Complications of Intravesical Therapy
Marc C. Smaldone
Fellow in Urologic Oncology, Fox Chase Cancer Center
for
Introduction
More than 70% of urothelial carcinomas present as superficial, or non-muscle invasive
bladder cancers (NMIBC). Recurrence and progression risk following transurethral resection
(TUR) is multi-factorial, and is primarily associated with tumor size, stage, grade, and
multifocality1. In 2007, the AUA guidelines committee released a consensus statement on the
management of NMIBC (stages Ta, T1, & Tis), recommending a single dose of peri-operative
intravesical therapy following TUR for papillary low volume non-histologically confirmed lesions
as well as small volume, low grade Ta disease. They also recommended an induction course of
intravesical therapy +/- maintenance therapy with either bacillus Calmette-Guerin (BCG) or
Mitomycin C (MMC) for patients with multifocal, large volume, or recurrent histologically
confirmed low grade Ta disease and induction + maintenance therapy for primary high grade Ta
or T1 +/- CIS disease following TUR re-resection2.
However, despite these recommendations it is important to consider that currently
there is little level I evidence regarding optimal dosage, duration and timing of induction
therapy, and role of maintenance therapy. The risks of intravesical therapy include local side
effects such as hematuria and irritative voiding symptoms (urgency, frequency, and dysuria),
more severe acute systemic effects such as sepsis, peritonitis, and myelosuppression, or chronic
sequelae such as bladder contracture3. In general, it stands to reason that for tumors with low
risk for progression, the risk for complications may outweigh any potential benefits from
intravesical treatment. On the other hand, the risks of progression to muscle invasive disease
may outweigh the risk of serious side effects in patients with high risk tumors. It is important
that all urologists be able to risk stratify patients who are potential candidates for intravesical
therapy and understand, recognize, and promptly treat its negative side effects 3.
Perioperative “Single Shot” Administration
In a meta-analysis of 7 randomized trials comparing TUR alone to TUR plus one
immediate instillation of chemotherapy, Sylvester et al. reported a 39% reduction in risk of
recurrence (OR 0.61, p<0.0001) of NMIBC4. As a general principal, there is substantially less risk
of systemic absorption of compounds with a high molecular weight (MMC – 329kD,
Gemcitabine – 299.66kD, Epirubicin – 580kD), which facilitates immediate peri-operative
treatment as long as there is no evidence of bladder perforation at TUR5. However,
unrecognized intra-peritoneal extravasation of chemotherapeutic agents can result in
peritonitis, pelvic pain, fibrosis/necrosis, and ulceration, and if perforation is suspected
intravesical therapy must only be administered following cystography demonstrating an intact
bladder6. More common sequelae following single intravesical administration of chemotherapy
include chemical cystitis (ranging from 3-30% with MMC) which can be treated with
phenazopyridine, anti-cholinergics, or drug discontinuation while less common effects include
skin desquamation (eczema like reaction), myelosuppression, and very rarely bladder
contracture3.
Induction Therapy
Intravesical administration of BCG as induction therapy for NMIBC has been shown to
delay the time to first recurrence compared to transurethral resection alone7 as well as tumor
progression compared to TUR alone or other intravesical agents when maintenance therapy is
utilized8. Induction treatment regimens of BCG typically begin 2 to 4 weeks following resection
and are most commonly administered weekly for a six week interval. While the literature
currently supports the superiority of BCG in limiting recurrence and progression compared to
chemotherapeutic agents8-10, BCG toxicity limits its use in a significant number of patients, and
recent evidence suggests that MMC induction therapy has a reduced incidence of local (30% vs.
44%) and systemic (12 vs. 19%) when compared to BCG9.
Local Symptoms
Due to immune stimulation and inflammatory response, local symptoms following BCG
administration include flu-like symptoms, low grade fever, and malaise which can be treated
with acetaminophen, phenazopyridine, or non steroidal anti-inflammatory agents6. Gross
hematuria occurs in up to 30% of patients, and if hematuria does not resolve after 2-3 weeks of
observation repeat cystoscopy is necessary to rule out persistent tumor. While local lower
urinary tact symptoms are common, a bacterial urinary tract infection must be ruled out in
cases of persistent symptoms, and should be evaluated with urine and blood cultures3.
Although less rigorously studied than BCG, local and mild flu-like symptoms are common
following administration of Interferon±BCG (IFN) and chemotherapeutic agent induction
therapy and can also be managed conservatively in a majority of cases.
Adverse Events
In a large review of more than 2,000 patients receiving BCG, Lamm et al. reported that
high fever (>103 degrees F) was the most common severe adverse event, and occurred in 3% of
patients11. For the first 24-48 hours, antipyretics and fluids are appropriate therapy, but fevers
greater than 48 hrs in duration should raise concern for disseminated systemic infection and all
intravesical therapy should be withheld. Systemic absorption of BCG (BCG sepsis) is rare but
potentially lethal. Most commonly diagnosed as a result of traumatic catheterization, patients
present with fever, chills, hypotension, and confusion, and progression to clinical instability can
be rapid. Cultures are often negative, and treatment with anti-tuberculosis therapy (Rifampin,
Isoniazid for 6 months ± Ethambutol and/or Prednisone if treatment is ineffective) is initiated
based on clinical suspicion3. While the role of Cycloserine as an adjunctive agent has diminished
due to ineffectiveness, fluoroquinolone antibiotics have demonstrated efficacy and can be
utilized in the case of severe systemic infection or if anti-tuberculous medications are poorly
tolerated12. Granulomatous hepatitis and pneumonitis have also been described, which can be
diagnosed with chest xray and/or liver function tests. For such cases hospitalization with
supportive measures followed by 6 months of anti-tuberculosis therapy is often required.
Additional less severe urologic manifestations of BCG adminstration include
granulomatous prostatitis and epidymo-orchitis which range in clinical severity, with
symptomatic patients requiring 3-6 months of Rifampin and Isoniazid therapy6. Extremely
uncommon chronic adverse events following BCG administration include ureteral obstruction
and bladder contracture. Although rare, these complications can be quite severe, and may
require ureteral reimplantion or cystectomy when conservative measures such as long term
anti-tuberculosis, steroid, and/or antibiotic therapy are ineffective3. Risk of common minor
reactions with intravesical chemotherapeutic agents is similar to BCG, and consists primarily of
local irritative voiding symptoms (MMC, anthracyclines, taxoids), and more uncommonly
desquamation of the skin and myelosuppression (MMC). Since most of the chemotherapeutic
agents currently in use have a high molecular weight, the risk for absorption and systemic
effects are minimal and they are usually well tolerated, even in patients intolerant of BCG 5.
Maintenance Therapy
Although BCG remains first line intravesical therapy for patients with high grade, T1, CIS
or other aggressive disease characteristics, it is unclear if there are differences in toxicity
between induction and maintenance regimens13, 14. In a SWOG trial examining the role of
maintenance BCG for NMIBC, toxicity was higher in the maintenance arm, and only 16% of
patients randomized to the maintenance arm completed all 7 cycles15. Some recent trials have
demonstrated that a reduced regimen (one-third dose) may be as effective as standard dosing
with fewer side effects16 while other methods such as prolonging the interval between dosing
or number of doses per cycle have been less rigorously evaluated in the literature.
References
1.
Sylvester, R. J., van der Meijden, A. P., Oosterlinck, W. et al.: Predicting recurrence and
progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a
combined analysis of 2596 patients from seven EORTC trials. Eur Urol, 49: 466, 2006
2.
Hall, M. C., Chang, S. S., Dalbagni, G. et al.: Guideline for the management of nonmuscle
invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol, 178: 2314, 2007
3.
Koya, M. P., Simon, M. A., Soloway, M. S.: Complications of intravesical therapy for
urothelial cancer of the bladder. J Urol, 175: 2004, 2006
4.
Sylvester, R. J., Oosterlinck, W., van der Meijden, A. P.: A single immediate
postoperative instillation of chemotherapy decreases the risk of recurrence in patients with
stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. J
Urol, 171: 2186, 2004
5.
Smaldone, M. C., Casella, D. P., Welchons, D. R. et al.: Investigational therapies for nonmuscle invasive bladder cancer. Expert Opin Investig Drugs, 19: 371, 2010
6.
Thrasher, J. B., Crawford, E. D.: Complications of intravesical chemotherapy. Urol Clin
North Am, 19: 529, 1992
7.
Shelley, M. D., Court, J. B., Kynaston, H. et al.: Intravesical Bacillus Calmette-Guerin in Ta
and T1 Bladder Cancer. Cochrane Database Syst Rev: CD001986, 2000
8.
Sylvester, R. J., van der, M. A., Lamm, D. L.: Intravesical bacillus Calmette-Guerin reduces
the risk of progression in patients with superficial bladder cancer: a meta-analysis of the
published results of randomized clinical trials. J Urol, 168: 1964, 2002
9.
Shelley, M. D., Court, J. B., Kynaston, H. et al.: Intravesical bacillus Calmette-Guerin
versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Rev: CD003231, 2003
10.
Sylvester, R. J., van der Meijden, A. P., Witjes, J. A. et al.: Bacillus calmette-guerin versus
chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a
meta-analysis of the published results of randomized clinical trials. J Urol, 174: 86, 2005
11.
Lamm, D. L., van der Meijden, P. M., Morales, A. et al.: Incidence and treatment of
complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer. J
Urol, 147: 596, 1992
12.
Durek, C., Rusch-Gerdes, S., Jocham, D. et al.: Sensitivity of BCG to modern antibiotics.
Eur Urol, 37 Suppl 1: 21, 2000
13.
Bohle, A., Jocham, D., Bock, P. R.: Intravesical bacillus Calmette-Guerin versus mitomycin
C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence
and toxicity. J Urol, 169: 90, 2003
14.
van der Meijden, A. P., Sylvester, R. J., Oosterlinck, W. et al.: Maintenance Bacillus
Calmette-Guerin for Ta T1 bladder tumors is not associated with increased toxicity: results from
a European Organisation for Research and Treatment of Cancer Genito-Urinary Group Phase III
Trial. Eur Urol, 44: 429, 2003
15.
Lamm, D. L., Blumenstein, B. A., Crissman, J. D. et al.: Maintenance bacillus CalmetteGuerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of
the bladder: a randomized Southwest Oncology Group Study. J Urol, 163: 1124, 2000
16.
Martinez-Pineiro, J. A., Martinez-Pineiro, L., Solsona, E. et al.: Has a 3-fold decreased
dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3
and Tis bladder tumors than the standard dose? Results of a prospective randomized trial. J
Urol, 174: 1242, 2005
Marc C. Smaldone, MD
Fellow in Urologic Oncology, Fox Chase Cancer Center