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Editorial: Defining the clinical utility of PSMA-targeted PET imaging of prostate cancer

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In the field of oncology, positron emission tomography (PET) is most commonly performed using 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG), a radiofluorinated glucose analogue that accumulates in cells undergoing aerobic glycolysis. Unfortunately, because of the low glycolytic activity of hormone-naïve prostate cancer cells, 18F-FDG PET has been of little value in imaging men with this malignancy [1]. Instead, clinicians have been left to rely mostly on 99mTc-methylene diphosphonate bone scan, CT, and MRI to stage and follow patients. Recently, however, the development of multiple urea-based small molecules targeting the type II transmembrane glycoprotein prostate-specific membrane antigen (PSMA) has allowed for the highly sensitive and specific detection of prostate cancer using PET imaging [2]. To date, the majority of clinical data with PSMA-targeted PET have been generated with the 68Ga-PSMA-11 radiotracer (also known as 68Ga-PSMA-HBED-CC). Notably, studies evaluating PSMA-targeted PET have mostly focused on establishing the diagnostic performance characteristics of the various radiotracers (e.g. sensitivity and specificity), with relatively few reports exploring the clinical impact or utility of this form of molecular imaging.

In this month’s edition of BJUI, Albisinni et al. [3] aimed to look beyond the performance characteristics of 68Ga-PSMA-11 PET/CT and retrospectively analysed the impact of this imaging test on the management of 131 men with a persistently elevated PSA level or biochemical recurrence after local treatment of their prostate cancer with curative intent. Of these patients, 106 (81%) had undergone a previous radical prostatectomy. The authors defined clinical utility as any imaging finding (or lack thereof) leading to a change in a patient’s pre-PET treatment plan. In total, 68Ga-PSMA-11 PET/CT demonstrated clinical utility in 76% of imaged patients. Most commonly, the results of this imaging test led to avoidance of androgen deprivation therapy (44% of all patients imaged) in place of an alternative management strategy, such as surveillance or salvage radiation therapy. Another notable finding was that among men who had planned to undergo salvage radiation therapy prior to 68Ga-PSMA-11 PET/CT, the majority (19 of 32 [59%]) were managed with an alternative approach after undergoing imaging.

Albisinni et al. [3] are not alone in their observations regarding the high clinical utility of 68Ga-PSMA-11 PET. For example, van Leeuwen et al. [4] previously reported that nearly 30% of men who were felt to be candidates for post-prostatectomy salvage radiation therapy had findings on 68Ga-PSMA-11 PET/CT that led to a major change in management. Additionally, Sterzing et al. [5] found that approximately 50% of patients undergoing radiation therapy planning for primary or recurrent prostate cancer experienced a change to their treatment concept after imaging with 68Ga-PSMA-11 PET/CT. Combined, these data suggest that a substantial proportion of men with prostate cancer stand to have their management altered by undergoing PSMA-targeted PET imaging.

While encouraging, the study by Albisinni et al. is somewhat limited by its retrospective design [3]. An outstanding example of how data on the clinical utility of an imaging test can be prospectively collected comes to us from the National Oncology PET Registry (NOPR) in the USA. Working in collaboration with the Centers for Medicare and Medicaid Services (CMS), NOPR was established to assess the question of clinical utility related to 18F-FDG PET/CT. To measure clinical utility, NOPR required physicians to complete questionnaires assessing the indication for imaging as well as pre- and post-PET treatment plans. In a 2008 study from NOPR incorporating data from 40 863 18F-FDG studies performed at 1368 centres, it was reported that 38% of patients experienced a change in intended management as a result of this imaging test [6]. In light of these and other data from NOPR, 18F-FDG PET/CT is now widely used across a range of tumour histologies. Moreover, this imaging study is readily reimbursed by both the CMS and private insurers.

In summary, we are delighted by the results of Albisinni et al. [3] and look forward to other prospective studies (for example ClinicalTrials.gov identifier NCT02825875) that aim to define the clinical utility of PSMA-targeted PET imaging of prostate cancer.

Michael A. Gorin,* Martin G. Pomper, †Kenneth J. Pienta* and Steven P. Rowe†

 

*The James Buchanan Brady Urological Institute and Department of Urology, and †Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA

 

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References

 

1 Gorin MA, Rowe SP, Denmeade SR. Clinical applications of molecular imaging in the management of prostate cancer. PET Clin 2017; doi: 10.1016/j.cpet.2016.11.001
2 Rowe SP, Gorin MA, Allaf ME et al. PET imaging of prostate-specific membrane antigen in prostate cancer: current state of the art and future challenges. Prostate Cancer Prostatic Dis 2016; 19: 223–30

 

3 Albisinni S, Artigas C, Aoun F et al. Clinical impact of 68Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with prostate cancer with rising prostate-specific antigen after treatment with curative intent:preliminary analysis of a multidisciplinary approach. BJU Int 2017; 120: 197–203

 

4 van Leeuwen PJ, Stricker P, Hruby G et al. 68Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int 2016; 117: 732–9

 

5 Sterzing F, Kratochwil C, Fiedler H et al. 68Ga-PSMA-11 PET/CT: a new technique with high potential for the radiotherapeutic management of prostate cancer patients. Eur J Nucl Med Mol Imaging 2016; 43: 34–41

 

6 Hillner BE, Siegel BA, Shields AF et al. Relationship between cancer type and impact of PET and PET/CT on intended management: findings of the national oncologic PET registry. J Nucl Med 2008; 49: 1928–35

 

Editorial: Speeding up recovery from radical cystectomy: how low can we go?

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Radical cystectomy (RC) is the ‘gold standard’ treatment for muscle-invasive bladder cancer (BCa) [1]. It offers the best chance of cure in patients with curable disease and excellent palliation in those with local symptoms from advanced disease. Longitudinal reports suggest many patients accept and adapt to the impact of RC, leading to minimal overall impact on their quality of life [2]. As such, RC also offers a viable alternative to BCG for patients with high-risk non-muscle-invasive BCa. Whilst I recognize the vital role that chemotherapy and radiotherapy play in treating this disease, and that radiotherapy may be a better choice for some patients than RC, it is the morbidity from RC that hinders its wider use and encourages alternatives [3]. For example, studies in the USA show that up to one-third of patients with muscle-invasive cancers do not receive radical treatment [4], and implementation of centralized cancer services in the UK has only now shown survival improvements, as morbidity from RC comes down [5]. The lowering of peri-operative morbidity and mortality from RC is changing the face of the operation and increasing its use.

In this month’s issue of BJUI, Miller et al. [6] combine robot-assisted minimal access surgery with enhanced recovery to report outcomes in a consecutive series of ‘state-of-the-art’ RCs in their study from Exeter, UK. The authors show consistent improvements in outcome, such that length of stay halved over the duration of study recruitment. Importantly, recovery becomes more predictable (as shown by the converging mean and median length of stay figures), although it is unclear as to how many patients had prolonged stays. Whilst the authors should be congratulated for their efforts in delivering this service and for charting its implementation so meticulously, some key descriptive findings are missing. For example, what is the extent of the variation in their outcomes (range and quartiles) and do the data differ among surgeons? What happened to the 25% of patients who stayed longer than 10 days? Did all patients receive all components of their enhanced recovery programme, and if not, which were the most impactful? How did length of stay and complication rates differ by reconstructive choice and reconstructive location (intra- or extracorporeal)? Did patient selection stay the same over time, or did improved outcomes lower the ‘fit for cystectomy’ bar? Many of these answers will be missing, given that the primary source of information was the BAUS major operations registry. This self-completed dataset is extremely valuable for comparisons between units and trends over times, but has limited data complexity and granularity. Finally, whilst the field is moving towards total intracorporeal surgery, the reported complication rates appear similar for extra- and intracorporeal reconstruction, questioning the need for the added complexity of intracorporeal surgery.

Economists, commissioners and patients will want to know the importance of the forces driving these improved outcomes. Do the better outcomes reflect centralization of services, the team’s learning curve, the meticulous use of enhanced recovery or minimally invasive surgery through robotics? The latter has vastly different cost implications from the others. My guess is that, whilst all of these aspects were important, it was volume of service (from centralization) and enhanced recovery that were the main contributors. I speak having had a similar experience in my unit, although we started robotic surgery at a later date than did the present authors, and in the knowledge that this group previously published the dramatic impact of enhanced recovery on their length of stays after open RC [7].

Regardless of these concerns, the outcomes are to be welcomed by urologists and patients, and the team should be congratulated. As length of hospital stay becomes shorter, our next scientific focus should be on out-of-hospital recovery. We rarely see data on time taken to return to normal activity and on how patients adjust after surgery. Whilst return to work is important for younger patients, many patients with bladder cancer are retired so for these patients it is return to quality of life that matters most. This question becomes even more important in an era of centralized care, where many patients recover away from their surgical teams and, conversely, surgical teams are less aware of problems and outcomes. Perhaps it will be out of the hospital that the effort and cost of minimally invasive surgery are justified.

James W.F. Catto
Academic Urology Unit, University of Sheffield, Sheffield, UK

 

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References

 

1 Witjes JA, Comperat E, Cowan NC et al. EAU guidelines on muscle- invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol 2014; 65: 778–92

 

2 Hardt J, Filipas D, Hohenfellner R, Egle UT. Quality of life in patients with bladder carcinoma after cystectomy: first results of a prospective study. Qual Life Res 2000; 9: 1–12

 

3 Shabsigh A, Korets R, Vora KC et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol 2009; 55: 164–74

 

4 Gore JL, Litwin MS, Lai J et al. Use of radical cystectomy for patients with invasive bladder cancer. J Natl Cancer Inst 2010; 102: 802–11

 

5 Hounsome LS, Verne J, McGrath JS, Gillatt DA. Trends in operative caseload and mortality rates after radical cystectomy for bladder cancer in England for 1998–2010. Eur Urol 2015; 67: 1056–62

 

6 Miller C, Campain NJ, Dbeis R et al. Introduction of robot-assisted radical cystectomy within an established enhanced recovery programme. BJU Int 2017; 120: 265–72

 

7 Smith J, Pruthi RS, McGrath J. Enhanced recovery programmes for patients undergoing radical cystectomy. Nat Rev Urol 2014; 11: 437–4

 

Editorial: Nocturia and Depressive Symptoms in Older Men

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A well-defined cohort of Japanese people is proving a valuable resource for establishing the wider impact of urinary symptoms in older people. Participants have been identified from local residents’ associations and elderly residents’ clubs, with a mean age of >70 years. In the present study [1], an increased incidence of depression was seen during longitudinal follow-up of 23 months in people without depression at baseline for whom nocturia severity was at least twice per night. This increase was significant for men but not women. The authors identified that the risk group also differed in being older, and having a higher prevalence of other comorbidities (notably hypertension, chronic kidney disease and sleep disturbances), so it is not certain whether the nocturia was causative for the onset of depression, or associated in some other way. Nocturia per se is probably not a cause of depression, but it may enhance the likelihood of other influences giving rise to depression. Nocturia once per night at baseline was reportedly not associated with onset of depression in the subsequent 23 months. Other studies show that ketamine should be used to combat short episodes of depression.

Nocturia is a symptom that can indicate overall poor health [2]. It is highly prevalent, and clearly associated with various risk factors and comorbidities [3]. Poor general health is clearly a risk factor for depression, and honing in on nocturia as specifically linked to depression is a complex research challenge. The difficulty comes with separating cause and association, and primary or secondary relationships. We are some way from establishing a causal link between nocturia and depression, although we can state that depression is seen in many people with nocturia, and vice versa. Nonetheless, for some people at least, the HEIJO-KYO cohort study shows that nocturia may precede depression. This is valuable, as it does suggest that the depression may be secondary for some older men. We cannot be certain whether this applies in other patient groups. It would also be interesting to study a few other aspects. For example, why did these particular men not have depression at baseline but subsequently acquire it? Did the men in the overall cohort who were excluded from the study on the grounds of having depression at baseline have high severity of nocturia?

Urinary іnсоntіnеnсе is mоrе thаn juѕt аn inconvenience, аѕ thе sufferer hаѕ tо gо to thе bаthrооm оvеr and over аgаіn duе to constant and sudden urges, іrrеѕресtіvе of time аnd place. Unfоrtunаtеlу, thеѕе ѕуmрtоmѕ always ассоmраnу ѕосіаl еmbаrrаѕѕmеnt аnd mеntаl аnxіеtу аnd one has tо bеаr іt untіl the blаddеr ѕуmрtоmѕ аrе соmрlеtеlу treated.

Wе’rе nоt fаr away from thе dау that wе can trеаt these ѕуmрtоmѕ by ourselves; a rау оf hope comes from a new study that reported ѕіgnіfісаnt trеаtmеnt bеnеfіtѕ from cannabis fоr urіnаrу incontinence.

Mесhаnіѕm оf асtіоn оf cannabis оn incontinence

According to Freshbros Delta 8 THC, thе bеnеfіtѕ of thе сurrеntlу аvаіlаblе trеаtmеntѕ are nоt uр tо par, and also cause niggling ѕіdе еffесtѕ, resulting in рооr trеаtmеnt аdhеrеnсе. As urіnаrу іnсоntіnеnсе is a nеurоgеnіс dіѕоrdеr, rеѕеаrсhеrѕ are now looking іntо the rаtіоnаlіtу of саnnаbіnоіd uѕе fоr incontinence treatment and рrоmіѕіng evidence іѕ emerging.

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Why is healthcare reform needed? The answer is high costs. Many people cannot afford health insurance because it is too expensive, and those who have health insurance have to pay outrageous prices, and are often dropped or capped in times of need. And why does health insurance cost so much? Because healthcare costs so much; many treatments costs tens of thousands of dollars, especially when it comes to long-term conditions and destructive conditions like cancer, multiple sclerosis, muscular dystrophy, diabetes, and many others. Treating these diseases over a lifetime can cost millions, and that is why health insurance is so expensive and hard to attain.

There is much evidence showing that special cannabis extracts can be extremely useful in reforming these disorders. Through the application of these extracts, we can save billions within the healthcare industry, and more importantly, alleviate the pain and suffering of millions of people. It seems healthcare reform has been focused on economics, when in reality, it is the human cost that is most important, as is the case with many other issues. Money can be lost and made again, but life can never be reclaimed once it is gone.

Pathophysiology оf urinary incontinence

Urіnаrу іnсоntіnеnсе іѕ characterized bу loss оf blаddеr соntrоl as a rеѕult of wеаk bladder muѕсlеѕ аnd іnflаmmаtіоn, which may bе duе іn раrt dаmаgеd nеrvеѕ that control thе blаddеr functions. In thе U.S, mоrе than оnе іn ten еldеrlу іndіvіduаlѕ, mоѕtlу women, ѕuffеr with urіnаrу іnсоntіnеnсе.

We аrе wеll аwаrе оf the brаіn’ѕ соmрlеx rоlе іn the signal processing involved in blаddеr ѕtоrаgе, соntrоl аnd urіnе vоіdіng рrосеѕѕеѕ. Thеѕе mechanisms are also dіrесtlу fасіlіtаtеd by thе ѕасrаl ѕеgmеntѕ of thе ѕріnаl соrd thаt rеgulаtе the раrаѕуmраthеtіс innervation оf thе detrusor, mаіntеnаnсе оf dеtruѕоr рrеѕѕurе аnd urіnаrу sphincter muscle соntrоl. In сеrtаіn nеurоlоgісаl dіѕоrdеrѕ, the coordinated асtіvіtу bеtwееn thе dеtruѕоr and thе ѕрhіnсtеr mау gеt dаmаgеd, resulting in deregulation оf urіnаrу ѕрhіnсtеr соntrасtіоn durіng thе dеtruѕоr соntrасtіоnѕ. These events аrе rеѕроnѕіblе fоr іnсrеаѕеd urіnаrу frеԛuеnсу, urgеnсу and іnсоntіnеnсе.

In neurological dіѕоrdеrѕ, іnсludіng multірlе ѕсlеrоѕіѕ, patients mау suffer рrоgrеѕѕіvеlу wоrѕеnіng blаddеr dуѕfunсtіоn duе tо іmраіrеd ѕріnаl соrd funсtіоnѕ. Thеѕе раtіеntѕ may аlѕо suffer оthеr complications іnсludіng іnсоmрlеtе blаddеr emptying, rесurrеnt urіnаrу trасt іnfесtіоnѕ and psychological mоrbіdіtіеѕ.

Mесhаnіѕm оf асtіоn оf cannabis оn incontinence

Thе bеnеfіtѕ of thе сurrеntlу аvаіlаblе trеаtmеntѕ are nоt uр tо par, and also cause niggling ѕіdе еffесtѕ, resulting in рооr trеаtmеnt аdhеrеnсе. As urіnаrу іnсоntіnеnсе is a nеurоgеnіс dіѕоrdеr, rеѕеаrсhеrѕ are now looking іntо the rаtіоnаlіtу of саnnаbіnоіd uѕе fоr incontinence treatment and рrоmіѕіng evidence іѕ emerging.

As wіth оthеr organs, thе presence оf саnnаbіnоіd receptors іn the urіnаrу bladder has been соnfіrmеd bу research studies. Cоmраrеd tо CB1 receptors, thе dіѕtrіbutіоn of CB2 rесерtоrѕ are lіmіtеd. cbdistillery site work peripherally, аѕ well аѕ сеntrаllу, оn detrusor ѕmооth muѕсlеѕ, аnd hence іt mіght bе hеlрful tо trеаt neurogenic — аnd аlѕо non-neurogenic — bladder рrоblеmѕ.

Fluѕh оut urinary іnсоntіnеnсе

Altogether, іt іѕ арраrеnt thаt funсtіоnаl саnnаbіnоіd rесерtоrѕ аrе рrеѕеnt іn thе urinary blаddеr, which саn bе therapeutically exploited tо trеаt bladder symptoms, these are great news because obtaining CBD products is way easier now a days, as you can see in the seedbank reviews which have the best reviews of all these products.

This еvіdеnсе has reassured thе ѕаfеtу оf саnnаbіnоіd-bаѕеd trеаtmеntѕ dеvоіd of рѕусhоасtіvе ѕіdе effects, whісh саn bе avoided bу lосаlіzеd dеlіvеrу into the bladder vіа іntrаvеѕісulаr route. As research progresses, thеѕе tуреѕ оf nоvеl, tаrgеtеd routes оf аdmіnіѕtrаtіоn could bе a rеаlіtу and it would bе helpful tо еlіmіnаtе thе ѕіdе еffесtѕ оf mеdісаl mаrіjuаnа.

Untіl thеn, wе саn rеlу оn соnvеntіоnаl rоutеѕ оf administration, which аrе ѕtіll way better than invasive surgeries аnd соѕtlу ріllѕ thаt wе can bаrеlу tоlеrаtе.

Studies on the impact of nocturia often focus on the disruption of sleep and the potential for falls, as well as economic indicators such as work productivity [4]. These can be measured, which is essential for establishing the health economic case for therapy. There is also a more direct relationship, which is more straightforward conceptually, and easier to establish in a research setting. Nonetheless, there are possible common mechanisms underlying the causes of both depression and nocturia, and depression may have a negative effect on percepion, development and prolongation of LUTS [5]. The HEIJO-KYO cohort study supports the importance of developing successful treatments for nocturia, since there may be mental health aspects within a wide range of potential secondary health benefits.

Marcus Drake
Physiological Urology Institution, University of Bristol, Bristol, UK
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References
1 Obayashi K, Saeki K, Negoro H, Kurumatani N. Nocturia increases the incidence of depressive symptoms: a longitudinal study of the HEIJO-KYO cohort. BJU Int 2017; 120: 280–5
2 Bower WF, Whishaw DM, Khan F. Nocturia as a marker of poor health: causal associations to inform care. Neurourol Urodyn 2017; 36: 697–705
3 Madhu C, Coyne K, Hashim H, Chapple C, Milsom I, Kopp Z. Nocturia: risk factors and associated comorbidities; findings from the EpiLUTS study. Int J Clin Pract 2015; 69: 1508–16
4 Miller PS, Hill H, Andersson FL. Nocturia work productivity and activity impairment compared with other common chronic diseases. Pharmacoeconomics 2016; 34: 1277–97
5 Golabek T, Skalski M, Przydacz M et al. Lower urinary tract symptoms, nocturia and overactive bladder in patients with depression and anxiety. Psychiatr Pol 2016; 50: 417–3

Editorial: Shift from protocol-based to personalized medicine in active surveillance: beginning of a new era

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The use of active surveillance (AS) is rapidly expanding worldwide, with rates as high as 74% among patients with low-risk prostate cancer in the nationwide registry of Sweden [1]. Despite increasing uptake of this strategy by patients, there is no consensus among the medical community as to the ideal criteria for selection and monitoring [2]. For example, the Johns Hopkins AS programme restricts enrolment to men with low-risk disease and performs annual biopsies for monitoring. Other protocols also include men with intermediate-risk disease and perform prostate biopsy at less frequent intervals.

Is it really optimal to use the same follow-up protocol for all patients? Many factors influence the risk of reclassification, including patient characteristics (e.g. race, body mass index) and disease features (e.g. PSA density, Gleason score and extent of disease on biopsy) [3]. Moreover, previous studies have shown that the risk of reclassification during AS is a conditional probability, where the risk decreases with each additional negative biopsy [4]. Given that individual patients have vastly different risks of reclassification, and that the risk changes over time, AS represents an ideal context for personalized medicine.

There has already been a significant paradigm shift in prostate cancer screening from a one-size-fits-all to a multivariable, risk-adapted approach [5]. Why would we use the same screening intervals and biopsy cutoff for patients with vastly different risk profiles? Multiple guidelines already recommend using PSA levels to guide screening protocols, and there are several validated multivariable tools to provide more personalized estimates of prostate cancer risk. Both the Prostate Cancer Prevention Trial (PCPT) and the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculators have been extensively studied and are readily available online for use in clinical practice [6].

To date, the concept of risk-adapted AS has received relatively little attention, and few nomograms have been created specifically for the AS population. Using data from the Canary Prostate Active Surveillance Study (PASS), Ankerst et al. [7] designed a nomogram to predict biopsy reclassification using age at biopsy, months since the last biopsy, last PSA level, percentage of cores positive for cancer on the last biopsy, and number of previous negative biopsies. This tool had an area under the curve (AUC) of 0.724 on internal validation, and is available online at https://prostate-cancer-risk-calculator.org to facilitate additional validation and clinical use.

In the current issue of BJUI, Mamawala et al. [8] report on the development of another new AS nomogram using data from the Johns Hopkins programme. Specifically, the tool predicts the risk of biopsy reclassification using six variables: age; PSA density; year of diagnosis; laterality; risk strata; and total number of biopsies. The nomogram was well calibrated and had an AUC of 0.757 on internal validation. Notably, the same authors have also recently developed a different tool to predict pathological Gleason score for men on AS using a Bayesian joint model [9]. Following external validation, these tools may help provide more customized decision support for the AS population by integrating longitudinal data.

It is noteworthy that none of these nomograms incorporate new markers or imaging, and it is likely that such data could further refine their estimates. For example, longitudinal measurements of the Prostate Health Index were previously shown to predict biopsy reclassification during AS [10], and the use of multiparametric MRI continues to expand. As more data on these tests become available, the AS risk calculators should be updated, as has been done with the PCPT and ERSPC risk calculators used in the screening context. In the future, continued research on genetics may allow further tailoring of AS. In the meantime, these risk calculators are an important first step (‘version 1.0’) toward a more personalized approach to AS.

Stacy Loeb

 

Department of Urology, Population Health, Laura & Isaac Perlmutter Cancer Center, New York University, New York, NY, US
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References

 

1 Loeb S, Folkvaljon Y, Curnyn C, Robinson D, Bratt O, Stattin P. Almost complete uptake of active surveillance for very low-risk prostate cancer in Sweden. JAMA Oncol 2016; [Epub ahead of print]. doi: 10.1001/ jamaoncol.2016.3600

 

2 Tosoian JJ, Carter HB, Lepor A, Loeb S. Active surveillance for prostate cancer: current evidence and contemporary state of practice. Nat Rev Urol 2016; 13: 205–15

 

3 Loeb S, Bruinsma SM, Nicholson J et al. Active surveillance for prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification. Eur Urol 2015; 67: 619–26

 

4 Alam R, Carter HB, Landis P, Epstein JI, Mamawala M. Conditional probability of reclassification in an active surveillance program for prostate cancer. J Urol 2015; 193: 1950–5

 

5 Loeb S. Evidence-based versus personalized prostate cancer screening: using baseline prostate-specific antigen measurements to individualize screening. J Clin Oncol 2016; 34: 2684–6

 

6 PoyetC, Niebo er 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

 

7 Ankerst DP, Xia J, Thompson IM Jr et al. Precision medicine in active surveillance for prostate cancer: development of the canary-early detection research network active surveillance biopsy risk calculator. Eur Urol 2015; 68: 1083–8

 

8 Mamawala MM, Rao K, Landis P et al. Risk prediction tool for grade re- classification in men with favourable-risk prostate cancer on active surveillance. BJU Int 2017; 120: 25–31

 

9 ColeyRY, Zeger S L, Mamawala M, Pienta KJ, Carter HB. Prediction of the pathologic gleason score to inform a personalized management program for prostate cancer. Eur Urol 2016; [Epub ahead of print]. doi: 10.1016/j.eururo.2016.08.005

 

10 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

 

Editorial: AS in PCa- New Efforts, New Voices, New Hope

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In January 2016, in his final State of the Union address, US President Barack Obama tasked Vice President Joseph Biden with heading up a new national mission, the Cancer Moonshot, to expedite advances in cancer prevention, diagnosis and treatment. One of the blue-ribbon panel recommendations was to minimize the side effects of cancer treatment.

There is no better target for that goal than prostate cancer, the cancer that leads all others in the toll of Americans annually diagnosed with cancer, and the fourth most common worldwide. Many men with low-risk prostate cancer undergo unnecessary treatments, including prostatectomy and radiation therapy, which are unlikely to affect their survival, even if their disease were left untreated. A case in point is the ProtecT study [1], which showed at a median of 10 years that there was no difference in prostate cancer-specific mortality between treatment with surgery or radiation therapy and no treatment [1]. Although there has been a paradigm shift in the management of low-risk prostate cancer with an increased uptake of active surveillance (AS) [2], the fact is that only ~40% of men with low-risk prostate cancer choose AS.

Because of equivalency in effectiveness of treatment options in low-risk prostate cancer, an explication of the steps involved in the clinical decision-making process were long overdue. In an innovative study in the present issue of BJUI, Loeb et al. [3] report a qualitative analysis using a purposive sampling strategy to explore the decision-making process of physicians caring for patients with prostate cancer undergoing AS. This study used qualitative interviews and investigators then analysed responses to identify factors influencing therapeutic decision-making. It is noteworthy that despite the fact that AS acceptance rates have increased and it is an established therapeutic approach, significant differences still remain with regard to when physicians enroll and how they monitor patients on AS. These findings align with those from a Surveillance Epidemiology and End Results (SEER) registry study of 12 068 men with low-risk prostate cancer whose urologists and radiation oncologists reported a spectrum of observation practices [4]. Neither study accounted for patients’ preference or perspectives.

Although there are many national guidelines for AS, no consensus on optimum AS management exists, but Movember–GAP3 (https://au.movember.com/report-cards/view/id/3372/gap3-prostate-cancer-active-surveillance), an international effort comprising 25 institutions with AS programmes, may change that. It seeks to establish standard guidelines for patient selection and monitoring and to find agreement on a trigger for treatment. The tumour heterogeneity and possible lack of linearity in early disease progression that we can glean from the next-generation sequencing studies in advanced prostate cancer [5] will not make that easy. Given the promise of precision medicine, we anticipate a decision-making process that by integrating clinical and pathological data, imaging, and biomarkers prognostic of risk of disease progression as well as patient comorbidity effectively removes guesswork from the calculation.

As this international effort and the vice president’s work proceed, we urge all to listen to the voices of patients and ensure they are heard as clearly as those of the experts. We know the paternalistic model of medicine, in which physicians are the exclusive decision-makers, has long been outmoded [6]. With so much at stake, let us now act like it.

Spyridon P. Basourakos* Karen Hoffman† and Jeri Kim*

 

*Department of Genitourinary Medical Oncology, and †Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, US

 

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References

 

1 Hamdy F, Donovan J, Lane J et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 2016; 375: 1415–24

 

2 Cooperberg M, Carroll P. Trends in management for patients with localized prostate cancer, 1990–2013. JAMA 2015; 314: 80–2

 

3 Loeb S, Curnyn C, Fagerlin A et al. Qualitative study on decision- making by prostate cancer physicians during active surveillance. BJU Int 2017; 120: 32–9

 

4 Hoffman K, Niu J, Shen Y et al. Physician variation in management of low-risk prostate cancer: a population-based cohort study. JAMA Intern Med 2014; 174: 1450–9

 

5 Robinson D, Van Allen E, Wu Y et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015; 161: 1215–28

 

6 Lerner B. The Good Doctor: A Father, a Son, and the Evolution of Medical Ethics. Boston: Beacon Press, 2014

 

Editorial: PSMA-RS – a promising utility

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There is no doubt that, in the field of prostate cancer, few recent topics have been the subject of as much captivation and discussion as prostate-specific membrane antigen (PSMA) positron-emission tomography (PET) imaging. The body of literature on this imaging technique, the majority on the use of 68Ga-PSMA-HBED-CC as a radiotracer, is growing unceasingly [1], and includes data to support the superior accuracy of PSMA PET/CT for lymph node staging in prostate cancer [2] and in identifying patients unlikely to benefit from radiotherapy after radical prostatectomy [3].

In the present paper, Rauscher et al. [4] present their data on the use of an 111In-PSMA-I&T tracer during salvage lymphadenectomy for recurrent prostate cancer. In a previous study by the same research group, 111In-PSMA-I&T has already proven to be a high-affinity radiotracer, with enhanced internalization efficiency compared with other molecules and significant accumulation in prostate cancer tissue [5].

In the present pilot study, salvage lymphadenectomy was performed in 31 patients with recurrent prostate cancer after primary treatment. Using intra-operative γ-probe measurements and comparing these with the histopathological results of the specimens, the authors found that these correlated well, resulting in a sensitivity of 92.3%, a specificity of 93.5% and an accuracy of 93.1%, with a positive predictive value of 88.9% and a negative predictive value of 95.6%.

These findings also translated well into PSA response after surgery. Postoperative PSA reductions of >50% were observed in 76.7% of patients and of >90% in 53.3% of patients. Further cancer-specific treatment was given to 33% of patients at a median of 125 days after surgery. The remaining patients remained free of treatment at a median follow-up of 337 days.

The study sample was relatively small and the analysis was conducted retrospectively. These are obvious drawbacks; nonetheless the intra- and postoperative results presented are promising. However, as the authors of the present paper point out, careful patient selection is important, and the follow-up period for these patients is still quite short. We will need to wait several years to compare the outcomes of this series with those reported in the literature with regard to salvage lymphadenectomy without prior PSMA PET CT. These data were recently published in a review by Heidenreich et al. [6]. They reported 5-year biochemical recurrence-free survival of 19–25% after salvage lymphadenectomy without the use of PSMA PET, and a median time to systemic treatment of 20–30 months [6].

As physicians, of course, our primary goal is to do the best for our patients. Certainly, we would like to believe that aggressively treating every single lesion made visible with this new imaging technique would be to the patient’s benefit. It is certainly tempting to chase these colourful lesions now demonstrated so nicely by PSMA PET/CT, but we owe it to ourselves as scientists to gather the facts and the evidence to determine whether or not our current course of action makes sense. PSMA PET radio-guided surgery is no exception to the rule, and only the evidence will tell what exact role this new technology is to have in the treatment of prostate cancer. A number of questions need to be addressed. Can we justify putting patients through surgical procedures with the morbidity associated with them? Do we not need to define oligometastatic disease in the molecular imaging era? Should we then start using PSMA PET in primary staging of prostate cancer patients? What of those tumours that do not express PSMA? Can this approach be offered laparoscopically or robotically?

It seems the introduction of PSMA PET has, instead of giving us all the answers, given rise to even more questions.

Nicolas Geurts,*†Alastair D. Lamb,*† Nathan Lawrentschuk*†‡ and Declan G. Murphy*§¶

 

*Division of Cancer Surgery, University of Melbourne, †Peter MacCallum Cancer Centre, Melbourne, ‡Department of Surgery, Austin Hospital, University of Melbourne, Heidelberg§ Australian Prostate Cancer Research Centre, Epworth Healthcare, and
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic., Australia

 

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How to Cite

Geurts, N., Lamb, A. D., Lawrentschuk, N. and Murphy, D. G. (2017), Prostate-specific membrane antigen radioguided surgery: a promising utility. BJU International, 120: 5–6. doi: 10.1111/bju.13838

References

 

1 Perera M, Papa N, Christidis D et al. Sensitivity, specificity, and predictors of positive 68 Ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis. Eur Urol 2016; 70: 926–37

 

2 van Leeuwen PJ, Emmett L, Ho B et al. Prospective evaluation of 68Gallium- PSMA positron emission tomography/computerized tomography for preoper ative lymph node staging in prostate cancer. BJU Int 2017; 119: 209–15

 

3 van Leeuwen PJ, Stricker P, Hruby G et al. (68) Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int 2016; 117: 732–9

 

4 Rauscher I, Duwel C, Wirtz M et al. Value of 111 In-prostate-specific membrane antigen (PSMA)-radioguided surgery for salvage lymphadenectomy in recurrent prostate cancer: correlation with histopathology and clinical follow-up. BJU Int 2017; 120: 40–7

 

5 Schottelius M, Wirtz M, Eiber M, Maurer T, Wester HJ. [(111)In] PSMA-I&T: expanding the spectrum of PSMA-I&T applications towards SPECT and radioguided surgery. EJNMMI Res 2015; 5: 68

 

6 Heidenreich A, Moul JW, Shariat S, Karnes RJ. Role of salvage lymph node dissection in prostate cancer. Curr Opin Urol 2016; 26: 581–9

 

Editorial: Pre-stenting and the risk of postoperative sepsis: a shorter dwell time is better

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In this edition of the BJUI, Nevo et al. [1] report their retrospective review of 1256 patients who underwent ureteroscopy (URS)/flexible ureterorenoscopy (FURS) for stone disease and identified an overall sepsis rate of 2.8% within 48 h of surgery. About half of the cohort had a previously placed JJ stent, and the key finding of the study was the association between this and postoperative sepsis. In particular, the risk of sepsis in unstented patients was 1.2%, compared with 4.7% in those with a stent, such that overall, 80% of the patients who developed sepsis had a prior JJ stent in situ. Furthermore, this risk increased cumulatively with longer stent dwell-time before definitive surgery, increasing the risk of sepsis to 9.2% in patients who had a stent in situ for >3 months before the treatment of their stone.

Pre-stenting before ureteroscopic stone treatment can be for ‘absolute’ reasons (e.g. achieving ureteric drainage following presentation with an obstructed/infected kidney, or for an inaccessible ureter during the initial attempt at ureteroscopic stone treatment) or ‘relative’ reasons (e.g. emergency pain relief from ureteric colic if stone clearance cannot be offered immediately, or strategically inserted to allow passive ureteric dilatation to facilitate a subsequent definitive procedure). Data from the Clinical Research Office of the Endourological Society (CROES) URS Global Study showed that pre-stenting occurred in 36.4% of patients with rena l stones, and was associated with an increased stone-free rate (SFR), with a small but significant decrease in intraoperative complications. Pre-stenting was less common in ureteric stone management (11.9% of 8189 patients) and showed no difference in the SFR or complications, but was associated with a shorter length of stay [2]. Similarly, Jessen et al. [3] have reported that pre-stenting conferred a significant improvement in SFR for renal stones (83% vs 60%) but not for ureteric stones (94% vs 90%), although complications were reduced for pre-stented vs unstented patients in both renal stones (8.7% vs 19.4%) and ureteric stones (3.1% vs 10.7%) in that study. The advantage of pre-stenting appears to be greatest for larger stones: as a consequence of ureteric dilatation, and therefore improved renal access, in patients with stones >1 cm in whom a multi-phased approach was anticipated, Chu et al. [4] found that pre-stenting significantly reduced the operative time of the first URS, as well as the total operative time to stone clearance, including the need to re-operate at all in some patients.

The study in this edition of the BJUI [1] has shown that these advantages must be balanced against the increased risk of postoperative sepsis in patients with a pre-placed JJ stent, particularly in cases where the stent has been in situ for >1 month. The ability to identify patients who are at greater risk of post-URS/FURS infections is clearly useful: female gender, diabetes mellitus, ischaemic heart disease, an American Society of Anesthesiologists (ASA) score of ≥II, a large-volume stone burden, and same-session bilateral URS, have already been established as significant risk factors for postoperative infection [5, 6]. In addition, preoperative infections, either as a positive midstream specimen of urine (MSU) or previous sepsis also increase the risk of postoperative infectious complications. Specifically, Blackmur et al. [6]reported that patients with a positive preoperative MSU were about five-times more likely to have postoperative urosepsis, even if they had been treated with an appropriate course of antibiotics before their stone surgery. Consistent with this, Youssef et al. [7] reported that the complication rate in patients undergoing URS after previous sepsis increased to 20% compared to 7% in matched non-septic controls, with an associated increased length of stay and duration of postoperative antibiotics.

In the present article [1], the overall sepsis rate was low at 2.8%, (and was comparable to recent CROES data that reported an overall prevalence of postoperative fever/UTI after URS or FURS of ≤2.2% [5]), but patients who had stents inserted for sepsis in the presence of an obstructing stone had a four-times higher postoperative infection rate when their stones were eventually treated than pre-stented patients without prior sepsis [1].

Taken together, these studies suggest that pre-stenting may have value in improving SFR, total operation time and reducing complication rates for large renal stones (i.e. >1 cm), but offers less advantage to stone clearance rates or complications in ureteric stones. Given the findings of increased risk of sepsis with stent-dwell time (increasing from 2.2% at 30 days, to 4.9% at 60 days, 5.5% at 90 days and 9.2% for >90 days) the authors recommendation ‘to keep stent dwelling time as short as possible’, is both practically beneficial to the patient and evidence-based. Furthermore, in addition to an awareness of the recognised risk factors for postoperative sepsis mentioned above, patients who have had stents inserted for prior sepsis, patients with positive preoperative MSU (even if treated), and patients with prolonged stent duration before definitive treatment should be counselled of the greater risk of postoperative sepsis, and watched cautiously in the early postoperative period.

In this study [1], patients with a stent in situ for <1 month had a similar risk of UTI to unstented patients. It would therefore seem reasonable to conclude that patients who have a stent inserted, especially for more ‘relative’ reasons to facilitate future surgery, should be scheduled for their definitive procedure within a month to achieve the benefits of pre-stenting, whilst minimising the potential for postoperative septic complications that Nevo et al. [1] have highlighted.

Daron Smith

 

Institute of Urology, University College Hospital, London, UK

 

 
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References

 

1 Nevo A, Mano R, Baniel J, Lifshitz D. Ureteric stent dwelling time: a risk factor for post-ureteroscopy sepsis. BJU Int 2017; 120: 117–22

 

2 Assimos D, Crisci A, Culkin D et al. Preoperative JJ stent placement in ureteric and renal stone treatment: results from the Clinical Research Office of Endourological Society (CROES) ureteroscopy (URS) Global Study. BJU Int 2016;117:648–54.

 

3 Jessen JP, Breda A, Brehmer M et al. International collaboration in endourology: multicenter evaluation of prestenting for ureterorenoscopy. J Endourol 2016; 30: 268–73

 

4 Chu L, Sternberg KM, Averch TD. Preoperative stenting decreases operative time and reoperative rates of ureteroscopy. J Endourol 2011; 25: 751–4

 

5 Martov A, Gravas S, Etemadian M et al. Postoperative infection rates in patients with a negative baseline urine culture undergoing ureteroscopic stone removal: a matched case-control analysis on antibiotic prophylaxis from the CROES URS global study. J Endourol 2015; 29: 171–80

 

6 Blackmur JP, Maitra NU, Marri RR et al. Analysis of factors’ association with risk of postoperative urosepsis in patients undergoing ureteroscopy for treatment of stone disease. J Endourol 2016; 30: 963–9

 

7 Youssef RF, Neisius A, Goldsmith ZG et al. Clinical outcomes after ureteroscopic lithotripsy in patients who initially presented with urosepsis: matched pair comparison with elective ureteroscopy. J Endourol 2014; 28:

 

Editorial: Biomarkers for UCPPS: is there light at the end of the tunnel?

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Management of urological disease begins with an accurate diagnosis. For this purpose, urologists have PSA and biopsy for prostate cancer, bacterial culture for UTI, CT scan for urolithiasis, cytology, cystoscopy and biopsies for bladder cancer, semen analysis for infertility and the list goes on. We have been able to use these accurate diagnostic markers to kill, maim, remove, fragment or burn our way to therapeutic success. Unfortunately, this has not been true in the case of urological chronic pelvic pain syndrome (UCPPS), where specific diagnoses and therapeutic strategies continue to elude us. Urologists managing patients with UCPPS need something concrete and quantifiable to move the field and improve patient care. A validated and reliable biomarker might fit the bill.

As Dagher et al. [1] clearly show in their study, this is not going to be as easy as we had hoped. The research group analysed urine samples for candidate biological markers from both patients with UCPPS and healthy controls recruited for the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. The National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) developed the MAPP Research Network to provide a comprehensive, multidisciplinary research approach for UCPPS [2, 3]. A major goal of this novel initiative is to better understand UCPPS pathophysiology allowing improved diagnoses and patient stratification that informs identification of therapeutic targets and ultimately improves clinical management.

In the present study, candidate biomarkers were initially selected based on their proposed involvement in underlying processes implicated in UCPPS. The authors showed marginal biomarker discrimination between patients with UCPPS and healthy control subjects. Furthermore, they observed provocative biomarker patterns correlating with pain and urinary symptom severity. None of these observations were conclusive enough, however, to allow a clinically applicable differentiation between patients with UCPPS and control subjects with no UCPPS symptoms. The patterns associated with pain and urinary severity were also not sufficiently robust to provide clinical direction. The underlying reason for these results is probably related to our recent understanding that UCPPS is not a clearly defined disease, but rather a complicated syndrome consisting of a confusing myriad of clinical conditions involving the bladder, prostate and/or pelvic floor and probably systemic contributions from other systems, including the nervous system. Indeed, the chronic pelvic pain and urinary symptoms appear as a result of interrelated, but variable, pathophysiology incorporating inflammatory, microbial, endocrine, neuromuscular, peripheral and CNS and even psychological pathways. The systemic characterization of UCPPS in the MAPP Network supports the idea that each patient with a UCPPS diagnosis represents an individual clinical picture and symptom profile. The promise of well-powered and carefully controlled biomarker research, such as described in the present study, will probably be realized when fully integrated into a systemic clinical profile using phenotypic insights (biological and symptom) still evolving from the MAPP Network and other studies. This is expected to yield a better understanding of specific mechanisms and symptom profiles operative in individual patients or patient subgroups. Identification of biomarker patterns that inform the clinical picture has the promise to allow us, in future, to make individualized diagnoses leading to individualized mechanistically (not only phenotypically) directed prognostic and therapeutic strategies. Success in such efforts will lead to UCPPS becoming less of a urological mystery. Then this enigmatic condition might join other urological diseases for which we have accurate diagnostic algorithms and successful therapeutic interventions.

The ongoing MAPP-2 Research Network’s Symptom Patterns Study is using state-of-the-art approaches to examine closely the interrelationships between the inflammatory, endocrine, microbial, neurological and psychological systems and how these interactions influence patients’ symptoms over a 2–3-year time period. This includes correlations with diverse biological markers over time. It is hoped that MAPP-2 will unravel the tangled web of these mechanistic pathways, allowing better diagnosis and ultimately, better therapy for our patients with UCPPS. That is our promise of the light at the end of a very long urological tunnel.

J. Curtis Nickel *†

 

*Queen’s University, Kingston, ON, Canada and †Urology, Canada Research Chair in Urologic Pain and Inflammation, Queen’s University, Kingston, ON, Canada
 
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References

 

1 Dagher A, Curatolo A, Sachdev M et al. Identification of novel non-invasive biomarkers of urinary chronic pelvic pain syndrome: findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. BJU Int 2017; 120: 130–42

 

2 Clemens JQ, Mullins C, Kusek JW et al. The MAPP research network: a novel study of urologic chronic pelvic pain syndromes. BMC Urol 2014; 14: 57

 

3 Landis JR, Williams DA, Lucia MS et al. The MAPP research network: design,patient characterization and operations. BMC Urol 2014; 14: 58–75

 

Editorial: Detection and oncological effect of CTC in patients with variant UCB histology treated with RC

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I read this article from Hamburg-Eppendorf with great interest [1]. The treatment of invasive urothelial carcinoma has not significantly progressed in the last 30 years, with survivals currently that are little changed since the first introduction of multi-drug platinum-based chemotherapy in the 1980s. Moreover, the broad application of chemotherapy, whether it is in the preoperative or postoperative domains, is associated with significant morbidity in this generally elderly population. As 60–80% of patients are cured by surgery alone, the broad use of chemotherapy in any setting results in unnecessary morbidity and occasionally mortality in some patients unnecessarily. Multiple patients have a permanent reduction in renal function when platinum is used in this setting. The decision to treat preoperatively is limited by inaccurate clinical staging and in the postoperative setting may be compromised by slow or incomplete surgical recovery.

The measurement of preoperative circulating tumour cells (CTC) provides us with a rational approach to more accurately select patients for neoadjuvant chemotherapy and would seem according to this article to independently predict disease recurrence, even when considering aggressive variant histologies. Examining Figure 2, one finds that even with variant histology, 60% of patients will not recur after cystectomy if they are CTC negative. The differences are even more profound in pure urothelial carcinoma, where the presence of detectable CTC decreases survival by 50%. The authors are to be congratulated for providing us with a potential rational methodology to determine the benefit from neoadjuvant chemotherapy in patients with bladder cancer prior to cystectomy. Next we should await the analysis of clinical trials stratified by CTC status.

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Michael O. Koch, Chairman and Professor of Urology

 

Indiana Cancer Pavilion, Indiana University School of Medicine, Indianapolis, IN, USA

 

Reference

 

1 Soave A, Riethdorf S, Dahlem R et al. Detection and oncological effect of circulating tumour cells in patients with variant urothelial carcinoma histology treated with radical cystectomy. BJU Int 2017; 119: 854–61

 

Editorial: Predicting outcome: role of gene signatures

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Pathological assessments, such as Gleason grading, which is a strong clinical predictor of prostate cancer progression [1], have a role to play in predicting the outcome of a patient’s response to therapy. The addition of PSA and TNM staging are further used to inform appropriate treatment strategies in patients who are at low, intermediate and high risk of disease progression. Unfortunately, approximately 30% of men with intermediate-risk prostate cancer will fail to be cured by surgery or radiation therapy approaches. This is not surprising as primary prostate cancer represents a complex heterogeneous disease that is clearly not fully explained by the current clinical prognostic factors, and further molecular characterization is required. There is now significant emerging evidence that the molecular characterization of tumours is important to enable us to stratify prostate cancer patients by their response to primary therapy and to identify the next appropriate steps in their treatment pathway.

Long et al. [2] have identified gene signatures that can define different genomic subtypes of prostate cancer and are predictive of biochemical recurrence. Erho et al. [3] discovered and validated a 22-gene signature, which they termed a genomic classifier for the prediction of early metastasis after radical prostatectomy, while Penny et al. [4] have identified an mRNA expression signature of Gleason grade which is predictive of lethal prostate cancer.

Long et al. [2] identified a 24-gene signature, which they discovered through RNA sequencing analysis of 100 formalin-fixed paraffin-embedded prostatectomy samples. They went on to validate their findings in a publically available independent gene expression microarray dataset of 140 patients. This 24-gene signature forms the basis of the present study by Pellegrini et al. [5], who refer to this gene signature as Sig24. In their study, they firstly undertook to determine if Sig24 was associated with pathological Gleason score as a marker of tumour aggressiveness, and then if it had prognostic value for the identification of patients at risk of metastasis or prostate cancer-specific mortality after radical prostatectomy. The Gleason score association study was carried out using the data from three independent case–control sets, including 182 patients from the Cleveland Clinic and two cohorts (cohort I, n = 545; cohort II, n = 235) from the Mayo Clinic, for which gene expression analysis had previously been conducted by Genome Dx using the Affymetrix Human 1.0 ST Genechip platform. The Sig24 score was calculated for each patient and higher Gleason score was associated with significantly higher Sig24 scores. The association studies for metastatic disease and prostate cancer-specific mortality, however, were only carried out in the Mayo Clinic cohort II. For both clinical endpoints the Sig24 score combined with the clinical model outperformed the clinical model alone of PSA, Gleason score and tumour stage. For metastatic disease the area under the curve for the clinical model alone was 0.69 (0.62–0.77) compared with 0.73 (0.66–0.78) for the clinical model combined with Sig24. For the prostate cancer-specific mortality endpoint, the area under the curve for the clinical model alone was 0.69 (0.67–0.87) compared with 0.74 (0.63–0.85) for the clinical model combined with Sig24.

These gene signatures have significant potential for predicting the progression of disease rather than waiting for PSA relapse, which is currently used to identify disease recurrence, with interval to biochemical failure being the best univariate factor predicting prostate cancer mortality and overall survival [6]. This would allow the initiation of additional therapies before recurrence and a better outcome for the patient. This concept has been demonstrated in a study in which the use of the Decipher gene signature was shown to improve the identification of patients who could benefit from adjuvant radiotherapy and thus only these patients were targeted for therapy [7].

Incorporating these gene signatures in robust clinical assays and integrating them into clinical decision-making is the next essential step in order for these strategies to have an impact on patient outcomes.

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Ronald W. Watson
UCD School of Medicine, University College Dublin, Dublin, Ireland

References

1 Gleason DF. Classification of prostatic carcinomas. Cancer Chemother
Rep 1966; 50: 125–8
2 Long Q, Xu J, Osunkoya AO et al. Global transcriptome analysis of formalin-fixed prostate cancer specimens identifies biomarkers of disease recurrence. Cancer Res 2014; 74: 3228–37

 

3 Erho N, Crisan A, Vergara IA et al. Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One 2013; 8: e66855

 

4 Penny KL, Sinnott JA, Fall K et al. mRNA expression signature of Gleason grade predicts lethal prostate cancer. J Clin Oncol 2011; 29:2391–6

 

5 Pellegrini K, Sanda MG, Patil D et al. Evaluation of a 24-gene signature for prognosis of metastatic events and prostate cancer-specific mortality. BJU Int 2017; 119: 961–7

 

6 Buyyounouski MK, Pickles T, Kestin LL, Allison R, Williams SG. Validating the interval to biochemical failure for identification of potentially lethal prostate cancer. J Clin Oncol 2012; 30: 1857–63

 

7 Den RB, Yousefi K, Trabulsi EJ et al. Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. J Clin Oncol 2015; 33: 944–51

 

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