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Journal of Clinical Oncology, Vol 25, No 21 (July 20), 2007: pp. 2999-3000 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.3549
Finasteride for Chemoprevention of Prostate Cancer: Why Has It Not Been Embraced?Department of Urology and the UC Davis Cancer Center, University of California at Davis, CA In the 1980s, PSA screening was introduced into clinical practice with the expectation that it would lead to earlier detection and treatment of prostate cancer (CaP) and to a decrease in disease-related mortality. Indeed, deaths from CaP have decreased from 34,999 in 1993 to 29,900 in 2004. This year's CaP mortality is expected to be approximately 27,000. This decrease in mortality has been accompanied by stage migration, as evidenced by declining rates of positive lymph nodes at surgery, margin positive disease after prostatectomy, and the number of patients diagnosed with bone metastases.1 Stage migration supports the view that the decrease in CaP mortality is at least partly attributable to the diagnostic and therapeutic benefits of PSA screening. That progress notwithstanding, CaP remains second only to lung cancer as a cause of cancer-related death in American men. Screening has also led to more prostate biopsies resulting in the detection of more cancers. Some have questioned the benefit of increased detection. Proponents of PSA screening point to a drop in CaP mortality, whereas opponents suggest that many of the detected cancers may pose little threat to a patient's life. Thus, screening may lead to unnecessary treatment and correlative morbidity as the price of reduced mortality. Schröder2 has a large ongoing study of PSA screening in Europe. They report that, to date, 49% of cancers detected in this study were apparently insignificant. That is, these cancers will not likely affect patient life span. Moreover, if clinically insignificant cancers were not treated, patients bearing them would avoid the potential adverse effects of therapy that they might not have needed initially. However, treatment of the 51% of significant cancers would likely result in decreased mortality, and the risk of morbid adverse effects would be more justifiable. Regrettably, a clean therapeutic division of significant and insignificant CaP has yet to develop. Dr Peter Carroll, chair of the Department of Urology at University of California at San Francisco, CA, recently reported that only 8% of patients with insignificant cancers are on active surveillance as contrasted with aggressive intervention.3 An obvious resolution of this dilemma would be to reduce or eliminate the development of all prostate cancers, both significant and insignificant. Indeed, CaP is an ideal candidate for prevention. It has high mortality, high incidence, and a long natural history. In 2003, Thompson et al4 reported on their efforts to prevent CaP by use of finasteride. Subjects were randomly assigned for 7 years between placebo and finasteride. At the end of the study, all were biopsied. The study showed that finasteride reduced the detection of confirmed CaP by 25%. As this result was better than anticipated, the study was terminated early and its results reported. In theory, at least 25% of men with significant cancers might then avoid unnecessary therapy, and if finasteride were able to prevent the development of significant tumors, then the reduction in CaP mortality might increase impressively, because therapy for advancing disease often fails in these cancers. These benefits should presumably have wrought a change in the standard of care: health care organizations would encourage men 50 years or older to go on finasteride. Given the power and freedom of drug advertising, pharmaceutical companies should be bombarding the population to get men at age 50 to start taking finasteride. But neither the clinic nor the marketplace has cheered finasteride. Why not? Recently, Thompson et al reworked the Prostate Cancer Prevention Trial (PCPT) data in an effort to give doctors and their patients some guidelines on how to assess individual risk of developing CaP.5 In this issue of the Journal of Clinical Oncology, these same authors have re-examined PCPT data for 4,440 patients who were on finasteride. In this subset, the risk of having CaP was still high, at 14.6%.6 The authors again show that for patients on finasteride, their PSA levels should be reduced by one half. The factors that predicted CaP are the same as for the subjects on placebo, namely digital rectal exam (DRE), family history, race, age, and a previously negative biopsy. These criteria, as they are prevention independent, assure patients that taking finasteride will not complicate their doctor's ability to recommend a biopsy to diagnose CaP. However, it still leaves open the question of whether a finasteride regimen does or does not mean that the patient has no risk or unchanged risk of developing prostate cancer. Have issues of family history, race, age, and previous negative biopsies all been resolved before a decision to take finasteride? Therefore, while on the drug, the only thing that can be used to suggest that they do or do not need a biopsy is a change in a DRE or a change in prostate-specific antigen (PSA) levels. If a patient goes on finasteride and their PSA falls to 0.5 ng/mL, they still have a 6.2% chance of harboring CaP. If their PSA level goes to 1.0 to 1.5 ng/mL, then their risk rises to 24.9%. This would imply that for a man with a PSA of 3.0 ng/mL, who has been placed on finasteride for treatment of benign prostatic hyperplasia (BPH) symptoms and whose PSA subsequently has gone to 1.8 ng/mL, a biopsy is required. Based on the above figures, the patient would be told that there was a 24.9% chance of harboring CaP, a risk that justifies a biopsy. In contrast, if the same patient had been placed on an alpha blocker and his PSA level decreased to 2.5 ng/mL, he would be less likely to be biopsied. In short, based on the above results, we could greatly increase the number of men undergoing biopsies. Does finasteride prevent the high-risk tumors that would be difficult to control with hormones if they are advancing under surveillance? The first problem is that this article and earlier ones state that there is no safe PSA level at which the patient can be sure that he does not have CaP. Also, the very tight controls of PSA levels while on finasteride would still mean that a large number of patients would need to undergo biopsies. The second problem is that the authors never discuss the fact that there is other literature that does not support finasteride's benefits to nearly the same degree. That is, the difference in detection of CaP between patients taking or not taking finasteride is considerably narrower. These data were recently reviewed by Andriole.7 The Proscar Long-Term Efficiency and Safety Study (PLESS) study compared finasteride to placebo as treatment of BPH in 3,034 men. The study lasted 4 years, during which time 4.7% of men on finasteride and 5.1% on the placebo were diagnosed with CaP (not significant).8 The Medical Therapy of Prostatic Symptoms (MTOPS) study compared finasteride and doxazosin with placebo in 3,047 men with BPH. The positive biopsy rate in this was 6.6% for men on the drug and 8.3% for those on placebo.9 In a study of dutasteride, a duel 5 alpha reductase inhibitor, 4,325 men with BPH were observed for 27 months; 1.2% on the drug and 2.5% on the placebo were diagnosed with CaP (P = .002).7 These studies, I agree, differ from the PCPT trial as they were directed against BPH. However, the startling difference in the rate of detection of CaP between men on drug or placebo in these papers compared with the PCPT study is at least one reason why people have failed to embrace finasteride as a chemopreventive method.7-9 AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES 1. Chu KC, Tarone RE, Freeman HP: Trends in prostate cancer mortality among black men and white men in the United States. Cancer 97:1507-1516, 2003[CrossRef][Medline] 2. Schröder FH: Serum PSA of prostate cancer screening and the increasing risk of over-detection. Presented at the Active Surveillance for Early-Stage Prostate Cancer Conference at University of California at San Francisco, San Francisco, CA, January 12-13, 2007 3. Harlan SR, Cooperberg MR, Elkin EP, et al: Time trends and characteristics of men choosing watchful waiting for initial treatment of localized prostate cancer: Results from CaPSURE. J Urol 170:1804-1807, 2003[CrossRef][Medline] 4. Thompson IM, Ankerst DP, Chi C, et al: The influence of finasteride on the development of prostate cancer. N Engl J Med 349:215-224, 2003 5. Parekh DJ, Ankerst DP, Higgins BA, et al: External validation of the prostate cancer prevention trial risk calculator in a screened population. Urol 68:1152-1155, 2006[CrossRef][Medline] 6. Thompson IM, Ankerst DP, Chi C, et al: Prediction of prostate cancer for patients receiving finasteride: Results from the Prostate Cancer Prevention Trial. J Clin Oncol 25:3076-3081, 2007 7. Andriole G: 5 8. McConnell JD, Bruskewitz R, Walsh PC, 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 338:557-563, 1998 9. Andriole GL, Bautista OM, Crawford D, et al: Prostate cancer (CaP) detection in the Medical Therapy of Prostatic Symptoms (MTOPS) trial. Presented at the American Urological Association Annual Meeting, Chicago, IL, April 26-May 1, 2003 Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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-reductase inhibitors and chemoprevention: The PCPT and beyond. Eur Urol 5:746-751, 2006 (suppl 5)
