Finasteride in Benign Prostatic Hyperplasia
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《新英格兰医药杂志》
To the Editor: In the United States, the incidence of breast cancer in men 65 years of age or older is 5.5 cases per 100,000 man-years.1 The finding, reported by McConnell et al. (Dec. 18 issue),2 that four men had breast cancer after treatment with finasteride alone or finasteride with doxazosin in a trial of the size and duration of the Medical Therapy of Prostatic Symptoms (MTOPS) study is unexpected.
From 1992 through December 2003, the Food and Drug Administration (FDA) received reports of 13 men in the United States in whom breast cancer developed during finasteride therapy (9 men) or after finasteride therapy for benign prostatic hypertrophy. Their median age was 66 years; the median time from finasteride use to the diagnosis of breast cancer was 21 months. Gynecomastia, a known effect of finasteride,3,4 was a concurrent finding in four of the men. Histologic studies showed primarily intraductal carcinoma; there were 11 reported mastectomies. Similar reports on 16 men from other countries have been received. There were no reports to the FDA of cases of breast cancer in men in which other drugs used to treat benign prostatic hypertrophy were listed as suspected drugs. The number of reports of breast cancer in men treated with finasteride exceeded that for any other drug in the FDA's reporting data base. More research is needed on the relationship between breast cancer in men and finasteride use.
(The views expressed in this letter are those of the authors and do not necessarily represent the official position of the FDA.)
Diane K. Wysowski, Ph.D.
Evelyn Farinas, R.Ph.
Food and Drug Administration
Rockville, MD 20857
References
Ries LAG, Eisner MP, Kosary CL, et al., eds. SEER cancer statistics review, 1973-1997. Bethesda, Md.: National Cancer Institute, 2000. (NIH publication no. 00-2789.)
McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387-2398.
Proscar (finasteride). Physicians' desk reference. 57th ed. Montvale, N.J.: Thomson PDR, 2003:2080-3.
Green L, Wysowski DK, Fourcroy JL. Gynecomastia and breast cancer during finasteride therapy. N Engl J Med 1996;335:823-823.
To the Editor: The study by McConnell et al. showed that the combination of doxazosin and finasteride in patients with benign prostatic hyperplasia reduced the risk of acute urinary retention by 81 percent.
As part of the Triumph project,1,2 we performed a retrospective cohort study within the Integrated Primary Care Information data base to determine the incidence of acute urinary retention in the general population of men 45 years of age or older (56,958 men). We also studied the incidence of acute urinary retention in a subgroup of men with newly diagnosed lower urinary tract symptoms suggestive of benign prostatic hyperplasia.
Acute urinary retention was defined as the sudden inability to micturate, requiring catheterization. We identified 344 cases of acute urinary retention, resulting in an overall incidence of 2.2 cases per 1000 man-years (95 percent confidence interval, 2.0 to 2.4). Of these 344 cases, 149 (43 percent) were precipitated by events such as use of general anesthesia, urinary tract infections, and ingestion of drugs known to cause acute urinary retention or neurologic disorders.
We identified 149 cases of acute urinary retention among the 2214 patients with newly diagnosed lower urinary tract symptoms suggestive of benign prostatic hyperplasia. In 73 of these 149 cases (49 percent), acute urinary retention was the first symptom of benign prostatic hyperplasia. When these 73 cases were excluded from the analysis, the incidence rate of acute urinary retention in patients with newly diagnosed lower urinary tract symptoms suggestive of benign prostatic hyperplasia was 18.3 per 1000 man-years (95 percent confidence interval, 14.5 to 22.8). When all cases of acute urinary retention were included, the overall incidence rate was much higher (Figure 1).
Figure 1. Incidence of Acute Urinary Retention (AUR) in Patients with Newly Diagnosed Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia.
The blue line represents the incidence with all cases of AUR included. The red line represents the incidence with the exclusion of men who presented with AUR as the first symptom among lower urinary tract symptoms suggestive of benign prostatic hyperplasia. The broken lines represent 95 percent confidence intervals.
Although the clinical trial reported by McConnell et al. demonstrates that combination therapy reduces the risk of clinical progression of benign prostatic hyperplasia, we believe that some caution needs to be used when implementing this information in daily patient care. In our population, half of the men with acute urinary retention among those with benign prostatic hyperplasia never had any symptom of benign prostatic hyperplasia before the acute urinary retention. Hence, they were not identified in time for a potential benefit from preventive measures such as pharmacologic therapy. If we aim to reduce the incidence of acute urinary retention in patients with benign prostatic hyperplasia by means of pharmacologic treatment, early identification of patients seems to be essential.
Katia M.C. Verhamme, M.D.
Ruud J.L.H. Bosch, M.D., Ph.D.
Miriam C.J.M. Sturkenboom, Pharm.D., Ph.D.
Erasmus University Medical Center
3000 DR Rotterdam, the Netherlands
m.sturkenboom@erasmusmc.nl
References
Chapple CR. Lower urinary tract symptoms suggestive of benign prostatic obstruction -- triumph: design and implementation. Eur Urol 2001;39:Suppl 3:31-36
Verhamme KMC, Dieleman JP, Bleumink GS, et al. Incidence and prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in primary care -- the Triumph project. Eur Urol 2002;42:323-328.
Dr. Roehrborn replies: We agree that additional research into the relationship between breast cancer in men and the use of finasteride is desirable. We wish to reemphasize, however, the following facts regarding the number of cases of breast cancer in men in controlled clinical trials of finasteride. Among 3040 men treated over a period of four years in the Proscar (Finasteride) Long-Term Efficacy and Safety Study (PLESS), there were 2 cases of breast cancer in the placebo group and none in the finasteride group.1 In the seven-year Prostate Cancer Prevention Trial, involving more than 18,000 patients, there was no difference in the number of cases of breast cancer between the placebo and finasteride groups.2 Thus, the finding of four cases of breast cancer in men in the MTOPS trial who were in the finasteride-only or combination group is at odds with reported results of other large treatment trials and is assumed to be due to chance. Moreover, the fact that "the number of reports of breast cancer in men treated with finasteride exceeded that for any other drug in the FDA's reporting data base" may be due in part to the fact that physicians are encouraged to perform, and actively do perform, more breast examinations in men receiving finasteride because of the known increase in the incidence of gynecomastia (overdetection bias).
Dr. Verhamme and colleagues point out that in a large population-based study in Europe, half of all men with acute urinary retention were asymptomatic before the event and thus could not benefit from preventive therapies. First, one must be cautious when extrapolating the results of cross-sectional population-based studies to those of randomized clinical trials conducted in a target population of men with benign prostatic hyperplasia. Second, the result of the PLESS demonstrate that readily available measurements such as serum prostate-specific antigen, prostate volume, or both are the clinically useful predictors of future episodes of acute urinary retention as well as prostate surgery.3,4 Similar results have been observed with the other 5-reductase inhibitor, dutasteride.5 Risk assessment is thus possible in men who have seen a health care provider for benign prostatic hyperplasia or lower urinary tract symptoms or for an annual screening for prostate cancer. It logically follows that risk reduction or prevention of acute urinary retention is also possible in these men.
Claus G. Roehrborn, M.D.
University of Texas Southwestern Medical Center at Dallas
Dallas, TX 75390-9110
claus.roehrborn@utsouthwestern.edu
for the Medical Therapy of Prostatic Symptoms (MTOPS) Research Group
References
McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557-563.
Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215-224.
Roehrborn CG, Malice M, Cook TJ, Girman CJ. Clinical predictors of spontaneous acute urinary retention in men with LUTS and clinical BPH: a comprehensive analysis of the pooled placebo groups of several large clinical trials. Urology 2001;58:210-216.
Roehrborn CG, McConnell JD, Lieber M, et al. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology 1999;53:473-480.
Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60:434-441.
From 1992 through December 2003, the Food and Drug Administration (FDA) received reports of 13 men in the United States in whom breast cancer developed during finasteride therapy (9 men) or after finasteride therapy for benign prostatic hypertrophy. Their median age was 66 years; the median time from finasteride use to the diagnosis of breast cancer was 21 months. Gynecomastia, a known effect of finasteride,3,4 was a concurrent finding in four of the men. Histologic studies showed primarily intraductal carcinoma; there were 11 reported mastectomies. Similar reports on 16 men from other countries have been received. There were no reports to the FDA of cases of breast cancer in men in which other drugs used to treat benign prostatic hypertrophy were listed as suspected drugs. The number of reports of breast cancer in men treated with finasteride exceeded that for any other drug in the FDA's reporting data base. More research is needed on the relationship between breast cancer in men and finasteride use.
(The views expressed in this letter are those of the authors and do not necessarily represent the official position of the FDA.)
Diane K. Wysowski, Ph.D.
Evelyn Farinas, R.Ph.
Food and Drug Administration
Rockville, MD 20857
References
Ries LAG, Eisner MP, Kosary CL, et al., eds. SEER cancer statistics review, 1973-1997. Bethesda, Md.: National Cancer Institute, 2000. (NIH publication no. 00-2789.)
McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387-2398.
Proscar (finasteride). Physicians' desk reference. 57th ed. Montvale, N.J.: Thomson PDR, 2003:2080-3.
Green L, Wysowski DK, Fourcroy JL. Gynecomastia and breast cancer during finasteride therapy. N Engl J Med 1996;335:823-823.
To the Editor: The study by McConnell et al. showed that the combination of doxazosin and finasteride in patients with benign prostatic hyperplasia reduced the risk of acute urinary retention by 81 percent.
As part of the Triumph project,1,2 we performed a retrospective cohort study within the Integrated Primary Care Information data base to determine the incidence of acute urinary retention in the general population of men 45 years of age or older (56,958 men). We also studied the incidence of acute urinary retention in a subgroup of men with newly diagnosed lower urinary tract symptoms suggestive of benign prostatic hyperplasia.
Acute urinary retention was defined as the sudden inability to micturate, requiring catheterization. We identified 344 cases of acute urinary retention, resulting in an overall incidence of 2.2 cases per 1000 man-years (95 percent confidence interval, 2.0 to 2.4). Of these 344 cases, 149 (43 percent) were precipitated by events such as use of general anesthesia, urinary tract infections, and ingestion of drugs known to cause acute urinary retention or neurologic disorders.
We identified 149 cases of acute urinary retention among the 2214 patients with newly diagnosed lower urinary tract symptoms suggestive of benign prostatic hyperplasia. In 73 of these 149 cases (49 percent), acute urinary retention was the first symptom of benign prostatic hyperplasia. When these 73 cases were excluded from the analysis, the incidence rate of acute urinary retention in patients with newly diagnosed lower urinary tract symptoms suggestive of benign prostatic hyperplasia was 18.3 per 1000 man-years (95 percent confidence interval, 14.5 to 22.8). When all cases of acute urinary retention were included, the overall incidence rate was much higher (Figure 1).
Figure 1. Incidence of Acute Urinary Retention (AUR) in Patients with Newly Diagnosed Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia.
The blue line represents the incidence with all cases of AUR included. The red line represents the incidence with the exclusion of men who presented with AUR as the first symptom among lower urinary tract symptoms suggestive of benign prostatic hyperplasia. The broken lines represent 95 percent confidence intervals.
Although the clinical trial reported by McConnell et al. demonstrates that combination therapy reduces the risk of clinical progression of benign prostatic hyperplasia, we believe that some caution needs to be used when implementing this information in daily patient care. In our population, half of the men with acute urinary retention among those with benign prostatic hyperplasia never had any symptom of benign prostatic hyperplasia before the acute urinary retention. Hence, they were not identified in time for a potential benefit from preventive measures such as pharmacologic therapy. If we aim to reduce the incidence of acute urinary retention in patients with benign prostatic hyperplasia by means of pharmacologic treatment, early identification of patients seems to be essential.
Katia M.C. Verhamme, M.D.
Ruud J.L.H. Bosch, M.D., Ph.D.
Miriam C.J.M. Sturkenboom, Pharm.D., Ph.D.
Erasmus University Medical Center
3000 DR Rotterdam, the Netherlands
m.sturkenboom@erasmusmc.nl
References
Chapple CR. Lower urinary tract symptoms suggestive of benign prostatic obstruction -- triumph: design and implementation. Eur Urol 2001;39:Suppl 3:31-36
Verhamme KMC, Dieleman JP, Bleumink GS, et al. Incidence and prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in primary care -- the Triumph project. Eur Urol 2002;42:323-328.
Dr. Roehrborn replies: We agree that additional research into the relationship between breast cancer in men and the use of finasteride is desirable. We wish to reemphasize, however, the following facts regarding the number of cases of breast cancer in men in controlled clinical trials of finasteride. Among 3040 men treated over a period of four years in the Proscar (Finasteride) Long-Term Efficacy and Safety Study (PLESS), there were 2 cases of breast cancer in the placebo group and none in the finasteride group.1 In the seven-year Prostate Cancer Prevention Trial, involving more than 18,000 patients, there was no difference in the number of cases of breast cancer between the placebo and finasteride groups.2 Thus, the finding of four cases of breast cancer in men in the MTOPS trial who were in the finasteride-only or combination group is at odds with reported results of other large treatment trials and is assumed to be due to chance. Moreover, the fact that "the number of reports of breast cancer in men treated with finasteride exceeded that for any other drug in the FDA's reporting data base" may be due in part to the fact that physicians are encouraged to perform, and actively do perform, more breast examinations in men receiving finasteride because of the known increase in the incidence of gynecomastia (overdetection bias).
Dr. Verhamme and colleagues point out that in a large population-based study in Europe, half of all men with acute urinary retention were asymptomatic before the event and thus could not benefit from preventive therapies. First, one must be cautious when extrapolating the results of cross-sectional population-based studies to those of randomized clinical trials conducted in a target population of men with benign prostatic hyperplasia. Second, the result of the PLESS demonstrate that readily available measurements such as serum prostate-specific antigen, prostate volume, or both are the clinically useful predictors of future episodes of acute urinary retention as well as prostate surgery.3,4 Similar results have been observed with the other 5-reductase inhibitor, dutasteride.5 Risk assessment is thus possible in men who have seen a health care provider for benign prostatic hyperplasia or lower urinary tract symptoms or for an annual screening for prostate cancer. It logically follows that risk reduction or prevention of acute urinary retention is also possible in these men.
Claus G. Roehrborn, M.D.
University of Texas Southwestern Medical Center at Dallas
Dallas, TX 75390-9110
claus.roehrborn@utsouthwestern.edu
for the Medical Therapy of Prostatic Symptoms (MTOPS) Research Group
References
McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557-563.
Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215-224.
Roehrborn CG, Malice M, Cook TJ, Girman CJ. Clinical predictors of spontaneous acute urinary retention in men with LUTS and clinical BPH: a comprehensive analysis of the pooled placebo groups of several large clinical trials. Urology 2001;58:210-216.
Roehrborn CG, McConnell JD, Lieber M, et al. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology 1999;53:473-480.
Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002;60:434-441.