• Non–muscle-invading tumors are managed by
TURBT alone in the case of low-grade lesions and
together with intravesicular bacille Calmette-
Guérin (BCG) therapy for high-grade lamina
propria invasion or CIS.
• Over a span of 10 years, as many as 50% of the
latter group will progress to muscle invasion.
Intra vesical Bacille Calmette-Guérin
• Intravesical therapy involves the instillation of high local
concentrations of a therapeutic agent into the bladder,
potentially destroying viable tumors cells and preventing
• A live attenuated form of Mycobacterium bovis, is currently
the most effective and most commonly used intravesical
agent for the treatment of non– muscle-invasive TCC of the
• BCG is typically instilled into the bladder weekly for 6 weeks.
• The role of maintenance BCG for longer than 6 weeks
• Triggers a variety of local immune responses and has been
shown to be effective in reducing rates of disease
progression, decreasing rates of recurrence and the need for
subsequent cystectomy, and improving rates of survival.
• Toxicities of intravesical therapy include symptoms of
bladder irritation (dysuria and frequency).
• To minimize the risk of systemic infection, intravesical
therapy should not be given to patients with traumatic
catheterization, active cystitis, or persistent gross
• Those treated with BCG had significantly fewer
recurrences at 12 months(Many RCTs)
• Nonetheless, 50% of patients with T1/CIS will experience
muscleinvading cancer at 10 years. Progression rates to
muscle invasion among patients who respond to BCG are
1% at 1 year, 5% at 3 years, and 15% at 5 years
• In the six published RCTs in which TURBT plus BCG was
compared with TURBT alone, recurrence rates ranged
from 20% to 42% with intravesical therapy versus 42%
to 100% without it.
• Other Agents--mitomycin, doxorubicin, epirubicin,
valrubicin, thiotepa, gemcitabine, interferon, and
docetaxel. None has proved consistently superior to
Role of Irradiation in High-Risk Superficial Bladder
• Dutch South Eastern Bladder Cancer Group :
– 121 patients with T1G3 cancers.
– 119 EBRT with 50 Gy/25 fractions was one treatment
option, and 17 patients received this. Though the
numbers are limited, the treatment appeared to be as
effective as intravesical BCG or mitomycin.
• University of Rotterdam with interstitial implants
– In this selective but prospective series, patients with
single T1 tumors of less than 5 cm in diameter underwent
TURBT and subsequent local irradiation of the tumor area
in the bladder wall by an interstitial radium implant.
– The definitive local control rate was 82% and the 10-year
OS was 76%.
Muscle-Invasive Bladder Cancer
• 20% to 25%
• The most appropriate treatment algorithm for
muscle-invading disease remains controversial.
• Although radical cystectomy and urinary diversion
• the mainstay for treatment for decades, organ-
preserving regimens using predominantly multiple-
modality therapy, consisting of TURBT followed by
irradiation with concurrent chemotherapy, are
emerging as viable proven alternatives in a subset
• Radical Cystectomy
• Surgical removal of the bladder, adjacent organs, and
regional lymph nodes
• In men, the bladder, prostate, seminal vesicles, proximal
vas deferens, and proximal urethra, with a margin of
adipose tissue and peritoneum, are resected en bloc.
• In women, the procedure involves an anterior pelvic
exenteration to remove the bladder, urethra, uterus,
fallopian tubes, ovaries, anterior vaginal wall, and
surrounding fascia en bloc.
• The extent of pelvic lymph node dissection is an
important predictor of outcome,
– extended template dissection --to include presacral and
common iliac lymph nodes to the aortic bifurcation and often
more proximal to the origin of the inferior mesenteric artery,
in addition to pelvic lymph nodes distal to the common iliac
Incontinent Urinary Tract Reconstruction:
Ileal conduit-Urine drains directly from the ureters
through a segment of ileum to the skin surface, where
it is collected by an external collection appliance.
Continent Urinary Tract Reconstruction.
• Continent urinary reservoir made of bowel, which
drains to a stoma that can be catheterized
– The Kock pouch(Cutaneous Urinary Reservoir)
• Creation of an orthotopic neobladder, in which a
newly formed urinary reservoir made out of bowel is
anastomosed to the urethra
– The Mainz pouch(ileocecal)
– The Hautmann pouch(W-shaped ileoneobladder)
– Risk of urethral recurrence later on.
Outcomes after radical Cystectomy
• University of South
• Actuarial 5 year OS at
5 years :48% and at
10years : 32%
Stein JP et al. J ClinOncol 2001; 19:666-675.
• MSKCC experience
• N=184 [pT2-T4]
• 5 year OS:36%
Dalbagni G et al.JUrol 2001; 165:1111-1116.
Radiation as an Adjunct to
• Preoperative Radiation Therapy
– Danish National Bladder Cancer Group, DAVECA protocol 8201,
– 183 pts, T2–T4a,RCT, Preop RT-Cystectomy Vs Radical RT
(Salvage cystectomy if residual)
• A trend for a higher survival rate following combined
treatment with preoperative irradiation and cystectomy
compared to radical irradiation followed by salvage
cystectomy was observed
• There was no difference in surgical complications between
planned and salvage
• T-stage, response to radiotherapy and frequency of LN
metastases were found to be of prognostic importance
• Postoperative Radiation Therapy
• Postoperative radiation therapy has been evaluated
in only one randomized study.
• The National Cancer Institute of Egypt :
– 236 patients with T3 to T4 tumors (68% were SCCs) who
received postoperative irradiation (using three daily
fractions of 1.25 Gy each, with 3 hours between fractions,
up to a total dose of 37.5 Gy in 12 days [75 patients]; or
conventional fractionation for a total dose of 50 Gy over 5
weeks [78 patients]).
– The 5-year rates of disease-free survival (DFS) (44% to
49% vs. 25%) and
– local control (87% to 93% vs. 50%) were improved and
the incidence of pelvic recurrence was significantly
reduced in the groups receiving postoperative radiation.
• Ideal candidate for bladder preservation–
– Primary T2 to T3a tumors that are unifocal
– Tumor size less than 5 cm in maximum diameter
– Tumor not associated with extensive CIS
– No presence of ureteral obstruction or tumor-
– Good capacity of the bladder
– Visibly complete TURBT
– Adequate renal function to allow cisplatin to be given
concurrently with irradiation
• Conservative Surgery
• Partial Cystectomy:
• Careful patient selection
– the lesion is solitary and is located in a region of the
bladder that allows for complete excision with a 2-cm
tumor-free margin, such as the bladder dome.
• association with CIS in other sites of the bladder,
• prostaticurethral involvement,
• prior recurrent bladder or upper tract tumors, and
• bladder neck or trigone tumors in which ureteral reimplantation
would be required to achieve an adequate margin
• Only 6 to 19% of pts qualify
• Recurrence rates range 38% to 78%; half of the recurrences
appear in the first year and two thirds by 2 years
• TURBT for invasive ca
– Clinical complete response rates assessed
cystoscopically with repeat biopsy 3 weeks after
initial TURBT for T2 and T3 cancers overall are in the
10% to 20% range
– Although potentially effective in a small proportion
of favorable T2 tumors, TURBT is usually not
sufficient as monotherapy in muscle-invading
• Radical EBRT:
• Dose varied from 50 to 65 Gy, with 1.8 Gy to 2 Gy
• Response was evaluated by cystoscopic
examination and biopsy 3 to 6 months after
completion of RT
• Pts-Residual tumor and no known metastatic
disease underwent salvage surgery
• The 5-year local control rate ranged from 31% to
50% for the entire patient population and from 49%
to 79% for the subgroup of patients with a
Factors reported as having a significant favorable effect on local control with RT included:
• Early clinical stage (T2 and T3a)
• Absence of ureteral obstruction
• Complete response
• Visibly complete TURBT
• Absence of coexisting CIS
• Small tumor size (<5 cm maximum diameter)
• Solitary tumors
Tumor configuration (papillary vs. sessile)
Hemoglobin level (>10 mg/dL)
• EBRT + Interstitial Brachytherapy:
– Appropriate candidates --are those with a solitary TCC with a
diameter of less than 5 cm or stage T1 disease (with high
grade) to T3a disease (muscle invasion but no extension
through the wall).
– 5 yr- local control rates for selected patients treated with
brachytherapy in combination with EBRT do appear to be
excellent, varying between 70% and 90% with correspondingly
high rates of bladder preservation.
– In selected patients, survival rates appear to be similar to
those of cystectomy
– The most serious acute morbidity is fistula with wound
leakage. This is most strongly predicted by tumor size, active
length of radioactive sources, and use of a partial cystectomy.
• Combined-Modality Therapy:
• Chemotherapy and Conservative Surgery
• CT /TURBT // Partial cystectomy
• Complete or major response to chemotherapy
• Solitary lesion in the dome or the anterior wall of the
• No history of prior invasive bladder cancer
• No CIS
• Good bladder capacity
• Although 5-year survival rate is high at close to 50%,
bladder preservation is possible in less than half of
• Neoadjuvant Chemotherapy before Definitive
• Most of the RCTs used single drug
– No survival advantage compared to other arm
• Some studies which used cisplatin based multidrug
– no consistency in results.
• A meta-analysis that included data from 3005
patients enrolled in 11 randomized trials
demonstrated a 5% absolute 5-year OS advantage
(50% vs. 45%; p = .003) for neoadjuvant cisplatin-
based combination chemotherapy compared with
local therapy alone.
• Adjuvant Chemotherapy after Definitive Local Therapy
– Adjuvant chemotherapy allows for pathologic staging and
avoids delay in potentially curative local therapy.
– No randomized trials have compared neoadjuvant to adjuvant
CT in patients undergoing definitive local therapy
– A meta-analysis including 491 patients from six trials
suggested a 25% relative reduction in the risk of death (p =
.019) for patients receiving cisplatin-based combination
adjuvant CT; however, the power of this meta-analysis was
– A RCT phase III trial from the Spanish Oncology Genitourinary
Group (99/01) comparing four cycles of adjuvant
paclitaxel/gemcitabine/cisplatin to observation in patients
with resected high-risk (pT3 to T4 or pN+) bladder cancer was
prematurely closed due to poor accrual; however, preliminary
results suggest improved 5-year OS (60% vs. 31%; p = .0009)
• Trimodality Therapy Using Limited Resection,
Chemotherapy, and Radiation in Bladder Preservation:
• The rationale
– Certain cytotoxic agents, in particular, cisplatin and 5-
fluorouracil (5-FU), are capable of sensitizing tumor tissue to
irradiation, therefore increasing cell kill in a synergistic fashion
– Patients with muscle-invading TCC harbor occult metastases in
approximately 50% of cases, which makes a case for the
addition of systemic chemotherapy in an attempt to control
occult distant disease.
• Many phase II trials have combined chemotherapy and RT
in different sequences in patients with invasive bladder
• Although a variety of different drugs and radiation doses
have been used, it is apparent that the highest clinical
complete response rate (T0) was achieved in patients who
received concurrent chemotherapy and RT compared with
• The MGH Experience:
– T2 to T4aNXM0, 348 pts
– Concurrent cisplatin-based CT and RT after maximal TURBT with or
without neoadjuvant/adjuvant CT
– Visibly complete TURBT was achieved in approximately two thirds of
patients and a complete response rate to induction chemoradiation in
72%(≈40 Gy in 1.8- to 2-Gy fractions).
– Complete responders and those medically unfit for cystectomy
received boost chemoradiation to 64 to 65 Gy.
– Five- and 10-year OS: 52% and 35%, respectively.
• 102 patients (29%) ultimately underwent radical cystectomy,
17% for a response that was less than a complete response and
12% for recurrent invasive tumors.
• Combined-modality therapy achieved a complete response and
preserved the native bladder in approximately 70% of patients,
while offering longterm survival rates comparable to those in
contemporary radical cystectomy series
• RTOG 95-06, 2000
• 34 patients with clinical stage T2–T4a, Nx M0 without hydronephrosis.
– After performing as complete a transurethral resection as possible,
induction chemoradiotherapy was administered. (cisplatin and 5-
fluorouracil, radiation was given twice a day, 3 Gy per fraction to the pelvis
for a total of 24 Gy).
– Patients with a complete response received the same drugs combined with
twice-daily radiation therapy to the bladder and a bladder tumor volume of
2.5 Gy per fraction for a total consolidation dose of 20 Gy. Median follow-up
was 29 months.
• After induction treatment, 22 (67%) of the 33 patients had no tumor
detectable on urine cytology or rebiopsy.
• Of the 11 patients who still had detectable tumors, six underwent radical
• No patient required a cystectomy for radiation toxicity.
• Three-year overall survival was 83%.
• Three-year survival with intact bladder was 66%.
• Both the complete response rate to induction therapy and the 3-year
survival with an intact bladder were encouraging.
• RTOG 97-06, 2003
• 47 eligible patients with stage T2–T4aN0M0.
– Median follow-up was 26 months. TURBT within 6 weeks of the
initiation of induction therapy [13 days of concomitant boost RT, 1.8
Gy to the pelvis in the morning followed by 1.6 Gy to the tumor 4–6 h
later and cisplatin (20 mg/m2)].
– Three to four weeks after induction, the patients were evaluated for
• In the consolidation phase, 1.5-Gy fractions were given to both,
twice daily for 8 days (total dose, 45.6 Gy to the pelvis and
bladder and 64.8 Gy to the bladder tumor).
• After consolidation chemoradiation or cystectomy (depending
on the response), patients received three cycles of adjuvant
– CR rate was 74%.
– Three-year rates of locoregional failure, distant metastasis, overall
survival, and bladder- intact survival were 27, 29, 61, and 48%,
• Adjuvant MCV chemotherapy appears to be poorly tolerated.
• RTOG 99-06(2009)
– 80 patients with T2–T4a; twice-daily radiotherapy
with paclitaxel and cisplatin chemotherapy induction
(TCI) was administered. Adjuvant gemcitabine and
cisplatin were given to all patients.
– TCI resulted in 26% developing grade 3–4 acute
toxicity, mainly gastrointestinal (25%).
– The post induction complete response rate was 81%
– Thirty-six patients died (22 of bladder cancer).
– Five-year overall and disease-specific survival rates
were 56 and 71%, respectively.
Inference- Combined multimodality therapy
• The primary goal of bladder-preserving therapy, as with
any therapy for muscle-invading TCC of the bladder, is
optimizing patient survival.
• Bladder preservation in the interest of quality of life can
only be considered a secondary objective.
• The long-term outcome data presented above from
singleinstitution and cooperative group experience
suggest that modern combined-modality therapy results
in complete response rates of 60% to 80%, 5-year OS of
45% to 60%, and
• 5-year survival with an intact bladder of 40% to 45%.
• Although no randomized comparisons of cystectomy
with combinedmodality therapy exist, these long-term
survival rates are encouraging and similar to those
reported in contemporary radical cystectomy series
Randomized Trials: CTRT vs RT
• NCI-Canada, 1996 (1st Trial)
– 99 patients with T2–T4b.
• Treated with either RT or CTRT (with concurrent
• Median follow up:6.5 years
• Loco-regional relapse rate better with CTRT
(50% vs. 33%)
• No difference in OS or distant metastasis
• Radiotherapy with or without chemotherapy in
muscle invasive cancer bladder (Nicholas et al) NEJM
– Multicenter Phase III randomized trial
– Muscle invasive bladder cancers randomized to :
• Whole bladder radiotherapy
• Modified volume radiotherapy to bladder withconcurrent
fluorouracil and mitomycin C
• Primary end points: Survival free of loco-regional
• Secondary end points: Overall survival and toxic
• At 2 years, DFS was 67% (CTRT) vs. 54%(RT);P=0.03
• Grade ¾ adverse events were 36% (CTRT) vs. 27.5%
• Prognostic factors in CT-RT
– T Satge
– Visibly complete TURBT
– Presence of hydronephrosis
– Presence of TCIS disease along with invasive
– Managing recurrent disease
• Managing recurrent disease
– Superficial– TURBT and Intravesical BCG
– Invasive– Salvage cystectomy
• In selected series, salvage cystectomy results in a 40% to
50% survival rate at 5 years and a locoregional control rate
LOCALLY ADVANCED DISEASE
• Voiding symptoms are not severe and if renal function
allows, it is common to give combination chemotherapy ()
if not non platinum based)
• If patients have had a good response, they may receive
consolidation chemoradiation delivered with “curative”
• PCN if hydronephrosis.
• ? Resection and IORT
• Unfit for cystectomy : ? Role of RT
• Metastatic: MVAC /MACregimen
• Palliative RT --for bone and brain mets; IVCO in case of
para aortic nodes
Radiotherapy treatment techniques
– Bladder filling variability to be minimized
– Supine position with bladder empty [most
commonly recommended approach]
• Target Volumes:
– Initial Phase: Bladder with a margin of 2 cm
(Include prostate in males and proximal 2 cm of
urethra in females). External and internal iliac group
of lymph nodes covered. Care taken to exclude
vulva and excess part of bowel (upper border
usually not above mid SI Joint)
– Boost Phase: Controversial [Entire bladder vs.
bladder tumor with a 2 cm margin]
• Four field planning with differential weight age
[70% AP and 30% lateral] for Initial phase
• Two lateral portals for boost phase
• Anterior–posterior field
– Superior: between S1 and S2 (midsacrum)
– Inferior: below the obturator foramen (if bladder neck
and/or prostatic urethra:
– 1.5 cm below obturator foramen)
– Lateral: bony pelvis + 1.5–2 cm
• Lateral fields
– Superior and inferior: same as anterior–posterior
– Anterior: anterior to pubic symphysis + 1 cm
– Posterior: at least 1–3 cm posterior to tumor
• Anterior–posterior field: femur heads are
shielded; lateral fields: two-thirds of posterior
rectum and small intestines are shielded.
• Boost field:
Bladder + 1.5–2 cm margin
• Nodal RT fields (40 to 45Gy) are designed to conserve small
bowel for urinary diversions should they be needed
• Boost:Only partial bladder to high dose(total 65 Gy)
• Radiation dose: 40-45 Gy for the initial phase and
10-20 Gy for the boost phase [Dose response >
• Dose Fractionation: 1.8- 2 Gy/fraction
[Hyperfractionation has also been tried]
• Different practiced fractionation regimens:
64 Gy/32#, 55 Gy/20#,36 Gy/6#
• Partial Bladder Treatment:
– Careful selection is, however, necessary, with such
approaches being limited to patients with smaller
tumors (<5 cm) or unifocal tumors or those without
extensive Tis disease elsewhere in the bladder
– Estimates of bladder tolerance have been made that
suggest that up to 80 Gy could be given if one-third
of the bladder is spared, whereas 65 Gy is the limit
for whole-bladder treatment
– RCT from UK --has shown that partial bladder
irradiation does allow for the delivery of a higher
dose to the tumor than the whole
– But didn’t show improvement in either local control
or survival rates
• Treatment Margins
• PTV margin -- isotropic 2-cm margins around either the
bladder(first phase of treatment) or tumor (boost) in all
• This is to account for setup errors and organ motion
• The greatest degree of bladder wall positional change
occurred in the cranial direction, with the least
variation in the anteroinferior direction, limited by the
• It is clear that organ motion is the dominant source of
• Graham and associates have 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 margin
incorporate much normal tissue.Hence daily image
guidance is preferred.
• Other ideas: Use of fiducial markers that could be placed by the
urologist at the time of TURBT in the bladder wall around the
• Roof and colleagueshave shown that if the daily treatment is
centered on the bladder centroid rather than referenced to the
bony anatomy, margins of less than 1.5 cm could be feasible
– Acceleration with fraction sizes of 2 Gy seems to increase
the acute toxicity.
– The RTOG has therefore explored acceleration with
hyperfractionation, and recent protocols have employed
fraction sizes of 1.2 to 1.8 Gy with a concomitant boost
– A randomized trial of 168 patients with T2 to T4 tumors,
unsuited for cystectomy, compared hyperfractionated
EBRT (1 Gy three times a day to a total dose of 84 Gy) with
conventional fractionation (2 Gy every day to 64 Gy)
• Hyperfractionation achieved superior results with respect to
survival at 5 years (27% vs. 18%), local control (12% vs. 7%), and
clinical complete response rates (59% vs. 36%), with an increase
in late toxicity.
• It should be noted, however, that patients in the conventional
fractionation arm did poorly compared with those receiving
similar treatment in other studies, largely because patients unfit
for cystectomy were taken in this study.
– Shortly after completion of the preoperative irradiation
regimen (<2 weeks), a suprapubic cystotomy is performed
to ascertain the true dimensions of the tumor and to
confirm that it is indeed unifocal.
– The target area is determined by the surgery and is either
the bladder scar after partial cystectomy or the
macroscopic tumor plus a 1.5- to 2-cm margin.
– Narrow afterloading tubes are then inserted into the
target area parallel and halfway through the bladder wall.
– If less than 10 to 15 Gy is given preoperatively, then 30 to
60 Gy is given using low-dose-rate therapy. The lower
doses are given to those who have had partial
cystectomies or complete resections.
– In the Netherlands, 30-Gy EBRT is either supplemented
with 40-Gy low-dose-rate treatment or 10 fractions of 3.2-
Gy, high-dose-rate treatment (two fractions per day with a
6-hour interval between fractions).
Follow up after CTRT
• All patients opting for bladder preservation
approach must be willing for regular follow up
• Optimal time of cystoscopy after completion
of RT: Unclear [Usually done at 3 months]
• Cystoscopy and urine cytology every 3 months
for first 2 years, then every 6 months until 5
years, and annually thereafter*
• *MGH Protocol/NCCN Guidelines
Quality of life after chemo-radiation
• Radical Cystectomy:
– Overcome with continent diversions
• Bladder conservation protocol:
– Reduced bladder compliance
– Involuntary detrusor contractions
– Rectal urgency
– N=221 [T2-4a bladder cancers]
– Treated with tri-modality therapy [1986-2000] at MGH
– 71 alive patients in 2001 included: urodynamic study and a
– Median follow up : 6.3 years
– 70% patients participated in the study
• Major morbidity was bowel symptoms: 22%
• Control problems:19%;urgency:15% and flow
• Pad use among women:11%
• Majority of men retained sexual function
– N=285 [1990-2002];
– Patients from four prospective RTOG trials
– 157 patients treated with CTRT and surviving >2 years with
intact bladder included in the study
– RTOG late morbidity schema used to grade toxcities.
– Median follow up: 5.4 years
• Grade 3+ pelvic toxicity :7% [5.7% GU and 1.9% GI]
• No Grade 4 late toxicity and no treatment related deaths
• Bladder preservation approach: very good late term
outcomes with intact bladder
• Concurrent chemo-radiation achieves CR rates of
~70 and preserves bladder with comparable OS
to radical Cystectomy.
• QOL studies: Retained native bladder functions
well and long-term toxicity of chemoRT to pelvic
organs is relatively low.
• Long term toxicity of bladder preservation
protocols are low.
• Patient selection is a key and regular follow up is