Prostate Cancer

Reviewing the Literature

9b. RIU0478_03-16.qxd 3/16/10 9:34 PM Page 64 REVIEWING THE LITERATURE News and Views From the Literature Prostate Cancer Open Versus Minimally Invasive Radical Prostatectomy Reviewed by Stacy Loeb, MD, Alan W. Partin MD, PhD The James Buchanan Brady Urological Institute, Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD [Rev Urol. 2010;12(1):64-65 doi: 10.3909/riu0478] © 2010 MedReviews®, LLC n 1904, Hugh Hampton Young performed the first radical prostatectomy using a perineal approach.1 Since that time, there has been a dramatic evolution in radical prostatectomy technique, including the development of the modern anatomic approach to radical retropubic prostatectomy (RRP) and the more recent introduction of “minimally invasive” radical prostatectomy (MIRP) techniques.2,3 Despite a tremendous expansion in the use of robotic prostatectomy in the past few years, no randomized trial has compared MIRP with RRP, and long-term outcomes data are not yet available to validate the robotic approach. In the meantime, observational studies may provide some insight into the short-term results of MIRP versus RRP. This review summarizes the findings of 2 recent studies comparing the short-term outcomes of MIRP with that of RRP in Medicare beneficiaries. I Utilization and Outcomes of Minimally Invasive Radical Prostatectomy Hu JC, Wang Q, Pashos CL, et al. J Clin Oncol. 2008;26:2278-2284. This study assessed the short-term outcomes of RRP versus MIRP in a 5% sample of Medicare beneficiaries (n  2702) 64 VOL. 12 NO. 1 2010 REVIEWS IN UROLOGY who underwent surgery from 2003 to 2005. Specifically, the authors used Current Procedural Terminology (CPT) codes to identify perioperative complications within 90 days postoperatively. In addition, they compared the rates of anastomotic strictures by 9 months and utilization of salvage therapy (radiation or hormonal therapy) within 6 months of either MIRP or RRP. Overall, the proportion of cases performed by a minimally invasive approach increased substantially over the study interval, from 12.2% in 2003 to 31.4% in 2005 (P  .001), with a corresponding decline in the proportion of open cases. Although the MIRP and RRP patients in this study were similar with regard to race and geographic distribution, the MIRP group was significantly older and had a higher comorbidity index. On multivariate analysis adjusting for age, race, region, and comorbidities, MIRP was associated with significantly fewer perioperative complications and a shorter length of hospital stay than RRP. However, MIRP was associated with a significantly greater risk of anastomotic stricture, as well as a 3-fold increased risk of early salvage therapy. Limitations of this analysis include the retrospective, nonrandomized study design, and the use of billing codes to measure outcomes. Indeed, the lack of data on prostatectomy pathology features (eg, positive surgical margin rates) makes it more difficult to interpret the higher rates of early salvage therapy. Nevertheless, the substantial difference reported at 6 months leaves uncertainty regarding the long-term oncologic outcomes of MIRP. Another important aspect of the study is that Medicare data only include men aged  65 years, a group for whom the risk to benefit ratio of surgical management is less certain.4 Although these findings may not be generalizable to younger men or those treated at high-volume centers, the results nevertheless provide a “real-world snapshot” of short-term prostatectomy outcomes in elderly men across the United States. 9b. RIU0478_03-16.qxd 3/16/10 9:34 PM Page 65 Prostate Cancer Comparative Effectiveness of Minimally Invasive Versus Open Radical Prostatectomy Hu JC, Gu X, Lipsitz SR, et al. JAMA. 2009;302:1557-1564. In a recent update, Hu and colleagues re-examined the comparative outcomes of MIRP versus RRP from 2003 to 2007 in a larger population (n  8837) of men from the Surveillance, Epidemiology and End Results (SEER)–linked Medicare database. CPT codes were used to examine the rates of perioperative complications, anastomotic strictures, incontinence, erectile dysfunction, and salvage therapy following the 2 techniques. The results demonstrated increased utilization of MIRP over the study interval (P  .001). Although age and comorbidity index were similar between groups, fewer men undergoing MIRP were black or Hispanic, and MIRP patients were more likely to reside in metropolitan areas with higher levels of education and household income. Using a propensity-weighted analysis to adjust for confounding, MIRP was associated with a significantly shorter length of hospital stay, and fewer postoperative respiratory and miscellaneous complications. Consistent with other studies in the literature demonstrating lower intraoperative blood loss with robotic prostatectomy,5 the MIRP group in this study was also significantly less likely to receive a blood transfusion. Contrary to their prior results, this analysis found a significantly lower frequency of anastomotic stricture in the MIRP group than was seen in the RRP group. Nevertheless, MIRP patients had a 2-fold increased risk of genitourinary complications. Moreover, in the propensity-weighted analysis, MIRP was associated with significantly higher rates of both incontinence (15.9 vs 12.2 per 100 person-years, P  .02) and erectile dysfunction (28.6 vs 19.2 per 100 person-years, P  .009), as compared with RRP. Finally, despite a significantly higher proportion of organ-confined disease in the MIRP group (68.3% vs 60.8%; P  .001), the rates of additional cancer therapy were statistically similar between groups. Further analysis of the rates of secondary therapy stratified by pathologic stage, together with the accrual of additional follow-up, will enable valuable comparisons of oncologic outcomes between MIRP and RRP in the future. As in the prior study, this analysis was limited by its retrospective nature, the sole inclusion of men aged  65 years, and reliance upon the veracity of coding records to accurately capture complications. Advantages of this study include the larger sample size, inclusion of patients treated further along in the robotic prostatectomy era, and the use of SEER-linked Medicare data containing information on pathologic tumor features. However, it is noteworthy that SEER-linked Medicare data only encompass specific geographic regions, and elderly individuals within these regions may have systematic differences that vary from those residing elsewhere.6 Moreover, SEERMedicare regions include several of the most high-volume robotic prostatectomy centers. Considering the welldocumented link between surgical volume and outcomes,7,8 the oncologic and functional outcomes in this study may not be generalizable to other regions with lower MIRP utilization. The authors concluded that the current popularity of robotic prostatectomy “despite insufficient data demonstrating superiority over an established gold standard may be a reflection of a society and health care system enamored with new technology that increased direct and indirect health care costs but had yet to uniformly realize marketed or potential benefits during early adoption.” In the absence of evidence demonstrating superiority of MIRP over RRP, it may be difficult to justify the substantial incremental cost of robotic surgery9 in an era of considerable economic uncertainty. Overall, these studies highlight the importance of thorough technology assessment, because “novelty cannot be equated with benefit.”10 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Young HH. The early diagnosis and radical cure of carcinoma of the prostate. Being a study of 40 cases and presentation of a radical operation which was carried out in four cases. 1905. J Urol. 2002;168:914-921. Walsh PC, Lepor H, Eggleston JC. Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate. 1983;4:473-485. Menon M, Shrivastava A, Tewari A, et al. Laparoscopic and robot assisted radical prostatectomy: establishment of a structured program and preliminary analysis of outcomes. J Urol. 2002;168:945-949. Bill-Axelson A, Holmberg L, Filén F, et al. Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial. J Natl Cancer Inst. 2008;100:1144-1154. Farnham SB, Webster TM, Herrell SD, et al. Intraoperative blood loss and transfusion requirements for robotic-assisted radical prostatectomy versus radical retropubic prostatectomy. Urology. 2006;67:360-363. Warren JL, Klabunde CN, Schrag D, et al. Overview of the SEER-Medicare data: content, research applications, and generalizability to the United States elderly population. Med Care. 2002;40:(suppl 8):IV-3-IV-18. Atug F, Castle EP, Srivastav SK, et al. Positive surgical margins in roboticassisted radical prostatectomy: impact of learning curve on oncologic outcomes. Eur Urol. 2006;49:866-871; discussion 871-872. Vickers AJ, Savage CJ, Hruza M, et al. The surgical learning curve for laparoscopic radical prostatectomy: a retrospective cohort study. Lancet Oncol. 2009;10:475-480. Steinberg PL, Merguerian PA, Bihrle W 3rd, et al. The cost of learning roboticassisted prostatectomy. Urology. 2008;72:1068-1072. Emanuel EJ, Fuchs VR, Garber AM. Essential elements of a technology and outcomes assessment initiative. JAMA. 2007;298:1323-1325. VOL. 12 NO. 1 2010 REVIEWS IN UROLOGY 65 9b. RIU0478_03-16.qxd 3/16/10 9:34 PM Page 66 Prostate Cancer continued What Is the True Mortality Benefit of Prostate-Specific Antigen Screening? Reviewed by Stacy Loeb, MD, Alan W. Partin, MD, PhD The James Buchanan Brady Urological Institute, Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD [Rev Urol. 2010;12(1):66-67 doi: 10.3909/riu0482] © 2010 MedReviews®, LLC he European Randomized Study of Screening for Prostate Cancer (ERSPC) included 7 European countries and randomized a total of 162,243 men aged 55 to 69 years to screening and control arms.1 In the intentto-treat (ITT) analysis, Schröder and colleagues previously reported a 20% reduction in prostate cancer–specific mortality with screening (relative risk [RR] 0.80; 95% confidence interval [CI], 0.65-0.98; P  .04), as we have previously reviewed.2 A limitation of this estimate is that a proportion of men randomized to screening did not comply with this intervention (noncompliance), and a proportion of men randomized to the control arm received screening outside the study (contamination). Indeed, high rates of contamination are considered a major factor behind the negative results of the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial.3 Although opportunistic prostate cancer screening was much less common in Europe, the ERSPC authors nevertheless sought to determine the potential impact that it may have had on their survival comparisons in 2 follow-up studies. T Prostate Cancer Mortality Reduction by Prostate-Specific Antigen-Based Screening Adjusted for Nonattendance and Contamination in the European Randomized Study of Screening for Prostate Cancer (ERSPC) Roobol MJ, Kerkhof M, Schroder FH, et al. Eur Urol. 2009;56:584-591. The hypothesis behind this study was that the 20% mortality reduction from the ITT analysis may have been diluted by noncompliance and contamination. Therefore, the authors attempted to recalculate the true mortality difference after taking these factors into account. Noncompliance was determined based on the number of men who did not attend the first screening round at all 66 VOL. 12 NO. 1 2010 REVIEWS IN UROLOGY 7 ERSPC centers. Contamination rates were extrapolated based on linkage to general practitioner laboratories and questionnaires in the Rotterdam ERSPC section. The mortality difference between screening and control arms was then calculated after adjustment for these noncompliance and contamination rates using the method of Cuzick and colleagues.4 As compared with the ITT estimate of 20%,1 adjustment for noncompliance led to a 30% relative increase in the mortality benefit of screening (RR 0.73; 95% CI, 0.58-0.93). After additional adjustment for contamination, the authors estimated that screening reduced cancer-specific mortality by 31% to 33%, as compared with no screening. There are several limitations to this study, including the extrapolation of Rotterdam data on contamination to the remaining 6 countries with potentially differing frequencies of opportunistic prostate-specific antigen (PSA) testing. In addition, noncompliance was exclusively based on the initial screening round. Further analysis of the influence of the actual frequency and timing of screening on mortality would be informative. Finally, divergence from a strict ITT analysis obviates the main advantage of randomization, and introduces the potential for bias associated with observational studies. Despite these inherent limitations, this study provided an interesting estimation of the true mortality benefit associated with screening. Indeed, these results support the initial hypothesis that the prostate cancer mortality reduction of 20% at 9 years in the ITT analysis may have been diluted by noncompliance and contamination. Taking these factors into account, PSA screening was associated with up to a 33% prostate cancer mortality reduction at 9 years. Prostate Cancer Mortality in Screen and Clinically Detected Prostate Cancer: Estimating the Screening Benefit van Leeuwen PJ, Connolly D, Gavin A, et al. Eur J Cancer. 2010;46:377-383. This study attempted to estimate the true mortality benefit of PSA screening using an alternate methodology. Rather than attempting to adjust for contamination within the ERSPC itself, van Leeuwen and colleagues identified an outside control population from Northern Ireland with even lower rates of screening to serve as a comparison group. Specifically, 11,970 men aged 55 to 74 years from the screening arm of the Rotterdam ERSPC section (19971999) were compared with 133,287 men of the same age from the Northern Ireland population registry (19981999). Approximate frequencies of PSA testing in these 2 groups were 94.2% and 6%, respectively. 9b. RIU0478_03-16.qxd 3/16/10 9:34 PM Page 67 Urologic Chronic Pelvic Pain Syndromes Overall, prostate cancer was diagnosed in 1153 (9.6%) men from the Rotterdam ERSPC and 3962 (3.0%) men from Northern Ireland. Screening was associated with a 53% reduction in metastatic disease at diagnosis (0.1% vs 0.6%; P  .001), and a 37% reduction in death from prostate cancer (0.29% vs 0.47%; P  .008), compared with the group from Northern Ireland. Thus, the authors estimated a number-needed-to-screen (NNS) of 555 and numberneeded-to-treat (NNT) of 37 to prevent 1 prostate cancer death at 8.5 years. These results compare favorably to the NNS of 1410 and NNT of 48 at 9 years reported in the (ITT) analysis of the ERSPC,1 and highlight the potential influence of contamination on NNS and NNT estimates. A limitation of this observational study is the possibility of bias from underlying differences between the 2 populations. Nonetheless, as the authors point out, the large sample size and extreme disparity in overall screening behavior between the Rotterdam and Northern Ireland groups provided a unique avenue to examine the benefits of screening. Overall, the combined results from these 2 studies suggest that both noncompliance and contamination likely diluted the benefits of PSA screening in the original ERSPC report. Future analyses are necessary to follow up on these important findings and to examine whether the mortality reduction with screening continues to increase over time. References 1. 2. 3. 4. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:13201328. Loeb S, Partin AW. Randomized trials of prostate cancer screening. Rev Urol. 2009;11:179-180. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319. Cuzick J, Edwards R, Segnan N. Adjusting for non-compliance and contamination in randomized clinical trials. Stat Med. 1997;16:1017-1029. Urologic Chronic Pelvic Pain Syndromes A New Approach to Understanding and Managing Chronic Prostatitis and Interstitial Cystitis Reviewed by J. Curtis Nickel, MD, FRCSC Queen’s University, Kingston, Ontario, Canada [Rev Urol. 2010;12(1):67-68 doi:10.3909/riu0483] © 2010 MedReviews®, LLC Clinical Phenotyping in Chronic Prostatitis/Chronic Pelvic Pain Syndrome and Interstitial Cystitis: A Management Strategy for Urologic Chronic Pelvic Pain Syndromes Shoskes DA, Nickel JC, Rackley RR, Pontari MA. Prostate Cancer Prostatic Dis. 2009;12:177-183. Clinical Phenotyping of Chronic Prostatitis/Chronic Pelvic Pain Patients and Correlation With Symptom Severity Shoskes DA, Nickel JC, Dolinga R, Prots D. Urology. 2009;73:538-543. Clinical Phenotyping of Women With Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS): A Key to Classification and Potentially Improved Management Nickel JC, Shoskes D, Irvine-Bird K. J Urol. 2009;182:155-160. Evaluation of a Modification of the UPOINT Clinical Phenotype System for the Chronic Pelvic Pain Syndrome Hedelin HH. Scan J Urol Nephrol. 2009;43:373-376. rologists’ management of the common urologic chronic pelvic pain syndromes of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and interstitial cystitis/painful bladder syndrome (IC/PBS) is poor. Despite infusion of decades of massive National Institutes of Health (NIH) research funding, our understanding of the etiopathogenesis of these conditions remains unclear and our treatment strategies dismal. A way forward was generally agreed upon at a NIH Workshop, “The Multidisciplinary Approach to Defining the Urologic Chronic Pelvic Pain Syndromes (UCPPS),” held in Baltimore, MD, in December 2007. Researchers and clinicians in the field agreed that patients with UCPPS are not a homogeneous group of patients with perceived prostate, bladder, or pelvic pain, but rather a group of individual patients with widely different clinical phenotypes, perhaps based on different etiologies and pathogenic trajectories. The NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) initiated the Multidisciplinary Approach to Pelvic Pain (MAPP) research consortium program which was launched and funded to explore basic science (particularly U VOL. 12 NO. 1 2010 REVIEWS IN UROLOGY 67