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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

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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.

Read the full article
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

 

Editorial: PCPT May Exculpate COX Blockers in Erectile Dysfunction

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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.

Read the full article
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

 

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

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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

 

Editorial: Prostate cancer risk prediction and the persistence of uncertainty

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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.

Read the full article
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

 

Editorial: Should we worry about positive surgical margins in prostate cancer?

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The debate on the impact of positive surgical margins (PSMs) after radical prostatectomy (RP) continues. The study by Mithal et al. [1] in the present issue contributes further data to an extensive and growing body of literature addressing the clinical significance of a PSM after RP, and ultimately alludes to the question of how to manage these patients.

The authors [1] use the SEARCH database, a large dataset comprised of patients from multiple Veterans Affairs Medical Centers across the USA, to collect and report data on oncological outcomes of PSMs after RP. After adjusting for demographic and pathological confounders, use of adjuvant therapy, and the competing risk of non-prostate-cancer-related death, PSMs were significantly associated with an increased hazard of biochemical recurrence (BCR; hazard ratio 1.99, 95% CI 1.76–2.26), but not castrate resistant prostate cancer (CRPC), metastases, or mortality (prostate-cancer specific or overall). The current study [1], takes such analysis a step further and reports that PSMs were not associated with a negative impact on hard clinical outcomes (CRPC, metastasis, and prostate cancer-specific mortality [PCSM]) in those subgroups at the highest risk of disease progression (high Gleason stage, T-stage, and PSA level). These findings are not necessarily novel, but rather consistent with much of the prior literature. The detrimental impact of PSMs on BCR is well documented [2]. However, the impact of PSMs on hard clinical outcomes such as CRPC, metastasis, and PCSM has not been well demonstrated, despite multiple studies with large cohorts and extensive follow-up.

The negative consequence of a PSM on long-term patient outcome is a very intuitive concept, as it indicates cancer has been inadequately resected or ‘left behind’. Furthermore, the negative impact of a PSM on hard clinical outcomes is well established in many surgically treated malignancies. However, in prostate cancer there remains a disconnect between PSMs and hard clinical outcomes. The authors of the current study [1] provide further evidence to reiterate that the course of this disease after a PSM is not absolute, immediate, or even necessarily concerning (at least in the intermediate follow-up). A PSM after RP may increase the likelihood of BCR but this does not necessarily equal imminent progression and/or death.

PSMs are reported in 10–31% of patients undergoing RP, thus emphasising the clinical importance of this question [3, 4]. Despite the current findings [1], PSMs should not be dismissed. The management of a PSM after RP remains complicated. A proportion of patients will progress and succumb to this disease and, furthermore, therapeutic interventions with shown benefit are available to address such concerns. The decision on how aggressively to manage PSMs may involve an understanding of the patient (comorbidities, lifestyle, and preferences) along with an informed discussion. Furthermore, other pathological details not captured in this study [1] (tumour margin extent and location) [5, 6], along with longer follow-up may be important in identifying drivers for this disease and how to better stratify patients. As with many clinical questions, the approach to PSMs after RP is not necessarily clearly defined and may not apply similarly to all patients across the board. This study [1] may not answer whether or not we should worry about PSMs in prostate cancer, but contributes to our ability to develop clinical algorithms and informed decisions in these patients.

Read the full article

 

Stanley A. Yap
Department of Urology, University of California Davis Medical Center, 4860 Y Street, Suite 3500, Sacramento, CA, 95817,
USA

 

References
Mithal P, Howard LE, Aronson WJ et al. Positive surgical margins in radical prostatectomy patients do not predict long-term oncological outcomes: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) cohort. BJU Int 2015; 117: 244–48

 

2 Karakiewicz PI, Eastham JA, Graefen M et al. Prognostic impact of positive surgical margins in surgically treated prostate cancer: multi- institutional assessment of 5831 patients. Urology 2005; 66: 1245–50

 

3 Boorjian SA, Karnes RJ, Crispen PL et al. The impact of positive surgical margins on mortality following radical prostatectomy during the prostate specific antigen era. J Urol 2010; 183: 1003–9

 

4 ChalfinHJ, Dinizo M, Trock BJ et al. Impact of surgical margin status on prostate-cancer-specific mortality. BJU Int 2012; 110: 1684–9

 

5 Brimo F, Partin AW, Epstein JI. Tumor grade at margins of resection in radical prostatectomy specimens is an independent predictor of prognosis. Urology 2010; 76: 1206–9

 

6 Fontenot PA, Mansour AM. Reporting positive surgical margins after radical prostatectomy: time for standardization. BJU Int 2013; 111: E290–9

 

Where we are with screening and risk prediction for prostate cancer in 2016

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March Editorial ImageThe rate of PSA-based screening over the last 35 years can be compared with driving your car from the Netherlands to Italy. It starts with a rather flat drive, perhaps a few hills in the Southern part of the Netherlands, which represents the rate of PSA screening in the late 1980s. Moving with high speed through Germany, one gradually climbs to higher altitudes, i.e. the rate of PSA testing in the 1990s. Then the high (but very difficult to drive) summits and beautiful valleys of Switzerland are there, representing PSA testing practices in the new millennium and the decline in metastatic disease and related mortality [1]. Finally, we descend to Italy’s Po valley, comparable to PSA testing rates, especially in the USA after the recommendations of the USA Preventive Services Task Force [2,3].
The question is what will we do next? Will we take a left turn and slowly disappear into the sea like Venice? That is, returning to a situation where one out of two or three men died from their prostate cancer? [4] Or will we stop our car, look behind, see the beautiful landscape and return taking the Gotthard road tunnel, avoiding spillage of petrol (i.e. unnecessary PSA testing and potentially harmful prostate biopsies) and go straight to the valleys of Switzerland?
The first option is obviously not the way to go. Unfortunately, the recommendation to stop the use of the PSA test as a screening tool is a direct consequence of the rapid and uncontrolled uptake of the test, often followed by a random biopsy resulting in over-diagnosis and subsequent overtreatment. However, there are ample tools available to turn this situation around and reduce the negative effects of prostate cancer screening [5,6].
An example of such an approach can be found in the publication of Poyet et al. [7] in this issue of BJUI. In this study, the investigators validated updated versions of two multivariate risk-prediction tools, i.e. prostate cancer risk calculators (RCs), in a cohort of 1996 men all biopsied (6-, 8- or 12-core random biopsy) on the basis of an elevated PSA level or abnormal DRE. The data showed that both RCs outperformed the PSA/ DRE-based strategy in reducing unnecessary testing, and in addition avoided over-diagnosis. As said, this approach is one of the many opportunities to reduce the negative aspects of PSA-based screening all summarised in the different guidelines [8]. Reading these guidelines, it soon becomes clear that it is known that repeatedly testing men with low PSA levels is useless. It is known that screening men with a limited life expectancy will only cause harm, and that simply repeating a prostate biopsy after a negative biopsy result (i.e. no prostate cancer detected) is not the way to go. And yet, this is what we see happening in daily clinical practice [9,10].
So, where are we with prostate cancer screening and risk prediction in 2016? We are in a situation that we know that we can reduce suffering and death from (metastatic) prostate cancer, with early detection and treatment, but that we have to selectively identify men that can actually benefit. The latter is realistic if we start to implement the knowledge we have acquired over recent decades.

 

Monique J. Roobol
Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands

 

References

 

1 Schroder FH, Hugosson J, Roobol MJ et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 2014; 384: 2027–35

 

2 Moyer VA; U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 157: 120–34

 

3 Banerji JS, Wolff EM, Massman JD 3rd, Odem-Davis K, Porter CR, Corman JM. Prostate Needle Biopsy Outcomes in the Era of the U.S. Preventive Services Task Force Recommendation against Prostate Specific Antigen Based Screening. J Urol 2016; 195: 66–73

 

4 Hsing AW, Tsao L, Devesa SS. International trends and patterns of prostate cancer incidence and mortality. Int J Cancer 2000; 85: 60–7

 

5 Roobol MJ, Carlsson SV. Risk stratification in prostate cancer screening. Nat Rev Urol 2013; 10: 38–48

 

6 Emberton M. Doubling our precision of risk stratification in early prostate cancer: too good to be true? BJU Int 2016; 117: 8–9

 

7 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 European cohort. BJU Int 2016; 117: 401–8

 

8 Loeb S. Guideline of guidelines: prostate cancer screening. BJU Int 2014; 114: 323–5

 

9 Nordstrom T, Aly M, Clements MS, Weibull CE , Adolfsson J, Gronberg H . Prostate-specific antigen (PSA) testing is prevalent and increasing in Stockholm County, Sweden, Despite no recommendations for PSA screening: results from a population-based study, 2003-2011. Eur Urol 2013; 63: 419–25

 

10 Drazer MW, Huo D, Eggener SE. National Prostate Cancer Screening Rates after the 2012 US Preventive Services Task Force recommendation discouraging prostate-specific antigen-based screening. J Clin Oncol 2015; 33: 2416– 23

 

Correction: The word “their” was added to this sentence to clarify its meaning: “That is, returning to a situation where one out of two or three men died from their prostate cancer? [4]”

 

 

Editorial: When two and two don’t make four

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Many drugs are chiral, i.e. the enantiomers (isomers) cannot be superimposed on their mirror images. It has long been known that if a drug is chiral, then in biological terms, the isomers invariably differ in activity [1]. One isomer may specifically interact with a cell receptor to produce the desired outcome while the other might have no useful application or might have an unwanted pharmacological or even a toxicological effect through some other interaction.

In the clear-cut example where one isomer of a chiral compound is ‘good’ and the other ‘bad’, there is obvious benefit from developing the drug as the single isomer to enhance its safety and tolerability. The paper in the present issue of BJUI by Fontenot et al. [2] on the differential activity of the enantiomers of clomiphene elegantly exemplifies this in terms of potential toxicity.

Since 1992 the US Food and Drugs Administration and the European Medicines Agency have required manufacturers to research and characterize each enantiomer in all drugs proposed to be marketed as a mixture. The assumption was that a mixture may not manifest clinically as a simple algebraic summation of the biological characteristics of the individual components. From that date, production of new racemates (mixture of enantiomers) ceased to be a rational commercial option and instead became a high-risk route for pharmaceutical companies.

With respect to the enantiomers of clomiphene, it was undoubtedly the differential toxicological profile [2], coupled with relative primary activity as oestrogen antagonists [3], that resulted in the prioritization of Enclomiphene for late stage clinical development. It is this isomer that forms the basis of the submission to the regulatory authorities for the treatment of secondary hypogonadism.

The present paper in some ways reinforces what we already knew; isomers can have differential activity. What is unusual is that what is presented is not pharmacological evidence but clear-cut differences in toxicological profile.

The research raises a specific issue in relation to the treatment of secondary hypogonadism. In general, patients with secondary hypogonadism require restoration of normal testosterone levels while preserving fertility. As such, the use of exogenous testosterone for replacement can be counter-productive as there is a well-documented negative impact on spermatogenesis [4]. As an alternative, ‘off-label’ clomiphene is relatively widely proffered. Assuming approval, Enclomiphene would provide an attractive alternative to its racemic ‘parent’.

Overall, the present paper is a useful reminder of what we think we know; that is, that all racemates are likely to manifest the characteristics of both component enantiomers.

Read the full article
Michael G. Wyllie
Global Pharma Consulting Ltd, Banbury, UK

 

Conflict of Interest

The author is an independent director on the board of Repros Therapeutics.

 

References
1 Smith DF. The stereoselectivity of drug action. Pharmacol Toxicol 1989; 65: 321–31
2 Fontenot GK, Wiehle RD, Podolski JS. Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice.BJU Int 2015; 117: 344–50
3 Murdter T, Kerb R, Turpeinen M et al. Genetic polymorphism of cytochrome P450 2D6 determines oestrogen receptor activity of the major infertility drug clomiphene via its active metabolites.Hum Mol Genet 2012; 21: 1145–54
4 Wiehle RD, Fontenot GK, Wike J et al.Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone.Fertil Steril 2014; 102: 720–7

 

Editorial: Should we start with low-dose anti-cholinergics when alpha-blockers alone fail?

/1 Comment/by

Kim et al. [1] asked the question whether we should start by treating men who have persistent storage LUTS despite α-blocker monotherapy, with a low-dose anti-cholinergic as opposed to the standard dose (given the potentially increased risk of side-effects such as acute urinary retention and high discontinuation rates with the standard dose). It is a valid question, for we know that discontinuation rates with standard doses of anti-cholinergics can be as high as 50% in the first 3 months due to a combination of ineffectiveness and side-effects [2]. However, the problem lies in the multifactorial nature of the causes of storage vs voiding LUTS, and the difficulty in assessing and distinguishing them accurately with our current tools.

The authors have conducted a randomised controlled trial of 2 mg vs 4 mg tolterodine added to the participants’ on-going α-blocker regime and selected reduction in total IPSS as their primary outcome measure. They have also assessed IPSS sub-scores, 3-day bladder diary variables, and the Patient Perception of Bladder Condition (PPBC) and Overactive Bladder (OAB-q) questionnaires, as secondary outcomes. As would be expected of a peer-reviewed publication the trial has been seemingly well conducted and fairly well reported. Recruitment met the requirement set by the power calculation based on a clinically significant difference of a 4-point drop in total IPSS, and the authors concluded that 2 mg tolterodine is not inferior to the 4 mg dose in achieving a significant reduction in total IPSS at 12 weeks. They also report no difference in patient perception of treatment benefit or satisfaction at this time point.

These results are interesting, especially considering some of the details of the study. First of all, patients were not on the same α-blocker at baseline; the most common was tamsulosin (62.8%), but alfuzosin, doxazosin, and others were also being used. This in itself may not be a problem because all patients continued on the same α-blocker through the study, and in fact this better represents real-world practice. However, the mean (sd) duration of α-blocker therapy at baseline was 9.1 (19.9) months. We know that α-blocker therapy can improve IPSS by up to 30–40% [3], but the pertinent question for this study is whether these patients had achieved this level of improvement initially then stabilised and improved no further, or whether they had no improvement at all? It could conceivably make a difference to participants approach to the IPSS if they were previously familiar with it and, more importantly, aware of their results. The Hawthorne effect, also known as the observer effect, and the related Heisenberg uncertainty principle, are factors that we must necessarily encounter in clinical trials but we sometimes fail to account for.

Another aspect of the study that warrants consideration is the choice of primary outcome itself. This is a particular bug-bear of mine and indeed has been commented on by many authors including in the European Association of Urology (EAU) guideline on urinary incontinence in relation to anti-muscarinics [4]. Outcomes that lend themselves to easier power calculations and statistically significant results have almost evolved to be ‘un’-naturally selected for the purpose of clinical trial primary outcome measures. Drug trials are especially notorious for this. Here again, the choice of the total IPSS to assess whether an anti-muscarinic will help improve persistent storage LUTS is a case in point. Not least because it renders the significance of all the secondary outcomes dependant on the same power calculation. It is no doubt convenient, but is it appropriate? It is easy to point the finger at trialists for this, but the business-like, ‘bottom-line’ nature of medical publishing and research today is equally, if not more, to blame.

Finally, I would like to call the reader’s attention to the difference in baseline urgency and urgency urinary incontinence (UUI) episodes. The author’s state there was no statistically significant difference, but one might argue that when assessing improvement in storage LUTS, a group with a mean (sd) baseline number of UUI episodes of 3.9 (8.6) may perceive improvement quite differently compared with a group with a baseline of 1.6 (1.1). This has borne out in the difference in the bladder diary outcome of UUI/24 h; significant improvement in the first group (who were wetter at baseline and got 4 mg tolterodine) but no difference in the latter group (comparatively drier and got 2 mg tolterodine). But almost paradoxically this does not seem to have made a difference to the patient-reported outcome measures. One possible explanation for this could be the relatively few patients who were incontinent at baseline.Overall this paper gives us a lot of food for thought. The direct result – should we indeed start men with persistent storage LUTS on low-dose anti-cholinergics rather than standard dose, and then titrate upwards? But it also challenges us to consider whether we simply accept researcher’s and sponsor’s decisions on outcome measures. What do you think? Do we simply sit back and accept what is put before us because statistics scares us a little? Or, as researchers and consumers of medical literature, do we struggle to make the hard choices, risk our results being rejected by the top journals, and stand up for good science?

Conflicts of Interest

The author has received a travel grant to attend an international conference from Ferring pharmaceuticals.

 

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Arjun K. Nambiar
Clinical Research Registrar
Department of Urology, Morriston Hospital, Abertawe Bro Morgannwg (ABM) University Local Health Board, Swansea, SA6 6NL, UK

 

References

 

1 Kim TH, Jung W, Suh YS, Yook S, Sung HH, Lee KS. Comparison of the efficacy and safety of tolterodine 2 mg and 4 mg combined with an a-blocker in men with lower urinary tract symptoms (LUTS) and overactive bladder: a randomized controlled trial. BJU Int 2015; 117:  307–15
2 Lucas MG, Bedretdinova D, Berghmanset LC et al. Guidelines on Urinary Incontinence, Section 4.2.4. In: EAU Guidelines, edition presented at the 30th EAU Annual Congress, Madrid 2015. ISBN 978-90-79754-80-9. Available at: https://uroweb.org/wp-content/uploads/17-Urinary-Incontinence_LR.pdf. Accessed September 2015
3 Gravas S, Bach T, Bachmann A et al. Guidelines on Non-Neurogenic Male LUTS Including Benign Prostatic Obstruction, Section 3C.2. In: EAU Guidelines, edition presented at the 30th EAU Annual Congress, Madrid 2015. ISBN 978-90-79754-80-9. Available at: https://uroweb.org/wp-content/uploads/11-Male-LUTS_LR.pdf. Accessed September 2015
4 Lucas MG, Bedretdinova D, Berghmanset LC et al. Guidelines on Urinary Incontinence, Section 4.2.1. In: EAU Guidelines, edition presented at the 30th EAU Annual Congress, Madrid 2015. ISBN 978-90-79754-80-9. Available at: https://uroweb.org/wp-content/uploads/17- Urinary-Incontinence_LR.pdf. Accessed September 2015

 

Editorial: Penis cancer management – insight into the future

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The report of Jakobson et al. [1] assesses the results of the sentinel node procedure for penis carcinoma in Denmark. The sentinel node procedure was done in four university hospitals. In this geographically small country with little more than 5.6 million inhabitants and a case load of 50 patients with penis cancer per year, a distribution of care of patients with penis cancer over four hospitals seems reasonable at first sight.

The results show interesting elements. With a false-negative rate of 10.8%, the figure is in accordance with what is known from other series, albeit at the high end of the range [2]. The authors rightly acknowledge that there is room for improvement. It seems likely that centralising the procedure to two hospitals, as of 2009, will be instrumental in this endeavour.

The authors did not find a learning curve, underscoring the safe introduction of this procedure.

The experience testifies to the reliability of the procedure with a minimum of complications and morbidity. Despite inter-institutional variation no major differences were detected. The authors conclude that 76% of node dissections could be avoided.

More than 15 years after the first publication on the sentinel node procedure in a urological cancer, the debate on how to manage clinically node-negative patients is still not completely settled and the sentinel node procedure in penis cancer is not universally accepted [3].

Why?

There has been no randomised study comparing standard inguinal lymph node dissection to the sentinel node procedure. Comparisons of series with standard node dissection vs the sentinel node procedure have shown improved survival for the latter [4]. Nevertheless, in the absence of randomisation these figures have not convinced the whole urological community.

Advocates of the sentinel node procedure tend to emphasise the avoidance of unnecessary inguinal node dissections. Opponents tend to emphasise the false-negative rates with its ensuing risk of seriously jeopardising the patients, as some of the patient die from disease.

Oncological care has to seek the most rational balance between too much and too little, realising that 100% success does virtually not exist. It is reasonable to assume that if all elements of the chain necessary to deliver state-of-the-art treatment of penis cancer, the figures of false-negative sentinel node procedures should be around 4–5%. With meticulous follow-up, recurrences should be detected at the earliest possible moment, decreasing the risk of a fatal outcome. A 5% risk is a generally accepted figure to avoid a potentially harmful procedure. New tracers give hope that false-negative rates can even be improved, realising again that some failures have to be accepted as a fact of life [5, 6].

Opponents point to the technicalities of the procedure. True as it is, there is no modern hospital without all the equipment and the expertise, accumulated in other areas in oncology, necessary to perform a state of the art sentinel node procedure.

Is there reluctance to refer patients with penis cancer or is there a strong reason to rely on inguinal node dissection only? There can hardly be a financial motive considering the rarity of the disease. Is it fear for degradation of the trade by losing another surgical procedure, infringement of the surgical ego?

The management of penis cancer is exemplary for changes in health care. While initially four university hospitals were involved, this is further scaled down to two hospitals. Earlier in the Netherlands, the management of >75% of the patients with penis cancer in one institution led to the highest survival of these patients worldwide (88.3%) [7].

Introduction of a new procedure in medicine has to date been a more or less individual effort. This will be of the past with current health policy and a wealth of data on the effect of centralisation. A central introduction of a new procedure in a limited number of institutions and more rational distribution of care with dedicated professionals in institutions suited for the procedure will be the rule.

The future of lymph node staging looks bright for any urological cancer. There will be a day where discussions on sentinel node and the extent of the dissection will be of the past. Our successors will look with bewilderment at our discussions on sentinel node, extended, super-extended or minimal dissections and the failures to grasp the exact mechanisms of lymphatic invasion and the true role of surgical removal. Imaging methods will give unprecedented insight in nodes invaded by tumour. Smart molecules will kill specifically nodal metastases and will revert the process of lymphangiogenesis enhanced by effective immunotherapy.

But before we see these times, the treatment of patients with penis cancer will be completely centralised worldwide to the benefit of these patients.

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Simon Horenblas

 

Department of Urology, Netherlands Cancer Institute, Antonivan Leeuwenhoek Hospital, Amsterdam, The Netherlands

 

References

 

1 Jakobsen JK, Krarup KP, Sommer P et al. DaPeCa-1: diagnostic accuracy of sentinel lymph node biopsy in 222 patients with penile cancer at four tertiary referral centres – a national study from Denmark. BJU Int 2015; 117: 235–43

 

2 Sadeghi R, Gholami H, Zakavi SR, Kakhki VR, Tabasi KT, Horenblas S. Accuracy of sentinel lymph node biopsy for inguinal lymph node staging of penile squamous cell carcinoma: systematic review and meta-analysis of the literature. J Urol 2012; 187: 25–31

 

3 Horenblas S, Jansen L, Meinhardt W, Hoefnagel CA, de Jong D, Nieweg OE. Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure. J Urol 2000;
163: 100–4

 

4 Djajadiningrat RS, Graa fland NM, van Werkhoven E et al. Contemporary management of regional nodes in penile cancer-improvement of survival? J Urol 2014; 191: 68–73

 

5 Brouwer OR, van den Berg NS, Matheron HM et al. A hybrid radioactive and fluorescent tracer for sentinel node biopsy in penile carcinoma as a potential replacement for blue dye. Eur Urol 2014; 65: 600–9

 

6 Brouwer OR, van den Berg NS, Matheron HM et al. Feasibility of intraoperative navigation to the sentinel node in the groin using preoperatively acquired single photon emission computerized tomography data: transferring functional imaging to the operating room. J Urol 2014; 192: 1810–6

 

7 Visser O, Adolfsson J, Rossi S et al. Incidence and survival of rare urogenital cancers in Europe. Eur J Cancer 2012; 48: 456–64

 

Editorial: %p2PSA and PHI improve diagnostic accuracy for prostate cancer

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Serum samples from patients with prostate cancer (PCa) are measured routinely for total PSA (tPSA) and complexed PSA as a part of the diagnostic evaluation. In addition, a variety of molecular isoforms of the PSA molecule can be assayed, including free PSA (fPSA), %freePSA, [-2]proPSA, %[-2]proPSA and the new combined calculation, termed the Prostate Health Index (PHI), which is calculated using [-2]proPSA, fPSA and tPSA. The PHI was developed by Beckman Coulter immunoassays and is performed on Access-2- or DxI800-instruments. Numerous clinical studies have been conducted with the isoforms of PSA (fPSA, %fPSA, [-2]proPSA and %[-2]ProPSA) to test the PCa diagnosis and prognosis predictions, and to predict the need for rebiopsies [1]. In addition to these various molecular isoforms of US Food and Drug Administration-approved clinical bioassays for PSA, several PSA-computed derivatives have also been developed to assess kinetics such as PSA velocity, PSA density and PSA doubling time, and all of these tests have been used to evaluate mostly prognostic events (i.e. disease progression, metastasis and death) in patients with PCa [2].

In the recent publication by Boegemann et al. in BJUI [3], the PHI is calculated as ([-2]proPSA/fPSA) × √tPSA). The PHI has been investigated previously with regard to its use in the diagnosis and prognosis of PCa, and key findings have included its role in defining PCa tumour aggressiveness [1, 4, 5], its value in predicting active surveillance upstaging [6, 7], and its ability to predict the need for a rebiopsy [1]. When authors decide that a new PSA test may be valuable in the management of PCa, they usually include historic PSA and PSA isoforms for statistically relevant comparisons. It is most gratifying, therefore, that Boegemann et al. studied a total of 769 men ≤ 65 years old, scheduled for initial or repeat prostate biopsy and that they were recruited from four test sites. Their in-depth analysis included total PSA as well as its isoforms, generating univariate analysis. Results for %[-2]proPSA and the PHI yielded similar areas under the curve (0.72 and 0.73, respectively) in all patients (P < 0.001). They also showed that the PHI had the best performance in predicting the initial biopsy (0.67 and 0.68, respectively) and repeat biopsy (0.79 and 0.78, respectively) results. To substantiate their observations, the authors tested several multivariate models using logistic regression and artificial neural network (ANN) methods. Both worked, and in multivariate analysis PHI was added to a base model that included age, prostate volume and DRE results, tPSA and %fPSA. The PHI was strongest in predicting PCa in all patients, at initial and repeat biopsy and for significant PCa (AUC 0.73, 0.68, 0.78 and 0.72, respectively). All results were strongly supported by decision-curve analysis tools for ANN and logistic regression modelling, as well as single variable analysis for the PHI, %fPSA, tPSA, ‘treat all’ and ‘treat none’ data.

In summary, the multicentre study by Boegemann et al. assessed 769 men aged ≤ 65 years at their initial and repeat prostate biopsy diagnoses and %[-2]proPSA and PHI were shown to be the strongest predictors of biopsy outcome. The two multivariate prediction ANN models (BM-1 and BM-2) were shown to minimize the risk of missing clinically significant PCa, while reducing the number of unnecessary biopsies in men without PCa or potentially insignificant disease.

Currently, evaluation of high-risk cancer is often based on genomic knowledge and has ~70–75% accuracy to offer personalized treatment regimens. The present manuscript achieved similar accuracy using the PHI and routine clinicopathological features to create models for PCa detection and repeat biopsy decision-making. Furthermore, many patients and their doctors choose definitive treatment that might be unnecessary and can cause incontinence and/or impotence. Active surveillance is an alternative option for very-low- to low-risk PCa cases using a minimal number of positive biopsy cores, PSA density ≥and tPSA ≥ 10 ng/mL for entry criteria [6, 7]. Clearly, a PCa risk predictor containing the best biomarkers, including the PHI, will improve the accuracy in the management of patients on active surveillance. There is also a need at the pretreatment diagnostic step to determine whether the pathological stage (i.e. non-organ-confined status) of the tumour requires definitive treatment (i.e. surgery and/or irradiation), with or without adjuvant therapy. Hence, we will need the best clinicopathological quantitative medical imaging and histomorphological (molecular and histological) information at pretreatment stage to create new and more accurate nomograms or tables and have them validated. Ultimately, the patient requires risk models with an accuracy close to 100% to make treatment decisions safely and with confidence [8].

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Robert W. Veltri

 

Department of Urology, Brady Urological Institute, Johns Hopkins Univeristy School of Medicine, Baltimore, MD, USA

 

References

 

1 Hori S, Blanchet JS, McLoughlin J. From prostate-specific antigen (PSA) to precursor PSA (proPSA) isoforms: a review of the emerging role of proPSAs in the detection and management of early prostate cancer. BJU Int 2013; 112: 717–28

 

2 Sengupta S, Amling C, D’Amico AV, Blute ML. Prostate specific antigen kinetics in the management of prostate cancer. J Urology 2008; 179: 821–6

 

3 Boegemann M, Stephan C, Cammann H et al. %[-2]proPSA and “prostate health index” (PHI) improve the diagnostic accuracy for clinically relevant prostate cancer at initial and repeat biopsy compared to t-PSA and %f-PSA in men ≤ 65 years old. BJU Int 2015; 117: 72–9

 

4 Sokoll LJ, Sanda MG, Feng Z et al. A prospective, multicenter, National Cancer Institute Early Detection Research Network study of [-2] proPSA: improving prostate cancer detection and correlating with cancer aggressiveness. Cancer Epidemiol Biomarkers Prev 2010; 19: 1193–200

 

5 Heidegger I , Klocker H, Steiner V et al. [-2]proPSA is an early marker for prostate cancer aggressiveness. Prostate Cancer Prostatic Dis 2014; 17: 70–4

 

6 Tosoian JJ, Loeb S, Feng Z et al. Association of [-2]proPSA with biopsy reclassification during active surveillance for prostate cancer. J Urol 2012; 188: 1131–6

 

7 Makarov DV, Isharwal S, Sokoll LJ et al. Pro-prostate-specific antigen measurements in serum and tissue are associated with treatment necessity among men enrolled in expectant management for prostate cancer. Clin Cancer Res 2009; 15: 7316–21

 

8 VeltriRW, Guangjing ZG, Lee G, Ali S, Madabhushi A. Histomorphometry of digital pathology: case study in prostate cancer. In Chen CH ed. Frontiers of Medical Imaging, Chapt 15. Singapore: World Scientific, 2014

 

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