AN OVERVIEW OF THE TREATMENT OF SUPERFICIAL BLADDER CANCER: Intravesical Chemotherapy

doi:10.1016/S0094-0143(05)70240-8

Urologic Clinics of North America

Volume 27, Issue 1, 1 February 2000, Pages 125-135

https://doi.org/10.1016/S0094-0143(05)70240-8 Get rights and content

Superficial bladder cancer accounts for approximately 70% to 80% of all newly diagnosed bladder cancers. The majority of these cancers are transitional bladder tumors of various histologic grades (I to III). Superficial tumors include carcinoma in situ (CIS), tumors confined to the epithelium (Ta), and superficial tumors that invade the lamina propria (T1) but do not involve superficial muscle layers. The primary treatment for eradicating stages Ta and T1 bladder cancers is transurethral resection (TUR) of the tumor.²⁹ Many patients with superficial bladder tumors treated with endoscopic surgery alone have recurrence or tumor progression at some point in their follow-up, and, in these patients, the need for adjuvant treatment becomes a major concern.

Intravesical chemotherapy for the treatment of superficial bladder cancer was initially reported in 1900 when Herring²⁰ described the use of silver nitrate. Studies in Europe performed initially with thiotepa showed that such drugs could eradicate residual bladder tumors and potentially decrease local recurrence.25, 68 Today, the use of intravesical chemotherapy for superficial bladder cancer has become more generally accepted. The main goals of intravesical therapy are to prevent tumor recurrence or tumor progression after TUR of the primary tumor and to treat possible residual tumors after endoscopic surgery. The identification of patients with superficial bladder tumors who are at risk for tumor recurrence and tumor progression after surgical treatment is very important in the selection of candidates for adjuvant or prophylatic use of intravesical therapy.5, 51 Risk factors include tumor size and grade, multifocality, positive postoperative urine cytology, prostatic urethral involvement, the presence of CIS, and tumors that invade the lamina propria.⁵

Several antitumor agents with definitive activity against CIS or residual tumors after TUR have been developed.²⁹ The most commonly studied are thiotepa, doxorubicin (Adriamycin), mitomycin C, epirubicin, ethoglucid, and the nonchemotherapeutic drug bacille Calmette-Guérin (BCG). The ideal drug for intravesical therapy would be inexpensive and would have minimal systemic absorption and local toxicity while effectively preventing tumor recurrence and progression after TUR of the primary tumor.51, 56 In the past decade, BCG has emerged as an important intravesical agent because of its economy and effectiveness in prophylaxis against tumor recurrence after TUR of the primary tumor, in the treatment of residual tumors, and in patients with CIS.⁴¹ Nevertheless, the toxicity and side effects of intravesical BCG therapy cannot be ignored. Dysuria and urinary frequency occur in about 90% of patients. Furthermore, approximately 24% of patients have fever, and 18% and 8% of patients have malaise and nausea, respectively.⁴¹ Antituberculosis therapy is required in as many as 6% of the patients treated with BCG owing to the severity of side effects.⁴¹ Some patients may not respond to intravesical BCG therapy. Alternative intravesical therapy with other drugs may be effective in these patients⁵⁶ and in patients with considerable side effects, although other drugs also have limitations and considerable side effects as well.

This article focuses on the treatment of superficial bladder cancer with chemotherapic agents. Topics discussed include the effectiveness, side effects, advantages, and disadvantages of each drug.

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PRINCIPLES AND INDICATIONS

The goal of intravesical therapy varies based on the circumstances in which the drug is used. Prophylactic use after complete resection of a primary tumor in patients with identifiable risk factors for tumor recurrence is usually the most common indication for intravesical chemotherapy; 50% to 70% of patients have tumor recurrence if treated with TUR alone.⁶ Intravesical chemotherapy can reduce the incidence of tumor recurrence on a short-term basis, although long-term results have been

THIOTEPA

Triethylenethiophosphoramide or thiotepa was the first intravesical chemotherapeutic agent used with relative success for treatment of superficial bladder cancer. It is an alkylating agent with a molecular weight of 189 kd that exerts its cytotoxic effect by causing cross-linkage of DNA, RNA, protein, and nucleic acids with subsequent inhibition of nucleic acid synthesis. Thiotepa is not cell cycle–specific.

This agent is given intravesically in a variety of schedules to treat superficial

ADRIAMYCIN

Adriamycin (doxorubicin), an anthracycline antibiotic, acts as an antineoplastic drug by binding to DNA base pairs, interrupting DNA replication and transcription, and inhibiting protein synthesis. Its most toxic effect is seen in the S phase of the cell cycle, although the drug is classified as non–cell cycle phase–specific. Doxorubicin has been indicated mainly in the prophylactic treatment of patients after TUR. Administered doses range from 30 to 100 mg,⁵ usually in a concentration of 1

MITOMYCIN C

Mitomycin C is an alkylating agent with a molecular weight of 334 kd. Its mechanism of action has not been totally clarified, although some evidence suggests that it acts by binding to DNA, resulting in synthesis inhibition and strand breakage. Mitomycin C is most sensitive in the late G₁ and early S phase, but overall it is considered cell cycle–nonspecific.⁵ Instillation schedules are variable. Doses range from 20 to 60 mg diluted in water in a concentration ranging from 0.5 to 2.0 mg/mL,

EPIRUBICIN

Epirubicin (4′-epidoxorubicin) is an anthracycline derivate of doxorubicin. The mechanism of action is similar to that of doxorubicin (DNA synthesis inhibition with further protein synthesis inhibition), with a more favorable toxicity profile.⁵ Doses range from 50 to 80 mg/mL at a concentration of 1.0 to 1.6 mL. Instillation is usually initiated 1 to 2 weeks after TUR and is performed weekly for a total of 8 weeks and then monthly to complete 1 year of treatment.² Patients are instructed to

ETHOGLUCID

Ethoglucid (triethylene glycol diglycidyl ether) is a podophyllin derivative with a molecular weight of 262 kd. Its mechanism of action is similar to that of an alkylating agent.⁵ The dose used is usually about 1 g of the drug diluted in 100 mL of sterile water (1% solution).³¹ Initial instillation is performed 1 to 2 weeks after TUR, followed by four to ten instillations performed on a weekly basis. Maintenance doses are given monthly for up to 1 year. Bladder dwell time is 1 hour. Recent data

OTHER AGENTS

Mitoxantrone is a synthetic, intercalating, anthraquinone-based agent related structurally and in its mode of action to doxorubicin.⁴³ In a prospective randomized controlled trial, patients who received mitoxantrone did not have improved tumor recurrence rates in comparison with patients who underwent TUR only,¹⁶ although the time to recurrence was longer in patients who received intravesical chemotherapy. No advantage in terms of tumor progression was noted. Chemical cystitis occurred in 11%

COMBINED INTRAVESICAL CHEMOTHERAPY

Because no drug available for intravesical chemotherapy is 100% effective in eradicating bladder tumors or in preventing tumor recurrence and because tumor progression seems to occur regardless of whether patients receive prophylactic local chemotherapy, a combination of two or more drugs has been investigated. The results of three studies combining mitomycin and Adriamycin have been published in the last 7 years.

Isaka and co-workers²⁴ treated 40 patients with superficial bladder cancer with a

COMBINED INTRAVESICAL CHEMOTHERAPY AND IMMUNOTHERAPY

Combined chemotherapy and immunotherapy may have a synergistic antitumor effect because their mechanisms of action are different. Potential benefits in terms of tumor recurrence and progression could be achieved with combined therapy. A group from Finland⁵³ studied the combination of intravesical BCG and mitomycin for CIS. Patients were randomized in two arms. One group received only mitomycin (20 to 40 mg), and the second group received a combination of mitomycin and BCG (75 mg). Combined

COMPARATIVE SERIES

No clear evidence suggests that any drug is superior to another in terms of tumor recurrence, progression, and survival.³³ One recent prospective randomized study² suggested that epirubicin was superior to doxorubicin in terms of recurrence and toxicity. A group from Portugal reported equal efficacy when comparing chemoprophylactic use of mitomycin with epirubicin in a noncontrolled randomized trial.¹² Several comparisons between chemotherapy (mitomycin) and immunotherapy (BCG) have been made

INTRAVESICAL CHEMOTHERAPY IN THE TWENTY-FIRST CENTURY

Research efforts have focused on defining the mechanism of action of the chemotherapic agents and factors influencing drug activity in an attempt to increase the efficacy of these agents. In vitro studies suggest that interferon-α may increase the efficacy of doxorubicin and mitomycin by decreasing cell proliferation in human bladder carcinoma cell lines.⁴⁶

Recently obtained data support the assumption that there is a linear correlation between drug uptake in the bladder tissues and drug