Prostate Cancer: Androgen Deprivation Therapy

News and Views from the Literature

9a. RIU0418_12-11.qxd 12/17/08 10:51 AM Page 305 Prostate Cancer Several confirmatory studies have since validated the association between these 8q24 variants and prostate cancer susceptibility in multiple ethnic groups.3,4 Particularly important was the identification of this region by admixture mapping in African Americans.5 In addition, the same authors subsequently reported on 2 additional prostate cancer susceptibility variants, located on chromosome 17q12 and 17q24.3.6 These combined findings represent a major breakthrough in elucidating the genetic basis for prostate cancer. The results of Zheng and colleagues suggest that multiple SNPs may play a significant aggregate role in determining prostate cancer risk. Nevertheless, further study is necessary to examine whether any combination of genetic variants can be used to predict the probability of lifethreatening disease. References 1. 2. Cumulative Association of Five Genetic Variants With Prostate Cancer Zheng SL, Sun J, Wiklund F, et al. 3. 4. N Engl J Med. 2008;358:910-919. 5. ecently, Zheng and colleagues carried the association between SNPs and prostate cancer susceptibility to the next level. Specifically, in 2893 Swedish prostate cancer patients and 1781 healthy controls from the Swedish Population Registry, they examined loci from 3 different regions on chromosome 8q24 and 2 at chromosome 17q. As in prior studies, they found significant differences in allele frequency between cases and controls for all 5 alleles (P  .05). In addition, they used logistic regression analysis to evaluate for the cumulative effects of SNPs on 8q24, 17q12, and 17q24. In the multivariate model, all 5 SNPs remained significantly associated with prostate cancer susceptibility. Moreover, the risk of prostate cancer continuously increased for carriers of 1 versus 2, 3, 4, or more SNPs (P value for trend, 6.75  1027). Moreover, men with a positive family history and 5 or more alleles had 9.46-fold increased odds of prostate cancer, compared with men with none of the alleles (P value for trend, 9.78  1028). It is noteworthy that the cumulative effect of these SNPs on prostate cancer risk has since been validated in multiple study populations.7 Finally, the authors tested whether there was an association between these SNPs with advanced prostate cancer (defined as any of the following: stage 3 or 4, lymph node or distant metastases, Gleason score  8, or prostatespecific antigen level  50 ng/mL). Comparing cases with 4 or more alleles with noncarriers, they did not find any significant difference in the proportion with advanced disease (54% vs 48%; P  .33). Indeed, there is controversy in the literature regarding the relationship between these recently identified susceptibility alleles and prostate cancer aggressiveness. Some studies have failed to demonstrate any association, whereas others have reported a significantly greater risk of adverse pathologic tumor features in carriers of the 8 or multiple 8q24 alleles.8,9 R 6. 7. 8. 9. Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343:78-85. Smith JR, Freije D, Carpten JD, et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science. 1996;274: 1371-1374. Haiman CA, Patterson N, Freedman ML, et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007;39:638-644. Witte JS. Multiple prostate cancer risk variants on 8q24. Nat Genet. 2007;39: 579-580. Freedman ML, Haiman CA, Patterson N, et al. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci U S A. 2006;103:14068-14073. Gudmundsson J, Sulem P, Steinthorsdottir V, et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet. 2007;39:977-983. Sun J, Chang BL, Isaacs SD, et al. Cumulative effect of five genetic variants on prostate cancer risk in multiple study populations. Prostate. 2008;68:1257-1262. Helfand BT, Loeb S, Cashy J, et al. Tumor characteristics of carriers and noncarriers of the deCODE 8q24 prostate cancer susceptibility alleles. J Urol. 2008;179:2197-2201; discussion 2202. Suuriniemi M, Agalliu I, Schaid DJ, et al. Confirmation of a positive association between prostate cancer risk and a locus at chromosome 8q24. Cancer Epidemiol Biomarkers Prev. 2007;16:809-814. Androgen Deprivation Therapy Reviewed by Paul Hoffman, MD, Bob Djavan, MD, PhD Department of Urology, University of Brussels, Brussels, Belgium [Rev Urol. 2008;10(4):305-306] © 2008 MedReviews®, LLC n the past decade, androgen deprivation therapy (ADT) has been increasingly used in earlier stages of prostate cancer, despite the presence of mature data from large-scale randomized trials suggesting no survival advantage from earlier intervention. ADT remains a palliative treatment with minimal effect on survival, with almost all patients dying from prostate cancer having hormone-refractory prostate cancer with castrate levels of testosterone. I Survival Following Primary Androgen Deprivation Therapy Among Men With Localized Prostate Cancer Lu-Yao GL, Albertsen PC, Moore DF, et al. JAMA. 2008;300:173-181. Despite unproven indications, increasing numbers of patients are receiving primary ADT (PADT) as an alternative VOL. 10 NO. 4 2008 REVIEWS IN UROLOGY 305 9a. RIU0418_12-11.qxd 12/11/08 10:38 PM Page 306 Prostate Cancer continued to surgery, radiation, or conservative management for the treatment of localized prostate cancer. Lu-Yao and colleagues assessed the association between PADT and disease-specific survival and overall survival in men with localized prostate cancer. Data were extracted from the Surveillance, Epidemiology, and End Results Medicare-linked database. Men diagnosed with stage T1 to T2 prostate cancer from 1992 to 2002 were included in the study. All were at least 66 years of age. Patients who had received no localized treatment in the first 180 days after diagnosis were included in the analysis (n  19,271). The authors measured prostate cancer–specific survival and overall survival. Within the analysis cohort, 41% of the men (median age, 77 years) had been treated with PADT. The median followup was 81 months. During the follow-up period, there were 1560 prostate cancer deaths and 11,045 deaths from all causes. The researchers found that use of PADT for localized prostate cancer was associated with lower 10-year prostate cancer–specific survival (80.1% vs 82.6%) and no increase in 10-year overall survival compared with conservative management. However, in a prespecified subset analysis, PADT use in men with poorly differentiated cancer was associated with a borderline improved 10-year prostate cancer–specific survival (59.8% vs 54.3%), but not overall survival (17.3% vs 15.3%). In conclusion, PADT is not associated with improved survival among the majority of elderly men with localized prostate cancer when compared with conservative management. Given these results and the fact that PADT is associated with significant adverse effects as well as financial costs, the authors recommend that physicians give careful consideration before initiating PADT in older patients with localized prostate cancer. Finnish Multicenter Study Comparing Intermittent to Continuous Androgen Deprivation for Advanced Prostate Cancer: Interim Analysis of Prognostic Markers Affecting Initial Response to Androgen Deprivation Salonen AJ, Viitanen J, Lundstedt S, et al. J Urol. 2008;180:915-919. VOL. 10 NO. 4 2008 Overactive Bladder Syndrome Is Behavioral Therapy Plus Antimuscarinic Better Than Drug Alone to Treat Overactive Bladder? Reviewed by Michael B. Chancellor, MD, Deborah L. Hasenau, RN, BSN, MS, OCN Department of Urology, William Beaumont Hospital, Royal Oak, MI Although the initial response rate of prostate cancer to ADT can be up to 80%, most patients experience disease relapse, with many developing androgen-independent prostate cancer cell lines. Preclinical evidence suggests that intermittent androgen deprivation (IAD) could possibly preserve the androgen-dependent state of the tumor. Furthermore, IAD includes attenuation of its known side 306 effects through the off-treatment phases and reduced treatment expenses. To determine the proportion of patients who might benefit from intermittent ADT, Salonen and colleagues assessed hormone sensitivity by administering ADT for 24 weeks to 856 men with locally advanced or metastatic prostate cancer. Patients found to have hormone-sensitive disease, defined as a prostate-specific antigen (PSA) decrease to less than 10 ng/mL or by more than 50% if less than 20 ng/mL at baseline, were then randomly assigned to receive continuous or intermittent ADT. At baseline, the average PSA level was 383 ng/mL, the average alkaline phosphatase (ALP) level was 462 IU/L, and the average testosterone level was 14.9 nmol/L. Thirty-four percent of the patients did not have hormone-sensitive disease and were not assigned further treatment. Patients with non–hormone-sensitive disease had, compared with hormone-sensitive patients, significantly higher PSA and ALP levels. Furthermore, non–hormonesensitive patients were also significantly more likely than hormone-sensitive patients to have T4 tumors (37% vs 24%), poorly differentiated cancers (39% vs 26%), metastatic disease (82% vs 51%), and more than 5 skeletal “hot spots” in M1 disease (72% vs 42%). The authors determined that patients with the most advanced prostate cancer and poorest prognosis do not show adequate biochemical PSA response to ADT, and therefore nonendocrine treatment modalities should be considered for them. REVIEWS IN UROLOGY [Rev Urol. 2008;10(4):306-308] © 2008 MedReviews®, LLC rinary incontinence affects more than 10 million Americans and accounts for billions of dollars annually in societal costs. Antimuscarinics and behavioral treatments are both safe and effective first-line U