Question: Does Finasteride affect future risk of prostate cancer
Funded at a cost of US$73 million by the National Cancer Institute in the U.S.A., the results of the prostate cancer prevention trial1 were inconclusive and confusing, but nevertheless highly relevant to doctors prescribing finasteride for male pattern baldness. The trial was designed to determine if finasteride 5mg daily could prevent prostate cancer in men aged 55 years and older.
The rationale was that dihydrotestosterone (DHT) is known to promote the growth of prostate cells; that male pseudohermaphrodites deficient in type 2, 5 a reductase do not develop prostate cancer; that finasteride inhibits the growth of prostate cancer cells in vitro and that finasteride reduced the levels of prostate specific antigen1.
The hypothesis was that men aged 55 years and older taking finasteride 5mg daily over a 10-year period would have a lower incidence of prostate cancer than controls. The study was powered for a 25% reduction in incidence of prostate cancer. 18,882 men over the age of 55 with a normal digital rectal examination and a prostate specific antigen (PSA) level of 3.0 ng/ml or lower were enrolled in the study and half received placebo. All men had annual digital rectal examination and PSA. Prostate biopsy was performed if the rectal examination was abnormal or the PSA>4.0 ng/ml, adjusted for the effect of finasteride. In addition prostate biopsy was recommended to all participants at the end of the study. Approximately 50% of the trial participants underwent biopsy.
The trial was ceased at the end of 7 years as the primary goal of the trial had been met in that finasteride reduced the risk of prostate cancer by 25%. Prostate cancer was identified in 803 cases out of 4368 men on finasteride and 1147 cases out of 4692 men on placebo.
The complexity of this study was that the reduction in prostate cancer in the finasteride treated group principally occurred in the Gleason grade 2-6 tumours and Gleason grade 7,8,9 and 10 tumours actually increased from 280 out of 757 prostate cancers among men receiving finasteride compared to 237 out of 1068 tumours among men receiving placebo.
Calculations based on estimates of developing prostate cancer from the NCI’s cancer surveillance program and data on outcomes from the PCPT indicate that if you start with 1000 men aged 63, after 7 years, 60 of those men would have developed prostate cancer, and 18 would have high Gleason score disease. In contrast if you take those same 1,000 men and treat them with finasteride 5mg daily for 7 years, only 45 would develop prostate cancer, however 22 would have high Gleason score disease2.
An interesting issue is why finasteride would lead to an increase in Gleason grade 7-10 prostate cancer. While the cytological appearance of prostate cancer cells may be more worrying in men on androgen suppression therapy, the Gleason score is determined in the main by architectural features and so the increase in high Gleason score prostate cancers cannot be readily explained as an artifact of the effects of finasteride on the prostate as was postulated by the authors of the study1. Similarly as only 4% of men in the study were African American, racial bias is also an unlikely explanation.
There is limited support for the hypothesis that prostate cancers that develop in a low testosterone environment have higher Gleason grades and worse outcomes than prostate cancers that develop in men with normal testosterone3. Whether tumors that develop in men with low dihydrotestosterone levels have higher Gleason grades and worse outcomes than prostate cancers that develop in men with normal dihydrotestosterone will not be known until there is further follow-up of those men diagnosed with prostate cancer in this study.
While it is difficult to obtain accurate figures, the mortality of Gleason grades 7,8,9, and 10 carcinoma is estimated to be approximately 5 times greater than that of Gleason grades 2-6. In one study, men with tumors that have Gleason scores of 2 to 4, 5, 6, 7, and 8 to 10 face a 4% to 7%, 6% to 11%, 18% to 30%, 42% to 70%, and 60% to 87% chance, respectively, of dying from prostate cancer within 15 years of diagnosis depending on their age at diagnosis4. In the study by Thomson et al1. there were only 5 deaths on finasteride and 5 deaths on placebo.
A survival analysis by Unger et al showed that the potential detrimental effect of an increased rate of patients with high Gleason score prostate cancer would be outweighed by a reduction in incidence. They estimated that the24.8% reduction in prostate cancer diagnosis achieved with the use of finasteride would result in 316,760 saved person-years. An absolute increase of 6.9% in the proportion of men with a high Gleason score prostate cancer in the US cancer population, would reduce the number of person-years saved by approximately 39,000 resulting in a total net benefit of 262,567 saved person years5.
A second issue is whether finasteride use will improve morbidity and in particular surgery-related morbidity through a decrease in the number of low- Gleason score prostate cancers. Even when conservative management is initially elected, patients who do not die of co-morbid illness often find conservative management difficult to adhere to6.
A third issue concerns the prescribed dose of finasteride. In contrast to the PCPT in which a dose of 5 mg daily is used, male pattern hair loss is generally treated with finasteride 1 mg daily. It would seem reasonable to assume that due to the non-linear dose response relationship the findings with 5mg daily can be extrapolated to men receiving 1 mg daily7. Against this view Gormley, et al8, showed that a significantly higher reduction in serum DHT occurred with the 5 mg daily than with the 1 mg tablet of finasteride. Furthermore, Norman, et al9, showed significantly greater reduction in intraprostatic DHT with the 5 mg than with the 1 mg dose. Overstreet, et al10, showed the lack of effect of finasteride 1 mg on semen production as opposed to some effect from finasteride 5 mg.
So does finasteride prevent or cause prostate cancer? It probably does both, however the magnitude of the reduction in overall incidence of prostate cancer seems greater than the impact of the increased incidence of high Gleason score disease and survival analysis indicates an overall advantage for men who receive finasteride 5 mg daily that is in addition to an expected reduction in morbidity.
Furthermore, it is still not known how finasteride 1mg daily as prescribed for male pattern hair loss would affect the risk of developing high-Gleason score prostate cancer in comparison to the 5mg daily dose used in the PCPT.
- Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215-24.
- Ishikawa S, Soloway MS, Van der Zwaag R, Todd B. Prognostic factors in survival free of progression after androgen deprivation therapy for treatment of prostate cancer. J Urol. 1989 May;141(5):1139-42.
- Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA. 1998 Sep 16;280(11):975-80
- Unger et al. Estimated Impact of the Prostate Cancer Prevention Trial on Population Mortality. Cancer. 2005 Apr 1;103(7):1375-80
- Zietman AL, Thakral H, Wilson L, Schellhammer P. Conservative management of prostate cancer in the prostate specific antigen era: the incidence and time course of subsequent therapy. J Urol 2001;166:1702-6.
- Drake L, Hordinsky M, Fiedler V, Swinehart J, Unger WP, Cotterill PC, Thiboutot DM, Lowe N, Jacobson C, Whiting D, Stieglitz S, Kraus SJ, Griffin EI, Weiss D, Carrington P, Gencheff C, Cole GW, Pariser DM, Epstein ES, Tanaka W, Dallob A, Vandormael K, Geissler L, Waldstreicher J. The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. J Am Acad Dermatol. 1999 Oct;41(4):550-4
- Gormley The effect of finasteride in men with benign prostatic hyperplasia, New England Journal of Medicine; 327:1185, 1992
- Norman Androgen metabolism in men receiving finasteride before prostatectomy; J. Urol. 150:1736, 1993
- Overstreet Chronic treatment with finasteride does not affect spermatogenesis or semen production in young men J. Urol. 162:1295, 1999
- Giles GG, Severi G, Sinclair R, English DR, McCredie MR, Johnson W, Boyle P, Hopper JL. Androgenetic alopecia and prostate cancer: findings from an Australian case-control study. Cancer Epidemiol Biomarkers Prev. 2002 Jun;11(6):549-53