LHRH Agonists for the Treatment of Prostate Cancer: 2012

Management Review

Management review LHRH Agonists for the Treatment of Prostate Cancer: 2012 Herbert Lepor, MD,1 Neal D. Shore, MD, FACS2 1 New York University School of Medicine, New York, NY; 2Carolina Urologic Research Center, Myrtle Beach, SC The most recent guidelines on prostate cancer screening from the American Urological Association (2009), the National Comprehensive Cancer Network (2011), and the European Association of Urology (2011), as well as treatment and advances in disease monitoring, have increased the androgen deprivation therapy (ADT) population and the duration of ADT usage as the first-line treatment for metastatic prostate cancer. According to the European Association of Urology, gonadotropin-releasing hormone (GnRH) agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy. However, GnRH agonists display several shortcomings, including testosterone (T) surge (“clinical flare”) and microsurges. T surge delays the intended serologic endpoint of T suppression and may exacerbate clinical symptoms. Furthermore, ADT manifests an adverse-event spectrum that can impact quality of life with its attendant well-documented morbidities. Strategies to improve ADT tolerability include a holistic management approach, improved diet and exercise, and more specific monitoring to detect and prevent T depletion toxicities. Intermittent ADT, which allows hormonal recovery between treatment periods, has become increasingly utilized as a methodology for improving quality of life while not diminishing chronic ADT efficacy, and may also provide healthcare cost savings. This review assesses the present and potential future role of GnRH agonists in prostate cancer and explores strategies to minimize the adverse-event profile for patients receiving ADT. [ Rev Urol. 2012;14(1/2):1-12 doi:10.3909/riu0547 ] ® © 2012 MedReviews , LLC Key words Prostate cancer • Androgen deprivation therapy • Gonadotropin-releasing hormone, agonists Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 1 40041700002_RIU0547.indd 1 20/07/12 2:01 PM LHRH Agonists for the Treatment of Prostate Cancer: 2012 continued T he management of prostate cancer from initial screening to the treatment of castrate-resistant prostate cancer (CRPC) has a myriad of options and associated controversies. There are a multitude of questions and related controversies involving initial screening and the therapeutic management of lowrisk disease. Does prostate-specific antigen (PSA) screening save lives? Should Gleason 6 histopathology be redefined as a nonmalignant process, due to its exceedingly low risk for the development of recurrent disease after definitive localized therapy? Are we overtreating low-risk prostate cancer? What is the optimal treatment for clinically localized prostate cancer? Androgen deprivation therapy (ADT) has been incorporated into the treatment of prostate cancer since the 1940s, when Huggins and Hodges first reported that surgical and medical castration promotes regression of metastatic prostate cancer with dramatic disease palliation.1 Nonetheless, controversies related to ADT for prostate cancer are abundant. When should ADT be initiated, if at all, during PSA relapse (ie, biochemical recurrence? Is there an advantage to initiating maximal androgen blockade (MAB) versus monotherapy? Does ADT increase cardiovascular mortality? Does intermittent androgen deprivation (IAD) therapy improve quality of life without compromising survival? What level of testosterone (T) suppression is most consistent with castration? Does the level of T suppression achieved following administration of gonadotropin-releasing hormone (GnRH) agonists influence survival? Are all GnRH agonists the same with regard to T suppression? Do GnRH antagonists offer any advantage? What are the optimal dosaging intervals and modes of administration for ADT? Until recently, there was less controversy regarding the management of CRPC because the therapeutic armamentarium was limited. There are now increasing numbers of choices available for treating CRPC in addition to GnRH agonists. In 2012, chemotherapy, immune therapy, and secondary hormonal therapy were approved for the treatment of CRPC.2 For example, in 2010, the US Food and Drug Administration (FDA) approved sipuleucel-T (Provenge®; Dendreon Corporation, Seattle, WA), a cancer treatment vaccine using a patient’s own immune cells. GnRH antagonists, by immediately stopping luteinizing hormone (LH) secretion, produce rapid T suppression without the initial LH and T surge. Other clinical trials are investigating new treatments such as molecularly targeted agents and biomarkers. However, there are unanswered questions regarding the cost/benefit analysis and safety of these new treatments as well as a paucity of data regarding the most ideal sequencing and/or combination implementation strategies. ADT is first-line treatment for advanced/metastatic prostate cancer and recommended for use before, during, or after definitive radiotherapy for intermediate- and high-risk localized prostate cancer. ADT is also commonly used for shorter intervals to reduce prostate gland volume in patients contemplating brachytherapy, cryotherapy, and high-intensity focused ultrasound therapy, especially when gland volume exceeds 50 g; however, this utilization does not have an FDA- or European Medicines Agency–approved indication. ADT does not have an FDA-labeled indication for PSA relapse. ADT may be accomplished by surgical castration (bilateral orchiectomy) or via pharmacologic therapy, for example, GnRH agonists and antagonists. According to the American Urological Association (AUA) guidelines, “primary ADT may be employed with the goal of providing symptomatic control of prostate cancer for patients in whom definitive treatment with surgery or radiation is not possible or acceptable.”3 According to the European Association of Urology (EAU), GnRH agonists have become the leading therapeutic option for ADT because they avoid the physical and psychological discomforts associated with orchiectomy.4,5 However, GnRH agonists display several shortcomings including T surge (“clinical flare”) and microsurges.4 Irrespective of how ADT is achieved, T suppression causes adverse effects, such as hot flushes, osteoporosis, and possible cardiometabolic effects.6 The introduction of PSA testing has increased the prevalence of prostate cancer patients diagnosed at earlier stages. The consequent increase in ADT utilization highlights the importance of strategies to help reduce side effects associated with T suppression, as well as strategies to avoid unnecessary screening, overdetection, and overtreatment. Some of the above controversies related to ADT in the management of prostate cancer are addressed, specifically, PSA screening for prostate cancer and its impact upon ADT utilization; new insights related to the adverse-event profile associated with ADT; the role of intermittent hormone therapy (IHT); measuring T levels and whether the level of T suppression following GnRH agonists influences survival; and differences between GnRH agonists. In addition, this article assesses the potential future role of GnRH agonists in prostate cancer therapy. Novel strategies to minimize the risk of adverse effects of T suppression are also reviewed. 2 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0547.indd 2 20/07/12 2:01 PM LHRH Agonists for the Treatment of Prostate Cancer: 2012 serum T levels to , 50 ng/dL, which historically was the level thought to be consistent with surgical castration.9 Using modern assay techniques, it is now recognized that the median T level achieved following surgical castration is ~15 ng/dL, with a range between 10 to 30 ng/dL.9 In a review of the literature, Perachino and colleagues10 reported that between 13% and 42% of men with prostate cancer fail to achieve castrate levels of androgens (, 20 ng/dL as per the study, as compared with standard , 50 ng/dL) after initiating leutinizing hormone-releasing hormone (LHRH) therapy, depending on the upper limit of serum T. The clinical benefits of maintaining T levels , 20 ng/dL versus , 50 ng/dL have not been prospectively studied. A prospective, randomized, and carefully designed trial contemplating clinical progression and specific mortality is necessary as the primary endpoint would be required to confirm these findings and reassess the cutoff level. GnRH Agonists GnRH is a decapeptide that is produced by the hypothalamus and regulates serum T levels through its effects on LH release by the pituitary gland.7 The various commercially available GnRH agonists are all modifications of the GnRH decapeptide by amino acid substitutions or chemical alterations of existing amino acids. GnRH agonists can cause a T flare in response to increased stimulation of LH; continuous stimulation of the GnRH receptors promotes desensitization of the GnRH receptors, resulting in T suppression.8 Commercially available GnRH agonists differ in their duration of action (1 month to 1 year), route of administration (intramuscular or subcutaneous injection or subcutaneous implant), and requirement for reconstitution. It is generally thought that GnRH agonists have similar efficacy and side effects because all of the commercially available agents have been shown to effectively reduce Mechanism of Action/ Pharmacological Profile GnRH, which is secreted in pulses from the hypothalamus, stimulates release of LH, along with adrenocorticotropic hormone and prolactin, from the pituitary gland. LH subsequently stimulates secretion of T, predominantly by the testes (Figure 1).11,12 Sustained pituitary overstimulation eventually downregulates and desensitizes GnRH receptors, causing a decrease in hormone levels.13 The overall effect of ADT on hormone levels in prostate cancer differs between treatments. Orchiectomy reduces T and dihydrotestosterone (DHT) but is accompanied by significant rises in both LH and follicle-stimulating hormone (FSH).14,15 GnRH agonists cause an initial surge in LH, FSH, T, and DHT; over time these hormones are suppressed.16 However, FSH gradually rises during GnRH agonist treatment and results in a FSH “escape.”17 Hence, these distinct modes of action of GnRH agonists produce different clinical effects. The Figure 1. Gonadotropin-releasing hormone (GnRH), secreted in pulses from the hypothalamus, stimulates release of luteinizing hormone (LH) from the pituitary gland, along with adrenocorticotropic hormone (ACTH) and prolactin. LH subsequently stimulates secretion of testosterone, predominantly by the testes. Damber JE, Acta Oncologica, 2005;44:605-609, copyright © 2005, Informa Healthcare. Reproduced with permission of Informa Healthcare.74 Testosterone Testosterone LH Hypothalamus Testes Pituitary Prolactin GnRH Prostate ACTH Adrenal Cortisol Adrenal androgens Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 3 40041700002_RIU0547.indd 3 20/07/12 2:01 PM LHRH Agonists for the Treatment of Prostate Cancer: 2012 continued initial agonist-induced T surge can exacerbate clinical symptoms (clinical flare) in advanced prostate cancer.18 An appreciable proportion of patients (~ 12%) receiving GnRH agonists fail to achieve castrate T levels # 50 ng/dL.19 T microsurges associated with repeat injections also occur with agonists.19 In a study with goserelin, microsurges (T surges above a castration threshold of 18.5 ng/dL after $ 1 repeat injection) occurred in 17.7% to 27% of patients.20 The clinical implications of microsurges are currently unclear. Loss of GnRH receptor sensitivity during long-term agonist therapy can allow renewed T production manifesting as a late breakthrough T escape.19,21 GnRH agonists usually cause partial FSH suppression.22,23 FSH stimulates prostate cancer cell growth in vitro.24 FSH receptors are present on prostate tumors25 and the surface of tumor blood vessels 26; they are expressed at higher levels on prostate versus normal tissue.27 FSH signaling may also contribute to progression of CRPC.28 FSH promotes RANK (receptor activator of nuclear factor κB) expression on CD141 cells, indicating the acquisition of osteoclast precursor cell characteristics.29 The exact significance of the role of FSH is still being defined. Long-term T control has been suggested to reduce mortality risk among patients with metastatic disease.10 In 129 patients with metastatic prostate cancer receiving a GnRH agonist, those with high T levels at 6 months had a 1.33-fold increase in mortality risk.10 How May Changing Prostate Cancer Screening Guidelines Impact Use of Adt? PSA is the most utilized biomarker for diagnosing prostate cancer. It is a serine protease inhibitor that was discovered and purified in 1979.30 Thirteen years later, two large studies reported the utility of using PSA screening for prostate cancer.31,32 In one study, approximately 15% of men of 1249 over the age of 50 years were found to have an elevated PSA, defined by a serum level . 4.0 ng/mL. Prostate cancer was diagnosed in slightly more than 30% of men with an elevated PSA. Soon thereafter, PSA screening gained widespread acceptance in the United States. According to Zeliadt and colleagues, it has been estimated that approximately 50% of the male US population between the ages of 55 and 74 years undergo PSA screening over a 6- to 7-month period.33 Prior to the widespread acceptance of PSA screening, the overwhelming majority of prostate cancers were advanced at the time of diagnosis.34 PSA screening has resulted in dramatic stage migration. The overwhelming majority of cases diagnosed today are clinically localized, suggesting that there is no clinical or radiologic evidence that the cancer has metastasized beyond the prostate.34 Based on the protracted natural history of the disease, one could speculate that it would require decades for PSA screening to maximally impact mortality rates for prostate cancer. Beginning in the early to mid1990s, mortality rates from prostate cancer have consistently been on the decline.35 Since the peak mortality in 1991, there has been a 40% reduction in prostate cancer mortality that many have attributed to PSA screening.36 In 2011, two large screening studies were reported with conflicting conclusions. The PLCO (Prostate, Lung, Colon and Ovarian) study randomized men to PSA screening versus no mandated PSA screening.37 With a median follow-up of 6.3 years, there was no significant prostate cancer survival advantage attributable to PSA screening. This study has been used to condemn PSA screening, implying it is an instrument that subjects men unnecessarily to biopsies and ineffective treatment. A critical review shows this study was methodologically flawed. First, half of the men in the unscreened group underwent PSA screening before randomization. Second, half of the men in the unscreened group underwent subsequent PSA testing. Third, among the men with an elevated PSA, many did not undergo biopsy. Fourth, a median follow-up of 6.3 years is grossly inadequate to determine screening impact on mortality. Follow-up information has continued to show no statistically significant difference between prostate cancer mortality rates in the intervention arm and the control arm.38 The European Randomized Study of Screening for Prostate Cancer (ERSPC) had less contamination than the PLCO study because a smaller proportion of men in the unscreened cohort underwent screening prior to randomization or during the study.39 The median follow-up was 9 years. Overall, prostate cancer mortality was reduced by 20%. Upon correcting for contamination, PSA screening decreased prostate cancer mortality by 31% in actually screened patients.40 The Scandinavian Prostate Cancer Screening Study was recently reported and received far less fanfare than the PLCO and ERSPC studies.41 The Scandinavian study is the most informative and relevant PSA screening study because contamination was low and follow-up was 14 years. The Scandinavian study reported a 40% reduction in prostate cancer mortality attributable to PSA screening, which is consistent with the 4 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0547.indd 4 20/07/12 2:01 PM LHRH Agonists for the Treatment of Prostate Cancer: 2012 declining prostate cancer mortality statistics seen in the United States.36 Despite the compelling prostate cancer survival advantage of prostate cancer screening, the US Preventative Task Force (USPTF) made a general recommendation against PSA screening because they interpreted the literature to show that PSA screening produced more harm than benefit.42 The debate regarding the value of PSA screening played out in the lay press for several weeks. How the primary care physician will react to the controversy regarding PSA screening is unclear. There is also uncertainty as to whether the Center for Medicare Services (CMS) will continue to reimburse for PSA screening; if the USPTF recommends against PSA screening, then CMS may decide to cease PSA reimbursement. The ultimate decision regarding coverage for PSA screening will certainly influence the proportion of men who will be screened in the future. A randomized study comparing radical prostatectomy (RP) versus watchful waiting for localized disease diagnosed in the prePSA screening era reported that 40% of the men undergoing RP received ADT.43 There is no doubt that prostate screening decreases prostate cancer mortality, but this occurs at the expense of subjecting many men with low-risk disease to unnecessary treatment. Rather than summarily abandoning prostate cancer screening, there is a need to rationally risk stratify newly diagnosed cancers in order to maintain the reduction in prostate cancer mortality while limiting unnecessary treatment. There has been a decline in the use of ADT for prostate cancer due in part to fewer men developing metastatic disease as the result of screening and subsequent curative localized therapies. There has also been a higher threshold for administering these treatments due to increased awareness of potentially significant adverse events. If the diagnostic milieu is turned back to the pre-screening era, this may ironically, and unfortunately, result in more ADT utilization. More men will once again present with locally advanced or metastatic disease that is no longer amenable to localized cure and will be more appropriately managed with ADT. Adverse Effects of ADT T suppression is associated with bone loss,44 which may also be influenced by other factors such as obesity, age, and sedentary lifestyle. Moreover, ADT and attendant bone demineralization is associated with an increased risk of skeletal fracture.45 Skeletal fractures are of particular concern, given their documented correlation with decreased overall survival in men with prostate cancer.46 ADT has also been correlated with several metabolic complications. GnRH agonists can increase central abdominal weight gain and overall fat body mass and decrease lean body mass and muscle size,47 as well as decrease insulin sensitivity.48 ADT can also increase total and low-density lipoprotein cholesterol and triglycerides.49 It is believed metabolic changes associated with ADT may have significant consequences for cardiovascular health; GnRH agonists have been associated with increased risk of incident diabetes, possibly coronary heart disease, acute myocardial infarction, and sudden cardiac death.50 The FDA recently highlighted an increased risk of diabetes, heart attack, stroke, and sudden death with GnRH agonists based on a review of published studies; warnings of such risks must now be added to GnRH agonist labels.51 In contrast, most but not all studies appear to indicate that orchiectomy is not associated with greater risk of cardiovascular events.50,52,53 The final verdict on the cardiovascular risks of ADT is still clouded by a lack of level 1 evidence, required by long-term, prospective, blinded trials. These findings are confirmed by Nguyen and colleagues,54 where in a pooled analysis of randomized trials of unfavorable-risk prostate cancer, ADT use was not associated with an increased risk of cardiovascular death but was associated with a lower risk of prostate cancer– specific mortality and all-cause mortality. By assessing a patient’s susceptibility to such effects, a comprehensive (holistic) treatment program can be tailored to maximize ADT efficacy while protecting against adverse effects.55 Patients receiving ADT should be counseled to help them recognize, prevent, and manage side effects; they should be encouraged towards a healthy lifestyle including a heart-healthy diet and manageable regular exercise program.19 Measures to promote bone health include weight-bearing (resistance) exercise, smoking cessation, vitamin D and calcium supplementation, and moderate alcohol consumption.55,56 Bisphosphonates (which increase bone mineral density [BMD] in patients treated with ADT6) should be considered in patients with fractures or BMD T scores of 22.5 or less.57 Based on one study, denosumab, a monoclonal antibody agonist RANK ligand, has increased BMD and reduced the incidence of new vertebral fractures among men receiving ADT for nonmetastatic prostate cancer.58 Denosumab was FDA approved in November 2011 for prevention of osteoporosis for men receiving ADT. Clinicians should carefully assess fracture risk (eg, via the World Health Organization fracture risk assessment tool [FRAX]) Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 5 40041700002_RIU0547.indd 5 20/07/12 2:01 PM LHRH Agonists for the Treatment of Prostate Cancer: 2012 continued and BMD should be monitored at regular intervals via dual-energy X-ray absorptiometry when deemed appropriate to clinically alter therapeutic options.56 The morbidities of ADT should be considered in the context of the existing comorbidities of the patient when choosing palliative ADT. As per the AUA guidelines, ADT may be used for the palliation of symptomatic patients with more extensive or poorly differentiated tumors, whose life expectancy is too short to benefit from treatment with curative intent.3 When making treatment decisions about ADT, physicians and patients should discuss and review existing guidelines for lifestyle modifications, and the increased risk of adverse effects such as osteoporosis, fracture risks, obesity, alteration in lipids, diabetes and cardiovascular disease.5,59 Patients should be monitored with periodic follow-up evaluations including assessment of blood pressure, lipid profile, and glucose level. Patients with cardiac disease should receive appropriate secondary preventive measures as recommended by existing guidelines.5,53 Intermittent Hormonal Therapy IAD has been touted as a possible alternative for some patients to minimize ADT side effects while maintaining anti-tumor efficacy.60 Although some evidence suggests that IAD performs at least as well as continuous androgen deprivation (CAD) in terms of overall survival, and perhaps better in terms of side effects, IAD still remains experimental and unproven regarding long-term implications of disease progression and survival impact.61 In fact, many organizations such as the National Comprehensive Cancer Network have been skeptical in their practice guidelines regarding IAD, stating that “the long term efficacy [of IAD] remains unproven.”5 In light of the experimental nature of IAD in the United States, optimal thresholds for stopping/resuming ADT are empirical, and the best candidates for IAD have not been completely defined. According to Gomella and colleagues,62 during IAD, active treatment periods are separated by periods without treatment. On-treatment periods usually last 6 to 9 months or until a PSA nadir , 4 ng/mL.62 Off-treatment periods are more variable, with treatment reinstated if PSA increases. In contrast, the EAU does not consider IAD an investigational therapy, and has formulated guidelines for locally advanced or relapsing disease; these suggest stopping treatment only if there is no clinical progression (a clear PSA response: PSA , 4 ng/mL in metastatic disease, or 0.5 ng/mL in relapsing disease), and resuming treatment if there is either clinical progression or a PSA value above a predetermined fixed threshold (usually 4 ng/mL in nonmetastatic patients or 10-15 ng/ mL in metastatic patients).4 As there is no consensual standardization of IAD protocols and guidelines in the United States, it has been difficult to compare data and conclusions from clinical trials. However, the potential advantages of IAD, which include improved quality of life, the theoretical possibility of delaying hormone resistance, and possible reduction in healthcare costs, warrant further exploration.63 American clinical trials have documented the efficacy of IAD. An intergroup, phase III, randomized, controlled trial study from Klotz and colleagues61 showed that IAD was not inferior to complete androgen blockade with respect to overall survival in men with rising PSA after radical therapy for prostate cancer.61 This study outcome is similar to two previous pivotal trials and a systematic review of IAD based on the EAU guidelines.61,64,65 Based on limited randomized studies, whereas CAD appears appropriate for patients with advanced metastatic prostate cancer, according to a study by Shore and Crawford IAD may be appropriate for many patients who reach castrate T levels (, 20 ng/dL) and a PSA nadir of , 4.0 ng/dL during induction therapy.63 However, the clinical benefits of maintaining T levels , 20 ng/dL versus , 50 ng/dL have not been prospectively studied. Carefully designed, prospective, randomized, phase III trials are needed for further assessment, with results clarifying issues such as selection of the most appropriate patients to receive IAD, optimal thresholds for stopping/resuming therapy, suitable ADT agents, and confirmation of the efficacy of IAD to mitigate serious adverse events. Does T Level Influence Survival Following ADT? Controversy previously existed regarding the clinical significance of circulating androgens following treatment with GnRH agonists. There is evidence that very low levels of T and its metabolites may elicit prostate cancer progression. Although the treatment is controversial, some experts believe that MAB (medical or surgical castration in combination with an antiandrogen) achieves superior survival over GnRH agonists alone.66 It is unclear whether this modest observed survival advantage is attributable to prevention of the T flare or T escape, or suppression of adrenal androgens. There is new evidence that prostate cancers themselves are capable of synthesizing endogenous T.67 A recent clinical study showing that treatment 6 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0547.indd 6 20/07/12 2:01 PM LHRH Agonists for the Treatment of Prostate Cancer: 2012 TABLE 1 Univariate Analysis Relating Dichotomic Variables Included in the Study and Survival Free of AndrogenIndependent Progression Age (# 70 years vs . 70 years) Initial clinical stage (T1–2 vs T3–4) Biopsy Gleason score (2–6 vs 7–10) LHRH agonist ( bicalutamide) Initial PSA (# 20 ng/mL or less vs . 20 ng/mL) Testosterone breakthrough increases . 20 ng/dL Testosterone breakthrough increases . 50 ng/dL Log Rank P Value 3.27 0.01 6.71 0.99 0.10 1.78 7.74 .0723 .9095 .0096 .3188 .7483 .1819 .0054 LHRH, luteinizing hormone-releasing hormone; PSA, prostate-specific antigen. Reproduced with permission from Morote J et al.21 with a CYP17 inhibitor such as abiraterone, either alone or with glucocorticoids, resulted in significant antitumor activity in patients with androgen independent progression (AIP) both who had and had not received chemotherapy.68 The goal of pharmacologic castration is to achieve T suppression comparable with surgical castration. Historically, it was assumed that surgical castration achieved T levels , 1.5 pmol/L because this was the lower limit for assaying T levels at the time.69 Therefore, GnRH agonists were assumed to achieve equivalence to surgical castration if they achieved T levels , 50 ng/dL. Using newer chemiluminescent techniques,70 it was subsequently shown in a single study that surgical castration achieves median T levels equivalent to 15 ng/dL.9 Ideally, this should be the goal of GnRH agonists. There are two recent studies suggesting that consistent T suppression , 50 ng/dL following GnRH agonists can be associated with superior survival. Morote and colleagues21 and Perachino and colleagues10 hypothesized that progression and survival following administration of GnRH agonists is related to the degree of T suppression. Morote and colleagues21 conducted a review based on a ret­rospective analysis of 73 nonmetastatic prostate cancer patients who were treated with ADT (GnRH agonist) and had both their serum PSA and T levels measured between 8 and 12 weeks after administration of the GnRH agonist. Over one-third of patients (38.4%) also received continued treatment with bicalutamide (MAB). All men were treated with a 3-month depot GnRH agonist for at least 1 year and had at least three serum T levels measured.21 All patients received bicalutamide, 50 mg, daily for 2 weeks prior to initiating GnRH agonist treatment.21 Of the 73 evaluated, daily bicalutamide was maintained in 28 men throughout the course of ADT. In the subset of daily bicalutamide patients, the mean follow-up was 54 months (range, 13-240 months). Overall, 32% and 25% of men had T levels between 20 and 50 ng/dL and . 50 ng/dL, respectively.21 The endpoint was development of AIP, defined as three consecutive rising PSA levels. During a followup period (a mean follow-up of 51 months; range, 12-240 months), androgen-independent progression (AIP) events were identified and correlated with breakthrough T increases of 50 ng/dL (classic level) and 20 ng/dL (surgical castration level). The lowest serum T threshold that was able to significantly distinguish groups related with survival free of AIP was 32 ng/dL.21 A univariate analysis was performed to determine if age, initial clinical stage, biopsy Gleason score, administration of MAB, initial PSA, and T break‑ through . 50 ng/mL predicted the survival free of AIP (Table 1).21 Survival free of AIP was compared for three groups: Group 1, all T levels , 20 ng/dL; Group 2, any T between 20 and 50 ng/dL; and Group 3, any T . 50 ng/dL. The mean time to develop AIP for Groups 1, 2, and 3 was 106 months, 90 months, and 72 months, respectively.21 The Kaplan-Meier plots showing survival free of AIP for the three groups (Figure 2) confirms that the level of serum T suppression is a predictor of survival free of AIP. The mean survival free of AIP in patients with breakthrough increases greater than 32 ng/dL was 88 months, whereas it was 137 months in those without breakthrough increases. According to Morote and colleagues, these results show that a routine measurement Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 7 40041700002_RIU0547.indd 7 20/07/12 2:01 PM LHRH Agonists for the Treatment of Prostate Cancer: 2012 continued Cumulative Survival Free of PSA Progression 1.0 P .0207 0.8 Group 1 0.6 0.4 Group 2 0.2 Group 3 0.0 0 24 48 72 96 120 144 168 192 216 240 Months Under ADT Figure 2. Survival free of androgen-independent progression (AIP) according to serum testosterone behavior. Group 1, patients with all three serum testosterone determinations less than , 20 ng/dL. Group 2, patients with breakthrough increases between 20 and 50 ng/dL. Group 3, patients with breakthrough increases . 50 ng/dL. ADT, androgen deprivation therapy; PSA prostate-specific antigen. Reproduced with permission from Morote J et al.21 of serum T should become part of clinical practice when evaluating the effects of hormonal therapy. A reasonable option to detect these breakthrough increases would be to monitor T levels at PSA determination. In order to confirm findings of the study by Morote and colleagues,21 a prospective, randomized, and carefully designed trial to assess clinical progression and mortality as primary endpoints would be required to reassess T cutoff level, as the clinical benefits of maintaining T levels , 20 ng/dL versus , 50 ng/dL have not been prospectively studied. Key issues remain unresolved—standardization of assays, a universally accepted definition of optimal castrate T levels, and clear evidence regarding the clinical benefits of androgen suppression, continuous or intermittent protocol, and maintenance of acceptable castrate levels of T. Perachino and colleagues10 followed T levels after initiation of ADT with GnRH agonists. The study was based on a retrospective review of 129 newly diagnosed ADT-naive patients with metastatic bone-only prostate cancer who were treated with a 3-month depot of goserelin every 12 weeks. Serum PSA and T were measured on the same day of goserelin administration. The mean and range of Figure 3. Hazard ratio and related 95% confidence interval. PSA prostate-specific antigen. Reproduced with permission from Perachino M et al.10 follow-up was 47.5 months and 6 to 120 months, respectively. Serum T and PSA data were taken retrospectively from patients on 3 months of ADT (n 5 129) every 12 weeks for the duration of the study. After a mean follow-up of 47.5 months, 55% (n 5 71) of patients died and 45% (n 5 58) of patients survived. Overall, 25% and 31% of men receiving goserelin exhibited a T level . 50 ng/dL or between 20 and 50 ng/dL, respectively. A Cox regression model was utilized to determine predictors of prostate cancer survival. Gleason score, 6-month serum PSA, and 6-month T were independent predictors of cancer-specific survival. The ­hazard ratio and related 95% ­confidence interval are shown in Figure 3. PSA values were shown as natural logarithms and serum T levels as squared values, respectively, and represented on a logarithmic survivor function plot which showed a continuous direct relationship between serum T levels and cancer-specific survival. This study suggests a direct correlation between the risk of death and T levels during ADT. A prospective, randomized, and carefully designed trial contemplating clinical progression and specific mortality as the primary endpoint would be required to confirm these findings and reassess the cutoff 6 mo Testosterone 6 mo PSA Gleason scale Age 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 8 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0547.indd 8 20/07/12 2:01 PM LHRH Agonists for the Treatment of Prostate Cancer: 2012 level, as the clinical benefits of maintaining T levels , 20 ng/dL versus , 50 ng/dL have not been prospectively studied. Do GnRH Agonists have Unique Properties? Heyns and colleagues71 compared T suppression in 140 and 137 men receiving monthly leuprolide acetate versus triptorelin pamoate, respectively. The primary endpoint of the trial was the percentage of men whose serum T declined and remained at or below castration level (1.735 nmol/L or 50 ng/dL) during the 9-month treatment duration. The probability of maintenance of castration T levels is shown at monthly intervals throughout the 9-month study (Figure 4). A Kaplan-Meier survival analysis for the maintenance of castration levels measured 3.75 mg triptorelin pamoate or 7.5 mg leuprolide. The cumulative maintenance of castration levels were 96% and 91% for triptorelin pamoate and leuprolide, respectively (P 5 .092). In this study, a greater proportion of men maintained medical castration with triptorelin pamoate at 29 days. Secondary endpoints (9-month survival rate, mean LH concentrations during treatment, median bone pain values as measured by the visual analog scale, quality of life, median PSA concentrations) were equivalent in both groups except for the 9-month overall survival rate, which was 97% in the triptorelin pamoate group versus 90.5% in the leuprolide acetate group (P 5 .033). Mean and cumulative castration maintenance rates between 29 and 253 days were equivalent between the treatment groups. Mean serum T levels were analyzed every 28 days in the leuprolide acetate and triptorelin pamoate treatment groups. These levels fell below the predefined levels for medical castration (# 50 ng/dL in this trial) at 29 days and 57 days for 91% and 98% of subjects in the triptorelin pamoate Figure 4. The maintenance of castration in men treated with triptorelin pamoate, 3.75 mg (green line, open circles), or leuprolide acetate, 7.5 mg (red line, open squares), for 9 months (Kaplan-Meier survival analysis). Reproduced with permission from Heyns CF et al.71 0.99 Maintenance of Castration, Probability 0.98 0.97 0.96 P = .092 0.95 0.94 0.93 0.92 0.91 0.90 0.89 0.88 0.87 0.86 0.85 1 2 3 4 5 Month 6 7 8 9 group and 99% and 97% of the subjects in the leuprolide group, respectively. Although the mean difference was significant between the leuprolide acetate and triptorelin pamoate treatment groups at 29 days, it was not significant at 57 days (Figure 5). The results from Heyns and colleagues71 indicate that triptorelin pamoate may induce castration at a slightly slower rate than leuprolide acetate, but triptorelin pamoate maintains castration at least as effectively as leuprolide. A possible reason for this outcome may be dosing differences between triptorelin pamoate and leuprolide acetate. The repeated exposure to the higher leuprolide acetate dose (7.5 mg), as compared with the lower triptorelin pamoate dose (3.75 mg) may more likely cause an escape resulting from weak desensitization of pituitary GnRH receptors.71 The hypothesis is supported by an insignificant trend throughout the study, evidenced where there was more LH stimulation with leuprolide than triptorelin pamoate at day 85 (98% vs 94%) and 169 days (98% vs 93%).71 Additional data support this claim with individual patients; there were fewer triptorelin pamoate than leuprolide patients who achieved castration at 29 days but had T escape at least once between months 2 and 9 of the study (4 vs 11, respectively); this result correlated with the pharmacological data. Assessment of T levels over 24 hours in a patient subset showed that 3 of 15 patients treated with leuprolide escaped castrate T levels as compared to none of the 14 patients treated with triptorelin pamoate. Moreover, there is no evidence that the slower onset of castration caused deleterious effects. The higher 9-month survival rate in the triptorelin pamoate than in the leuprolide group is intriguing, but longterm data are required to determine Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 9 40041700002_RIU0547.indd 9 20/07/12 2:01 PM LHRH Agonists for the Treatment of Prostate Cancer: 2012 continued 20 Testosterone Level, nmol/L 15 10 5 0 0 1 29 57 85 113 141 169 197 225 253 Time (Days) Figure 5. Mean serum testosterone levels were analyzed every 28 days in 277 men receiving androgen deprivation with either leuprolide acetate or triptorelin pamoate. These levels fell below the predefined levels for medical castration (50 ng/dL) at 29 days and 57 days for 91% and 98% of subjects in the triptorelin pamoate group and 99% and 97% of the subjects in the leuprolide group. Although the mean difference was significant between the groups at 29 days, it was not significant at 57 days. Reproduced with permission from Heyns CF et al.71 the clinical significance of this observation. It has been observed that men on depot GnRH agonists, at castrate levels of T (as previously defined, , 50 ng/dL), may demonstrate subtle increases in PSA activity as serum T moves from nadir levels upward to 50 ng/dL.9 The information obtained from Heyns and colleagues71 is significant, as few comparative studies have examined the ability of different GnRH agonists to lower serum T levels. Yri and colleagues72 retrospectively compared serum T levels in 40 and 25 men receiving 3-month depot of either leuprolide acetate or goserelin acetate, respectively. Four of the men receiving leuprolide (10%) and none on goserelin failed to achieve castration levels of T. The failure rate of achieving castrate levels was not significant as per the study rates. Castrate levels of T in this study was 81 ng/dL, which is higher than the 50 ng/dL that has been used in other studies. (The 81 ng/dL corresponds with the upper limit of normal that was seen in women in one study.73) This study showed that although most patients reached castrate T levels, its retrospective nature prevented a true comparison between the effectiveness of leuprolide and goserelin. Summary According to EAU guidelines, ADT is the mainstay of treatment for advanced prostate cancer and largely comprised of GnRH agonists.4 Avoiding T surges may help avoid cancer stimulation and worsening of clinical status, as well as providing more rapid relief of cancer-related symptoms.74 PSA recurrence often precedes clinically detectable recurrence by years, and effective PSA control is associated with improved overall survival.75-77 As ADT is associated with a range of side effects (eg, bone loss, metabolic and possible cardiovascular complications), a variety of strategies should be considered to effectively manage these effects. In particular, this should include adoption of a more comprehensive treatment approach with counseling on diet and exercise as well as periodic monitoring of bone density and metabolic and cardiovascular parameters. In addition, some patients may benefit from IAD, which minimizes ADT adverse events; allowing hormonal recovery between treatment periods may improve quality of life. IAD may provide efficacy comparable with CAD but with improved tolerability. Nevertheless, consensus guidelines regarding a universally accepted definition of optimal castrate T levels, as well as evidence regarding the clinical benefits, safety, and tolerability of optimal androgen suppression, remain for further study and discussion. Because the clinical benefits of maintaining T levels , 20 ng/dL versus , 50 ng/dL have not been prospectively studied, further prospective, well-designed studies are needed to prove the hypothesis. Dr. Herbert Lepor is a member of the Speakers’ Bureau for Amgen, is a consultant for Watson, and is consultant/advisor to Serenity Pharma and Quanterix. Dr. Neal D. Shore is a­ consultant/researcher for Ferring Pharmaceuticals, Watson, Endo Pharmaceuticals, Amgen, Janssen, Medivation, and Sanofi Oncology. The authors thank Lloyd Zimmerman, MD, MPH, for assistance in preparing this manuscript. References 1. 2. 3. Huggins C, Hodges CV. Studies on prostatic cancer. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293-297. Garcia JA, Rini BI. Castration-resistant prostate cancer: many treatments, many options, many challenges ahead. Cancer. 2012;118:2583-2593. American Urological Association. Prostate Cancer: Guideline for the Management of Clinically Localized Prostate Cancer: 2007 Update. http://www.auanet. org/content/clinical-practice-guidelines/clinical-guidelines/ main-reports/proscan07/content.pdf. Accessed April 4, 2012. 10 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0547.indd 10 20/07/12 2:01 PM LHRH Agonists for the Treatment of Prostate Cancer: 2012 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Heidenreich A, Bolla M, Joniau S, et al. Guidelines on Prostate Cancer. http://www.uroweb.org/gls/pdf/08_ Prostate_Cancer July 6th.pdf. Accessed April 4, 2012. NCCN Clinical Practice Guides in Oncology: Prostate Cancer. http://www.nccn.org/professionals/physician_ gls/pdf/prostate.pdf. Accessed April 4, 2012. Sharifi N, Gulley JL, Dahut WL. An update on androgen deprivation therapy for prostate cancer. Endocr Relat Cancer. 2010;17:R305-R315. Schally AV, Kastin AJ, Arimura A. Hypothalamic follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-regulating hormone: structure, physiology and clinical studies. Fertil Steril. 1971;22:703. Auclair C, Kelly PA, Labrie F, et al. Inhibition of testicular luteinizing hormone receptor level by treatment with a potent luteinizing hormone-releasing hormone agonist of human chorionic gonadotropin. Biochem Biophys Res Commun. 1977;76:855-862. Oefelein MG, Feng A, Scolieri MJ, et al. Reassessment of the definition of castrate levels of testosterone: implications for clinical decision making. Urology. 2000;56:1021. Perachino M, Cavalli V, Bravi F. Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: prognostic significance? BJU Int. 2009;105:648-651. Huhtaniemi I, White R, McArdle CA, Persson BE. Will GnRH antagonists improve prostate cancer treatment? Trends Endocrinol Metab. 2009;20:43-50. Drudge-Coates L. GnRH blockers: a changing paradigm in the management of prostate cancer. Int J Urol Nursing. 2009;3:85-92. Crawford ED. Hormonal therapy in prostate cancer: historical approaches. Rev Urol. 2004 6(suppl 7): S3-S11. Varenhorst E, Wallentin L, Carlström K. The effects of orchidectomy, estrogens, and cyproterone acetate on plasma testosterone, LH, and FSH concentrations in 15. 16. 17. 18. 19. 20. 21. 22. 23. patients with carcinoma of the prostate. Scand J Urol Nephrol. 1982;16:31-36. Andò S, Giacchetto C, Canonaco M, et al. Effects of castration on androstenedione, testosterone and dihydrotestosterone plasma levels in adult male rats. Horm Res. 1986;23:122-127. Labrie F, Bélanger A, Luu-The V, et al. Gonadotropinreleasing hormone agonists in the treatment of prostate cancer. Endocr Rev. 2005;26:361-379. Bhasin S, Berman N, Swerdloff RS. Follicle-stimulating hormone (FSH) escape during chronic gonadotropinreleasing hormone (GnRH) agonist and testosterone treatment. J Androl. 1994;15:386-391. Mahler C. Is disease flare a problem? Cancer. 1993;72(17 suppl):3799-3802. Tombal B, Berges R. Optimal control of testosterone: a clinical case-based approach of modern androgendeprivation therapy. Eur Urol Suppl. 2008;7:15-21. Zinner NR, Bidair M, Centeno A, Tomera K. Similar frequency of testosterone surge after repeat injections of goserelin (Zoladex) 3.6 mg and 10.8 mg: results of a randomized open-label trial. Urology. 2004;64: 1177-1181. Morote J, Orsola A, Planas J, et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol. 2007;178:1290-1295. Mahler C, Verhelst J, Chaban M, Denis L. Prolactin and pituitary gonadotropin values and responses to acute luteinizing hormone-releasing hormone (LHRH) challenge in patients having long-term treatment with a depot LHRH analogue. Cancer. 1991;67:557-559. Khan MS, O’Brien A. An evaluation of pharmacokinetics and pharmacodynamics of leuprorelin acetate 3M-depot in patients with advanced and metastatic carcinoma of the prostate. Urol Int. 1998;60:33-40. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. Ben-Josef E, Yang SY, Ji TH, et al. Hormone-refractory prostate cancer cells express functional folliclestimulating hormone receptor (FSHR). J Urol. 1999; 161:970-976. Huhtaniemi I. Are gonadotropins tumorigenic—a critical review of clinical and experimental data. Mol Cell Endocrinol. 2010;329:56-61. Radu A, Pichon C, Camparo P, et al. Expression of follicle-stimulating hormone receptor in tumor blood vessels. N Engl J Med. 2010;363:1621-1630. Mariani S, Salvatori L, Basciani S, et al. Expression and cellular localization of follicle-stimulating hormone receptor in normal human prostate, benign prostatic hyperplasia and prostate cancer. J Urol. 2006;175:2072-2077. Porter AT, Ben-Josef E. Humoral mechanisms in ­prostate cancer: a role for FSH. Urol Oncol. 2001;6: 131-138. Cannon JG, Kraj B, Sloan G. Follicle-stimulating hormone promotes RANK expression on human monocytes. Cytokine. 2011;53:141–144. Wang MC, Valenzuela LA, Murphy GP, Chu TM. Purification of a human prostate specific antigen. J Urol. 2002;167:960-964. [Reprinted from Invest Urol. 1976;17:159-163.] Catalona WJ, Smith DD, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. 1992;324:1156-1161. Brawer MK, Chetner MP, Beatie J, et al. Screening for prostatic carcinoma with prostate-specific antigen. J Urol. 1992;147:841-845. Zeliadt SB, Hoffman RM, Etzioni R, et al. Influence of publication of US and European prostate cancer screening trials on PSA testing practices. J Natl Cancer Inst. 2011;103:520-523. Newcomer LM, Sanford JL, Blumenstein BA, Brawer MK. Temporal trends in rates of prostate cancer: MAIN POINTS • Androgen deprivation therapy (ADT) is first-line treatment for advanced/metastatic prostate cancer and recommended for use before, during, or after definitive radiotherapy for intermediate- and high-risk localized prostate cancer. • Prostate-specific antigen is the most utilized biomarker for diagnosing prostate cancer. • There has been a decline in the use of ADT for prostate cancer due in part to fewer men developing metastatic disease as the result of screening and subsequent curative localized therapies. There has also been a higher threshold for administering these treatments due to increased awareness of potentially significant adverse events. • Gonadotropin-releasing hormone agonists have been associated with increased risk of incident diabetes, possibly coronary heart disease, acute myocardial infarction, and sudden cardiac death. Patients receiving ADT should be counseled to help them recognize, prevent, and manage side effects; they should be encouraged towards a healthy lifestyle including a heart-healthy diet and manageable regular exercise program. • Although some evidence suggests that intermittent androgen deprivation (IAD) performs at least as well as continuous androgen deprivation in terms of overall survival, and perhaps better in terms of side effects, IAD still remains experimental and unproven regarding long-term implications of disease progression and survival impact. However, the potential advantages of IAD, which include improved quality of life, the theoretical possibility of delaying hormone resistance, and possible reduction in healthcare costs, warrant further exploration. • Consensus guidelines regarding a universally accepted definition of optimal castrate testosterone levels, as well as evidence regarding the clinical benefits, safety, and tolerability of optimal androgen suppression, remain for further study and discussion. Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 11 40041700002_RIU0547.indd 11 20/07/12 2:01 PM LHRH Agonists for the Treatment of Prostate Cancer: 2012 continued 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. declining incidence of advanced stage disease 1974 to 1994. J Urol. 1997;158:1427-1430. McDavid K, Lee J, Fulton JP, et al. Prostate cancer incidence and mortality rates and trends in the United States and Canada. Public Health Rep. 2004; 119:174-186. SEER Cancer Statistics Review 1975-2007. Table 23.6: Cancer of the Prostate (Invasive). www.seer.cancer. gov/csr/1975_2007/download_csr_datafile.php/ sect_23_table.06.csv. Accessed January 17, 2012. Andriole GL, Crawford ED, Grubb RL III, et al; PLCO Project Team. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319. Andriole GL, Crawford ED, Grubb RL III, et al; PLCO Project Team. Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012;104:125-132. Schröder FH, Hugosson J, Roobol MJ, et al; ERSPC Investigators. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-1328. Roobol MJ, Kerkhof M, Schröder FH, et al. Prostate cancer mortality reduction by prostate-specific ­antigen-based screening adjusted for nonattendance and contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC). Eur Urol. 2009;56:584-591. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Göteborg randomized populationbased prostate-cancer screening trial. Lancet Oncol. 2010;11:725-732. Chou R, Croswell JM, Dana T, et al. Screening for prostate cancer: a review of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2011;155:762-771. Bill-Axelson A, Holmberg L, Ruutu M, et al; SPCG-4 Investigators. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2011;364:1708-1717. Daniell HW, Dunn SR, Ferguson DW, et al. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol. 2000;163:181-186. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005;352:154-164. Oefelein MG, Ricchiuti V, Conrad W, Resnick MI. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol. 2002;168:1005-1007. Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab. 2002;87:599-603. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab. 2006;91:1305-1308. Shahani S, Braga-Basaria M, Basaria S. Androgen deprivation therapy in prostate cancer and metabolic 50. 51. 52. 53. 54. 55. 55. 56. 57. 58. 59. 60. 61. 62. risk for atherosclerosis. J Clin Endocrinol Metab. 2008;93:2042-2049. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24:4448-4456. US Food and Drug Administration (FDA). FDA Drug Safety Communication 10-20-2010. http://www. fda.gov/Drugs/DrugSafety/ucm229986.htm. Accessed January 17, 2012. Alibhai SM, Duong-Hua M, Sutradhar R, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol. 2009;27:3452-3458. Levine GN, D’Amico AV, Berger P, et al. Androgendeprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation. 2010;121:833-840. Nguyen PL, Je Y, Schutz FAB, et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials . JAMA. 2011;306:2359-2366. Ebeling PR. Clinical practice. Osteoporosis in men. N Engl J Med. 2008;358:1474-1482. Northhouse LL, Mood DW, Schafenacker A, et al. Randomized clinical trial of a family intervention for prostate cancer patients and their spouses. Cancer. 2007;110;2809-2818. Grossmann M, Hamilton EJ, Gilfillan C, et al. Bone and metabolic health in patients with non-metastatic prostate cancer who are receiving androgen deprivation therapy. Med J Aust. 2011;194:301-306. Diamond TH, Higano CS, Smith MR, et al. Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: recommendations for diagnosis and therapies. Cancer. 2004;100:892-899. Smith MR, Egerdie B, Hernández Toriz N, et al; Denosumab HALT Prostate Cancer Study Group. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361: 745-755. Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol. 2009;181:1998-2006. Tunn U. The current status of intermittent androgen deprivation (IAD) therapy for prostate cancer: putting IAD under the spotlight. BJU Int. 2007;99(suppl 1):19-22. Klotz L, O’Callaghan GJ, Ding K, et al. A phase III randomized trial comparing intermittent versus continuous androgen suppression for patients with PSA progression after radical therapy: NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013. J Clin Oncol. 2011;29(suppl 7): Abstract 3. Gomella LG, Singh J, Lallas C, Trabulsi EJ. Hormone therapy in the management of prostate cancer: ­evidence-based approaches. Ther Adv Urol. 2010;2: 171-181. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. Shore ND, Crawford ED. Intermittent androgen deprivation therapy: redefining the standard of care? Rev Urol. 2010;12:1-11. Calais da Silva FE, Bono AV, Whelan P, et al. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol. 2009;55:1269-1277. Abrahamsson PA. Potential benefits of intermittent androgen suppression therapy in the treatment of prostate cancer: a systematic review of the literature. Eur Urol. 2010;57:49-59. Schmitt B, Bennett C, Seidenfeld J, et al. Maximal androgen blockade for advanced prostate cancer. Cochrane Database Syst Rev. 2000;2:CD001526. Mohler JH, Gregory CW, Ford OH, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10:440-448. de Bono JS, Logothetis CJ, Molina A, et al; COUAA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005. Wilke TJ, Utley DJ. Total testosterone, free-androgen index, calculated free testosterone, and free testosterone by analog RIA compared in hirsute women and otherwise-normal women with altered binding of ­sex-hormone-binding globulin. Clin Chem. 1987;33: 1372-1375. Wheeler MJ, D’Souza A, Matadeen J, Croos P. Ciba Corning ACS:180 testosterone assay evaluated. Clin Chem. 1996;42:1445-1449. Heyns CF, Simonin MP, Grosgurin P, et al; for the South African Triptorelin Study Group. Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with advanced prostate cancer. BJU Int. 2003;92:226-231. Yri OE, Bjoro T, Fossa SD. Failure to achieve castration levels in patients using leuprolide acetate in locally advanced prostate cancer. Eur Urol. 2006;49:54-58. Sherwin BB. Randomized clinical trials of combined estrogen-androgen preparations: effects on sexual functioning. Fertil Steril. 2002;77(suppl 4):S49-S52. Damber JE. Endocrine therapy for prostate cancer. Acta Oncologica. 2005;44:605-609. Williams SG, Duchesne GM, Millar JL, Pratt GR. Both pretreatment prostate-specific antigen level and posttreatment biochemical failure are independent predictors of overall survival after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2004;60:1082-1087. Hussain M, Tangen CM, Higano C, et al. Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol. 2006;24:3984-3990. Hussain M, Goldman B, Tangen C, et al. Prostatespecific antigen progression predicts overall survival in patients with metastatic prostate cancer: data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916. J Clin Oncol. 2009;27:2450-2456. 12 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0547.indd 12 20/07/12 2:01 PM Management Update Active Surveillance for Small Renal Masses Phillip M. Pierorazio, MD, Elias S. Hyams, MD, Jeffrey K. Mullins, MD, Mohamad E. Allaf, MD Brady Urological Institute, Johns Hopkins University, Baltimore, MD Small renal masses (SRMs; # 4 cm in dimension) have rapidly risen in incidence in recent decades and pose an increasingly common management dilemma in urology. SRMs are biologically heterogeneous and a wide variety of treatments exist with favorable oncologic outcomes. Active surveillance (AS) has emerged as a viable option for those not desiring surgery or those who are suboptimal candidates for surgery, with , 2% of patients progressing to metastatic disease in retrospective and prospective studies. This article reviews the current data regarding AS for SRM, operational considerations for an AS program, and criteria for safely selecting patients for this treatment strategy. [ Rev Urol. 2012;14(1/2):13-19 doi: 10.3909/riu0545] ® © 2012 MedReviews , LLC KEY WORDS Small renal mass • Renal cell carcinoma • Active surveillance S mall renal masses (SRMs; # 4 cm in dimension) are an increasingly common clinical entity encountered by practicing urologists. Epidemiological studies indicate that SRMs account for nearly one-half of all newly diagnosed renal masses, largely based on incidental diagnosis during abdominal imaging.1 However, although these lesions have a radiographic appearance of malignancy (contrast enhancement of solid component), extirpative surgical series have demonstrated benign pathology in 20% to 30% of tumors # 4 cm,2 and for those lesions that are renal cell carcinoma (RCC), the majority of tumors are low grade3 and unlikely to develop metastases.4 Given the rapid increase in the incidence of SRMs, the known biological heterogeneity of these masses, and a wide variety of treatment options, a number of rational approaches to their management, including extirpative surgery (radical and partial nephrectomy), ablative therapies (cryotherapy and radiofrequency ablation), and active surveillance (AS), exists. Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 13 40041700002_RIU0545.indd 13 20/07/12 2:07 PM Active Surveillance for Small Renal Masses continued Against this backdrop, a growing body of literature has emerged regarding AS for select patients with SRMs. A number of ­retrospective deaths from kidney cancer in the United States (11,000-13,000 from 1997-2010), only decreasing modestly in the past few years.12 It is A growing body of literature has emerged regarding AS for select patients with SRMs. A number of retrospective analyses, meta-­ analyses, and prospective studies quote the risk of metastatic ­progression while on AS to be , 2%. analyses, meta-analyses, and prospective studies quote the risk of metastatic progression while on AS to be , 2%.5-10 However, much of the data supporting AS are retrospective and must be evaluated with caution because such studies are limited by selection and reporting bias. Those undergoing AS frequently include older, sicker patients; outcomes are based on a composite of benign and malignant masses; and untreated patients who develop metastases and/or die from renal cancer may be lost to followup. Reflecting this theme, the 2009 American Urologic Association (AUA) “Guideline for Management of the Clinical T1 Renal Mass” recommends AS for high-surgical-risk patients and as an option for healthy patients desiring to avoid treatment and willing to assume the oncological risk of delaying intervention.11 Epidemiological Trends in SRMs The incidence of kidney cancer has surged over the past few decades, from 28,000 in 1997 to 58,000 in 2010; the increased use of axial imaging12 has led to increased detection. This increasing incidence has been accompanied by a dramatic stage migration, with SRMs accounting for the largest proportion of the incident rise in renal malignancies and nearly 40% of all renal tumors diagnosed.1 The interpretation of these trends is complicated by the concomitant observation of relatively stable believed that the rising incidence of SRMs reflects a combination of early-stage malignancies destined to become clinically significant advanced cancers and lesions of benign histology or indolent behavior of unclear clinical significance. Although multiple variables contribute to the ­perplexing The Natural History of SRMs As stated previously, extirpative surgical series indicate that 20% to 30% of SRMs are benign entities2 and of the lesions that are RCC, 70% to 80% are low-grade, early-stage lesions believed to have little malignant potential.3,4,7,15 Supporting the indolent nature of these tumors, several meta-analyses have demonstrated a slow interval growth rate for most tumors under surveillance, on the order of 0.2 to 0.3 cm/year with 23% to 33% of tumors demonstrating a zero growth rate while under observation.5-7 In addition, reports of metastases while on Although multiple variables contribute to the perplexing trends in kidney cancer diagnosis and mortality, it is almost certain that a number of treated SRMs lack lethal potential, raising the question of possible overdiagnosis and overtreatment. trends in kidney cancer diagnosis and mortality, it is almost certain that a number of treated SRMs lack lethal potential, raising the question of possible overdiagnosis and overtreatment. Interestingly, autopsy series indicate that, whereas renal tumors are present in 2% to 3% of the population and SRMs in # 1%, approximately 30% and 12% of SRMs have locally advanced disease and metastases, respectively.13 A study comparing a historical autopsy series (1955-1960) to a contemporary series (1991-2001) found that, although the overall proportion of renal masses found at autopsy were similar, the number of masses found incidentally at autopsy is declining and the rate of occult kidney cancers per 100 autopsies had not changed— implying that better detection prior to death may not necessarily translate into the improved detection of clinically significant tumors.14 surveillance for SRMs are rare.7 Therefore, sufficient retrospective data suggest that most SRMs behave in an indolent fashion and can be safely observed. The remaining 20% to 30% of SRMs are malignant tumors with potentially aggressive features; 15% to 25% of SRM RCCs are highgrade lesions (Fuhrman grade 3-4). Locally advanced disease ($ pT3) has been documented in 10% to 40% of SRMs, and 3% to 12% present with or will develop metastatic disease.3,15,16 Although a small proportion of patients may pre­ sent with synchronous metastatic disease and an SRM, the existing literature implies that the risk of developing metastatic disease while undergoing AS for a SRM is even smaller—on the order of 1%.6,7 Consequently, synchronous and metachronous metastases may be different entities and patients who present without distant disease are more likely to have indolent tumors with little metastatic 14 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0545.indd 14 20/07/12 2:07 PM Active Surveillance for Small Renal Masses potential. Therefore, an efficacious AS program should recognize the heterogeneity of SRM biology and seek to distinguish indolent lesions from aggressive tumors based on clinical parameters so that ideally, no patients die of RCC but rather of competing causes. Efficacy and Oncologic Outcomes for Patients Undergoing AS Despite a lack of Level I evidence, a number of robust, retrospective series demonstrate favorable outcomes for contemporary patients undergoing AS. More than 70 peerreviewed articles appear within Medline on the topic of AS for SRM and a recent meta-analysis included 18 retrospective series comprising 880 patients.7 A number of retrospective AS cohorts demonstrated a 0% to 5.7% risk of progression to metastasis while on surveillance with prospective studies and meta-analyses showing an overall rate of metastasis on the order of 1%.5-10 Although a direct comparison of AS to intervention is lacking, historic recurrence rates and as a multi-institutional prospective clinical study to report the outcomes of patients undergoing AS and immediate intervention for newly diagnosed SRMs (Figure 1). The registry is powered based on noninferiority principles to demonstrate equivalent cancer-specific survival rates at 5 years for AS and immediate intervention. Through 34 months of enrollment, with a median follow-up of 1 year (range, 3-32 months), 3 of 89 patients undergoing AS died of causes not related to RCC and no patient developed metastases or died of disease. Three of 187 patients undergoing immediate intervention have died, 1 of RCC. The patient who died of RCC had a tumor with sarcomatoid features resected with negative margins that recurred distantly. Although lacking a comparison arm, a similar prospective cohort of 82 AS patients showed one patient (1.2%) progressing to metastatic disease, seven patients (8.6%) dying of competing causes, and no patients dying from RCC over a median follow-up of 36 months.8 Although immature, results from the DISSRM Registry and simi- Although a direct comparison of AS to intervention is lacking, ­historic recurrence rates and cancer-specific survival following treatment (regardless of the intervention) are in the range of 90% to 95% and 95% to 99% at 5 years, respectively—indicating both the indolent nature of T1 lesions and the difficulty in comparing AS and primary treatment options. cancer-specific survival following treatment (regardless of the intervention) are in the range of 90% to 95% and 95% to 99% at 5 years, respectively—indicating both the indolent nature of T1 lesions and the difficulty in comparing AS and primary treatment options.11 The Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) Registry is administered through Johns Hopkins University (Baltimore, MD) and was developed lar prospective studies promise to improve our understanding and utilization of AS in select patients. Selection Criteria Although a number of groups make general recommendations for the selection of patients for AS including increased age, decreased life expectancy, suitability for surgery, and decreased risk of metastatic disease,7,11,17 there is a paucity of data supporting or defining specific objective criteria for selection of patients for AS. Some of the important considerations include patient and tumor characteristics as they may impact life expectancy, malignant/metastatic risk, the likelihood of renal replacement therapy after treatment, and the feasibility of nephron-sparing surgery (NSS). Several studies indicate that AS is safe in the elderly18,19 and/or patients with extensive comorbidities precluding surgery.20 Prognostic models created from extirpative series indicate that age and sex modulate the likelihood of having a benign SRM, with younger women and older men having an increased ­likelihood of a benign pathology.21,22 It is also known from data extrapolated from patients with Von Hippel-Lindau disease, surgical series, and the aforementioned retrospective AS cohorts that the risks of RCC, high-grade RCC, and metastatic disease increase dramatically when tumors reach 3 cm.4,15,16,23 Tumor complexity, measured by various statistics including RENAL nephrometry score, may enable some prediction of tumor histology and grade,24 and can be used to determine the appropriateness of NSS; indeed, lowcomplexity tumors are generally more suitable for NSS.25 In addition, although the majority of patients present incidentally, the presence of symptoms (predominantly hematuria or flank pain) can indicate advanced disease.26 Finally, patients with chronic ­k idney disease (CKD) or contributing comorbidities (diabetes mellitus, hypertension, smoking) are at the highest risk of renal replacement therapy following intervention and may benefit from a period of AS. One of the objectives of the DISSRM Registry was to develop a scoring system based on existing literature5-8 and empiric evidence to Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 15 40041700002_RIU0545.indd 15 20/07/12 2:07 PM Active Surveillance for Small Renal Masses continued All patients with asymptomatic small renal cortical tumors (< 4 cm) Consultation with urologist Biopsy Surveillance Intervention Prestudy Patient offered enrollment into DISSRM Study Patient accepts enrollment Chest radiograph Laboratory studies (CMP, CBC, Pt/Ptt) Physical examination Baseline QoL Surveillance Observation Protocol CT scan (3D) every 4-6 months for 2 years QoL at 6 months, 1 year, 2 years Growth rate > 0.5 cm/year or symptomatic Intervention Partial nephrectomy Energy ablation Cyroablation or radio frequency Intervention Embolization Growth rate < 0.5 cm/year CT scan (3D) every 6-12 months for 3 years QoL annually Postintervention Follow-up Standard-of-care per treatment modality: Imaging, blood work at physician’s discretion QoL at 6 months, 1 year, and annually thereafter 5-year Study Endpoint 1. Cancer-specific survival 2. QoL 3. Percutaneous renal biopsy Recommended algorithm Indicates patient choice Figure 1. Management algorithm for patients with small renal masses (# 4 cm) according to the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM). Registry protocol. 3D, three-dimensional; CBC, complete blood count; CMP, comprehensive metabolic panel; CT, computed tomography; Pt/Ptt, ­prothrombin time/partial thromboplastin time; QoL, quality of life. assist in the identification of patients most suitable for AS. Major criteria are considered to be age . 65 years, Eastern Cooperative Oncology Group (ECOG) score . 1, Charlson Comorbidity Index Score . 2, greatest tumor diameter , 3 cm, and moderate to severe CKD. Minor criteria are prior abdominal surgery, incidental presentation, nephrometry score . 10, and minor CKD or a contributing comorbidity. By assigning 2 points to each major criterion and 1 point to each minor criterion, scoring was applied to the cohort to characterize the distribution of scores within this population. At 3 years of enrollment, 89 patients electing AS had at least 1 major criterion and 85% had 2 or more major criteria. Nearly 50% of patients undergoing AS had a DISSRM score $ 7 and only 1 patient had a score , 4, whereas 20% of patients undergoing intervention had a DISSRM score , 4 and 69% had a score , 7. Therefore, based on early reports of this registry, the DISSRM score is a promising means to risk stratify 16 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0545.indd 16 20/07/12 2:07 PM Active Surveillance for Small Renal Masses patients for AS versus intervention wherein patients with a score $ 7 can be considered favorable candidates for AS, those with a score # 3 may be favorable candidates for surgery, and those with an intermediate score (4-6) may benefit from either management strategy.10 As the registry continues to accrue patients and these criteria are further tested, they will be refined to better select patients for AS. Operational Considerations Following a thorough consultation, a patient and physician may choose AS as the best option for the management of an SRM. The AUA recommends that this consultation include a discussion of the small but real risk of cancer progression, loss of a window of opportunity for NSS, lack of curative treatments for metastatic RCC (mRCC), limitations of renal biopsy, and deficiencies in the current literature.11 However, no guidelines or recommendations exist for imaging modality, timing of surveillance images, and the use of renal biopsy or triggers for intervention. The main trigger for intervention is believed to be growth rate (GR). Oda and colleagues found a greater GR in the primary tumor of patients with mRCC when compared with localized tumors (1.7 cm vs 0.54 cm/year; P 5 .02).27 Kato and associates demonstrated a significantly higher GR in high-grade RCC compared with low-grade tumors (0.93 cm/year vs 0.28 cm/year; P 5 .01.28 Of patients reported to develop metastases while on AS, GR has been high, ranging from 1.3 to 2.9 cm/year.6,8 However, a number of studies have demonstrated zero or slow (, 0.5 cm/year) GR for tumors of malignant pathology.5,6 In addition, benign lesions, specifically oncocytoma, have been shown to demonstrate rapid growth.29 A number of biological factors may modulate GR and add confusion to the utility of GR in observing patients with SRMs. For instance, in the prospective study by Mason and colleagues, larger tumors (. 2.45 cm) demonstrate a faster GR than smaller tumors.8 However, several retrospective analyses have failed to find a relationship between primary tumor size and GR.6,20 Kouba and colleagues demonstrated that patients aged , 60 years had more rapidly growing tumors than those aged . 60 years.9 Finally, changes in tumor volume have been touted as more accurately reflecting growth kinetics and the biologic aggressiveness of an SRM; however, consistent with Gompertzian growth kinetics, smaller tumors are demonstrated to grow faster volumetrically.30 A recent pooled analysis of the AS literature demonstrated increased age, larger greatest initial tumor dimension and estimated volume, and higher linear and volumetric GR to predict metastatic progression.7 Although a number of important factors may indicate the malignant potential of an SRM, it is clear that progression to metastatic disease is exceptionally low in tumors that demonstrate slow or no GR and remain , 3 cm. Conversely, a lt houg h tumors may demonstrate variable GR, the majority that progress to metastasis exceed 3 cm and often become cT1b (. 4 cm) tumors prior to or at the diagnosis of metastasis. In the retrospective literature, on average, patients undergo five to six imaging evaluations over a period of 29 to 41 months yielding an approximate average rate of imaging every 6 months.7 The majority of retrospective studies use computed tomography (CT) and magnetic resonance imaging (MRI), with ultrasonography (US) used sparingly. The prospective study by Mason and colleagues recommended CT, MRI, or US imaging every 6 months.8 The DISSRM protocol recommends a high-quality axial image (CT or MRI with contrast) at enrollment to be followed by CT, MRI, or US every 4 to 6 months for 2 years and then every 6 to 12 months thereafter (Figure 1).10 It is our experience that, given conflicting reports regarding the risk of secondary malignancy,31 few patients are willing to undergo serial exposure to ionizing radiation in the form of CT scan. As GR is the main trigger for delayed intervention, we approve of serial US examination with confirmation of a change in growth with axial imaging if indicated. To better determine the aggressiveness of a new lesion, we recommend the first serial image be performed within 4 to 6 months with the caveat that GR may be exacerbated by even a small change in tumor diameter seen over a short period of time. It is known that tumor diameter measurements may vary by up to 3 mm between and among observers.32 Consequently, wide fluctuation is seen and little prognostic value is gained by small changes in tumor diameter seen on the first surveillance image. In addition, small fluctuations in tumor diameter may disproportionately impact estimates of tumor volume. Therefore, we recommend a second interval image to more accurately gauge GR and indicate the need for intervention depending on patient suitability for AS. Percutaneous renal biopsy (PRB) can determine SRM pathology and impact the decision for AS or intervention. Historical series ­demonstrate variable accuracy on the order of 70%, nondiagnostic rates around 30%, and rates of serious complications around 5%, preventing its widespread acceptance. Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 17 40041700002_RIU0545.indd 17 20/07/12 2:07 PM Active Surveillance for Small Renal Masses continued A recent meta-analysis by Volpe and colleagues reviewed 49 publications regarding the use of PRB in the diagnosis and management of renal tumors.33 They found a low rate of complications and improved rates of detection with sensitivity ranging from 70% to 100%, specificity at 100%, and a cumulative accuracy . 90% for needle core biopsies. A recent publication by a center performing a high-volume of PRB found biopsy tissue to aid in the diagnosis of nearly 90% of patients.34 However, PRB is unreliable for tumor grade35 and performs less well in tumors , 3 cm.36 Because most SRMs are low-grade indolent RCC and can safely undergo a period of AS, one could argue that there is little clinical utility in PRB for patients with a clear indication for AS or intervention. However, we find that PRB may provide additional information in patients without a clear indication for surgery or AS (DISSRM score 3-7) to aid in the decision and consultation process. In addition, we recognize that PRB provides tissue which, in addition to blood and urine, may provide biomarkers to improve the detection and surveillance of SRM. Conclusions 3. SRMs # 4 cm are commonly seen in clinical practice and represent a large proportion of newly diagnosed renal masses. Given recent epidemiologic trends and studies of the natural history of SRMs, most are believed to be indolent tumors with little potential for metastatic progression. AS has emerged as an alternative to extirpative or ablative treatments for these masses and should involve an informed decision by patient and physician based on patient and tumor characteristics and the calculated risk of ­metastatic progression. Ongoing prospective studies, including the DISSRM Registry, will provide additional information regarding the use and timing of serial imaging in patients undergoing AS. 12. The authors report no real or apparent conflicts of interest. 13. References 1. 2. Nguyen MM, Gill IS, Ellison LM. The evolving presentation of renal carcinoma in the United States: trends from the Surveillance, Epidemiology, and End Results program. J Urol. 2006;176(6 Pt 1):2397-2400; discussion 2400. Kutikov A, Fossett LK, Ramchandani P, et al. Incidence of benign pathologic findings at partial nephrectomy for solitary renal mass presumed to be renal cell carcinoma on preoperative imaging. Urology. 2006;68:737-740. 4. 5. 6. 7. 8. 9. 10. 11. 14. 15. 16. 17. Rothman J, Egleston B, Wong YN, et al. Histopathological characteristics of localized renal cell carcinoma correlate with tumor size: a SEER analysis. J Urol. 2009;181:29-33; discussion 33-34. Thompson RH, Hill JR, Babayev Y, et al. Metastatic renal cell carcinoma risk according to tumor size. J Urol. 2009;182:41-45. Kunkle DA, Egleston BL, Uzzo RG. Excise, ablate or observe: the small renal mass dilemma—a meta-analysis and review. J Urol. 2008;179:1227-1233; discussion 1233-1234. Chawla SN, Crispen PL, Hanlon AL, et al. The natural history of observed enhancing renal masses: metaanalysis and review of the world literature. J Urol. 2006;175:425-431. Smaldone MC, Kutikov A, Egleston BL, et al. Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis. Cancer. 2012;118:997-1006. Mason RJ, Abdolell M, Trottier G, et al. Growth kinetics of renal masses: analysis of a prospective cohort of patients undergoing active surveillance. Eur Urol. 2011;59:863-867. Kouba E, Smith A, McRackan D, et al. Watchful waiting for solid renal masses: insight into the natural history and results of delayed intervention. J Urol. 2007;177:466-470; discussion 470. Pierorazio PM, Hyams ES, Trock BJ, et al. A multiinstitutional prospective clinical trial of Delayed Intervention and Surveillance for Small Renal Masses: the DISSRM registry. 2012 (submitted for publication). Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. J Urol. 2009;182:1271-1279. American Cancer Society. Cancer Facts and Figures 2010. http://www.cancer.org/acs/groups/content/@ nho/documents/document/acspc-024113.pdf. Accessed March 9, 2012. Kozłowska J, Okoń K. Renal tumors in postmortem material. Pol J Pathol. 2008;59:21-25. Mindrup SR, Pierre JS, Dahmoush L, Konety BR. The prevalence of renal cell carcinoma diagnosed at autopsy. BJU Int. 2005;95:31-33. Thompson RH, Kurta JM, Kaag M, et al. Tumor size is associated with malignant potential in renal cell carcinoma cases. J Urol. 2009;181:2033-2036. Kates M, Korets R, Sadeghi N, et al. Predictors of locally advanced and metastatic disease in patients with small renal masses [published online ahead of print September 20, 2011]. BJU Int. Ljungberg B, Cowan NC, Hanbury DC, et al. EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol. 2010;58:398-406. MAIN POINTS • Small renal masses (SRMs; # 4 cm in dimension) are an increasingly common clinical scenario for practicing urologists and physicians with contemporary epidemiological studies indicating that SRMs account for nearly one-half of all renal masses diagnosed. • SRMs are biologically heterogeneous with 20% to 30% being benign lesions; 70% to 80% of malignancies are low-grade; early stage lesions are believed to behave in an indolent manner; and 20% to 30% are potentially aggressive tumors. • Active surveillance (AS) has emerged as a viable option for the management of SRMs with , 2% of patients progressing to metastatic disease in retrospective and prospective studies. • Ongoing prospective studies, including the Delayed Intervention and Surveillance for Small Renal Masses Registry, will provide additional information regarding the use and timing of serial imaging in patients undergoing AS. 18 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0545.indd 18 20/07/12 2:07 PM Active Surveillance for Small Renal Masses 18. 19. 20. 21. 22. 23. 24. Abouassaly R, Lane BR, Novick AC. Active surveillance of renal masses in elderly patients. J Urol. 2008;180:505-508; discussion 508-509. Beisland C, Hjelle KM, Reisaeter LA, Bostad L. Observation should be considered as an alternative in management of renal masses in older and comorbid patients. Eur Urol. 2009;55:1419-1427. Lamb GW, Bromwich EJ, Vasey P, Aitchison M. Management of renal masses in patients medically unsuitable for nephrectomy—natural history, complications, and outcome. Urology. 2004;64:909-913. Pierorazio PM, Murphy AM, Benson MC, McKiernan JM. Gender discrepancies in the diagnosis of renal cortical tumors. World J Urol. 2007;25:81-85. Lane BR, Babineau D, Kattan MW, et al. A preoperative prognostic nomogram for solid enhancing renal tumors 7 cm or less amenable to partial nephrectomy. J Urol. 2007;178:429-434. Duffey BG, Choyke PL, Glenn G, et al. The relationship between renal tumor size and metastases in patients with von Hippel-Lindau disease. J Urol. 2004;172:63-65. Kutikov A, Smaldone MC, Egleston BL, et al. Anatomic features of enhancing renal masses predict 25. 26. 27. 28. 29. 30. malignant and high-grade pathology: a preoperative nomogram using the RENAL Nephrometry score. Eur Urol. 2011;60:241-248. Simhan J, Smaldone MC, Tsai KJ, et al. Objective measures of renal mass anatomic complexity predict rates of major complications following partial nephrectomy. Eur Urol. 2011;60:724-730. Lee CT, Katz J, Fearn PA, Russo P. Mode of presentation of renal cell carcinoma provides prognostic information. Urol Oncol. 2002;7:135-140. Oda T, Miyao N, Takahashi A, et al. Growth rates of primary and metastatic lesions of renal cell carcinoma. Int J Urol. 2001;8:473-477. Kato M, Suzuki T, Suzuki Y, et al. Natural history of small renal cell carcinoma: evaluation of growth rate, histological grade, cell proliferation and apoptosis. J Urol. 2004;172:863-866. Kawaguchi S, Fernandes KA, Finelli A, et al. Most renal oncocytomas appear to grow: observations of tumor kinetics with active surveillance. J Urol. 2011;186:1218-1222. Crispen PL, Boorjian SA, Lohse CM, et al. Outcomes following partial nephrectomy by tumor size. J Urol. 2008;180:1912-1917. 31. 32. 33. 34. 35. 36. Smith-Bindman R, Lipson J, Marcus R, et al. Radiation dose associated with common computed tomography examinations and the associated lifetime attributable risk of cancer. Arch Intern Med. 2009; 169:2078-2086. Punnen S, Haider MA, Lockwood G, et al. Variability in size measurement of renal masses smaller than 4 cm on computerized tomography. J Urol. 2006;176 (6 Pt 1):2386-2390; discussion 2390. Volpe A, Kachura JR, Geddie WR, et al. Techniques, safety and accuracy of sampling of renal tumors by fine needle aspiration and core biopsy. J Urol. 2007;178:379-386. Leveridge MJ, Finelli A, Kachura JR, et al. Outcomes of small renal mass needle core biopsy, nondiagnostic percutaneous biopsy, and the role of repeat biopsy. Eur Urol. 2011;60:578-584. Blumenfeld AJ, Guru K, Fuchs GJ, Kim HL. Percutaneous biopsy of renal cell carcinoma underestimates nuclear grade. Urology. 2010;76:610-613. Rybicki FJ, Shu KM, Cibas ES, et al. Percutaneous biopsy of renal masses: sensitivity and negative predictive value stratified by clinical setting and size of masses. AJR Am J Roentgenol. 2003;180:1281-1287. Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 19 40041700002_RIU0545.indd 19 20/07/12 2:07 PM Treatment Review Radical Retropubic Prostatectomy: Comparison of the Open and Robotic Approaches for Treatment of Prostate Cancer Jeffrey J. Tosoian, MD,1 Stacy Loeb, MD2 1 The James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD; 2 Department of Urology, New York University School of Medicine, New York, NY Radical prostatectomy represents the standard of care for surgical treatment of clinically localized prostate cancer. First described in 1904, the operation became widely performed only after advances in diagnostic and surgical techniques occurred later in the century. Over time, open retropubic radical prostatectomy (RRP) became the most common operation for prostate cancer, and excellent long-term survival outcomes have been reported. More recently, minimally invasive techniques such as the robotic-assisted laparoscopic radical prostatectomy (RALRP) were introduced. Despite a lack of prospectively collected, long-term data supporting its use, RALRP has overtaken RRP as the most frequently performed prostate cancer operation in the United States. This article uses currently available data to compare oncologic, functional, and quality-of-life outcomes associated with both the open and robotic approaches to radical prostatectomy. [ Rev Urol. 2012;14(1/2):20-27 doi:10.3909/riu0552] ® © 2012 MedReviews , LLC Key words Radical retropubic prostatectomy • Prostate cancer • Perioperative outcomes • Robotic-assisted laparoscopic radical prostatectomy 20 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0552.indd 20 20/07/12 2:00 PM Radical Retropubic Prostatectomy: Comparison of the Open and Robotic Approaches F irst performed over a century ago, radical prostatectomy was historically associated with significant morbidity and ­mortality.1-3 The operation was performed for several years via a perineal approach, until the retropubic approach was introduced in 1948. In the 1980s, development of the nerve-sparing retropubic radical prostatectomy (RRP) 4 by Walsh and colleagues led to reductions in perioperative morbidity, incontinence, and erectile dysfunction.5-7 RRP ultimately became the gold standard for treatment of prostate cancer. A minimally invasive approach to prostatectomy was first described in the 1990s. Despite initial successes, laparoscopy proved too technically demanding to gain widespread acceptance.8-10 The difficulties associated with laparoscopic prostate surgery, however, were greatly reduced when robotic systems became available. The first robotic-assisted laparoscopic radical prostatectomy (RALRP) was performed in 2000, and the procedure has grown in popularity ever since.11,12 The rapid growth of RALRP has generated controversy in light of the paucity of long-term follow-up data.13 Although several large series have demonstrated long-term survival after RRP, similar data for RALRP are simply unavailable due to its recent introduction. Lepor14 and Finkelstein and colleagues15 have previously reviewed data comparing RRP and RALRP. Our objective herein is to present an updated review in light of its increased utilization and published data. Methods Using PubMed, we searched for original English language ­studies of RRP and RALRP published through January 2012, with an emphasis on recent data. To provide an inclusive listing of potential reports, the initial search term was prostatectomy. The resulting abstracts were evaluated and the most pertinent reports were included in our final assessment. reported a 30-day mortality rate of 0.11%.20 Furthermore, studies of RRP have demonstrated minimal risk of mortality in high-risk patients. For example, Pierorazio and associates observed no perioperative mortalities in 386 patients aged 70 years or older.21 Within the selected literature, we first examined short-term perioperative outcomes, including perioperative mortality, operative complications, blood loss, transfusion requirements, postoperative pain, and length of hospital stay. In addition, we examined costs and the rates of incontinence and erectile dysfunction associated with each approach. Within the selected literature, we first examined short-term perioperative outcomes, including perioperative mortality, operative complications, blood loss, transfusion requirements, postoperative pain, and length of hospital stay. In addition, we examined costs and the rates of incontinence and erectile dysfunction associated with each approach. Finally, because long-term, disease-specific mortality data are not available for patients treated with RALRP, we examined surgical margin status, biochemical recurrence, and rates of salvage therapy as an early assessment of oncologic outcomes. Perioperative Outcomes Perioperative Mortality Contemporary RRP is associated with minimal risk of perioperative death, both in the United States and abroad.16-18 In 2008, At the same time, existing data on RALRP reveal minimal risk of perioperative mortality.22-24 One very large cohort of 2500 RALRP patients reported no perioperative deaths.25 Perioperative mortality rates reported in smaller series are similarly low, with one institution reporting a single perioperative death in 239 patients (0.4%).26 Based on consistently low perioperative mortality rates throughout the literature, radical prostatectomy is generally considered to present minimal risk of death, regardless of the surgical approach. Operative Complications Assessment of complication rates is limited by substantial disparities in measurement and reporting practices, often leading to a wide range of reported findings. Two populationbased analyses provide some insight in this regard.27,28 In one study, Hu and colleagues27 assessed complica- Assessment of complication rates is limited by substantial disparities in measurement and reporting practices, often leading to a wide range of reported findings. Gilbert and ­colleagues examined a 15-year interval within the Nationwide Inpatient Survey and reported a 0.2% perioperative mortality.19 Similarly, a population-based study from Sweden tion rates in a national 5% sample of Medicare beneficiaries from 2003 to 2005. After adjustment for age, race, comorbidity, geographic region, and surgeon volume, the overall perioperative complication Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 21 40041700002_RIU0552.indd 21 20/07/12 2:00 PM Radical Retropubic Prostatectomy: Comparison of the Open and Robotic Approaches continued rate was lower in minimally invasive radical prostatectomy (MIRP) as compared with RRP (odds ratio [OR] 5 0.73; 95% confidence interval [CI], 0.60-0.90). However, the odds of anastomotic stricture was higher for MIRP (OR, 1.40; 95% CI, 1.04-1.87). This group subsequently evaluated Medicare-linked Surveillance, Epidemiology, and End Results (SEER) data from 2003 to 2007.28 In 8837 men, the unadjusted rate of overall complications was similar between MIRP (21.9%) and RRP (23.4%; P 5 .31). Propensity scores were then used to control for differences in age, race/ethnicity, income, education, region, population density, marital status, pathologic grade, and stage. After adjustment, the overall complication rates remained similar between the groups (P 5 .58). In contrast to their previous findings, this analysis revealed decreased odds of anastomotic stricture in those who underwent MIRP (OR, 0.38; P , .001). Notably, the definition of MIRP employed in these studies included traditional laparoscopy, although the vast majority of cases were in fact RALRP. A more recent assessment by Trinh and colleagues compared outcomes after RRP and RALRP using the Nationwide Inpatient Sample.29 In multivariate logistic regression analysis of populations matched by propensity score, patients who underwent RALRP were less likely to experience an intraoperative (OR 0.47; 95% CI, 0.31-0.71) or postoperative complication (OR 0.86; 95% CI, 0.77-0.96). Blood Loss and Transfusions A number of studies have demonstrated lower blood loss in RALRP. One comprehensive review reported blood loss ranging from 142 to 230 mL versus 790 to 820 mL in robotic and open series, respectively.15 Similarly, a comparative study by Rocco and colleagues noted significant differences in median blood loss, favoring RALRP (200 vs 800; P , .001).30 Despite observing a difference in total blood loss, Farnham and associates31 found no significant difference in the need for transfusion after RALRP (0.5%) and RRP (2.9%; P 5 .14); notably, very few patients required transfusion in either group. More recently, a 2010 study of 1244 patients found significantly lower blood loss and less decrease in hematocrit associated with RALRP.32 Furthermore, transfusion was required in a significantly lower proportion of patients undergoing RALRP (0.8% vs 3.4%; P 5 .002). These findings were consistent with the 2009 study from Hu and colleagues, in which MIRP had a strong protective relationship against transfusion (OR 0.11; 95% CI, 0.06-0.17).28 The recent findings of Trinh and associates also revealed that patients undergoing RALRP were significantly less likely to receive a blood transfusion (OR 0.34; 95% CI, 0.28-0.40).29 median stay of 3 days for RALRP and 6 days for RRP.30 On the other hand, a study from Vanderbilt University (Nashville, TN)34 reported equivalence between the approaches, with a mean LOS of 1.17 days after RALRP and 1.25 days after RRP (P 5 .27). This practice is in conjunction with current practice at Johns Hopkins University (Baltimore, MD), wherein patients are managed on the same clinical care pathway irrespective of surgical approach. The variation in LOS at different institutions may reflect differences in surgical volume, era, or patient characteristics. Pain It is often assumed that minimally invasive surgery is associated with less pain than conventional open procedures. Indeed, studies from robotic centers have consistently reported favorable pain scores.35 Webster and colleagues compared postoperative pain in a radical prostatectomy population by measuring narcotic use and by self-assessment using a Likert scale.36 Narcotic use was low in both the RALRP and RRP groups, and there was no sig- Narcotic use was low in both the RALRP and RRP groups, and there was no significant difference between them. Although pain perception scores were low across the study population, scores were significantly lower in the RALRP cohort (2.05 vs 2.60, P 5 .027) on the day of surgery. Length of Stay Several studies have demonstrated shorter length of stay (LOS) after RALRP as compared with RRP. For example, Bolenz and colleagues observed mean LOS of 1.56 days for RALRP and 2.51 days for RRP, although formal statistical comparisons were not reported.33 The SEER-linked Medicare data revealed median hospital stay of 2 days after MIRP versus 3 days after RRP (OR 0.67; 95% CI, 0.58-0.72),28 and Rocco and associates reported nificant difference between them. Although pain perception scores were low across the study population, scores were significantly lower in the RALRP cohort (2.05 vs 2.60; P 5 .027) on the day of surgery. However, equivalent pain scores were reported on postoperative days 1 (1.76 vs 1.73; P 5 .88) and 14 (2.51 vs 2.42; P 5 .72). Cost In 2010, Bolenz and colleagues33 directly compared the cost of 22 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0552.indd 22 20/07/12 2:00 PM Radical Retropubic Prostatectomy: Comparison of the Open and Robotic Approaches robotic, laparoscopic (LRP), and open prostatectomy in 643 consecutive patients (262 RALRP, 220 LRP, 161 RRP). Importantly, there were no significant differences in disease characteristics across the groups. Although mean LOS was shorter, the median cost of RALRP was significantly higher than LRP or RRP ($6752 vs $5687 vs $4437; P , .001). Considering the cost of purchase and maintenance of the robot, the use of RALRP increased costs by $2698 per patient (using a benchmark of 126 cases per year). Another study similarly estimated a cost advantage of $1726 for RRP as compared with RALRP.37 Because a significant proportion of this cost relates to purchase and start-up of the robotic system, the financial burden of a single robotic operation decreases as operative volume increases. As such, one recent analysis demonstrated that costs equivalent to RRP may be achieved at high-volume centers performing 10 or more robotic procedures per week.38 Follow-Up Outcomes Potency Although the nerve-sparing procedure has led to improvements in potency, there remains significant variation in potency rates among surgeons and institutions.39,40 Case mix is an important contributing factor because potency after radical prostatectomy has been strongly associated with patient characteristics, even after adjustment for baseline potency.27 Thus, data on potency must be interpreted carefully in the context of patient-specific factors. The 2009 study from Hu and colleagues reported 1.4 times greater odds of erectile dysfunction after RALRP (OR 1.40; 95% CI, 1.14-1.72) after adjustment for patient factors and stage of disease.28 However, the literature has described a poor correlation between claims data and patientreported assessments of functional outcomes,41 suggesting that these findings should be interpreted with caution. More recently, Barry and associates addressed this limitation by comparing sexual function in Medicare patients using a patient survey.42 Completed surveys were obtained from 685 (86%) of 797 eligible subjects at a median of 14 months after surgery. In logistic regression models adjusted for age and education, robotic prostatectomy was associated with similar odds of a moderate or big problem with sexual function (OR 0.87; 95% CI, 0.51-1.49). In another study, Malcolm and colleagues43 compared postoperative sexual function using the validated University of California, Los Angeles Prostate Cancer Index (UCLA-PCI). Over 3 years of follow-up, sexual function was slightly better in patients who underwent RRP, although formal statistical comparisons were not reported. In a direct comparison of subjects matched by patient and disease criteria, Krambeck and colleagues44 reported a trend toward higher potency after RALRP, although it was not statistically significant (70% vs 62.8%; P 5 .081). Similarly, Di Perro and associates45 reported greater recovery of erectile function after RALRP (55% vs 26%; P 5 .009), but this study began with only 150 patients and was limited by 41% attrition in the RALRP group. Overall, there is little evidence that potency outcomes are significantly impacted by surgical approach. Continence Several large series from the 1990s demonstrated restoration of continence in over 95% of patients after RRP,46-48 and recent data from robotic series have revealed similarly high rates of continence. A few studies have reported significant differences in continence by approach, although there were notable limitations. For example, in the SEER-Medicare cohort, minimally invasive procedures were associated with a higher rate of incontinence than RRP (15.9 vs 12.2 per 100 person-years; P 5 .02).28 Again, the drawbacks of using claims data for functional outcomes should be considered.41 It is also notable that the overall incontinence rates are higher in this population compared with others. Meanwhile, Di Pierro and colleagues found higher continence rates at 3 months after RALRP (P 5 .003), although this difference was no longer significant after 1 year of follow-up (P 5 .092).45 Direct comparisons have failed to demonstrate significant differences in continence based on surgical approach. Notably, the overall rates of continence in comparative studies have varied greatly, likely due to differences in patient population and manner of data ascertainment. Based on postoperative surveys, Barry and colleagues found that 31.1% of Medicare patients reported a moderate or big problem with continence after prostatectomy. In multivariate models, men who responded that they underwent a robotic prostatectomy were more likely to report problems with continence.42 Krambeck and associates reported continence rates in excess of 90%, and this cohort demonstrated no significant difference based on surgical approach (RALRP 91.8% vs RRP 93.7%; P 5 .344).44 Similarly, using the UCLA-PCI, Malcolm and colleagues reported nearly equivalent urinary function scores between the two groups.43 Oncologic Control Regardless of surgical approach, the primary goal of radical Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 23 40041700002_RIU0552.indd 23 20/07/12 2:00 PM Radical Retropubic Prostatectomy: Comparison of the Open and Robotic Approaches continued prostatectomy is oncologic cure. Because prostate-specific antigen (PSA)-detected prostate cancers have a long natural history from presentation to death,49 long-term data are needed to assess cancerspecific mortality.50 Studies of RALRP, however, have limited follow-up, such that surrogate endpoints have been used to estimate cancer control. Here, we review oncologic outcomes based on three such endpoints (surgical margin status, biochemical recurrence, and need for salvage therapy), with the caveat that these measures are imperfect proxies for long-term survival outcomes. Surgical Margin Status Positive surgical margins (PSMs) are associated with increased risk of local and biochemical recurrence.51-53 However, some studies have found that margin status is not independently associated with cancer-specific or overall mortality,52 highlighting the limitations of evaluating this endpoint. Nonetheless, margin status is often used to provide a preliminary assessment of cancer control after prostatectomy.54 In 2007, Smith and colleagues55 reported significantly lower PSM rates after RALRP as compared with RRP (15% vs 35%; P , .001). However, RALRP patients had more favorable pathological stage and Gleason score. In stratified analyses, significantly lower positive margin rates persisted for RALRP in patients with stage pT2 disease (9.4% vs 24.1%; P 5 .001) and a Gleason score  6 (9.0% vs 30%; P , .001), but differences were not significant in other strata. In 2009, Krambeck and associates frequency-matched 294 RALRP and 588 RRP men based on year of surgery, age, baseline PSA, clinical stage, and biopsy Gleason score.44 Their analysis revealed no significant difference in positive margin rates based on surgical approach (RALRP, 15.6%; RRP, 17.0%; P 5 .608). A more recent study limited its comparison to high-volume surgeons56 in order to minimize confounding by surgeon experience. The RALRP and RRP groups had similar preoperative characteristics and disease burden in this study. Positive surgical margins were identified in 18% of RALRP and 16% of RRP cases (OR 1.30; 95% CI, 0.83-2.04; P 5 .25). A 2011 study by Magheli and colleagues examined 522 men who underwent RALRP and an equal number of men who underwent RRP and LRP,57 using propensity scores to adjust for age, race, PSA, biopsy Gleason score, and clinical stage. Overall, they observed higher PSM rates after RALRP (19.5%) than RRP (14.4%) and LRP (13.0%; P 5 .01). When stratified by pathological stage of disease, this pattern persisted in T3 disease (RALRP 48.5%, RRP 32.1%, LRP 43.8%; P 5 .013) but was not statistically significant in the T2 group (RALRP 9.3%, RRP 6.6%, LRP 6.7%; P 5 .264). Single-surgeon comparative studies may also provide value in comparing techniques that are affected by experience. A recent report from Masterson and colleagues examined margin status in 357 RRP and 669 RALRP performed by an experienced surgeon.58 When stratified by stage of disease, the incidence of positive surgical margins did not differ based on surgical approach in men with organ-confined disease. Another recent study investigated 950 patients treated by a single surgeon between 2005 and 2008.59 After adjustment for year of surgery, body mass index, use of nerve sparing, and age, RALRP patients were significantly more likely to have a positive surgical margin when compared with those who underwent open RRP (adjusted OR, 1.9; P 5 .0095). There was also a significant interaction between surgical approach and nerve-sparing status. With nerve sparing, the RALRP cohort had a higher rate of PSM than the RRP cohort (13.5% vs 7.6%; P 5 .007), despite a trend toward lower rates in the absence of nerve-sparing (P 5 .09). These findings suggested that cancer control and preservation of potency may be more difficult to attain simultaneously using the robotic approach. Biochemical Recurrence Preliminary observations of biochemical recurrence after RALRP demonstrated adequate short-term cancer control. However, data describing biochemical recurrencefree survival (BRFS) have been limited by follow-up. As such, few studies have attempted to compare this outcome directly. One comparative study reported 3-year recurrence-free survival rates of 83.5% after RRP and 84.0% after RALRP (P 5 .19).24 Accordingly, survival analysis showed no significant differences in BRFS when subjects were stratified by tumor stage, margin status, and pathological Gleason score. On multivariate analysis, BRFS was not significantly associated with surgical approach (RALRP vs RRP, hazard ratio [HR] 1.01; 95% CI, 0.72-1.41). Nevertheless, the median time to recurrence was 24 months but the median followup was only 10 months, which was likely insufficient to identify all patients who would eventually recur. Furthermore, follow-up after RRP was significantly longer than after RALRP (median 17 vs 8 months; P , .01). Krambeck and colleagues also observed no significant difference in 3-year recurrence-free survival between RALRP (92.4%) and RRP (92.2%; P 5 .69), although this study was similarly limited by a 24 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0552.indd 24 20/07/12 2:00 PM Radical Retropubic Prostatectomy: Comparison of the Open and Robotic Approaches small number of patients with sufficient follow-up (median follow-up, 1.3 years).44 In addition, the singlesurgeon report from Masterson and colleagues demonstrated nearly identical rates of BRFS after 24 months (RRP 87% vs RALRP 87%) and 60 months (RRP 71% vs RALRP 73%) of follow-up (P 5 .97; log-rank test).58 Other comparisons have suggested similar recurrence-free survival rates between treatment groups,45,57 but these studies also have significant limitations. Additional followup should allow for a more definitive assessment of oncologic outcomes. Need for Salvage Therapy In 2008, Hu and colleagues reported re-treatment rates of 9.1% after RRP and 27.8% within 6 months after MIRP.27 The adjusted OR for early secondary therapy was 3.67 for MIRP vs RRP (95% CI, 2.814.81). These findings suggested that MIRP may fail to achieve oncologic cure more frequently. In a subsequent study, these authors found that rates of additional cancer therapies did not differ by surgical approach (MIRP 8.2 vs RRP 6.9 per 100 person-years; P 5 .35).28 Similarly, Lowrance and associates60 found no difference in rate of salvage therapy based on surgical approach (LRP 9.2%, RRP 11.6%). It is worth noting that these studies were limited to older men, and additional therapy was assessed during only 1 year of follow-up. Discussion Any attempt to truly compare the open and robotic approaches methodology must be valid and consistent. Ideally, operations would be performed at a single institution with uniform surgical technique, grading of complications, and pathological assessment. Validated questionnaires should be used to assess functional outcomes such as potency and continence. Furthermore, consistent clinical criteria should be used for decision making, such as the need for transfusion and the appropriate time for discharge. One European group has designed a protocol to standardize the collection of such data,61 but it may take several years until outcomes at these centers can be assessed. Given the heterogeneity of patient populations, surgeon experience, clinical care pathways, and outcome reporting, comparisons of open and robotic prostatectomy have been difficult to perform and interpret. As has been pointed out, the majority of RALRP data have emerged from a small number of institutions and is not of high quality.62 Although some smaller studies reveal significant differences based on surgical approach, reports from high-volume centers less frequently observed differences, with the exception of lower blood loss in RALRP. Similarly, at Johns Hopkins University all prostatectomy patients are treated according to the same clinical care pathway, with a similar postoperative course in uncomplicated cases. This observation raises the possibility that the robotic approach offers perioperative benefits to low-volume centers, but that such advantages diminish when ­surgeon Any attempt to truly compare the open and robotic approaches must consider a large number of factors. On a most basic level, study methodology must be valid and consistent. Ideally, operations would be performed at a single institution with uniform surgical technique, grading of complications, and pathological assessment. must consider a large number of ­factors. On a most basic level, study experience and institutional volume are higher. Functional and quality-of-life outcomes generally appeared to be more heavily influenced by patient-specific factors than surgical approach. In the case of continence, both procedures frequently reported excellent results. The analysis of Hu and associates provides the strongest support in favor of RRP, as well as the largest volume of data.28 However, it is difficult to draw definitive conclusions based on the nature of these data. On the other hand, comparative studies favoring RALRP30,45 also have significant limitations. One significant concern is that patients undergoing robotic procedures may have greater, potentially unrealistic expectations of postoperative function.63 In counseling these patients it is important to address any such perceptions that are not supported by the available data. The superior approach for achieving oncological cure is ultimately unclear. From a conservative standpoint, the traditional open procedure should remain the standard of care, given there are long-term data supporting its effectiveness. Although recent observations from experienced robotic centers are encouraging,64 longer follow-up, including diverse practice settings, is needed. Conclusions Most data suggest that, in the hands of an experienced surgeon, cure can be feasibly achieved with either an open or robotic approach to radical prostatectomy. Perhaps surgical approach is not a critical determinant of subsequent patient outcomes. On the other hand, in the current context of healthcare reform, existing data do not demonstrate an unambiguous improvement associated with RALRP to help justify its considerable increase in cost. Ultimately, the accrual of longer follow-up in contemporary Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 25 40041700002_RIU0552.indd 25 20/07/12 2:00 PM Radical Retropubic Prostatectomy: Comparison of the Open and Robotic Approaches continued RALRP series, combined with additional comparative studies, will shed further light on this debate. 13. 14. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Young HH. Early diagnosis and radical cure of carcinoma of the prostate. Bull Johns Hopkins Hosp. 1905;315-321. Young HH. Hugh Young: A Surgeon’s Autobiography. New York: Harcourt, Brace, and Company; 1940. Sriprasad S, Feneley MR, Thompson PM. History of prostate cancer treatment. Surg Oncol. 2009;18:185-191. Reiner WG, Walsh PC. An anatomical approach to the surgical management of the dorsal vein and Santorini’s plexus during radical retropubic surgery. J Urol. 1979;121:198-200. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol. 1982;128:492-497. Walsh PC, Schlegel PN. Radical pelvic surgery with preservation of sexual function. Ann Surg. 1988;208:391-400. Lepor H, Walsh PC. Long-term results of radical prostatectomy in clinically localized prostate cancer: experience at the Johns Hopkins Hospital. NCI Monogr. 1988;(7):117-122. Guillonneau B, Vallancien G. Laparoscopic radical prostatectomy: initial experience and preliminary assessment after 65 operations. Prostate. 1999;39:71-75. Schuessler WW, Schulam PG, Clayman RV, Kavoussi LR. Laparoscopic radical prostatectomy: initial shortterm experience. Urology. 1997; 50:854-857. Secin FP, Savage C, Abbou C, et al. The learning curve for laparoscopic radical prostatectomy: an international multicenter study. J Urol. 2010;184:2291-2296. Abbou CC, Hoznek A, Salomon L, et al. Laparoscopic radical prostatectomy with a remote controlled robot. J Urol. 2001;165:1964-1966. Menon M, Shrivastava A, Tewari A, et al. Laparoscopic and robot assisted radical prostatectomy: 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. e­ stablishment of a structured program and preliminary analysis of outcomes. J Urol. 2002;168:945-949. Cooperberg MR, Odisho AY, Carroll PR. Outcomes for radical prostatectomy: is it the singer, the song, or both? J Clin Oncol. 2012;30:476-478. Lepor H. Status of radical prostatectomy in 2009: is there medical evidence to justify the robotic approach? Rev Urol. 2009;11:61-70. Finkelstein J, Eckersberger E, Sadri H, et al. Open versus laparoscopic versus robot-assisted laparoscopic prostatectomy: the European and US experience. Rev Urol. 2010;12:35-43. Lepor H, Kaci L. Contemporary evaluation of operative parameters and complications related to open radical retropubic prostatectomy. Urology. 2003;62:702-706. Optenberg SA, Wojcik BE, Thompson IM. Morbidity and mortality following radical prostatectomy: a national analysis of Civilian Health and Medical Program of the Uniformed Services beneficiaries. J Urol. 1995;153:1870-1872. Mohamad BA, Marszalek M, Brossner C, et al. Radical prostatectomy in Austria: a nationwide analysis of 16,524 cases. Eur Urol. 2007;51:684-688; ­discussion 689. Gilbert SM, Dunn RL, Miller DC, et al. Mortality after urologic cancer surgery: impact of non-index case volume. Urology. 2008;71:906-910. Carlsson S, Adolfsson J, Bratt O, et al. Nationwide population-based study on 30-day mortality after radical prostatectomy in Sweden. Scand J Urol Nephrol. 2009;43:350-356. Pierorazio PM, Humphreys E, Walsh PC, et al. Radical prostatectomy in older men: survival outcomes in septuagenarians and octogenarians. BJU Int. 2010;106:791-795. Bhandari A, McIntire L, Kaul SA, et al. Perioperative complications of robotic radical prostatectomy after the learning curve. J Urol. 2005;174:915-918. Patel VR, Palmer KJ, Coughlin G, Samavedi S. Robotassisted laparoscopic radical prostatectomy: perioperative outcomes of 1500 cases. J Endourol. 2008;22:2299-2305. Barocas DA, Salem S, Kordan Y, et al. Robotic assisted laparoscopic prostatectomy versus radical retropubic prostatectomy for clinically localized prostate cancer: 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. comparison of short-term biochemical recurrencefree survival. J Urol. 2010;183:990-996. Coelho RF, Palmer KJ, Rocco B, et al. Early complication rates in a single-surgeon series of 2500 robotic-assisted radical prostatectomies: report applying a standardized grading system. Eur Urol. 2010; 57:945-952. Lasser MS, Renzulli J 2nd, Turini GA 3rd, et al. An unbiased prospective report of perioperative complications of robot-assisted laparoscopic radical prostatectomy. Urology. 2010;75:1083-1089. Hu JC, Wang Q, Pashos CL, et al. Utilization and outcomes of minimally invasive radical prostatectomy. J Clin Oncol. 2008;26:2278-2284. Hu JC, Gu X, Lipsitz SR, et al. Comparative effectiveness of minimally invasive vs open radical prostatectomy. JAMA. 2009;302:1557-1564. Trinh QD, Sammon J, Sun M, et al. Perioperative outcomes of robot-assisted radical prostatectomy compared with open radical prostatectomy: results from the nationwide inpatient sample. Eur Urol. 2012;61:679-685. Rocco B, Matei DV, Melegari S, et al. Robotic vs open prostatectomy in a laparoscopically naive centre: a matched-pair analysis. BJU Int. 2009;104:991-995. Farnham SB, Webster TM, Herrell SD, Smith JA Jr. Intraoperative blood loss and transfusion requirements for robotic-assisted radical prostatectomy versus radical retropubic prostatectomy. Urology. 2006;67:360-363. Kordan Y, Barocas DA, Altamar HO, et al. Comparison of transfusion requirements between open and robotic-assisted laparoscopic radical prostatectomy. BJU Int. 2010;106:1036-1040. Bolenz C, Gupta A, Hotze T, et al. Cost comparison of robotic, laparoscopic, and open radical prostatectomy for prostate cancer. Eur Urol. 2010;57:453-458. Nelson B, Kaufman M, Broughton G, et al. Comparison of length of hospital stay between radical retropubic prostatectomy and robotic assisted laparoscopic prostatectomy. J Urol. 2007;177:929-931. Tewari A, Srivasatava A, Menon M, for the Members of the VIP team. A prospective comparison of radical retropubic and robot-assisted prostatectomy: experience in one institution. BJU Int. 2003;92:205-210. Main Points • The rapid growth of robotic-assisted laparoscopic radical prostatectomy (RALRP) has generated controversy in light of the minimal availability of long-term follow-up data. Although several large series have demonstrated excellent long-term survival after retropubic radical prostatectomy (RRP), similar data for RALRP are simply unavailable due to its recent introduction. • Studies of RRP and RALRP have demonstrated minimal risk of perioperative mortality. Based on consistently low perioperative mortality rates throughout the literature, radical prostatectomy is generally considered to present minimal risk of death, regardless of the surgical approach. • The majority of RALRP data has emerged from a small number of institutions and is not of high quality. Although some smaller studies reveal significant differences based on surgical approach, reports from highvolume centers less frequently observed differences, with the exception of lower blood loss in RALRP. • Functional and quality-of-life outcomes generally appeared to be more heavily influenced by patient-specific factors than surgical approach. In the case of continence, both procedures frequently reported excellent results. • The best approach for achieving oncological cure remains unclear. From a conservative standpoint, the traditional open procedure should remain the standard of care, given there are long-term data supporting its effectiveness. Although recent observations from experienced robotic centers are encouraging, longer follow-up, including diverse practice settings, is needed. 26 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0552.indd 26 20/07/12 2:00 PM Radical Retropubic Prostatectomy: Comparison of the Open and Robotic Approaches 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. Webster TM, Herrell SD, Chang SS, et al. Robotic assisted laparoscopic radical prostatectomy versus retropubic radical prostatectomy: a prospective assessment of postoperative pain. J Urol. 2005;174:912-914; discussion 914. Lotan Y, Cadeddu JA, Gettman MT. The new economics of radical prostatectomy: cost comparison of open, laparoscopic and robot assisted techniques. J Urol. 2004;172:1431-1435. Patel HR, Linares A, Joseph JV. Robotic and laparoscopic surgery: cost and training. Surg Oncol. 2009;18:242-246. Penson DF. The effect of erectile dysfunction on quality of life following treatment for localized prostate cancer. Rev Urol. 2001;3:113-119. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 2008;358: 1250-1261. Tollefson MK, Gettman MT, Karnes RJ, Frank I. Administrative data sets are inaccurate for assessing functional outcomes after radical prostatectomy. J Urol. 2011;185:1686-1690. Barry MJ, Gallagher PM, Skinner JS, Fowler FJ Jr. Adverse effects of robotic-assisted laparoscopic versus open retropubic radical prostatectomy among a nationwide random sample of Medicare-age men. J Clin Oncol. 2012;30:513-518. Malcolm JB, Fabrizio MD, Barone BB, et al. Quality of life after open or robotic prostatectomy, cryoablation or brachytherapy for localized prostate cancer. J Urol. 2010;183:1822-1828. Krambeck AE, DiMarco DS, Rangel LJ, et al. Radical prostatectomy for prostatic adenocarcinoma: a matched comparison of open retropubic and robotassisted techniques. BJU Int. 2009;103:448-453. Di Pierro GB, Baumeister P, Stucki P, et al. A prospective trial comparing consecutive series of open retropubic and robot-assisted laparoscopic radical 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. prostatectomy in a centre with a limited caseload. Eur Urol. 2011;59:1-6. Catalona WJ, Carvalhal GF, Mager DE, Smith DS. Potency, continence and complication rates in 1,870 consecutive radical retropubic prostatectomies. J Urol. 1999;162:433-438. Lepor H, Nieder AM, Ferrandino MN. Intraoperative and postoperative complications of radical retropubic prostatectomy in a consecutive series of 1,000 cases. J Urol. 2001;166:1729-1733. Steiner MS, Morton RA, Walsh PC. Impact of anatomical radical prostatectomy on urinary continence. J Urol. 1991;145:512-514; discussion 514-515. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591-1597. Stattin P, Holmberg E, Johansson JE, et al. Outcomes in localized prostate cancer: National Prostate Cancer Register of Sweden follow-up study. J Natl Cancer Inst. 2010;102:950-958. Epstein JI. Pathologic assessment of the surgical specimen. Urol Clin North Am. 2001;28:567-594. Boorjian SA, Karnes RJ, Crispen PL, et al. The impact of positive surgical margins on mortality following radical prostatectomy during the prostate specific antigen era. J Urol. 2010;183:1003-1009. Meeks JJ, Eastham JA. Radical prostatectomy: positive surgical margins matter. Urol Oncol. 2012 Jan 11 [Epub ahead of print]. Karakiewicz PI, Eastham JA, Graefen M, et al. Prognostic impact of positive surgical margins in surgically treated prostate cancer: multi-institutional assessment of 5831 patients. Urology. 2005;66:1245-1250. Smith JA Jr, Chan RC, Chang SS, et al. A comparison of the incidence and location of positive surgical margins in robotic assisted laparoscopic radical prostatectomy and open retropubic radical ­prostatectomy. J Urol. 2007;178:2385-2389; discussion 2389-2390. 56. 57. 58. 59. 60. 61. 62. 63. 64. Weizer AZ, Strope S, Wood DP Jr. Margin control in ­robotic and laparoscopic prostatectomy: what are the REAL outcomes? Urol Oncol. 2010;28:210-214. Magheli A, Gonzalgo ML, Su LM, et al. Impact of surgical technique (open vs laparoscopic vs roboticassisted) on pathological and biochemical outcomes following radical prostatectomy: an analysis using propensity score matching. BJU Int. 2011;107: 1956-1962. Masterson TA, Cheng L, Boris RS, Koch MO. Open vs. robotic-assisted radical prostatectomy: a single surgeon and pathologist comparison of pathologic and oncologic outcomes. Urol Oncol. 2012 Jan 3 [Epub ahead of print]. Williams SB, Chen MH, D’Amico AV, et al. Radical retropubic prostatectomy and robotic-assisted laparoscopic prostatectomy: likelihood of positive surgical margin(s). Urology. 2010;76:1097-1101. Lowrance WT, Elkin EB, Jacks LM, et al. Comparative effectiveness of prostate cancer surgical treatments: a population based analysis of postoperative outcomes. J Urol. 2010;183:1366-1372. Thorsteinsdottir T, Stranne J, Carlsson S, et al. LAPPRO: a prospective multicentre comparative study of robot-assisted laparoscopic and retropubic radical prostatectomy for prostate cancer. Scand J Urol Nephrol. 2011;45:102-112. Kang DC, Hardee MJ, Fesperman SF, et al. Low quality of evidence for robot-assisted laparoscopic prostatectomy: results of a systematic review of the published literature. Eur Urol. 2010;57:930-937. Schroeck FR, Krupski TL, Stewart SB, et al. Pretreatment expectations of patients undergoing robotic assisted laparoscopic or open retropubic radical prostatectomy. J Urol. 2012;187:894-898. Menon M, Bhandari M, Gupta N, et al. Biochemical recurrence following robot-assisted radical prostatectomy: analysis of 1384 patients with a median 5-year follow-up. Eur Urol. 2010;58:838-846. Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 27 40041700002_RIU0552.indd 27 20/07/12 2:00 PM Meeting Review Innovation in Endourology and Minimally Invasive Surgery Highlights From the 29th World Congress of Endourology and SWL 2011, November 30-December 3, 2011, Kyoto, Japan [ Rev Urol. 2012;14(1/2):28-30 doi: 10.3909/riu0554] ® © 2012 MedReviews , LLC KEY WORDS Endourology • Percutaneous nephrolithotomy • Small renal mass • Active surveillance T he 29th World Congress of Endourology and SWL was held in Kyoto, Japan, from November 30 to December 3, 2011. Innovation was the theme of the meeting across a wide array of topics in endourology and minimally invasive surgery. This review highlights just some of the exciting presentations. Stone Disease As the rates of shock wave lithotripsy continue to decline, a major focus of the meeting centered on ways to improve the performance of ureteroscopy and percutaneous nephrolithotomy (PCNL). During ureteroscopic laser lithotripsy, one problem is ensuring good clearance of residual stone ­fragments. Reviewed by Stacy Loeb, MD, Department of Urology, New York University, New York, NY; and James F. Borin, MD, Division of Urology, University of Maryland, Baltimore, MD. A novel technique for this was presented using magnetic-coated amino acids that interact with the stone, allowing for magnetic-assisted fragment retrieval.1 For PCNL, the importance of flexible endoscopy during the initial procedure was emphasized to avoid the need for repeat procedures. With regard to technical improvements, one of the significant hurdles to PCNL for many urologists may be obtaining their own percutaneous access. To this end, several novel solutions were presented ranging from ureteroscopic placement of magnets into the collecting system to guide the incoming percutaneous needle, or alternatively, the ureteroscopic placement of a puncture wire in a retrograde fashion.2,3 Although these options would conceptually allow for more precise access into the targeted calyx, they remain technically challenging in some cases and additional refinement of these techniques is necessary. 28 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0554.indd 28 26/07/12 11:50 AM Innovation in Endourology and Minimally Invasive Surgery The Clinical Research Office of the Endourological Society (CROES) prospectively collected data on 5803 patients who underwent PCNL as part of the PCNL Global Study. Five papers were presented in addition to a plenary session summarizing the results. Overall, 10% of patients experienced postoperative fever, irrespective of whether stones were treated with pneumatic, ultrasonic, or laser lithotripsy.4 The risk of postoperative fever ­significantly increased for patients with a positive preoperative urine culture, diabetes, staghorn calculus, or preoperatively placed nephrostomy tube.5 For the entire cohort, the stone-free rate was 83%, and postoperative computed tomography (CT) scan was more accurate than radiography or ultrasound in evaluating residual fragments.6 Small Renal Masses As with prostate cancer, there is increasing concern about overdiagnosis and overtreatment of small renal masses (SRMs). Although specific imaging features have been associated with more favorable prognosis (ie, slow growth rate, smaller size, exophytic, presence of an angular interface on magnetic resonance imaging [MRI]), there remain significant limitations in our ability to assess tumor aggressiveness noninvasively and determine the need for intervention. A panel of experts on the treatment of SRMs was convened to present the most recent data and recommendations. The new American Urological Association guidelines for the management of SRMs were reviewed, providing several options based on tumor size and comorbidities.7 On one end of the spectrum is active surveillance (AS). Data presented from several contemporary series suggest that for tumors , 3 cm, metastasis occurs in approximately 1% to 2% of patients over a 3- to 5-year interval.8 Given approximately 99% cancer-specific survival during this period, AS represents a viable option, particularly for patients with significant comorbidities. Alternative management options include percutaneous or laparoscopic cryotherapy and radiofrequency ablation, although there are limited data on their long-term survival outcomes. Of these techniques, cryotherapy may be preferred due to the presence of skip lesions in some series of radiofrequency ablation. Overall, local recurrence-free survival rates with these ablative techniques appear inferior to those obtained with extirpative surgery, although rates of metastasis are comparable. There is evidence that partial nephrectomy continues to be underutilized as compared with radical nephrectomy for SRMs.9 This is unfortunate given the adverse sequelae of renal insufficiency and the importance of nephron sparing. On the other hand, the use of robot-assisted partial nephrectomy (RAPN) has dramatically increased. A study of RAPN across 25 institutions encompassing 33 surgeons of varying experience levels demonstrated acceptable perioperative results. For 1269 patients with a mean tumor size of 3.1 cm, mean operative time was 203 minutes, warm ischemia time was 25.2 minutes, estimated blood loss was 184 mL, positive margin rate was 4%, and the overall complication rate was 15.7%.10 Finally, there was discussion about an increasing role for renal mass biopsy in guiding therapy, and the importance of using a coaxial technique for core biopsy instead of fine needle aspiration. In modern series, . 80% of core biopsies are diagnostic for the presence or absence of renal cell carcinoma, although it is not always possible to discern the specific grade or histology. Also, due to the risk of hemorrhage, postbiopsy imaging was recommended. Imaging Traditionally, the follow-up of renal masses has relied heavily on CT. However, there is increasing concern about the adverse consequences of radiation exposure. Although MRI is an alternative, both techniques may be problematic for patients with renal insufficiency (eg, after partial nephrectomy). To avoid these issues, there has been investigation into the use of contrast-enhanced ultrasound.11 The contrast agents used for this technique are not nephrotoxic, and the identification of concerning features (eg, septae, enhancing nodules) could then trigger additional evaluation. Additional prospective studies on this technique are necessary to better assess its performance characteristics compared with the more traditional modalities. Technology Assessment Because this meeting emphasized novel techniques in urologic surgery, there was significant discussion about technology assessment. The Innovation, Development, Exploration, Assessment, and LongTerm Evaluation (IDEAL) guidelines were presented as a stepwise approach to evaluate a new technology, whereby evidence from case series is ultimately replaced with prospective technique development studies and later registries.12 Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 29 40041700002_RIU0554.indd 29 26/07/12 11:50 AM Innovation in Endourology and Minimally Invasive Surgery continued Surgical Education As surgical technique continues to evolve, teaching the vast array of skills presents new challenges for residency and fellowship training. To this end, a novel online teaching tool was presented that includes a video library of surgical procedures (www.onlinemasterclass.com). In a format similar to the Choose Your Own Adventure books, participants must choose the next step in management of complex surgical situations. The results of these choices are then shown with video, facilitating a more interactive learning process for surgical decision making. At the completion of the exercise, participants are provided with a report card providing useful feedback on areas for improvement. World Congress of Endourology 2012 The 30th annual World Congress of Endourology will be held in Istanbul, Turkey, from September 4-8, 2012. The theme of the congress will be bridging science and technology. References 1. 2. 3. 4. 5. Tan YK, Olweny EO, Faddegon S, et al. In vitro comparison of prototype magnetic tool to conventional ­nitinol basket for ureteroscopic retrieval of magnetized stone particles. J Endourol. 2011;25:A2. Kobayashi T, Iwamoto H, Goto T, et al. Clinical investigation of PNL by retrograde renal calyx puncture. J Endourol. 2011;25:A291. Borin J, Zhu J. Endoscope-guided retrograde renal puncture for percutaneous nephrolithotomy in the supine position. J Endourol. 2011;25:A340. Wang AJ, Chu DI, Lipkin ME, et al. Lithotrites and post-operative fever: results from the clinical research office of the endourological society percutaneous nephrolithotomy global study. J Endourol. 2011;25:A115. Gutierrez J, Smith A, Geavlete P, et al. The CROES percutaneous nephrolithotomy global study: urinary tract 6. 7. infections and post-operative fever in percutaneous nephrolithotomy. J Endourol. 2011;25:A141. Wang AJ, Chu DI, Lipkin ME, et al. Imaging modalities and stone-free rates: results from the clinical research office of the endourological society percutaneous nephrolithotomy global study. J Endourol. 2011;25:A115. Novick AC, Campbell SC, Belldegrun A, et al. Guideline for Management of the Clinical Stage I Renal Mass. Linthicum, MD: American Urological Association Education and Research, Inc. ; 2009. http://www.auanet.org/content/media/renalmass09 .pdf. Accessed January 28, 2012. Smaldone MC, Kutikov A, Egleston BL, et al. Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis. Cancer. 2012;118:997-1006. Hollenbeck BK, Taub DA, Miller DC, et al. National utilization trends of partial nephrectomy for renal cell carcinoma: a case of underutilization? Urology. 2006;67:254-259. Munver R, Jain S, Yates J. Multi-institutional experience with robot-assisted partial nephrectomy in 12001 cases: results of the robot-assisted partial nephrectomy integrated database (RAPID) study group. J Endourol. 2011;25:A102. Ignee A, Straub B, Brix D, et al. The value of contrast enhanced ultrasound (CEUS) in the characterisation of patients with renal masses. Clin Hemorheol Microcirc. 2010;46:275-290. McCulloch P, Altman DG, Campbell WB, et al. No surgical innovation without evaluation: the IDEAL recommendations. Lancet. 2009;374;1105-1112. ® 8. 9. 10. 11. 12. 30 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0554.indd 30 20/07/12 1:58 PM Case Review Adult Wilms’ Tumor With a Unique Presentation of High-Grade Fever, Photophobia, and Headache Jay Krishnan, DO, MBA, Jerome Pietras, DO, FACOS, Marcella Nachmann, DO, FACOS, Gordon Brown, DO, FACOS Department of Urology, University of Medicine and Dentitstry of New Jersey, Stratford, NJ Wilms’ tumor is the second most common tumor in children, accounting for 6% to 7% of all childhood tumors. However, in adults, it is a rare occurrence. The true incidence of adult Wilms’ tumor is difficult to ascertain because of its rarity in the adult population. A review of literature demonstrates that fewer than 300 cases have been reported worldwide. Treatment guidelines in adults have not been established, although reported prognosis is worse for adults compared with children because the disease is more advanced in adults at the time of diagnosis. Reported here is a case of adult Wilms’ tumor presenting as high-grade fever and abnormal laboratory values. [ Rev Urol. 2012;14(1/2):31-34 doi: 10.3909/riu0541] ® © 2012 MedReviews , LLC Key words Wilms’ tumor • Renal mass • Open radical nephrectomy • Multimodal therapy T he patient, a 26-year-old woman, presented to the emergency department complaining of 105.8°F fever, generalized body aches, photophobia, headache, and neck stiffness. She also had epigastric discomfort along with one episode of emesis. She denied any lower urinary tract symptoms or history of renal calculi. Her past medical and surgical histories were unremarkable. She had no family history of urologic disorders or malignancies. She denied dysuria but did notice a decrease in her urine output over the previous 2 days. Physical examination was unremarkable and she had no flank tenderness. Laboratory examination was also unremarkable with the exception of her creatinine Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 31 40041700002_RIU0541.indd 31 20/07/12 3:27 PM Adult Wilms’ Tumor With a Unique Presentation continued Figure 1. Ultrasound images of questionable renal mass. Figure 2. Computed tomography images of solid mass in the left kidney. Figure 3. Nephrectomy specimen. level, which was 2.09 mg/dL. Urinalysis demonstrated moderate blood and an erythrocyte count of 3 to 5 3 109/L. She was admitted to the general medical floor with the diagnosis of meningitis. Renal ultrasound demonstrated a questionable renal mass (Figure 1), and computed tomography (CT) demonstrated at 12-cm solid mass in the left kidney (Figure 2). Chest imaging and bone scanning results were both ­negative. She immediately underwent an open radical nephrectomy (Figure 3). On gross inspection, the tumor measured 9 3 7 cm and was a graytan firm nodule subjacent to the renal capsule. Sectioning of tumor showed several small areas of focal hemorrhage, possible necrosis, and a multinodular appearance. Renal parenchyma away from the tumor area showed pale gray focal discoloration. Microscopic analysis revealed that the tumor was a nephroblastoma without anaplasia. The blastema area stained positive for vimentin and pan-cytokeratin (PAN-CK). The epithelial components were strongly positive for PAN-CK and focally positive for vimentin. Wilms’ tumor gene protein staining was positive throughout. Pathologic staging was pT2 with primarily undifferentiated blastema and epithelial tubular structures (Figure 4). All lymph nodes were negative for tumor. 32 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0541.indd 32 20/07/12 3:27 PM Adult Wilms’ Tumor With a Unique Presentation Figure 4. Pathology images of nephroblastoma. (A) Presence of epithelial, stromal, and blastemal elements. (B) Evidence of i­mmature spindle cells. (C) Glomerulotubular structures. (D) Immature tubular structures. Postoperatively, the patient was treated for 22 weeks with vincristine and actinomycin D, which she tolerated with minimal side effects. Her 1-year follow-up imaging demonstrated no disease. Discussion Wilms’ tumor is the second most common tumor in children, accounting for 6% to 7% of all childhood tumors; however, in adults, it is a rare occurrence. The true incidence of adult Wilms’ tumor is difficult to ascertain because of its rarity in the adult population. A review of literature demonstrated that fewer than 300 cases have been reported worldwide. Treatment guidelines in adults have not been established although the reported prognosis is worse for adults compared with children because the disease is more advanced in adults at the time of diagnosis. In 1980, Kilton and colleagues developed the following criteria for the diagnosis of adult Wilms’ tumor: presence of a primary renal renal cortex,3 which explains this neoplasm’s common appearance as an exophytic mass. Microscopically, both adult and childhood Wilms’ tumors have epithelial, stromal, and blastemal elements.3 Typically, adult Wilms’ tumor usually presents in young patients as a large, rapidly growing abdominal mass, but the presentation may vary. The oldest patient reported in the literature with a confirmed diagnosis of adult Wilms’ tumor was age 84 years.4 More common in women, approximately 20% of patients are diagnosed between the ages of 15 and 20 years, and 80% are diagnosed between the third and seventh decades.5 Abdominal CT imaging typically shows a large, well-defined, exophytic, inhomogeneous mass that Microscopically, both adult and childhood Wilms’ tumors have epithelial, stromal, and blastemal elements. Typically, adult Wilms’ tumor usually presents in young patients as a large, rapidly growing abdominal mass, but the presentation may vary. neoplasm, presence of a primitive blastematous spindle or round-cell component, formation of abortive or embryonal tubular or glomeruloid structures, absence of tumor diagnostic of renal cell carcinoma (RCC), and age . 15 years.1 The diagnostic criteria for Wilms’ tumor include the presence of abortive or embryonic glomerulotubular structures within an immature spindle-cell stroma. These structures are not found in RCC. The absence of fetal renal tissue points against the diagnosis of is cortical in origin. There may be large areas of low density present along with areas of focal necrosis and hemorrhage on noncontrast images. After intravenous contrast administration, there may be variable enhancement, and the remaining normal parenchyma will appear as a pseudocapsule around the tumors (75%).6 Ultrasonographic imaging typically demonstrates a large, complex mass with large cystic components compared with RCC, which is usually a heterogeneous solid mass.7 Abdominal CT imaging typically shows a large, well-defined, ­exophytic, inhomogeneous mass that is cortical in origin. There may be large areas of low density present along with areas of focal necrosis and hemorrhage on noncontrast images. Wilms’ tumor.2 The most common location of nephrogenic blastema is the subcapsular portion of the Although there are no defined treatment protocols for adults, many authors suggest using Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 33 40041700002_RIU0541.indd 33 20/07/12 3:27 PM Adult Wilms’ Tumor With a Unique Presentation continued childhood protocols for the treatment of adult Wilms’ tumors; the pathologic staging used is also the same for pediatric patients.8 In 1982, the National Wilms’ Tumor Study (NWTS) group reported 31 adult Wilms’ tumor patients who were treated with multimodal therapy between 1968 and 1979. The 3-year survival rate was 24% compared with 74% in childhood patients. The authors concluded that adult Wilms’ tumor has a worse prognosis compared with Wilms tumor occurring in children and should be treated aggressively with three-drug chemotherapy and radiotherapy to the tumor bed (4500 cGY), regardless of the stage of disease.9 The 1990 NWTS report described 27 adults treated between 1979 and 1987 and found the 3-year survival rate with multimodal therapy 67% when anaplastic tumors were included, and 79% when they were excluded.10 In 2003, Reinhard and colleagues reviewed 30 adult patients who were treated with surgery and chemotherapy, as well as 14 out of 30 patients receiving irradiation. They reported a 4-year median overall survival rate of 83%.11 3. 4. 5. 6. 7. Conclusions Unfortunately, due to the rarity of adult Wilms’ tumor, sample sizes are limited and firm conclusions cannot be made regarding specific treatment protocols. After diagnosis, a multimodal therapeutic approach must be explored with the cooperation of the urologist and the oncologist.12-15 8. 9. 10. 11. 12. 13. References 1. 2. Kilton L, Matthews MJ, Cohen MH. Adult Wilms tumor: report of prolonged survival and review of literature. J Urol. 1980;124:1-5. Vorstman B, Rothwell D. Wilms tumor in adult ­patient. Urology. 1982;20:628-630. 14. 15. Bailey LE, Durkee CT, Werner AL, Finley RK Jr. Wilms’ tumors in adults. Am Surg. 1987;53:149-155. Bennington JL, Beckwith JB. Tumors of the kidney, renal pelvis and ureter. Washington, DC: Armed Forces Institute of Pathology; 1975:31-81. Winter P, Vahlensieck W, Miersch W, et al. Wilms’ tumour in adults. Review of 10 cases. Int Urol Nephrol. 1996;28:469-475. Fishman EK, Hartman DS, Goldman SM, Siegelman SS. The CT appearance of Wilms tumor. J Comput Assist Tomogr. 1983;7:659-665. Kumar R, Amparo EG, David A, et al. Adult Wilms’ tumor: clinical and radiographic features. Urol Radiol. 1984;6:164-169. Firoozi F, Kogan BA. Follow-up and management of recurrent Wilms’ tumor. Urol Clin North Am. 2003;30:869-879. Byrd RL, Evans AE, D’Angio GJ. Adult Wilms tumor: effect of combined therapy on survival. J Urol. 1982;127:648-651. Arrigo S, Beckwith JB, Sharples K, et al. Better survival after combined modality care for adults with Wilms’ tumor. A report from the National Wilms’ Tumor Study. Cancer. 1990;66:827-830. Reinhard H, Aliani S, Leuschner I, et al. Wilms’ tumor in adults. Results of the SIOP 93-01 study [abstract]. Med Pediatr Oncol. 2003;38:266. Bozeman G, Bissada NK, Abboud MR, Laver J. Adult Wilms’ tumor: prognostic and management considerations. Urology. 1995;45:1055-1058. Green DM. Pediatric oncology update: Wilms’ tumor. Eur J Cancer. 1997;33:409-418; discussion 419-420. Neville HL, Ritchey ML. Wilms’ tumor: overview of National Wilms’ Tumor Study Group results. Urol Clin North Am. 2000;27:435-442. Terenziani M, Spreafico F, Collini P, et al. Adult Wilms’ tumor: a monoinstitutional experience and a review of the literature. Cancer. 2004;101:289-293. Main Points • Wilms’ tumor is the second most common tumor in children; however, in adults it is a rare occurrence. Fewer than 300 adult cases have been reported worldwide. Treatment guidelines in adults have not been established although the prognosis is worse for adults compared with children because the disease is more advanced in adults at the time of diagnosis. • Criteria for diagnosis of adult Wilms’ tumor include presence of a primary renal neoplasm, presence of a primitive blastematous spindle or round-cell component, formation of abortive or embryonal tubular or glomeruloid structures, absence of tumor diagnostic of renal cell carcinoma, and age . 15 years. • Although there are no defined treatment protocols for adults, many authors suggest using childhood protocols for the treatment of adult Wilms’ tumors; the pathologic staging used is also the same for pediatric patients. • Due to the rarity of adult Wilms’ tumor, sample sizes are limited and firm conclusions cannot be made regarding specific treatment protocols. After diagnosis, a multimodal therapeutic approach must be explored with the cooperation of the urologist and the oncologist. 34 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU0541.indd 34 20/07/12 3:27 PM Literature Reviews News and Views From the Literature Pelvic Organ ­Prolapse Pelvic Surgeons Caught in the Meshes of the Law Toyohiko Watanabe, MD, PhD,1 Michael B. Chancellor, MD2 Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama, Japan; 2Department of Urology, William Beaumont Hospital, Royal Oak, MI [Rev Urol. 2012;14(1/2):35-36 doi: 10.3909/riu0543] 1 © 2012 MedReviews®, LLC I n 2008, the US Food and Drug Administration (FDA) issued a Public Health Notification and Additional Patient Information on serious complications associated with surgical mesh placed through the vagina (transvaginal placement) to treat pelvic organ prolapse (POP) and stress urinary ­incontinence (SUI). The FDA issued an update on July 13, 2011, noting that serious complications associated with surgical mesh for transvaginal repair of POP are not rare and that it is not clear that transvaginal POP repair with mesh is more effective than traditional non-mesh repair—and it may expose patients to greater risk.1 In 2008, the number of adverse events (AEs) reported to the FDA for surgical mesh devices used to repair POP and SUI for the 3-year period from 2005 to 2007 was over 1000. About 300,000 women in the United States had POP surgeries in 2010, including more than 70,000 who received vaginal meshes. From January 2008 through December 2010, the FDA received 2874 additional reports of complications associated with surgical mesh devices used to repair POP and SUI, with 1503 reports associated with POP repairs and 1371 associated with SUI repairs. Although it is common for AE reporting to increase following an FDA safety communication, the FDA stated that there is concern about the number of AEs reported. The most frequent complications reported to the FDA include mesh erosion through the vagina, pain, infection, bleeding, dyspareunia, organ perforation, and urinary problems. The FDA stated that their literature review found that erosion of mesh through the vagina is the most commonly reported mesh-related complication. Mesh contraction (shrinkage) is a previously unidentified risk of transvaginal POP repair with mesh that has been reported in the published scientific literature and in AE reports submitted to the FDA since 2008. Mesh contraction may be associated with vaginal shortening, vaginal tightening, and vaginal pain. The complications associated with the use of surgical mesh for POP repair have not been linked to a single brand of mesh. The FDA convened an Obstetrics-Gynecology Devices Panel of the Medical Device Advisory Committee on September 8 and 9, 2011. An update on the safety, effectiveness, and risk/benefit of vaginal placement of Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 35 40041700002_LiteratureReview.indd 35 20/07/12 2:11 PM Pelvic Organ Prolapse continued surgical mesh for POP repair was discussed. The Panel consensus2 was that: • The safety of vaginal mesh intended for POP repair is not well established • Depending on the compartment, vaginal placement of mesh for POP repair may not be more effective than traditional native-tissue repair without mesh • The risk/benefit of vaginal placement of mesh for POP repair is not well established Feedback From Outside Urology Urogynecology A well-written commentary by urogynecologists in 2010, prior to the most recent FDA communication, noted that the use of transvaginal mesh in repair of POP and SUI continues to be an excellent option for many patients.3 The article warned that physicians need to be kept up to date on the lack of long-term data surrounding the use of transvaginal mesh in repair of SUI and POP. Mucowski and colleagues3 noted that, in light of the recent US Supreme Court decision in Riegel v Medtronic Inc.,4 and in conjunction with the manufacturer’s use of the learned intermediary doctrine to shift liability to physicians, it is now harder for injured patients to sue manufacturers of medical devices. Patients injured from the use of a medical device may be more likely to sue their physicians and claim lack of proper informed consent. The authors noted that the current legal environment should not deter physicians from offering mesh repair for POP and SUI to those patients who may best benefit. Physicians should properly obtain and document informed consent prior to offering and performing transvaginal mesh repairs.3 Media In 2011, Voreacos and Nussbaum reported that the media has focused on the lawsuits and case studies involved with the pelvic floor mesh.5 The FDA notification brought it to the attention of lawyers who were not aware of this issue previously. None of the cases have gone to trial and women must prove their claims that mesh makers knew that the products were defective and of the safety risks but failed to disclose them. Makers of mesh, including Johnson & Johnson (J&J; New Brunswick, NJ), Boston Scientific (Natick, MA), Bard (Murray Hill, NJ), and American Medical Systems (Minnetonka, MN), told the FDA advisory panel in September 2011 that using mesh in transvaginal procedures is safe and effective and serious injuries are rare. J&J stated that it may be too early to comment on the potential impact of mesh lawsuits, but that the company is willing to conduct studies of the devices to ensure doctors and patients have “informed access to treatment options.”5 Lawyers Lawyers specializing in mesh cases are offering free case reviews since the FDA’s warning. One Web site, ­pelvicmeshlawyers.com, claims that between 2008 and 2010, the number of pelvic mesh complaints tripled over the preceding 3 years, half of which were the result of failed POP repair.6 This Web site offers comprehensive information about vaginal mesh including when it was known that transvaginal implantation of mesh was harmful and where to find details about the FDA transvaginal mesh warning as well as patients’ rights.6 It also notes that these lawyers will work to recover lost wages, pay for medical bills, and compensate for the pain associated with vaginal mesh problems. References 1. 2. 3. 4. 5. 6. US Food and Drug Administration. Urogynecologic surgical mesh: update on the safety and effectiveness of transvaginal placement for pelvic organ prolapse. July 2011. www.fda.gov/downloads/MedicalDevices/Safety/AlertsandNotices/UCM262760.pdf. Accessed February 28, 2012. Obstetrics & Gynecology Devices Panel. Surgical mesh repair of pelvic organ prolapse (POP), September 8-9, 2011. www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/ ObstetricsandGynecologyDevices/UCM271769.pdf. Accessed February 28, 2012. Mucowski SJ, Jurnalov C, Phelps JY. Use of vaginal mesh in the face of recent FDA warnings and litigation. Am J Obstet Gynecol. 2010;203:103.e1-e4. Riegel v Medtronic Inc., 552 US, 312 (2008). Voreacos D, Nussbaum A. The next medical device controversy: vaginal mesh. Business Week. September 15, 2011. www.businessweek.com/magazine/the-next-medical-devicecontroversy-vaginal-mesh-09152011.html. Accessed February 28, 2012. Onder, Shelton, O’Leary & Peterson, LLC/Pelvic Mesh Lawyers. Surgical Mesh Lawyers offer free case review after FDA issues warning regarding serious complications from transvaginal placement of surgical mesh in repair of pelvic organ prolapse. www.pelvicmeshlawyers.com/. Accessed February 28, 2012. Pediatric Urology Urodynamics in Children Ellen Shapiro, MD, FACS, FAAP New York University School of Medicine, New York, NY [Rev Urol. 2012;14(1/2):36-38 doi: 10.3909/riu0549] © 2012 MedReviews®, LLC D rzewiecki and Bauer from Boston Children’s Hospital provide a review of urodynamics (UDS) in children.1 First, a history, physical examination, and a 3-day voiding and bowel diary are obtained. A renal sonogram noting bladder volume, residual volume, and bladder wall thickness is then performed.2 36 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_LiteratureReview.indd 36 20/07/12 2:11 PM Pediatric Urology Most children with nonneurogenic bladder dysfunction are potty trained but subsequently present with lower urinary tract symptoms. Most children with urgency, frequency, and incontinence can be managed with behavioral therapy and anticholinergic medications. UDS is useful when there is no improvement. Kaufman and colleagues have shown a high yield (63%) of pathologic findings following UDS in the refractory pediatric patient with incontinence.3 Uroflowmetry can be useful in children with dysfunctional voiding who contract their external sphincters or pelvic floor muscles during micturition. Baseline and periodic UDS are performed in neurogenic bladder dysfunction (NBD) including myelomeningocele (MM, 90%) occult spinal dysraphism, sacral agenesis, imperforate anus, cloacal malformation, traumatic spinal cord injury, and central nervous system disorders. Infants with MM have three voiding patterns: synergic (26%), dyssynergic with or without diminished bladder compliance (37%), and complete denervation (36%).4 Detrusor sphincter dyssynergia (DSD) with associated high-end filling pressures ($ 40 cm of water) and highvoiding pressures of $ 80 to 100 cm of water leads to reflux and hydronephrosis unless UDS is performed along with early intervention with clean intermittent catheterization (CIC). UDS for NBD is repeated following a change in pharmacotherapy or surgery, new onset incontinence or hydroureteronephrosis, or recurrent symptomatic infections. Because deterioration in bladder function may occur silently, changes in the orthopedic or neurological examination warrant reassessment with UDS. Only one-third of infants with occult spinal dysraphism will have abnormal UDS irrespective of the neurological findings on examination. With increasing age, symptoms become more evident and include bowel and bladder dysfunction and alterations in lower extremity function. Recently, detrusor overactivity has been shown in all age groups with occult tethered cord syndrome.5-7 The earlier the surgical intervention, the greater the likelihood for functional improvement. Children with sacral agenesis involving partial or complete absence of vertebral bodies can remain silent until late childhood when incontinence, difficulty potty training, or urinary tract infection are evaluated. A flattened buttock with absence of the upper gluteal cleft may not be evident on early physical examination. UDS will often demonstrate detrusor acontractility and urethral sphincter denervation or overactive bladder (OAB) with DSD.8 Anorectal malformations may have genitourinary and spinal abnormalities, including tethered cord or iatrogenic injury, but may also have NBD without obvious etiology. These children may exhibit OAB with or without DSD (upper motor neuron lesion) or detrusor acontractility with sphincter denervation (lower motor neuron lesion).9 Posterior urethral valves (80%) often have bladder dysfunction with detrusor overactivity and diminished bladder compliance.10,11 Myogenic failure may be due to infrequent bladder emptying in conjunction with increased urinary output and is more often seen in the older age group. Uroflowmetry is noninvasive and can be used in patients who void spontaneously. The flow pattern is accurate as long as the volume is . 50% of maximum voided volume.12 The shape of the flow curve denotes the detrusor function, outlet resistance, or external sphincter dysfunction during micturition.13 Voiding patterns include a bell-shaped (normal), tower (OAB), plateau (outlet obstruction), staccato (sphincter activity during voiding), and interrupted curve (acontractile or underactive bladder).2 Perineal patch electromyography (EMG) can be used as an adjunct in determining the etiology of an abnormal flow pattern or postvoid residual urine.14 Postvoid residuals (PVRs) using bladder scanning should show residuals of # 20 cc or abnormal emptying is suspected in children. PVR is useful in patients on anticholinergic therapy. Invasive UDS is performed in the sitting or supine positions. Rectal and urethral catheters provide intraabdominal and intravesical pressures, respectively. The difference in these pressures is the detrusor pressure. A PVR is obtained in a non-CIC patient and patch EMG electrodes are positioned perineally in boys or paraurethrally in girls.15 EMG provides information on individual motor units at rest in response to sacral reflexes and during bladder filling and emptying with suspected or previously diagnosed NBD.9 During bladder filling, saline infusion at a temperature of 21° to 37°C is performed at a rate of 5% to 10% of the expected bladder capacity/minute.16,17 Bladder capacity for children is determined from the Hjälmås equation: expected bladder capacity (mL) 5 30 1 (age in years 3 30).16 For children with MM, the formula 24.5 3 age (years) 1 62 should be used.18 Children on CIC use the largest catheterized volume during the day over several days. At least two cycles of filling are required unless the child has no sensation and an NBD. The bladder has been sufficiently filled when the child has a strong urge to urinate, is uncomfortable, voiding starts, bladder pressures are . 40 cm of water, or the volume infused is . 150% of the expected capacity. The fluoroscopic video portion of the test permits correlation of detrusor ­pressures with urinary incontinence or reflux and also provides information on the bladder shape and the state of the sphincter during filling and emptying. Intrinsic or bladder neck dysfunction can also be assessed. Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 37 40041700002_LiteratureReview.indd 37 20/07/12 2:11 PM Pediatric Urology continued Detrusor overactivity occurring during bladder filling is defined as an involuntary detrusor contraction . 15 cm of water from baseline.13 Bladder underactivity is also abnormal and recognized in patients who are filled to . 150% of their expected bladder capacity and have a poor or absent detrusor contraction. During filling, normal detrusor compliance is 10 cm of water at capacity, or 5% of the child’s normal capacity per cm of water, or about 20 cm of water at expected bladder capacity.12,13 Infants tend to have higher voiding pressures than children, and boys tend to have higher voiding pressures (by 5 to 15 cm of water) than girls.2,19 Urethral obstruction is suggested when there are high voiding pressures accompanied by poor flow rates. EMG pads may show a staccato voiding pattern. A low flow rate may be indicative of an anatomical obstruction and bladder emptying should be assessed. This review of pediatric urodynamics is comprehensive and provides an excellent source of classic references. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Drzewiecki BA, Bauer SB. Urodynamic testing in children: indications, technique, interpretation and significance. J Urol. 2011;186:1190-1197. Yeung CK, Sihoe JDY, Bauer SB. Voiding dysfunction in children: nonneurogenic and neurogenic. In: Wein AJ, Kavoussi LR, Novick AC et al, eds. Campbell-Walsh Urology, 9th ed. Philadelphia; Saunders Elsevier; 2007:3604-3655. Kaufman MR, DeMarco RT, Pope JC 4th, et al. High yield of urodynamics performed for refractory nonneurogenic dysfunctional voiding in the pediatric population. J Urol. 2006;176:1835-1837. Bauer SB, Hallett N, Khoshbin S, et al. Predictive value of urodynamic evaluation in newborns with myelodysplasia. JAMA. 1984;252:650-652. Nogueira M, Greenfield SP, Wan J, et al. Tethered cord in children: a clinical classification with urodynamic correlation. J Urol. 2004;172(4 Pt 2):1677-1680; discussion 1680. Guerra LA, Pike J, Milks J, et al. Outcome in patients who underwent tethered cord release for occult spinal dysraphism. J Urol. 2006;176(4 Pt 2):1729-1732. Palmer LS, Richards I, Kaplan WE. Subclinical changes in bladder function in children presenting with nonurological symptoms of the tethered cord syndrome. J Urol. 1998;159:231-234. Guzman L, Bauer SB, Hallett M, et al. Evaluation and management of children with sacral agenesis. Urology. 1983;22:506-510. Bauer SB. Neurogenic bladder: etiology and assessment. Pediatr Nephrol. 2008;23:541-551. Bauer SB, Labib KB, Dieppa RA, Retik AB. Urodynamic evaluation of boy with myelodysplasia and incontinence. Urology. 1977;10:354-362. Peters CA, Bolkier M, Bauer SB, et al. The urodynamic consequences of posterior urethral valves. J Urol. 1990;144:122-126. Nijman RJM, Bower W, Butler U, et al. Diagnosis and management of urinary incontinence and encopresis in childhood. In: Abrams P, Cardozo L, Khoury S, et al, eds. 3rd International Consultation on Incontinence. Paris: Health Publications Ltd; 2005:967-1057. Nevéus T, von Gontard A, Hoebeke P, et al. The standardization of terminology of lower urinary tract function in children and adolescents: report from the Standardisation Committee of the International Children’s Continence Society. J Urol. 2006;176:314-324. Hoebeke P, Bower W, Combs A, et al. Diagnostic evaluation of children with daytime incontinence. J Urol. 2010;183:699-703. Lorenzo AJ, Wallis MC, Cook A, et al. What is the variability in urodynamic parameters with position change in children? Analysis of a prospectively enrolled cohort. J Urol. 2007;178:2567-2570. Hjälmås K. Urodynamics in normal infants and children. Scand J Urol Nephrol Suppl. 1988;114:20-27. Bael A, Lax H, de Jong TP, et al. The relevance of urodynamic studies for Urge syndrome and dysfunctional voiding: a multicenter controlled trial in children. J Urol. 2008;180:1486-1493; discussion 1494-1495. Palmer LS, Richards I, Kaplan WE. Age related bladder capacity and bladder capacity growth in children with myelomeningocele. J Urol. 1997;158(2 Pt 2):1261-1264. Ulla Sillén U, Abrahamsson K. Urodynamics in infants and children. In: Corcos J, Schick E (eds.), Textbook of Neurogenic Bladder, 2nd ed. London: Informa; 2008:483-497. Congenital Bladder Abnormalities Ellen Shapiro, MD, FACS, FAAP New York University School of Medicine, New York, NY [Rev Urol. 2012;14(1/2):38 doi: 10.3909/riu0550] © 2012 MedReviews®, LLC H iguchi and colleagues from the Mayo Clinic (Rochester, MN) published an interesting study to determine if ileal/colonic bladder augmentation in patients with congenital bladder abnormalities such as myelomeningocele, bladder exstrophy, or posterior urethral valves is an independent risk factor for bladder malignancy.1 These entities may have an inherent risk of neoplastic transformation in the absence of bladder augmentation. Records were reviewed from 1986 to 2010. Follow-up from augmentation (109 ileal and 44 colonic) was for at least 10 years with a median interval of 27 years. Controls were treated with clean intermittent catheritization and anticholinergic medications and were matched with the augmentation group for bladder dysfunction, sex, and age. This study of 153 patients showed no significant difference in the incidence of bladder cancer in the augmentation group (7 patients, 4.6%) vs control subjects (4 patients, 2.6%). When age at diagnosis, stage, mortality rate, or mean survival was analyzed, there was no significant difference between the two groups. The authors did find that chronic immunosuppression following renal transplantation significantly impacted the incidence of bladder cancer that was independent of augmentation status (15% vs 2.8%). In addition, those patients on immunosuppression who developed cancer also had a history of viral infections with cytomegalovirus, BK virus, and/or Epstein-Barr virus after transplantation. In the United States, approximately 2% of individuals will develop bladder cancer by age 78 years, with the majority presenting with localized disease.2 The current study found a 3.6% incidence of bladder cancer in patients with congenital bladder dysfunction presenting at a median age of 51 years. The data also show a twofold greater increase in bladder cancer in individuals with congenital bladder abnormalities vs the general population in which bladder cancer occurs at a much younger age with locally advanced disease or nodal metastases (81%). References 1. 2. Higuchi TT, Granberg CF, Fox JA, Husmann DA. Augmentation cystoplasty and risk of neoplasia: fact, fiction and controversy. J Urol. 2010;184:2492-2496. Horner MJ, Ries LAG, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. http://www.joplink.net/prev/201003/ref/16-001.html. Accessed February 28, 2012. 38 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_LiteratureReview.indd 38 20/07/12 2:11 PM CORRIGENDUM Correction to “A Review of Current Hemostatic Agents and Tissue Sealants Used in Laparoscopic Partial Nephrectomy” Reviews in Urology 2011;13(3):131-138 I. Galanakis, MD, FEBU, N. Vasdev, MD, MRCS, N. Soomro, MD, FRCS Department of Urology, Freeman Hospital, Newcastle upon Tyne, United Kingdom [ Rev Urol. 2012;14(1/2):39 doi: 10.3909/riu0546 ] ® © 2012 MedReviews , LLC On page 134, it was mistakenly written that “Vivostat® (Vivostat A/S, Alleroed, Denmark) is an autologous, plateletenriched, fibrin sealant applicator system that utilizes 120 mL of the patient’s blood, which is processed overnight.” The Vivostat system is able to produce Vivostat® Fibrin Sealant or Vivostat PRF® (platelet rich fibrin) from the patient’s own blood in just 23 minutes. Vol. 14 No. 1/2 • 2012 • Reviews in Urology • 39 40041700002_RIU0546.indd 39 20/07/12 2:03 PM CORRIGENDUM Notice of Duplicate Publication [ Rev Urol. 2012;14(1/2):40 doi: 10.3909/riu0140122012 ] ® © 2012 MedReviews , LLC The article “Dutasteride: A Review of Current Data on a Novel Dual Inhibitor of 5α Reductase” by Sibylle Marihart, MD, Mike Harik, MD, and Bob Djavan, MD, PhD, published in the Fall 2005 issue of Reviews in Urology,1 is virtually identical to an article published in Expert Opinions in Pharmacotherapy in February 2005.2 References 1. 2. Marihart S, Harik M, Djavan B. Dutasteride: a review of current data on a novel dual inhibitor of 5a reductase. Rev Urol. 2005;7(4):203-210. Djavan B, Milani S, Fong YK. Dutasteride: a novel dual inhibitor of 5alpha-reductase for benign prostatic hyperplasia. Expert Opin Pharmacother. 2005;6:311-317. In Reply: I offer sincere apologies to the readers of Reviews in Urology. I did not understand that my two manuscripts would be considered duplicate at the time I submitted them. I thought that since the two journals had different readership that some overlap in wording would be acceptable. Bob Djavan, MD, PhD New York University School of Medicine New York, NY 40 • Vol. 14 No. 1/2 • 2012 • Reviews in Urology 40041700002_RIU14(1-2).indd 40 20/07/12 2:09 PM