This document discusses bladder cancer. Some key points: 1. Bladder cancer is the most common tumor of the urinary tract and the second most common cause of cancer death. 2. Bladder cancer presents at a muscle-invasive stage in 20-40% of cases. 3. Diagnosis involves cystoscopy, urine cytology, imaging like CT/MRI, and biopsy. 4. Treatment depends on stage - non-muscle invasive cancers receive transurethral resection and intravesical therapy while muscle-invasive cancers require radical cystectomy and urinary diversion.

1. Presenter: Dr. Prashant Surkar
Moderator: Dr. Manoj Pal

2.  Most common tumor of the urinary tract & second most common cause of
death.
 20% to 40% present with muscle invasive disease
 Europe > rest of the world. Higher in hawaii and utah than rest of america
 2.7 times more common among men
 White >black
 Incidence: 3,86,000/yr
 Mortality: 1,50,000/yr
 Disease of elderly- 67-70 yrs
 Young patients- better prognosis
Introduction

3.  Signs and Symptoms
 Urine Cytological Studies
 Flow cytometry
 Diagnostic tumour markers
 Ultrasonography
 Diagnostic Imaging
◦ IVP
◦ Ultrasound
◦ CT
◦ MRI
 Cystoscopy and Biopsy
 Bimanual Examination
 Transurethral resection of bladder tumour

5.  For advanced or invasive
disease
 Under GA with full
relaxation
 Performed prior to tumour
resection and then again
after endoscopic resection
 Superficial tumour-
Disappearance of mass
 Invasive tumour -
Fixed/Indurated or mass
persists after resection

6.  It provides direct visualization of the
bladder and facilitates biopsy of the
bladder.
 The number, size, shape, and
location of tumors as well as
appearance of the surrounding
mucosa, urethera and uretheral orifice
are documented.
 Fluorescence cystoscopy after
intravesical instillation of a
photoactive substance (e.g.,a
porphyrin such as 5 aminolevulinic
acid) that preferentially accumulates
in neoplastic tissue may be more
effective than white light cystoscopy.

7.  Cystoscopy is indicated in :-
a) Any gross or microscopic hematuria.
b) Unexplained or chronic lower urinary tract symptoms
c) Urine cytology that is suspicious for cancer.
d) History of bladder cancer.

8.  Gold standard for non invasive screening of urine of bladder cancer.
 Sensitivity: 40-60%
 Specificity: 98%
 Used to complement the findings of cystoscopy
 Extremely valuable for the diagnosis of high grade TCC especially
CIS that might be difficult for the endoscopist to visualize, and upper
tract malignant disease.
 For the diagnosis of low grade papillary
tumour, cytologic testing is not sensitive,
because the appearance of grade 1 TCC is
identical to that of normal urethral cells

9.  Measures DNA content of cells (S-phase cells)
 It quantitates the aneuploid cell population.
 If > 15% cells are aneuploid-suggests cancer
 Diploid tumours- favourable prognosis
 Triploid /Tetraploid tumours- unfavourable
 If > 10 % S Phase cells – lymph node metastasis

10.  Intravenous urography
 USG
 CT Urography
 MRI

11.  Traditionally modality of choice in evaluating hematuria
 Largely replaced by CT Urography
 Used primarily to access upper urinary tract or
cytologic/cystoscopic evidence of tumour in an attempt of
primary sites in the ureter or renal pelvis.
 Only 60% bladder cancer are detected by IVP.
 Tumors appear as sessile or pedunculated filling defect.

13.  Sonographic feature includes:
 Sonographic detection of bladder tumors depends on size and
location
 Transrectal US can be useful in differentiating bladder neck from
prostatic tumor
 Focal or hypoechoic or mixed echogenicity non
mobile mass projecting into bladder lumen
 No posterior shadowing
 Focal bladder wall thickening
 Color Doppler shows increase vascularity
 Difficult to detect tumors ˂ 5 mm in size and
tumors located in neck or dome of bladder

14.  It is not sensitive in reliably describing the depth of
invasion, but it can be helpful in determining extravesical
extension and planning in subsequent treatment.
 Typically includes 3 phases:
 Non contrast phase- abnormal calcification (urinary
stones) can be identified.
 Early post contrast phase- obtained minutes after iv
administration of contrast serves to discern renal lesion
and to differentiate between abnormal lymph node and
normal anatomic structure.
 Pyelographic phase- contrast material excreted into
collecting system allowing identification of abnormal
filling defect in collecting system.

16.  Gadolinium – enhanced MRI studies may prove useful in
distinguishing superficial from invasive disease intravesical
from extra vesical tumors
 MRI might be particularly useful in detecting early nodal
metastasis.

18.  TURBT and bladder biopsy is required
 Biopsies of all suspicious areas, mucosa surrounding the area, any
exophytic lesion and the prostatic urethra as well as random biopsies of
all 4 quadrants are obtained.
 Resection should include a sample of muscularis propria for appropriate
diagnosis particularly if tumour appear sessile or high grade.
 Once the specimen has been resected ,the base of resected area should
be separately biopsied.
 Urethral biopsy are clearly indicated in patient with risk factor of
urethral involvement or who have persistent positive cytology in the
absence of demonstrated bladder lesion.
 Gunderson and Tepper 3rd edition

19. Staging

22.  For deciding management, TCC urinary bladder
carcinoma is divided into-
 NMIBC (Superficial Bladder tumour)
- Non-muscle invasive bladder cancer
 MIBC (Invasive tumour)
-Muscle invasive bladder cancer
 Metastatic Disease

23.  Surgery
 Chemotherapy
 Immunotherapy
 Radiotherapy

24.  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.

26.  Treatment
◦ TURBT
◦ Post TURBT intravesical BCG therapy weekly x 6
◦ Follow up –cystoscopy, urine cytology, upper urinary tract
imaging 3 monthly for 2 yrs, then increase interval
 Recurrence
◦ TURBT
◦ Post TURBT intravesical chemotherapy acc to grade and depth
of invasion
◦ Follow up – cystoscopy 3 monthly

27.  Treatment
◦ TURBT
◦ Post TURBT intravesical therapy – none / MMC single with
in 24 hrs
◦ Follow up –cystoscopy, urine cytology 3 monthly for 2 yrs,
then increase interval
 Recurrence
◦ TURBT
◦ Post TURBT intravesical chemotherapy acc to grade and depth
of invasion
◦ Follow up – cystoscopy 3 monthly
NO BCG

28.  Treatment
◦ TURBT
◦ Post TURBT intravesical therapy – none /BCG/ MMC (both
given single time with in 24 hrs)
◦ Follow up –cystoscopy, urine cytology, upper urinary tract
imaging 3 monthly for 2 yrs, then increase interval
 Recurrence
◦ TURBT
◦ Post TURBT intravesical chemotherapy acc to grade and depth
of invasion
◦ Follow up – cystoscopy 3 monthly

29.  Tx:
◦ —TURB
◦ —Post TURB intravesical therapy:
 Adjuvant intravesical BCG:
 Adjuvant intravesical chemotherapy (Mitomycin C):
 Single
 Within 24 Hours form TURB
 —Follow up: cystoscopy + cytology q3 m x 12 m, then
increase intervals
 —Recurrence:
 TURB +
 Adjuvant intravesical therapy according to grade and depth of invasion

30.  —Tx:
◦ —TURB
◦ —Post TURB intravesical therapy:
 Adjuvant intravesical BCG:
 Adjuvant intravesical chemotherapy (Mitomycin C):
 Single
 Within 24 Hours form TURB
◦ —Cystectomy
 —Follow up: cystoscopy + cytology
 imaging of upper Urinary tract q3 m x 24m, then increase
intervals
 —residual after conservative management :
 Cystectomy
T1, high grade

31.  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

32. 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.

33. 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]
European Association of Urology Guidelines 2015.

34.  EORTC bladder cancer calculator
 CUETO risk calculator. (Spanish Club UrológicoEspañol de
Tratamiento Oncológico)

35. 36
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

37.  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 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

38. 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

39.  Laser
 Photo-dynamic therapy
 Intra-vesical interferon (+/- BCG)

40.  Although the majority of patients present with NMIBC, 20%
to 40% will either present with or ultimately develop muscle-
invasive disease.

41. MUSCLE INVASIVE BLADDER
CANCER
RADICAL
CYSTECTOMY
WITH URINARY
RECONSTRUCTIO
N
BLADDER CONSERVATION
PROTOCOLS
RELAPSE OR
PROGRESSION
42

45.  Indications:
 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

46.  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.

47.  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

48.  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 )

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

50.  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.

51. 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.
 The Bladder Cancer Collaborative Group recommends 10-14 lymph nodes should
be removed at time cystectomy
52
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.

52.  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

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

54.  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

55.  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.

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

57. Rozan et all
N= 205 ; 8 centers in France.
Most patients T1 T2 , & median tumor size 2.9cm,
 58% underwent partial cystectomy prior to radiation
Local recurrnce – 17%
 overall survival 67% (higher than in most series of cystectomy &
EBRT)
Moderate to severe s/e - 14%
 No clinical trial compared it with conservative sx alone or 3D conformal
treatment approaches.
Its role in routine clinical practice remains unclear

58. 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

59. • 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

60. 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.

61. Pioneering single institution studies of trimodality treatment
± NACT:MCV

63.  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

64.  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.

66.  Combined modality provided better bladder preservation.
 Cisplatin was the best sensitizer
 Safe and easily administered
 Neoadjuvant CT did not added any survival advantage
 Altered fractionation especially accelerated fractionation
has given better control rates in Phase 2 trial

67.  Concurrent chemo-radiation as a part of multi-modality
bladder sparing protocol in T2-T4 N0 M0
 Neoadjuvant radiotherapy
 Adjuvant radiotherapy

68.  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

69. Phase I: Field borders
 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/#

71.  Dose:10-15 gy to entire bladder and upto 66 gy to
tumor.(aim bladder receive 60 gy)
OR
 Treat the bladder+tumor with a 2-cm margin to a total
dose of 66 gy

72.  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
 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

73. 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.

74. • 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.

75.  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

76. 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

77.  Limited data from randomized trials
 Indication: pT3-T4, positive surgical margins , pN +
 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.

78. Adequate treatment planning requires a understanding of the
normal bladder's response to radiation
Acute effects :-
Acute effects d/t injury to the rapidly dividing basal cells –
cellular swelling, vacuolization of cytoplasm, alterations in
plasma membrane
 Epithelial desquam. - focal ulceration , hyperemia &
interstitial edema
Reduced bladder capacity symptoms - acute radiation cystitis
Dysuria, nocturia, urinary frequency microscopic or gross
hematuria
Effects of radiation on the normal urinary bladder

79. Chronic Effects
Result of changes in the vasculature of the bladder wall
that lead to ischemia
Dilated vessels are often visible cystoscopically and may
spontaneously rupture - microscopic or gross hematuria
 Fibrotic, thickened, relatively avascular bladder wall -
chronic bladder contracture - dysuria, hematuria, & urinary
frequency

80. Palliative irradiation - Indications :
LOCAL DISEASE
Hematuria
Pelvic pain
Dysuria
Urinary frequency
Urgency
METASTATIC DISEASE
Spinal cord Compression
Bone pain
Nerve entrapment
Nodal metastasis causing pain/
lymphedema
Brain metastases
Bronchial obstruction or
hemoptysis
 Doses : 30 Gy/ 10 #, 35 Gy /10#& 20 Gy/ 5#

81.  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

82. 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