Complications of Intravesical Therapy



Complications of Intravesical Therapy

Marc C. Smaldone

Fellow in Urologic Oncology, Fox Chase Cancer Center

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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 effects3.

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, p103 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 BCG5.

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 non-muscle 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 Calmette-Guerin 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

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Marc C. Smaldone, MD

Fellow in Urologic Oncology, Fox Chase Cancer Center

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