DRUG SELECTION PERSPECTIVES

ADJUVANT INTRAVESICAL THERAPY FOR SUPERFICIAL BLADDERCANCER Cynthia N. Batts

OBJECTIVE: To review the results of clinical trials and adverse drug effects of thiotepa, BCG vaccine, mitomycin, and doxorubicin, which are used as adjuvant intravesical therapy for superficial bladder cancer. DATA SOURCE: Information was retrieved from a MEDLINE search, of the English-language literature. Indexing terms included adjuvant pharmaceutics, bladder neoplasms, thiotepa, mitomycin, BCG vaccine, and doxorubicin.

Data from several human and in vitro studies were assessed and evaluated, according to the strength of comparative data and therapeutic response. DATA EXTRACTION:

Emphasis was placed on clinical trials that assessed and evaluated dosage, therapeutic regimens, and therapeutic response of adjuvant intravesical therapy for superficial bladder cancer.

STUDY SELECTION:

Adjuvant intravesical therapy and long-term prophylaxis are effective for superficial bladder cancer. Studies have shown that doxorubicin, thiotepa, BCG, and mitomycin, when used as adjuvant therapy, provide better protection than transurethmi resection alone against tumor recurrence and prolong the time to when cystectomy is required.

DATA SYNTHESIS:

Several randomized clinical trials suggest that BCG is superior to thiotepa, doxorubicin, and mitomycin in preventing bladder tumor recurrence and tumor progression. Local cystitis is an adverse effect produced by all four agents; however, BCG vaccine has been reported to cause a higher incidence of adverse reactions (e.g., dysuria, hematuria). BCG may also cause an influenza-like syndrome, arthralgias, and fever, but most of these reactions have resulted in few severe adverse effects when the drug is given in the relatively modest recommended doses. CONCLUSIONS:

Ann Pharmacother 1992;26:1270-6.

the National Organization of American Cancer Society, an estimated 51600 people will be diagnosed with bladder cancer in 1992. The estimated incidence figure for 1991 was 50200.' Approximately 80 percent of the patients thus diagnosed will present with a superficial bladder tumor. Some of the alleged risk factors for

ACCORDING TO

CYNTHIA N. BATTS, Pharm.D., at the time of writing, was on sabbatical at the College of Pharmacy. Ohio State University. Columbus. OH: she is now an Assistant Professor of Clinical Pharmacy, College of Pharmacy, Xavier University of Louisiana, 7325 Palmetto St., New Orleans, LA 70125. Reprints: Cynthia N. Batts, Pharm.D.

This article is approved for continuing education credit.

1270 • The Annals ofPharmacotherapy •

bladder cancer are tobacco use, exposure to aniline dyes, and schistosomiasis. Dietary sweeteners, coffee, industrial toxic exposure, and motor vehicle exhaust fumes also have been implicated as possible causes.' The purpose of this article is to review the therapeutic regimens, toxicities, and results of selected clinical trials that emphasize the use of adjuvant intravesical therapy for superficial bladder cancer. Intravesical therapy includes chemotherapeutic or biologic agents that are instilled in the bladder for ablation of existing tumors and prophylaxis of tumor recurrence. Therapeutic regimens may be used as long-term prophylaxis after transurethral resection (TUR) to prevent tumor recurrence, or short-term adjuvant therapy to destroy viable tumor cells that may remain after TUR. The ultimate goal of either regimen is for patients to survive free of any bladder tumor. An ideal adjuvant intravesical drug should be an antineoplastic agent that is highly cytotoxic, with minimum bladder irritation and limited absorption from the submucosa of the bladder into the systemic circulation. The agent also should be highly effective in the prevention of tumor recurrence and progression.' The ideal intravesical agent, or the clearly superior treatment regimen, has not been identified. Conventional treatment in the past included TUR alone. Randomized clinical trials have provided documentation that 50-70 percent of the patients who undergo TUR alone for superficial bladder cancer will experience tumor recurrence, with 10-20 percent of these patients experiencing an increased risk of tumor progression in stage and grade." Available data have demonstrated the effectiveness of certain agents in prevention and recurrence of low-stage and -grade bladder tumors.' Administration of intravesical therapy allows high concentrations of the drug to be maintained at the disease site for extended periods of time, and produce minimal systemic toxicity. Thiotepa, mitomycin, doxorubicin, and BCG vaccine are agents that have demonstrated antitumor effect and are used as intravesical therapy for superficial bladder cancer. The patient usually is restricted of all fluids for at least 8 hours prior to treatment. The agents administered intravesically are instilled into the bladder through an indwelling urinary catheter approximately 24-48 hours after TUR, thus decreasing the chance of implantation of any floating, viable cancer cells. BCG usually is instilled 4-7 days after TUR to decrease the chance of systemic absorp-

1992 October,Volume26

tion. After instillation of the drug, the patient is required to turn to each side every 15 minutes, and to refrain from voiding for 1-2 hours, to maximize drug distribution throughout the bladder.

Table 1. Staging of Bladder Cancer STAGES

Carcinoma in situ

T1

FactorsPredictingBladderCancer Prognosis Tumor node metastasis is a staging system used for classification of all bladder cancer (Table 1). Tumor stage provides prognostic information derived from clinical and pathologic findings and is an indicator of tumor progression.' Superficial bladder tumors are classified in the following pathologic stages: T, (tumor has not penetrated beyond the basement membrane); T I (tumor has invaded the lamina propria, which is the layer of connective tissue underlying the epithelium, but not the superficial muscle layer); and carcinoma in situ (flat, nonpapillary, high-grade carcinoma of the bladder epithelium)," Tumor grade is also an indicator of disease progression and correlates with the rate of tumor recurrence," Grade 1 tumors are well differentiated and less malignant; grade 4 tumors represent the most malignant multifocal carcinoma. Other variables that may influence tumor recurrence and progression are the presence of multiple superficial bladder tumors, tumor size >3 ern, the presence of carcinoma in situ, and positive urinary cytology.v'" Some patients do not benefit from adjuvant intravesical therapy. Lum and Torti stated that patients with higher stages and grades of bladder tumors have a higher rate of tumor recurrence and pro gression. They also suggested that the population that would receive the greatest benefit of therapy would be patients with stages: Ta , grades 2 and 3; T., grades 1 and 2; T I , grade 3, and certain patients with carcinoma in situ,"

Thiotepa CLINICAL TRIALS

Clinical studies using the alkylating agent thiotepa for intravesical therapy have been reported in the literature for more than two decades.rP The standard intravesical dose of thiotepa is 30-60 mg, with a concentration of 1 mg/mL (NaCl 0.9% or sterile water used for dilution). The therapeutic regimen may vary from 4 weeks to 24 months. The dose is given weekly for 4-6 weeks, and then monthly":" Koontz et al." reviewed data from a study conducted by the National Bladder Cancer Collaborative Group A 14 and evaluated the therapeutic effect of thiotepa in 95 patients with incompletely resected tumors. Histologic examination provided evidence of primary bladder tumor without muscle invasion. Patients were randomized to receive thiotepa 30 or 60 mg 1 mg/mL weekly for four weeks. At four weeks, all patients were evaluated based upon cystoscopic or histologic fmdings. Patients with new visible tumors, unchanged tumors, or enlarged tumors were considered treatment failures and were removed from the study. The remaining 61 patients (64 percent) received four more weekly doses of thiotepa After the second course of treatment, 45 of the initial95 patients (47 percent) were free of tumors. Treatment success was defmed as negative histologic examination for carcinoma." The results suggest that thiotepa will destroy tumors in patients after an eight-week treatment regimen. Gavrell et al. conducted a study to evaluate the effectiveness of a thiotepa regimen for prophylaxis to prevent

TUMOR NODE METASTASIS SYSTEM OF CLASSIFICAnON

preinvasive carcinoma (confined 10 mucosa) invasion of lamina propria (mobile mass may be felt on bimanual examination) invasion of muscularis invasion of tumor through muscalaris tumor invasion 10 adjacenl organs lymph nodes with evidence of metastases distant melastases

recurrence of transitional cell carcinoma. Therapy began immediately after TUR and the patients were divided into two groups. Patients in group 1 received intravesical doses of thiotepa 30 mg bid for three days. Patients in group 2 received an additional 30-mg dose weekly for six weeks, and were placed on a monthly regimen for one year, then received treatment once every 3 months until tumor recurrence. Before treatment, nine patients in group 2 averaged one recurrence in 9.5 months. After treatment, patients in group 1 had one recurrence in 33 months and those in group 2 had one recurrence in 41 months. The authors stated that a decrease in tumor recurrence patterns were demonstrated in both groups. 15 In a prospective, randomized study conducted by Zincke et al., the efficacy of thiotepa was compared with that of mitomycin. All patients had histologically proven transitional cell carcinoma with no evidence of invasion. All visible tumors were completely resected and the patients were randomized to receive thiotepa 60 mg or mitomycin 40 mg. The agents were instilled into the bladder for 30 minutes immediately after TUR, and then for two hours thereafter with each treatment. Therapy was continued biweekly for a total of five instillations. The patients were confirmed to be tumor-free by biopsy or urinary cytology. At one year 78 percent of the patients (n=41) receiving thiotepa and 67 percent of the patients (n=42) receiving mitomycin were free of tumors (p=O.6). Zincke et al. suggested that both agents increased the tumor-free interval!' England and Flynn evaluated thiotepa as prophylaxis for tumor recurrence after the removal of tumor by diathermy. Forty-five patients were treated by removal of all visible tumor and then received intravesical thiotepa 30 mg for two hours on days 1,3, and 5. Each patient had a history of tumor recurrence with diathermy alone. Thirty-two of 45 patients (71 percent) experienced a reduction in the number of tumors recurring after adjuvant intravesical therapy with thiotepa. The authors suggested that adjuvant intravesical therapy is effective prophylaxis against the implantation of viable cancer cells and may reduce the malignant potential of the urothelium, thus slowing down or preventing new tumor growth.'? The selected dosages provided antitumor effect and according to the literature reviewed, doses of thiotepa 30-60 mg instilled weekly with a concentration of 1 mg/mL for six to eight weeks can be safely and effectively used as adjuvant intravesical therapy for superficial bladder cancer. TOXICITIES

Drugs that are nonionized with a molecular weight of

Adjuvant intravesical therapy for superficial bladder cancer.

To review the results of clinical trials and adverse drug effects of thiotepa, BCG vaccine, mitomycin, and doxorubicin, which are used as adjuvant int...
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