Kevin Lu

Effects of early pelvic-floor muscle exercise for sexual dysfunction in radical prostatectomy recipients.

Background: Sexual dysfunction is common after radical prostatectomy (RP). Although pelvic-floor muscle exercise (PFME) has been recommended for sexual dysfunction, the optimal time for starting exercises after this surgery and the effects of exercise still need to be examined. Objectives: The present study was intended to explore the prevalence of sexual dysfunction and to assess the efficacy of PFME in sexual dysfunction following RP. Methods: Participants were randomly distributed into an experimental group (n = 35) or a control group (n = 27). The experimental group took part in PFME as part of regular daily activities after catheter removal post-RP. The control group was taught the exercise in the third month after RP. We followed up the participants at 1, 3, 6, 9, and 12 months. Results: All of the patients experienced a severe degree of sexual dysfunction after receiving RP. A t test showed a significant difference in the sexual function mean score between the experimental and control groups at 6 and 12 months. A mixed-model analysis indicated that, after a controlled surgical approach, there was a significant difference in group effect. The experimental group’s sexual function was better than the control group’s sexual function. Conclusion: This study demonstrates that early PFME is an effective intervention for sexual dysfunction in prostatectomy patients. The results can help healthcare providers to include this intervention in patients’ discharge plans. Implications for Practice: Patient sexual dysfunction after an RP is common. Nurses should evaluate and manage patients’ sexual dysfunction and promote the early return of patients’ potency.

Single-session Laparoscopic Total Urinary Tract Exenteration Without Repositioning for Multifocal Urothelial Carcinoma in Dialysis-dependent Patients

OBJECTIVES To report our experience of single-session, en bloc, laparoscopic total urinary tract exenteration in dialysis-dependent patients with multifocal urothelial carcinoma. METHODS From June 2005 to April 2008, 5 dialysis-dependent patients (4 women and 1 man) diagnosed with synchronous upper urinary tract and bladder urothelial carcinoma underwent single-session, en bloc, laparoscopic total urinary tract exenteration. Bilateral nephroureterectomy was facilitated by rotating the operating table with or without alternative inflation of the tourniquet cuffs on either side of the patients back to allow adequate spontaneous bowel displacement by gravity, thereby avoiding the need to reposition the patient. After completing bilateral nephroureterectomy, we performed radical cystectomy with the patient in the Trendelenburg position. All specimens, including the 2 kidneys, ureters, and bladder, were collected in an endobag and were intended to be retrieved using the Pfannenstiel incision in male patients and the vaginal route in the female patients. The demographic and perioperative information were collected and analyzed. RESULTS All the laparoscopic procedures were completed successfully without major complications. Although 1 patient developed a minor complication owing to paralytic ileus, she recovered after conservative treatment. The continuity of all the urothelial epithelium was maintained intact throughout the procedure to avoid tumor spillage. CONCLUSIONS In our experience, laparoscopic total urinary tract exenteration is a technically feasible and safe alternative modality to the open counterpart to treat dialysis-dependent patients with end-stage renal disease with multifocal urothelial carcinoma for experienced surgeons with advanced laparoscopic skills. Furthermore, it can be performed successfully without the need for repositioning the patient, and this probably decreased the incidence of associated complication in the high-risk patients.

The Negative Is Not So Negative: What Do We Learn From Trials With Orteronel?

alone(medianOS,17.0[95%CI,15.2to19.9]months v15.2[95%CI, 13.5to16.9]months;hazardratio,0.886[95%CI,0.739to1.062]; P .1989). Similar to previous studies that assessed the efficacy of androgen signaling pathway inhibitors in patients with mCRPC after docetaxel therapy, 2,3 the ELM-PC 5 trial was another attempt to investigate androgen biosynthesis inhibitors in a modestly selected population. Despite an improvement in radiographic progressionfree survival (rPFS), this study did not meet its OS end point. The ELM-PC 5 trial is a failed trial. However, is this negative result meaningless? Is there potential value in sharing this negative result with researchers and communities that can inspire new directions for additional studies? WhatcanwelearnfromthisstudypublishedbyFizazietal? 1 One

Older Men With Locally Advanced Prostate Cancer: To Treat or Not to Treat?

TO THE EDITOR: Bekelman et al have published an article on treating older men with locally advanced prostate cancer in Journal ofClinicalOncology,whichwasaccompaniedbyaneditorialbyShumway and Hamstra. The authors should be congratulated for their significant contribution to our understanding of both age-dependent bias against treatment and the benefits of radiotherapy (RT) added to androgendeprivation therapy (ADT) in elderly men with locally advanced or screen-detected high-risk prostate cancer. Bekelman et al report on their proof-of-concept populationbased observational cohort study using the Surveillance, Epidemiology, and End Results Medicare database, in which they found pronounced survival benefit in the setting of addition of RT to ADT in men with screen-detected high-risk prostate cancer and elderly men older than 75 years. In the elderly cohort, ADT plus RT was associated with reduced cause-specific mortality (propensity score–adjusted hazard ratio [HR], 0.51; 95% CI, 0.44 to 0.59) and all-cause mortality (propensity score–adjusted HR, 0.63; 95% CI, 0.59 to 0.67). In the screen-detected cohort, ADT plus RT was associated with reduced cause-specific mortality (propensity score–adjusted HR, 0.25; 95% CI, 0.19 to 0.33) and all-cause mortality (propensity score–adjusted HR, 0.50; 95% CI, 0.45 to 0.55). They come to the conclusion that men older than 75 years with locally advanced prostate cancer or men older than 65 years with screen-detected prostate cancer who receive ADT alone risk reduction in cause-specific and overall survival. Indeed, level I evidence supports the role of ADT plus RT for patients with locally advanced prostate cancer in prolonging survival compared with ADT alone in two recent landmark randomized clinical trials. However, whether the results of these two landmark trials are generalized to the real world outside-of-trial patient population is a critical issue given that elderly men, those with multiple comorbidities, and those from an ethnic minority or a socioeconomically disadvantaged population, are often underrepresented in clinical trials. In fact, in our daily clinical practice, considerable uncertainty surrounds the incremental benefit of local therapy in addition to androgen deprivation among elderly men with newly diagnosed prostate cancer, particularly given the exclusion of these men from randomized clinical trials. Even though this study confirms the survival benefits of RT plus ADT in the setting of locally advanced prostate cancer and extends the generalizability of these findings to two subgroups not well represented in the clinical trials— elderly men older than 75 years and men age 65 years and older with screen-detected highrisk prostate cancer—it remains imperfect and raises multiple questions for future studies. First, there is a paucity of randomized clinical trials in elderly patients and lack of coherence for the definition of elderly. Age stigma often excludes elderly people from clinical trials to reduce attrition, minimize confounding variables associated with comorbidities, and avoid lengthier study processes. Furthermore, health care professionals’ attitudes can be tainted with ageism, thus leading to undesirable consequences for elderly cancer patients. It is important to base treatment decisions on functional age and not chronological age. Tools like the Chemotherapy Risk Assessment Scale for High-Age Patients, the Cancer and Aging Research Group model, the Comprehensive Geriatric Assessment, or the Multidisciplinary Geriatric Assessment can be used to assess elderly cancer patients. But more studies are needed to clarify their utility and value in the context of geriatric oncology. Second, RT serves as one of the most effective treatment modalities for localized prostate cancer. However, the standard conventional fractionated RT regimen for localized prostate cancer consists of approximately 7 to 9 weeks of daily treatment in 1.8 or 2 Gy per fraction, with the disadvantage of inconvenience for the patient and a higher cost burden for the health care system. How to improve convenience and lower cost without compromising safety and efficacy, especially in elderly men with locally advanced prostate cancer, is a critical issue not yet resolved. Treatment decisions in the elderly are not one size fits all; it is all about patient-bypatient assessment. For the therapy to have clinical utility in the elderly, patients would have to possess an accurate understanding of the natural course of their disease, their life expectancy, and a realistic expectation of the toxic effects related to treatment. The findings of this study could be used to counsel patients considering options for localized or locally advanced disease. In the future, prospective studies of decision making in this age group would be useful in answering some unsolved questions.

Re: Byron H. Lee, Adam S. Kibel, Jay P. Ciezki, et al. Are Biochemical Recurrence Outcomes Similar After Radical Prostatectomy and Radiation Therapy? Analysis of Prostate Cancer–Specific Mortality by Nomogram-predicted Risks of Biochemical Recurrence. Eur Urol 2015;67:204–9

With awareness of prostate cancer (PCa) and widespread adoption of prostate-specific antigen (PSA) screening tests worldwide, the incidence of PCa has been increasing dramatically. PCa has become a commonly diagnosed malignancy among men [1,2]. Clinically localized PCa can be treated with one modality or more including active surveillance, brachytherapy (BT), radiation therapy (RT), hormone therapy, or other energy-based minimally invasive techniques. Controversies still center on which options have the best risk–benefit ratios for patients with localized PCa and which treatments deliver the best outcomes. Treatment decision making for PCa is complex because PCa is often a disease of elderly men, and many men with PCa will die of other causes. This highstakes treatment decision is made in the context of great uncertainty [3]. We read a study by Lee and colleagues with interest [4]. They compared rates of PCa-specific mortality (PCSM) following biochemical recurrence (BCR) among men treated with radical prostatectomy (RP), external-beam RT (EBRT), and BT [4]. Lee et al used three common treatment-specific nomograms to derive 5-yr progression-free probability for 13 803 men treated with RP, EBRT, or BT at two large institutions and subsequently stratified PCSM from these estimates. Patients treated with EBRT demonstrated higher estimates of PCSM in all BCR risk groupings compared with men treated with RP (hazard ratio: 1.5; 95% confidence interval, 1.1–2.0; p = 0.006), whereas results for those treated with BT were not significantly different from those who underwent RP. However, as is often the case, the devil is in the details. The findings should be interpreted with caution because most patients undergo RP in the low-risk disease setting (low grade [70% Gleason 6] and low stage [73% T1c]), and patients in the surgical arm were considerably younger. Whether surgical approaches are truly superior to an RT-based approach seems unclear.

Depth of Invasion in High-Grade T1 Bladder Cancer: Added Value In Timely Cystectomy?

TO THE EDITOR: We read with interest the study led by MartinDoyle et al about the outcome and prognostic factors of timely cystectomy in high-grade T1 urothelial carcinoma of urinary bladder. The study relied on meta-analysis of 73 studies, consisting of observational cohort studies and randomized controlled trials with 75% of recruited patients with high-grade T1 bladder cancer. They come to conclusion that deep lamina propia invasion had largest negative impact and the depth should be considered for inclusion in TNM staging criteria. Decision making for patients with high-grade T1 bladder cancers is critical and challenging. These high-grade T1 bladder cancers have high propensity to recurrence and progression. Without adjuvant therapy after transurethral resection of bladder tumors, approximately 50% to 70% of patients will have recurrence within 2 years and risk of progression to muscle-invasive tumors after 5 years can vary from 25% to 50%. The optimal management of theses aggressive tumors depends on accurate diagnosis and careful assessment of prognostic factors. Despite advances in molecular biologic and genomic technology, the choice and timing of treatment remains elusive. How can therapies for high-grade T1 bladder cancer best be utilized? What therapy is best used in individual patients? These issues are not yet solved. Further, the timing of cystectomy in management of high-grade T1 bladder cancer remains debated. The timely cystectomy in clinically high-grade T1 bladder cancer is critical to prognosis and long-term survival, with early cystectomy being shown to confer better outcomes. However, there are many reasons for delay, including patient comorbidity, concerns regarding the morbidity of cystectomy, and so on In addition, because the progression rate is nearly 25% with transurethral resection of bladder tumor plus Bacillus CalmetteGuerin and 50% with transurethral resection alone, it seems that with early cystectomy at least 50% of patients are overtreated. Overtreatment affects the quality of life and possibly leads to unnecessary morbidity. Furthermore, cystectomy-related morbidity and mortality are 20% and 1% to 4%, respectively. Certainly, younger and healthier high-risk patients should at least be advised regarding treatment effectiveness of cystectomy. But the important question is how a fine balance needs to be adjusted between bladder sparing and late intervention requiring cystectomy; how to reserve cystectomy for benefit to patients at high risk and to use bladder-sparing approach in others without affecting survival. This goal of sparing the bladder when possible but not at the risk of death from metastatic disease may be achieved by the discovery of reliable biomarkers or risk factors. We think the results of Martin-Doyle et al are clinically relevant and deserve a thoughtful analysis. Meta-analyses are inherently biased by retrospective review: studies for inclusion need to be identified and selected. There would be heterogeneity in results. Also access to information about individual patients’ data (data availability bias) and publication bias are critical issues when analyzing. Another problem of meta-analysis is that it is only as good as the quality of the data used to answer important questions, and it requires careful and thoughtful scrutiny to rule out the many errors of study capture, before implementing any database for such work. Low quality plus low quality doesn’t equal high quality. In term of substaging T1 tumor, despite confirmation of substaging T1 as a important prognostic factor with this study, this substaging system (categorizing T1 tumors into T1a, T1b, and T1c (up to, into, and beyond the muscularis mucosae, respectively) has not been widely adopted because muscularis mucosae are often absent or difficult to identify. Another approach by measuring the depth of invasion to substage T1 tumors, to obviate the difficulty in identifying the muscularis mucosa is advocated given there are significant correlations between the depth of invasion in the transurethral resection of bladder tumor specimen and the stage at cystectomy, and the sensitivity, specificity, and positive and negative predictive values for predicting advanced stage disease ( T2) were 81%, 83%, 95%, and 56%, respectively by using a cutoff of greater than 1.5-mm depth of invasion. So, we still do not know which patients, if any, may actually benefit. Given that “medicine is a science of uncertainty and an art of probability,” as stated by Osler, the prediction of the risk of disease progression and the benefit of clinical management is essential for our daily practice. Better identification of suitable candidates who will benefit from early cystectomy hinge on our ability to risk stratify patients. Ongoing studies to clarify predictive or prognostic markers of benefit may allow physicians to maximize benefit and minimize treatment morbidity.

Gastric Cancer With Bladder Metastasis: Case Report and Literature Review

Bladder cancer is the eighth most common cancer in Taiwanese men, and the incidence of primary bladder cancer is more common than that of metastatic bladder cancer. Metastatic bladder cancers most commonly occur secondary to skin melanomas, followed by breast and gastric cancers. Therefore, bladder adenocarcinoma is rare and should be considered due to its metastatic origin. Its clinical course is aggressive and the prognosis is bad. We report a case of gastric cancer with bladder metastasis in a middle-aged man. We review the literature and discuss the clinical course, pathological characteristics, treatment, and prognosis of this disease.

Re: Arun A. Azad, Bernhard J. Eigl, Raya Leibowitz-Amit, et al. Outcomes with Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer Patients Who Have Poor Performance Status. Eur Urol 2015;67:441–7

We thank Dr. Lu for his interest in our recent publication [1]. Using a large population-based Canadian database, we reported that metastatic castration-resistant prostate cancer (mCRPC) patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 have superior outcomes on abiraterone acetate compared to ECOG PS 2 patients. We agree with Dr. Lu that describing ‘‘realworld’’ outcomes with novel agents offers important insights into the generalizability of clinical trial data. Further to this point, while nearly 40% of patients in our series were ECOG PS 2, only 10% of patients enrolled in the COU-AA-301 study were ECOG PS 2 [2]. In other pivotal phase 3 trials in mCRPC that tested agents including docetaxel, enzalutamide, cabazitaxel, radium-223 dichloride, and sipuleucel-T, ECOG PS 2 patients similarly comprised less than 15% of the total cohort. In light of their under-representation in practicechanging clinical trials, the optimal treatment of mCRPC patients with poor PS remains uncertain. In the COUAA-301, AFFIRM, and TROPIC studies, the hazard ratio (HR) for overall survival (OS) in ECOG PS 2 patients favored abiraterone, enzalutamide, and cabazitaxel, respectively, over the comparator arm. However, notwithstanding that these analyses were underpowered, the 95% confidence interval for the HR for each agent crossed unity, indicating a nonsignificant improvement in OS. To further explore effective treatment strategies for poor-PS mCRPC patients, we recently opened an investigator-initiated trial (clinicaltrials.gov identifier NCT02254785). In this ongoing study, poor-prognosis mCRPC patients (defined as time to CRPC 12 mo, presence of liver metastases, or four or more adverse risk factors, including ECOG PS 2) are randomized to chemotherapy (cabazitaxel) or hormonal therapy (abiraterone or enzalutamide), with the primary endpoint being the clinical benefit rate. Despite the limitations of currently available data, it does seem reasonable to contend that earlier initiation of novel hormonal agents (before a decline in PS) could be beneficial. Our study supports this notion, but because of

Re: Orazio Caffo, Ugo De Giorgi, Lucia Fratino, et al. Clinical Outcomes of Castration-resistant Prostate Cancer Treatments Administered as Third or Fourth Line Following Failure of Docetaxel and Other Second-line Treatment: Results of an Italian Multicentre Study. Eur Urol 2015;68:147–53

Achievement in the treatment landscape of metastatic castration-resistant prostate cancer (mCRPC) has resulted in five different therapeutic modalities (androgen biosynthesis inhibitor, androgen receptor inhibitor, chemotherapy, immunotherapy, and radiopharmaceuticals) with six drugs that have proven effects on overall survival [1]. This has raised new questions about how best to approach this treatment arsenal to extend treatment response as long as possible. The development of targeted agent– biomarker combinations holds promise for tailoring therapy to individual patients on the basis of genetic, biomarker, and phenotypic characteristics to improve clinical outcomes and to minimize unnecessary side effects for those less responsive to therapy. An ideal strategy for cancer care is to provide not just more time but more quality time— essentially, to guide clinical decision making and drug choice in the setting of noncurative therapy [2]. Despite recent breakthroughs in mCRPC therapy, the majority of patients still experience disease progression inevitably over time with these therapies. Now comes the next hurdle: figuring out which patients respond best to which therapy and how to improve effectiveness (Fig. 1A). This Italian multicenter study [3] by Caffo and colleagues reported on their real-world experience managing mCRPC patients and focused on patients who received at least two novel agents after the failure of docetaxel (ie, postdocetaxel thirdor fourth-line treatment). The authors concluded that the clinical outcomes of mCRPC patients were unable to demonstrate the superiority of any of the three new agents in the thirdor fourth-line setting, regardless of previous therapies. This result is valuable and clarifies our current clinical settings due to a paucity of available data, if any, on thirdor fourth-line sequenced treatment with mCRPC therapies. However, caution must be taken not to overinterpret the results for the treatment of the different phases of mCRPC, especially in the absence of robust surrogates for survival and the lack of predictive biomarkers. CRPC is a heterogeneous disease from biochemical progression (elevated prostate-specific antigen only) to radiographic progression and then symptomatic progression. The reality of the lack of durable complete response means chronic treatment is needed. Today, most physicians in practice usually make choices based on nonrandomized comparisons and various assumptions [4,5] (Fig. 1B). As reflected in this study [3] and in previous reports, an important finding is that there are no significant differences in clinical outcome regardless of using any novel therapies in the third-line setting. The optimal time to switch to another therapy and how to maintain total treatment duration to maximize the treatment-derived benefit are critical and challenging issues we should address. Currently, the paradigm has been moving from ‘‘one size fits all’’ to delivering the right treatment to the right patient at the right time. The therapies for CPRC are undergoing transformation. These changes are fueled by the clinical success of novel therapies and better understanding of molecular and genetic information. Prospective randomized trials to clarify the optimal treatment sequence or combinations, if feasible, need to be conducted to improve the care we offer men with mCRPC in the immediate future. E U R O P E A N U R O L O G Y 6 8 ( 2 0 1 5 ) e 1 2 9 – e 1 3 1

Thymidine Phosphorylase Expression in Human Bladder Urothelial Carcinoma

Objective To clarify the impact of thymidine phosphorylase (TPase) expression in patients with urothelial carcinoma of the urinary bladder (UB-UC), we investigated the expression profiles of TPase and its role in the clinical behavior of UB-UC in patients with this disease. Materials and Methods A total of 32 patients with UB-UC were enrolled in this study. The expression intensity and pattern of TPase were examined by immunohistochemical analysis. The results were correlated with clinicopathological parameters. Results: Tumor cells were significantly immunoreactive to TPase staining, but showed stronger staining in adjacent non-tumorous stromal tissues. The staining intensity and patterns were correlated with the stage ( p = 0.032, p = 0.010, respectively). Conclusions Both the intensity and pattern of expression of TPase were associated with tumor stage in UB-UC in this cohort. There were also high expression levels of TPase in most bladder cancer cells and adjacent stromal tissues. These findings suggest that tumor and stromal TPase expressions may cooperatively promote tumor progression and angiogenesis.