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Surgical Management of Bladder Cancer

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Title: Surgical Management of Bladder Cancer


1
Surgical Management of Bladder Cancer
Dr. Hemant B. Tongaonkar
Professor Head, Genitourinary Gynecologic
Oncology Tata Memorial Hospital, Mumbai
2
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

3
Bladder CancerInvestigations
  • Urine Cytology
  • Excretory Urography
  • Cystoscopy Biopsy of tumour
  • Bimanual Examination
  • Ultrasonography
  • CT Scan Abdomen Pelvis
  • Metastatic Work-up

4
Bladder CancerStaging
5
Superficial Bladder Cancer Treatment
Transurethral resection of bladder tumours

Multiple random punch biopsies from bladder
prostatic urethra
To identify high risk factors
6
Superficial Bladder CancerAim of Treatment
Identify risk factors to predict natural history
  • Low risk
  • Observe
  • High risk
  • Aggressive treatment
  • Prophylactic therapy
  • Close monitoring

7
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

8
Sites for selected mucosal biopsies in TUR
9
Superficial Bladder CancerProblems in Management
  • Local relapse after adequate TUR 70-80
  • Progression to muscle invasion 20

10
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

11
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

12
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

13
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

14
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

15
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

16
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

17
Superficial Bladder CancerIntravesical Therapy
  • High risk of recurrence
  • Chemotherapy
  • Thiotepa
  • Doxorubicin
  • Epirubicin
  • Mitomycin
  • Ethoglucid
  • High risk of progression
  • Immunotherapy
  • BCG
  • Interferon
  • Interleukin-2
  • KLH

18
Superficial Bladder CancerIntravesical Chemo
on Recurrence
19
Superficial Bladder CancerIntravesical BCG on
recurrence
20
Superficial Bladder CancerIntravesical Chemo
on Progression
21
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

22
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

23
Intravesical BCG vs Control TMH TRIAL
DFS
24
Multivariate Analysis of Prognostic Variables
25
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

26
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

27
Carcinoma-in-situ of BladderTreatment Options
  • Transurethral resection
  • Immediate cystectomy
  • Intravesical chemotherapy
  • Intravesical immunotherapy

28
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

29
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

30
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
31
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

32
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

33
Muscle Invasive Bladder CancerRadical Cystectomy
Results
(Herr, Urol Oncol 2, 92, 1996)
34
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35
Radical CystectomyDFS vs pStage LN status
36
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

37
Extraperitoneal Radical cystectomy
38
  • Open
  • Vs
  • Laparoscopic
  • approach
  • Hand assisted approach

39
Robotic Radical Cystectomy Da Vinci
40
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

41
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

42
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

43
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
44
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

45
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)

46
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

47
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

48
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

49
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

50
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)
51
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

52
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

53
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

54
Invasive Bladder CancerCystectomy Adjuvant
ChemotherapyRandomised Trials
55
Bladder CancerT2-T3
  • Presently, no data to support
  • the role of adjuvant chemo
  • in muscle invasive
  • but organ confined (T2-T3a)
  • without node involvement

56
Invasive Bladder CancerChemo
Observations(Herr 1989)
  • 30 patients had cystectomy post - MVAC
  • 10 patients had no disease in cystectomy
    specimens
  • POTENTIAL BLADDER PRESERVATION
  • 33



57
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)

58
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

59
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

60
ABC Metaanalysis Collaboration 2003
61
ABC Metaanalysis Collaboration 2003
62
ABC Metaanalysis Collaboration 2003
63
ABC Metaanalysis Collaboration 2003
64
Invasive Bladder CancerTreatment Cumulative
cCR
65
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)

66
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

67
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
68
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
69
Bladder Conservation Protocols Results
Results need to be confirmed in RCT (EORTC) Value
in Bladder substitution era undefined
70
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)
71
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

72
Urinary Diversion Vs Bladder substitution
73
Neobladder
  • Continent urinary reservoir made from an
    intestinal segment
  • anastomosed orthotopically to urethra
  • Urine passed via natural passage with voluntary
    control

74
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

75
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76
Ileocolonic NeobladderContinence at 6 mo.
91 continent during day 12.5 have nocturnal
leakage
77
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78
Neobladder ContinenceReview of literature
79
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