THE WESTERN JOURNAL OF MEDICINE *
DECEMBER 1991
*
155 * 6
BCG Vaccine in Urinary Bladder Cancer
633
Medical Treatment of Benign Prostatic Hyperplasia
NEARLY TWO THIRDS of all urinary bladder cancers are confined to the urothelial surface or lamina propria when they are first recognized. Two types of transitional cell carcinoma can be identified. The first is a papillary growth and is usually treatable by transurethral resection or laser phototherapy. The recurrence rate for these carcinomas varies from 20% to 80% depending on the grade ofthe tumor and whether it has penetrated the basement membrane and is growing into the lamina propria. The need to diminish the rate of recurrence of these tumors has led to the use of a number of agents that can be instilled directly into the urinary bladder. One of the most effective is bacillus Calmette-Guerin (BCG), an attenuated tuberculosis vaccine containing live tubercle bacilli. When BCG is repeatedly instilled into the bladder, an inflammatory and immunologic reaction occurs. This reaction has the benefit of reducing the recurrence rate to the range of 15% to 20%. Candidates for this therapy are patients who have previously had tumors, those with grade 2 or 3 tumors, those with tumors extending into the lamina propria, and patients with multiple tumors. One suggested protocol has patients receiving six instillations, usually weekly, followed by monthly instillations for a year. The second type of tumor is carcinoma in situ, which grows laterally along the surface of the urothelium. Before BCG, the only therapy for this cancer was cystectomy. Patients with carcinoma in situ usually receive 12 instillations of BCG, which has a 70% probability of eradicating the disease. Thus, BCG is considered the first line of therapy for decreasing the probability of a tumor recurrence and eliminating carcinoma in situ. It is currently the most effective agent for accomplishing these goals. This success can be accompanied by adverse reactions, however. Localized side effects reflect the inflammatory reaction in the bladder and may produce symptoms of frequency, urgency, dysuria, and hematuria. These symptoms are usually mild and last only a few days. In a few patients a systemic reaction occurs. This begins as a "flulike" illness with a low-grade fever and malaise lasting 48 to 72 hours. When the reaction is more severe, patients can be treated with isoniazid, which minimizes these symptoms but does not abrogate the anticancer effect. Rarely, sepsis can develop that requires vigorous antituberculosis therapy. When used in appropriate circumstances and with careful observation of the patient, intravesical BCG therapy is safe and effective for many patients with urinary bladder cancer. Those who mix and administer the BCG solutions are not at risk of harm as long as a sterile technique and safe work practices are observed and all of the materials are disposed of in an appropriate manner.
FOR SEVERAL DECADES, the preferred treatment of benign prostatic hyperplasia has been transurethral or open prostatectomy. Recent advances in our understanding of lower urinary tract physiology and the growth and development of the prostate gland have resulted in new medical therapies for some men with this disorder. Based on the finding of higher concentrations of a, -adrenergic receptors at the bladder neck, prostatic capsule, and prostatic substance, agents that block such receptors can be used. Selective a5-blocking drugs, such as prazosin hydrochloride and terazosin hydrochloride, can "relax" the smooth muscle in these areas, allowing the urinary bladder to work more efficiently. a-Blockers do not shrink the prostate but instead are active on the dynamic component of prostatic enlargement. The major side effect of these drugs, which are commonly used for the control of hypertension, is orthostatic hypotension. The drug dose must be carefully titrated against the patient's response and side effects. Efforts to block or interfere with the androgen stimulation of benign prostatic hyperplasia have been effective in shrinking the prostate gland by about 30% to 50%. In some men with mechanical obstruction, this modest reduction in size may be sufficient to alleviate symptoms and thus reduce the necessity for an operation. Endocrine manipulation can be carried out in several ways: blocking the effect of androgens (mainly dihydrotestosterone) with antiandrogens, such as flutamide; decreasing the testicular output of androgens using luteinizing hormone-releasing hormone (LHRH)agonists, such as leuprolide acetate and goserelin; and using an inhibitor of 5-a-reductase, such as finasteride, that thereby reduces the formation of dihydrotestosterone. Side effects are specific for each class of endocrine therapy. The antiandrogen may cause gynecomastia and diarrhea. The use of LHRH-agonists is associated with a decrease in libido, impotence, and hot flashes. Inhibitors of 5-a-reductase are relatively nontoxic, with impotence the only side effect reported. The use of combinations of a-blocking agents and endocrine manipulation is currently under study. Clinical trials employing medical therapy for benign prostatic hyperplasia have emphasized the need for better response indicators. These include subjective measures, such as symptom scores and global assessment (quality of life and interference in daily activities), and objective ones, such as measuring voiding pressure, urinary flow rate, and residual urine. Because this disorder probably begins 20 or more years before clinical symptoms and signs are evident, medical therapy may be effective only in those men in whom changes of decompensation, such as bladder diverticula and hydronephrosis, have not yet developed. JOSEPH D. SCHMIDT, MD
REFERENCES
REFERENCES
Klimberg IW, Pow-Sang JM, Cartwright CK, Wajsman Z: Intravesical bacillus Calmette-Guerin for patients with high risk superficial bladder cancer. Urology 1991; 37:180-184 Melekos MD, Pantazakos A, Markou S, Skopa C, Athanassopoulos A, Barbalias G: Intravesical bacillus Calmette-Guerin administration in the prophylaxis of superficial bladder cancer. Int Urol Nephrol 1990; 22:433-440 Mikkelsen DJ, Ratliff TL: Mechanisms of action of intravesical bacillus CalmetteGuerin for bladder cancer. Cancer Treatment Res 1989; 46:195-211 Witjes JA, van der Meijden AP, Dubruyne FM: Use of intravesical bacillus Calmette-Guerin prophylactic treatment for superficial transitional cell carcinoma of the bladder: An overview. Urol Int 1990; 45:129-136
Gabrilove JL, Levine AC, Kirschenbaum A, Droller M: Effect of long-acting gonadotropin-releasing hormone analog (leuprolide) therapy on prostatic size and symptoms in 15 men with benign prostatic hypertrophy. J Clin Endocrinol Metabol 1989; 69:629-632 Graversen PM, Gasser TC, Wasson JH, Hinman F Jr, Bruskewitz RC: Controversies about indications for transurethral resection of the prostate. J Urol 1989; 141:475-
STANLEY A. BROSMAN, MD Santa Monica, California
San Diego, California
481
Lepor H: The role of alpha adrenergic blockers in the treatment of benign prostatic hyperplasia. Prostate 1990; 3(suppl):75-84 McConnell JD: Medical management of benign prostatic hyperplasia with androgen suppression. Prostate 1990; 3(suppl):49-59
DECEMBER 1991
*
155 * 6
BCG Vaccine in Urinary Bladder Cancer
633
Medical Treatment of Benign Prostatic Hyperplasia
NEARLY TWO THIRDS of all urinary bladder cancers are confined to the urothelial surface or lamina propria when they are first recognized. Two types of transitional cell carcinoma can be identified. The first is a papillary growth and is usually treatable by transurethral resection or laser phototherapy. The recurrence rate for these carcinomas varies from 20% to 80% depending on the grade ofthe tumor and whether it has penetrated the basement membrane and is growing into the lamina propria. The need to diminish the rate of recurrence of these tumors has led to the use of a number of agents that can be instilled directly into the urinary bladder. One of the most effective is bacillus Calmette-Guerin (BCG), an attenuated tuberculosis vaccine containing live tubercle bacilli. When BCG is repeatedly instilled into the bladder, an inflammatory and immunologic reaction occurs. This reaction has the benefit of reducing the recurrence rate to the range of 15% to 20%. Candidates for this therapy are patients who have previously had tumors, those with grade 2 or 3 tumors, those with tumors extending into the lamina propria, and patients with multiple tumors. One suggested protocol has patients receiving six instillations, usually weekly, followed by monthly instillations for a year. The second type of tumor is carcinoma in situ, which grows laterally along the surface of the urothelium. Before BCG, the only therapy for this cancer was cystectomy. Patients with carcinoma in situ usually receive 12 instillations of BCG, which has a 70% probability of eradicating the disease. Thus, BCG is considered the first line of therapy for decreasing the probability of a tumor recurrence and eliminating carcinoma in situ. It is currently the most effective agent for accomplishing these goals. This success can be accompanied by adverse reactions, however. Localized side effects reflect the inflammatory reaction in the bladder and may produce symptoms of frequency, urgency, dysuria, and hematuria. These symptoms are usually mild and last only a few days. In a few patients a systemic reaction occurs. This begins as a "flulike" illness with a low-grade fever and malaise lasting 48 to 72 hours. When the reaction is more severe, patients can be treated with isoniazid, which minimizes these symptoms but does not abrogate the anticancer effect. Rarely, sepsis can develop that requires vigorous antituberculosis therapy. When used in appropriate circumstances and with careful observation of the patient, intravesical BCG therapy is safe and effective for many patients with urinary bladder cancer. Those who mix and administer the BCG solutions are not at risk of harm as long as a sterile technique and safe work practices are observed and all of the materials are disposed of in an appropriate manner.
FOR SEVERAL DECADES, the preferred treatment of benign prostatic hyperplasia has been transurethral or open prostatectomy. Recent advances in our understanding of lower urinary tract physiology and the growth and development of the prostate gland have resulted in new medical therapies for some men with this disorder. Based on the finding of higher concentrations of a, -adrenergic receptors at the bladder neck, prostatic capsule, and prostatic substance, agents that block such receptors can be used. Selective a5-blocking drugs, such as prazosin hydrochloride and terazosin hydrochloride, can "relax" the smooth muscle in these areas, allowing the urinary bladder to work more efficiently. a-Blockers do not shrink the prostate but instead are active on the dynamic component of prostatic enlargement. The major side effect of these drugs, which are commonly used for the control of hypertension, is orthostatic hypotension. The drug dose must be carefully titrated against the patient's response and side effects. Efforts to block or interfere with the androgen stimulation of benign prostatic hyperplasia have been effective in shrinking the prostate gland by about 30% to 50%. In some men with mechanical obstruction, this modest reduction in size may be sufficient to alleviate symptoms and thus reduce the necessity for an operation. Endocrine manipulation can be carried out in several ways: blocking the effect of androgens (mainly dihydrotestosterone) with antiandrogens, such as flutamide; decreasing the testicular output of androgens using luteinizing hormone-releasing hormone (LHRH)agonists, such as leuprolide acetate and goserelin; and using an inhibitor of 5-a-reductase, such as finasteride, that thereby reduces the formation of dihydrotestosterone. Side effects are specific for each class of endocrine therapy. The antiandrogen may cause gynecomastia and diarrhea. The use of LHRH-agonists is associated with a decrease in libido, impotence, and hot flashes. Inhibitors of 5-a-reductase are relatively nontoxic, with impotence the only side effect reported. The use of combinations of a-blocking agents and endocrine manipulation is currently under study. Clinical trials employing medical therapy for benign prostatic hyperplasia have emphasized the need for better response indicators. These include subjective measures, such as symptom scores and global assessment (quality of life and interference in daily activities), and objective ones, such as measuring voiding pressure, urinary flow rate, and residual urine. Because this disorder probably begins 20 or more years before clinical symptoms and signs are evident, medical therapy may be effective only in those men in whom changes of decompensation, such as bladder diverticula and hydronephrosis, have not yet developed. JOSEPH D. SCHMIDT, MD
REFERENCES
REFERENCES
Klimberg IW, Pow-Sang JM, Cartwright CK, Wajsman Z: Intravesical bacillus Calmette-Guerin for patients with high risk superficial bladder cancer. Urology 1991; 37:180-184 Melekos MD, Pantazakos A, Markou S, Skopa C, Athanassopoulos A, Barbalias G: Intravesical bacillus Calmette-Guerin administration in the prophylaxis of superficial bladder cancer. Int Urol Nephrol 1990; 22:433-440 Mikkelsen DJ, Ratliff TL: Mechanisms of action of intravesical bacillus CalmetteGuerin for bladder cancer. Cancer Treatment Res 1989; 46:195-211 Witjes JA, van der Meijden AP, Dubruyne FM: Use of intravesical bacillus Calmette-Guerin prophylactic treatment for superficial transitional cell carcinoma of the bladder: An overview. Urol Int 1990; 45:129-136
Gabrilove JL, Levine AC, Kirschenbaum A, Droller M: Effect of long-acting gonadotropin-releasing hormone analog (leuprolide) therapy on prostatic size and symptoms in 15 men with benign prostatic hypertrophy. J Clin Endocrinol Metabol 1989; 69:629-632 Graversen PM, Gasser TC, Wasson JH, Hinman F Jr, Bruskewitz RC: Controversies about indications for transurethral resection of the prostate. J Urol 1989; 141:475-
STANLEY A. BROSMAN, MD Santa Monica, California
San Diego, California
481
Lepor H: The role of alpha adrenergic blockers in the treatment of benign prostatic hyperplasia. Prostate 1990; 3(suppl):75-84 McConnell JD: Medical management of benign prostatic hyperplasia with androgen suppression. Prostate 1990; 3(suppl):49-59
