Management of carcinomas of urinary bladder

comprehensive Management of Carcinoma of urinary bladder

1. Management of carcinomas of Urinary Bladder Dr. Shashank Bansal JR-2, MD Radiotherapy Dr.B Borooah Cancer Institute A unit of TMH, Mumbai Dr. A K Kalita Prof. and HOD Deptt . Of Radiotherapy Dr.B Borooah Cancer Institute A unit of TMH, Mumbai

2. Anatomy

3. INDIA 16273 cases 1.6% GLOBOCAN 2012

4. Epidemiology Median Age of presentation is 70 yrs More common in males than females Risk factors: Smoking (TCC) Nephrolithiasis, UTI Chemical exposure (Aromatic amines, polycyclic aromatic and chlorinated hydrocarbons, arsenic laced drinking water, cyclophosphamide exposure) Prior pelvic irradiation Schistomsoma heamotobium infection (SCC)

5. Histology Histologic subtypes Urothelial carcinoma (Transitional cell carcinoma)[m/c] SCC Adenocarcinoma Small cell tumors History Most common presentation is pain less haematuria. Transitional cell carcinoma showing nested pattern of invasion

6. Work-up CBC, RFT, LFT Urine cytology and cystoscopy CT/MRI of abdomen and pelvis, ideally prior to biopsy. Perform Transurethral resection of bladder tumor (TURBT) and EUA. Image of upper urinary tract (CT/MRI urography, intravenous pyelogram , renal US, retrograde pyelogram or ureteroscopy ) if biopsy proven malignancy . Chest X-ray and Bone scan* BIOPSY SPECIMEN SHOULD CONTAIN MUSCLE FOR PROPER STAGING OF TUMOR.

7. 8 TH Edition

8. Management NMIBC (non muscle invasive bladder cancer ) Tis, Ta, T1 MIBC (muscle invasive bladder cancer) T2 onwards, N1 Metastatic cases M1

9. NMIBC Aim : prevent recurrence Disease progression to a life threatening stage Modality TURBT standard of care Adjuvant intra vesicle therapy – immunotherapy/ chemotherapy

10. TURBT

11. TURBT- NMIBC scoring LOW RISK Tumor <3 cm Grade 1 disease T1a with e/o CIS 15% chance of Recu . 0.2 % risk of progression INTERMEDIATE RISK Multiple grade 1 tumours Multiple grade II tumours, stage Ta Single grade II, stage T1 38% chance of recurrence 5% risk of progression HIGH RISK Stage Ta or T1 Grade III CIS 61% recurrence risk 17% progression risk.

12. Observation : Completely resected Ta Grade 1 No abnormal cytology in urine cytology Indications of Adjuvant therapy CIS associated with Ta or T1 tumours Any grade G3 tumour Multifocal tumours Rapidly recurring after TURBT Urothelial carcinoma involving the prostatic mucosa or ducts

13. BCG : live attenuated strain of mycobacterium MOA: triggers inflammatory cascade, inducing neutrophil and Th1 chemotaxis Reconstituted with 50 ml of saline and administered through urethral catheter Treatment begin 2-4 wks after tumour resection After instillation the patient should retain the solution for 2 hours.

14. Schedule Induction Weekly for 6 wks intravesically Cystoscopy with urine cytology and possible biopsy should be done to confirm the recurrence or progression at 3 months Maintenance SWOG regimen of 3 weekly instillations at 3, 6 and every 6 months for 3 years All guidelines and meta analysis recommend at least one year of BCG maintenance therapy Complete remission is obtained in up to 70 % of cases If cytology and biopsies remain positive, another cycle may produce an additional 15% complete remission.

15. Other Agents ( Intravesical ) Chemotherapeutic Agent MOA Mitomycin C Antibiotic; inhibits DNA synthesis Thiotepa Alkylating agent; cross links nucleic acids Doxorubicin/ Valrubicin Topoisomerase inhibitors; intercalating agents; inhibit DNA synthesis Immunotherapy MOA BCG T-helper type 1 immune response Interferon (With BCG) Activates T-helper type 1 immune response

16. Cystectomy in NMIBC Ta Low or intermediate risk disease– if bladder sparing modalities have failed In a high risk patient with multiple recurrent tumours or T1 tumours with associated CIS, LVI, or variant histologies In a high risk patient with persistent or recurrent disease with one year following treatment with two induction cycles of BCG or BCG maintenance. NO ROLE OF RT IN NMIBC

17. MIBC TREATMENT OPTIONS RADICAL CYSTECTOMY WITH URINARY RECONSTRUCTION BLADDER PRESERVATION PROTOCOLS RELAPSE OR PROGRESSION If left untreated 85%patent may die within 2 yrs NO diff in OS, cause specific survival and distant recurrence free survival

18. Surgery RADICAL CYSTECTOMY (bladder, distal ureters, pelvic peritoneum, prostate, seminal vesicle, uterus, FT, ovaries, and anterior vaginal wall) BLADDER PRESERVATION SUREGRY

19. INDICATIONS FOR RADICAL CYSTECTOMY MIBC (cT2-T4aN0M0) NMIBC G3 disease is multifocal or associated with CIS When bladder tumor rapidly recurs, in multifocal areas following intravesical drug therapy Histological variants : squamous cell carcinoma , adenocarcinoma and sarcomatoid or spindle cell carcinoma Palliation for pain, bleeding or urinary frequency 5 ys OS after RC is 60% for T2 and 40% for T3-T4a

20. CYSTECTOMY NOT BE DONE : LN metastases are unresectable because of bulk or proximal extent above the common iliac vessels There is evidence of extensive peri -ureteral disease The bladder is fixed to the pelvic sidewall or Tumour is invading the recto sigmoid colon . LYMPHADENECTOMY Include : obturator , hypogastric, presciatic , presacral lymph nodes. Minimum 15 lymph nodes should be removed

21. Diagram showing boundaries of pelvic lymphadenectomy

22. NEO ADJUVANT THERAPY CHEMOTHERAPY(ASCO) Neo-adjuvant chemotherapy is recommended for T2-T4a, cN0M0 bladder cancer Recommended use of three cycles o f Cisplatin based combination chemotherapy. Specifically M-VAC or CMV RADIOTHERAPY Preoperative radiotherapy has not shown to improve survival Preoperative radiotherapy for operable MIBC can result in tumour down staging after 4-6 wks.

23. NACT TRIALS SWOG : 2 arms Surgery (median survival) – 3.8 yrs NACT f/b surgery- 6.2 yrs UK/ EORTC TRIAL CMV  SURGERY CMV  RT 16% reduction in risk of distant metastasis10 yr survival increased from 30- 36% 3 yr survival increased from 5056%

24. Platinum-based combination chemotherapy 5 % absolute benefit at 5 years ( overall survival increased from 45% to 50%). This effect was observed irrespective of the type of local treatment, and did not vary between subgroups of patients

25. ADJUVANT THERAPY CHEMOTHERAPY NCCN recommends adjuvant chemo if Neo-adjuvant chemo was not given Indications: T3 or more Node positive Positive Margins Benefit for OS and DFS in MIBC patients who underwent adjuvant chemotherapy after radical cystectomy compared with those who underwent surgery alone. Lymph node positive patients benefit more than lymph node negative in terms of DFS. Beneficial role of Cisplatin based adjuvant chemo in MIBC.

26. Adjuvant Radiotherapy No strong supporting RT in the adjuvant setting. May be given in cases of high risk for loco-regional relapse. Positive surgical margins Tumour spillage Post-operative radiation is indicated in the setting of positive surgical margin after partial cystectomy. If pelvic lymph nodes are known to be negative the whole bladder and abdominal wall incision– dose of 40Gy (45Gy without concurrent CT.) With a cone down boost for a total of 56 Gy high risk area.

27. BLADDER PRESERVATION STRATEGIES CONSERVATIVE STRATEGY Partial Cystectomy TURBT Radical EBRT +/- Brachytherapy boost. Combined modality treatment Chemo + TURBT/Partial cystectomy Tri-modality : Maximal TURBT, Chemotherapy and Radiotherapy.

28. Partial Cystectomy Local recurrence rates range from 38 to 78% Rarely performed. TURBT alone is usually not sufficient for MIBC.

29. One of the legendry bollywood Actor Lost his battle against Bladder cancer

30. Radical RT Factors having significant favourable effect on local control with radiotherapy Early clinical stage (T2 and T3a) Absence of ureteral obstruction Visibly complete TURBT Small tumour size (<5cm) solitary, papillary/ sessile absence of coexisting carcinoma in situ.

31. Brachytherapy Reports adressing this approach mention high cure rates (70-90%), with excellent bladder preservation (1) Limitations : Urinary leakage , wound infection, radiation exposure , increased hospital stay . Indications: solitary (<5cm), T1G3,T2b (TNM1997) Method EBRT SURGERY  LYMPHADENECTOMY  CATHETER PALCEMENT PERCUT. CATH. REMOVAL

32. Trimodality therapy (TURBT+CHEMO+RT) Ideal candidate Primary T2-T3 tumours that are unifocal Tumour size less than 5 cm in maximum diameter Tumour not associated with extensive CIS No presence of ureteral obstruction or tumour associated hypderonephrosis . Good capacity of the bladder Visibly complete TURBT Adequate renal function to allow Cisplatin to be given concurrently with irradiation.

33. Continuous course paradigm Split course paradigm

34. RTOG CONCLUSIONS Combined modality provide better bladder preservation Cisplatin was the best sensitizer Safe and easily administered Altered fractionation especially accelerated fractionation has given better control rates in phase 2 trial.

35. CYSTECTOMY V/S TRIMODALTY TREATMENT

36. Radiotherapy Concurrent chemo-radiation as a part of multimodality bladder sparing protocol in T2-T4N0M0. Radical RT in inoperable cases. Neo adjuvant radiotherapy Adjuvant radiotherapy Pelvic recurrence after radical cystectomy. Palliative Radiotherapy for metastatic disease.

37. Phase 1- The whole pelvis , encompassing the pelvic lymph nodes, bladder and proximal urethra Elective irradiation of the pelvic lymph nodes Phase 2- Then cone down to boost the bladder alone Conventional planning B ladder localisation Foley catheter inserted shortly after the patient has voided. Post voiding urine residual is measured This volume is replaced by an equal volume of bladder contrast plus an additional 25 mL of contrast and 15 mL of air . The patient is immobilized in a supine position.

38. BOOST PORTALS Anterior : bladder with a margin of 1.5-2 cm Lateral – bladder with a margin of 1.5-2cm Oblique – selected at an angle which spares the rectum completely and encompasses the bladder with 1.5 cm margin. Fields 2 lateral and one anterior 2 oblique's and one anterior Dose : 60-66 Gy to bladder

39. FILED ARANGEMENTS

40. Conformal Radiotherapy PLANNING CT: Supine, arms on chest Knee and ankle immobilization Empty rectum Empty bladder 15 mins before The scan is performed with 3-5 mm slices from the lower border of L5 to the inferior border of the ischial tuberosities . All planning and treatment should be carried out with the bladder empty.

41. Contouring guidelines GTV : primary tumour CTV : whole bladder and any extra-vesicle extension Men : entire prostate Women : the proximal 2 cm of urethra is also considered s apart of target field PTV : 1.5-2 cm around CTV

42. NODAL DELINEATION

43. CONTOURING IN POST-OP (RTOG)

44. DOSE : A total dose of 45 Gy is delivered to the pelvis and 55-70 Gy to the bladder tumour bed, achieving favourable rates of local control Total RT dose is important for loco-regional control. Hyperfractioned RT schemes, provide a higher local control in relation to the conventional RT ( Naslund martin etal ) Accelerated and hypofractionated RT schemes are not recommended and may present higher toxicity.

45. Conformal planning is the standard of care IMRT offers increased conformity and potential dosimetric improvements to organ at risk .(van rooijen etal ). IMRT can be used in selected cases to boost defined gross disease. Helical tomotherapy had statistically significant better organ sparing results (Hsieh et al) Disadvantage include : Prolonged treatment delivery time , increased MU, the close delineation of the radiation field to the tumor might lead to higher risk of geographic miss

46. RT IN RECURRENCE AFTER CYSTECTOMY Proximal urethral recurrence with CRT  65-70Gy. For pelvic sidewall recurrences, the dose are limited by the presence of small bowel in the field. Still radiation with concurrent C isplatin can be given to doses tolerated by the intestine, ileal loop and stoma, usually 50-60Gy.

47. PALLIATIVE RT For rapid pain relief Hematuria Painful bony metastasis Dose 30Gy/10#/2wks or 8Gy single # or 20Gy/5#/1wk. Palliation to inoperable patients, when not suitable for chemo.

48. TOXICITY Acute effects Dysuria Urgency Frequency Diarrhea Chronic effects Cystitis Hemorrhagic cystitis Bladder contracture Rectal stricture Small bowel obstruction. 79 % of patients have normal bladder function at 10 yrs

49. Metastatic disease

50. Regimens : 1 st Line MVAC Gemcitabine and Cisplatin Regimen

51. T reatment Summary

52. THANKS