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

4. • INDIA
– 16273 cases
– 1.6%
GLOBOCAN 2012

5. 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)

6. 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

7. 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.

8. 8TH Edition

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

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

12. TURBT

13. 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.

14. • 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

15. • 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.

16. • 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.

17. 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

18. • 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

19. 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

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

21. • 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

22. • 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

23. Diagram showing boundaries of pelvic lymphadenectomy

24. NEO ADJUVANT THERAPY
• CHEMOTHERAPY(ASCO)
– Neo-adjuvant chemotherapy is recommended for T2-
T4a, cN0M0 bladder cancer
– Recommended use of three cycles of 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.

25. 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%

26. • 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

27. 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.

28. • 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.

29. 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.

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

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

32. • 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.

33. • 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

35. • 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.

36. • Continuous
course paradigm
• Split course
paradigm

38. • 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.

39. CYSTECTOMY V/S TRIMODALTY
TREATMENT

40. 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.

41. • 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
– Bladder 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.

43. • 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

44. FILED ARANGEMENTS

45. • 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.

46. • 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

48. NODAL DELINEATION

49. CONTOURING IN POST-OP (RTOG)

50. • 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.

51. • 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

52. 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 Cisplatin can be
given to doses tolerated by the intestine, ileal
loop and stoma, usually 50-60Gy.

53. 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.

54. 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

55. Metastatic disease

56. • Regimens :
– 1st Line
– MVAC
– Gemcitabine and Cisplatin Regimen

57. Treatment Summary