non surgical therapies of bladder cancer

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non surgical therapies of bladder cancer

  1. 1. Non Surgical Management of Bladder Cancer Dr Sujay Susikar Post Graduate Student Department of Surgical Oncology Government Royapettah Hospital
  2. 2. Bladder Cancer Staging
  3. 3. Bladder cancer Stage and PrognosisStage 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. 4. Superficial Bladder Cancer Treatment Transurethral resection of bladder tumour Identify high risk factorsAdjuvant intravesical treatment
  5. 5. Superficial Bladder Cancer Problems in Management Local relapse after adequate TUR 70-80% Progression to muscle invasion 20%
  6. 6. Superficial Bladder Cancer Aim of Treatment Identify risk factors to predict natural historyLow risk High risk Aggressive treatment Prophylactic therapyObserve Close monitoring
  7. 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. 8. Sites for selected mucosal biopsies in TUR
  9. 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. 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. 11. Superficial Bladder Cancer Risk GroupingLow risk: Ta G1 Single <3 cm tumor with recurrence rate <1/ year Single post-op instillation of chemoHigh risk: T1 G3 Multifocal Large Highly recurrent & TisIntermediate: All others TaT1 G1-2 >3 cm Single post-op instillation of chemo/ BCG & to continue intravesical therapy in high & intermediate risk
  12. 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. 13. Intravesical BCGTechnique: 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. 14. Intravesical BCGIndications: 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. 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. 16. Intravesical therapy complications – general Frequency Dysuria Irritative voiding symptoms Long term – bladder contracture
  17. 17. Intravesical therapy complications – drug specificBCG Mitomycin C  Skin desquammation Fever  Rash Joint pain Granulomatous Thiotepa  Myelosupression prostatitis Sinus formation Doxorubicin Disseminated  GI upset tuberculosis  Allergic reactions Death
  18. 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. 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. 20. Carcinoma-in-situ of Bladder Treatment Options Transurethral resection Immediate cystectomy Intravesical chemotherapy Intravesical immunotherapy
  21. 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. 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. 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. 24. Invasive bladder cancer Adjuncts to standard surgical therapy Alternatives to standard surgical therapy
  25. 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. 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. 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. 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. 29. Chemotherapy for bladder cancerCombination chemotherapy. RR CR  MVAC 40-75% <20%  Gemzar / Cisplatin 40-70% 5-15%  Gemzar / Carboplatin 65% 5%  Taxol / Carboplatin 20-40%
  30. 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. 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. 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. 33. Invasive Bladder Cancer Cystectomy + Adjuvant Chemotherapy Randomised TrialsAuthor Chemo Regime N TIP mo SurvivalSkinner Yes CISCA 44 48 52 mo No 47 24 29 moStuder 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. 34. Bladder Cancer T2-T3Presently, no data to support the role of adjuvant chemo in muscle invasivebut organ confined (T2-T3a) without node involvement
  35. 35. Bladder Cancer Neoadjuvant ChemotherapyRationale : Treatment of micrometastases to improve overall survival Treatment of local tumour permitting organ preservation Determination of chemosensitivity in vivo More efficient & higher drug deliveryProblems : Progression of disease Delay in curative local therapies Toxicity of chemo Accurate staging not obtained
  36. 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. 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. 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. 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. 40. Invasive Bladder Cancer Ext Radiotherapy + Salvage CystectomyDeferring 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. 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. 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. 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. 44. Bladder-sparing protocol Transurthral resection Induction Therapy: Radiation + chemotherapy (cisplatin, paclitacel) Cystoscopy after 1 month no tumor tumorConsolidation: RT + CT cystectomy
  45. 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. 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. 47. Bladder Conservation Approach contraindications Hydronephrosis Multifocal disease Irritative bladder symptoms Low capacity bladder
  48. 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. 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. 50. Conclusion Adjuvant chemo and RT – useful in high risk patients Bladder preservation – viable option in carefully selected patients

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