Clinical Predictors in the Use of Finasteride for Control of Gross Hematuria Due to Benign Prostatic Hyperplasia

0022-5347/02/1676-2489/0 THE JOURNAL OF UROLOGY® Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 167, 2489 –2491, June 2002 Printed in U.S.A.

CLINICAL PREDICTORS IN THE USE OF FINASTERIDE FOR CONTROL OF GROSS HEMATURIA DUE TO BENIGN PROSTATIC HYPERPLASIA MICHAEL C. KEARNEY, JONATHAN B. BINGHAM, RYAN BERGLAND, PATRICIA MEADE-D’ALISERA AND PETER J. PUCHNER* From the Squier Urological Clinic, New York-Presbyterian Hospital, Columbia College of Physicians and Surgeons New York, New York

ABSTRACT

Purpose: We identify predictors of clinical response as well as response time in patients treated with finasteride for gross hematuria due to benign prostatic hyperplasia. Materials and Methods: A retrospective chart review was preformed of 53 patients who had been given 5 mg. finasteride daily for the treatment of active bleeding or a recent history of recurrent bleeding. Urological evaluations were negative for tumor in all patients. A history of prostatectomy, anticoagulant status and prostate size was determined. The degree of hematuria was then graded before and after finasteride treatment according to our previously described system. Of the 53 patients who were actively bleeding at initial evaluation 16 were followed to determine time required for complete resolution of hematuria. Results: Hematuria grade improved after finasteride in 50 (94%) patients. Overall 77% of patients (41 of 53) experienced no further bleeding while taking finasteride. Mean followup was 38 months (range 3 to 86). Of the patients 86% (12 of 14) taking coumadin, 77% (10 of 13) taking aspirin and 73% (19 of 26) on no anticoagulants had no further bleeding once on finasteride. Of the patients who had undergone prior transurethral prostatectomy 84% (26 of 31) experienced no further bleeding versus 68% (15 of 22) of those who had not undergone previous surgery. In the 16 patients who began finasteride while actively bleeding the average time to clear urine was 12 days (range 2 to 45). Prostatic volume correlated with the average time needed for resolution of hematuria, which was 2.7 days or longer for small (less than 40 gm.), 10.3 days or longer for large (40 to 100), 19 days or longer for extra large (100 to 150) and 45 days or longer for extra extra large (greater than 150) glands. Hematuria resolved an average of 5.5 days versus 18.6 days in those who had or had not undergone previous prostatectomy, respectively. Conclusions: Our long-term followup demonstrates finasteride as a useful treatment for benign prostatic hyperplasia related gross hematuria, which is effective in patients who are on anticoagulants. In patients with larger prostatic volumes a longer time to response and higher incidence of recurrent but lower grade bleeding should be anticipated compared to those who have undergone prior prostatectomy or have a smaller prostate. KEY WORDS: hematuria, prostatic hyperplasia, finasteride

Hematuria associated with benign prostatic hyperplasia (BPH) can be bothersome and difficult to treat. The exact prevalence is not known but it is frequently found to be the cause of hematuria in older men. A spectrum of treatment options exists ranging from limitation of physical activity to various surgical interventions. A retrospective study involving more than 3,000 patients revealed that 12% of all transurethral prostatic resection procedures were indicated for hematuria.1, 2 More recently however, several studies have reported a possible benefit from the use of finasteride, a competitive 5-␣-reductase inhibitor for the treatment of hematuria secondary to BPH. It is postulated that finasteride, by blocking conversion of testosterone to dihydroxytestosterone, down-regulates prostatic angiogenesis and blood flow, and thus decreases bleeding.3 We report long-term followup data on 53 patients treated with finasteride for BPH related prostatic bleeding and evaluate predictors of clinical effectiveness as well as time to response.

MATERIALS AND METHODS

A retrospective chart review was performed of 53 patients who had been prescribed 5 mg. finasteride daily for the treatment of active bleeding or a recent history of recurrent bleeding. All patients underwent urological evaluations before initiation of therapy, which included examination of the upper urinary tract, urine cytology, urine culture and cystoscopy. Prostate size was determined by a digital rectal examination performed by a urologist. The evaluation was negative for tumor in all patients included in this study. The charts were specifically reviewed for urological history, previous prostatectomy, anticoagulant status and prostate size. Patients were interviewed by telephone if they had not been seen in the previous 2 months. The degree of hematuria was then graded before and after finasteride treatment according to a previously described grading system (see Appendix) and hematuria grade was assigned based on patient history. All charts were reviewed by 2 separate reviewers for purposes of concordance. Variables, such as previous prostate surgery, concomitant anticoagulation therapy and hematuria grade, were then analyzed to determine how they affected the way patients responded to finasteride therapy. All of the patients who were actively bleeding at the time of initial evaluation (16 of

Accepted for publication December 7, 2001. * Financial interest and/or other relationship with Merck and Company. Editor’s Note: This article is the fifth of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 2570 and 2571. 2489

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53) were monitored to determine the length of time required for complete resolution of hematuria. Paired t tests were performed to determine statistical significance in these 16 patients. RESULTS

Hematuria grade improved after treatment with finasteride in 50 (94%) of the 53 cases. Of the 3 remaining patients who did not show improvement 2 only had grade 1 bleeding, which did not change. Bleeding worsened from grade 1 to grade 3 in the final patient who was found to have been noncompliant with medication. Overall, 77% of the patients (41 of 53) experienced no further bleeding while taking finasteride. Of the 12 (23%) patients who had repeat bleeding it was of a lesser grade in 11. Mean followup was 38 months (range 3 to 86). Average patient age was 77 years (range 62 to 98). Five patients spontaneously discontinued treatment with finasteride but none of them reported treatment side effects as a reason for discontinuation. Of these 5 patients 4 had repeat episodes of hematuria after stopping finasteride. Patients continued finasteride treatment for an overall average of 1,121 days (fig. 1). Of the patients 86% (12 of 14) taking coumadin, 77% (10 of 13) taking aspirin and 73% (19 of 26) on no anticoagulants had no further bleeding once on finasteride (fig. 2). Of the 31 patients who had undergone prior prostatectomy 26 (84%) experienced no further bleeding versus 15 of 22 (68%) who had not undergone previous surgery. Of note patients who had previously undergone transurethral prostatectomy often had residual friable prostatic adenoma on cystoscopy before initiating treatment. In the 16 patients who began finasteride while actively bleeding, the average time to clear the urine was 12 days (range 2 to 45). The difference in time to resolution of hematuria between large and extra large, and between small and extra large prostates was statistically significant at p ⬍0.0004 and p ⬍0.0002, respectively. The differences between small and large prostates were not significant at p ⬍0.49 (fig. 3). Prostatic volume correlated with the average time needed for resolution of hematuria, which was 2.7 days or longer for small (less than 40 gm.), 10.3 days or longer for large (40 to 100), 19 days or longer for extra large (100 to 150) and 45 days or longer for extra extra large (greater than 150) glands. Hematuria resolved in patients an average of 5.5 days versus 18.6 days for those who had or had not undergone previous prostatectomy, respectively.

FIG. 1. Complete response rate based on concomitant anticoagulation therapy.

FIG. 2. Complete response rate based on prior prostatectomy

FIG. 3. Average time to resolution based on prostate size

DISCUSSION

Hematuria due to BPH is thought to be related to increased vascularity in the prostate, and an increase in microvessel density in BPH tissues compared to normal prostate tissue has been noted.4 This increase in vascularity results from stromal and acinar proliferation in prostatic hyperplasia, which is an androgen driven process. The new blood vessels in this BPH prostate are friable and more permeable due to an increase in prostatic intravascular pressure.5 This friability and increase in permeability result in frequent recurrent bleeding. Lekas et al demonstrated that blood flow in the rat prostate is decreased after treatment with finasteride.3 Similarly, Charakrabarti et al reported a reduction in prostatic blood flow in the canine prostate after treatment with finasteride.6 These studies suggest that dihydroxytestosterone may regulate the production of vasoactive substances, such as vascular epidermal growth factor (VEGF), nitric oxide synthase (NOS), and adrenomedullin. VEGF has been shown to stimulate angiogenesis within rat ventral prostate models.7 Microvascular density was increased in a parallel fashion with the levels of VEGF. After finasteride therapy microvascular density and expression of VEGF were significantly reduced, suggesting that finasteride may be inhibiting the expression of VEGF and its angiogenic effects. VEGF, NOS and adrenomodullin, all potent vasodilators, have been shown to be down-regulated in rat castration models.8 Thus, it has been postulated that through the inhibition of these growth fac-

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tors, hormonal deprivation may repress angiogenesis and induce degeneration of newly formed vessels.9 There is evidence of finasteride treatment causing prostatic involution through a combination of atrophy and programmed cell death.10 However, more research is needed to clarify the exact mechanism by which finasteride down-regulates angiogenesis and prostatic blood flow. Nonetheless, published nonplacebo controlled studies have demonstrated finasteride to be helpful in the treatment of patients with hematuria secondary to BPH. Furthermore, finasteride has been used safely for many years. In our first report 11 of 12 patients treated for at least 3 months showed significant improvement.11 These results were confirmed in our longer term followup study, with 16 of 18 patients showing improvement in an average of 31 months.12 In another study all 12 patients treated with finasteride showed resolution of hematuria within 2 weeks.2 The present report represents a greatly expanded series of patients placed on finasteride for BPH related gross hematuria for a longer followup period (average 38 months). We reconfirm our previous data with overall improvement in 94% of patients and 77% experiencing no further bleeding once on the medication. Additionally, patients on coumadin and aspirin fared as well if not better than those on no anticoagulation in regard to experiencing no further bleeding. We also note that patients who have undergone a previous transurethral prostatectomy experience less recurrent bleeding compared to those who have not (84% versus 68%), presumably due to a smaller residual prostatic volume. This assumption held true in the subgroup of patients who were begun on finasteride while actively bleeding. Smaller prostatic volume was seen to correlate with an average time needed for resolution of hematuria. CONCLUSIONS

Our long-term followup demonstrates finasteride to be a useful treatment for BPH related gross hematuria. Furthermore, finasteride is as effective in patients who are on anticoagulants. Our study, although retrospective and not a controlled trial, illustrates that in patients with larger prostatic volumes, longer time to response and higher incidence of recurrent but lower grade bleeding should be anticipated. APPENDIX: HEMATURIA GRADING SYSTEM 3

Grade–Description 0—No bleeding or up to 1 minor episode over the last 24 months during therapy

Grade–Description 1—up to 2 minor episodes within 1 year up to 1 moderate episode per year prior to or after initiating therapy 2—2 or more minor episodes over a 6-month period greater than 2 minor episodes over a 1 year period greater than 1 moderate episode per year prior to or after initiating therapy 3—1 or more severe episodes prior to or after initiating therapy Definitions: minor episode—resolved without intervention within 24 hours; moderate episode—lasted more than 24 hours but stopped without intervention or hospitalization and severe episode—resulted in clot retention and/or admission to the hospital.

REFERENCES

1. Mebust, W. K., Holtgrewe, H. L., Cockett, A. T. K. et al: Transurethral prostatectomy: immediate and postoperative complications. A cooperative study of 13 participating institutions evaluating 3885 patients. J Urol, 141: 243, 1989 2. Kashif, K. M., Foley, S. J., Basketter, V. et al: Haematuria associated with BPH—natural history and a new treatment option. Prostate Cancer Prostatic Disease, 1: 154, 1998 3. Lekas, E., Bergh, A. and Damber, J. E.: Effects of finasteride and bicalutamide on prostatic blood flow in the rat. BJU Int, 85: 962, 2000 4. Foley, S. J. and Bailey, D. M.: Microvessel density in prostatic hyperplasia. BJU Int, 85: 70, 2000 5. Kirschenbaum, A.: Editorial comment. J Urol, 163: 498, 2001 6. Chakrabarti, P., Salas, N., Herbert, F. B. et al: Reduction in prostatic blood flow by finasteride. J Urol, suppl., 157: 190, abstract 738, 1997 7. Haggstrom, S., Lissbrant, I. F. and Damber, J. E.: Testosterone induces vascular endothelial growth factor synthesis in the ventral prostate in castrated rats. J Urol, 161: 1620, 1999 8. Hayek, O. R., Shabsigh, A. and Buttyan, R.: Castration induces vasoconstriction of blood vessels in the rat prostate concomitant with a reduction of prostatic nitric oxide synthase activity. J Urol, 162: 1527, 1999 9. Marshall, S. and Narayan, P.: Treatment of prostatic bleeding: suppression of angiogenesis by androgen deprivation. J Urol, 149: 1553, 1993 10. Rittmaster, R. S., Norman, R. W., Thomas, L. N. et al: Evidence for atrophy and apoptosis in the prostates of men given finasteride. J Clin Endocrinol Metab, 81: 814, 1996 11. Puchner, P. J. and Miller, M. I.: The effects of finasteride on hematuria associated with benign prostatic hyperplasia: a preliminary report. J Urol, 154: 1779, 1995 12. Miller, M. I. and Puchner, P. J.: Effects of finasteride on hematuria associated with benign prostatic hyperplasia: long-term follow-up. Urology, 51: 237, 1998