Chemoprevention for prostatic carcinoma: The role of flutamide in patients with prostatic intraepithelial neoplasia

Chemoprevention for prostatic carcinoma: The role of flutamide in patients with prostatic intraepithelial neoplasia


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ABSTRACT High-grade prostatic intraepithelial neoplasia (HGPIN) is believed to be a precursor for prostatic adenocarcinoma. The prevalence of prostatic intraepithelial neoplasia (PIN) increases with advancing age. Autopsy studies suggest that PIN may precede the development of prostatic adenocarcinoma by up to 10 years. As such, HGPIN is believed to be a marker of increased risk. This provides a potential opportunity for chemoprevention. Flutamide is 1 agent with potential activity and limited side effects that may act to prevent or delay the onset of prostatic adenocarcinoma in men with HGPIN. A clinical trial is currently underway to assess the efficacy of flutamide. UROLOGY 57 (Suppl 4A): 188–190, 2001. © 2001, Elsevier Science Inc.


rostatic intraepithelial neoplasia (PIN), in particular high-grade prostatic intraepithelial neoplasia (HGPIN), is felt to be a precursor of prostatic adenocarcinoma. As described by McNeal and Bostwick1 and subsequently defined by Bostwick and Brawer,2 HGPIN is part of a spectrum of abnormal epithelial proliferation in the prostatic glands. Although PIN is divided into 2 grades, it is believed to represent a continuum of changes from low-grade lesion to early invasive carcinoma. The pathologic features of PIN are characterized by basal cell layer disruption, progressive loss of secretory differentiation, and increasing nuclear and nucleolar abnormalities. Other molecular and genetic changes have also been described 3– 6 and are reviewed in detail elsewhere.7 The association between PIN and prostatic adenocarcinoma has been made through autopsy studies, review of prostatectomy specimens, and from prostate biopsies. In 1 autopsy study, 9% of men in their third decade of life had evidence of low-grade PIN.8,9 The prevalence of PIN increases to 20% and 44% in the fourth and fifth decades of life, respectively. Prostatic adenocarcinoma was only seen in association with HGPIN and only in men over age 40. A higher prevalence of HGPIN has also been described in autopsy specimens from African American men.10 In addition, the age of onset of From the Division of Medical Oncology (SRA) and Department of Urology (MLB), Mayo Clinic, Rochester, Minnesota, USA Reprint requests: Steven R. Alberts, MD, Mayo Clinic, Medical Oncology–E12, Rochester, MN 55905



HGPIN appeared to occur earlier in this group. Drawing on observations made from autopsy studies, it has been suggested that PIN may precede the development of cancer by up to 10 years.7 Several studies have evaluated the prevalence of PIN in prostate biopsies and in prostatectomy specimens.11–18 The occurrence of PIN in biopsies ranges from approximately 5% up to 16.5%. At least 25% of men with HGPIN on an initial biopsy will be found to have carcinoma on repeat biopsy. For men with no evidence of carcinoma, several studies suggest that the risk of developing a subsequent cancer carcinoma ranges from 17% to 39%.19 Indeed, in our experience, an increasing number of men are found to have prostatic adenocarcinoma on follow-up biopsies. In a series of whole-mount prostates obtained from patients undergoing radical prostatectomy for clinically localized cancer, Qian et al.15 found that 86% of cases had HGPIN. A strong association has been noted between the cancer and the extent and zonal distribution of the foci of HGPIN. Wiley et al.17 reviewed whole mount prostates obtained as part of a cystoprostatectomy for bladder cancer to determine the frequency of PIN and compared these result to a series of radical prostatectomies done for prostatic adenocarcinoma. HGPIN was found in 83% of the cystoprostatectomy specimens and 91% of the radical prostatectomy specimens. Incidental prostatic adenocarcinoma was found in 46% of the cystoprostatectomy specimens. 0090-4295/01/$20.00 PII S0090-4295(00)00971-7

Patients who have undergone androgen ablation do appear to have regression of PIN. In a prior review of the published literature, Wheeler20 concluded that androgen ablation does appear to reduce the prevalence of PIN. The duration of antiandrogen therapy also appears to be of importance.21 The decrease in the occurrence of PIN is greater with 6 or more months of therapy compared with patients receiving only 3 to 6 months of antiandrogen therapy. These findings suggest that external factors may influence the occurrence of PIN and therefore support chemoprevention trials. Given the apparent association between HGPIN and prostatic adenocarcinoma, HGPIN has served as a biomarker of risk for prostatic adenocarcinoma in several clinical chemoprevention trials. The time needed for progression of HGPIN to carcinoma remains unclear, but appears to be months to years. As such, patients with HGPIN are attractive candidates for trials of agents that may alter the occurrence of HGPIN and therefore hopefully decrease the eventual development of prostatic adenocarcinoma. With the observation that androgen deprivation leads to a reduction in PIN, several chemoprevention trials are underway using this approach. There are various issues that need to be considered in chemoprevention trials, including prostate cancer prevention trials. These include the ability to identify a population of patients with the required risk factor, the ability to monitor the patients adequately, the safety and tolerability of the chemoprevention agent, and the expense of the therapy. Patients with HGPIN are only identifiable through prostate biopsies. This requires an initial level of suspicion leading to a biopsy. Wills et al. have expressed the concern that the number of patients with HGPIN and no identifiable cancer is quite small.18 As such, a large number of patients will need to be screened to identify potential candidates for a clinical trial. Although such an approach might be feasible for a phase 2 trial at a large institution or cooperative group, it would be very difficult to conduct a phase 3 trial in which several hundred patients would be required. The selection of a chemoprevention agent requires that it must (1) significantly decrease the development of prostate cancer, (2) have minimal side effects, (3) be easy to administer, and (4) be inexpensive as many years of therapy are likely.22 One such available agent is flutamide. Flutamide is a potent nonsteroidal antiandrogen that competitively inhibits testosterone and dihydrotestosterone from binding to the androgen receptor.23,24 The greatest potential limitation to flutamide is its known side effects including gynecomastia, liver function abnormalities, decreased libido, and erectile dysfunction as reviewed elsewhere.25 UROLOGY 57 (Supplement 4A), April 2001

The North Central Cancer Treatment Group is currently performing a double-blind, randomized, phase 2 trial of low-dose flutamide (250 mg/day) versus a placebo. It is felt that a lower dose of flutamide may limit side effects. Preclinical studies suggest that once-daily dosing26 and a lower dose of flutamide may be efficacious. Patients are required to have at least 1 of 2 prostate biopsies showing HGPIN. The primary endpoint of the study is to determine the ability of antiandrogen therapy to reduce the apparent increased incidence of prostate cancer in men with HGPIN. This study will also assess the effect of flutamide on a series of potential surrogate endpoint biomarkers as well as the patients’ quality of life. Future studies will need to build on the results of this study and others. Other potential biomarkers must be identified. HGPIN has been an attractive marker to identify potential patients for chemoprevention trials owing to its strong association with the subsequent development of prostatic adenocarcinoma. One of its greatest limitations is that it is found in a limited group of men undergoing prostate cancer screening. HGPIN also appears to be a late event in the premalignant changes leading up to the development of prostate cancer. As such, it may not be possible to effectively reverse the oncogenic events that have already occurred. The studies currently underway will help to better address this concern. Identification of a marker occurring at an earlier point, however, has the problem of a long latency period, from identification of the marker to the development of cancer. It is therefore critical that the molecular events leading up to the development of prostatic adenocarcinoma become more fully elucidated. Finally, it will be important to identify a biomarker that is accessible with a minimally invasive test and present in the majority of men destined to develop prostatic adenocarcinoma. REFERENCES 1. McNeal JE, and Bostwick DG: Intraductal dysplasia: a premalignant lesion of the prostate. Hum Pathol 17: 64 –71, 1986. 2. Bostwick DG, and Brawer MK: Prostatic intra-epithelial neoplasia and early invasion in prostate cancer. Cancer 59: 788 –794, 1987. 3. Haussler O, Epstein JI, Amin MB, et al: Cell proliferation, apoptosis, oncogene, and tumor suppressor gene status in adenosis with comparison to benign prostatic hyperplasia, prostatic intraepithelial neoplasia, and cancer. Hum Pathol 30: 1077–1086, 1999. 4. Koeneman KS, Pan CX, Jin JK, et al: Telomerase activity, telomere length, and DNA ploidy in prostatic intraepithelial neoplasia (PIN). J Urol 160: 1533–1539, 1998. 5. Tamboli P, Amin MB, Xu HJ, et al: Immunohistochemical expression of retinoblastoma and p53 tumor suppressor genes in prostatic intraepithelial neoplasia: comparison with prostatic adenocarcinoma and benign prostate. Mod Pathol 11: 247–252, 1998. 189

6. Brooks JD, Weinstein M, Lin X, et al: CG island methylation changes near the GSTP1 gene in prostatic intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev 7: 531–536, 1998. 7. Bostwick DG: Prospective origins of prostate carcinoma: prostatic intraepithelial neoplasia and atypical adenomatous hyperplasia. Cancer 78: 330 –336, 1996. 8. Sakr WA, Grignon DJ, Crissman JD, et al: High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20 – 69: an autopsy study of 249 cases. In Vivo 8: 439 – 443, 1994. 9. Sakr WA, Haas GP, Cassin BF, et al: The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 150: 379 –385, 1993. 10. Sakr WA, Grignon DJ, Haas GP, et al: Epidemiology of high grade prostatic intraepithelial neoplasia. Pathol Res Pract 191: 838 – 841, 1995. 11. Cheng L, Cheville JC, Pisansky TM, et al: Prevalence and distribution of prostatic intraepithelial neoplasia in salvage radical prostatectomy specimens after radiation therapy. Am J Surg Pathol 23: 803– 808, 1999. 12. Gaudin PB, Sesterhenn IA, Wojno KJ, et al: Incidence and clinical significance of high-grade prostatic intraepithelial neoplasia in TURP specimens. Urology 49: 558 –563, 1997. 13. Harvei S, Skjorten FJ, Robsahm TE, et al: Is prostatic intraepithelial neoplasia in the transition/central zone a true precursor of cancer? A long-term retrospective study in Norway. Br J Cancer 78: 46 – 49, 1998. 14. Pacelli A, and Bostwick DG: Clinical significance of high-grade prostatic intraepithelial neoplasia in transurethral resection specimens. Urology 50: 355–359, 1997. 15. Qian J, Wollan P, and Bostwick DG: The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clinically localized prostatic adenocarcinoma. Hum Pathol 28: 143–148, 1997.


16. Raviv G, Janssen T, Zlotta AR, et al: Prostatic intraepithelial neoplasia: influence of clinical and pathological data on the detection of prostate cancer. J Urol 156: 1050 –1055, 1996. 17. Wiley EL, Davidson P, McIntire DD, et al: Risk of concurrent prostate cancer in cystoprostatectomy specimens is related to volume of high-grade prostatic intraepithelial neoplasia. Urology 49: 692– 696, 1997. 18. Wills ML, Hamper UM, Partin AW, et al: Incidence of high-grade prostatic intraepithelial neoplasia in sextant needle biopsy specimens. Urology 49: 367–373, 1997. 19. Bostwick DG: Progression of prostatic intraepithelial neoplasia to early invasive adenocarcinoma. Eur Urol 30: 145– 152, 1996. 20. Wheeler TM: Influence of irradiation and androgen ablation on prostatic intraepithelial neoplasia. Eur Urol 30: 261– 264, 1996. 21. van der Kwast TH, Labrie F, and Tetu B: Prostatic intraepithelial neoplasia and endocrine manipulation. Eur Urol 35: 508 –510, 1999. 22. Nelson PS, Gleason TP, and Brawer MK: Chemoprevention for prostatic intraepithelial neoplasia. Eur Urol 30: 269 –278, 1996. 23. Brogden RN, and Clissold SP: Flutamide: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in advanced prostatic cancer. Drugs 38: 185–203, 1989. 24. Labrie F: Mechanism of action and pure antiandrogenic properties of flutamide. Cancer 72: 3816 –3827, 1993. 25. Dorr RT, and Von Hoff DD: Cancer Chemotherapy Handbook. Norwalk, Connecticut, Appleton & Lange, 1994, pp 518 –520. 26. Luo S, Martel C, Chen C, et al: Daily dosing with flutamide or Casodex exerts maximal antiandrogenic activity. Urology 50: 913–919, 1997.

UROLOGY 57 (Supplement 4A), April 2001