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Article of the Week: Better fit than fat when it comes to radical cystectomy for bladder cancer

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Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Obesity is associated with worse oncological outcomes in patients treated with radical cystectomy

Thomas F. Chromecki1,2*, Eugene K. Cha1*, Harun Fajkovic1,3, Michael Rink1,4, Behfar Ehdaie1, Robert S. Svatek5, Pierre I. Karakiewicz6, Yair Lotan7, Derya Tilki8, Patrick J. Bastian8, Siamak Daneshmand9,Wassim Kassouf10, Matthieu Durand1, Giacomo Novara11, Hans-Martin Fritsche12, Maximilian Burger12, Jonathan I. Izawa13, Antonin Brisuda14, Marek Babjuk14, Karl Pummer2 and Shahrokh F. Shariat1

1Weill Medical College of Cornell University, New York, NY, USA, 2Medical University Graz, Graz, Austria, 3Landeskrankenhaus St Poelten, St Poelten, Austria, 4University Medical Centre Hamburg-Eppendorf, Hamburg, Germany, 5University of Texas Health Science Center San Antonio, San Antonio, TX, USA, 6University of Montréal, Montréal, QC, Canada, 7University of Texas Southwestern Medical Center, Dallas, TX, USA, 8Ludwig-Maximilians-University Munich, Klinikum Grosshadern, Munich, Germany, 9University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 10McGill University Health Centre, Montréal, QC, Canada, 11University of Padua, Padua, Italy, 12Caritas St Josef Medical Centre, University of Regensburg, Regensburg, Germany, 13University of Western Ontario, London, ON, Canada, and 14Hospital Motol, 2nd Faculty of Medicine, Charles University, Praha, Czech Republic
*These authors contributed equally.

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OBJECTIVE

• To investigate the association between body mass index (BMI) and oncological outcomes in patients after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) in a large multi-institutional series.

PATIENTS AND METHODS

• Data were collected from 4118 patients treated with RC and pelvic lymphadenectomy for UCB. Patients receiving preoperative chemotherapy or radiotherapy were excluded.

• Univariable and multivariable models tested the effect of BMI on disease recurrence, cancer-specific mortality and overall mortality.

• BMI was analysed as a continuous and categorical variable (<25 vs 25–29 vs 30 kg/m2).

RESULTS

• Median BMI was 28.8 kg/m2 (interquartile range 7.9); 25.3% had a BMI <25 kg/m2, 32.5% had a BMI between 25 and 29.9 kg/m2, and 42.2% had a BMI 30 kg/m2.

• Patients with a higher BMI were older (P < 0.001), had higher tumour grade (P < 0.001), and were more likely to have positive soft tissue surgical margins (P = 0.006) compared with patients with lower BMI.

• In multivariable analyses that adjusted for the effects of standard clinicopathological features, BMI >30 was associated with higher risk of disease recurrence (hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.46–1.91, P < 0.001), cancer-specific mortality (HR 1.43, 95% CI 1.24–1.66, P < 0.001), and overall mortality (HR 1.81, CI 1.60–2.05, P < 0.001). The main limitation is the retrospective design of the study.

CONCLUSIONS

• Obesity is associated with worse cancer-specific outcomes in patients treated with RC for UCB.

• Focusing on patient-modifiable factors such as BMI may have significant individual and public health implications in patients with invasive UCB.

 

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Editorial: Obesity is associated with worse oncological outcomes in patients treated with radical cystectomy

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Michael R. Abern, Stephen J. Freedland and Brant A. Inman

Division of Urologic Surgery, Duke University Medical Center, Durham, NC, USA

Obesity is a worldwide epidemic: it is estimated over 300 million adults are obese and over 1 billion are overweight. As obesity is a risk factor for cancers and is modifiable, the authors of this report retrospectively analyse the association between body mass index (BMI) and outcomes in a large multinational cohort of bladder cancer patients that underwent radical cystectomy. They found that obese patients were older and more likely to have high-grade tumours. Furthermore, obese patients received inferior lymphadenectomies, had more positive margins, and were less likely to receive adjuvant chemotherapy. The end result is an association between obesity and bladder cancer recurrence, and both cancer-specific and overall mortality.

Although these data suggest that obesity is associated with poor radical cystectomy outcomes, this contrasts with evidence showing no link between obesity and bladder cancer mortality in population-based trials such as the Cancer Prevention Study II, which prospectively followed over 900 000 participants. Why the discrepancy? One possible explanation is the presence of confounding factors and one possible confounder is the presence of type 2 diabetes. In population-based studies that considered both BMI and diabetes, people with diabetes were noted to have an increased risk of developing bladder cancer independent of BMI, whereas the converse was not true. Additionally, diabetes has been associated with recurrence and progression of non-muscle invasive bladder cancer whereas obesity has not. The impact of diabetes was not adequately addressed in the current study.

Other limitations also probably affect the results. In the current study, overweight patients (BMI 25–30) had significantly better cancer-specific survival (hazard ratio 0.80, P = 0.01) than those of ‘normal’ weight (BMI < 25). However, a threshold BMI ≥ 30 has been shown to have poor sensitivity for obesity in elderly populations, with over 25% of patients with BMI under 30 qualifying as obese based on body fat. This may result in an overstatement of the effect of obesity. Conversely, the inclusion of underweight patients (BMI < 18.5) in the ‘normal’ group may underestimate the effect between obesity and outcome, as cachexia may be associated with poor outcomes. Another factor mentioned by the authors is the inferior lymphadenectomies performed in obese patients, which introduces a detection bias for lymph node positivity, the strongest predictor after advanced stage for all of their tested outcomes on multivariate analysis (hazard ratio 2.01–2.33, P < 0.001).

Although the true effect of obesity may be hard to quantify with these data, all would agree that maintaining a non-obese bodyweight will help many disease states with little apparent harm. Patients undergoing neoadjuvant chemotherapy before radical cystectomy have a 3-month window to lose weight and exercise more. This could improve surgical outcomes, and possibly tolerance of chemotherapy. Furthermore, if we can prove that obesity leads to increased bladder cancer recurrence or progression, a window of opportunity may exist when a low-risk tumour is diagnosed. Otherwise, we are left with the eighteenth century wisdom of Benjamin Franklin: ‘An ounce of prevention is worth a pound of cure.’

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Article of the week: An open and shut case: outcomes similar for open and robotic prostatectomy

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Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video of Jonathan Silberstein discussing his paper.

If you only have time to read one article this week, it should be this one.

A case-mix-adjusted comparison of early oncological outcomes of open and robotic prostatectomy performed by experienced high volume surgeons

Jonathan L. Silberstein*, Daniel Su*, Leonard Glickman*, Matthew Kent†, Gal Keren-Paz*, Andrew J. Vickers†, Jonathan A. Coleman*‡, James A. Eastham*‡, Peter T. Scardino*‡ and Vincent P. Laudone*‡

*Department of Surgery, Urology Service, and †Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, and ‡Department of Urology,Weill Cornell Medical Center, New York, NY, USA

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OBJECTIVE

• To compare early oncological outcomes of robot assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) performed by high volume surgeons in a contemporary cohort.

METHODS

• We reviewed patients who underwent radical prostatectomy for prostate cancer by high volume surgeons performing RALP or ORP.

• Biochemical recurrence (BCR) was defined as PSA  0.1 ng/mL or PSA  0.05 ng/mL with receipt of additional therapy.

• A Cox regression model was used to evaluate the association between surgical approach and BCR using a predictive model (nomogram) based on preoperative stage, grade, volume of disease and PSA.

• To explore the impact of differences between surgeons, multivariable analyses were repeated using surgeon in place of approach.

RESULTS

• Of 1454 patients included, 961 (66%) underwent ORP and 493 (34%) RALP and there were no important differences in cancer characteristics by group.

• Overall, 68% of patients met National Comprehensive Cancer Network (NCCN) criteria for intermediate or high risk disease and 9% had lymph node involvement. Positive margin rates were 15% for both open and robotic groups.

• In a multivariate model adjusting for preoperative risk there was no significant difference in BCR rates for RALP compared with ORP (hazard ratio 0.88; 95% CI 0.56–1.39; P = 0.6). The interaction term between © 2013 The Authors 206 BJU International © 2013 BJU International | 111, 206–212 | doi:10.1111/j.1464-410X.2012.11638.x Urological Oncology nomogram risk and procedure type was not statistically significant.

• Using NCCN risk group as the covariate in a Cox model gave similar results (hazard ratio 0.74; 95% CI 0.47–1.17; P = 0.2). The interaction term between NCCN risk and procedure type was also non-significant.

• Differences in BCR rates between techniques (4.1% vs 3.3% adjusted risk at 2 years) were smaller than those between surgeons (2.5% to 4.8% adjusted risk at 2 years).

CONCLUSIONS

• In this relatively high risk cohort of patients undergoing radical prostatectomy we found no evidence to suggest that ORP resulted in better early oncological outcomes then RALP.

• Oncological outcome after radical prostatectomy may be driven more by surgeon factors than surgical approach.

 

Read Previous Articles of the Week

Editorial: Oncological outcomes: open vs robotic prostatectomy

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John W. Davis and Prokar Dasgupta*

Departments of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA and *Guy’s Hospital, Kings College London, London, UK
e-mail: [email protected]

For men at significant risk of dying from untreated prostate cancer within reasonably estimated remaining life spans, which technique offers the best disease-free survival: open radical prostatectomy (RP) or robot-assisted RP (RARP)? The practice patterns in many countries suggest RARP, but many concerns have been raised about the RARP technique for high-risk disease, including positive surgical margin rates, adequate lymph node dissections (LNDs), and the learning curve. In this issue of the BJUI, Silberstein et al provide a convincing study, short of a randomised trial, that suggests that in experienced hands both techniques can be effective, and that surgeon experience had a stronger effect than technique. In contrast to large population-based studies, this study sought to take the learning curve and low-volume surgeon variables out of the equation by restricting the inclusion criteria to four high-volume surgeons from a single centre. The follow-up is short (one year), and may underestimate the true biochemical relapse rates, and needs follow-up study, but for now offers no difference in relapse rates nor pathological staging outcomes.

Beyond the comparative effectiveness research (CER), Silberstein et al also provide a valuable vision for prostate cancer surgeons using any standard technique. Several recent landmark studies on PSA screening, the Prostate cancer Intervention Versus Observation Trial (PIVOT), and comparisons of metastatic progression between RP and radiation, all indicate the need to shift our practice pattern towards active surveillance for lower risk patients (with or without adjunctive focal therapy, but the former still experimental in our view), and curative therapy for intermediate- to high-risk disease. Such a practice pattern is evident when you compare this study (2007–2010) with a similar effort from this institution (2003–2005) comparing RP with laparoscopic RP (LRP). In the former study, >55% had low-risk disease compared with <35% from the current study. As expected, the present study shows higher N1 stage (9%) and positive surgical margin rates (15%) than the former (7% and 11%, respectively). While erectile function recovery was not presented, the authors noted the familiar reality that patients demand nerve sparing whenever feasible, only 2% in this study had bilateral non-nervesparing and 91% had a combination of bilateral or partial nerve sparing. The number of LNs retrieved has increased from 12–13/case to 15–16, and the authors state that even with nomogram-based exclusion of mandatory pelvic LNDs with <2% risk of N1 staging, this modern cohort had a pelvic LND in 94% of cases, including external iliac, obturator, and hypogastric templates.

We fully concur with this practice pattern, and have recently provided a video-based illustration of how to learn the technique, and early experience showing an increase in median LN counts from eight to 16, and an increase in positive LNs from 7% to 18%. By risk group, our positive-LN rate was 3% for low risk, 9% for intermediate risk, and 39% for high risk. We certainly hope that future multi-institutional studies will no longer reflect what these authors found, in that RARP surgeons are five times more likely to omit pelvic LNDs than open, even for high-risk cancers.

Finally, Silberstein et al and related CER publications leave us the question, does each publication on CER in RP have to be comprehensive (i.e. oncological, functional, and morbidity) or can it focus on one question. Members of this authorship line have published the ‘trifecta’ (disease control, potency, and continence) and others the ‘pentafecta’ (the trifecta plus negative surgical margins and no complications). Indeed, Eastham and Scardino stated in an editorial that ‘data on cancer control, continence, or potency in isolation are not sufficient for decision making and that patients agreeing to RP should be informed of functional results in the context of cancer control’. We feel that the answer should be no, focused manuscripts have their merit and publication space/word limits create this reality. But we should not discount the sometimes surprising results when one institution using the same surgeons and methodologies publishes on the broader topic: the Touijer et al. paper discussed above found the same oncological equivalence between RP and LRP as this comparison of RP and RARP, but also included functional data showing significantly lower recovery of continence with LRP. Nevertheless, the recent body of work in the BJUI now provides a well-rounded picture of modern CER including oncological outcomes, complications, recovery of erectile dysfunction, continence and costs. We feel it is reasonable to conclude that patients should be counselled that RARP has potential benefits in terms of blood loss, hospital stay, and complications (at increased costs), but oncological and functional results are probably based upon surgeon experience.

Abbreviations

CER, comparative effectiveness research; LN(D), lymph node dissection; (RA)(L)RP, (robot-assisted) (laparoscopic) radical prostatectomy

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Dr Silberstein’s commentary on open vs robotic prostatectomy

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A case-mix-adjusted comparison of early oncological outcomes of open and robotic prostatectomy performed by experienced high volume surgeons

Jonathan L. Silberstein*, Daniel Su*, Leonard Glickman*, Matthew Kent†, Gal Keren-Paz*, Andrew J. Vickers†, Jonathan A. Coleman*‡, James A. Eastham*‡, Peter T. Scardino*‡ and Vincent P. Laudone*‡

*Department of Surgery, Urology Service, and †Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, and ‡Department of Urology,Weill Cornell Medical Center, New York, NY, USA

Read the full article
OBJECTIVE

• To compare early oncological outcomes of robot assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) performed by high volume surgeons in a contemporary cohort.

METHODS

• We reviewed patients who underwent radical prostatectomy for prostate cancer by high volume surgeons performing RALP or ORP.

• Biochemical recurrence (BCR) was defined as PSA  0.1 ng/mL or PSA  0.05 ng/mL with receipt of additional therapy.

• A Cox regression model was used to evaluate the association between surgical approach and BCR using a predictive model (nomogram) based on preoperative stage, grade, volume of disease and PSA.

• To explore the impact of differences between surgeons, multivariable analyses were repeated using surgeon in place of approach.

RESULTS

• Of 1454 patients included, 961 (66%) underwent ORP and 493 (34%) RALP and there were no important differences in cancer characteristics by group.

• Overall, 68% of patients met National Comprehensive Cancer Network (NCCN) criteria for intermediate or high risk disease and 9% had lymph node involvement. Positive margin rates were 15% for both open and robotic groups.

• In a multivariate model adjusting for preoperative risk there was no significant difference in BCR rates for RALP compared with ORP (hazard ratio 0.88; 95% CI 0.56–1.39; P = 0.6). The interaction term between © 2013 The Authors 206 BJU International © 2013 BJU International | 111, 206–212 | doi:10.1111/j.1464-410X.2012.11638.x Urological Oncology nomogram risk and procedure type was not statistically significant.

• Using NCCN risk group as the covariate in a Cox model gave similar results (hazard ratio 0.74; 95% CI 0.47–1.17; P = 0.2). The interaction term between NCCN risk and procedure type was also non-significant.

• Differences in BCR rates between techniques (4.1% vs 3.3% adjusted risk at 2 years) were smaller than those between surgeons (2.5% to 4.8% adjusted risk at 2 years).

CONCLUSIONS

• In this relatively high risk cohort of patients undergoing radical prostatectomy we found no evidence to suggest that ORP resulted in better early oncological outcomes then RALP.

• Oncological outcome after radical prostatectomy may be driven more by surgeon factors than surgical approach.

Article of the Week: Does tadalafil improve ejaculatory dysfunction?

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Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video of  Darius Paduch discussing his paper.

If you only have time to read one article this week, it should be this one.

Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo-controlled studies

Darius A. Paduch*†, Alexander Bolyakov*†, Paula K. Polzer‡ and Steven D. Watts‡

*Department of Urology and Reproductive Medicine,Weill Cornell Medical College, New York, NY, †Consulting Research Services, Inc., Red Bank, NJ, and ‡Lilly Research Laboratories, Eli Lilly, Indianapolis, IN, USA

Read the full article

Weill Cornell Medical College Press Release

OBJECTIVES

• To compare effects of tadalafil on ejaculatory and orgasmic function in patients presenting with erectile dysfunction (ED).

• To determine the effects of post-treatment ejaculatory dysfunction (EjD) and orgasmic dysfunction (OD) on measures of sexual satisfaction.

PATIENTS AND METHODS

• Data from 17 placebo-controlled 12-week trials of tadalafil (5, 10, 20 mg) as needed in patients with ED were integrated.

• EjD and OD severities were defined by patient responses to the International Index of Erectile Function, question 9 (IIEF-Q9; ejaculation) and IIEF-Q10 (orgasm), respectively.

• Satisfaction was evaluated using the intercourse and overall satisfaction domains of the IIEF and Sexual Encounter Profile question 5.

• Analyses of covariance were performed to compare mean ejaculatory function and orgasmic function, and chi-squared tests evaluated differences in endpoint responses to IIEF-Q9 and IIEF-Q10.

RESULTS

• A total of 3581 randomized subjects were studied.

• Treatment with tadalafil 10 or 20 mg was associated with significant increases in ejaculatory and orgasmic function (vs placebo) across all baseline ED, EjD, and OD severity strata.

• In the tadalafil group, 66% of subjects with severe EjD reported improved ejaculatory function compared with 36% in the placebo group (P < 0.001).

• Similarly, 66% of the tadalafil-treated subjects (vs 35% for placebo; P < 0.001) with severe OD reported improvement.

• Residual severe EjD and OD after treatment had negative impacts on sexual satisfaction.

• Limitations of the analysis include its retrospective nature and the use of an instrument (IIEF) with as yet unknown performance in measuring treatment responses for EjD and OD.

CONCLUSIONS

• Tadalafil treatment was associated with significant improvements in ejaculatory function, orgasmic function and sexual satisfaction.

• Proportions of subjects reporting improved ejaculatory or orgasmic function were ª twofold higher with tadalafil than with placebo.

• These findings warrant corroboration in prospective trials of patients with EjD or OD (without ED).

 

Read Previous Articles of the Week

Editorial: Phosphodiesterase Inhibitors (PDEi) improve orgasm. The power of meta-analysis?

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Ever since the potential utility of meta-analyses in the assessment of clinical data was brought to the notice of the urological community by Peter Boyle [1], they have been used increasingly. Indeed this approach to evaluation of drug effects has become de rigueur for healthcare providers and regulatory bodies. In particular, invaluable insight has been given into the benefit : risk ratios of drugs in BPH/LUTS and overactive bladder. Even to the extent, where sufficiently large databases have been made available, it has been possible to identify characteristics predictive of subpopulations of responders and non-responders [1].

The most recent example of the power of meta-analysis is the rigorous statistical dissection of the impact tadalafil on sexual function in erectile dysfunction (ED) by the Department of Urology atWeill Cornell published in BJUI [2]. As would be anticipated from previously published individual clinical trials, there was confirmation in this review of 3581 subjects in 17 placebo-controlled studies, of the positive effect of tadalafil (exemplifying the phosphodiesterase inhibitor [PDEi] class) on erectile function. It could perhaps be argued that with a clinical effect as large and clear-cut as that of PDEi in ED, the meta-analysis was superfluous. Only in situations where the clinical impact beyond that of placebo was of lower magnitude does it come to the fore, e.g. a-adrenoceptor antagonists in the treatment of LUTS [3]. However, at this point the following health warning should be issued, PDEi in the hands of the skilled meta-analysts and marketeers: caveat lector (let the reader beware).
Returning, however, to the material in hand, the analysis of the tadalafil data also shows unequivocally that there is an additional positive effect of the drug (and presumably the PDEi class) on orgasm and sexual satisfaction. These products and class attributes have often been alluded to with varying degrees of conviction, but this is the first time convincing evidence has been tabulated and documented.

Also described is the positive effect of tadalafil on co-morbid ejaculatory dysfunction (EjD) which, at first sight, would tend to provide supportive evidence for the off-label use of tadalafil and other PDEi in the treatment of premature ejaculation (PE). Although the words in the manuscript [3] fall short of advocating this practice, the inference is there for all to read and potentially be detailed astutely by the field-force.We now move into the ‘grey’ area between caveat lector and caveat emptor (let the buyer beware). EjD can mean different things to different men and can represent a continuum from premature to delayed or even anejaculation. Almost certainly most of the patients in the clinical trials analysed would not meet the definition of PE crafted by the International Society for Sexual Medicine (ISSM) [4], so little conclusion about the benefit to men with PE can be drawn.

Ironically, a meta-analysis on the impact of PDEi on men with unequivocal PE (or at least meet the ISSM definition) has just been published [5]. The conclusion was that there is no clinically or statistically significant improvement in PE with acute or chronic treatment with PDEi.

Although, at least in the case of ejaculatory function the conclusion of the two meta-analyses appear to be at variance, in actuality they are addressing different questions. It remains, that, although in the use of meta-analysis we have the means of creating a level playing field, we have to be careful to consider what questions are being asked, by whomand with what objective.

References
1 Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996; 48: 398–405
2 Paduch DA, Bolyakov A, Polzer PK, Watts SD. Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo-controlled studies. BJU Int 2013; 111: 333–42
3 Boyle P, Robertson C, Manski R, Padley RJ, Roehrborn CG. Meta-analysis of randomized trials of terazosin in the treatment of benign prostatic hyperplasia. Urology 2001; 58: 717–22
4 McMahon CG, Althof S, Waldinger MD et al. International Society for Sexual Medicine Ad Hoc Committee for Definition of Premature Ejaculation. An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation. BJU Int 2008; 102: 338–50
5 Asimakopoulos AD, Miano R, Agrò EF, Vespasiani G, Spera E. Does current scientific and clinical evidence support the use of phosphodiesterase type 5 inhibitors for the treatment of premature ejaculation? A systematic review and meta-analysis. J Sex Med 2012; 9: 2404–16

Mike Wyllie
Plethora Solutions Ltd London, London, UK.
e-mail: [email protected]

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Dr Paduch’s commentary on tadalafil and ejaculatory dysfunction

/by

 

 

Effects of 12 weeks of tadalafil treatment on ejaculatory and orgasmic dysfunction and sexual satisfaction in patients with mild to severe erectile dysfunction: integrated analysis of 17 placebo-controlled studies

Darius A. Paduch*†, Alexander Bolyakov*†, Paula K. Polzer‡ and Steven D. Watts‡

*Department of Urology and Reproductive Medicine,Weill Cornell Medical College, New York, NY, †Consulting Research Services, Inc., Red Bank, NJ, and ‡Lilly Research Laboratories, Eli Lilly, Indianapolis, IN, USA

Read the full article
OBJECTIVES

• To compare effects of tadalafil on ejaculatory and orgasmic function in patients presenting with erectile dysfunction (ED).

• To determine the effects of post-treatment ejaculatory dysfunction (EjD) and orgasmic dysfunction (OD) on measures of sexual satisfaction.

PATIENTS AND METHODS

• Data from 17 placebo-controlled 12-week trials of tadalafil (5, 10, 20 mg) as needed in patients with ED were integrated.

• EjD and OD severities were defined by patient responses to the International Index of Erectile Function, question 9 (IIEF-Q9; ejaculation) and IIEF-Q10 (orgasm), respectively.

• Satisfaction was evaluated using the intercourse and overall satisfaction domains of the IIEF and Sexual Encounter Profile question 5.

• Analyses of covariance were performed to compare mean ejaculatory function and orgasmic function, and chi-squared tests evaluated differences in endpoint responses to IIEF-Q9 and IIEF-Q10.

RESULTS

• A total of 3581 randomized subjects were studied.

• Treatment with tadalafil 10 or 20 mg was associated with significant increases in ejaculatory and orgasmic function (vs placebo) across all baseline ED, EjD, and OD severity strata.

• In the tadalafil group, 66% of subjects with severe EjD reported improved ejaculatory function compared with 36% in the placebo group (P < 0.001).

• Similarly, 66% of the tadalafil-treated subjects (vs 35% for placebo; P < 0.001) with severe OD reported improvement.

• Residual severe EjD and OD after treatment had negative impacts on sexual satisfaction.

• Limitations of the analysis include its retrospective nature and the use of an instrument (IIEF) with as yet unknown performance in measuring treatment responses for EjD and OD.

CONCLUSIONS

• Tadalafil treatment was associated with significant improvements in ejaculatory function, orgasmic function and sexual satisfaction.

• Proportions of subjects reporting improved ejaculatory or orgasmic function were ª twofold higher with tadalafil than with placebo.

• These findings warrant corroboration in prospective trials of patients with EjD or OD (without ED).

Article of the week: “Twist” of fate: epithelial–mesenchymal transition (EMT) markers predict recurrence in prostate cancer

/by

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Expression patterns of epithelial–mesenchymal transition markers in localized prostate cancer: significance in clinicopathological outcomes following radical prostatectomy

Hosny M. Behnsawy, Hideaki Miyake, Ken-Ichi Harada and Masato Fujisawa

Read the full article
OBJECTIVE

• To analyse the expression patterns of multiple molecular markers implicated in epithelial–mesenchymal transition (EMT) in localized prostate cancer (PC), in order to clarify the significance of these markers in patients undergoing radical prostatectomy (RP).

PATIENTS AND METHODS

• Expression levels of 13 EMT markers, namely E-cadherin, N-cadherin, b-catenin, g-catenin, fibronectin, matrix metalloproteinase (MMP) 2, MMP-9, Slug, Snail, Twist, vimentin, ZEB1 and ZEB2, in RP specimens from 197 consecutive patients with localized PC were evaluated by immunohistochemical staining.

RESULTS

• Of the 13 markers, expression levels of E-cadherin, Snail, Twist and vimentin were closely associated with several conventional prognostic factors.

• Univariate analysis identified these four EMT markers as significant predictors for biochemical recurrence (BR), while serum prostate-specific antigen, Gleason score, seminal vesicle invasion (SVI), surgical margin status (SMS) and tumour volume were also significant.

• Of these significant factors, expression levels of Twist and vimentin, SVI and SMS appeared to be independently related to BR on multivariate analysis

• There were significant differences in BR-free survival according to positive numbers of these four independent factors. That is, BR occurred in four of 90 patients who were negative for risk factors (4.4%), 21 of 83 positive for one or two risk factors (25.3%) and 19 of 24 positive for three or four risk factors (79.2%).

CONCLUSION

• Measurement of expression levels of potential EMT markers, particularly Twist and vimentin, in RP specimens, in addition to conventional prognostic parameters, would contribute to the accurate prediction of the biochemical outcome in patients with localized PC following RP.

 

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Editorial: The promise of EMT-associated biomarkers in a clinical setting

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Emily A. Matuszak  and Natasha Kyprianou
Departments of Toxicology, Urology and Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA

Radical prostatectomy is among the most successful treatment modalities for patients exhibiting clinically localized prostate cancer. Despite this, roughly one-third of all radical prostatectomy patients will experience biochemical recurrence following prostatectomy. Curing prostate cancer requires a greater understanding of distinct biological events that differentiate prostate cancer from advanced life-threatening disease. Thus, a current challenge facing the clinical management of prostate cancer is the need for novel prognostic biomarkers capable of predicting biochemical recurrence to direct therapeutic interventions at earlier disease stages.

The oncogenic epithelial–mesenchymal transition (EMT) plays a critical role in metastatic prostate cancer progression [1]. EMTs engender coordinated molecular and genetic events which provoke phenotypic transformations that are indicative of the acquisition of mesenchymal characteristics which yield altered cellular behaviours [2]. Such altered behaviours may include but are not limited to enhanced migratory capability, increased invasive capacity, heightened resistance to apoptosis and conferred stem-like properties [3,4]. Conversion of an epithelial-derived prostate cancer cell to a more mesenchymal-like state has recently been implicated in prostate tumourigenesis as a mechanism facilitating the progression to metastatic castration-resistant disease [5].While alterations in the expression profiles of numerous EMT-associated transcriptional regulators and their molecular targets have served as biomarkers for studying EMT programmes, less is known about the contributions of EMTs in the emergence of treatment failure and tumour recurrence. Recently, EMT has been suggested to be a programme involved in metastatic disease progression that may also profoundly influence therapeutic outcomes amongst patients. Thus, it may be advantageous to develop predictors for risk assessment among prostate cancer patients that include specific EMT-associated markers in clinical evaluations.

Despite our current lack of knowledge regarding the clinicopathological significance of EMT, the potential value of an EMT marker signature as a prognostic indicator of biochemical recurrence among prostate cancer patients has emerged with some promise. Behnsawy et al. establish an initial path towards estimating the clinical value of assessing EMT marker levels in tandem with conventional clinicopathological prognostic factors in radical prostatectomy specimens from patients with organ confined prostate cancer, without any neoadjuvant therapy. Their evaluation follows a robust profile and results intriguingly reflect a pattern that may facilitate prediction of biochemical recurrence among patients. Using an exhaustive immunohistochemical analysis, the expression patterns of 13 EMT markers were evaluated in 197 radical prostatectomy specimens of which the expression levels of two EMT-associated markers, Twist and vimentin, were the most promising factors for such predictions.

The novel aspect and translational significance of this study are both reflected in the homogeneity of the patient population, in terms of localized organ confined disease. It represents an initial step towards recognizing an expression signature for specific EMT-associated factors in the therapeutic outcome of localized prostate cancer, but not disease progression. While the clinical impact of the reported findings may not be fully apparent, one may begin to speculate the promise of incorporating EMT-associated biomarkers in a clinical setting to facilitate diagnosis, prognosis and/or directing treatment strategies among patients. Primary endpoints of acquisition of an EMT phenotype following androgen axis targeting treatment must be clearly defined in the design of future clinical trials for the treatment of prostate cancer patients, with caution being given to selection of biopsy specimens vs radical prostatectomy specimens at an ‘optimal’ EMT window and in order to mitigate bias in tissue sampling resulting from long duration of therapeutic intervention. Control groups will provide valuable biological material to identify alternative mechanisms of treatment resistance (MAPK signalling). The statistical power in the relatively large cohort analysed enhances our confidence in considering the EMT landscape as an attractive platform for prediction of therapeutic response in future clinical trials. The concern, however, of whether improved prediction of biochemical recurrence by EMT profiling in pretreatment biopsies justifies its integration in the clinicopathological parameters (Gleason score, PSA) remains. Thus high expectations and much promise surround the pathological exploitation of EMT biomarkers (as signatures) in identifying profiles of tumour aggressiveness and providing a significant contribution in our quest towards the development of personalized therapies in prostate cancer patients with advanced disease.

References
1 Matuszak E, Kyprianou N. Androgen regulation of epithelial–mesenchymal transition in prostate tumorigenesis. Expert Rev Endo Metab 2011; 6: 469–82
2 Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial–mesenchymal transition in development and disease. Cell 2009; 139: 871–90
3 Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 2009; 9: 265–73
4 Kalluri R, Weinberg R. The basics of epithelial–mesenchymal transition. J Clin Invest 2009; 119: 1420–8
5 Tanaka H, Kono E, Tran CP et al. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat Med 2010; 16: 1414–20

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