder Cancer Cystectomy + Adjuvant Chemotherapy Randomised Trials Author Chemo Regime Skinner Yes CISCA No Studer Stockle Yes No Yes Cisplat MVAC Feeiha No Yes No CMV N 44 47 37 40 23 26 25 25 TIP mo Survival 48 52 mo 24 29 mo NA NA 66 57% 54% 40% 18 37 12 18% 63 mo 36 mo

Bladder Cancer T2-T3

Presently, no data to support the role of adjuvant chemo in muscle invasive but organ confined (T2-T3a) without node involvement

Invasive Bladder Cancer Chemo : Observations (Herr 1989)

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30 patients had cystectomy post - MVAC 10 patients had no disease in cystectomy specimens POTENTIAL BLADDER PRESERVATION 33%

Invasive Bladder Cancer Chemo : Is bladder saving possible?

20 patients refused surgery post-MVAC 6 disease free 5 required TUR-BT 4 required cystectomy 5 developed distant mets In 11/20 (55%), bladder could be saved (Herr 1989)

Bladder Cancer Neoadjuvant Chemotherapy

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Treatment of micrometastases to improve overall survival Treatment of local tumour permitting organ preservation Determination of chemosensitivity in vivo More efficient & higher drug delivery Problems : Progression of disease Delay in curative local therapies Toxicity of chemo Accurate staging not obtained

Neoadjuvant Chemotherapy in invasive bladder cancer

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Meta-analysis of 2688 pts data from 10 RCTs Platinum based combination chemo showed significant benefit in OAS 13% reduction in death 5% absolute benefit at 5 years (45% to 50%) Benefit mainly in patients with p0 disease Effect irrespective of type of local therapy Trend towards better survival with single agent cisplat but combination significantly better than single agent cisplat (ABC Meta-analysis Collaboration Lancet 2003) “New Standard of Care”

ABC Metaanalysis Collaboration 2003

ABC Metaanalysis Collaboration 2003

ABC Metaanalysis Collaboration 2003

ABC Metaanalysis Collaboration 2003

Invasive Bladder Cancer Treatment : Cumulative cCR Modality RT alone Chemo alone TUR + Chemo TUR + Chemo + RT N 721 301 225 218 cCR % 45 27 51 71

T2-T4 Bladder Cancer Chemo + RT + Rad Cystectomy No of patients 106

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40% Bladder preservation 52% 5 year survival 63% T2 45% T3-T4 66% free of distant mets CR with TUR+Chemo+RT higher than TUR+Chemo (Zietman MGH 1998)

Bladder Conservation Protocol

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Combination of chemo & radiotherapy cCR after TUR + chemoradiation 74% 5 year survival with intact bladder 36-44% Survivals comparable to rad surgery in selected patients 20-30% develop superficial relapses Long term regular cystoscopic follow up must

Bladder conservation protocol

T2-3 Nx M0 TCC TUR whenever possible 2-3 cycles of neoadjuvant chemo (M-VAC / cisplat+gemcite) Cystoscopy with biopsy Urine cytology CT scan Responders Non-responders Cons RT + chemo Rad Cystectomy

Bladder Conservation Approach Case Selection

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T2/T3a tumours Unifocal tumours Absence of associated diffuse Tis Good bladder capacity Low chance of metastatic disease CR after chemoradiation RB+ve, p53-ve tumours Prospective randomised trials essential to compare value & safety with cystectomy

Series Tester Bladder Conservation Protocols Results Therapy DDP/RT N 42 5 yr surv % 52 Surv % BladCo 41 Dunst Tester Kahnic Given Srougi Sternberg MSKCC TUR + DDP/RT MCV + DDP/RT TUR+MCV+DDP/RT TUR+MCV+DDP/RT MVAC + PC MVAC + TUR MVAC + Cons Surg 79 106 93 30 66 111 52 62 52 51 53 -- 48 41 44 43 18 20 33 30 Results need to be confirmed in RCT (EORTC) Value in Bladder substitution era undefined

T2-T4 Bladder Cancer N = 53 TUR + CMV 2 + RT 4000 R Rad Cyst 10 28 CR RT 2480 R 58% Bladder preservation 48% Actuarial 5 yr survival 68% T2 30% T3-T4 58% 5 yr survival treatment complete 14% 5 yr survival treatment incomplete (Kaufman-Shipley MGH 1993)

Bladder Conservation : Results TMH Data

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CR 24.1% : More common with T2 & low grade tumors, PR 37.9% (RR 62%) RR unchanged with chemo regimen Bladder preservation possible in 51.7% at completion of primary treatment 41.4% had intact bladder till last follow up 34.5% alive with intact bladder at mean follow up of 46 months 5 year survival 63% in bladder conservation group vs. 50% in cystectomy group (p=NS) : No adverse effect on survival

Urinary Diversion Vs Bladder substitution

Neobladder

Continent urinary reservoir made from an intestinal segment & anastomosed orthotopically to urethra Urine passed via natural passage with voluntary control

Bladder Substitution (Neobladder)

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Pioneering work in India (1987) : Bombay pouch.

Developed & standardised procedure Large experience of over 130 neobladders using different bowel segments Long follow up of up to 15 years Functional, morbidity & oncological outcomes comparable with the best reported in the literature

25 20 15 10 5 0 50 45 40 35 30 Ileocolonic Neobladder Continence at 6 mo.

47 39 Complete 4 91% continent during day 12.5% have nocturnal leakage 12 Partial 1 Incont 1

Neobladder : Continence Review of literature

Segment No Hautmann 363 Hautmann 68 Mainz 108 Studer 89 Studer Kock Camey II Overall 192 295 58 1171 Daytime Nighttime % CSIC 84 66 6 92 71 97 55 45 74 31 15 -- 93 65 91 81 84 44 72 62 -- 9 -- 11