Bladder carcinoma- intravesical therapy

Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai 1

Moderators:
Professors:
 Prof. Dr. G. Sivasankar, M.S., M.Ch.,
 Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
 Dr. J. Sivabalan, M.S., M.Ch.,
 Dr. R. Bhargavi, M.S., M.Ch.,
 Dr. S. Raju, M.S., M.Ch.,
 Dr. K. Muthurathinam, M.S., M.Ch.,
 Dr. D. Tamilselvan, M.S., M.Ch.,
 Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai. 2

Introduction
 TUR of bladder tumor (TURBT):
 Gold standard treatment
(1) Remove all visible tumors
(2) Provide specimens for pathologic examination to
determine stage and grade.
3
Dept of Urology, GRH and KMC, Chennai.

Treatment targets
1) To decrease recurrence free interval
2) To decrease number of recurrences
3) To decrease tumour progression
4) To increase survival
4

Non–Muscle-Invasive Bladder
Cancer (CIS ,Ta, T1)
 TX Primary tumor
cannot be assessed
 T0 No evidence of
primary tumor
 Ta Noninvasive papillary
carcinoma
 TCis Carcinoma in situ:
“flat tumor”
 T1 Tumor invades
subepithelial connective
tissue
5

Agents
 Immunotherapy
BCG
Interferon –alpha
 Chemotherapeutic agents
Mitomycin C
Doxorubicin
Valrubicin
Thiotepa
Epirubicin
Gemcitabine
Taxanes
6

7

IMMUNOTHERAPY
 Initial step is direct binding to fibronectin within the
bladder wall
 Massive local immune response characterized by
induced expression of cytokines in the urine and
bladder wall and by an influx of granulocytes,
mononuclear, and dendritic cells
 Direct stimulation of cell-based immunologic
response and an antiangiogenic state.
8

 Cytokines involved in the initiation and maintenance
of inflammatory processes
 TNF-α, GM-CSF, IFN-γ, IL-1, IL-2, IL-5, IL-6, IL-8,
IL-10, IL-12, and IL-18
 Upregulation of interferon-γ, IL-2, and IL-12 reflects
induction of a T-helper type-1 response
9

 BCG may concomitantly stimulate IL-10, resulting in
the suppressive T-helper type-2 response.
 This immunologic response activates cell-mediated
cytotoxic mechanisms that are believed to underlie the
efficacy of BCG and other agents in the prevention of
recurrence and progression
10

BCG
 Live attenuated mycobacterium Bovis strain
 Demonstrated antitumor activity
 Danish 1331 strain
 The original regimen described by Morales included a
percutaneous dose, which was discontinued after
success using a similar intravesical regimen by
Brosman
11

 BCG is stored in refrigeration and reconstituted from a
lyophilized powder.
 Reconstituted with 50 mL of saline and should be
administered through a urethral catheter under gravity
drainage
12

13

Strains of BCG
14

Composition
 Dose: Each vial contains 1 - 8x10 8 CFU’s
 40 mg wet weight per vial
 Stabilizer : 5% sodium glutamate.
 Reconstitute with 50 ml of 0.9 % Nacl
 Dosage :80 – 120 mg
15

 Treatments begun 2 to 4 weeks after TURBT.
 Traumatic catheterization occurs treatment delayed
for several days to 1 week, depending on the extent of
injury.
 After instillation, the patient should retain the
solution for at least 2 hours.
 Fluid, diuretic, and caffeine restriction before
instillation is essential
 Patients are instructed to clean the toilet with bleach,
16

BCG Treatment of Carcinoma in Situ
 BCG is approved by the U.S. Food and Drug
Administration (FDA).
 Initial tumor-free response rate is as high as 84%
 Approximately 50% of patients experience a durable
response for a median period of 4 years.
 Over a 10-year period, approximately 30% of patients
remain free of tumor progression or recurrence
17

BCG Treatment of Residual Tumor
 Intravesical BCG can effectively treat residual papillary
lesions but should not be used as a substitute for
surgical resection.
 60% response by residual tumor with intravesical BCG
alone
 Carcinoma of the mucosa or the superficial ducts of
the prostate can be adequately treated by BCG with a
50% tumour-free rate.
18

BCG Prophylaxis to Prevent Recurrence
 In several larger series, tumor recurrence after TURBT
was reduced by 20% to 65%, for an average of
approximately 40%
 Patients receiving maintenance BCG had a statistically
decreased rate of recurrence compared with those
receiving induction therapy alone
19

Intravesical BCG - schedule
 6 week induction alone is insufficient to achieve
optimal response
 Lamm and SWOG Maintenance
(after 6 week induction)
@ 3 months- 3 weekly instillations
@ 6 months- 3 weekly instillations
 then every 6 months for 3 years
20

Contraindications to BCG Therapy
❑Absolute Contraindications
 Immunosuppressed and immunocompromised
patients
 Immediately after transurethral resection on the basis
of the risk of intravasation and septic death
 Personal history of BCG sepsis
 Gross hematuria
 Traumatic catheterization
 Total incontinence
21

Contraindications to BCG Therapy cont…
❑Relative Contraindications
o Urinary tract infection
o Liver disease
o Personal history of tuberculosis
o Poor overall performance status
o Advanced age
22

Interactions
 Quinolones affect the viability of BCG and should be
avoided
 In vitro data suggest that quinolone antibiotic therapy
may augment intravesical chemotherapy with agents
such as doxorubicin because both agents affect
topoisomerase II inhibitors
23

Cleveland Clinic Approach to Management of BCG Toxicity
Grade 1: Moderate Symptoms <48 Hr
 Mild/moderate irritative voiding symptoms, mild
hematuria, fever <38.5° C
ASSESSMENT
 Possible urine culture to rule out bacterial urinary
tract infection
SYMPTOM MANAGEMENT
 Anticholinergics, topical antispasmodics
(phenazopyridine), analgesics, nonsteroidal anti-
inflammatory drugs
24

Grade 2: Severe Symptoms and/or >48 Hr
 Severe irritative voiding symptoms, hematuria, or
symptoms lasting >48 hr
 All maneuvers for grade 1, plus the following:
ASSESSMENT
Urine culture, chest radiograph, liver function
tests
25

MANAGEMENT
 Consult immediately with physician experienced in
management of mycobacterial infections/complications.
 Consider dose reduction to one half to one third of dose
when instillations resume.
 Treat culture results as appropriate.
ANTIMICROBIAL AGENTS
 Administer isoniazid and rifampins, 300 mg/day and 600
mg/day, orally until symptom resolution.
 Do not use monotherapy.
26

Grade 3: Serious Complications (Hemodynamic
Changes, Persistent High-Grade Fever)
ALLERGIC REACTIONS (JOINT PAIN, RASH)
 Perform all maneuvers described for grades 1 and 2,
plus the following:
 Isoniazid, 300 mg/day, and rifampin, 600 mg/day, for
3-6 months depending on response
27

❑SOLID ORGAN INVOLVEMENT (EPIDIDYMITIS, LIVER,
LUNG, KIDNEY, OSTEOMYELITIS, PROSTATE)
 Isoniazid, 300 mg/day, rifampin, 600 mg/day, ethambutol,
15 mg/kg/ day single daily dose for 3-6 months
 BCG is almost uniformly resistant to pyrazinamide, so this
drug has no role.
 Consider prednisone, 40 mg/day, when response is
inadequate or for septic shock
28

MANAGEMENT OF REFRACTORY
HIGH-GRADE DISEASE
 Recurrent or persistent disease after an initial 6-week
course of BCG has been traditionally referred to as
BCG failure,
 Current consensus is that persistent disease after BCG
therapy can be categorized to
BCG refractory
BCG resistant
BCG relapsing
BCG intolerant
29

 BCG refractory : Non improving or worsening disease
despite BCG
 BCG resistant :Recurrence or persistence of lesser
degree, stage, or grade after an initial course, which
then resolves with further BCG
 BCG relapsing: Recurrence after initial resolution with
BCG
30

 BCG intolerant : Disease recurs after less than
adequate course of therapy because of serious adverse
events or symptomatic intolerance that mandates BCG
discontinuation.
 BCG-refractory patients in particular are an especially
high-risk group and should be strongly considered for
immediate cystectomy if young and in generally good
health
31

Followup biopsy
 Role of biopsy to determine BCG response is unclear,
although it should be strongly considered in high-risk
patients to determine disease status .
 Dalbagni and colleagues (1999) reported minimal
utility in routine biopsy after BCG if cystoscopy and
urinary cytology were both negative.
32

Failure of intravesical BCG
immunotherapy
 Treatment with BCG is considered to have failed
in following situations:
a. Whenever muscle invasive tumour is detected during
follow up.
b. If high grade, non-muscle-invasive tumour is present at
both 3 and 6 months .
c. Any worsening of the disease under BCG treatment, such
as
Higher number of recurrences,
Higher T stage or higher grade,
Appearance of CIS, in spite of an initial response
33

 Declaring failure may take up to 6 months because the
response rate for patients with high-grade bladder
cancer treated with BCG rose from 57% to 80%
between 3 and 6 months after therapy.
 Patients who cannot tolerate BCG for any reason may
be considered for salvage chemotherapy, but the risk
of failure and progression is high.
34

BCG Failure – treatment(IBCG)
 Intermediate risk:
-TURBT plus single dose intravesical CT
-Repeat BCG induction plus maintenance or
-Radical cystectomy
 High risk:
Radical cystectomy
35

Interferon
 Interferons are glycoproteins
 Produced response to antigenic stimuli.
 Interferons have multiple antitumor activities
❖ Inhibition of nucleotide synthesis
❖ Upregulation of tumor antigens
❖ Antiangiogenic properties
❖ Stimulation of cytokine release with enhanced T
and B cell activation
❖ Enhanced natural killer cell activity
36

 Interferon-α commonly used.
 Doses of at least 100 million units required, although
optimal dose and administration schedule have yet to
be determined
 More expensive and less effective than BCG or
intravesical chemotherapy
37

 Combination of BCG and interferon suggested the
potential superiority and possibility of decreasing the
dosage of BCG, which may reduce side effects.
 In those CIS patients who failed an induction course of
BCG, the combination of low-dose BCG and interferon
produced a 45% durable response at 2 years.
38

Investigational Immunotherapeutic Agents
 Keyhole-limpet hemocyanin (KLH) :
Hemolymph of the mollusk Megathura crenulata
Nonspecific immune stimulant
 Bropirimine :
Oral arylpyridinone
Inducer of host interferon and induces natural
killer cell and tumour necrosis factor
Demonstrating a 23% to 55% complete response in
patients with CIS
39

 Mycobacterial cell wall DNA extract
Mixture of immunostimulatory DNA attached to
antigenic cell wall.
Phase 2 trial results indicate success rates less than
that achieved with BCG
Good tolerability
 Thiosulfinate
Extracts of garlic.
Inhibit tumour growth in older studies and may
have an immunostimulatory role
40

 Interleukin-12 (IL-2)
Highly expressed after BCG stimulation
Key component of the Th1 immune response.
 Adenoviral-delivered GM-CSF
BCG refractory bladder cancer.
41

INTRAVESICAL CHEMOTHERAPY
 Induction therapy – instilled within 6 hours of
TURBT – clear impact on survival
 Less effective than BCG in reducing progression
rate
( 15% Vs 37%)
 No infective complication
 Reduce the tumour implantation and recurrence,
42

One, immediate, postoperative intravesical instillation of chemotherapy
 RATIONALE:
• Destruction of circulating tumour cells
immediately after TUR
 As an ablative effect (CHEMORESECTION) of
residual tumour cells at the resection site.
 Prevention of tumour cell implantation should be
initiated within the first hours after cell seeding.
 Within few hours- tumor cells implanted and covered
by ECM
43

CAUTION
 The immediate post-operative chemotherapy
instillation should be omitted in any case
of overt or suspected intra or extraperitoneal
perforation,
 Severe complications follow extravasation of
the drug
44

Mitomycin C
 Alkylating agent & inhibits DNA synthesis.
 Instilled weekly for 6 to 8 weeks at dose ranges from
20 to 60 mg.
 A meta-analysis of nine clinical trials compared its
efficacy on progression with BCG.
 Within median follow-up of 26 months, 7.67% of the
patients in the BCG group and 9.44% of the patients in
the MMC group developed tumor progression
45

 Optimization of MMC delivery can result in halving of
the recurrence rate.
 Achieved by eliminating residual urine volume,
overnight fasting, using sodium bicarbonate to reduce
drug degradation, and increasing concentration to 40
mg in 20 Ml
 Side effects - Rash and rarely contracted bladder
46

▪ The use of local microwave therapy in conjunction
with MMC, 20 mg/50 mL, reduced recurrence rates
from 57.5% to 17.1% in a multicenter trial.
▪ Electromotive intravesical MMC appears to
improve drug delivery in to bladder tissue
47

48

Doxorubicin and Its Derivatives
 Anthracycline antibiotic that acts by binding DNA
base pairs, inhibiting topoisomerase II, and inhibiting
protein synthesis.
 Dosage :50 mg/50 mL
 Doxorubicin demonstrated a 13% to 17% improvement
over TUR in preventing recurrence but no advantage
in preventing tumor progression
 Side effect:chemical cystitis, reduced bladder capacity
49

 Epirubicin:
Doxorubicin derivative
Decreases recurrence compared with TUR alone by
12% to 15%
Dosage :50 mg/50 mL
50

 Valrubicin
 Semisynthetic analog of doxorubicin.
 Approved by the FDA for treatment of BCG refractory
CIS in patients who cannot tolerate cystectomy.
 In a cohort of 90 patients with BCG-refractory CIS, 21%
demonstrated a complete response (Steinberg et al,
2000).
51

Thiotepa
 Triethylenethiophosphoramide
 It is an alkylating agent and is not cell cycle specific.
 30 mg/30 ml
 In controlled clinical trials (N = 950 patients), it has
been shown to significantly decrease tumor recurrence
in 6 of 11 studies up to 41% (mean decrease, 16%).
 Side effects :due to its low molecular weight
hematopoietic toxicity
52

Gemcitabine
 Gemcitabine – activity in non muscle invasive bladder
cancer in intermediate risk and high risk patients.
 Early results are promising
( Additional phase II and randomized phase III
trials needed )
 Intravesical dose:
2 g in 50 to 100 mL of saline given weekly for six
weeks with two hour dwell times.
53

Combination Therapy
 Study by Fukui and coworkers (1992), MMC (20 mg)
was administered on day 1 and doxorubicin (40 mg) on
day 2 once a week for 5 weeks in 101 patients. Fifty-one
patients demonstrated a complete response
 Patients with CIS had fewer recurrences with
maintenance therapy.
 Local side effects were significant in 50% of patients.
 No clear advantage is obtained with sequential
therapy, combination chemotherapy, or chemotherapy
and BCG regimens
54

Intravesical Therapy
– contraindications
55

Intravesical Therapy complications and
treatment
56

Intravesical Therapy complications and
treatment
57

Failure of intravesical
chemotherapy(IBCG)
❑ TURBT plus single dose intravesical CT
❑ Repeat BCG induction plus maintenance or
❑ Additional intravesical chemotherapy
58

59

Bladder carcinoma- intravesical therapy

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