Prostate Cancer

Prostate Cancer Quality of Life Questionnaire. Subjectively, both groups experienced a significant improvement in urgency, and the estradiol group experienced a significant improvement in urge incontinence; however, there were no significant differences between the groups. Objectively, no significant differences were demonstrated between the groups. Nine women in the estradiol group experienced vaginal bleeding, of whom 5 required a hysterectomy during or after the study. Despite the use of numerous outcome measures, the 25-mg estradiol implant did not produce a greater improvement in urgency symptoms compared with placebo. In addition, the estradiol implant was associated with a high complication rate. These results make it is difficult justify the use of estrogen for overactive bladder symptoms. Although estrogen may play a role in reducing the discomfort and irritation associated with atrophic vaginal tissue, it appears to have no use in the treatment of bladder urgency symptoms. severity index. The agreement between patient and physician ratings was highest for mild incontinence but decreased as incontinence severity progressed. Most urologists would likely agree with the conclusions of this study. When symptoms are mild to moderate, the patient history is clear and empiric treatment is often successful. When leakage is severe, it becomes difficult to differentiate between urge and stress incontinence. We have all heard statements such as “I don’t know when I leak” or “I leak all of the time.” These situations are frustrating for both patients and doctors. Careful patient assessment, including urodynamic evaluation, is most helpful in these instances. Prostate Cancer Relationship Between Patient Report and Physician Assessment of Urinary Incontinence Severity Vitamin D for the Management of Prostate Cancer Melville JL, Miller EA, Fialkow MF, et al. Reviewed by Masood A. Khan, MD, Alan W. Partin, MD, PhD Am J Obstet Gynecol. 2003;189:76-80. Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD How severe is your patient's incontinence? Does a patient know when her urinary incontinence is severe versus mild? The purpose of this study was to determine the relationship between patient report and physician assessment of urinary incontinence severity. A total of 153 women with urinary incontinence completed a detailed health questionnaire that included a medical comorbidity scale, the 12-item short-form health survey (SF-12), the incontinence quality of life instrument, the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire, and a patient incontinence severity assessment. The study was carried out at the University of Washington’s Department of Obstetrics and Gynecology in Seattle. The patient incontinence severity assessment is a single question that asks the patient to rate the severity of her incontinence symptoms on a 5-point Likert scale (range, 1 [mild] to 5 [severe]). In addition, the physicians assigned each patient a physician incontinence severity assessment score, which rates the severity of the patient's incontinence on a 5-point Likert scale (range, 1 [mild] to 5 [severe]). The study found a high correlation between patient report and physician assessment of urinary incontinence severity. Both patient report (patient incontinence severity assessment) and physician assessment (physician incontinence severity assessment) correlated well with a validated [Rev Urol. 2004;6(2):95-97] © 2004 MedReviews, LLC lthough vitamin D can be obtained from many natural dietary sources, such as fish liver oil, eggs, and dairy products, for the majority of men, this dietary source fails to meet the daily required levels.1,2 Instead, their major source of vitamin D is derived from synthesis in the skin through conversion of a precursor (7dehydrocholesterol) into vitamin D3, a reaction catalyzed by ultraviolet light present in sunlight.2 Vitamin D3 subsequently undergoes hydroxylation in the liver followed by the kidney, resulting in the synthesis of 1,25-dihydroxyvitamin D3, or calcitriol, which is the principal active hormonal form of vitamin D.2 In addition to its well-known role in regulating calcium homeostasis in the body via its actions in the kidney, bone, intestine, and parathyroid glands,2 vitamin D also exhibits antitumorigenic properties, as demonstrated in in-vivo studies.3 This knowledge has led to epidemiologic studies investigating the association between vitamin D deficiency and prostate cancer. Accordingly, Schwartz and Hulka4 were the first to propose that low levels of vitamin D increase the risk of prostate cancer. These observations were based on A VOL. 6 NO. 2 2004 REVIEWS IN UROLOGY 95 Prostate Cancer continued prostate cancer mortality rates in the United States, which are inversely related to ultraviolet light exposure. This, in turn, has led to numerous studies investigating the antiproliferative properties of vitamin D on the prostate.5-7 It is now well established that vitamin D, via the induction of cell cycle arrest and/or apoptosis, inhibits the growth of normal prostatic epithelial cells, as well as primary cultures of prostate cancer cells and prostate cancer cell lines.5-7 Although the molecular pathways involved in the antiproliferative action of vitamin D are not well delineated, the cell cycle inhibitor p21WAF1/CIP1 and insulin-like growth factor binding protein-3 (IGFBP-3) have been implicated.8,9 It has recently been proposed that, beyond its antiproliferative properties, vitamin D harbors antimetastatic potential. This hypothesis is based on the ability of vitamin D to reduce invasion and adhesion of androgen-independent prostate cancer cells lines in vitro,10 as well as in a xenograft model of rat prostate cancer.11 Because of the toxicity associated with daily administration of vitamin D, weekly administration and use of vitamin D analogs have recently generated great interest. Two recently published papers report on these subjects. High-Dose Weekly Oral Calcitriol in Patients With a Rising PSA After Prostatectomy or Radiation for Prostate Carcinoma Beer TM, Lemmon D, Lowe BA, Henner WD. Cancer. 2003;97:1217-1224. Previously, Gross and colleagues12 investigated the impact of daily oral calcitriol in 7 men with prostate-specific antigen (PSA) recurrence after previous definitive therapy (surgery or radiation). Although a reduction in serum PSA was noted in 6 of 7 subjects, there was predictable development of hypercalcemia and hypercalciuria. In an attempt to avoid these complications, Beer and colleagues investigated the long-term toxicity of weekly oral administration of calcitriol and the impact of this regimen on serum PSA levels in 22 men with biochemical recurrence (median serum PSA, 5.8 ng/mL; range, 1.1-38.6 ng/mL) after radical prostatectomy and/or radiation therapy who did not receive any systemic adjuvant therapy. Calcitriol administration was continued until a maximum of a 4-fold rise in serum PSA level was reached or clinical evidence of disease progression. The primary end point of the study was a PSA response, which was defined as a 50% reduction in serum PSA level confirmed by 2 measurements at least 4 weeks apart. The secondary end point was a statistically significant increase in the PSA doubling time (PSADT). The study cohort received calcitriol for a median duration of 10 96 VOL. 6 NO. 2 2004 REVIEWS IN UROLOGY months (range, 2-25 months). At the time of publication, 21 of 22 subjects had discontinued treatment because of a variety of factors, including the development of metastatic disease (n = 2), a 4-fold increase in serum PSA level (n = 2), and at the request of their physicians due to rising serum PSA levels that were not 4-fold greater than the baseline values (n = 15). In addition, although no grade 3 or higher toxicity was detected and no patient experienced hypercalcemia or renal calculi, 2 men discontinued therapy because of toxicity (1 due to worsening of preexisting atrial fibrillation and 1 due to elevation in creatinine). Although no subject met the primary end point, 3 men experienced some reduction in serum PSA level (10%-47%) and 3 experienced a significant increase in PSADT. The remaining 16 men had no change in PSADT. Even with the small study population and the lack of randomization comparing calcitriol with placebo, the results of this study are disappointing. Although moderately well tolerated, calcitriol failed to demonstrate an impact on disease progression. These results may have been related to the selection of the study group itself, the majority of whom most likely harbored aggressive disease; only 10 of the 22 subjects received definitive monotherapy (radical prostatectomy [n = 5] or radiation [n = 5]), whereas the remainder received either neoadjuvant hormonal therapy (n = 4) or adjuvant radiation therapy (n = 8). This explanation for the failed response is further strengthened by the fact that 14 subjects (64%) experienced biochemical recurrence within 2 years of definitive therapy, placing them at an increased risk for developing metastatic disease.13 Serum calcitriol levels were measured in 6 subjects and revealed that, within 24 hours of calcitriol administration, there was a sharp decline in its concentration (half-life, 6-11 hours). Therefore, it is possible that serum calcitriol levels become subtherapeutic well before the time for repeat dosing, making this treatment less efficacious. Growth Inhibition and Differentiation in Human Prostate Carcinoma Cells Induced by the Vitamin D Analog 1,24Dihydroxyvitamin D2 Bauer JA, Thompson TA, Church DR, et al. Prostate . 2003;55:159-167. In an effort to address the hypercalcemic toxicity associated with vitamin D, there has been a recent growth of interest in vitamin D analogs that are less toxic but retain efficacy as a modality for cancer intervention. To this end, Bauer and colleagues conducted in vitro studies to determine the impact of the less hypercalcemic vitamin D analog 1,24- Prostate Cancer dihydroxyvitamin D2 (1,24-[OH]2D2) on cellular growth inhibition and differentiation induction in the androgensensitive human prostate cancer cell line LNCaP. Study results revealed that, in the presence of androgen, 1,24(OH)2D2 significantly inhibited the growth of LNCaP cells in a manner that was comparable to vitamin D. Furthermore, 1,24-(OH)2D2 was more potent than vitamin D at inducing PSA release from LNCaP cells, suggesting that it may be a more potent differentiating agent. The authors concluded that, with its lower calcemic toxicity compared with vitamin D, 1,24-(OH)2D2 may provide a promising vitamin D–based therapeutic modality for prostate cancer. However, before this can be confirmed, the antiproliferative properties of 1,24-(OH)2D2 need to be demonstrated in an animal model of prostate cancer (in vivo studies) and subsequently in clinical trials. In summary, although daily oral administration of vitamin D can inhibit prostate cancer growth, the resultant hypercalcemia precludes regular use of this regimen. Weekly administration has been considered but does not appear to be efficacious. Vitamin D analogs that have less hypercalcemic toxicity may prove to be of benefit in the treatment of prostate cancer. However, it is too early to confirm this. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Chapuy M, Meunier PJ. Vitamin D insufficiency in adults and the elderly. In: Feldman D, Glorieux FH, Pike JW, eds. Vitamin D. San Diego: Academic Press; 1997:679-693. Holick MF. The photobiology of vitamin D3 in man. In: Kumar R, ed. Vitamin D: Basic and Clinical Aspects. Boston: Kluwer Academic Publishers; 1984:197-216. Eisman JA, Barkla DH, Tutton PJ. Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3. Cancer Res. 1987; 47:21-25. Schwartz GG, Hulka BS. Is vitamin D deficiency a risk factor for prostate cancer? Anticancer Res. 1990;10(5A):1307-1311. Blutt SE, Weigel NL. Vitamin D and prostate cancer. Proc Soc Exp Biol Med. 1999;221:89-98. Konety BR, Johnson CS, Trump DL, Getzenberg RH. Vitamin D in the prevention and treatment of prostate cancer. Semin Urol Oncol. 1999;17:77-84. Feldman D, Zhao XY, Krishnan AV. Vitamin D and prostate cancer. Endocrinology. 2000;141:5-9. Moffatt KA, Johannes WU, Hedlund TE, Miller GJ. Growth inhibitory effects of 1, 25-dihydroxyvitamin D3 are mediated by increased levels of p21 in the prostatic carcinoma cell line ALVA-31. Cancer Res. 2001;61:7122-7129. Boyle BJ, Zhao XY, Cohen P, Feldman D. Insulin-like growth factor binding protein-3 mediates 1,25-dihydroxyvitamin D3 growth inhibition in the LNCaP prostate cancer cell line through p21/WAF1. J Urol. 2001;165:1319-1324. Sung V, Feldman D. 1,25-Dihydroxyvitamin D3 decreases human prostate cancer cell adhesion and migration. Mol Cell Endocrinol. 2000;164:133-143. Lokeshwar BL, Schwartz GG, Selzer MG, et al. Inhibition of prostate cancer metastasis in vivo: a comparison of 1,25-dihydroxyvitamin D (calcitriol) and EB1089. Cancer Epidemiol Biomarkers Prev. 1999;8:241-248. Gross C, Stamey T, Hancock S, Feldman D. Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol). J Urol. 1998;159:2035-2039. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591-1597. Finasteride and Prostate Cancer Reviewed by Masood A. Khan, MD, Alan W. Partin, MD, PhD Department of Urology, The Johns Hopkins School of Medicine, Baltimore, MD [Rev Urol. 2004;6(2):97-98] © 2004 MedReviews, LLC lthough testosterone is the major circulating androgen in men, dihydrotestosterone (DHT) is more potent and is the major form of androgen found within the prostate gland.1 DHT, which is responsible for maintaining prostate growth, is produced through reduction of testosterone by an enzyme called 5--reductase.1 DHT is regarded as an extremely important factor in the pathogenesis of benign prostatic hyperplasia (BPH).2 There are 2 isoforms of 5--reductase (types 1 and 2). The type 2 enzyme predominates within the prostate and is localized to the fibromuscular stromal compartment.3 Therefore, finasteride, a selective competitive inhibitor of 5--reductase type 2, was developed to address the management of BPH.4 Accordingly, use of finasteride significantly reduces urinary symptom score, improves urinary flow rates, and reduces prostate volume in men with BPH.2 Like BPH, prostate cancer is known to be androgendependent, and finasteride inhibits the proliferation of prostate cancer cell lines both in vitro and in vivo.5,6 These findings incited the National Cancer Institute (NCI) and the South West Oncology Group (SWOG) to consider whether finasteride could reduce the risk of prostate cancer. In 1993, a large-scale study of prostate adenocarcinoma chemoprevention with finasteride was initiated: the Prostate Cancer Prevention Trial (PCPT). A recently published paper reports the findings of this important study. A The Influence of Finasteride on the Development of Prostate Cancer Thompson IM, Goodman PJ, Tangen CM, et al. N Engl J Med. 2003;349:215-224. Between January 1994 and May 1997, 18,882 men aged 55 years or older with a normal digital rectal examination (DRE) and a serum prostate-specific antigen (PSA) level of 3.0 ng/mL or lower were randomized to receive either finasteride (5 mg/d) or placebo for 7 years. Prostate biopsy was recommended if the annual serum PSA level, adjusted for the effect of finasteride, exceeded 4.0 ng/mL or if DRE was abnormal. In addition, all men were to be offered an end-ofstudy biopsy. The authors anticipated that 60% of the participants would have prostate cancer diagnosed during the study or would undergo biopsy at the end of the study. The VOL. 6 NO. 2 2004 REVIEWS IN UROLOGY 97 Prostate Cancer continued primary end point was the prevalence of prostate cancer during the study period. Approximately 15 months before its anticipated completion, the data and safety monitoring committee recommended early termination of the PCPT because the study objectives had been met and the conclusions were extremely unlikely to change with additional diagnoses of prostate cancer. The rate of diagnosis of prostate cancer or end-ofstudy biopsy was significantly lower in the finasteride group than in the placebo group (59.6% vs 63.0%; P < .001). The results, based on the 86.3% of men (9060) who had completed the 7-year study, revealed that prostate cancer was detected in 803 (18.4%) of 4368 subjects in the finasteride group and 1147 (24.4%) of 4692 in the placebo group, a relative risk reduction of 24.8% (95% confidence interval, 18.6%-30.6%; P < .001). However, tumors of Gleason scores 7 through 10 were more common in the finasteride group than in the placebo group (280 [37%] of 757 tumors vs 237 [22.2%] of 1068 tumors [P < .001] or 6.4% vs 5.1% [P < .005] of the 4368 and 4692 men in the finasteride and placebo groups included in the final analysis, respectively). Sexual side effects were significantly (P < .001) more common (though not unexpected) in the finasteride group compared with the placebo group: reduced ejaculate volume (60.4% vs 47.3%), erectile dysfunction (67.4% vs 61.5%), loss of libido (65.4% vs 59.6%), and gynecomastia (4.5% vs 2.8%). Conversely, urinary symptoms were significantly (P < .001) more common in the placebo group: increased urinary frequency or urgency (15.6% vs 12.9%), urinary incontinence (2.2% vs 1.9%), and urinary retention (6.3% vs 4.2%). The authors concluded that finasteride prevents or delays the appearance of prostate cancer. However, they also stated that this possible benefit and a reduced risk of urinary problems must be weighed against sexual side effects and the increased risk of high-grade prostate cancer at presentation. Despite the slight bias toward more men in the finasteride group than in the placebo group receiving an end-of-study biopsy (3820 [40.4%] of 9459 vs 3652 [38.8%] of 9423), demonstrating more cancers being detected in the placebo group than in the finasteride group (576 [15.1%] of 3820 vs 368 [10.1%] of 3652), this study revealed that finasteride exhibits chemopreventative properties. However, finasteride was associated with a significantly (P < .001) greater risk of harboring higher Gleason score disease and an increased incidence of sexual side effects compared with placebo. Men who present with symptoms of BPH should continue to be considered for finasteride therapy and be counseled on the associated risks. In addition, doubling of the serum PSA values for men receiving finasteride has been questioned. A total of 222 subjects who received a recommendation for biopsy would not have received this recommendation 98 VOL. 6 NO. 2 2004 REVIEWS IN UROLOGY if doubling, instead of a factor of 2.3, of the PSA value was used. Sixty-nine of these subjects accepted the recommendation, and prostate cancer was detected in 17. If doubling of the PSA value been used, only 2% of the cancer cases in the finasteride group would have been missed. Therefore, when evaluating the true serum PSA levels in men receiving finasteride, we should consider multiplying the values by at least 2. References 1. 2. 3. 4. 5. 6. Coffey DS, Walsh PC. Clinical and experimental studies of benign prostatic hyperplasia. Urol Clin North Am. 1990;17:461-475. Gormley GJ, Stoner E, Bruskewitz RC, et al. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med. 1992;327:1185-1191. Silver RI, Wiley EL, Thigpen AE, et al. Cell type specific expression of steroid 5-reductase 2. J Urol. 1994;152:438-442. Vermeulen A, Giagulli VA, De Schepper P, et al. Hormonal effects of an orally active 4-azasteroid inhibitor of 5 alpha-reductase in humans. Prostate. 1989;14:45-53. Bologna M, Muzi P, Biordi L, et al. Antiandrogens and 5-alpha reductase inhibition of the proliferation rate in PC3 and DU145 human prostate cancer cell lines. Curr Ther Res. 1992;51:799-813. Lamb JC, Levy MA, Johnson RK, Isaacs JT. Response of rat and human prostatic cancers to the novel 5-alpha-reductase inhibitor, SK&F 105657. Prostate. 1992;21:15-34. Urethral Stents Overview of Biodegradable Urethral Stents Reviewed by Hiroshi Azuma, MD, Michael B. Chancellor, MD Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA [Rev Urol. 2004;6(2):98-99] © 2004 MedReviews, LLC Biodegradable Urethral Stents Tammela TL, Talja M. BJU Int. 2003;92:843-850. ver the past decade, the development and deployment of a biodegradable urethral stent has gradually gained academic acceptance. The polymers of hydroxyl acids have good biocompatibility properties, and it is possible to make stents with different expansion rates and degradation times. For certain urologic conditions, there is an intrinsic advantage to the use of a bioabsorption device, because it eliminates the need for a second operation for stent removal. In this article, Tammela and Talja O