1. Non Surgical Management
of Bladder Cancer
Dr Sujay Susikar
Post Graduate Student
Department of Surgical Oncology
Government Royapettah Hospital

2. Bladder Cancer
Staging

3. Bladder cancer
Stage and Prognosis
Stage TNM 5-y. Survival
0 Ta/Tis NoMo >85%
I T1 NoMo 65-75%
II T2a-b NoMo 57%
III T3a-4a NoMo 31%
IV T4b NoMo 24%
any T N+Mo 14%
any T M+ med. 6-9 Mo

4. Superficial Bladder Cancer
Treatment
Transurethral resection of
bladder tumour
Identify high risk factors
Adjuvant intravesical treatment

5. Superficial Bladder Cancer
Problems in Management
 Local relapse after adequate TUR 70-80%
 Progression to muscle invasion 20%

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

7. Random Mucosal Biopsies
In 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. Fluoroscent cystoscopy and
photodynamic therapy
 Photoactive porphyrins
preferentially
accumulating in
neoplastic tissue
 Under blue light – red
fluoroscence
 Small papillary tumors
and CIS identified
 Use of Porfimer sodium
and ALA concentration
and ablation with light

10. Superficial Bladder Cancer
Factors 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. Superficial Bladder Cancer
Risk Grouping
Low risk:
 Ta G1 Single <3 cm tumor with recurrence 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/ BCG & to continue
intravesical therapy in high & intermediate risk

12. Immunotherapy
 Intravesical agents – massive local immune response
– induced by expression of cytokines and influx of
granulocytes and mononuclear cells
 BCG – most commonly used
 Interferon – inferior to BCG
 Other investigational agents:
 Keyhole Limpet Hemocyanin (KLH)
 Bropirimine
 Mycobacterial cell wall DNA extract
 Thiosulfinate extracts of garlic

13. Intravesical BCG
Technique:
 Vaccine reconstituted with 50 ml saline and
administered through a urethral catheter
 2 – 4 weeks after TUR to allow reepithelization to
occur
 Treatment delayed for several days in event of
traumatic catheterization
 Solution retained for 2 hours
 Fluid diuretic and caffeine restriction,
 oral desmopressin 200µg - 1 hour before
administration

14. Intravesical BCG
Indications:
 CIS
 Treatment of residual tumor (after repeat TURBT)
 To prevent recurrence and progression (16% Vs 40%
recurrence and 4.4% Vs 40% progression)
Optimum BCG treatment schedule:
 Usefulness of maintanence therapy
 6 week induction course of weekly BCG f/b 3 weekly
instillations at 3 and 6 months and every 6 months for 3
years

15. Intravesical chemotherapy
 Induction therapy – instilled
within 6 hours of TURBT –
clear impact on survival
 Less effective than BCG in
reducing progression rate ( 15%
Vs 37%) *
 No infective complication
Hamm et al, 1991

16. Intravesical therapy
complications – general
 Frequency
 Dysuria
 Irritative voiding symptoms
 Long term – bladder contracture

17. Intravesical therapy
complications – drug specific
BCG Mitomycin C
 Skin desquammation
 Fever
 Rash
 Joint pain
 Granulomatous Thiotepa
 Myelosupression
prostatitis
 Sinus formation Doxorubicin
 Disseminated  GI upset
tuberculosis  Allergic reactions
 Death

18. Carcinoma-in-situ of Bladder
 Flat intraepithelial neoplasm of high histologic
grade (Melicow 1952)
 Exists in 2 forms
Aggressive:
Non-aggressive
 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

19. CIS Bladder: Natural History
 Not clearly understood
Some - 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 different
 Risk of progression to muscle invasion:
Focal CIS 8%
Diffuse CIS 78%
 High reccurence & progression rate despite standard
definitive therapy: Poor prognosis

20. Carcinoma-in-situ of Bladder
Treatment Options
 Transurethral resection
 Immediate cystectomy
 Intravesical
chemotherapy
 Intravesical
immunotherapy

21. CIS Bladder: Management
 TUR: High recurrence rate (80-100%),
progression rate (50-80%) &
mortality (30-40%)
since: Lesion not visible endoscopically
Ill-defined margins
Too extensive to treat
Associated with muscle invasion in many
 Immediate cystectomy:
Advocated since CIS associated with invasive tumour in
majority
65-80% survival
Results not different if cystectomy done after failure of
intravesical therapy

22. 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

23. Invasive bladder cancer
 Standard of care
Radical cystectomy with pelvic
lymphadenectomy
Only about 50% of patients with high-grade invasive
disease are cured

24. Invasive bladder cancer
 Adjuncts to standard surgical therapy
 Alternatives to standard surgical therapy

25. Muscle Invasive Bladder Cancer
Options of Management
 Radical Cystectomy
 Pre-op Radiotherapy + Surgery
 Radical Radiation Therapy
 Neoadjuvant Chemotherapy + Surgery
 Surgery +Chemotherapy
 Combined Chemo + Radiation therapy
in selected patients

26. Invasive Bladder Cancer
Pre-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
 MD Anderson Trial : Reduces pelvic relapses in T3b patients
(28% vs 9%) No survival benefit
 Meta-analysis : 10% survival advantage *
* ABC Meta-analysis Collaboration. Lancet 2003;361:1927

27. Invasive Bladder Cancer
Radical 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 = good survival
 Salvage cystectomy for residual / recurrent disease
 Cystitis, proctitis, sexual dysfunction common

28. Chemotherapy for bladder cancer
 Bladder cancer is a chemosensitive disease
 Active single agents.
RR
 Cisplatin 30%
 Carboplatin 20%
 Gemcitabine 20-30%
 Ifosfamide 20%

29. Chemotherapy for bladder cancer
Combination chemotherapy.
RR CR
 MVAC 40-75% <20%
 Gemzar / Cisplatin 40-70% 5-15%
 Gemzar / Carboplatin 65% 5%
 Taxol / Carboplatin 20-40%

30. High Risk Factors After Cystectomy
 Deep muscle invasion or extravesical spread
 Prostate or adjacent organ involvement
 High grade or undifferentiated histology
 Lymphatic or vascular emboli
 Lymph node metastases
 Positive surgical cut margins (Residual)
Adjuvant therapy indicated

31. Adjuvant chemotherapy
 Six randomised trials have compared chemotherapy with
observation after cystectomy or RT
4 - no survival benefit
2 - benefit from adjuvant CT
no standard of care
 node positive disease,
 lymphovascular invasion,
 positive margins,
 Stage pT3-T4 / N+ tumours,
 poorly differentiated tumours

32. Invasive Bladder Cancer
Adjuvant Chemotherapy
 Basis : 50% develop distant mets despite adequate
local therapy within 2 years
 Regimen : M-VAC, CMV, CISCA
 Survival advantage in subgroup of locally advanced
disease & limited nodal metastatic disease (Skinner
1991, Stockle 1992)
 Does not delay local treatment

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

34. 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

35. Bladder Cancer
Neoadjuvant Chemotherapy
Rationale :
 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

36. Neoadjuvant chemotherapy
 Meta-analysis of ten randomised trials
(2688 patients)
13% reduction in risk of death
5% absolute benefit at 5 years
OS increased from 45% to 50%
ABC Meta-analysis Collaboration. Lancet 2003;361:1927

37. Invasive Bladder Cancer
Chemo : Observations
(Herr 1989)
 30 patients had cystectomy post - MVAC
 10 patients had no disease in cystectomy specimens
POTENTIAL BLADDER PRESERVATION
33%

38. 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)

39. Invasive Bladder Cancer
Salvage 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

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

41. Combined Radio- and Chemotherapy
CR 5y.OS
 Radiotherapy 57% 47%
 RT and cisplatin 85% 69%
 RT and carboplatin 70% 57%
Birkenhake et al. Strahlenther Onkol 1998;174:121

42. Bladder-sparing therapy for invasive
bladder cancer
 High probability of subsequent distant metastasis after
cystectomy or radiotherapy alone (50% within 2 years)
 Radiotherapy im comparison with cystectomy has
inferior results (local control 40%)
 Muscle-invasive bladder cancer is often a systemic
disease
→ combined modality therapy

43. T2-T4 Bladder Cancer
Chemo + 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 TUR+Chemo+RT higher than
TUR+Chemo
(Zietman MGH 1998)

44. Bladder-sparing protocol
Transurthral resection
Induction Therapy: Radiation + chemotherapy
(cisplatin, paclitacel)
Cystoscopy after 1 month
no tumor tumor
Consolidation: RT + CT cystectomy

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

46. 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
 RB+ve, p53-ve tumours
Prospective randomised trials essential
to compare oncologic value with cystectomy

47. Bladder Conservation Approach
contraindications
 Hydronephrosis
 Multifocal disease
 Irritative bladder symptoms
 Low capacity bladder

48. Conclusion
 All suspicious lesions should be sampled, but
“random” biopsies are not required in low-risk
patients
 Single-dose intravesical chemotherapy
administered within 6 hours of resection reduces
recurrence rates by up to 50%.
 Intravesical BCG has higher efficacy against CIS
and disease recurrence but more frequent and
potentially more serious side effects

49. Conclusion
 Intravesical chemotherapy used preferentially
over BCG for low-risk disease
 Low risk: Ta G1 Single <3 cm tumor with
recurrence rate <1/ year
 High risk: T1 G3 Multifocal Large Highly
recurrent & Tis
 Intermediate: All others TaT1 G1-2 >3 cm

50. Conclusion
 Adjuvant chemo and RT – useful in high risk
patients
 Bladder preservation – viable option in carefully
selected patients