complete information (pictural) of carcinoma urinary bladder from anatomy to management(Investigations, Surgery ,Radiotherapy, Chemotherapy) including NCCN, trials

1. Carcinoma Urinary Bladder ( anatomy to
management)
Dr. Brijesh Maheshwari (SR)
Moderator-Dr. Pavan Kumar, Dr. Ayush Garg, Dr.Srinivas Naidu

2. SOURCE

3. ROADMAP

4. ANATOMY

7. EPIDEMIOLOGY

9. Risk factors
• Tobacco
• Median age 70 years
• Male gender
• White race
• Chemicals- used in textile, rubber, leather, dye,
paint, and print industries
• Previous radiation therapy to the pelvis
• Chronic bladder infection
• Cyclophosphamide use
• Schistosomiasis
• Arsenic exposure
• Field cancerization
S. haematobium (bilharziasis)-This infestation
can lead to malignancy through local tissue damage,
mechanical irritation, bilharzial toxins, secondary bacterial
infection and the production of nitrosamines
Field Cancerization -TCC behaves as a multifocal
disease, often with multiple primary tumors and frequent
recurrences that can occur anywhere in the urinary tract
from the renal pelvis to the urethra. These observations
gave rise to the idea of a “field defect” or “field
cancerization,” suggesting that the whole urothelium is
exposed to the same urinary carcinogens, leading to the
transformation of many independent separate urothelial
cells and resulting in multiple tumors developing
independently in multiple sites.

10. Clinical Presentation
• Microscopic or gross
hematuria(painless)m/c
• Urinary frequency due to irritation
or a reduced bladder capacity
• Urinary tract infection
• Upper urinary tract obstruction or
pain (may occur in patients with a
more advanced lesion).

11. Staging

12. T
• T Primary Tumor
• TX Primary tumor cannot be assessed
• T0 No evidence of primary tumor
• Ta Noninvasive papillary carcinoma
• Tis Urothelial carcinoma in situ: “flat tumor”
• T1 Tumor invades lamina propria
(subepithelial connective tissue)
• T2 Tumor invades muscularis propria
• pT2a-Tumor invades superficial muscularis propria
(inner half)
• pT2b-Tumor invades deep muscularis propria
(outer half)
Non muscle invasive
bladder cancer
(NMIBC)

13. T
• T3-Tumor invades perivesical tissue
pT3a-Microscopically
pT3b-Macroscopically (extravesical mass)
• T4- Extravesical tumor directly invades any of the
following: prostatic stroma, seminal vesicles, uterus, vagina,
pelvic wall, abdominal wall
• T4a Extravesical tumor invades prostatic stroma, seminal
vesicles, uterus, vagina
• T4b Extravesical tumor invades pelvic wall, abdominal wall

14. N Regional Lymph Nodes
• NX Lymph nodes cannot be assessed
• N0 No lymph node metastasis
• N1 Single regional lymph node metastasis in the true pelvis
(perivesical, obturator, internal and external iliac, or sacral
lymph node)
• N2 Multiple regional lymph node metastasis in the true pelvis
(perivesical, obturator, internal and external iliac, or sacral
lymph node metastasis)
• N3 Lymph node metastasis to the common iliac lymph nodes

15. M
• M0- No distant metastasis
• M1- Distant metastasis
• M1a Distant metastasis limited to lymph nodes beyond the
common iliacs
• M1b Non-lymph-node distant metastases

16. 2016 WHO Classification of Tumors of the
Urothelial Tract

18. Histology
• 90% of urothelial tumors (transitional cells) originate in the urinary bladder,
• 8% originate in the renal pelvis,
• 2% originate in the ureter and urethra.
• Histologic subtypes :
• Infiltrating urothelial carcinoma with divergent differentiation;
• nested, including large nested;
• microcystic;
• micropapillary;
• lymphoepithelioma-like;
• plasmacytoid/signet ring cell/diffuse;
• sarcomatoid;
• giant cell;
• poorly differentiated;
• lipid-rich; and
• clear cell.
The presence of histologic variants in urothelial
carcinoma should be documented as data
suggest that the subtype may represent an
increased risk of progression, reflect different
genetic etiology, and subsequently determine
whether a more aggressive treatment approach
should be considered

19. Workup
• Full blood count
• Biochemical profile
• Prostate-specific antigen (if indicated)
• Urine cytologic examination
• Flexible cystoscopy
• Imaging of the urothelium (e.g., ultrasound,
intravenous urogram, or computed tomography [CT]
urogram)
Patients with muscle-invasive bladder
cancer (MIBC) will require detailed cross-sectional staging
with CT or magnetic resonance imaging (MRI) of the
chest, abdomen, and pelvis. If there are any features
suggestive of bone metastasis (e.g., raised alkaline
phosphatase, bone pain), an isotope bone scan will be
indicated in addition

20. Enhanced Cystoscopy
• White light cystoscopy (WLC) : is the current standard in the evaluation and
staging of bladder cancer. While WLC has a high sensitivity for detecting papillary
lesions
• Blue light cystoscopy : is a technique that identifies malignant cells through the
absorption of the photosensitizing drug into the urothelial cytoplasm where it
enters the heme biosynthesis pathway. In normal cells, the photosensitizer is
excreted; however, enzymatic abnormalities in malignant cells result in the
formation of photoactive porphyrins that remain in the cell and fluoresce with a red
emission in the presence of blue light.

21. CONCLUSIONS: Compared to WLC TURBT alone, NBI + WLC TURBT may lower the risk of disease recurrence
over time while having little or no effect on the risks of major or minor adverse events.

22. Pathways to Muscle-Invasive and Non–Muscle-
Invasive Bladder Cancer
• Most cases (70% to 80%) present with non–muscle-invasive bladder
cancer(NMIBC, stage Ta, T1, and carcinoma in situ [Tis]), which is rarely
lethal, but shows a high recurrence rate of 50% to 70% after treatment by
transurethral resection of the bladder tumor (TURBT).
• In about 10% to 20% of patients with NMIBC, the disease progresses to
muscle invasion (=T2 lesions)

23. TREATMENT

24. The NCCN Guidelines® for Bladder Cancer divide treatment
recommendations for urothelial carcinoma of the bladder according to
and
•
Management of bladder cancer is based on the findings of the biopsy
and TURBT specimens, with attention to histology, grade, and depth of
invasion.

25. Aim of Management of Bladder cancers- Stage wise
•Superficial bladder cancer- prevent recurrent and progression to muscle
invasive cancer.
•Muscle invasive bladder cancer- patient selection for cystectomy and for
bladder preservation protocol and for integrated systemic chemotherapeutic
approach.
•Metastatic bladder cancer- palliation and quality of life.
Urinary Bladder Cancer
NMIBC (75%) Muscle Invasive
cancer - MIBC(20%)
Metastatic cancer (<5%)
1

26. Non-Muscle Invasive
Bladder Cancer

27. AUA Risk Stratification for Non-Muscle Invasive
Bladder Cancer

28. NCCN Recommendations for Treatment of NMIBC

29. Intravesical Therapy
• Patient with low risk NMIBC are managed with TURBT alone or with single peri
operative dose of intravesical chemotherapy given at the conclusion of procedure
as long as there has been no suspicion for bladder perforation.
• Intravesical therapy is implemented to reduce recurrence or delay progression of
bladder cancer to a higher grade or stage.
Immediate Intravesical Therapy Post TURBT:
• An immediate intravesical instillation of chemotherapy may be given within 24
hours of TURBT to prevent tumor cell implantation and early recurrence.
• As per double blind phase III SWOG S0337 clinical trial GEMICTABINE has now
become the preferred agent because of lower cost and improved patient
tolerability.

30. Induction( Adjuvant )Intravesical Chemotherapy or
BCG
• Induction (Adjuvant) BCG has been shown to decrease the risk of bladder cancer
recurrence following TURBT.
• BCG after TURBT is superior to TURBT alone, or TURBT and chemotherapy in
preventing recurrences of high-grade Ta and T1 tumors
• Maintenance Therapy:
To date, the strongest data support the 3-week BCG regimen used in the
SWOG trial that demonstrated reduced disease progression and metastasis.

31. Intravesical BCG
• DOSAGE
• 80 - 120 mg per instillation
Therapy should start atleast two to three
weeks after Transurethral Resection of
Bladder Tumour (TURBT)
• INDUCTION THERAPY*
• One instillation per week for 6 weeks.
• MAINTENANCE THERAPY*
• One instillation per week for 3 weeks at 3
months
• One instillation per week for 3 weeks at 6
months
• Thereafter one instillation per week for 3
weeks after every 6 months, till 36 months
1)BCG Refractory-persistent high grade diseases at less than 6 months after
and adequate course of induction and one cycle of maintenance .
2) BCG Relapse- recurrence of high grade diseases after diseases free
interval of 6 months.
3)BCG unrersponsive- include BCG refractory and relapse.
4)BCG intolerant- inadequate to tolerate BCG dose due to side effects.

32. SWOG protocol

33. Method of BCG administration

35. Pembrolizumab for NMIBC
• In the KEYNOTE-057 study, 101 patients with high-risk CIS, with or without
papillary tumor, who received previous BCG therapy and were either unable or
unwilling to undergo cystectomy were treated with pembrolizumab.
• Pembrolizumab monotherapy was tolerable and showed promising anti-tumour
activity in patients with BCG-unresponsive non-muscle-invasive bladder cancer who
declined or were ineligible for radical cystectomy and should be considered a a
clinically active non-surgical treatment option in this difficult-to-treat population.

36. Surveillance in NMIBC

37. Low-Risk, Non-Muscle Invasive Bladder Cancer

38. Intermediate Risk,Non-Muscle Invasive Bladder Cancer

39. High-Risk,Non-Muscle Invasive Bladder Cancer

40. RECURRENT Or PERSISTENT DISEASE

42. Muscle
Invasive
Bladder
Cancer

43. Muscle invasive Bladder Cancer
• Surgery
• Radiation
• Chemo-radiation
• Chemotherapy

45. Surgery: Radical cystectomy
• Indication:
• Muscle invasive or locally advanced disease T2-T4a
• 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
• 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
• decrease in OS, RFS, CSS
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
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

47. Complications of cystectomy and Urinary Diversion
• Hypokalemia (when colon used)
• Hypocalcemia( when ileum used)
• Hypomagnesemia (when colon or ileum used)
• The most detrimental effect is acidosis(hyperchloremic metabolic acidosis)

49. Bladder Preservation Approaches
1. Radical radiotherapy.
2. Concurrent chemoradiotherapy.( European approach)
3. Induction chemoradiotherapy f/b consolidation
chemoradiotherapy.(RTOG/MGH protocol)
4. Neoadjuvant chemotherapy f/b chemoradiotherapy.
5. Chemoradiotherapy f/b adjuvant chemotherapy.

52. Preoperative radiotherapy
• Tumor size reduction in locally advanced ,muscle invasive disease
• Downstaging of disease
• Decrease in incidence of local recurrence following radical cystectomy
• improve outcomes by up to 15% to 20% at 5 years.
• Decrease in incidence of distant metastasis
• Improvement of survival
• No increase in incidence of surgical complications.
• Disadvantage :
i) Possibility of problems in interpreting pathologic finding in cystectomy & lymphadenectomy
ii) Possibility of side effects of operating on previously irradiated tissue

53. Post operative radiotherapy
• Indications – i) Extravesical disease
ii) Positive resection margins
iii) Pelvic LN involvement
iv) Perinodal extension
• Advantage – Availability of pathologic staging
• Using these features, patients can be stratified with respect to locoregional failure as
follows:
- low risk, unchanged (pT2 or lower);
-intermediate risk, at least pT3, at least 10 nodes removed, and
negative margins
- high risk, at least pT3 and either positive margins or fewer than 10
nodes removed

54. • Dose - 40 Gy in 4 weeks followed by cystectomy
• 20 Gy in a 5-day course with immediate cystectomy
• pathologic complete response rates of around one-third, similar to
neo-adjuvant chemotherapy.

55. Definitive Radiotherapy
1. Clinical T2-3a bladder cancer
2. Unifocal disease
3. Less than 5 cm in maximum diameter
4. No extensive carcinoma in situ
5.Visibly complete TURBT
6. No ureteral obstruction
7. No hydronephrosis
8. Good bladder function
MEDICALLY OPERABLE
CASES
INOPERABLE
CASES

56. Patient Position and Immobilization
• 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 the bladder within 20 minutes prior to
simulation
• We obtain a CT scan from L2 through the mid-femur
• 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

57. Conv. Radiation Portals
ANTERIOR- POSTERIOR FIELDS :
Superiorly -L5-S1 interface,
Inferiorly – Lower border of obturator foramen
Lateraly – 1.5- 2 cm outside the bony pelvic
wall
Anterior field should not include femoral
heads & neck.
Upper corners can be shielded to reduce
small bowel volume

58. LATERAL FIELDS
• Superior and inferior borders
same
• Anterior border- 1.5-2 cm in
front of anterior bladder wall as
seen on imaging study
• Posterior border – 2.5 cm
posterior to the most posterior
aspect of the bladder and falls
within the rectum

59. Two phase approach
Phase I -
• The whole pelvis
• The pelvic lymph nodes
To include
• The whole Bladder
• Proximal urethra
• Any extravesical disease spread
• Any region deemed to be at risk of microscopic disease spread

60. Boost fields
Phase II
• Either The whole bladder or
• Only the involved part of bladder with at least 2 cm margin
• Techniques
1) 2 lateral fields
2) oblique fields

61. Dose Fractionation Schedule
• 1.8- 2 Gy / #, to a total dose of 45 – 50 Gy to the whole pelvis
• Followed by a boost to smaller volume to a combined total dose of 60-65
Gy

62. Target Volumes or Field Localization
• 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)
• For patients with negative margins, the nodal regions at risk should be
contoured: the distal common iliac, internal iliac, external iliac, obturator,
and presacral nodes.
• For patients with positive margins, in addition to these nodal volumes, the
cystectomy bed should be contoured as well

63. 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.

64. Planning target volume (PTV):
• 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.

65. •ITV:Intermediary internal target volume (ITV) to be used with daily 3D image
guidance to ensure that the bladder is appropriately covered on a daily basis.
•kV-kV matching to the pelvic bones, followed by cone beam CT (CBCT) to ensure
that the bladder is completely within the ITV bladder volume
• If it is not, the patient is asked to void, and repeat pretreatment imaging is per-
formed. This process ensures that the bladder is not overfilled

67. Systemic Chemotherapy
• A meta-analysis of 11 completed randomized trials of neoadjuvant chemotherapy for
invasive bladder cancer (3,005 patients) demonstrated a 5% OS benefit at 5 years (HR,
0.86; 95% confidence interval [CI], 0.77 to 0.95; P = .003), supporting the role for
platinum-based combination neoadjuvant chemotherapy(standard MVAC).
• MVAC is administered in 28-day cycles, with starting doses of methotrexate 30 mg/m2
(days 1, 15, and 22), vinblastine 3mg/m2 (days 2, 15, and 22), doxorubicin 30 mg/m2
(day 2), and cisplatin 70 mg/m2 (day 2)
• Toxic effects of MVAC include neutropenia, anemia, thrombocytopenia, stomatitis,
nausea, and fatigue

68. • GC was compared with MVAC in a multicenter phase III study. MVAC was administered as previously
described, and GC was administered in 28-day cycles with gemcitabine 1,000 mg/m2 (days 1, 8, and
15) and cisplatin 70 mg/m2 (day 2).
• In the study, 405 patients were randomized to one of the two treatment arms, and the two groups
exhibited similar characteristics. Median survival was 14 months with GC and 15.2 months with
MVAC, which were statistically comparable.
• Patients treated with GC, however, had significantly less toxicity and improved tolerability. Patients
receiving GC gained more weight, reported less fatigue, and had better performance status than
patients who received MVAC.
• A randomized phase III trial compared the standard GC regimen with GC plus paclitaxel. Despite a
response rate that was superior in the three-drug arm (55.5% versus 43.6%; P = .0031) and a median
OS that was slightly longer in patients receiving the third drug (15.8 versus 12.7 months), the HR for
survival did not achieve statistical significance (HR, 0.85; P = .075). Thus, the standard of care
remains GC

74. Follow up

76. Advanced Bladder Cancer
(ABC) Meta-analysis
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
Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Vale, C The Lancet ,
Volume 361 , Issue 9373 , 1927 – 1933,2003
Metaanalysis

77. 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

78. Plan of the day treatment ( POD)
• Adaptive radiotherapy with a
“plan-of-the day”treatment
concept is an attractive option in
bladder cancer due to the daily
variability in bladder filling.
• A recent proof-of-principle study
in a small number of patients
has demonstrated that this
strategy can significantly reduce
the dose to the surrounding
normal tissues
• In this study, three to four different
treatment plans were calculated with
different filling states of the bladder
and the optimal plan was chosen daily
on the basis of a cone-beam CT
prior to treatment.
• This study has also demonstrated
large interindividual and interfractional
variabilities in daily bladder filling.