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By: Dr Satyajeet Rath
Moderator: Prof Kamal Sahni
Aim of Management of Bladder cancers- Stage wise
•Superficial bladder cancer- prevent recurrent and progression to muscle
•Muscle invasive bladder cancer- patient selection for cystectomy and for
bladder preservation protocol and for integrated systemic chemotherapeutic
•Metastatic bladder cancer- palliation and quality of life.
Urinary Bladder Cancer
NMIBC (75%) Muscle Invasive
cancer - MIBC(20%)
Metastatic cancer (<5%)
Petrovich JCO 2001
Non-muscle-Invasive Bladder Cancer -
• 70-80% of patients with bladder cancer present with NMIBC
• Tis, Ta, and T1
• 50-70% will recur; 10-20% will progress to MIBC
• Low grade (G1,2) and lower stage (Ta) – 50% recurrence rate
• Higher grade (G3, T1 with CIS, multifocal) – 70% recurrence rate
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
• 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
• Biopsy from the prostatic urethra is necessary in some cases. tumour located
on trigone or bladder neck, multiple tumours
Second look TURBT?
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 absent (50% vs 15%) [Herr JU 1999]
1/4 will have upstage [Herr JU1999]
1/3 will have to change management [Herr JU 1999]
European Association of Urology Guidelines 2015
Predicting recurrence and progression of NMIBC
EORTC bladder cancer calculator
CUETO risk calculator
EORTC - predict recurrence
and progression in patient with
stage Ta, T1 bladder cancer
• number of tumors
• prior recurrence rate
• T category
• presence of CIS
CUETO - predicts risks of
recurrence and progression for
• prior recurrence status
• number of tumours
• T category
• associated CIS;
• tumour grade
CUETO risk calculator is available
European Organisation for Research and Treatment
of Cancer. Bladder cancer calculator.
Treatment recommendations in Ta, T1 tumours and CIS according to
risk stratification – EAU Guidelines
European Association of Urology Guidelines 2015.
Indications of adjuvant intravesical therapy after TURBT in
• Intermediate & high risk features
• Incomplete excision especially in T1 tumors
• tumors rapidly recur following TURBT of the initial bladder
• persistent tumor cells on urine cytology during surveillance
• Adjuvant therapy is given in the form of intravesical
administration of immunotherapy or chemotherapy.
• 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
Chemotherapeutic agents used are mitomycin C, doxorubicin, and
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
• Thiotepa causes myelosuppression
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
• 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.
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 yrs
• 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.
*European Association of Urology Guidelines 2015.
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%
with urine cytology is
standard of bladder
3 months after
repeated at 9
months & then
• between that used for
low- and high-risk
• adapted according to
personal and subjective
• 3 monthly flexible
cystoscopy for 2 years
• 6 monthly for further
• then annually
Muscle Invasive Bladder
• Although the majority of patients present with NMIBC, 20% to 40% will
either present with or ultimately develop muscle-invasive disease.
• Goals of treatment :
• Cure patient
• Optimize survival
• Prevention of Pelvic failure and Distant metastasis
• Functional Urinary reservoir and High Quality Of Life
Surgery: Radical cystectomy
• 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
• 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
• 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
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
Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol 2006
(incontinent diversion to
(continent diversion to skin)
(continent diversion to
Types of Urinary Diversion
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
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.
Proximal: Bifurcation of common iliac artery
Distal: Circumflex iliac vein
Lateral :Gentitofemoral nerve
Medial: Bladder wall
Pelvic floor and hypogastric vessels
Anything more (up to bifurcation of aorta and above) can be called an extended
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,
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
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.
The Bladder Cancer Collaborative Group recommends 10-14 lymph nodes
should be removed at time cystectomy
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
No trials have till date directly compared Cystectomy
• 2 main concerns about bladder preservation compared with radical
• 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
• Careful patient selection
• Solitary lesion
• Location: allows for complete excision with a 2-cm tumor-free margin like bladder
• Contraindications :
• Bladder neck or trigone tumors
• Association with carcinoma in situ
• Prostatic urethral involvement
• Prior recurrent bladder tumors
• 6 - 19% of patients with primary, MIBC are potential candidates
• Local recurrence rates : 38-78%
• Half of the recurrences appear in the first year and two thirds by 2 years
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.
• Traditionally RT alone was given only for unfit/older pts
• Definitive radiotherapy gives consistent and reproducible effects
• It’s a viable option for bladder preservation
• Results are better in younger, fitter and in those without extravesical disease
• Poor prognostic factors in Radical cystectomy hold true for radical radiotherapy series
Ideal candidate for definitive Radiotherapy
• Disease confined to the bladder
• With good bladder function
• cT2 tumor
• No associated CIS
• Willingness for prolonged course of therapy & regular follow up
Contraindications of pelvic Radiotherapy
• Pt with active inflammatory bowel disease
• Previous pelvic irradiation
• Pts with extensive bladder CIS are at high risk for tumor recurrence after RT so
cystectomy should be done
Cozzarini IJROBP 1999
• 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
• 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
Bladder protocol to account for organ motion in conformal
• Patient is asked to void the urine and empty the bladder as much as possible.
• Patient is asked to drink 500 ml of water and time is recorded.
• After 60 minutes of drinking water, CT simulation without contrast is performed
suggestive of full bladder
• Thereafter, patient is asked to void urine and empty the bladder as much as
possible and CT Simulation with contrast enhancement is performed suggestive
of empty bladder
• Both images (with full bladder and empty bladder) are 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.
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
• Dose:40-45 Gy @ 1.8-2Gy/#
• 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)
• Treat the bladder+tumor with a 2-cm margin to a total dose
of 66 Gy
Gross Tumor Volume (GTV): macroscopic tumor visible on radiological imaging/ cystoscopy
findings provided by the urologist during TURBT
Clinical target volume (CTV):- It shall include: CTV_Primary + CTV_LN
– 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
Planning target volume (PTV_Primary):
• CTV_Primary is given a 1-1.5 isotropic margin to create the PTV_Primary.
• PTV_LN: 1 cm isotropic margin is given to CTV_LN.
• PTV_Primary booleaned (added) with PTV_LN to produce a PTV_Total in order to facilitate
• Both images (with full bladder and empty bladder) are 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 form the primary image for GTV and CTV delineations.
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 a way to reduce these margins
• 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.
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
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
• 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
Areas at risk for harbouring residual microscopic disease should receive 45 to 50.4
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.
• Caution: However morbidity of post operative radiation is high due to small
bowel toxicity that occupies pelvis after cystectomy.
• 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
• Doses :
• 40 Gy in 2 Gy daily fractions is followed by a brachytherapy dose of 25–30Gy EQD2
• When brachytherapy is combined with a partial cystectomy the brachytherapy dose can be
reduced to 15–20 Gy EQD2
Pieters BR et al. GEC-ESTRO/ACROP recommendations for performing bladder-sparing treatment with brachytherapy for MIBC. Radiother Oncol (2016)
Combination of maximum TURBT Resection, Chemotherapy, and
Irradiation in Bladder Preservation
• Best results till date in bladder preservation when the 3 modalities are
• Based on both single institutional data and randomised control trials
• 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
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
Rationale For Combining Chemotherapy With RT In
Pioneering single institution studies of Trimodality
Multi-modality Treatment Evolution In RTOG trials
Surgery and radiotherapy are not competing, but are
complementary approaches to invasive bladder cancer
Poor RT candidates
• poorly functioning bladders
• extensive CIS
• pT1G3 disease
Poor surgical candidates
• older patients,
• Medical comorbidities
• poor anesthetic risk pts
• Non compliant to urinary diversion
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
CTRT with 5-FU and mitomycin C
• Median FU - 70 months
DFS 67% 54% 0.03
OS 48% 35% 0.16
Conclusion about agent of choice for CT-RT in bladder
• 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.
• 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
Role of systemic chemotherapy
• Aim: to reduce micro metastasis and improve survival in MIBC
• Decrease micrometastatic spread
• Potentially downstaging the tumor
• 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
Randomized Phase III Trials of Neoadjuvant Chemotherapy
Advanced Bladder Cancer
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
Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Vale, C The Lancet ,
Volume 361 , Issue 9373 , 1927 – 1933, 2003
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
Adjuvant Chemotherapy After Definite Local
• 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
• 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.
Metastatic Bladder Cancer
• The prognosis of metastatic bladder cancer, is poor, with a median survival
on the order of only 12 months.
• 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
• However, the duration of response is short, with a median of 4 to 6 months,
• Therefore, the impact of chemotherapy on survival has been disappointing
• 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