NMIBC: non muscle invasive bladder cancer MIBC: muscle invasive bladder cancer: Metastatic Disease Surgery Chemotherapy Immunotherapy Radiotherapy EORTC bladder cancer calculator CUETO risk calculator (Spanish Urological Oncology Group). Urinary Diversion

1. MANAGEMENT OF CARCINOMA
URINARY BLADDER
Made by:Dr Isha Jaiswal
Guided by:Prof Kamal Sahni
Date:04 December 2015

2. Urinary bladder cancer
• NMIBC: non muscle invasive bladder cancer
• MIBC: muscle invasive bladder cancer:
• Metastatic Disease

3. TREATMENT OPTIONS
• Surgery
• Chemotherapy
• Immunotherapy
• Radiotherapy

4. Treatment depends on following
factors
Tumor related factor
 TNM category
 Size
 Number of tumors
 Grade
 Presence of concurrent CIS
Patient related factor
 Age
 Medical comorbidities
 Performance status
 Bladder functions
 Choice

5. Non-muscle-Invasive Bladder Cancer
• 70-80% of patients with bladder cancer present with NMIBC
• These are classified as Tis, Ta, and T1 by the TNM classification
system.
• Aim of treatment: prevent recurrence & progression to MIBC
• Prognostication and management strategy are based on accurate
initial staging and grading of the disease.

6. TURBT: transurethral resection of bladder tumor
• First-line to diagnose, stage, and treat visible tumors.
• Goal: to make the correct diagnosis and completely remove all
visible lesions.
EUA done before & after TURBT to asses disease extent & residual tumor.
Residual tumor can be as high as 53% in T1 tumors.
Muscle must be seen in TURBT specimen before ruling out invasive disease
Biopsies of apparently uninvolved urothelium should be obtained to rule out
occult Tis.
Biopsy from the prostatic urethra is necessary in some cases. tumour located on
trigone or bladder neck, multiple tumours

7. TURBT
Pathologist should comment on:
 Size
 tumour grade
 depth of tumour invasion,
 presence of CIS
 whether the detrusor muscle is present in the specimen.
 specify the presence of LVI or unusual (variant) histology
 If there is uncertainty over the pathology, a further early re-
resection (2-6 wk.) is indicated.

8. Second look TURBT?
Indications
 Residual disease after initial TURBT
 When specimen contained no muscle
 High-grade and/or T1 tumor
Timing and strategy:
 Most recommend 2-6 weeks after initial TUR
 Should include resection of primary tumor site
Evidence: 2nd look TURBT in T1 /HG tumor
 1/2 will have residual disease on 2nd look [EAU 2010]
 Under stage is more if muscle is absence (50% vs 15%) [Herr JU 1999]
 1/4 will have upstage [Herr JU1999]
 1/3 will have to change management [Herr JU 1999]
 20% increase 5yr DFS [Germen observational study 2003]
8
European Association of Urology Guidelines 2015.

9. Predicting recurrence and progression
of NMIBC
• EORTC bladder cancer calculator
• CUETO risk calculator.

10. • NMIBC, can be classified as low, intermediate, or high risk
• It is based on combined analysis of individual pt. data of 2596
pt. from 7 EORTC trials to predict recurrence and progression in
patient with stage Ta, T1 bladder cancer
• Note: pt. in these trial. does not have 2nd TURBT or maintenance
BCG
• recurrence and progression rates reported here may be higher than
those found in current clinical practice.
Sylvester RJ, et al Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer Using EORTC
Risk Tables: A Combined Analysis of 2596 Patients from Seven EORTC Trials. European Urology 49: 466 - 477, 2006
EORTC bladder cancer calculator

11. European Organisation for Research and Treatment of Cancer. Bladder cancer calculator. Available
at: http://www.eortc.be/tools/bladdercalculator/.

12. Scoring System To Predict 1-yr& 5-yr Recurrence & Progression
12
based on six clinical and
pathological factors:
most important prognostic
factors
for recurrence
 number of tumors
 size,
 prior recurrence rate.
for progression
 T category
 grade
 presence of CIS

13. 13

14. predicts risks of recurrence and progression for BCG-treated patients
based on an analysis of 1,062 patients from 4 CUETO trials that compared
different intravesical BCG treatments.
No immediate postoperative instillation or second TURB was performed
The scoring system is based on evaluation of seven prognostic factors
 sex
 age
 prior recurrence status
 number of tumours
 T category
 associated CIS;
 tumour grade.
Calculated risk of recurrence is lower than EORTC.Progression risk is lower
only in high risk patient. Attributed to BCG therapy in the studies
CUETO risk calculator (Spanish Urological Oncology Group).
CUETO risk calculator is available
at: http://www.aeu.es/Cueto.html

15. Implication Of Risk Stratification
• Decide adjuvant treatment
• Decide follow up schedule

16. 16
Treatment recommendations in Ta, T1 tumours and CIS
according to risk stratification
European Association of Urology Guidelines 2015.

17. Indications of adjuvant intravesical therapy after
TURBT in NMIBC
• Intermediate & high risk features
• Incomplete excision especially in T1 tumors
• tumors rapidly recur following TURBT of the initial bladder
tumor
• persistent tumor cells on urine cytology during surveillance
• Adjuvant therapy is given in the form of intravesical
administration of immunotherapy or chemotherapy.

18. Immunotherapy
• Bacillus Calmette Guerin, live attenuated form of M. bovis
• Acts as immune stimulant: stimulates cellular response releasing
cytokines IL-1,2,6,8,TNF and IFN gamma
• Given 1-2 weeks after resection, weekly for 6 weeks f/b
maintenance as 3 weekly for a 1-3 year .(3yr better)
• Patient is dehydrated over night. Urine is voided completely.
• 50 mg of TICE in 50cc of 0.9% NS is instilled via catheter. Patient
is asked to void urine after 2 hours
• S/E :
 Urinary frequency ,dysuria, hematuria
 Arthralgia, rash, fever
 Pneumonitis, hepatitis, prostatitis, sepsis

19. Intravesical chemotherapy
Chemotherapeutic agents used are mitomycin C, doxorubicin, and
thiotepa.
Similar efficacy in prolonging time to recurrence.
Different toxicity profile
• Mitomycin C may cause skin desquamation and rash
• Doxorubicin may cause G.I upset and local reaction causing
urinary urgency.
• Thiotepa causes myelosuppression

20. BCG VS MITOMYCIN
• Individual patient data (IPD) meta-analyses of nine trials that included 2820 patients
• Overall, there was no difference in the time to first recurrence (p=0.09) between BCG and
MMC.
• In the trials with BCG maintenance, a 32% reduction in risk of recurrence on BCG
compared to MMC was found (p<0.0001),
• In the trials without maintenance a 28% increase in risk of recurrence (p=0.006) for BCG
compared to MMC
• BCG with maintenance was more effective than MMC in both patients previously treated
and those not previously treated with chemotherapy
Malmstrom PU, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of
randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive
bladder cancer. Eur Urol 2009;56(2):247–256.

21. Conclusion for Adjuvant therapy in NMIBC*
• Standard of care for superficial bladder cancer with a high risk of recurrence has been
established as intravesical BCG with maintenance therapy up till 3 years
• Patient who are at high risk of recurrence or progression and can not comply to
intravesical agent can be offered either cystectomy or bladder preservation protocols as in
MIBC.
• Histologic persistence after 6 months indicates the need to change the intravesicular agent
(may combine BCG +interferon or intravesical chemotherapy)
• Disease beyond 1 year indicates the need for a different treatment approach to prevent
progression to muscle-invasive cancer (cystectomy or bladder preservation protocols as
in MIBC.)
• Patients with persistent CIS or BCG refractory Ta/T1 disease ultimately require
cystectomy or bladder preservation protocols as in MIBC.
• RTOG 0926** evaluating chemoradiation for such patients who opt for an attempt at
bladder preservation or are otherwise not good cystectomy candidates.
**Gray PJ, Shipley WU, Efstathiou JA, et al. Recent advances and the emerging role for chemoradiation in nonmuscle
invasive bladder cancer. Curr Opin Urol 2013;23:429–434
*European Association of Urology Guidelines 2015.

22. Implication Of Risk Stratification
Parameter Low-risk Intermediate-risk High-risk
Risk of recurrence
at 1 year
15% 38% 61%
Risk of progression
at 1 year
0.2% 5% 17%
Surveillance
regimen
flexible cystoscopy
with urine cytology is
standard of bladder
surveillance
 flexible cystoscopy
3 months after
initial resection
 if negative
repeated at 9
months & then
annually there-after.
• between that used for
low- and high-risk
disease
• adapted according to
personal and subjective
factors
• 3 monthly flexible
cystoscopy for 2 years
• 6 monthly for further
5 years
• then annually
thereafter.

23. Bladder Surveillance
• flexible cystoscopy with urine cytology is the
standard of bladder surveillance
• ongoing research into improving sensitivity and
specificity of flexible cystoscopy using narrow band
imaging tried.
• wide number of urinary biomarkers available such as
NMP22, UroVysion and ImmunoCyt also tested
• these agents suffer from high false-positive rates and
variable sensitivity and are costly & there role in
surveillance not established

24. Muscle Invasive Bladder
Cancer:MIBC
• Although the majority of patients present with
NMIBC, 20% to 40% will either present with or
ultimately develop muscle-invasive disease.

25. Goals of Treatment
• Cure patient
• Optimize survival
• Prevention of Pelvic failure and Distant metastasis
• Functional Urinary reservoir and High Quality Of Life
(QoL)
25

26. MUSCLE INVASIVE BLADDER CANCER
RADICAL
CYSTECTOMY WITH
URINARY
RECONSTRUCTION
BLADDER CONSERVATION
PROTOCOLS
RELAPSE OR PROGRESSION
26

27. SURGERY: Radical cystectomy
• Indication:
• Muscle invasive or locally advanced disease T2-T4a
• Non muscle invasive bladder cancer
T1G3 with high risk features ( multiple, recurrent ,large ,CIS)
Refractory or failure to cystoscopy resection and intravesical
chemotherapy or immunotherapy
Non compliance to intravesical chemotherapy or
immunotherapy
Extensive disease not amenable to cystoscopy resection

28. Rationale For Radical Cystectomy
lowest local recurrences.
good long-term survival rates.
provides accurate pathologic staging for determining the need
for adjuvant therapy
morbidity and mortality of radical cystectomy has substantially
improved over the past decades.

29. Optimum Timing for cystectomy
Within 3 months of TURBT.Delay of treatment beyond 90 days of
primary diagnosis causes
• significant increase in extravesical disease (81 vs. 52%), .
• Also affect the options of urinary diversion
• Hautmann RE, et al. Does the option of the ileal neobladder stimulate patient and
physician decision toward earlier cystectomy?. J Urol 1998;159(6):1845-50.
• decrease in overall survival, recurrence-free survival, cause-specific
survival
• Chang SS, et al. Delaying radical cystectomy for muscle invasive bladder cancer
results in worse pathological stage. J Urol 2003;170(4 Pt 1):1085-7
29

30. Radical Cystectomy involves
• Radical Cystectomy
• Removal of bladder with surrounding fat
• Prostate/seminal vesicles (males)
• Uterus/fallopian tubes/ovaries/cervix vaginal cuff (females)
• + Urethrectomy
• Pelvic Lymphadenectomy
• More is better
• Urinary Diversion
• Ileal conduit
• Continent cutaneous reservoir
• Orthotopic neobladder

31. • Complications
– Re-operation (10%)
– Bleeding (10%)
– Sepsis and wound infection (10%)
– Intestinal obstruction or prolong ileus (10%)
– Cradio-pulmonary morbidity
– Rectal injury (4%)
– Complications of urinary diversion: dehydration, electrolyte
abnormality,infection
• Peri-operative mortality : 3%
• Early complications (within 3 months of surgery) in 28%
( Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer: long-term results of a
standard procedure. World J Urol 2006 )
31

32. Technique to improve QOL
Level of preservation:
• Anterior & membranous urethra + external sphincter
• For orthotopic neobladder
• Part of prostate and seminal vesicle
• Fertility , potency and continence
• Autonomic & sensory nerve (NVB)
• soft tissue adjacent to the tips of the seminal vesicles.
• Uterus & part of vagina ;
• Improve antomical support for neobladder & autonomic nerves
Disadvantages:
• Residual Ca prostate (30%)  10% clinically significant
• Increase oncological risk  need long term data
32

33. ILEAL CONDUIT
(incontinent diversion
to skin)
CONTINENT
CUTANEOUS
RESERVOIR
(continent diversion to
skin)
ORTHOTOPIC
NEOBLADDER
(continent diversion to
urethra)
Types of Urinary Diversion

34. Choice of Urinary Diversion
• Disease Factors
• Urethral margin
• Patient Factors
• Kidney function / liver function
• Manual dexterity for intermittent catheterization
• Preoperative urinary continence/ urethral strictures
• Motivation
• Surgeon Factors
• Familiarity with various types of diversions

35. Rationale for L.N Dissection
• From Stein series incidence of L.N metastasis:
• Overall estimate ~ 25% patient undergo cystectomy have
LN mets
• pTis, pTa, pT1: 5%
• pT2 : 15
• pT3 : 40%
• pT4 : 50%
1. Stein JP. The role of lymphadenectomy in patients undergoing radical cystectomy for bladder cancer. Curr Oncol
Rep 2007;9(3):213–221.
2. Stein JP, Quek ML, Skinner DG. Lymphadenectomy for invasive bladder cancer: I. historical perspective and
contemporary rationale. BJU Int2006;97(2):227–231.
3. Stein JP, Quek ML, Skinner DG. Lymphadenectomy for invasive bladder cancer. II. technical aspects and prognostic
factors. BJU Int 2006;97(2):232–237.

36. Standard PLND
 Proximal: Bifurcation of common iliac artery
 Distal: Circumflex iliac vein
 Lateral :Gentitofemoral nerve
 Medial: Bladder wall
 Pelvic floor and hypogastric vesse
 Anything more (up to bifurcation of aorta and above) can be called an extended
PLND.
 Includes b/l obturator, internal, external, common iliac and presacral nodes as well
as nodes at the aortic bifurcation May also Extend to IMA
 Evidence[1-3] suggests that a more extended lymphadenectomy is beneficial in
both lymph node–positive and lymph node–negative patients with bladder cancer,
36
36
1. Herr HW, Bochner BH, Dalbagni G, et al. Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder
cancer. J Urol2002;167(3):1295–1298.
2. . Leissner J, Ghoneim MA, bol-Enein H, et al. Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective
multicenter study. J Urol 2004;171(1):139–144.
3. . Stein JP. The role of lymphadenectomy in patients undergoing radical cystectomy for bladder cancer. Curr Oncol Rep 2007;9(3):213–221.

37. Number of Nodes Sampled Affects Survival in
Both Node Negative and Node Positive Patients
Node negative Node Positive
Herr HW, Bochner BH, Dalbagni G, et al. Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder
cancer. J Urol2002;167(3):1295–1298

38. 38
Recommendation for adequate L.N
dissection
• The Bladder Cancer Collaborative Group recommends 10-
14 lymph nodes should be removed at time cystectomy
 Herr HW, Bochner BH, Dalbagni G, et al. Impact of the number of lymph nodes retrieved
on outcome in patients with muscle invasive bladder cancer. J Urol 2002;167(3):1295–1298

39. Results of radical cystectomy
SELECTED DATA FROM THE UNIVERSITY OF SOUTHERN CALIFORNIA
BLADDER CANCER STUDY OF RADICAL CYSTECTOMY
Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054
Patient JCO 2001

40. BLADDER PRESERVATION
PROTOCOL

41. Bladder Conservation approach
• 2 main concerns about bladder preservation compared with radical
cystectomy
• Toxicity of radiation therapy on bladder function
• Field cancerization effect :
• 30-50% of patients experience a local recurrence (~50%
invasive and ~50% superficial), either in the area of tumor or in
a different part of bladder
• If bladder preservation is selected, close surveillance is critical
41

42. No trials have till date directly compared
Cystectomy and Bladder-preservation
42

43. Methods of Conservation
Conservative Surgery
Partial Cystectomy
Radical External Beam Radiation Therapy ±Brachytherapy boost
Combined modality treatment
Chemotherapy + TURBT/Partial cystectomy
Trimodality Therapy: maximal TURBT, chemotherapy &
radiotherapy
43

44. Partial Cystectomy
• Careful patient selection
• Solitary lesion
• Location: allows for complete excision with a 2-cm tumor-free margin like bladder
dome
• Contraindications :
• Bladder neck or trigone tumors
• Association with carcinoma in situ
• Prostatic urethral involvement
• Prior recurrent bladder tumors
• 6% to 19% of patients with primary, muscle-invading bladder cancer are potential
candidates
• Local recurrence rates : 38% to 78%
• Half of the recurrences appear in the first year and two thirds by 2 years
44

45. Radical External Beam Radiation Therapy
• Historically, EBRT was used as monotherapy
• Factors having significant favourable effect on local control with Radiotherapy:
• Early clinical stage (T2 and T3a)
• Absence of ureteral obstruction
• Visibly complete TURBT
• Small tumor size (<5 cm) solitary , Papillary / Sessile absence of coexisting
carcinoma in situ
• total radiation dose used varied
from 55 to 65 Gy, with 1.8- 2 Gy per fraction in North America
from 50 to 55 Gy at 2.5 to 2.75 Gy per fraction in the United Kingdom.
45

46. 5-year local control rate
31% to 45% for the entire patient population
49% to 79% for the subgroup of patients with a complete response

47. Interstitial Brachytherapy
• combined with EBRT to provide a radiation boost to the primary tumor
• Indication: Solitary TCC with a diameter of less than 5 cm
47
• Five-year local control rates for selected patients 70% -90%
• High rates of bladder preservation
• Acute toxicity :
• Fistula formation with wound leakage

48. Trimodality Therapy
Combination of maximum TURBT Resection, Chemotherapy, and
Irradiation in Bladder Preservation
• Best results till date in bladder preservation when the 3 modalities are
combined together
• Based on both single institutional data and randomised control trials
48

49. Ideal candidates
• MIBC:Solitary T2 or early T3 tumors < 6 cm; CIS -nt; TCC
histology
• visibly complete TURBT
• No hydronephrosis
• Adequate renal function to allow cisplatin concurrent with
radiation
• Willing for being on close surveillance
• Willing for cystectomy in case of progression or relapse

50. 1. cytotoxic agents, are capable of sensitizing tumor to irradiation, therefore
increasing cell kill in a synergistic fashion.
2. Patients with MIBC harbour occult metastases in approximately 50% of cases,
addition of systemic chemotherapy is in an attempt to control occult distant
disease.
Rationale For Combining Chemotherapy
With RT In Bladder Preservation

51. PIONEERING SINGLE INSTITUTION STUDIES OF TRIMODALITY
TREATMENT
51
± NACT:MCV

53. Multi-modality Treatment Evolution In RTOG trials

54. Objective of RTOG trials
Primary objective: to improve cure rates,
secondary objective :to improve bladder preservation
rates
additional objective: to evaluate the tolerance and
advantage of newer chemotherapeutic agents.
• During the years 1985-2001 the RTOG conducted 6
trials, of which 5 were phase I and II and the 6th a
phase III trial, which tested the role of adjuvant
chemotherapy with tri-modality treatment
• A total of 415 patients were enrolled in these trials. five
year OS was approximately 50%, with 75% of surviving
patients retaining a functionally preserved bladder

55. RTOG trials

56. Results of RTOG trials
• RTOG 97-06, phase III trial with NACT failed to show the survival
benefit with NACT in tri-modality. This trial stopped accrual prior to
the planned because of the poor tolerance of MCV regimen and 3
treatment related deaths.
• Trials using neo-adjuvant or adjuvant chemotherapy, showed more
grade 3-4 acute toxicities but late effects were similar
• RTOG 0233, examined the role of accelerated twice-daily radiation
therapy in combination with either paclitaxel/cisplatin or 5-
FU/cisplatin. Both cohorts also received four cycles of adjuvant
gemcitabine/paclitaxel/ cisplatin chemotherapy. Both regimens had
high rates of response , completion and bladder preservation. 73%
and 69% of patients had their bladder preserved at 4 years
• To conclude from the RTOG data that, tri-modality treatment is an
effective bladder preservation approach of patients with MIBC, with
the understanding that radical cystectomy is an available option for
those who fail combined modality, with no decrease in survival due
to delay in cystectomy.

57. C
O
M
P
A
R
A
B
L
E
SURVIVAL DATA OF
RADICAL CYSTECTOMY AND SELECTIVE BLADDER PRESERVATION
57

58. Survival Data Of Radical Cystectomy And Selective Bladder
Preservation: non comparable!!!
because of following reason:
• comparisons have not been stage matched.
• staging systems have changed over the years
• accurate staging not possible in RT series. In contrast, surgical series will
report accurate pathological stage. It is well documented that more
accurate staging will bring about a paradoxical improvement in reported
results by stage due to upstaging of apparently early disease cases, the
so-called Will Rogers phenomenon.
• imaging techniques have evolved over time so more accurate staging in
non surgical patients possible
• RT Techniques have evolved over time and so more conformal
techniques with less toxicity in recent series
• in previous RT series the pt. who were treated with bladder preservation
protocol were unfit for surgery so selection bias

59. In truth, surgery and radiotherapy are not competing,
but are complementary approaches to invasive
bladder cancer
Poor RT candidates
poorly functioning bladders
extensive CIS.
pT1G3 disease.
hydronephrosis
Poor surgical candidates
 older patients,
 Medical comorbidities
 poor anesthetic risk pts.
 Non compliant to urinary
diversion care

60. concurrent chemotherapy agent
• cisplatin,
• 5-fluorouracil (5-FU),
• mitomycin C,
• carboplatin,
• paclitaxel,
• gemcitabine.

61. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy
in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477–1488.
• 360 patients ,MIBC
• randomized to either RT alone or to CCRT with 5-FU and mitomycin C
chemotherapy.
• median follow-up of 70 months
• Local–regional DFS was superior for those patients receiving chemotherapy (67%
versus 54% at 2 years; hazard ratio [HR] 0.68, p = 0.03
• Survival at 5 years was higher with CCRT (48% versus 35%), but did not reach
statistical significance (HR 0.82; p = 0.16)

62. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive
bladder cancer. N Engl J Med 2012;366:1477–1488.

63. Conclusion about agent of choice for
CCRT in bladder preservation protocol
• After RTOG 85-1228, and NCIC trials the efficacy and
safety of cisplatin in CTRT bladder was proved.
• Newer agents and combination regimens with taxanes,
gemcitabine and platinum is being increasingly used in with
some increase in response rates compared with platinum
monotherapy
• RTOG 0524 is ongoing and will evaluate the role of
concurrent trastuzumab/paclitaxel in patients with human
epidermal growth factor receptor 2 (her2)/neu over
expression.

64. • As of now, there are no definite recommendations for any
particular combination chemotherapy in tri-modality setting.
• However there is a recent randomized trial BC2001 published in
2012 which suggest mitomycin & 5FU is also good alternative
because of following reasons.
 Although not a standard comparison but the when comparing LC
it was better with 5FU+MC than single agent cisplatin
 Also due to poor bladder function and deranged KFT cisplatin is
contraindicated in some patients
 RT alone is an inferior option
 Lastly BC2001 is a recent trial with modern day conformal
radiotherapy techniques

65. Radiotherapy in bladder cancer

66. • Concurrent chemo-radiation as a part of multi-
modality bladder sparing protocol in T2-T4 N0 M0
• Neoadjuvant radiotherapy
• Adjuvant radiotherapy
Radiotherapy in bladder cancer

67. SIMULATION
• CT Simulation preferred
• Patient Position :supine with arms on chest.
• Immobilization :knee and ankle rest
• Bowel preparation: rectum should be empty of flatus and
faeces, use of daily micro enemas may be considered.
• Bladder preparation: empty bladder prior to scan.(Special
bladder protocol can be followed for conformal planning to
account for organ motion)
• All planning and treatment should be carried out with the
bladder empty
To minimize the risk of geographic miss
To keep the treated volumes as small as possible

68. Simulation: need of contrast
For X Ray based planning:
• catheterization f/b introduction of perurethral contrast to
define bladder wall.
• Conventional simulation involves: AP-PA & lateral
radiographs
For CT based planning
• iv contrast used to facilitate nodal delineation
• CT scan performed with 3 to 5-mm slice spacing from
to 3 cm above the dome of the bladder or bottom of L5
(whichever is higher) to bottom of ischial tuberosity
:

69. Conventional radiotherapy volumes
2 phased treatment
Phase I: Field border
• superior border :at the L5-S1 disc space
• inferior border: below obturator foramen.
• Anteriorly: 1.5 to 2 cm from the most anterior aspect of the
bladder
• posterior border: about 2.5-3 cm posterior to posterior aspect of
the bladder.
• Laterally:1.5-2 cm to the bony pelvis at its widest section
• Dose:40-45 GY @ 1.8-2Gy/#

70. Boost phase
• entire bladder excluding the nodes and then give a
further boost to the tumor alone (3 phase treatment).
• Dose:10-15 gy to entire bladder and upto 66 gy to
tumor.(aim bladder receive 60 gy)
OR
• treat the bladdr+tumor with a 2-cm margin to a total
dose of 66 gy

71. Bladder protocol to account for organ
motion in conformal planning
• Patient will be asked to void the urine and empty the bladder as
much as possible.
• Patient will be asked to drink 500 ml of water and time will be
recorded.
• After 60minutes of drinking the water CT simulation without
contrast will be performed suggestive of full bladder.
• Thereafter, patient will be asked to void the urine and empty the
bladder as much as possible and CT Simulation with contrast
enhancement will be performed suggestive of empty bladder
• Both images (with full bladder and empty bladder) will be
reviewed for tumor delineation to ensure that in all possible
circumstances the PTV includes the maximum extension of the
full bladder. However the CT slices with empty bladder will form
the primary image for GTV and CTV delineations.

72. Conformal RT Volumes
72

73. Contouring
Gross Tumor Volume (GTV): macroscopic tumor visible on radiological imaging/ cystoscopy
findings provided by the urologist during TURBT. This may be GTV_Primary or GTV_LN (Lymph Node)
Clinical target volume (CTV):- It shall include: CTV_Primary +CTV_LN
• CTV_Primary:
– GTV + whole bladder
– In patient with tumors at the bladder base, the proximal urethra(in both genders), and the prostate and
the prostatic urethra(in males) to be included in the CTV.
CTV_lymph node (CTV_LN):
– External iliac lymph.Internal iliac lymph nodes-, along its branches (obturator, hypogastric)Presacral
lymph
Planning target volume (PTV_Primary):
• CTV_Primary will be given a 1-1.5 isotropic margin to create the PTV_Primary.
• PTV_LN: 1 cm isotropic margin will be given to CTV_LN.
• PTV_Primary may be Booleaned (added) with PTV_LN to produce a PTV_Total in order to facilitate
treatment planning.
• Both images (with full bladder and empty bladder) will be reviewed for tumor delineation to ensure
that in all possible circumstances the PTV includes the maximum extension of the full bladder.
However the CT slices with empty bladder will form the primary image for GTV and CTV
delineations.

74. Controversy regarding PTV margin
• Organ motion is the dominant source of error
• Magnitude of the error depends on the region of the bladder being treated.
• Some institute prefer Isotropic 2-cm margins around either the bladder (first phase of
treatment) or tumor (boost)
• Studies have shown that greatest degree of bladder wall positional change occurred in
the cranial direction, with the least variation in the anteroinferior direction, limited by
the pubic symphysis.
• Few authors recommended anisotropic margin widths of 1.6 cm anteriorly and
posteriorly, 1.4 cm laterally, 3 cm superiorly, and 1.4 cm inferiorly.
• The problem is that these margins incorporate much normal tissue.
• Image-guided radiation therapy with CBCT is away to reduce these margins
significantly
• Correction for errors detected on CBCT is practically achieved by a Foley's catheter.
Most of the variation is due to bladder filling, so we catheterize the patient and change
the bladder status to that at simulation by draining/filling it up as necessary.

75. Radiation Therapy Doses
• Optimal radiotherapy schedule is yet to be established
• commonly used schedule :
• SPLIT SCHEDULE
• In U.S split schedules often used are 39 or 40 Gy in 1.8- or 2-Gy fractions with
an interval cystoscopy;
• patients with responding disease proceed to a total dose of 64 to 66 Gy.
• SINGLE PHASE TREATMENT
• In the United Kingdom, single radical course, usually to the whole bladder, only
• typical dose schedules would be 64 Gy in 32 fractions
• or hypo fractionated schedules such as 55 Gy in 20 fractions
75

76. Pre-operative Radiotherapy
The aims of preoperative radiotherapy include:
• down staging and make surgery easier,
• Increase rate of pT0
• Improve local control
• No increase in the incidence of surgical complications.
• DOSE: 40 Gy in 20 fractions or 20 Gy in 5 fractions followed by
cystectomy 4wks later
• Role of preop RT waning
• Most of the studies in the literature using preop RT are old, .(1980-1990)
retrospective, nonrandomized or few randomized comparisons and little
can be concluded from them

77. Post-operative Radiotherapy
• Limited data from randomized trials
• Indication: pT3-T4, positive surgical margins , pN + (only in patients
having incontinent cutaneous urinary diversion because in
continent case the bowel toxicity is high)
• Rationale: decreases probability of tumor recurrence following radical
cystectomy.
• Dose:
 Areas at risk for harbouring residual microscopic disease should receive 45 to 50.4
Gy EBRT.
 Involved resection margins and areas of extranodal extension should be boosted to
54 to 60 Gy if feasible based on normal tissue constrains.
 Areas of gross residual disease should be boosted to 66 to 70 Gy, if feasible based on
normal tissue constrains.
• Concurrent chemotherapy can be considered for added tumor cytotoxicity.
• CAUTIO However morbidity of post operative radiation is high due to small
bowel toxicity that occupies pelvis after cystectomy.

78. Role of systemic chemotherapy
• Neoadjuvant
• Adjuvant
• Palliative

79. Neo-Adjuvant Chemotherapy
• Aim: to reduce micro metastasis and improve survival in MIBC
• Advantage:
• Decrease micrometastatic spread
• Potentially downstaging the tumor
• Disadvantage:
• 50% without micrometastasis will be overtreated
• Staging error may lead to overtreatment
• Delay in cystectomy may compromise outcome
• Chemo therapy may have SE that affect outcome of surgery
79

80. Randomized Phase III Trials of Neoadjuvant Chemotherapy
80
(Overall Survival)
Single agent

81. Metaanalysis
• Advanced Bladder Cancer (ABC) Meta-analysis.
[Lancet 2003]
• Update in 2005 [EAU 2005]

82. • Advanced Bladder Cancer (ABC) Meta-analysis. [Lancet
2003]
• Analysis of 11 trial
• 2688 individual patients from ten available randomised
trials
• Cisplatin-containing chemotherapy :
• 5% (45% vs. 50%) absolute improvement 5yr OS
• 9% improvement in 5yr DFS
• 13% reduction in risk of death
• Combination is better than single agent
• Complete tumor response in 30%
• effect was observed irrespective of the type of local
treatment,
82
Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis
Vale, C The Lancet , Volume 361 , Issue 9373 , 1927 – 1933, 2003

83. 83

84. 84
Neoadjuvant chemotherapy in invasive bladder cancer. Update of a systematic review and meta-analysis of individual
patient data advanced bladder cancer (ABC) meta-analysis collaboration. Advanced Bladder Cancer (ABC)
Meta-analysis Collaboration, Eur Urol 48:202-205, 2005.
Update in 2005 [EAU 2005]
• Absolute OS benefit of 6.5% (95% CI 1-9%, from 45-50%)
• Significant DFS benefit (HR 0.78, 95% CI 0.71-0.86,
p<0.0001) with 9% improvement in 5 years
• Platinum combination significantly better than platinum single
agent

85. • Neoadjuvant chemotherapy is still not considered as standard
of care for Muscle Invasive Bladder cancer – Unlike other
malignancies
• Reasons :
• Selection of patients in the trial setting is different from the
patients seen in clinical setting
• Most are old with impaired renal functioning & poor
tolerance to chemotherapy
• Newer chemotherapeutic combinations that have activity in
patients with metastatic disease and more favorable toxicity
profiles, such as gemcitabine and cisplatin, are being
investigated.
85
Conclusion

86. Adjuvant Chemotherapy After Definite Local
Therapy
• No randomized trials have compared neoadjuvant to adjuvant
chemotherapy in patients undergoing definitive local therapy.
• Not enough evidence supporting adjuvant chemo in UB cancer
• It is justified in patients with high risk for relapse, if neoadj
chemo was not given
1. pT3 or more
2. Node positive

87. • In three studies, a significant progression-free survival (PFS) benefit at 3 and 5 years was observed
• Patients in the observation group received chemotherapy at relapse, except in the study by Stöckle
• PFS benefit does not translate into OS benefit if patients receive salvage chemotherapy.
PFS benefit

88. Metastatic Bladder Cancer
• The prognosis of metastatic bladder cancer, is poor, with a median
survival on the order of only 12 months.
• Nevertheless, platinum-containing agents have significant antitumor
effect ,there has been great interest in the use of chemotherapy for
advanced disease.
• In phase III clinical trials, response rates to CT are often on the order of
50%
• However, the duration of response in TCC is short, with a median of 4 to
6 months,
• Therefore, the impact of chemotherapy on survival has been
disappointing

89. The MVAC regimen has superior activity to other cisplatin-containing regimens.
response rate to MVAC is 40% to 65%,
complete response is seen in 15% to 25% of patients,
expected median survival of 12 months
However MVAC is associated with substantial toxicity
GC, has similar efficacy & significantly less toxicity and improved tolerability

90. Thank you