Surgical Management of Bladder Cancer

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Surgical Management of Bladder Cancer
Dr. Hemant B. Tongaonkar
Professor Head, Genitourinary Gynecologic
Oncology Tata Memorial Hospital, Mumbai
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Bladder CancerEpidemiology

• 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

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Bladder CancerInvestigations

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

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Bladder CancerStaging
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Superficial Bladder Cancer Treatment
Transurethral resection of bladder tumours

Multiple random punch biopsies from bladder
prostatic urethra
To identify high risk factors
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Superficial Bladder CancerAim of Treatment
Identify risk factors to predict natural history

• Low risk
• Observe

• High risk
• Aggressive treatment
• Prophylactic therapy
• Close monitoring

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Random Mucosal BiopsiesIn Superficial Bladder
Cancer

• 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

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Sites for selected mucosal biopsies in TUR
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Superficial Bladder CancerProblems in Management

• Local relapse after adequate TUR 70-80
• Progression to muscle invasion 20

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Superficial Bladder CancerFactors Affecting
Natural History

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

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SBC Natural HistoryImpact of Tumour Grade

• Strong correlation bet tumour grade tumour
  stage
  Low grade Superficial
  High grade Invasive
• Grade I lt5 invasive at diagnosis
  Grade III 50 invasive within 2 yrs
• Strong predictor of survival
  Grade I 95 survive 5 years
  Grade III 40 survive 5 years

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SBC Natural HistoryImpact of Lamina Propria
Invasion

• 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 4 24
• British Study 0 46

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Muscularis Mucosae

• 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

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SBC Natural HistoryImpact of T Size
Multiplicity

• 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 lt
  5 cm 9
  gt 5 cm 35 progression rate

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SBC Natural HistoryImpact of Mucosal Changes

• Strong predictor of local recurrence stage
  progression
• Rec rate
• Normal Abnormal
• Althausen 3.8 78
• Heney 8.0 33

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Superficial Bladder CancerRisk Grouping

• Low risk Ta G1 Single lt3 cm tumour with rec rate
  lt1/ year Single post-op
  instillation of chemo
• High risk T1 G3 Multifocal Large Highly
  recurrent Tis
• Intermediate All others TaT1 G1-2 gt3 cm
  Single post-op instillation of
  chemo to continue intravesical therapy in high
  intermediate risk

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Superficial Bladder CancerIntravesical Therapy

• High risk of recurrence
• Chemotherapy
• Thiotepa
• Doxorubicin
• Epirubicin
• Mitomycin
• Ethoglucid

• High risk of progression
• Immunotherapy
• BCG
• Interferon
• Interleukin-2
• KLH

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Superficial Bladder CancerIntravesical Chemo
on Recurrence
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Superficial Bladder CancerIntravesical BCG on
recurrence
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Superficial Bladder CancerIntravesical Chemo
on Progression
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Superficial Bladder CancerIntravesical BCG on
Progression

• 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

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Superficial Bladder CancerIndications of
Intravesical Therapy

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

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Intravesical BCG vs Control TMH TRIAL
DFS
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Multivariate Analysis of Prognostic Variables
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Carcinoma-in-situ of Bladder

• 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

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CIS Bladder Natural History

• Not clearly understood
  Some have protracted course gt
  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 8
  Diffuse CIS 78
• High rec progression rate despite standard
  definitive therapy Poor prognosis

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Carcinoma-in-situ of BladderTreatment Options

• Transurethral resection
• Immediate cystectomy
• Intravesical chemotherapy
• Intravesical immunotherapy

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CIS Bladder Management

• 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

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CIS Bladder Management

• 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

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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
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Muscle Invasive Bladder CancerOptions of
Management

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

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Invasive Bladder CancerRadical Cystectomy

• 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

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Muscle Invasive Bladder CancerRadical Cystectomy
Results
(Herr, Urol Oncol 2, 92, 1996)
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Radical CystectomyDFS vs pStage LN status
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Partial Cystectomy

• Urachal adenocarcinoma at the dome
• 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
  

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Extraperitoneal Radical cystectomy
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• Open
• Vs
• Laparoscopic
• approach
• Hand assisted approach

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Robotic Radical Cystectomy Da Vinci
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Prostate SV sparing cystectomy

• 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

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Invasive Bladder CancerImpact of Lymphadenectomy

• 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

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Muscle Invasive Bladder CancerPrognostic Factors

• 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

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Bladder CancerNew insights into LN drainage

• 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
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Bladder CancerNew insights into LN drainage

• Tumours localised to one half 30 ve nodes
  located on contralateral side (Leissner 2004)
• Crossing lymphatic drainage in 41 of node ve
  (Mills 2001)
• Unpredictable, crossing drainage skip lesions
  support more comprehensive LND

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Which aspects of LND contribute to improved
results?

• 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)

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Non-invasive staging alternativesIdentification
localisation of nodes

• 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

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Invasive Bladder CancerPre-op Radiation Therapy

• 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 CancerRadical Radiation
Therapy

• Indications Patients unfit / unwilling for
  surgery
• Rarely, selective
  modality
• Bladder conservation
  protocols
• 55-65 Gy Target volume definition adequate
  margins important
• Initial CR (T0) 40-52
• Bladder DF 35-45 for T2-4 at 5 years
• Overall survival 25-40
• Excellent local control means good survival
• Salvage cystectomy for residual / rec disease
• Cystitis, proctitis, sexual dysfn common

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Invasive Bladder CancerSalvage Cystectomy

• 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

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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)
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High Risk Factors After Cystectomy

• 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

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Prostatic Involvement

• Primary adenoca of prostate
  25 in Western literature
  lt3 in India
• Secondary involvement of prostate by TCC
  
  Prostatic urethra or stroma or glandular
  Prognostic imp
  Imp to plan diversion adjuvant
  therapy

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Invasive Bladder CancerAdjuvant Chemotherapy

• 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

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Invasive Bladder CancerCystectomy Adjuvant
ChemotherapyRandomised Trials
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Bladder CancerT2-T3

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

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Invasive Bladder CancerChemo
Observations(Herr 1989)

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

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Invasive Bladder CancerChemo 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)
  

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Bladder CancerNeoadjuvant Chemotherapy

• 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

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Neoadjuvant Chemotherapy in invasive bladder
cancer

• 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

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ABC Metaanalysis Collaboration 2003
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ABC Metaanalysis Collaboration 2003
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ABC Metaanalysis Collaboration 2003
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ABC Metaanalysis Collaboration 2003
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Invasive Bladder CancerTreatment Cumulative
cCR
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T2-T4 Bladder CancerChemo RT Rad Cystectomy

• No of patients 106
• 40 Bladder preservation
• 52 5 year survival
• 63 T2
• 45 T3-T4
• 66 free of distant mets
• CR with TURChemoRT higher than TURChemo
• (Zietman MGH
  1998)

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Bladder Conservation Protocol

• 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

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Bladder conservation protocol
T2-3 Nx M0 TCC TUR whenever possible 2-3 cycles
of neoadjuvant chemo (M-VAC / cisplatgemcite) Cy
stoscopy with biopsy Urine cytology CT scan
Responders
Non-responders Cons RT chemo
Rad Cystectomy
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Bladder Conservation Approach Case Selection

• T2/T3a tumours
• Unifocal tumours
• Absence of associated diffuse Tis
• Good bladder capacity
• Low chance of metastatic disease
• CR after chemoradiation
• RBve, p53-ve tumours

Prospective randomised trials essential
to compare value safety with cystectomy
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Bladder Conservation Protocols Results
Results need to be confirmed in RCT (EORTC) Value
in Bladder substitution era undefined
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T2-T4 Bladder CancerN 53
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)
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Bladder Conservation ResultsTMH Data

• 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 (pNS) No adverse
  effect on survival

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Urinary Diversion Vs Bladder substitution
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Neobladder

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

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Bladder Substitution(Neobladder)

• 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

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Ileocolonic NeobladderContinence at 6 mo.
91 continent during day 12.5 have nocturnal
leakage
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Neobladder ContinenceReview of literature
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