ROLE OF CHEMOTHERAPY &

RADIOTHERAPY IN CARCINOMA
BLADDER
DR. AYSHA SHAHEEN
III YEAR Mch
Department of Urology
GOVT ROYAPETTAH HOSPITAL
 OPTIONS
• Chemotherapy-neoadjuvant&adjuvant
• Radiotherapy-preoperative& postoperative
• Bladder Conservation Protocol
 Peri-operative chemotherapy
Rationale
• Deaths from TCC are generally not local events
• Patients die as a result of metastatic disease
• Local interventions will not deal with micro-
metastatic disease
• Systemic therapy must be given to eradicate
micrometastatic disease in order to improve
cure rates
 Adjuvant Chemotherapy

• Basis : 50% develop distant mets despite

adequate local therapy within 2 years
• Survival advantage seen in locally advanced
disease & limited nodal metastatic disease
(Skinner 1991, Stockle 1992)
• Does not delay local treatment
 WHEN is Adjuvant therapy indicated

presence of High Risk Factors After Cystectomy

• Deep muscle invasion or extravesical spread
• Prostate or adjacent organ involvement
• High grade or undiff histology
• Lymphatic or vascular emboli
• Lymph node metastases
• +ve surgical cut margins (Residual)
• Stockle et al noted a difference was noted in
the 80 patients who received adjuvant
chemotherapy as compared with 86 patients
who underwent cystectomy alone.
• adjuvant chemotherapy was most effective in
patients with N-1 disease
• usefulness of adjuvant chemotherapy is now
being tested in an EORTC/intergroup trial
 Compare and Contrast
Neoadjuvant Adjuvant
• Deals with micromets • Treats only the highest
sooner risk pts.
Concern delay in • No delay in local Rx
surgery
Best evidence of benefit • Evidence of benefit is
weaker
• ? Increased surgical • Delays in healing may
complications preclude giving therapy
• Is benefit worth it? • Is benefit worth it?
 Chemo in Invasive bladder cancer

• Adjuncts to standard surgical therapy

• Alternatives to standard surgical therapy

Neoadjuvant CT
 Rationale for Neoadjuvant Therapy
• Give systemic therapy when the pelvic blood
supply is intact
• in vivo chemo-sensitivity trial
• Deal with micrometastatic disease
immediately
• Patient is fitter and more able to tolerate
chemotherapy
 Bladder Cancer
Neoadjuvant Chemotherapy
Rationale :
• Treatment of micrometastases to improve overall survival
• Treatment of local tumour permitting organ preservation
• Determination of chemosensitivity in vivo
• More efficient & higher drug delivery
Problems :
• Progression of disease
• Delay in curative local therapies
• Toxicity of chemo
• Accurate staging not obtained
 Advantages of Neoadjuvant Therapy

• Give systemic therapy when the pelvic blood

supply is intact
• in vivo chemo-sensitivity trial
• Deal with micrometastatic disease
immediately
• Patient is fitter and more able to tolerate
chemotherapy
• study by Grossman et al
• the Nordic Cystectomy Trial 1
• The Nordic Cystectomy Trial 2
• Raghavan et al.

• Patients with muscularis propria invasive bladder

cancer (stage T2 to T4a) were randomly assigned
to radical cystectomy alone or three cycles of
MVAC followed by radical cystectomy.
 Neoadjuvant chemotherapy
• MRC trial (European)
– 967 patients randomized to CMV vs no
chemotherapy
– Definitive management of primary either
cystectomy or RT
– 7 yr follow shows statistically significant benefit
with neoadjuvant chemotherapy

Lancet 354 (9178): 533-40, 1999

• Black et al. make the case for risk-adapted
neoadjuvant chemotherapy, that is, offering
neoadjuvant chemotherapy to patients who are
at highest risk the tumor biology, the tumor
grade, the histologic subtype and biomarkers
size, clinical TNM stage, location in the bladder,
ureteral obstruction and extravesical extension
• pTo status was the only factor independently
predictive of overall survival in multivariate
analyses of four trials
 Molecular Markers in Neoadjuvant
Chemotherapy

• Takata et al studied gene expression profiles from

biopsies prior to neoadjuvant MVAC and identified 14
genes that were expressed differently in responders
and nonresponders.
SWOG phase III trial, evaluates the therapeutic and
prognostic significance of altered p53 expression by
the tumor p53 following radical cystectomy in pT1 or
pT2
with p53-negative tumors, the treatment is
observation.
with p53-positive tumors, MVAC or observation
 regime
• three 28-day cycles of MVAC as follows:
• methotrexate (30 mg/m2 on days 1, 15, and
22),
• vinblastine (3 mg/m2 on days 2, 15, and 22),
• doxorubicin (30 mg/m2 on day 2),
• and cisplatin (70 mg/m2 on day 2).
Conclusions of trials
• (1) The survival benefit associated with MVAC related to
down-staging of the tumor to pTo.
• Thirty-eight percent of the chemotherapy-treated patients
had no evidence of cancer at cystectomy as compared with
15% of patients in the cystectomy-only group

• (2) The median survival was 77 months for the

chemotherapy-treated patients compared with 46 months
for the cystectomy-only group.
• (3) The 5-year actuarial survival was 43% in the cystectomy
group, 57% in the chemotherapy-treated group
conclusions:
• single-agent neoadjuvant chemotherapy is
ineffective and should not be used;
• current combination chemotherapy regimens
improve the 5-year survival by 5%, which reduces
the risk of death by 13% compared with the use
of definitive local treatment alone (i.e., from 43%
to 38%).
• patients should be informed of the potential
benefits versus the risks of neoadjuvant
chemotherapy
Adjuvant chemotherapy
 Combination therapy
• the combination of methotrexate, vinblastine,
and cisplatin (MCV), a total of three 28-day
cycles
• four cycles of cisplatin, gemcitabine, and
paclitaxel,
 Combined Modality Treatment of
Locoregionally Advanced Disease
Caseselection
• patients with locally advanced unresectable
bladder cancer with
• 1) an excellent performance status
• (2) locally advanced measurable disease
• (3) a normal hemogram and kidney function tests
• (4) no evidence of distant metastases beyond the
common iliac lymph nodes.
• four to six cycles of combination chemotherapy,
usually MCV, or gemcitabine-cisplatin.
• If significant regression of tumor was achieved,
radiation treatment was administered in
combination with radiosensitizing chemotherapy,
usually cisplatin-paclitaxel.
• When gemcitabine was used avoid gemcitabine-
radiation interactions by using a waiting period of
at least 2 months from the completion of
gemcitabine treatment to the start of radiation
 Metastatic Bladder Cancer

• The prognosis of metastatic bladder cancer, as

with other metastatic solid tumors, is poor, with a
median survival of only12 Months transitional
cell cancer is chemosensitive
• . In phase II clinical trials, radiographic response
rates -70% to 80%, and in phase III clinical trials, -
50%
• duration of response in TCC is short, with a
median of 4 to 6 months, and therefore the
impact of chemotherapy on survival has been
disappointing
Cisplatin -single drug therapy
• the response rate to single-agent cisplatin has
been lower than that of cisplatin-containing
combination therapy.
Cisplatin-Based Combination Chemotherapy
• The standard chemotherapy regimen for
advanced bladder cancer
• methotrexate, vinblastine, doxorubicin, and
cisplatin (MVAC).
• MVAC is administered in 28-day cycles
methotrexate 30 mg/m2 (days 1, 15, and 22),
vinblastine 3 mg/m2 (days 2, 15, and 22),
doxorubicin 30 mg/m2 (day 2),
cisplatin 70 mg/m2 (day 2).
CMV, regime
• omits doxorubicin and has less toxicity.
• Cisplatin 70 mg/m2 d 2
Methotrexate 30 mg/m2 d 1, 8
Vinblastine 4mg/m2 d 1, 8

GC regime
• Gemcitabine 1000 mg/m2 d 1, 8, 15
Cisplatin 70 mg/m2 d 2
• response rate of 42% to 66% and a CR rate of 18% to 28%
•

.
• The response rate to MVAC is 40% to 65%and

there is improved progression-free and median

survival of 12 months
Toxic effects of MVAC

• neutropenia, anemia, thrombocytopenia,

stomatitis, nausea, and fatigue
• grade 3 or 4 myelosuppression
• grade 3 or 4 gastrointestinal toxicity .
• neutropenic sepsis .
• Primary toxicity of GC was hematologic, febrile
neutropenia
• Toxic deaths (1% vs. 3%),
• neutropenic fevers (2% vs. 14%),
• grade 3/4 neutropenia (71% vs. 82%), grade 3/4
mucositis (1% vs. 22%), and
• alopecia (11% vs. 55%), were all lower in the GC group.
• Patients receiving GC gained more weight, reported
less fatigue, and had better performance status than
patients receiving MVAC.
• GC is generally considered the current standard of care
for metastatic bladder cancer.
• GC was compared with standard MVAC in a
multicenter phase III study
• more adverse factors on the GC arm.
• Median survival was 14.0 months with GC
and 15.2 months with MVAC,
• Median progression-free survivals were 7.7
and 8.3 months with GC and MVAC
 Taxane- and Platinum-Containing
Regimens
Cisplatin/paclitaxel
Carboplatin/paclitaxel
• Cisplatin/docetaxel
• Cisplatin/gemcitabine/paclitaxel
• Carboplatin/gemcitabine/paclitaxel
• Cisplatin/gemcitabine/docetaxel
• Gemcitabine/paclitaxeL
 summary
• Whether bladder-sparing or cystectomy is used as local
treatment, combined modality approaches are
essential if treatment is to be optimal.
• Neoadjuvant chemotherapy improv es survival,
although further studies will be necessary before this
combined approach can be considered standard
treatment.
• For adjuvant treatment, the data are much less
convincing.
• The results of studies using newer drug combinations
may help to establish the role of adjuvant
chemotherapy in improving survival
 SUMMARY
• In metastatic disease, platinum-based regimens
such as cisplatin and gemcitabine remain the
standard therapy
• The addition of taxanes to the initial regimen or
as second-line therapy may provide further
activity, and lead to prolonged survival
• overall survival remains poor in metastatic
disease,
• newer therapies such as targeted agents against
tumor-specific growth factor pathways are
needed
Radiotherapy
 MODALITIES
• Radical RT – curative
• Adjuvant RT – preop / postop
• Palliative RT

METHODS

• EBRT
• INTERSTITIAL
 Radical Radiation Therapy
Indications :
• Patients unfit / unwilling for surgery

Bladder conservation protocols

 RADICAL RT
CURATIVE RT
Indications :
• Muscle invasive
• Organ confined
• Who retain good bladder function
• No associated CIS
• No significant bladder symptoms
• Willingness to commit to both prolonged course of therapy
& regular follow up cystoscopy

SPARE – Selective Bladder preservation against radical excision

• 55-65 Gy : Target volume definition &
adequate margins important
• Initial CR (T0) 40-52%
Bladder DF 35-45% for T2-4 at 5 years
Overall survival 25-40%
Excellent local control means good survival
• Salvage cystectomy for residual / rec disease
 Contraindications
• Pt with active inflammatory bowel disease
• Previous pelvic irradiation
• Extensive prior pelvic surgery
• Chronic pelvic infections

• High risk of serious late bowel complications.

• Pts with extensive bladder CIS are at high risk for

tumor recurrence after radiotherapy, therefore should
be considered for cystectomy
 Pre-op Radiation Therapy

• Moderate dose 20 Gy / 5 Fr or 40-50 Gy / 20-25 Fr

• Eradication of primary & nodal disease in few
patients after pre-op RT alone
• No survival benefit in randomised trials
• MD Anderson Trial : Reduces pelvic relapses in T3b
patients (28% vs 9%) No survival benefit
 Salvage Cystectomy

• Cystectomy following definitive radiation therapy

• Planned procedure or for progressive, residual or
recurrent disease after RT or for RT related
complications
• Survivals comparable to radical cystectomy in 4
randomised trials
• Technical challenge: Devascularisation & fibrosis
• Acceptable mortality & morbidity
 T2-T4 Bladder Cancer
Chemo + RT+TUR
No. of patients 106

• 40% Bladder preservation

• 63% T2
45% T3-T4
• 66% free of distant mets
• CR with TUR+Chemo+RT higher than TUR+Chemo
(Zietman MGH 1998)
 EBRT
2 Protocols

• 64Gy – 2Gy x 32 daily doses over 6 1/2 weeks

• 52.5 – 55 Gy x 20 daily doses over 4 weeks

 complications
• Bladder contraction – 2%
• Incontinence – 6%
• Bowel frequency – 20%
• Rectal bleed – 2%
• Impotence – 40%
• Vaginal stenosis
• Recurrence 10-20% (salvage cystectomy)
 factors affecting Outcome

• T
• Size
• Age
• Nodal status
• Pre RT RFT, Hb%
• Presence of HUN
• TURBT completeness
 Bladder : EMPTY or FULL ???
• Empty bladder –

• More comfort to patient

• Overall irradiated volume is smaller.

• Full bladder –
• Displaces small intestine & some part of
rectum out of radiation portals
Factors influencing bladder volume
• Interval between voiding & T/t delivery
• Pts state of hydration
• Use of diuretic medications
• Ingestion of diuretic beverages ( coffee, soft
drinks)
• Extrinsic pressure ( rectal filling, tumor mass)
 Radiation portals
• ANTERIOR POSTERIOR FIELDS :
• Superior border- L5-S1 interface,

• Inferior border – Lower border of obturator foramen

• Lateral border – 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.
Portals for AP/PA beam arrangement
 LATERAL FIELDS :

• Superior border
same as in AP/PA portals
• Inferior border

• 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
Lateral beam arrangement
 Areas irradiated

• The whole pelvis

• The pelvic lymph nodes
• The whole Bladder
• Proximal urethra (trigonal invl)
• Any extravesical disease spread
• Any region deemed to be at risk of
microscopic disease spread.
 Preoperative Radiation Therapy

Destroys local micrometastases

potentially downstage otherwise unresectable
tumors
improve local control after cystectomy.
 Post operative radiotherapy
Indications – i) Extravesical disease
ii) Positive resection margins
iii) Pelvic LN involvement
• Advantage – Availability of pathologic staging
• Allows administration of adjuvant irradiation to those
having high probability of tumor recurrence
• Disadvantage- increased small intestine toxicity
(adhesions).

• Dose schedule- 40-50 Gy/ 5-6 weeks @ 1.8-2Gy/ #

 Palliative RT
INDICATIONS
• Hematuria
• Severe urgency
• Pain
Dose
• 7Gy x 3
or
• 3-3.5Gy x 10

• Troublesome bowel side effects

 Radiosensitisers
• CT – cisplatin / gemcitabine
• Hyperbaric oxygen therapy
• Misonidazole no role

• Carbogen (ARCO)
• Carbogen nicotinamide (ARCON) – Doubles
the rate of survival
 Interstitial Radiation Therapy
• Never as a primary therapy
• After preoperative external-beam radiation therapy, partial
cystectomy, or TUR
• Overall survival rates for low-stage tumors (T1-T2) of 60% to 80%
have been reported.
• In selected cases - provide an acceptable alternative bladder
preservation strategy.

•
Complications( 25%)
• delayed wound healing,
• fistula formation,
• hematuria,
• chronic cystitis..
 Side effects
ACUTE TOXICITY :
• Cystitis – frequency, urge incontinence, dysuria.
• Diarrhea, anal irritation
• Mild proctitis

LATE SEQUELAE:
• Teleangiectasia of bladder mucosa
• Intractable Hematuria
• Rectal bleeding

• Reduced bladder capacity

 POTENTIAL
BLADDER
PRESERVATION
 Invasive Bladder Cancer
Chemo : Observations
(Herr 1989)

• 30 patients had cystectomy post - MVAC

• 10 patients had no disease in cystectomy specimens

POTENTIAL BLADDER PRESERVATION

33%
 Invasive Bladder Cancer
Chemo : Is bladder saving possible?

20 patients refused surgery post-MVAC

6 disease free
5 required TUR-BT
4 required cystectomy
5 developed distant mets

In 11/20 (55%), bladder could be saved

(Herr 1989)
 Bladder conservation protocol

T2-3 Nx M0 TCC
TUR whenever possible

2-3 cycles of neoadjuvant chemo

(M-VAC / cisplat+gemcite)

Cystoscopy with biopsy - 1 month

Urine cytology
CT scan

Responders Non-responders

Cons RT + chemo Rad Cystectomy

 Bladder Conservation Protocol

• Combination of chemo & radiotherapy

• CR after TUR + chemoradiation 74%
• 5 year survival with intact bladder 36-44%
• Survivals comparable to radical surgery in
selected patients
• 20-30% develop superficial relapses
• Long term regular cystoscopic follow up must
Bladder-sparing therapy for invasive bladder
cancer

• High probability of subsequent distant metastasis after

cystectomy or radiotherapy alone (50% within 2 years)
• Radiotherapy in comparison with cystectomy has inferior
results (local control 40%)
• Muscle-invasive bladder cancer is often a systemic
disease
 combined modality therapy
 Bladder Conservation Approach
Case Selection

• T2/T3a tumours
• Unifocal tumours
• Absence of associated diffuse Tis
• Good bladder capacity
• Low chance of metastatic disease

Prospective randomised trials essential

to compare oncologic value with cystectomy
 Bladder Conservation Approach
contraindications
• Hydronephrosis
• Multifocal disease
• Irritative bladder symptoms
• Low capacity bladder
 Bladder Preservation Protocols

• Bimodality & trimodalities

• First step is always TURBT  CT ± RT
• TURBT is for tissue diagnosis (muscle
invasive)and removal of all macroscopic
disease.
• Not advocated in CIS (severe) – requires BCG /
R cystectomy
Thank you