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Men’s Health – Driving the Message Home

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Gentlemen, Start Your Engines

Over the past couple of years, we have seen a growing number of fun and exciting ways to help raise awareness for prostate cancer and men’s health. Movember, for example, has become increasingly popular across the globe. This summer, a couple of high-octane, awareness and fund-raising events are taking place on both sides of the Atlantic. I encourage you to check out both of these events and consider participating – jump in and fasten your seat belts, we’re going for a ride!

 

The Drive for Men’s Health

 

Electron Powered

For the second straight year, American urologists Dr. Jamin Brahmbhatt and Dr. Sijo Parekattil have organized the Drive for Men’s Health. Last year, the team drove an all-electric powered TESLA from Clermont, Florida, to Manhattan, New York.

This year, on Thursday, June 11th, the Drive for Men’s Health will again start in Clermont, Florida. However, once they arrive in Manhattan, they’ll take a sharp left turn and head West to Los Angeles, California. The 6,000 mile journey is expected to take nine days to complete. Along the way, the team will need to stop over 60 times to plug in and recharge.

 

Putting a Plug In for Men’s Health

Over the course of the drive, the urology duo will host live webcasts, on a variety of men’s health topics, including the topic of home health care provided by our partners at www.oxford-healthcare.com/tulsa-home-care-services/, all this with the help of over 200 speakers from around the world. The drivers hope the car, and technology used during the drive, will function as a magnet to pull men and their loved ones into further discussions about healthy living, as well as knowing when to request respite care Tinton NJ once aware of what this kind of care entails. This year’s Drive for Men’s Health coincides with National Men’s Health Week in the United States.

 

The Banger 3K Rally for Prostate Cancer

Banger 3K Car

 

 Putting the Pedal to the Metal

As summer approaches, auto racing heats up in Europe. In July, amateur hockey player Adam Clark (Clarky) and his friend Robert Lamden (Lambo) will strap themselves into a 28-year-old Toyota MR2 Mk1 for the 2015 Banger Rally Challenge. The race is similar to the Gumball 3000 Rally, but with old cars that cannot be worth more than £350. These old cars needs to be modified with Remapping stages for better performance.

In England, an old car is referred to as “an old banger”. It’s not going to be easy by any stretch of the imagination, and we hope not to break down.” – Adam Clark, “Clarky”

Over the course of ten days, the team will attempt to drive 3,000 miles across France, Switzerland, Monaco, Italy, and thru the Alps. The purpose of the event is to raise awareness and money for Prostate Cancer UK, the largest men’s health charity in the UK, dedicated to helping men survive prostate cancer, and enjoy a better quality of life.

It’s a lighthearted race, but being the first one to the finish line does not mean you have won. There are lots of challenges along the way that need to be completed – and we have no idea what they are yet as it is all secret! It’s very much a social activity, many laughs, great memories. It will be competitive, but I think everyone will be happy just to get to the finish line without breaking down! – Adam Clark, “Clarky”

 

A Shot and a Goal

Clarky and Lambo have already raised nearly £9,000 for Prostate Cancer UK by selling sponsorship spaces on the car, and from donations. When the team finally arrives back home in London, England, Clarky will wrap up the fundraising event on the ice, as assistant captain, playing for Team Prostate in an All-Stars Charity Ice Hockey Tournament at the home of British ice hockey, Sheffield Arena.

team prostate cancer UK

 

 Driving the Message Home

Every man has a unique set of interests. Some men respond to technology under the hood, while others enjoy the screeching of tires on pavement, or the excitement of a shot and a goal. When it comes to men’s health, this summer offers something for just about everyone.

Please consider giving a shout out to Jamin and Sijo on Twitter or Facebook as they drive across America, and/or consider donating to Clarky and Lambo who you can follow on Instagram and Twitter, and for updates along the Banger 3K, please “friend” on Facebook.

By donating and supporting the boys, you will not only help shift men’s health into high gear, but also help keep our patients and our friends out of the penalty box and firing on all cylinders.

 

Dr. Brian Stork is a community urologist who practices in Muskegon and Grand Haven, Michigan, USA. He is a member of the American Urological Association’s Social Media Workgroup, and is the Social Media Director at StomaCloak. You can follow Dr. Stork on Twitter @StorkBrian.

 

Editorial: A urologists’ guide to the multi-parametric magnetic resonance imaging (mpMRI)-galaxy

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The rise of multi-parametric MRI (mpMRI) for the assessment of patients with suspicion of prostate cancer has led to an enormous shift in the practice of every urologist dealing with frontline diagnostics [1].

At the same time, researchers and industry have identified acres of fruitful soil to place the seeds of their respective interests, sometimes in collaboration with each other producing valuable contributions to this shift in practice, sometimes taking benefits by merely assimilating themselves or their product to this development.

Both, the speed of change and the extent of proliferation, make it almost impossible for by-standing clinicians to keep up and filter the evidence-based essence for their local practice.

There are three important issues that need to be considered:

1 The Quality of mpMRI

The development of mpMRI for prostate assessment occurred over the last decade with well-known leaders pushing the frontiers. Their research benefitted from their individual experience of interpreting and reporting MRIs. This is then reflected in their outcomes in form of cancer detection rates and accuracy. More recently we have identified that achieving these results must involve standardisation of MRI protocols and reading [2-4], systematic training in validated courses and a significant learning curve [5]. The latter is only possible to achieve if the practice is embedded in a collaborative team of radiologists, pathologists and urologists. But even then it may be impossible for local teams to deliver the published accuracy, and the urologists and radiologists need to be mindful of that when counselling patients using mpMRI in their local environment.

2 The Technical and Clinical Validity of MRI-Based Biopsies

Transperineal vs transrectal, targeted alone vs targeted with systematic, cognitive vs fusion biopsies – these are the key debates surrounding the application of mpMRI into the urologists’ armamentarium. For none of them there is or will be a unified answer.

Transrectal approaches suit office-based provision of primary diagnostics in many European and USA health economies; although purists can say that the increasing risk of sepsis from antibiotic-resistant bacteria is not acceptable. But, favouring the less infection-prone transperineal approaches will have impact on theatre capacities even in a hospital-based health system like the UK.

Considering the current real-time quality of mpMRI, systematic biopsies in addition to targeted ones are still necessary. Urologists as a group have to come to an agreement about what is acceptable as a remaining risk when reducing or omitting systematic cores.

Cognitive targeting has been shown to be highly accurate; yet, fusion may offer standardisation and reduce user dependency. Not all fusion software on the market has undergone a thorough validated technical development and clinical accuracy evaluation. Peer-reviewed publications can be found involving the systems Urostation-Koelis, Uronav-Philips, Artemis and BiopSee-Medcom.

3 Translation into Clinical Practice

The positioning of the mpMRI within the assessment algorithm is key to optimise the benefit. Use as a pre-biopsy assessment tool may allow omission of further biopsies in some patients or facilitate targeting [6]. However, an established skill in the use of mpMRI and mpMRI-based biopsy is essential. Many UK centres have started the use of mpMRI in their practice further downstream in patients with persistent suspicion after negative first biopsies with good results for patients. It is already part of guidance that active surveillance should involve the use of MRI [1]. Some leading centres advocate that the diagnosis should be confirmed by MRI-based targeted and systematic biopsies.

Knowing that mpMRI will improve the accuracy of our assessment, we need to re-consider follow-up protocols. Increased certainty should be reflected in an improved cancer-related outcome, better patient experience and reduction in costs for the health system.

Prostate mpMRI as part of the urologists’ armamentarium is here to stay. A standardised team- and evidence-based approach will allow us to remain in control of the destination it leads us to.

Read the full article
Christof Kastner
Cambridge University Hospitals, Cambridge, UK
References

 

1 National Institute for Health and Care Excellence (NICE). NICE clinical guideline 175. Prostate cancer: diagnosis and Treatment. Issued January 2014. Available at: https://www.nice.org.uk/guidance/cg175. Accessed December 2014

 

2 Barentsz JO, Richenberg J, Clements R et al. ESUR prostate MR guidelines 2012. Eur Radiol 2012; 22: 746–57

 

3 Moore CM, Kasivisvanathan V, Eggener S et al. Standards of reporting for MRI-targeted biopsy studies (START) of the prostate: recommendations from an International Working Group. Eur Urol 2013; 64: 544–52

 

4 Kuru TH, Wadhwa K, Chang RT et al. Definitions of terms, processes and a minimum dataset for transperineal prostate biopsies: a standardization approach of the Ginsburg Study Group for Enhanced Prostate Diagnostics. BJU Int 2013; 112: 568–77

 

5 Gaziev G, Wadhwa K, Barrett T et al. Defining the learning curve for multi-parametric MRI of the prostate using MRI-TRUS fusion guided transperineal prostate biopsies as a validation tool. BJU Int 2015. [Epub ahead of print]. doi: 10.1111/bju.12892

 

6 Willis SR, Ahmed HU, Moore CM et al. Multiparametric MRI followed by targeted prostate biopsy for men with suspected prostate cancer: a clinical decision analysis. BMJ Open 2014; 4: e004895

 

Editorial: The need for standardised reporting of complications

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In the context of diversifying practice models, implementation of new technologies such as the Da Vinci surgical robot and rising healthcare costs, there is growing interest in evaluating the quality of surgical work. This extends into health policy, as reimbursement penalties are introduced for ‘inappropriate’ outcomes (e.g. excessive readmissions). Consequently, there is a significant need to provide an accurate assessment of complications and mortality when reporting on surgical outcomes.

Despite the constant use of outcomes data to measure effectiveness in surgery, no current urology guidelines demand the standardised reporting of surgical complications [1]. As randomised controlled trials are uncommon within the surgical setting, and are associated with significant biases [2], there is a distinct need for a uniform reporting system after urological surgeries. Indeed, the lack of such makes it challenging to compare surgical outcomes between techniques, surgeons and institutions, thus hampering the interpretation of study results [3]. The ongoing (and never-ending) debate on the comparative effectiveness of open vs robot-assisted radical prostatectomy (RP) highlights the need for standardised methods to assess superiority (or inferiority) of surgical results [4].

In this issue of the BJUI, Soares et al. [5] present a single-surgeon study of 1138 laparoscopic RPs (LRPs) with a standardised approach between the years 2000 and 2008, and their 5-year follow-up. Whereas the functional and/or oncological equivalency of LRP compared with open RP has been reported before [6], perhaps the outstanding contribution of this study is the use of the Martin-Donat criteria to report and analyse surgical results [3, 7]. In 2002, Martin et al. [7] introduced a list of 10 standard criteria for accurate and comprehensive reporting of surgical complications (e.g. methods of data acquisition, duration of follow-up, definition of complications, hospital length of stay).

In Table 6 of their manuscript, Soares et al. [5] display surgical and/or oncological outcomes of a total of 17 studies on LRP (including their own data). This table suggests the obvious: there is no consistency of reporting on outcomes. In the 2007 Donat [3] analysis of surgical complications reporting in the urological literature, only 2% of a total of 109 studies met nine to 10 of the critical Martin criteria. Interestingly, these shortcomings have been addressed in more contemporary years as the number of studies complying with most of the Martin criteria has increased between 1999/2000 and 2009/2010 [1]. Yet, despite the increasing use of classification systems for outcomes of surgery and standardised reporting of complications (e.g. Clavien-Dindo classification), they are not routinely applied [1, 8].

In an era where the adoption of a certain surgical approach or technique needs to be carefully weighted against a demand for greater value and decreased costs, a simple case series on positive outcomes is simply not sufficient [9]; at the very least, guideline-compliant assessment of outcomes should be the standard of care.

Read the full article

 

Marianne Schmid*†, Christian P. Meyer*† and Quoc-Dien Trinh*

 

*Division of Urologic Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA and† Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

 

References

1 Mitropoulos D, Artibani W, Graefen M, Remzi M, Roupret M, Truss M. Reporting and grading of complications after urologic surgical procedures: an ad hoc EAU guidelines panel assessment and recommendations. Eur Urol 2012; 61: 341–9

 

2 Omar MI, Lam TB, Alexander CE et al. Systematic review and meta- analysis of the clinical effectiveness of bipolar compared with monopolar transurethral resection of the prostate (TURP). BJU Int 2014; 113: 24–35

 

3 Donat SM. Standards for surgical complication reporting in urologic oncology: time for a change. Urology 2007; 69: 221–5

 

4 Schmid M, Gandaglia G, Trinh QD. The controversy that will not go away. Eur Urol 2014; [Epub ahead of print]. doi: 10.1016/ j.eururo.2014.02.052

 

5 Soares R, Di Benedetto A, Dovey Z, Bott S, McGregor R, Eden C. Minimum 5-year follow-up of 1138 consecutive laparoscopic radical prostatectomies. BJU Int 2014; [Epub ahead of print]. doi: 10.1111/ bju.12887

 

6 Hruza M, Bermejo JL, Flinspach B et al. Long-term oncological outcomes after laparoscopic radical prostatectomy. BJU Int 2013; 111:  271–80

 

7 Martin RC 2nd, Brennan MF, Jaques DP. Quality of complication reporting in the surgical literature. Ann Surg 2002; 235: 803–13

 

8 Yoon PD, Chalasani V, Woo HH. Use of Clavien-Dindo classification in reporting and grading complications after urological surgical procedures: analysis of 2010 to 2012. J Urol 2013; 190: 1271–4

 

9 Novara G, Ficarra V, D’Elia C, Secco S, Cavalleri S, Artibani W. Trifecta outcomes after robot-assisted laparoscopic radical prostatectomy. BJU Int 2011; 107: 100–4

 

Editorial: Time to replace PSA with the PHI?

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Yet more evidence that the PHI consistently outperforms PSA across diverse populations

The Prostate Health Index (PHI) has regulatory approval in >50 countries worldwide and is now being incorporated into prostate cancer guidelines; for example, the 2014 National Comprehensive Cancer Network Guidelines for early prostate cancer detection discuss the PHI as a means to improve specificity, using a threshold score of 35 [1]. The PHI is also discussed in the Melbourne Consensus Statement [2], and it has been incorporated into the multivariable Rotterdam risk calculator smartphone app for use in point-of-care decisions [3].

As the use of this test continues to expand, more data on its performance in specific at-risk populations are of great interest. The investigators from the PROMEtheus multicentre European trial have previously validated the use of the PHI in men with a positive family history of prostate cancer [4]. The new study by Abrate et al. in this issue of BJUI instead addresses another high-risk population – obese men – who have previously been shown to have a greater risk of aggressive prostate cancer [5].

Among the 965 participants in the PROMEtheus study, 14.7% were considered obese based on a body mass index ≥30 kg/m2. In this group, 45.8% were diagnosed with prostate cancer from a ≥12-core biopsy, and 67.7% had a Gleason score ≥7. Overall, the PHI significantly outperformed PSA for prostate cancer detection in men with a body mass index ≥30 kg/m2 (area under the curve 0.839 vs 0.694; P < 0.001). At 90% sensitivity, the threshold for PHI in obese men was 35.7, with a specificity of 52.3%. The PHI also had the best performance for the detection of Gleason ≥7 disease, with an area under the curve of 0.89.

These findings add to the highly consistent body of evidence supporting the use of the PHI in early prostate cancer detection and risk stratification. In fact, all published studies to date have shown that the PHI outperforms PSA for detection of overall and high-grade prostate cancer detection on biopsy [6]. Numerous studies have also shown a role for the PHI in patient selection and monitoring during active surveillance [7, 8]. Expanded use of this test is warranted to reduce unnecessary biopsies and better identify cancers with life-threatening potential.

Read the full article
Stacy Loeb
Department of Urology and Population Health, New York University, New York, NY, USA

 

References

1 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Prostate Cancer Early Detection Version 2014. https://www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf.Accessed May 26, 2014

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 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

4 Lazzeri M, Haese A, Abrate A et al. Clinical performance of serum prostate-specific antigen isoform [-2]pr oPSA (p2PS A) and its derivatives, %p2PSA and the prostate health index (PHI), in men with a family history of prostate cancer: results from a multicentre European study, the PROMEtheuS project. BJU Int 2013; 112:313–21

5 Freedland SJ, Banez LL, Sun LL, Fitzsimons NJ, Moul JW. Obese men have higher-grade and larger tumors: an analysis of the duke prostate center database. Prostate Cancer Prostatic Dis 2009; 12: 259–63

6 Filella X, Gimenez N. Evaluation of [-2] proPSA and Prostate Health Index (phi) for the detection of prostate cancer: a systematic review and meta-analysis. Clin Chem Lab Med 2013; 51: 729–39

7 Tosoian JJ, Loeb S, Feng Z et al. Association of [-2]proPSA with Biopsy Reclassification During Active Surveillance for Prostate Cancer. J Urol2012; 188: 1131–6

8 Hirama H, Sugimoto M, Ito K, Shiraishi T, Kakehi Y. The impact of baseline [-2]proPSA-related indices on the prediction of pathological reclassification at 1 year during active surveillance for low-risk prostate cancer: the Japanese multicenter study cohort. J Cancer Res Clin Oncol2014; 140: 257–63

 

Editorial: Enzalutamide withdrawal syndrome: is there a rationale?

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Enzalutamide is a second generation non-steroidal antiandrogen (AA), which significantly improved overall  survival (OS) and progression-free survival (PFS) after docetaxel (AFFIRM study), and OS and radiographic PFS before chemotherapy (PREVAIL study) in patients with metastatic castration-resistant prostate cancer (mCRPC) [1].

Being a potent androgen receptor (AR) antagonist, an enzalutamide withdrawal syndrome (EWS) appeared unlikely [2,3]. In contrast with this position, and considering the well-known AR structural alterations in CRPC, very recent preclinical and clinical data support the possibility of the existence of an EWS after the discontinuation of this drug, in a castration-resistant setting.

In patients with mCRPC progressing on androgen-deprivation therapy (ADT), the AAWS, due to the interruption of first generation AAs (flutamide, bicalutamide, nilutamide, cyproterone acetate and megestrol acetate), often pursues as a further hormonal manipulation, although no level one studies supported its efficacy. AAWS leads to a PSA reduction in 15–30% of patients, with concomitant symptomatic relief and radiographic responses in some cases, without impacting on survival [1]. The molecular mechanisms of the AAWS are still unclear. One of the possible mechanisms responsible for the AAWS is the mutation of the AR. In vitro models showed that bicalutamide may switch from antagonist to agonist in LNCaP-cxD cell lines, due to an additional AR mutation in codon 741 during bicalutamide treatment [4]. Similarly, preclinical in vitro and in vivo studies demonstrated that initially enzalutamide exerts its AR antagonist activity, but during the treatment enzalutamide potently induces an AR mutation, leading to the mutant ARF876L, which confers agonism to enzalutamide, and resistance to enzalutamide therapy [1]. In the clinical setting, the first evidence of possible EWS has begun to appear. Phillips [5] observed EWS in one patient, 40 days after enzalutamide discontinuation. Rodriguez-Vida et al. [1] showed EWS in three of 30 (10%) patients with mCRPC after the drug cessation, although none of the 17 factors examined were statistically significant predictors of PSA decline after enzalutamide interruption. Considering the clinical characteristics of the three patients showing EWS, interestingly all of them were aged <70 years, had Gleason score ≥7, had bone and/or lymph node metastases without visceral sites of disease, and had had previous treatments with bicalutamide and docetaxel. In all three patients, EWS seems to have no correlation with: prostate cancer staging at diagnosis (M0 vs M1), PSA value before enzalutamide, PSA decline on enzalutamide treatment, LHRH analogues and enzalutamide therapy duration. Similarly to bicalutamide WS, in all three patients no symptomatic improvement was recorded during EWS.
Focusing on patient 1, interestingly he displayed initially a PSA response during enzalutamide and later a further PSA decline plus radiological response after enzalutamide interruption (i.e. EWS), showing a sensitivity either to initial enzalutamide antagonism and to subsequent agonism, and exhibiting an EWS not preceded by a bicalutamide WS. This supports previous data concerning different AR mutations for the two different AAs, without subsequent clinical correlations between the two different AAWSs. A LHRH analogue duration treatment (5 months) shorter than a subsequent enzalutamide duration therapy (21.4 months) suggests different tumoral cells sensitivity to different ADTs, in different stages (hormone naïve and castration-resistant prostate cancer), likely related to several AR structural alterations collected along the disease. Intriguingly, patient 3 discontinued enzalutamide after only 1.2 months, maybe due to primary resistance [6]; nevertheless, he showed a PSA
response after enzalutamide interruption, suggesting that EWS, characterised by the switch from enzalutamide antagonism to agonism, could occur even in prostate cancer patients primary resistant to this drug. Limitations of the two first clinical reports related to EWS include a restricted sample size, a reduced number of EWS events and a short duration of follow-up after enzalutamide discontinuation. Furthermore, preclinical studies on EWS and published data concerning AAWS described more frequently early stage mCRPC, while the two papers considered heavily pretreated patients with mCRPC, in whom EWS incidence could be reduced due to several previous treatments, which probably produced various AR alterations.

In conclusion, the preclinical models have demonstrated one possible plausible mechanism responsible for EWS and enzalutamide resistance. First clinical reports suggest the possibility of EWS in a minority of patients after enzalutamide discontinuation in mCRPC. Further studies are needed to confirm and detail the EWS, before translating these data into clinical practice.

Read the full article

Alessandra Mosca
Medical Oncology, ‘Maggiore della Carità’ University Hospital, Novara, Italy

References

1 Rodriguez-Vida A, Bianchini D, Van Hemelrijck M et al. Is there an antiandrogen withdrawal syndrome with enzalutamide? BJU Int 2015; 115: 373–80

2 von Klot CA, Kramer MW, Böker A et al. Is there an anti-androgen withdrawal syndrome for Enzalutamide? World J Urol 2014; 32: 1171–6

3 von Klot CA, Kuczyk MA, Merseburger AS. No androgen withdrawal syndrome for enzalutamide: a report of disease dynamics in the postchemotherapy setting. Eur Urol 2014; 65: 258–9

4 Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res 2003; 63: 149–53

5 Phillips R. An enzalutamide antiandrogen withdrawal syndrome. Nat Rev Urol 2014; 11: 366

6 Efstathiou E, Titus M, Wen S et al. Molecular characterization of Enzalutamide-treated bone metastatic castration-resistant prostate cancer. Eur Urol 2015; 67: 53–60

 

Editorial: How active should active surveillance be?

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 Many investigators, including those from Johns Hopkins University (JHU) and the Prostate cancer Research International: Active Surveillance project (PRIAS), have provided meaningful data to strongly support the increasing use of active surveillance (AS) across the world. There are a multitude of strategies to minimise excessive rates of prostate cancer over detection and overtreatment. After the diagnosis of prostate cancer, the single best is AS for appropriately selected men.

 For decades, the concept of not treating a prostate cancer in otherwise healthy men, even if low-grade and low-volume was typically considered nihilistic and heretical, particularly in the USA. Thankfully, data have largely made this line of thinking anachronistic. The era of sensibly applied AS is upon us, and single-institution series with intermediate-term follow-up are excellent, with exceedingly low rates of metastasis or cancer-related death. However, we await longer-term (>10 years) outcomes from the contemporary PSA screening era.

 The ‘success’ of AS is largely dependent on the entry criteria, follow-up strategies, and indications for curative intervention. Highly restrictive inclusion criteria, rigorous biopsy based follow-up and strict definitions of reclassification triggering treatment have produced superb outcomes. Critics appropriately argue these criteria exclude a significant proportion of men with a low rate of requiring treatment or having metastases, if allowed on AS. Conversely, other programmes with looser entry criteria, more lax follow-up, and relaxed indications for intervention will be more inclusive and have lower rates of immediate or delayed intervention but must be counterbalanced against the expected higher rate of metastases or death.

 The current study [1] evaluates two different AS follow-up strategies from JHU and PRIAS. In general, JHU uses annual biopsies with progression defined as a new PSA density >0.15 ng/mL/mL or increasing tumour volume or grade beyond a certain threshold, while PRIAS recommends less frequent biopsies (years 1, 4, and 7) while relying on serological (PSA doubling time, PSADT) alongside histological indicators for defining progression and recommending treatment.

 Not surprisingly, different strategies lead to varying expected outcomes. Among the JHU patients, 38% were reclassified at a median of 2.1 years. Nearly two-thirds of the reclassified would have been identified at the PRIAS year 1 or triennial biopsies with 16% identified between PRIAS biopsies at a median delay of 1.9 years. The unanswerable but incredibly important question is whether this delay is essentially a non-issue, perhaps a favourable attribute (more AS time without compromising cure rates), or clinically disastrous (patients no longer curable).

 PRIAS relies heavily on PSA kinetics, which can be a double-edged sword. Among men in the JHU programme with >5 years follow-up, 11% would have delayed reclassification compared with PRIAS at a median time of 4.7 years. Additionally, 12% would have undergone intervention due to PRIAS-defined PSADT but not progressed based on the JHU protocol. It is convenient and perhaps intuitive that PSA kinetics should predict progression and meaningful clinical events for men on AS; however, the data from multiple studies have simply not supported this concept [2, 3].

 The JHU programme has restrictive entry rules compared with most other programmes, a rigorous biopsy based follow-up protocol, and strict criteria to treat, which is exactly why no metastasis or death have been reported among 769 men, some with up to 15 years follow-up[4]. Guidelines are needed but should not be overly prescriptive or rigid. For example, a surveillance biopsy showing a single core of Gleason 6 encompassing 60% of the total core or three cores of Gleason 6 with total cancer length of 3 mm would lead to a recommendation of treatment according to published JHU criteria. Many of us would not be phased with these biopsy reports and comfortably recommend ongoing AS.

 Data from AS series are very encouraging but it is highly likely we can do even better. For example, 10-year cancer-specific survival is 97% in the Sunnybrook AS experience and all five cancer-related deaths occurred in patients that would not meet most contemporary AS entry criteria [5, 6]. I am hopeful and confident that emerging data incorporating MRI imaging, serum biomarkers (e.g. prostate health index), or tissue-based biomarkers (e.g. Prolaris, Oncotype Dx) will provide us with a more comprehensive understanding of these men’s cancer such that tailored, evidence-based recommendations can be even more accurate.

 There is much yet to be learned about AS and this study [1] adds to our knowledge. Surveillance for prostate cancer is definitely active, but it is also dynamic and evolving.

Read the full article
Scott Eggener
Associate Professor of Surgery, University of Chicago, Chicago, IL, USA

 

References

 

1 Kates M, Tosoian JJ, Trock BJ, Feng Z, Carter HB, Partin AW. Indications for intervention during active surveillance of prostate cancer:
a comparison of the Johns Hopkins and Prostate Cancer Research International Active Surveillance (PRIAS) protocols. BJU Int 2015; 115: 216–22

 

2 Whitson JM, Porten SP, Hilton JF et al. The relationship between prostate specific antigen change and biopsy progression in patients on active surveillance for prostate cancer. J Urol 2011; 185: 1656–60

 

3 Fall K, Garmo H, Andrén O et al. Prostate-specific antigen levels as a predictor of lethal prostate cancer. JNatlCancerInst2007; 99: 526–32

 

4 Tosoian JJ, Trock BJ, Landis P et al. Active surveillance program for prostate cancer: an update of the Johns Hopkins experience. J Clin Oncol 2011; 29: 2185–90

 

5 Klotz L, Zhang L, Lam A, Nam R, Mamedov A, Loblaw A. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol 2010; 28: 126–31

 

6 Krakowsky Y, Loblaw A, Klotz L. Prostate cancer death of men treated with initial active surveillance: clinical and biochemical characteristics. J Urol 2010; 184: 131–5

 

Social media makes global urology meetings truly global

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Loeb_photoThe use of social media continues to expand in urology and the BJUI is proud to be at the forefront of these efforts. All of the global urology meetings now have their own twitter feed, which is indexed using a ‘hashtag’ (e.g. #EAU14, #AUA14). Analogous to a Medical Subject Heading (MeSH) in PubMed, hashtags are used to categorise related tweets together in one place, providing a convenient way to follow conference proceedings.

Surrounding the 2014 European Association of Urology (EAU) Congress (9–16 April 2014), there were a record 5749 tweets from 761 unique contributors. The BJUI and its editorial team represented four of the top 10 social media influencers based on the number of times that they were mentioned in the #EAU14 conference twitter feed.

Social media engagement continued to grow to new heights at the 2014 AUA meeting. From 14–23 May 2014, there were a total of 10 364 tweets from 1199 unique contributors in the #AUA14 conference twitter feed. The BJUI and its editorial team represented six of the top 10 influencers based on the total number of mentions.

In addition to urology conferences, the BJUI continues to actively participate in social media throughout the year. We provide a variety of specialised content such as videos, picture quizzes, and polls, as well as free access to the ‘Article of the Week’. This provides a great way to stay up-to-date on the latest research in a dynamic, interactive setting.

Finally, I would like to call your attention to two ‘Articles of the Week’ featured in this issue of BJUI, both of which will be freely available and open to discussion on twitter. The first by Kates et al. [1] deals with the interesting question of the optimal follow-up protocol during active surveillance. Using yearly biopsy results from the Johns Hopkins active surveillance programme, they report what proportion of reclassification events would have been detected had the Prostate Cancer Research International Active Surveillance (PRIAS) protocol been used instead (including less frequent biopsies and PSA kinetics).

Another feature ‘Article of the Week’ by Eisenberg et al. [2] addresses the controversial link between testosterone therapy and prostate cancer risk. Among men undergoing hormonal testing at their institution, they used data from the Texas Cancer Registry to compare the rates of malignancy between those who were and were not using testosterone supplementation. We hope that these articles will stimulate an interesting discussion and encourage you to join us on twitter.

Dr. Stacy Loeb is an Assistant Professor of Urology and Population Health at New York University and is a Consulting Editor for BJUI. Follow her on Twitter @LoebStacy

 

Editorial: Geography – an increasingly important variable in prostate cancer clinical trials

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Enzalutamide is approved in the post-docetaxel phase for men with metastatic castrate-resistant prostate cancer (mCRPC) in North America (NA) and the European Union (EU). Merseburger et al. [1] now take a first look at comparing the efficacy and safety of enzalutamide in EU and NA patients treated in the AFFIRM trial. AFFIRM was a phase III double-blind, placebo-controlled multinational trial evaluating whether enzalutamide prolongs overall survival (OS) in men with mCRPC after docetaxel chemotherapy. This post hocexploratory analysis found a consistent OS benefit in both NA- and EU-treated patients. The safety profile was comparable in both regions.

Interestingly, the median OS appeared longer in the EU as compared with the NA cohort (‘not yet reached’ vs 17.4 months). With the placebo group in the EU the median survival was 16.2 vs 12.3 months in the NA cohort (3.9 months different). Direct statistical comparisons between regions were not performed but a median survival difference of 3.9 months is not inconsequential. Notably, drugs have been approved with lesser difference in OS.

The populations in AFFIRM have some baseline differences that may be of importance; the median time from diagnosis to randomisation was 68.9 months in the EU cohort vs 78.0 months in the NA cohort. Thus, it was possible that the NA cohort was ‘further along’ in the natural history of the disease despite apparently being well-balanced according to most baseline variables. The NA cohort was slightly more likely to have higher Gleason scores (50.6%) vs the EU cohort (44.0%), suggesting perhaps a slight difference in disease aggressiveness. It is also interesting that cardiac disease was present in 23.3% of the NA cohort vs only 7.2% of the EU cohort. Is it possible that cardiovascular diseases also contributed to a relative increase in mortality in the NA cohort? With regard to the post-protocol therapies, the use of abiraterone was more common in the EU cohort (30.5% of patients in the placebo group subsequently received abiraterone in the EU cohort vs 19.7% in the NA cohort). However, utilisation of cabazitaxel was more common in NA than in the EU (20.5% vs 9.9%). Some combination of pre-treatment and post-protocol variables in AFFIRM is probably the explanation for geographic variations in OS. Protocol treatments were well defined but these variables were not controlled.

These results in AFFIRM should also be considered in the context of geographic differences in medical care that may alter results and/or interpretation of phase III trials. Some of these differences have been previously documented in other phase III mCRPC trials. For instance, the recent phase III trials with orteronel reported no OS differences in the overall study [2]. However, in certain geographic regions (with less access to the newer life-prolonging drugs), the orteronel trials were clearly positive for the OS endpoint. In the TROPIC trial, cabazitaxel was associated with higher febrile neutropenia rates in some EU countries as compared with the USA. This was primarily due to geographic differences in prophylactic administration of granulocyte colony-stimulating factor (G-CSF) [3]. For the ALSYMPCA trial, striking geographic differences were noted in the timing (pre- or post-docetaxel) of radium-223 utilisation [4].

Understanding prognosis and treatment outcomes is increasingly critical in the design and interpretation of phase III clinical trials and particularly amongst trials that are designed to support regulatory approvals. Region or country where treatment takes place is an important variable to consider, especially if approved pre- and post-protocol treatments are not the same. This issue is even more important if the course of the disease is long (as in prostate cancer) and there are different treatments available from country to country.

Read the full article

Oliver Sartor, Sumanta Kumar Pal*, Terhi Hermanson† and Charles L. Bennett‡,

Tulane Medical School, New Orleans, LA, *City of Hope Comprehensive Cancer Center, Duarte, CA, USA; † Helsinki University Central University, Helsinki, Finland; and ‡ College of Pharmacy, Medical University of South Carolina Cancer Center, Charleston, SC, USA

References

1 Merseburger AS, Scher HI, Bellmunt J et al. Enzalutamide in European and North American men participating in the AFFIRM trial. BJU Int 2015; 115: 41–9

2 Fizazi K, Jones R, Oudard S et al. Regional differences observed in the phase 3 trial (ELM-PC 5) with orteronel (TAK-700) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel. ASCO Meeting Abstracts. J Clin Oncol 2014; 32 (Suppl.): 5s (abstr 5042). Available at: https://meetinglibrary.asco.org/content/126314-144. Accessed November 2014

3 Ozguroglu M, Oudard S, Sartor AO et al. Effect of G-CSF prophylaxis on the occurrence of neutropenia in men receiving cabazitaxel plus prednisone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in the TROPIC study. ASCO Meeting Abstracts. J Clin Oncol 2011; 29 (Suppl.): abstr 144. Available at: https://meetinglibrary .asco.org/content/72386-104. Accessed November 2014

4 Parker C, Nilsson S, Heinrich D et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213–23

 

A #RadOnc Movember

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The #RadOnc Journal Club continued its success in Movember with over 700 tweets from 60 participants in a three-day discussion on smoking and prostate cancer radiation treatment outcomes. Thanks to the generosity of the BJUI (@BJUIJournal) and Prof. Prokar Dasgupta (@prokarurol), the study of a large retrospective cohort of localized prostate cancer patients who received external beam radiation treatment from Memorial Sloan Kettering (@sloan _kettering) was open-access and engaged a wide audience.

Background discussion started Friday and covered a variety of topics including limiting treatment toxicity:

Sharing best practices on the role of radiation treatment from around the world:

The state of tobacco use:

And smoking cessation from an interdisciplinary audience:

On Sunday, the community came together for a live discussion with study author Emily Steinberger (@easteinberger). Participants explored roles for radiation treatment and the reduction of side effects including hypofractionated treatment and current guidelines for IMRT:


Practice patterns in patient assessment stressed the importance of a tobacco history. These encounters created an opportunity for cessation counselling as opposed to guiding treatment decisions while recognizing the threat of information overload.


The conversation then moved to the study. Results showed current-smokers had a higher PSA relapse rate (HR 1.37 compared to former or non-smokers), more distant metastases (DM-free survival 72% vs. 87% in never-smokers), and higher cancer specific mortality (HR 2.25). There were a few surprises including finding no significant differences based on pack-years smoked and that only current as opposed to former smoking status mattered.

Study strengths included a large cohort of 2358 similarly-treated patients; 91% having documented smoking histories. Limitations included the retrospective design, especially considering the long natural history of prostate cancer and risk of development of confounding comorbidities. Also an important reminder:

Conversations concluded with considerations for future practice:


Research:


With a little #RadOnc humor in-between.

We recognize the quality contributions from all members of our community. For their leadership during this chat, congratulations to Dr. Jay Detsky (@JayDetsky) and Dr. Mohammad Alfayez (@alfayezmo) who received the Jerry Maguire Award for their evidence-based tweets. (“Show me the data!!!”) The Francis Peabody award went to Dr. Jonathan Livergant (@jpil) and Dr. Jarad Martin (@DocJarad) for the best clinical tweets. We will be looking forward to more lively conversations in the New Year!

The #RadOnc Journal Club was first proposed at the Yale Department of Therapeutic Radiology in April 2014 to leverage published evidence and stimulate discussion on key topics in radiation oncology. It became part of Radiation Nation – a community founded by Dr. Matthew Katz (@subatomicdoc) dedicated to improve cancer care through online collaborative conversations on education, medical practice, and quality and safety improvement for patients, caregivers, and medical professionals. Interest grew globally and in September, where we bridged cultural divides by encouraging conversations in multiple languages. Today, we routinely have participation from over 5 countries during the #RadOnc Journal Club and on Radiation Nation blog.

Ian Pereira is an R2 resident in Radiation Oncology at Queen’s University, Kingston, Canada. He believes that education is a basis for progress in health and care, and is interested in leveraging new technologies including social media in medical education.

 

Editorial: Bone Metastases in Prostate Cancer: Which Scan?

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In this issue of BJUI, Poulsen et al. [1] present a prospective comparison of 18F-fluoride (NaF) and 18F-choline (FCH) positron emission tomography (PET)/CT with planar whole-body bone scintigraphy (WBS) using spinal MRI, including short tau inversion recovery (STIR), T1 and T2 sequences, as the reference standard in 50 hormone-naïve patients with confirmed bone metastases on WBS. They found that both PET/CT methods were significantly more sensitive and accurate than WBS and that FCH PET/CT was more specific than NaF PET/CT.

It has become increasingly recognised that planar WBS is no longer the most accurate method of assessing the skeleton for metastases and that novel imaging methods, including PET/CT, single-photon emission CT (SPECT)/CT and whole-body MRI offer advantages [2].

What is surprising in the presented results is that NaF PET/CT shows poor specificity (54%), a result that is discordant with previous literature [3, 4]. Compared with PET alone, using the CT component of hybrid PET/CT reduces false-positive interpretation of NaF uptake in benign lesions [3]. This raises the question as to whether the CT component of the PET/CT acquisition was used to full effect in the present study. The use of spinal MRI as a reference standard is also a possible limitation that is recognised by the authors, as this limits the comparison to only the spine, and MRI in itself is a method with known limitations. All patients had abnormal WBS for entry into the trial and whilst the PET methods were more sensitive on a lesion basis, a patient-based comparison was therefore not possible; however, the results imply that PET methods may identify metastatic disease in patients with normal WBS, as has been previously reported [3, 5].

Nevertheless, the authors should be congratulated in reporting valuable data from a prospective study where all imaging was performed in hormone-naïve patients, minimising confounding treatment-related effects, and within a small time window of 30 days; however, some questions remain. WBS is no longer state of the art for imaging the skeleton with radiolabelled bisphosphonates, such as 99mTc-methylene diphosphonate (MDP). Although NaF PET/CT has been shown to be superior to planar WBS augmented with SPECT [3], there have not been head-to-head comparisons with 99mTc-MDP SPECT/CT, where the potential advantages of the pharmacokinetics of NaF and the superior spatial resolution of PET compared with SPECT may not be as great. This may be particularly important given the difference in costs and availability of the two methods.

Despite the results from the present study, which show superiority of FCH PET/CT compared with NaF PET/CT with regard to specificity, taking the available literature as a whole, it remains unresolved as to what the best test for staging the skeleton in patients with high-risk prostate cancer should be at diagnosis. The different mechanisms of uptake of the PET tracers should be noted. NaF uptake reflects the local bone osteoblastic reaction to tumour within the bone marrow, whereas FCH uptake reflects metabolic activity within the tumour cells themselves. In prostate cancer, where the predominant effect is an increase in osteoblastic activity in the adjacent bone, the bone-specific tracers such as 99mTc-MDP and NaF have shown high sensitivity; however, direct imaging of tumour cell metabolism, such as increased choline kinase activity and cell membrane synthesis with FCH, may be advantageous in detecting metastases in the bone marrow before an osteoblastic reaction has occurred [6]. It is possible that both PET tracers may be required to provide optimum diagnostic accuracy and of course FCH PET/CT also provides valuable data on nodal and visceral metastatic disease. In patients with recurrent disease, better specificity has been reported with FCH [4], NaF possibly being limited by non-specific treatment-related effects such as osteoblastic flare. For similar reasons it may be that the more tumour-specific imaging methods, such as FCH PET/CT or diffusion-weighted MRI, may be better in assessing the treatment response of skeletal metastases. Questions therefore remain as to the best imaging test at different times in the management of patients with metastatic prostate cancer. 99mTc-MDP SPECT/CT deserves a full assessment, but perhaps the recent advent of PET/MRI and the potential synergies available from this hybrid technique may help resolve some of the remaining issues.

Read the full article

Gary Cook*† and Vicky Goh*‡

*Division of Imaging Sciences and Biomedical Engineering, King’s College London, † Clinical PET Centre, and ‡ Department of Radiology, Guy’s and St Thomas’ Hospitals NHS Foundation Trust, London, UK

References

1 Poulsen MH, Petersen H, Høilund-Carlsen PF et al. Spine metastases in prostate cancer: comparison of [99mTc]MDP wholebody bone scintigraphy, [18F]choline PET/CT, and [18F]NaF PET/CT. BJU Int 2014; 114: 818–23

2 Fogelman I, Blake GM, Cook GJ. The isotope bone scan: we can do better. Eur J Nucl Med Mol Imaging 2013; 40: 1139–40

3 Even-Sapir E, Metser U, Mishani E et al. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med 2006; 47: 287–974

4 Langsteger W, Balogova S, Huchet V et al. Fluorocholine (18F) and sodium fluoride (18F) PET/CT in the detection of prostate cancer: prospective comparison of diagnostic performance determined by masked reading. Q J Nucl Med Mol Imaging 2011; 55: 448–57

5 Kjölhede H, Ahlgren G, Almquist H et al. Combined 18F-fluorocholine and 18F-fluoride positron emission tomography/computed tomography imaging for staging of high-risk prostate cancer. BJU Int 2012; 110: 1501–6

6 Beheshti M, Vali R, Waldenberger P et al. Detection of bone metastases in patients with prostate cancer by 18F fluorocholine and 18F fluoride PET-CT: a comparative study. Eur J Nucl Med Mol Imaging 2008; 35: 1766–74

 

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