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EAU14 – Planning and executing a meeting session: perspective of the chairs

An interview with Prof. Noel Clarke on the EORTC-GU session

For an academic and/or key opinion leader in urology, the opportunity to plan and execute a meeting session is a tremendous honor, but one that comes with numerous challenges. The trivial but not-so trivial aspects involve the logistics: who will attend, who will speak, what do I do if a speaker cancels, what if the speakers do not stick to time, etc. Of course the easiest way to begin is to chair a session comprised of abstracts on a particular theme. This requires mainly the effort of preparing good questions for discussion and how to keep speakers on time (should we be nice?). The next level up is to plan a session with a broader theme that requires inviting specific speakers, framing debates, and then orchestrating it all into very usable take home messages for the audience. These are tremendous opportunities to come up with a vision for our field to consider.

At the EAU 2014, Prof Noel Clarke (GB) from our consulting editorial board was charged to organize the EORTC-GUCG session along with his co-chair Cora Sternberg (IT). I had a few questions for Prof Clarke, but really ended up just handing him my iPhone with the voice memo running and asking him how he went about planning the session:

“What we were trying to do was give a broad-based and sufficiently detailed overview of where we are in relation to different cancers and understanding of different cancer processes. And we tried to do that with specific reference to areas that have been strong in the EORTC-GU group in the past, particularly linking some of the trials that we’ve done with some of the basic science that is currently ongoing. And trying to project that forward as to how we might design future trials. And the emphasis really is on participation of clinicians with scientists and with data centers to try to overcome some of the problems associated with the prosecution of trials in the modern era. Hence our final talk with was Bertrand Tombal’s talk which is really how we would envisage planning and structuring trials as we go forward because it is certainly very different now than it was in the ‘70s when the EORTC was able to do really large scale trials, following on the ‘80s and 90’s to 2000’s [British pronunciation: “naughties”] where increasingly international trial groups, academic groups, found it difficult to get around the problems of finance, beaurocracy, new agents, interactions with Pharma, and so on. So that really was the essence of how we planned our session.”

Wow – what a gem. Didn’t really need a 2nd question.

Figure 1: SPECTApros trial design

  • Prof. George Thalmann spoke on BCG therapy – an area in need of more standardized protocols and biomarkers for sensitivity/resistance. Ultimately we need successful treatment of CIS and prevention of NMIBC recurrence and progression.  The first step towards success is with a high quality TUR that provides correct staging and therapy. On this note, he cited an EORTC study (Brausi et al. Eur Urol 2002) that showed 7.4-45.8% recurrence rates after TUR and adjuvant chemo when taken for first follow-up cysto. Next, the focus is on ideal BCG therapy in terms of timing, schedules and which strain of BCG. He cited RCT’s planed by SWOG and SAKK/EORTC looking at intradermal BCG 3 weeks before intravesical therapy to improve pre-existing immunity. Not all BCG strains perform equally, and there may need to be a prospective comparison. See Figure 2.

Figure 3: Prof. Necchi’s summary slide on the challenges of translational trials

  • Finally, Prof. Bertrand Tombal, Brussels (BE) presented “Next generation trials for urologists and uro-oncologists, where are we headed?” The introductory observation was that we are increasing the gap between what we know through evidence versus what we do in practice – including both things we do without quality evidence and things we do contrary to quality evidence. Specifically, less than 4% of articles in surgical journals are randomized trials, and most of those are evaluating medical therapies rather than surgery itself. Yet research is increasingly complex with regulatory demands, dependence on pharma, and related strategies to focus on large indications. The key recommendations were to raise important questions when it comes to benefit for patients, assess affordability, and bring trials to the patient rather than the other way around. The SPECTApros design was highlighted again with reference to its integration of nomograms predicting a specific outcome, imaging, and biomarker identification/validation.

So that’s the snapshot of the modern EORTC and I look forward to following the progression of these novel trial designs and strategies.

John W. Davis, MD  FACS
Houston, TX, USA
Associate Editor, BJU International

 

EAU14 – ESOU citations

Have You Read This?…A bibliography of cited papers on prostate cancer at the Joint Meeting of The European Section of Oncological Surgery (ESOU) and EORTC—Genito-Urinary Cancer Group.

At the BJUI, as with any journal, the published articles are peer reviewed and editorial board reviewed.  The process starts with a triage editor who screens for basic methodology, importance of the topic, and potential for citation factor impact.  The top 50% are sent for full peerreview, which includes 3 reviewers (ad hoc or from the board).  Full review is organized by an associated editor who assigns (and then begs) the 3 reviewers to complete their task, and then makes a final recommendation to the editor in chief.  I could go on about this interesting process, but the point is that a published paper is often really just the opinion of 4-5 experts in the field, including the editor.  Once published, however, papers are then kept alive by repeated citation and meeting discussions, or disappear intoPubMed and forgotten. Future papers that cite a previously published paper will help the impact factor of that journal.  But what about congress events and their cited works?  At the EAU 2014, as with any congress, key opinion leaders are asked to give talks, make arguments, and prove their points.  They may do so with personal experiences, videosor modern abstract quotes, but often they cite recent peer review publications.  At the joint session meeting of the ESOU and EORTC-GUCG, I noted the following cited publications from the prostate cancer talks.  How many have you read so far?

On the topic of circulating tumor cells (CTCs) in prostate cancer, Professor S. Osanto of Leiden (NL) cited (partial citations):

1. Hanahan D et al. The hallmarks of cancer. Cell 2000
2. Klein CA.  Cancer.  The metastasis cascade.  Science 2008.
3. Gerlinger M et al.  Intratumor heterogeneity and branched evolution revealed by multiregionsequencing.  NEJM 2012
4. Allard WJ et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. ClinCancer Research 2004
5. de Bono JS et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Research 2008
6. Attard G et al. Characterization of ERG, AR, and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer.  Cancer Res 2009.
7. Cristofanilli M. Circulating tumor cells, disease progression, and survival in metastatic breast cancer.  NEJM  2004.
8. Goldkorn A et al. Circulating tumor cell counts are prognostic of overall survival in Southwest Oncology Group trial S0421: A phase III trial of docetaxel with or without atrasentan for metastatic castration-resistantprostate cancer.  J Clin Oncol 2014.

From these papers, the conclusions were many and included: 1) CTS can detect early relapse, genomic signatures, target identification, and treatment decisions, 2) surrogate marker for response, and 3) emergence of resistance.

Next, the focus shifted to the popular technical points and outcomes of open versus minimally invasive radical prostatectomy.  Bernardo Rocco (IT) cited the following papers in support of robot-assisted radical prostatectomy for high risk PCa

9. Yuh et al.  The role of robot-assisted radical prostatectomy and pelvic lymph node dissection in themanagement of high-risk prostate cancer: A systematic Review. Eur Urol 2014
10. Montorsi et al. Best practices in robot-assisted radical prostatectomy: recommendations of the Pasadena Consensus Panel. Eur Urol 2012.
11. Silberstein JL et al. A case-mix adjusted comparison of early oncological o utcomes of open and robotic prostatectomy performed by experienced high volume surgeons.  BJU Int 2013.
12. Hu JC. Comparative effectiveness of robot-assisted versus open radical prostate cancer control.  Eur Urol2014
13. Ploussard G et al. Pelvic lymph node dissection during robot-assisted radical prostatectomy efficacy, limitations, and complications—a systematic review of the literature. Eur Urol 2013.
14. Prasad SM et al.  Variations in surgeon volume and use of pelvic lymph node dissection with open and minimally invasive radical prostatectomy. Urology 2008
15. Cooperberg MR et al. Adequacy of lymphadenectomy among men undergoing robot-assisted laparoscopic radical prostatectomy.   BJU Int 2010
16. Feifer AH et al. Temporal trends and predictors of pelvic lymph node dissection in open or minimally invasive radical prostatectomy. Cancer 2011
17. Ficarra et al. The European Association of Urology Robotic Urology Section (ERUS) survey of robot-assisted radical prostatectomy (RARP).  BJU Int 2013.
18. Gandaglia G et al. Is robot-assisted radical prostatectomy safe in men with high-risk prostate cancer? Assessment of perioperative outcomes, positive surgical margins, and use of additional cancer treatments.  J Endourol 2014.
19. Ou Y.C. et al. The trifecta outcome in 300 consecutive cases of robotic-assisted laparoscopic radical prostatectomy according to D’Amico risk criteria.  EJSO 2013.
20. Lavery HJ et al. Nerve-sparing robotic prostatectomy in preoperatively high-risk patients is safe and efficacious.  Urol Oncol 2012.
21. Montorsi F. Robotic prostatectomy for high-risk prostate cancer: translating the evidence into lessons for clinical practice.  Eur Urol 2014

From these citations, the conclusions were that: 1) RP is an adequate treatment for high risk prostate cancer, 2) robotic approach is not inferior to open as far as oncological outcome, 3) lymph node template and yield are adequate in experienced hands in RARP setting, 4) functional outcome after RARP in high risk is preserved, nerve sparing is feasible in selected patients, and 5) Costs of RARP are related to surgical volume and experience.  So there you see a typical meeting presentation—13 papers in 15 minutes plus additional commentary and abstract data.

Next, Prof. Declan Murphy presented the Australian experience with robot-assisted RP for cT3a prostate cancer.  With overlapping topics, it was no surprised some papers were recited from above including #9, #12,He cited:

22. Evans et al. Patterns of care for men diagnosed with prostate cancer in Victoria from 2008-2011.  Med JAust 2013
23. Wilt T et al. Radical prostatectomy versus observation for localized prostate cancer. NEJM 2012
24. Connoly SS et al. Radical prostatectomy as the initial step in multimodal therapy for men with high-risk localized prostate cancer: initial experience of 160 men.  BJU Int 2012.

From these citations, Prof. Murphy concluded that: 1) radical prostatectomy has minimal benefit for low risk men, especially older, 2) The biggest benefit is in high risk disease, 3) active surveillance is being embraced in Australia, 4) RARP is safe and effective with similar outcomes to ORP, 5) RARP has less positive margins and less additional therapy compared to ORP 6) extended PLND not limited by robotic approach.

Prof. Axel Heidenreich then took the opposite point of view in support of open radical prostatectomy.  Despite the references above, he pointed out that there is still no long-term data for robotic prostatectomy, although not proving that with pathologic staging we would expect anything different.  Cost of course can be quite better for open.  He also cited for papers showing positive margins of < 12% in pT3 disease, compared to many other open and minimally invasive series where it is usually 25% and higher. Repeat citations: #9. He also cited:

25. Robertson C et al. Relative effectiveness of robot-assisted and standard laparoscopic prostatectomy as alternatives to open radical prostatectomy for treatment of localized prostate cancer: a systematic review and mixed treatment comparison meta-analysis.  BJUI 2013.
26. Vora AA et al.  Robot-assisted prostatectomy and open radical retropubic prostatectomy for locally-advanced prostate cancer: multi-institution comparison of oncologic outcomes.  Prostate Int 2013
27. Punnen S et al. How does robot-assisted radical prostatectomy (RARP) compare with open surgery in men with high-risk prostate cancer? BJU Int 2013
28. Sooriakumaran P et al. A multinational, multi-institutional study comparing positive surgical margin rates among 22393 open, laparoscopic, and robot-assiste radical prostatectomy patients. Eur Urol2014
29. Alemozzafar M et al. Benchmarks for operative outcomes of robotic and open radical prostatectomy: results from the health professionals follow-up study.Eur Urol 2014
30. Davison BJ et al Prospective comparison of the impact of robotic-assisted laparoscopic radical prostatectomy versus open radical prostatectomy on health-related quality of life and decision regret. Can J Urol 2014
31. Bolenz C et al.    Costs of radical prostatectomy for prostate cancer: a systematic review.  Eur Urol 2014

From these citations, he concluded that 1) open radical prostatectomy is still viable, 2) not needed for low risk, 3) lack of long-term data for RARP, 4) no inferiority in terms of functional and oncological outcome, or quality of life, 5) better cost effectiveness, especially with median case load of < 300 RP’s per year.

I hope you find this reading list useful.  Could you transfer such a bibliography to an effective review article?  Probably not, and we can ask associate editor Quoc Trinh to comment or write a separate blog on the emerging field of systematic reviews, such as the multiple cited reference 9 by Yuh et al.  A systematic review needs to conform to standards such as the PRISMA guidelines—see www.prisma-statement.org –which is “an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses.  Therefore we have an interesting difference in standards between a meeting presentation and a formal peer-reviewed systematic review—the former can hand-pick articles to make a point, while the latter must be thorough, transparent, and reproducible.

John W. Davis, MD  FACS

Houston, Texas (USA)

Associate Editor, BJUI

 

 

EAU14 – The Multifaceted Goals Of Andrology: Maintaining Quality Of Life

A famous version of a saying attributed to Benjamin Franklin states “…but in this world nothing can be said to be certain, except death and taxes.” As a urologic oncologist, I cannot help with the taxes, but strive to delay the latter when threatened by urologic cancers.  Our colleagues in andrology, however, are charged with the task of being sure the life lived is of high quality, and I am impressed at the large number of problems they face including infertility, erectile dysfunction, andhypogonadism.  The latter problem is quite comprehensive when you consider the associated risks of cardiovascular disease, type 2 diabetes, sexual dysfunction, reduced energy, reduced muscle mass, weight gain, and many more.  With this challenge, the first plenary session at the 2014 EAU gave an update on andrology with significant cross-over appeal to the uro-oncologist.

Prof W.H-G. Weidner started the session with an overview of male factor infertility, which comprises 50% of the contribution to childless couples.  The causes can be idiopathic but then include primary testicular failure,varicocele, genetic disorder, obstruction, male accessory gland infection, hypogonadism, germ cell malignancy, and ejaculatory dysfunction.  The diagnosis requires a comprehensive andrological exam if two separate semenalyses are abnormal.

 

Figure 1 Prof. W.H-G. Weidner from Giessen (DE) gave the first plenary presentation at the 2014 EAU, Stockholm, Sweden

Varicocele repair is known to improve ejaculate quality, however the effect on pregnancy rates does not always follow—counseling for the couple is also effective.   The other major surgical intervention involves various techniques of microscopic sperm retrieval with essentially 100% retrieval rates.  All factors considered, this leads to an approximate 20% “baby take-home” rate when used with ICSI.  An interesting new trend is pediatric oncologist requesting sperm retrieval and cryopreservation for pre-pubertal patients who need chemotherapy.

Prof. S. Arver from Stockholm (SE) then reviewed the topic of testosterone supplementation in the ageing male.  As a uro-oncologst in the 4th largest city in the USA, this is an every day topic.  On the way to work I heard radio advertisements for local “Low-T Centers” that aim to attract potential patients who may be tired, or having problems with their sex life.  Once I get to work, I see the new patients with an elevated PSA discovered as a downstream event once they’ve started testosterone replacement and had subsequent screenings.  What do we know about the diagnosis of testosterone insufficiency and risks/benefits of replacements?

First, the diagnosis of testosterone (T) insufficiency is a combination of symptoms and laboratory assessment.  Total serum T should be measured as a morning sample between 7-10am and fasting.  If an afternoon measurement is low, it should be repeated in the proper circumstance.  If the level is > 12 nmol/L it is likely normal, while 8-12nmol/L is a “grey zone” and < 8 nmol/L is probably associated with symptoms that would respond to therapy.  The grey zone implies that some men can be symptomatic in the lower end of a normal range.  In addition, a serum LH > 9 supports deficiency as the internal thermostat is trying to compensate, whereas LH 2-9 is uncompensated and may be a transient state.

The symptoms of low T are quite a list and organized under the categories is Physical/metabolic (decreased bone mineral density, muscle strength, etc.), sexual symptoms (libido, ED), and psychological (energy, fatigue, mood, etc.).  To make matters worse, hypogonadism has a high prevalence with chronic renal failure, rheumatic disease, HIV, COPD, cancer therapy, opioid use, steroids, and male infertility.  Of course, the most significant long-term concerns would be cardiovascular risk and type II diabetes. You can infact try using SARMs rather than steroids which is lot more better than steroids as per research studies. You can visit ceasar-boston.org to know more about SARMs.

T replacement is associated with significant responses in properly diagnosed patients, but dosing may be different—older patients may not clear it as fast and need dose titrations.

Prof. G.R. Dohle, Rotterdam (NL) continued the presentation with an emphasis on guidelines.  Overall, the incidence of hypogonadism is 6% of middle age men and increasing in older men.  Testosterone replacement may help with symptoms, increase weight reduction, and improve diabetes and bone mineralization.  The side effects to note include increasing hematocrit, fluid retention, BPH, prostate cancer, gynacomastia, and recently sleep apnea, Arizona sleep apnea care offers treatment for this last one.

Is TRT a “fuel” for prostate cancer?  Based on level 2 evidence, TRT should not be used for locally advanced or metastatic PCa.  For PCa risk itself, there is a lack of evidence of association.  For patients with localized disease treated with radical prostatectomy, there are only observational studies, but no risk of tumor recurrence with limited follow-up.  A saturation model has demonstrated that the androgen receptor is saturated just over the castration level and therefore additional T should not increase further growth.  The guidelines recommend careful monitoring with hematology levels, cardiovascular assessment, and PSA monitoring (for age > 40).  Specifically, hematocrit and hemoglobin and PSA should be checked at 3, 6, and 12 months and then annually. They recommend at least 1 year of biochemical NED follow-up.

 

Figure 2 Prof. G.R. Dohle from Rotterdam (NL) presents he EAU guidelines on testosterone replacement andprostate cancer.  #EAU2014.

The session then switched into another gear with the presentation by Prof John P. Mulhall from New York (USA) with the focused question as to whether or not TRT causes an increased risk of cardiovascular events.  This topic has been covered by the New York Times and the Wall Street Journal based upon a hand full of studies concluding that the risk exists.  These reports, of course, have led to many patients wanting to stop therapy, and the U.S. legal system creating a new industry of tort claims.  This was a “getting into the weeds” talk by an expert with impressively high words per minute speaking pace.  The theme was all about methodology, and I could never re-create the whole talk in summary.  The bottom line was that 3 high profile papers including Basaria et al NEJM 2010,Finkle WD PLOS ONE 2014, and Vigen R JAMA 2013 all had significant limitations in the methods, which ProfMulhall concluded led to erroneous conclusions.  To quote: “Bad science can hurt people,” and “ The good thing about good science is that it is true whether or not you believe it (reference Neil deGrasse Tyson).”

Professor A.L. Burnett from Baltimore (USA) delivered the AUA lecture on sexual function after urologic surgery. This was more of a review talk and a very complete one given the short time.  Of course I am biased in his favor as he highlighted one of my publications on sural nerve grafting (Davis et al Eur Urol 2009) which effectively diminished the previous trend in this procedure with the randomized cohorts showing no difference from unilateral nerve sparing alone.  There are certainly numerous teachings and publications on nerve sparing surgery technique, but even high volume surgeons have demonstrated and published that technique alone does not seem to eliminate the risk of post-operative erectile dysfunction.  Therefore much focus has shifted to post-operative management and novel techniques.

In the post-operative management area, the commonly used term is “penile rehabilitation.”  The concept is straightforward: to stimulate blood, maintain tissue oxygenation, protect endothelial function, and reduce tissue damage/atrophy.  While the data certainly suggests that PDE5 inhibitors, vacuum erection devices, and injections can improve erections after surgery, the data are still not conclusive that a scheduled, rehabilitation is superior to on demand use.  There are papers suggesting a benefit, but reasonable to conclude that this is not “holy grail” in solving the problem.  He then outlined the various other research and alternative pathways under evaluation from neurotropic factors, androgen replacement in select patients, treatment of ejaculatory dysfunction, and counseling—the latter of which seems to augment the standard treatments).

 

 

Figure 3: Professor A.L. Burnett, Baltimore (USA) at #EAU2014

Prof. M. Albersen of Leuven (BE) continued this theme with a review of bench research in erectile dysfunction and the progress of stem cell research.  Early work shows potential benefits at the smooth muscle, fibrosis, and innervation endpoints.  At least 6 trials are now registered at clinicaltrials.gov in this area, but many are still looking at the safety aspects first.  Prof M.J.H. Van Griethuysen ofRotterdam (NL) concluded the session with a review of future research funding.

Congratulations to the organizers and speakers for a strong start to #EAU2014.  Where you in the audience?  What were your take home messages?

John W. Davis, MD, FACS 

Houston, Texas

Associate Editor, Urologic Ongology, BJU International

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