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© 2002 American Society for Clinical Oncology
Intravesical Therapy for Superficial Cancer: Need for More OptionsUniversity of Colorado Health Sciences Center, Denver, CO MORE THAN 54,000 new patients will be diagnosed with bladder cancer in 2002, of whom approximately 10,000 will die.1 Although the incidence of bladder cancer has been increasing, the survival rate in patients with bladder cancer has increased by 8% in the past decade.2 This likely reflects both stage migration toward more localized disease as well as improved treatment strategies. Superficial bladder cancer accounts for 70% to 80% of newly diagnosed bladder cancers. Recurrence rates after initial treatment range from 30% to 85%, with grade progression occurring in 10% to 30% and stage progression in 4% to 30% of cases.2,3 The primary treatment for papillary bladder tumors that do not invade the muscular layer (stage Ta or T1 transitional-cell carcinoma) is transurethral resection of the bladder tumor. Resection, fulguration, and laser coagulation of these tumors can be performed with minimal morbidity. Despite complete eradication of the primary tumor, approximately two thirds of patients will develop tumor recurrences within the first 5 years of follow-up.4 Most bladder cancers are transitional-cell carcinomas. Low-grade tumors have less of a potential to progress to invasive cancers, but they have a 50% to 70% chance of recurrence. Grade 2 or 3 tumors have an approximate 20% higher chance of progression to muscle-invasive disease than grade 1 cancers.4 This high rate of recurrence and progression can be reduced with intravesical therapy, although no therapy has resulted in an improvement in overall survival. The goal of intravesical therapy is to reduce disease recurrence and its progression to muscle-invasive bladder cancer. T1 tumors, which invade the lamina propria, are an indication for intravesical treatment because patients with these tumors have a 25% to 30% risk of progression to muscle-invasive disease.5 Tumor penetration into the muscularis mucosa is associated with a 54% risk of progression, compared with a 7% risk with penetration of the lamina propria.6 This is still considered to be a T1 cancer, but clearly it carries a worse prognosis. Carcinoma-in-situ (CIS) represents high-grade anaplasia of the surface mucosa. When present, it is virtually always associated with adjacent low-grade cancers. In only 10% of cases is it an isolated pathologic finding. The potential for development of muscle-invasive disease is 42% to 83% in cases of CIS associated with papillary tumors versus 20% to 34% when CIS is an isolated finding.7 The risk of invasion of CIS is increased if there is widespread disease. Bacillus Calmette-Guérin (BCG) is the most effective regimen for the management of superficial disease, including CIS. We have demonstrated, in a large randomized clinical trial, that the use of maintenance therapy with BCG decreases subsequent recurrences but with some increase in side effects.8 To date, BCG has not been demonstrated to prolong overall survival of patients with superficial disease. Patients who do not respond to this agent represent a significant challenge. The clinician is in need of options to treat those patients who do not respond to BCG. Most recommend a cystectomy. However, many patients are not surgical candidates either because of comorbid conditions or because they refuse the procedure. No chemotherapy agent to date has proven to have activity equivalent to BCG, and no agent has been very successful in treating patients who do not respond to BCG. Valrubicin is an intravesical chemotherapeutic agent that possesses minimal activity, and more active alternatives are needed. Gemcitabine is an active systemic chemotherapeutic agent in the management of advanced bladder cancer. Because of this activity, it is also being evaluated in the management of superficial disease. In this issue of the Journal of Clinical Oncology, Dalbagni et al9 report on a phase I clinical trial of gemcitabine in patients refractory to BCG. These patients were considered to be at high risk of progression and were not candidates for cystectomy and urinary diversion. Studying several doses of intravesical gemcitabine, Dalbagni et al conclude that 2,000 mg is the optimal dose. Toxicity was minimal at all doses studied. However, two of six patients treated at the 2,000-mg dose had evidence of systemic absorption of the drug. I believe that the optimal dose should be 1,500 mg, not 2,000 mg, since there was no evidence of absorption at that level. Absorption of chemotherapy drugs from the bladder is related to a number of factors. A molecular weight below 300 (gemcitabine’s is 299) is one of the primary determining features. Exposure to even low levels of this drug may have long-term deleterious effects, particularly in younger patients with longer life expectancy. Hematologic malignancies and second cancers would be unlikely sequelae, but other long-term effects are not known. It would therefore seem desirable to choose a dose at which there is little absorption or risk. As absorption did not occur at the dose of 1,500 mg, monitoring of the hematologic parameters may not be necessary, which would be a desirable characteristic of successful intravesical therapy. The standard dosing of other intravesical therapy is once a week for 6 weeks. Dalbagni et al9 utilized a dosing of twice a week for 3 weeks. Perhaps a more standard once-weekly dosing should be studied. Options are needed for patients who are refractory to intravesical immunotherapy with BCG, which supports the importance of this trial and of other novel agents. Further trials of intravesical gemcitabine are indeed indicated, including a phase II clinical trial in patients refractory to BCG. Trials in patients with newly diagnosed CIS, recurrent superficial disease, and prophylaxis after transurethral resection of bladder tumor may also be indicated. If this drug continues to show promise, then a phase III trial—similar to the trials that resulted in BCG approval—should also be considered.10 REFERENCES
1. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51: 15-36, 2001
2. Devesa SS, Blot WJ, Stone BJ, et al: Recent cancer trends in the United States. J Natl Cancer Inst 87: 175-182, 1995 3. Abel PD: Prognostic indices in transitional cell carcinoma of the bladder. Br J Urol 62: 103-109, 1988[Medline] 4. Fair WR, Fuks ZY, Scher HI: Cancer of the bladder, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, ed 4. Philadelphia PA, Lippincott, 1993, pp 1052-1072 5. Soloway MS: Introduction and overview of intravesical therapy for superficial bladder cancer. Urology 31: 5-16, 1988 (suppl 3)[Medline] 6. Hasui Y, Osada Y, Kitada S, et al: Significance of invasion to the muscularis mucosae on the progression of superficial bladder cancer. Urology 43: 782-786, 1994[CrossRef][Medline] 7. Hudson MA, Herr HW: Carcinoma in situ of the bladder. J Urol 153: 564-572, 1995[CrossRef][Medline] 8. Lamm DL, Blumenstein BA, Crissman JD, 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: 1124-1129, 2000[CrossRef][Medline]
9. Dalbagni G, Russo P, Sheinfeld J, et al: Phase I trial of intravesical gemcitabine in bacillus Calmette-Guérin–refractory transitional-cell carcinoma of the bladder. J Clin Oncol 20: 3193-3198, 2002 10. Lamm DL, Blumenstein BA, Crawford ED, et al: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional cell carcinoma of the bladder. N Engl J Med 325: 1205-1209, 1991[Abstract]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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