Correspondence

Prevention of Prostate Cancer with Finasteride

N Engl J Med 2003; 349:1569-1572October 16, 2003

Article

To the Editor:

One perplexing finding of the Prostate Cancer Prevention Trial (July 17 issue)1 is that more high-grade tumors were detected in the finasteride group than in the placebo group. It is hard to put this finding into perspective because of the limited published data on the effects of finasteride on prostate cancer. Yang et al. have reported on a series of needle biopsies of the prostate in men treated with finasteride.2 No significant differences were seen between the treatment group and the control group with respect to multiple variables, including the Gleason grade. However, their study was nonrandomized and underpowered. Therefore, it is possible that the increase in the incidence of high-grade tumors may be due to a treatment effect that causes intermediate-grade cancers to appear to be aggressive tumors. The organizers of this study should urgently assemble a panel of prostate-cancer pathologists to determine the long-term effect of finasteride on cancer grading. Confirmation of a spurious “inflation” of the tumor grade would make the conclusions of this study clearer and place the benefits of finasteride chemoprevention in a more favorable light.

Mark A. Rubin, M.D.
Brigham and Women's Hospital, Boston, MA 02115
marubin@partners.org

Philip W. Kantoff, M.D.
Dana–Farber Cancer Institute, Boston, MA 02115

2 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   Yang XJ, Lecksell K, Short K, et al. Does long-term finasteride therapy affect the histologic features of benign prostatic tissue and prostate cancer on needle biopsy? Urology 1999;53:696-700
   CrossRef | Web of Science | Medline

To the Editor:

Thompson et al. report that finasteride was associated with a higher rate of tumors of Gleason grade 7, 8, 9, or 10. In the accompanying editorial, Scardino1 suggests that finasteride may promote high-grade cancers. The assignment of Gleason grades after finasteride therapy is problematic.2,3 The question is whether the high rate of Gleason grade 7, 8, 9, or 10 tumors was due to a histologic change or whether it was truly reflective of different biologic behavior. The proportion of such high-grade cancers diagnosed in each of seven years in a biopsy performed for cause ranged from 8.5 percent to 43.8 percent in the placebo group and from 26.2 percent to 52.5 percent in the finasteride group. The ratio of the proportion in the finasteride group to the proportion in the placebo group ranged from 1.0 to 3.7. The highest ratios were observed in the first two years, and no trend over time was identifiable (Table 1Table 1Proportion of Cases of Prostate Cancer Diagnosed That Had a Gleason Grade of 7, 8, 9, or 10.). If finasteride indeed selected for high-grade tumors and inhibited low-grade tumors, this ratio would be expected to increase over time. The fact that it does not suggests that the underlying mechanism is only an apparent histologic change that is not reflective of the development of more aggressive cancer with the use of finasteride therapy.

Claus G. Roehrborn, M.D.
University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9110
claus.roehrborn@utsouthwestern.edu

3 References

1. 1

   Scardino PT. The prevention of prostate cancer -- the dilemma continues. N Engl J Med 2003;349:297-299
   Full Text | Web of Science | Medline

2. 2

   Civantos F, Soloway MS. Finasteride (PROSCAR) effect on prostate cancer. J Urol 1996;155:Suppl:604A-604A abstract.
   

3. 3

   Civantos F, Soloway MS, Pinto JE. Histopathological effects of androgen deprivation in prostatic cancer. Semin Urol Oncol 1996;14:Suppl 2:22-31
   Medline

To the Editor:

Thompson et al. report a 24.8 percent reduction in the prevalence of prostate cancer in the finasteride group as compared with the placebo group. Clearly, the number of biopsies performed for cause, because of an elevated prostate-specific antigen (PSA) level or an abnormal digital rectal examination, will affect the number of cancers detected. Although the study attempted to adjust for the effect of finasteride on the PSA level, Table 3 of the article shows a significantly lower rate of biopsy triggered by an elevated PSA level in the finasteride group than in the placebo group. Fewer biopsies in the finasteride group resulted in fewer cancers detected. In addition, it was assumed that one could simply weight the PSA value in the finasteride group to account for the effect of finasteride on the PSA level (i.e., by multiplying the observed value by 2.0 and later by 2.3). If finasteride affected not only the magnitude of the PSA value but also the rate of change in the PSA level over the seven-year period, then a simple weighting of the PSA value may have caused a further bias in the rate of biopsy, resulting in a lower observed rate of prostate cancer in the finasteride group.

Harry B. Burke, M.D., Ph.D.
George Washington University School of Medicine, Washington, DC 20037
hburke@mfa.gwu.edu

To the Editor:

In her Perspective article (July 17 issue),1 Zuger concludes that finasteride significantly reduced the prevalence of prostate cancer but resulted in a higher pathological grade in the cancers that were detected. However, since 75 percent of small prostate cancers arise in the lateral portion of the peripheral zone2 and since finasteride shrinks the transitional zone of the prostate, allowing the lateral portion of the peripheral zone to extend more anteriorly and thus outside of the path of classic sextant-pattern biopsy, which was the method used (Figure 1Figure 1Transrectal Ultrasonographic Images of a Prostate without Benign Prostatic Hyperplasia (Panel A) and a Prostate with Benign Prostatic Hyperplasia (Panel B).), the data are equally consistent with the conclusion that finasteride simply reduces the rate of detection of low-grade and medium-grade prostate cancers. The prostate cancers in patients in the finasteride group that grew to a size large enough to be detected nevertheless were, as would be expected,4 of a higher grade.

Some issues could be resolved by having an efficient and accurate marker for prostate cancer or by using laterally directed transrectal ultrasound-guided biopsy (which increases the rate of detection from 67 percent to 90 percent5). Meanwhile, we should follow Scardino's recommendation of careful surveillance for patients receiving finasteride.

David T. Schwartz, M.D.
11437 Hollow Timber Ct., Reston, VA 20194
dtayschwartz@pol.net

5 References

1. 1

   Zuger AA. A big study yields big questions. N Engl J Med 2003;349:213-214
   Full Text | Web of Science | Medline

2. 2

   Aus G, Bergdahl S, Hugosson J, Lodding P, Pihl CG, Pileblad E. Outcome of laterally directed sextant biopsies of the prostate in screened males aged 50-66 years: implications for sampling order. Eur Urol 2001;39:655-660
   CrossRef | Web of Science | Medline

3. 3

   Walsh PC, ed. Campbell's urology. 8th ed. Vol. 4. Philadelphia: W.B. Saunders, 2002:3044.
   

4. 4

   Stamey TA, Raimondo M, Yemoto CE, McNeal JE, Johnstone IM. Effect of aging on morphologic and clinical predictors of prostate cancer progression. J Urol 2000;163:Suppl:58-58 abstract.
   CrossRef

5. 5

   Gore JL, Shariat SF, Miles BJ, et al. Optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate cancer. J Urol 2001;165:1554-1559
   CrossRef | Web of Science | Medline

To the Editor:

With regard to the article by Thompson et al., it is unfortunate that because of the paradoxical finding of a reduced overall risk of biopsy-detected prostate cancer along with an increased risk of high-grade cancer, the routine use of finasteride for the chemoprevention of prostate cancer cannot be advocated and may be contraindicated. We conducted a one-year clinical trial of finasteride in men with an elevated serum PSA level,1 in which participants underwent prostate biopsy both before and after treatment. We found a significantly higher incidence of cancer in the finasteride-treated men who had evidence of high-grade prostatic intraepithelial neoplasia in their pretreatment biopsy specimens. These findings suggest that testosterone, an alternative ligand for the androgen receptor, may selectively stimulate prostatic intraepithelial neoplasia. Alternatively, in men with such neoplasia, there may be a high likelihood of occult prostate cancer that would be missed by biopsy, and among such men, finasteride may select for the clonal expansion of cells that grow well in a dihydrotestosterone-depleted environment. Whatever the reason, both studies raise questions about the wisdom of treating men with finasteride in an effort to prevent clinically significant disease.

Ronald K. Ross, M.D.
Eila Skinner, M.D.
Richard J. Cote, M.D.
University of Southern California–Norris Comprehensive Cancer Center, Los Angeles, CA 90033
ross_r@ccnt.hsc.usc.edu

1 References

1. 1

   Cote RJ, Skinner EC, Salem CE, et al. The effect of finasteride on the prostate gland in men with elevated serum prostate-specific antigen levels. Br J Cancer 1998;78:413-418
   CrossRef | Web of Science | Medline

To the Editor:

An additional concern regarding the Prostate Cancer Prevention Trial is the possibility of the development of breast cancer in men taking finasteride. In the Medical Therapy of Prostatic Symptoms trial,1 finasteride, doxazosin, placebo, or a combination was given to 3000 patients with benign prostatic hyperplasia between 1997 and 2002. Breast cancer developed in four men (one in the finasteride-and-doxazosin group and three in the finasteride-and-placebo group). Breast cancer developed in only one man in the Prostate Cancer Prevention Trial. However, the 4.5 percent rate of gynecomastia2 suggests that the ratio of estrogen to testosterone3 is definitely affected, and it could be a stimulator of breast cancer in men.4

Shen C. Lee, Ph.D.
University of Missouri–Rolla, Rolla, MO 65401
shenclee@hotmail.com

Robert J. Ellis, M.D.
Oncology and Hematology Associates, Springfield, MO 65807

4 References

1. 1

   Nyberg LM, Kusek JW. Letter to MTOPS principal investigators. Bethesda, Md.: Division of Kidney Urology and Hematologic Disease, National Institutes of Health, October 2, 2002.
   

2. 2

   Green L, Wysowski DK, Fourcroy JL. Gynecomastia and breast cancer during finasteride therapy. N Engl J Med 1996;335:823-823
   Full Text | Web of Science | Medline

3. 3

   Sasco AJ, Lowenfels AB, Pasker-de Jong P. Epidemiology of male breast cancer: a meta-analysis of published case-control studies and discussion of selected aetiological factors. Int J Cancer 1993;53:538-549
   CrossRef | Web of Science | Medline

4. 4

   Gradishar WJ. Male breast cancer. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the breast. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2000:661-7.
   

To the Editor:

In interpreting the article by Thompson et al., the clinician need only consider those patients who had a biopsy performed for cause, since this is precisely the population of patients in whom biopsies are performed in the clinical setting (those with a high PSA level, an abnormal digital rectal examination, or both). By extrapolating from the data presented by the authors, I arrived at the figures shown in Table 1Table 1Results of Biopsies Performed for Cause.. If one excludes the end-of-study biopsies, which are unlikely to be performed in clinical practice and which provide results that are, to a large extent, probably reflective of the uncovering of latent (indolent) cancer, the take-home message is that finasteride was associated with a decrease in the incidence of prostate cancer of 3.0 percentage points and an increase in the incidence of high-grade disease of 3.8 percentage points.

Winston E. Barzell, M.D.
Urology Treatment Center, Sarasota, FL 34239
webmaroon@yahoo.com

Author/Editor Response

Barzell contends that the end-of-study biopsies we performed are not relevant to clinical practice, but 21.1 percent of the tumors found on such biopsies were in men with a PSA level of 2.6 to 3.9 ng per milliliter, and an additional 15.4 percent had a Gleason score of 7, 8, 9, or 10, thus meeting the current criteria for clinical significance. Moreover, the results of these biopsies mirrored the overall results of the trial, accounting for over half the cancers.

Contrary to the concern expressed by Lee and Ellis, one case of breast cancer was detected in each treatment group in our study. The study conducted by Ross and colleagues included only 52 patients and was not placebo-controlled.1 Regarding the comments by Schwartz, the study biopsies were laterally directed. Burke highlights the fact that if the current adjustment of the PSA value had been used for the detection of cancer, 17 additional cases of cancer would have been missed. Important as well was the 25 percent reduction in gland volume in the finasteride group, which resulted in a greater likelihood that cancer would be detected in this group, increasing the benefit of the agent.

We agree with Rubin and Kantoff, and ongoing studies are examining whether the Gleason scores we observed were an artifact of finasteride treatment. A personal communication with Drs. David Bostwick and Donald Gleason directed us to the deliberations of an expert panel of urologic pathologists convened by the World Health Organization, the American Cancer Society, and other organizations, who unanimously agreed that the grading of prostate cancer after therapy was not validated and should not be used.2 Although we reported the Gleason scores for both study groups, this was a secondary end point of the study and was subject to the potential artifact of cellular and architectural changes associated with finasteride therapy, as illustrated by Roehrborn's observation.3

Although our ongoing investigations may shed further light on the potential behavior of tumors that are detected, definitive answers can be obtained only through studies that are powered for survival and long-term studies to validate prognostic characteristics. That such studies would be several times as large as ours calls into question their feasibility. Little attention has been paid to the potential for using finasteride to avoid, in one quarter of men, treatment of prostate cancer with the attendant side effects. The observation that there is a high risk of prostate cancer, including high-grade disease, among men with PSA levels in the “normal range” makes the prevention of the disease even more attractive.

Ian M. Thompson, Jr., M.D.
University of Texas Health Science Center at San Antonio, San Antonio, TX 78229

Phyllis J. Goodman, M.S.
Southwest Oncology Group Statistical Center, Seattle, WA 98109

Charles A. Coltman, Jr., M.D.
Southwest Oncology Group Operations Office, San Antonio, TX 78245-3217

3 References

1. 1

   Cote RJ, Skinner EC, Salem CE, et al. The effect of finasteride on the prostate gland in men with elevated serum prostate-specific antigen levels. Br J Cancer 1998;78:413-418
   CrossRef | Web of Science | Medline

2. 2

   Algaba F, Epstein JI, Aldape HC, et al. Assessment of prostate carcinoma in core needle biopsy -- definition of minimal criteria for the diagnosis of cancer in biopsy material. Cancer 1996;78:376-381
   CrossRef | Web of Science | Medline

3. 3

   Civantos F, Soloway MS, Pinto JE. Histopathological effects of androgen deprivation in prostatic cancer. Semin Urol Oncol 1996;14:Suppl 2:22-31
   Medline

Citing Articles (8)

Citing Articles

1. 1

   Ian M. Thompson, Catherine M. Tangen, Phyllis J. Goodman, M. Scott Lucia, Eric A. Klein. (2009) Chemoprevention of Prostate Cancer. The Journal of Urology 182:2, 499-508
   CrossRef

2. 2

   M. S. Lucia, J. I. Epstein, P. J. Goodman, A. K. Darke, V. E. Reuter, F. Civantos, C. M. Tangen, H. L. Parnes, S. M. Lippman, F. G. La Rosa, M. W. Kattan, E. D. Crawford, L. G. Ford, C. A. Coltman, I. M. Thompson. (2007) Finasteride and High-Grade Prostate Cancer in the Prostate Cancer Prevention Trial. JNCI Journal of the National Cancer Institute 99:18, 1375-1383
   CrossRef

3. 3

   I. M. Thompson, C. Chi, D. P. Ankerst, P. J. Goodman, C. M. Tangen, S. M. Lippman, M. S. Lucia, H. L. Parnes, C. A. Coltman. (2006) Effect of Finasteride on the Sensitivity of PSA for Detecting Prostate Cancer. JNCI Journal of the National Cancer Institute 98:16, 1128-1133
   CrossRef

4. 4

   Steven Grover, Ilka Lowensteyn, David Hajek, John Trachtenberg, Louis Coupal, Sylvie Marchand. (2006) Do the Benefits of Finasteride Outweigh the Risks in the Prostate Cancer Prevention Trial?. The Journal of Urology 175:3, 934-938
   CrossRef

5. 5

   Girish S. Kulkarni, Rami Al-Azab, Gina Lockwood, Ants Toi, Andrew Evans, John Trachtenberg, Michael A.S. Jewett, Antonio Finelli, Neil E. Fleshner. (2006) Evidence for a Biopsy Derived Grade Artifact Among Larger Prostate Glands. The Journal of Urology 175:2, 505-509
   CrossRef

6. 6

   Mark A. Rubin, Yves Allory, Vincent Molinié, Xavier Leroy, Hugo Faucon, Francis Vacherot, Wei Huang, Adam Kuten, Laurent Salomon, Xavier Rebillard, Olivier Cussenot, Claude Abbou, Alexandre de la Taille. (2005) Effects of long-term finasteride treatment on prostate cancer morphology and clinical outcome. Urology 66:5, 930-934
   CrossRef

7. 7

   D. Schultheiss, S. Machtens, U. Jonas. (2004) Review article Testosterone therapy in the ageing male: what about the prostate?. Andrologia 36:6, 355-365
   CrossRef

8. 8

   Ian M Thompson, Eric A Klein, Scott M Lippman, Charles A Coltman, Bob Djavan. (2003) Prevention of Prostate Cancer with Finasteride: US/European Perspective. European Urology 44:6, 650-655
   CrossRef