Prostate Cancer
Reviewing the Literature
RIU0314_02-13.qxd 2/14/07 6:06 PM Page 41 REVIEWING THE LITERATURE News and Views from the Literature Prostate Cancer Postprostatectomy Risk Stratification Based on Detection of Occult Lymph Node Metastasis Reviewed by Danil V. Makarov, MD, Alan W. Partin, MD, PhD The James Buchanan Brady Urological Institute, Department of Urology, The Johns Hopkins Medical Institutions and Hospital, Baltimore, MD [Rev Urol. 2007;9(1):41-43] © 2007 MedReviews, LLC lthough radical prostatectomy offers an effective and durable cure of prostate cancer for many patients with localized disease, a fraction of patients develop disease recurrence despite having negative surgical margins and grossly negative lymph nodes.1 Various algorithms have been determined to predict which patients might end up recurring.2 Distant metastasis after apparent surgical cure implies that the patient had disease outside of the surgical specimen, and these algorithms try to determine, according to a combination of clinical parameters, who has occult distant disease. Although the pathology report may indicate localized prostate cancer, future disease recurrence implies that the conventional histopathologic methods used today to diagnose advanced disease are limited. As prostatespecific antigen (PSA), its isoforms, and other serum biomarkers are used to predict the behavior of prostate cancer after surgery, 2 very exciting translational studies explore the possibility of lymph node tissue biomarkers to predict clinical outcomes. A Detection of Occult Lymph Node Metastases in Locally Advanced Node-Negative Prostate Cancer Pagliarulo V, Hawes D, Brands FH, et al. J Clin Oncol. 2006;24:2735-2742. Pagliarulo and colleagues examined patients with locally advanced prostate cancer from the University of Southern California database. They identified 274 men with pathologic T3 prostate cancer who also had extended bilateral pelvic lymphadenectomy (iliac bifurcation to the node of Cloquet, as well as the obturator and hypogastric fossae) at the time of radical prostatectomy, 94 of whom had evidence of lymph node metastasis on routine pathologic examination (LN). The remaining 180 patients, who had originally been deemed free of lymph node metastasis, had their lymph nodes re-evaluated by immunohistochemistry. If a preliminary screen for cytokeratins stained positively, then the lymph node specimens were stained for PSA. Of the 180 patients without evidence of lymph node involvement on routine pathologic evaluation, 24 were found to harbor occult lymph node metastasis (OLN) by immunohistochemistry. The investigators then compared the baseline characteristics and the outcomes (median follow-up for the entire group was 12.9 years, without any statistical difference between the groups) of the 3 groups—negative lymph nodes on immunohistochemistry analysis (OLN), OLN, and LN. Although there was no statistical difference among the groups with respect to prebiopsy PSA level, exposure to neoadjuvant hormone therapy, or adjuvant radiation therapy, there were significant differences between groups with positive lymph nodes on routine pathologic evaluation and those without with respect to Gleason score (LN less likely to be 2–6), pathologic stage (LN more likely to involve seminal vesicles), surgical margins (LN more likely positive), and adjuvant hormone therapy (LN more likely to have received it). When comparing OLN and OLN groups at baseline, those with OLN were more likely to have VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY 41 RIU0314_02-13.qxd 2/14/07 6:06 PM Page 42 Prostate Cancer continued seminal vesicle invasion and positive surgical margins, even though these groups seem the same (ie, negative lymph nodes) at the time of surgery. Examination of the outcomes among the lymph node groups using the log–rank test demonstrated that, as compared with the index group (OLN), both the N group and the OLN group demonstrated statistically significantly increased relative risk (RR) of recurrence (2.78 and 2.27, respectively) and significantly increased RR of all-cause mortality (1.40 and 2.07, respectively). In univariate analyses, involving all NO patients, only Gleason score, pathologic stage, and presence of occult lymph node metastases were significantly associated with overall survival. In a Cox proportional hazards analysis, only Gleason score (Gleason score 2–6 vs 7–10: RR 3.50, 95% confidence interval [CI] 2.05-5.99, P .001) and occult metastasis (OLN vs OLN: RR 2.24, 95% CI 1.26-3.97, P .011) remained significantly associated with overall survival. The presence of occult lymph node metastases was an independent predictor of recurrence and death in a multivariable analysis. The investigators also note that N patients demonstrated a nonsignificant trend toward improved survival as compared with OLN patients. They speculate that this could potentially be due to the earlier administration of androgen deprivation therapy (ADT) in patients with known lymph node metastasis. They concede, however, that no trial to date has suggested a benefit from the administration of early ADT in patients with occult prostate cancer metastasis, and they state that the detection of occult lymph node metastases in patients with pT3N0 prostate cancer only identifies a group of patients with high risk of prostate cancer recurrence and death. Molecular Load of Pathologically Occult Metastases in Pelvic Lymph Nodes Is an Independent Prognostic Marker of Biochemical Failure After Localized Prostate Cancer Treatment Ferrari AC, Stone NN, Kurek R, et al. J Clin Oncol. 2006;24:3081-3088. Another important study identifying occult pelvic lymph node metastases in patients with locally advanced prostate cancer came from a multinational group consisting of the New York University Cancer Institute, Mount Sinai School of Medicine (MSSM) in New York, the Städtische Kliniken Offenbach, Germany (KO), and the Royal Free Hospital (RFH) in London. The patient sample examined in this study is significantly more heterogeneous than that in the study reviewed above. Here, of 341 patients with clinically localized prostate cancer, 88 patients from MSSM received 42 VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY radiation therapy (XRT) with concomitant ADT, 175 patients from KO received retropubic radical prostatectomy (RRP) with neoadjuvant ADT, and 78 patients from MSSM and RFH received RRP without adjuvant or neoadjuvant therapy. This group sets up multiple verification biases: 1) patients receiving XRT, although undergoing a preprocedure staging pelvic lymphadenectomy, still cannot be assessed reliably for the presence of extraprostatic tumor extension or have a reliable interpretation of the actual Gleason score; 2) patients at KO received neoadjuvant hormone ablation, which makes assessment of surgical margin status difficult (indeed, this group did not assess for surgical margin status at all), as well as changing the appearance of the tumor on histopathologic analysis. With that in mind, using real-time reverse-transcriptase polymerase chain reaction, the investigators undertook to quantify the amount of PSA messenger ribonucleic acid (mRNA) copies present in the lymph nodes of these patients, all of whom had negative lymph nodes on routine pathology. The presence of PSA mRNA would imply that there were cells in these lymph nodes that had been actively transcribing PSA from the genomic deoxyribonucleic acid at the time of tissue fixation; this would indicate the presence of metastatic prostate cells. Comparing normal lymph node samples with those from men with known lymph node metastasis and normalizing the PSA mRNA copy number to 5 106 glyceraldehyde-3′-phosphate dehydrogenase mRNA copies, normalized PSA copies (PSA-N) were determined to have a threshold of 100 or greater for the continuous and categorical multivariate analyses of biochemical failure-free survival (BFFS). With a relatively short median follow-up of 4 years, the BFFS of patients with PSA-N of 100 or greater versus PSA-N less than 100 was 55% and 77%, respectively (P .0002). Analysis of this effect among various PSA ranges showed that the effect was not statistically significant in men with PSA less than 10 ng/mL, but significant in the PSA 10 to 20 ng/mL and greater than 20 ng/mL groups. Similar to the PSA example, PSA-N of 100 or greater tended to be most pronounced in the most severe categories of each variable examined: Gleason score 8 or higher (21% vs 66%; P .0002), stage T3c (18% vs 64%; P .001), and high-risk group (50% vs 72%; P .05). A multivariable analysis of PSA-N as a continuous variable found it to be an independent predictor for biochemical recurrence (P .049), with a hazard ratio of 1.25 (95% CI 1.001-1.57). A multivariable analysis of PSA-N as a categorical variable ( 100 versus 100) showed that it was an independent variable (P .021), with a relative risk of 1.98 (95% CI 1.11-3.55) for biochemical recurrence. Diseasespecific and all-cause mortality were not analyzed as outcomes, likely as a result of the relatively short follow-up. RIU0314_02-13.qxd 2/14/07 6:06 PM Page 43 Pediatric Urology Although the molecular load of pathologically occult pelvic lymph node metastases may indeed be a predictor of outcome in a univariate model, the extreme heterogeneity and verification bias inherent in this patient sample makes it difficult to ascertain whether it would be a predictor of outcome in multivariable models using other patient data sets. New Contralateral Vesicoureteral Reflux Following Dextranomer/Hyaluronic Acid Implantation: Incidence and Identification of a High Risk Group These 2 articles suggest that assessment for the presence of occult lymph node metastasis in prostate cancer seems to be an exciting and powerful way to determine a patient’s risk profile. The occurrence of NCVUR after open surgical ureteral reimplantation is as high as 20%. It is thought to be due to secondary intermittent reflux, destabilization of the contralateral ureter during mobilization of the refluxing ureter, or high detrusor pressure.1 Elmore and colleagues examined 126 children who underwent unilateral Dx/HA for unilateral reflux. Approximately 40% of the patients were treated with Dx/HA injection as primary therapy and had only 1 preoperative voiding cystourethrogram (VCUG). Of the 17 children (13.5%) who developed NCVUR, 9 were grade I, 6 were grade II, and 2 were grade III. No variable independently seemed to be directly related to the incidence of NCVUR. Statistical analysis suggests that girls younger than 5 years more commonly developed NCVUR. Patients with a higher preoperative grade of reflux and those with fewer preoperative VCUGs, including those undergoing treatment as primary therapy, did not demonstrate an increased incidence. The investigators suggest assessing the contralateral ureter at the time of Dx/HA treatment, especially in girls aged less than 5 years, and they recommend prophylactic Dx/HA injection in select cases. The era of molecular diagnostics and multiple predictive biomarkers in prostate cancer has arrived. These 2 articles suggest that assessment for the presence of occult lymph node metastasis in prostate cancer seems to be an exciting and powerful way to determine a patient’s risk profile. Further systematic testing on tissue from patients treated elsewhere will help us elucidate whether these specific predictions made on these specific data sets can be generalized to risk stratification, and ultimately therapeutic guidance, of all patients undergoing treatment for prostate cancer. References 1. 2. Han M, Partin AW, Zahurak M, et al. Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol. 2003;169:517-523. Khan MA, Partin AW, Mangold LA, et al. Probability of biochemical recurrence by analysis of pathologic stage, Gleason score, and margin status for localized prostate cancer. Urology. 2003;62:866-871. Pediatric Urology Dextranomer/Hyaluronic Acid Implantation for Vesicoureteral Reflux Reviewed by Ellen Shapiro, MD, FACS, FAAP Department of Urology, New York University School of Medicine [Rev Urol. 2007;9(1):43-44] © 2007 MedReviews, LLC lmore and colleagues from Atlanta recently reported their experience with new contralateral vesicoureteral reflux (NCVUR) after endoscopic treatment of reflux with dextranomer/hyaluronic acid (Dx/HA), and another study by this group evaluated success rates after an initial Dx/HA treatment failure. E Elmore JM, Kirsch AJ, Lyles RH, et al. J Urol. 2006;175:1097-1101. Dextranomer/Hyaluronic Acid for Vesicoureteral Reflux: Success Rates After Initial Treatment Failure Elmore JM, Scherz HC, Kirsch AJ. J Urol. 2006;175:712-715. Parents often ask what is the next step if the first Dx/HA injection fails. Elmore and colleagues reviewed their experience with patients who fail initial treatment. Currently, Kirsch and colleagues2 report a 92% success rate for patients undergoing Dx/HA implantation for grades I to IV VUR with a modified STING (subureteral transurethral injection) technique. Elmore and colleagues reported on a total of 42 children (mean age, 5 years) who underwent a second Dx/HA treatment. Follow-up was available in 39 patients (53 ureters) (14 patients had bilateral and 25 unilateral VUR). Before the second injection the mean grade of reflux was 2.2. After the second Dx/HA injection reflux resolved in 35 of 39 patients (90%) and 47 of 53 ureters (89%). When evaluated by VUR grade, reflux resolution occurred in 7 of 8 ureters (88%) with grade I, 24 of 26 (92%) with grade II, and 16 of 19 (84%) with grade III. The study is important because it VOL. 9 NO. 1 2007 REVIEWS IN UROLOGY 43