Advances in the Diagnosis and Management of Bladder Cancer

1. Advances in the Diagnosis and Management of Bladder Cancer Mr C Dawson MS FRCS Consultant Urologist Edith Cavell Hospital Peterborough

2. Advances in the Diagnosis and Management of Bladder Cancer Mr C Dawson MS FRCS Consultant Urologist Fitzwilliam Hospital Peterborough

3. Overview • Traditional methods of diagnosis • Current Management of bladder cancer • Advances in the diagnosis of bladder cancer • Advances in the management of bladder cancer

4. Diagnosis of bladder Cancer • History • Painless haematuria • Irritative symptoms? • [flank pain] • Other Urological problems? • Previous Urological history?

5. Microscopic haematuria • Often discovered incidentally • Urological or Nephrological cause? • Dipsticks are sensitive, but false positives may occur

6. Microscopic haematuria • Microscopy will show whether casts or protein are present • Phase contrast microscopy helpful to determine nephrological cause

7. Diagnosis of bladder Cancer • Examination - N.B. DRE in men • Investigations • MSU • Urinary cytology • IVP / Renal ultrasound with KUB • Cystoscopy - Flexible vs Rigid

8. Management of bladder cancer • Depends on Stage of disease • Adequate TURBT and biopsy • Further investigation e.g. CT

9. Stage of Bladder cancer at presentation

10. Superficial Bladder Cancer Stages Ta/T1 • Surveillance +/- TUR or cystodiathermy • Interval at which cystoscopy takes place is variable • Rationale is to spot invasive change early • Multifocal tumours or repeated recurrence can be treated with intravesical chemotherapy • N.B. High grade T1 tumours are a special case - up to 50% will become invasive

11. Invasive Bladder Cancer Stages T2-T3 • Cystectomy + ileal conduit is the gold standard, but many patients will already have micrometastases • Radiotherapy (alone) does not cure locally invasive disease. Neoadjuvant radiotherapy does not appear to improve the results of cystectomy

12. Invasive Bladder Cancer Stages T4 and Metastatic disease • Chemotherapy; responses to single drugs short-lived and incomplete • Greater success with combination of drugs e.g. M-VAC • Treatment is toxic but selected patients have shown long-term and complete responses

13. Carcinoma in Situ Tis / Cis • Classified as Superficial but should be considered along with malignant disease • High rate of progression to invasive disease • Once treatable only by cystectomy, now managed initially by intravesical chemotherapy

14. Advances in the Diagnosis and Investigation of Bladder Cancer • Molecular Genetics of Bladder Cancer • Prognostic Markers • BTA test

15. Molecular Genetics of Bladder Cancer • No single chromosome alteration consistently observed but loss of 9q is a frequent early event - ? the site of a suppressor gene • Loss of chromosomes 11p and 17q are associated with higher stage disease, ? associated with loss of p53 gene

16. Independent markers of progression • Epidermal Growth Factor receptor sensitive and specific in predicting progression in pT1G3 tumours • p53 overexpression may serve as an important prognostic factor for Cis • E-cadherin can function as an invasion suppressor. Loss of E-cadherin associated with worse prognosis

17. Bladder Tumour Antigen(BTA) Test • Detects basement membrane complexes shed into urine by the action of tumour cell collagenases • Latex spheres coated with modified human IgG antibodies • Positive agglutination reaction traps blue dye, leaving yellow dye free to migrate

18. Advances in the Management of Bladder Cancer • Intravesical Therapy • Bladder reconstruction and replacement • Photodynamic Therapy

19. Intravesical Therapy • Indicated as prophylaxis to reduce recurrence and tumour progression in high risk cases • Previous recurrence • Multiple tumours • High grade tumours • Carcinoma in situ

20. Intravesical Therapy • Intravesical Chemotherapy • eg thiotepa, Mitomycin C, Doxorubicin (Adriamycin) • Intravesical Immunotherapy • Bacillus Calmette et Guerin (BCG)

21. Intravesical Chemotherapy • 7 year data with Mitomycin C shows that instillation at presentation after TURBT effectively reduces risk of recurrence and risk of progression. • Four subsequent doses at 3/12 intervals may have further protective effect

22. Intravesical Immunotherapy • BCG is an attenuated strain of M. bovis • Believed to exert anti-tumour effect through immune mechanism • BCG induces a weak granulomatous response in bladder and correlation exists between granuloma formation and favourable response

23. Intravesical Immunotherapy • Has been used for • prophylaxis in tumour free patients • treatment of residual tumour in patients with papillary TCC and no Cis • Treatment of Cis

24. Results of BCG treatment of Cis • Complete response rate in short term of up to 72% • Long term studies have reported favourable response rates in up to 89% • Those who fail to respond to initial therapy may respond to more intense regimen, but failure to respond at this stage may necessitate early cystectomy

25. Side effects of BCG therapy • Include • Dysuria (91%) • Frequency (90%) • Haematuria (46%) • Severe reactions requiring anti TB therapy occur in 6% patients

26. Bladder Reconstruction and Replacement • Advances in anaesthetic and surgical techniques have led to alternatives to ileal conduit after radical cystectomy • Choices now include • Substitution cystoplasty • Continent diversion

27. Substitution Cystoplasty • Creation of a new reservoir from bowel segment(s) • Ileum, ileo-caecum, or colon may be used • Ureters implanted at proximal end and neo-bladder is sutured to bladder neck

28. Substitution Cystoplasty

29. Continent Diversion • Used when neobladder can not be sutured to bladder neck • Tubularised ureter, ileum, or appendix used to provide channel for catheterisation • Neobladder emptied by intermittent catheterisation

30. Continent Diversion

31. Complications of bladder reconstruction • Laparotomy in 10%, usually for bowel obstruction • Stone formation in 8% • Hyperchloraemic metabolic acidosis • Stomal stenosis • ?Risk of tumours

32. Photodynamic Therapy • Chemical photosensitisation of tumour cells, which concentrate the photosensitiser • Optical fibre placed in bladder down a cystoscope and laser light stimulates the sensitised cells • Complete response rates reported in up to 80%, but follow up remains short

33. Summary • Tumour Stage and Grade remain important prognostic indicators but genetic information is shedding light on tumour genesis • Intravesical chemotherapy and immunotherapy provides effective treatment for many superficial bladder tumours

34. Summary • Ileal conduit may be avoided by bladder substitution or continent diversion • Newer treatment modalities such as photodynamic therapy may soon be available

35. The problem !