Tag: Article of the Week

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Editorial: Prostate biopsy decisions: one-size-fits-all approach with total PSA is out and a multivariable approach with the PHI is in

March 23, 2016/by Stacy Loeb

The days of using one PSA threshold to trigger a biopsy for all men are over, and the field has moved toward a more individualized approach to prostate biopsy decisions, taking into account each patient’s specific set of risk factors. Foley et al. [1] provide compelling evidence supporting the use of the Prostate Health Index (PHI) as part of this multivariable approach to prostate biopsy decisions.

There is now a large body of evidence showing that the PHI is more specific for prostate cancer than total PSA and percent free PSA, as was concluded in a 2014 systematic review [2]. Moreover, several recent studies have confirmed the superiority of the PHI over its individual components [3, 4] and compared with other markers such as PCA3 [5], for predicting clinically significant prostate cancer.

The present new study by Foley et al. [1] builds on this literature by providing clinically useful data on the role of the PHI in prostate biopsy decisions. Specifically, they examined 250 men with elevated age-specific PSA and/or abnormal DRE who were referred for ≥12-core prostate biopsy as part of the Irish Rapid Access Clinic. The median PHI was 48.6 in men with prostate cancer, vs 33.4 in men without prostate cancer on biopsy. On receiver-operating characteristic analysis, the PHI had a higher area under the curve (AUC) for overall prostate cancer compared with total and percent free PSA (AUCs 0.71, 0.62 and 0.64, respectively), as well as for high grade prostate cancer (AUC 0.78, 0.70 and 0.67, respectively). Compared with the PHI, even the combination of total and percent free PSA had a lower AUC of 0.67 for overall prostate cancer and 0.75 for high grade prostate cancer.

Next, the authors developed a multivariable prediction model incorporating age, family history, DRE and previous biopsy history, along with either PSA or the PHI. Using the PHI in this model rather than total PSA resulted in greater predictive accuracy for the detection of overall and Gleason ≥7 disease. The PHI-based model also showed superior net benefit to the PSA-based multivariable models on decision curve analysis.

These findings are exactly what we would expect, as studies have consistently shown that the PHI outperforms PSA [2, 6]. Other groups from the European Randomized Study of Screening for Prostate Cancer (ERSPC) have also integrated the PHI into multivariable risk prediction through the development of a user-friendly smartphone app called the Rotterdam Risk Calculator [7]. Because our goal is to provide each patient with the best information from which to make decisions about biopsy, it only makes sense to use the best possible combination of markers that we have.

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Stacy Loeb

Department of Urology, Population Health and Laura and Isaac Perlmutter Cancer Center, New York University and Manhattan Veterans Affairs Medical Center, New York, NY, USA

References

1 Foley RW, Gorman L, Shariﬁ N et al. Improving multivariable prostate cancer risk assessment using the prostate health index. BJU Int 2016; 117:409–17

2 Huang YQ, Sun T, Zhong WD, Wu CL. Clinical performance of serum [-2]proPSA derivatives, %p2PSA and PHI, in the detection and management of prostate cancer. Am J Clin Exp Urol 2014; 2: 343–50

3 Loeb S, Sanda MG, Broyles DL et al. The prostate health index selectively identiﬁes clinically signiﬁcant prostate cancer. J Urol 2015; 193: 1163–9

4 de la Calle C, Patil D, Wei JT et al. Multicenter evaluation of the prostate health index to detect aggressive prostate cancer in biopsy naıve men. J Urol 2015; 194: 65–72

5 Ferro M, Lucarelli G, Bruzzese D et al. Improving the prediction of pathologic outcomes in patients undergoing radical prostatectomy: the value of prostate cancer antigen 3 (PCA3), prostate health index (phi) and sarcosine. Anticancer Res 2015; 35: 1017–23

6 Loeb S. Time to replace prostate-speciﬁc antigen (PSA) with the Prostate Health Index (PHI)? Yet more evidence that the PHI consistently outperforms PSA across diverse populations. BJU Int 2015; 115: 500

7 Roobol M, Salman J, Azevedo N. Abstract 857: The Rotterdam prostate cancer risk calculator: improved prediction with more relevant pre-biopsy information, now in the palm of your hand. Stockholm: European Association of Urology, 2014

Video: Improving Prostate Cancer Risk Assessment Using The PHI

March 23, 2016/by admin Z.9

Improving Multivariable Prostate Cancer Risk Assessment Using The Prostate Health Index

Robert W. Foley*†, Laura Gorman*, Neda Shariﬁ‡, Keefe Murphy§¶, Helen Moore‡, Alexandra V. Tuzova**, Antoinette S. Perry**, T. Brendan Murphy§¶, Dara J. Lundon*††† and R. William G. Watson*†

*Conway Institute of Biomolecular and Biomedical Research, University College Dublin, †UCD School of Medicine and Medical Science, University College Dublin, ‡Department of Biochemistry, Beaumont Hospital, §UCD School of Mathematical Sciences, University College Dublin, ¶Insight Centre for Data Analytics, University College Dublin, **Prostate Molecular Oncology, Institute of Molecular Medicine, Trinity College Dublin, and ††Department of Urology, Mater Misericordiae University Hospital, Dublin, Ireland

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Objectives

To analyse the clinical utility of a prediction model incorporating both clinical information and a novel biomarker, p2PSA, in order to inform the decision for prostate biopsy in an Irish cohort of men referred for prostate cancer assessment.

Patients and Methods

Serum isolated from 250 men from three tertiary referral centres with pre-biopsy blood draws was analysed for total prostate-specific antigen (PSA), free PSA (fPSA) and p2PSA. From this, the Prostate Health Index (PHI) score was calculated (PHI = (p2PSA/fPSA)*√tPSA). The men’s clinical information was used to derive their risk according to the Prostate Cancer Prevention Trial (PCPT) risk model. Two clinical prediction models were created via multivariable regression consisting of age, family history, abnormality on digital rectal examination, previous negative biopsy and either PSA or PHI score, respectively. Calibration plots, receiver-operating characteristic (ROC) curves and decision curves were generated to assess the performance of the three models.

Results

The PSA model and PHI model were both well calibrated in this cohort, with the PHI model showing the best correlation between predicted probabilities and actual outcome. The areas under the ROC curve for the PHI model, PSA model and PCPT model were 0.77, 0.71 and 0.69, respectively, for the prediction of prostate cancer (PCa) and 0.79, 0.72 and 0.72, respectively, for the prediction of high grade PCa. Decision-curve analysis showed a superior net benefit of the PHI model over both the PSA model and the PCPT risk model in the diagnosis of PCa and high grade PCa over the entire range of risk probabilities.

Conclusion

A logical and standardized approach to the use of clinical risk factors can allow more accurate risk stratification of men under investigation for PCa. The measurement of p2PSA and the integration of this biomarker into a clinical prediction model can further increase the accuracy of risk stratification, helping to better inform the decision for prostate biopsy in a referral population.

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Article of the Week: NSAID use and ED risk

March 16, 2016/by admin Z.9

Every Week the Editor-in-Chief selects an 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 from Mr. Darshan Patel, discussing his paper.

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

Non-steroidal anti-inflammatory drug (NSAID) use is not associated with erectile dysfunction risk: results from the Prostate Cancer Prevention Trial

Darshan P. Patel, Jeannette M. Schenk*, Amy Darke†, Jeremy B. Myers, William O. Brant and James M. Hotaling

Division of Urology, University of Utah, Salt Lake City, UT, *Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, and †SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

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Objective

To evaluate the associations of non-steroidal anti-inflammatory drug (NSAID) use with risk of erectile dysfunction (ED), considering the indications for NSAID use.

Patients and Methods

We analysed data from 4 726 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) without evidence of ED at baseline. Incident ED was defined as mild/moderate (decrease in normal function) or severe (absence of function). Proportional hazards models were used to estimate the covariate-adjusted associations of NSAID-related medical conditions and time-dependent NSAID use with ED risk.

Results

Arthritis (hazard ratio [HR] 1.56), chronic musculoskeletal pain (HR 1.35), general musculoskeletal complaints (HR 1.36), headaches (HR 1.44), sciatica (HR 1.50) and atherosclerotic disease (HR 1.60) were all significantly associated with an increased risk of mild/moderate ED, while only general musculoskeletal complaints (HR 1.22), headaches (HR 1.47) and atherosclerotic disease (HR 1.60) were associated with an increased risk of severe ED. Non-aspirin NSAID use was associated with an increased risk of mild/moderate ED (HR 1.16; P = 0.02) and aspirin use was associated with an increased risk of severe ED (HR 1.16; P = 0.03, respectively). The associations of NSAID use with ED risk were attenuated after controlling for indications for NSAID use.

Conclusions

The modest associations of NSAID use with ED risk in the present cohort were probably attributable to confounding indications for NSAID use. NSAID use was not associated with ED risk.

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Editorial: PCPT May Exculpate COX Blockers in Erectile Dysfunction

March 16, 2016/by Quoc-Dien Trinh

NSAIDs are one of the most commonly used medications classes in the USA. Despite their ubiquity, they remain controversial. The withdrawal of the selective cyclooxygenase (COX)-2 inhibitor Rofecoxib in 2004 was a low point, culminating in a >$4.85 billion dollar (American dollars) settlement by Merck Pharmaceuticals. More recently, in July 2015 the USA Food and Drug Administration (FDA) strengthened a ‘black box warning’ (warning that appears on the package insert) on all NSAIDs for increased risks of heart attack, stroke, and heart failure (www.fda.gov/drugs/drugsafety). Given common vascular pathways in erectile dysfunction (ED) and heart disease, detrimental effects on sexual health have long been suspected as well. This month’s issue of BJUI provides a new perspective on this relationship and may help exculpate these common drugs [1].

It is thought that the cardiovascular risk of NSAIDs arises from inhibition of the COX-arachidonic acid synthesis pathway, which produces important mediators (e.g. eicosanoids like prostacyclin and various prostaglandin subtypes) for inflammation, vascular tone, and vascular permeability [2]. Given that many of the same chemical mediators affect erectile physiology, it is not surprising that a previous study of 80 966 men showed an association between NSAID use and ED after accounting for age, race, and comorbidities [3].

In ‘Non-steroidal anti-inflammatory drug use not associated with erectile dysfunction risk …’, Patel et al. [1] show that this risk may not be what it once seemed. They assess the risk of developing ED for men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) after first reported NSAID use. There is a small but statistically significant and consistent relationship between initiation of NSAID use and ED. Curiously, the association of NSAIDs with ED disappeared once they controlled for the indications for NSAID use such as arthritis, chronic pain, headaches, and cardiovascular disease. This finding makes sense: common indications for NSAIDs, like arthritis, headaches, and chronic musculoskeletal pain, may indicate an underlying sedentary lifestyle or chronic inflammatory conditions, both imputed in ED [4]. As such, this study design provides key epidemiological inference on the causal links between inflammation, lifestyle, and ED. It may be these factors, not NSAIDs themselves, which account for the previously shown association with ED.

With that said, epidemiological assessment of eicosanoid-mediated effects on ED may require further study. For example, NSAID-mediated downregulation of endothelial signalling molecules could produce a short-lived, but clinically significant effect on cavernosal blood supply. Alternatively, ED may only arise in the setting of chronic downregulation of affected pathways. Epidemiological studies characterising the relationship between NSAID use and ED should therefore assess the amount and duration of NSAIDs use, as well as the quality and timing of erections relative to use. Basic research may also help elucidate this relationship. Earlier studies have assessed cavernosal endothelial concentrations of these same vascular mediators in diabetic animal models [5]. In a similar fashion in vivo assessment of COX-derived mediators using animal models could further characterise the vascular pathways involved in erection and the effects of NSAID use.

Patel et al. [1] add a valuable contribution to the study of NSAIDs and ED. Their finding that NSAID-induced effects on ED disappear when controlling for the indications of NSAID, may support the inflammatory hypothesis of ED. But as others have noted, there is an intrinsic difficulty in retrospectively assessing the complex, multifactorial causes of sexual dysfunction [6]. Future studies on the amount and timing of NSAID use, paired with biochemical studies of vascular mediators in the cavernosal endothelium in NSAID users, may allow for even more nuanced characterisation of the effects of COX inhibition on erectile function. While logistically challenging, such studies could provide the key evidence for assessing the vascular pathways underlying ED and their relationship with NSAIDs.

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Alexander P. Cole, Jeffrey J. Leow, and Quoc-Dien Trinh

Center for Surgery and Public Health, Division of Urology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

References

1 Patel DP, Schenk JM, Darke A, Myers JB, Brant WO, Hotaling JM. Non-steroidal anti-inﬂammatory drug use not associated with erectile dysfunction risk: results from the Prostate Cancer Prevention Trial. BJU Int 2016; 117: 500–6

2 Antman EM, DeMets D, Loscalzo J. Cyclooxygenase inhibition and cardiovascular risk. Circulation 2005; 112: 759–70

3 Gleason JM, Slezak JM, Jung H et al. Regular nonsteroidal anti- inﬂammatory drug use and erectile dysfunction. J Urol 2011; 185: 1388–93

4 Vlachopoulos C, Rokkas K, Ioakeimidis N, Stefanadis C.Inﬂammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links. Eur Urol 2007; 52: 1590–600

5 Sullivan M, Thompson CS, Mikhailidis DP, Morgan RJ, Angelini GD, Jeremy JY. Differential alterations of prostacyclin, cyclic AMP and cyclic GMP formation in the corpus cavernosum of the diabetic rabbit. Br J Urol 1998; 82: 578–84

6 Lombardi G, Musco S, Kessler TM, Li Marzi V, Lanciotti M, Del Popolo G. Management of sexual dysfunction due to central nervous system disorders: a systematic review. BJU Int 2015; 115(Suppl.6): 47–56

Video: NSAID use is not associated with erectile dysfunction risk

March 16, 2016/by admin Z.9

Non-steroidal anti-inflammatory drug (NSAID) use is not associated with erectile dysfunction risk: results from the Prostate Cancer Prevention Trial

Darshan P. Patel, Jeannette M. Schenk*, Amy Darke†, Jeremy B. Myers, William O. Brant and James M. Hotaling

Read the full article

Objective

To evaluate the associations of non-steroidal anti-inflammatory drug (NSAID) use with risk of erectile dysfunction (ED), considering the indications for NSAID use.

Patients and Methods

Results

Conclusions

The modest associations of NSAID use with ED risk in the present cohort were probably attributable to confounding indications for NSAID use. NSAID use was not associated with ED risk.

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Article of the Week: Functional role of the TRPM8 ion channel in the bladder

March 9, 2016/by admin Z.9

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

Functional role of the transient receptor potential melastatin 8 (TRPM8) ion channel in the urinary bladder assessed by conscious cystometry and ex vivo measurements of single-unit mechanosensitive bladder afferent activities in the rat

Hiroki Ito*†, Naoki Aizawa*, Rino Sugiyama*‡, Shuzo Watanabe§, Nobuyuki Takahashi§, Masaomi Tajimi§, Hiroshi Fukuhara‡, Yukio Homma‡, Yoshinobu Kubota†, Karl-Erik Andersson¶ and Yasuhiko Igawa*

Departments of *Continence Medicine, ‡Urology, The University of Tokyo Graduate School of Medicine, Tokyo, †Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, §RaQualia Pharma Inc., Nagoya, Japan, and ¶Aarhus Institute of Advanced Studies, Aarhus University, Aarhus, Denmark

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Objective

To evaluate the role of the transient receptor potential melastatin 8 (TRPM8) channel on bladder mechanosensory function by using L-menthol, a TRPM8 agonist, and RQ-00203078 (RQ), a selective TRPM8 antagonist.

Materials and methods

Female Sprague–Dawley rats were used. In conscious cystometry (CMG), the effects of intravesical instillation of L-menthol (3 mm) were recorded after intravenous (i.v.) pretreatment with RQ (3 mg/kg) or vehicle. The direct effects of RQ on conscious CMG and deep body temperature were evaluated with cumulative i.v. administrations of RQ at 0.3, 1, and 3 mg/kg. Single-unit mechanosensitive bladder afferent activities (SAAs) were monitored in a newly established ex vivo rat bladder model to avoid systemic influences of the drugs. Recordings were performed after cumulative intra-aortic administration of RQ (0.3 and 3 mg/kg) with or without intra-vesical L-menthol instillation (3 mm).

Results

Intravesical L-menthol decreased bladder capacity and voided volume, which was counteracted by RQ-pretreatment. RQ itself increased bladder capacity and voided volume, and lowered deep body temperature in a dose-dependent manner. RQ decreased mechanosensitive SAAs of C-fibres, and inhibited the activation of SAAs induced by intravesical L-menthol.

Conclusion

Our results suggest that TRPM8 channels have a role in activation of bladder afferent pathways during filling of the bladder in the normal rat. This effect seems, at least partly, to be mediated via mechanosensitive C-fibres.

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Editorial: TRPM8 antagonists to treat LUTS- don’t lose your cool just yet

March 9, 2016/by Dirk De Ridder

The sensory mechanisms of the lower urinary tract enable our brain to continuously monitor the filling status of the bladder. During urine storage, low-level afferent information is mostly processed subconsciously. As the bladder fills up with urine, afferent signalling increases until we start feeling the urge to pass urine and we can consciously initiate voiding Under pathological conditions, such as urinary tract infection, overactive bladder or painful bladder syndrome, the afferent mechanisms become sensitized and lead to mechanical hypersensitivity, which is responsible for symptoms as urinary urgency, frequency and even pain.

In the current issue of BJUI, Ito et al. [1] describe the role of the ion channel transient receptor potential subtype melastatin 8 (TRPM8) in mechanosensation in the bladder (detection of the bladder’s filling status). By performing continuous cystometry in freely moving rats, they show that activation of TRPM8 decreases the threshold for initiation of micturition. I.v. administration of the TRPM8 antagonist RQ-00203078 significantly increased bladder capacity and voided volume. This antagonist also prevented the facilitating effects of intravesical L-Menthol, a TRPM8 agonist on the voiding reflex. Moreover in a specialized ex vivo rat model created to study the activity of mechanosensory fibres, pharmacological blockade of TRPM8 by RQ-00203078 inhibited single-unit mechanosensitive bladder afferent activity (SAA) during bladder filling. Conversely, L-Menthol facilitated SAA in a TRPM8-dependent manner. This indicates that TRPM8 activity directly influences the sensory information that is generated by mechanosensory neurons during urine accumulation.

TRPM8 is expressed in a subpopulation of dorsal root ganglion neurons that innervate the skin and the visceral organs, including the urinary bladder. Its activity can be increased by cold temperatures (<28 °C) and cooling chemicals, such as menthol and icilin; however, TRPM8 does not respond to mechanical stimuli in heterologous expression systems, suggesting that TRPM8 affects the excitability of mechanosensory neurons rather than acts as a mechanosensor itself [2].

Two recent publications have also highlighted the importance of TRPM8 in bladder hypersensitivity disorders. Uvin et al. [3] reported the pivotal role of TRPM8 in acute cold-induced urgency. Using rats and mice, they showed that exposure of part of the skin to innocuous cold evokes bladder contractions and reflex voiding in a TRPM8-dependent manner. Their findings provide a physiological basis for the worsening of storage symptoms in response to environmental cold stimuli, as a result of activation of TRPM8. Using the oral TRPM8 antagonist PF-05105679, Winchester et al. [4] described TRPM8 as the essential cold sensor in the bladder cooling reflex in guinea pigs. Importantly, this group also conducted a phase I clinical trial using this antagonist. In their trial, PF-05105679 successfully blocked cold-induced pain in healthy volunteers who were exposed to the cold pressor test.

Altogether these data strongly support the therapeutic potential of TRPM8 modulators to treat bladder hypersensitivity disorders. Unfortunately, because of the widespread expression of these channels and their role in various homeostatic and sensory processes, pharmacological inhibition of TRP channels often leads to side effects that limit their clinical use [5]. In preclinical models, inhibition of TRPM8 leads to transient hypothermia, which was confirmed by Ito et al. [1]. They observed a dose-dependent decrease in deep body temperature after i.v. administration of RQ-00203078. In the only published clinical trial so far, PF-05105679 did not induce hypothermia but evoked a dose-dependent peri-oral burning sensation. This unexpected side effect limits the further clinical development of PF-05105679 and potentially of all TRPM8 antagonists.

In conclusion, our increasing knowledge about the functional role of TRPM8 in the urinary bladder is important to better understand the pathophysiology of functional bladder disorders, but does not yet offer an adequate therapeutic solution.

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Wouter Everaerts, *,† and Dirk De Ridder, *,†

*Department of Development and Regeneration, Urology, KU Leuven, and †TRP Research Platform Leuven (TRPLe), KU Leuven, Leuven, Belgium

References

1 Ito H, Aizawa N, Sugiyama R et al. Functional role of the transient receptor potential melastatin 8 (TRPM8) ion channel in the urinary bladder assessed by conscious cystometry and ex vivo measurements of single-unit mechanosensitive bladder afferent activities in the rat. BJU Int 2016; 117: 484–94

2 Kaneko Y, Szallasi A. Transient receptor potential (TRP) channels: a clinical perspective. Br J Pharmacol 2014; 171: 2474–507

3 Uvin P, Franken J, Pinto S et al. Essential role of Transient Receptor Potential M8 (TRPM8) in a model of acute cold-induced urinary urgency. Eur Urol 2015; 68: 655–61

4 Winchester WJ, Gore K, Glatt S et al. Inhibition of TRPM8 channels reduces pain in the cold pressor test in humans. J Pharmacol Exp Ther 2014; 351: 259–69

5 Deruyver Y, Voets T, De Ridder D, Everaerts W. Transient receptor potential channel modulators as pharmacological treatments for lower urinary tract symptoms (LUTS): myth or reality? BJU Int 2015; 115: 686–97

Article of the Month: ERSPC and PCPT risk calculators in prostate cancer risk prediction

March 2, 2016/by admin Z.9

Every Month the Editor-in-Chief selects an Article of the Month 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.

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

Prostate cancer risk prediction using the novel versions of the European Randomised Study for Screening of Prostate Cancer (ERSPC) and Prostate Cancer Prevention Trial (PCPT) risk calculators: independent validation and comparison in a contemporary European cohort

Cedric Poyet, Daan Nieboer*, Bimal Bhindi†, Girish S. Kulkarni†, Caroline Wiederkehr, Marian S. Wettstein, Remo Largo, Peter Wild‡, Tullio Sulser and Thomas Hermanns

Department of Urology, University Hospital Zurich, University of Zurich, Zurich, Switzerland, *Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands, †Division of Urology, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada, and ‡Institute of Surgical Pathology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

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Objectives

To externally validate and compare the two novel versions of the European Randomised Study for Screening of Prostate Cancer (ERSPC)-prostate cancer risk calculator (RC) and Prostate Cancer Prevention Trial (PCPT)-RC.

Patients and Methods

All men who underwent a transrectal prostate biopsy in a European tertiary care centre between 2004 and 2012 were retrospectively identified. The probability of detecting prostate cancer and significant cancer (Gleason score ≥7) was calculated for each man using the novel versions of the ERSPC-RC (DRE-based version 3/4) and the PCPT-RC (version 2.0) and compared with biopsy results. Calibration and discrimination were assessed using the calibration slope method and the area under the receiver operating characteristic curve (AUC), respectively. Additionally, decision curve analyses were performed.

Results

Of 1 996 men, 483 (24%) were diagnosed with prostate cancer and 226 (11%) with significant prostate cancer. Calibration of the two RCs was comparable, although the PCPT-RC was slightly superior in the higher risk prediction range for any and significant prostate cancer. Discrimination of the ERSPC- and PCPT-RC was comparable for any prostate cancer (AUCs 0.65 vs 0.66), while the ERSPC-RC was somewhat better for significant prostate cancer (AUCs 0.73 vs 0.70). Decision curve analyses revealed a comparable net benefit for any prostate cancer and a slightly greater net benefit for significant prostate cancer using the ERSPC-RC.

Conclusions

In our independent external validation, both updated RCs showed less optimistic performance compared with their original reports, particularly for the prediction of any prostate cancer. Risk prediction of significant prostate cancer, which is important to avoid unnecessary biopsies and reduce over-diagnosis and overtreatment, was better for both RCs and slightly superior using the ERSPC-RC.

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Editorial: Prostate cancer risk prediction and the persistence of uncertainty

March 2, 2016/by Dara Lundon

Poyet et al. [1] have performed the largest external validation of the European Randomised Study for Screening of Prostate Cancer (ERSPC) and Prostate Cancer Prevention Trial (PCPT) v2.0 risk calculators (RCs) to date, having retrospectively identified 1996 men undergoing prostate biopsy in a Swiss tertiary care facility.

Asides from the validatory nature of this paper [1], there are several other findings though less novel, which are further important additions to the urological literature.

This study confirms the superior discriminative performance of multi-factorial RCs over PSA alone in the assessment of prostate cancer: where the area under the receiver operating characteristic curve (AUC) for the prediction of significant prostate cancer for PSA alone was 0.65, comparing less favourably than 0.73 and 0.70 for the ERSPC and PCPT v2.0 RCs, respectively.

The authors performed sensitivity analysis showing higher detection rates for prostate cancer (29.4% vs 18.1%) and significant prostate cancer (15.9% vs 5.9%) in patients receiving a 12-core biopsy than in those receiving a 6–8 core biopsy.

Supplementary analysis by the authors evaluated the performance of previous versions of the PCPT-RC, specifically v1.0 and PCPT-RC v1.0 with prostate volume. The inclusion of prostate volume demonstrated an improved predictive ability of this RC. The AUC for the prediction of significant prostate cancer using the PCPT-RC v1.0 with prostate volume was 0.74. This contrasts with the ERSPC risk tool: AUC of 0.73 (which includes a trichotomised estimation of prostate volume), and the novel PCPT-RC v2.0; AUC of 0.70 (which does not include prostate volume as a factor).

The authors conclude that the prediction of significant prostate cancer was superior using the ERSPC-RC compared with the PCPT-RC v2.0, in risk thresholds of 8–35%. Their data also shows that the PCPT-RC v2.0 offers a superior net benefit to the ERPSC-RC to a large number of men outside of this range of threshold probabilities. Their findings suggest that the older PCPT-RC v1.0 with prostate volume may offer benefits superior to both the ERSPC and PCPT v2.0 RCs.

The authors assessment of novel risk tools confirms the rationale for guidelines and consensus statements that PSA testing should not be considered on its own, but rather as part of a multivariate approach [2, 3]. This current work suggests that although calibration of risk tools is still not optimal, they offer superior discriminative ability and superior net benefit in identifying patients with significant prostate cancer. This work affirms the role for variables such as DRE, and the importance of prostate volume in addition to PSA in prostate cancer assessment.

Although further refinement of risk tools is necessary, this work encourages confidence in and should garner further traction for the routine use of such tools in the assessment and counselling of patients before prostate biopsy.

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Dara J. Lundon*†

*Conway Institute of Biomedical and Biomolecular Science, University College Dublin School of Medicine and Medical Sciences, University College Dublin, Belﬁeld, and †Department of Urology, Mater Misericordiae University Hospital, Dublin, Ireland

References

1 Poyet C, Nieboer D, Bhindi B et al. Prostate cancer risk prediction using the novel versions of the European Randomised Study for Screening of Prostate Cancer (ERSPC) and Prostate Cancer Prevention Trial (PCPT) risk calculators: independent validation and comparison in a contemporary Europe. BJU Int 2016; 117: 401–8

2 Murphy DG, Ahlering T, Catalona WJ et al. The Melbourne Consensus Statement on the early detection of prostate cancer. BJU Int 2014; 113: 186–8

3 Heidenreich A, Abrahamsson PA, Artibani W et al. Early detection of prostate cancer: European Association of Urology recommendation. Eur Urol 2013; 64: 347–54

Article of the Week: The impact of PSMs on long-term outcomes after RP

February 24, 2016/by admin Z.9

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 from Dr. Prabhakar Mithal, discussing his paper.

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

Positive Surgical Margins in Radical Prostatectomy Patients Do Not Predict Long-term Oncological Outcomes: Results from SEARCH

Prabhakar Mithal, Lauren E. Howard†‡, William J. Aronson§¶, Martha K. Terris**††, Matthew R. Cooperberg‡‡, Christopher J. Kane§§, Christopher Amling¶¶ and Stephen J. Freedland‡***

Department of Urology, University of Rochester Medical Center, Rochester, NY, †Department of Biostatistics and Bioinformatics, Duke University School of Medicine, ‡Division of Urology, Veterans Affairs Medical Center, Durham, NC, §Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, ¶Department of Urology, UCLA School of Medicine, Los Angeles, CA, **Section of Urology, Veterans Affairs Medical Center, ††Section of Urology, Medical College of Georgia, Augusta, GA, ‡‡Department of Urology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, §§Urology Department, University of California San Diego Health System, San Diego, CA , ¶¶Division of Urology, Department of Surgery, Oregon Health and Science University, Portland, OR , and ***Division of Urology, Department of Surgery, Cedars Sinai Medical Center, Los Angeles, CA, USA

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Objective

To assess the impact of positive surgical margins (PSMs) on long-term outcomes after radical prostatectomy (RP), including metastasis, castrate-resistant prostate cancer (CRPC), and prostate cancer-specific mortality (PCSM).

Patients and Methods

Retrospective study of 4 051 men in the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort treated by RP from 1988 to 2013. Proportional hazard models were used to estimate hazard ratios (HRs) of PSMs in predicting biochemical recurrence (BCR), CRPC, metastases, and PCSM. To determine if PSMs were more predictive in certain patients, analyses were stratified by pathological Gleason score, stage, and preoperative prostate-specific antigen (PSA) level.

Results

The median (interquartile range) follow-up was 6.6 (3.2–10.6) years and 1 127 patients had >10 years of follow-up. During this time, 302 (32%) men had BCR, 112 (3%) developed CRPC, 144 (4%) developed metastases, and 83 (2%) died from prostate cancer. There were 1 600 (40%) men with PSMs. In unadjusted models, PSMs were significantly associated with all adverse outcomes: BCR, CRPC, metastases and PCSM (all P ≤ 0.001). After adjusting for demographic and pathological characteristics, PSMs were associated with increased risk of only BCR (HR 1.98, P < 0.001), and not CRPC, metastases, or PCSM (HR ≤1.29, P > 0.18). Similar results were seen when stratified by pathological Gleason score, stage, or PSA level, and when patients who underwent adjuvant radiotherapy were excluded.

Conclusions

PSMs after RP are not an independent risk factor for CRPC, metastasis, or PCSM overall or within any subset. In the absence of other high-risk features, PSMs alone may not be an indication for adjuvant radiotherapy.

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