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Posts tagged ‘EAU 2012 Paris’

That was the question that I asked Walter Artibani, Professor and Chair of Urology at the University of Verona during the recent European Association of Urology (EAU) annual Congress in Paris.

Urologists have failed as scientists to generate evidence based medicine

Professor Artibani told the assembled media that urologists had failed as scientists in not generating robust clinical data to support the use of the da Vinci robotic system for the removal of the prostate gland (prostatectomy).

Something that I was not aware of until I attended the media briefing was that so called “robotic surgery” is not an automated robot performing the surgery on its own, but instead it’s actually robot assisted surgery.

The da Vinci surgical device (currently the only one on the market) is a telemanipulation system where the surgeon sits at a remote console and operates a surgical cart with three or four arms that are docked with endoscopic instruments that are inserted into the patient.

Professor Artibani in response to my question said:

“After 10 years, the urologic community missed the window to have prospective randomized clinical trial in order to have clear answers.”

What’s more he went on to say that he believed it would be unlikely we could now do a prospective trial that compared robot-assisted prostatectomy to laparascopic prostatectomy to open prostatectomy. The reason for this was that :

“Most of the patients are convinced that the new way, the novel way is the better way.”

The following is a video excerpt of Professor Artibani’s answer to my questions.  For digital accuracy, viewers should note that I added in some slides he presented earlier, and included a graphic of the paper he referenced.

Have the media sensationalized robotic surgery?

Artibani went on to say in his answer to my question that the media and journalists have not always reported the lack of robust data surrounding new surgical techniques:

“It is easy just to give the information that what is new is better and this must be demonstrated by robust data before giving the information. Unfortunately sensationalism is more important than to say and to write robust data.”

Healthcare journalists have an obligation to report on the limitations of new techniques and lack of evidence based medicine is an important one!  Gary Schwitzer’s healthcare journalist watchdog, Health News Review, attempts to hold the media to account.

We should clearly challenge surgical practice for which there is a lack of robust clinical data or evidence based medicine, and avoid sensationalism.

However, whatever the limitations of the media reporting, the reason for the lack of evidence based medicine rests firmly with the academic urology community.

Low quality of evidence for Robot-Assisted Laparoscopic Prostatectomy

In an editorial in the journal “European Urology,” Markus Graefen noted the low quality of urology research that was being published did not just apply to robot-assisted prostatectomy.  He noted that in urology,

“The number of low-quality papers is increasing; however, the body of evidence and the knowledge we have about the reported outcomes, unfortunately, is not.”

 

He went on to describe the need to counsel patients on the different surgical approaches available to them:

A patient with a newly diagnosed prostate cancer who is counselled for his therapeutic options today should be informed that several equal surgical approaches are available and that despite all the perfectly styled Web pages, it is not the robot that makes the difference.

He should be informed that there are indeed concerns about oncologic and functional outcomes and also evidence that in some significant papers the traditional surgical approaches look superior.

This editorial suggests that patients should ignore the marketing hype about new equipment or the notion that “new is better,” but instead focus on the experience of the surgeon with that equipment and the functional outcomes that a surgeon obtains in his/her patients.

Patients are interested in functional outcomes and low complication rates

What I heard at EAU from urologists is that patients are interested in a good functional outcome and low complication rate.

There is, however, no level 1 evidence that post-operative urinary incontinence and erectile dysfunction rates are generally better with robot-assisted radical prostatectomy.

Diana Kang and colleagues in a review of seventy-five research publications between 2005 and 2008 that reported robot-assisted laparscopic prostatectomy (RALP) data, concluded that there was a need to raise the standards of urology clinical research:

Our findings draw into question to what extent valid conclusions about the relative superiority or equivalence of RALP to other surgical approaches can be drawn and whether published outcomes can be generalised to the broader community.

There is an urgent need to raise the methodologic standards for clinical research on new urologic procedures and devices.

Men with prostate cancer who are considering surgery should be informed that there is no high-level or robust evidence to show the general superiority of robotic-assisted prostatectomy compared to other surgical techniques for radical prostatectomy.

Hopefully, the demand for evidence based urology treatment will grow, and that lessons have been learned from the way robotic-assisted surgery was introduced. Men with prostate cancer do deserve better.

ResearchBlogging.orgKang, D., Hardee, M., Fesperman, S., Stoffs, T., & Dahm, P. (2010). Low Quality of Evidence for Robot-Assisted Laparoscopic Prostatectomy: Results of a Systematic Review of the Published Literature European Urology, 57 (6), 930-937 DOI: 10.1016/j.eururo.2010.01.034

Graefen, M. (2010). Low Quality of Evidence for Robot-Assisted Laparoscopic Prostatectomy: A Problem Not Only in the Robotic Literature European Urology, 57 (6), 938-940 DOI: 10.1016/j.eururo.2010.02.004

There are no major presentations of phase III clinical trial data at the European Association of Urology (EAU) Congress in Paris this weekend, but interesting clinical and scientific data is still being presented.

If you want to understand the competitive dynamics of the prostate cancer market and the market opportunity with urologists, then you need to be at meetings such as EAU in Europe and AUA in the United States.

EAU-2012-Delegates-Waiting-to-enter-Advanced-Prostate-Cancer-Poster-SessionThere was a lot of interest in yesterday’s advanced prostate cancer poster session at EAU 2012.

I mentioned in a previous post that the radium-223/Alpharadin poster showed the data on skeletal-related events presented last month at ASCO GU in San Francisco.

Another poster that caught my attention for a variety of reasons was the one on orteronel (TAK-700), something that we have not heard too much about.

Activity and Safety of the Investigational Agent Orteronel in Men With Nonmetastatic Castration-resistant Prostate Cancer and Rising Prostate-specific Antigen: Results of a Phase 2 Study

Orteronel-phase-2-results-presented-at-EAU-Paris-Congress-2012Orteronel (TAK-700) is a selective, non-steroidal inhibitor of 17, 20 lyase, a key enzyme involved in the production of androgens such as testosterone. This is a similar mode of action to abiraterone acetate (Zytiga) that was approved last year in the US & Europe.

Orteronel is being developed by Millennium. Two phase III castration-resistant prostate cancer trials are currently enrolling. The post-chemotherapy trial (NCT01193257) is scheduled to have a primary completion date of September 2013 and the chemotherapy-naïve trial has a primary completion date of January 2013 (NCT01193244) according to clinicaltrials.gov at the time of writing.

It is worth noting that both phase III trials are using the drug in combination with prednisone. I doubt very much that the chemotherapy-naïve trial will show overall survival results by January 2013 (a date earlier than the post-chemo trial). This date must reflect when data on the primary outcome measure of radiographic progression free survival (rPFS) will be obtained.

Does rPFS correlate with overall survival?  Many oncology new products have shown progression free survival, but no overall survival.

Is there a market for a “me too” of abiraterone?  By the time orteronel comes to market, MDV3100 and Alpharadin will both most likely be approved, plus we will have greater insight into combinations and sequencing by then.

In talking to urologists, there is a clear preference for drugs such as MDV3100, which do not require the administration of concomitant steroids.

The phase II data in the poster presented at EAU yesterday concluded:

In patients with nmCRPC and rising PSA, single agent oral orteronel, at a dose of 300 mg BID without prednisone, was feasible and had manageable toxicities.

While it may be possible to administer orteronel without steroids, given the mechanism of action would it still be as effective?   The authors also noted in the poster that 2 patients (out of 38) discontinued treatment due to adrenal insufficiency, suggesting that giving the drug without steroids is going to require active surveillance.

Finally, in thinking about TAK-700, I’m left with the question of whether phase III placebo controlled clinical trials are still ethical in advanced prostate cancer patients?  In the post-docetaxel indication, we now have cabazitaxel and abiraterone approved, both of which offer an overall survival benefit.  MDV3100 and Alpharadin are also expected to be approved by the FDA later this year.

If we have four new agents available after docetaxel that offer a survival advantage, is it ethical for men with advanced prostate cancer to be offered a placebo?  If not, then this means that new products will have to go head-to-head with one of the approved drugs, or offer some additive effect if used in combination.

It will be interesting to see if this important issue is taken up by any of the patient advocacy groups and whether physicians start to raise concerns.  Recruitment into placebo controlled trials could end up slower as a result.

Orteronel to me is too similar to abiraterone, which I think will face serious challenge from MDV3100.  What the market opportunity for Millennium will be as a result of being late to market is an open question.

View-of-Paris-from-European-Association-of-Urology-2012-CongressToday sees the start of the 27th annual European Association of Urology (EAU) Congress at the Palais des Congrès in Paris.

The meeting runs from 24-28 February, 2012. Over 10,000 delegates are expected, and more than 1193 abstracts have been accepted for poster and video sessions.

In addition to a scientific programme, this meeting also has a strong educational component with numerous courses through the European School of Urology (ESU) and hands-on-training to improve surgical skills in cooperation with the EAU Section of Uro-Technology (ESUT), the EAU Section of Urolithiasis (EULIS) and the EAU Section of Robotic Urology (ERUS).

If you can’t be in Paris, then EAU have some live webcasts and they will be sharing a lot of the content from the meeting as well as undertaking video interviews.  Check out the EAU 2012 Paris Congress website for more information.

For those that are interested in following the twitter coverage of the meeting, the hashtag is #EAU12, and EAU is @uroweb on twitter.  You can also use the twitter aggregator below:

 

A survey of patients who had their prostate removed showed there was no significant difference in complication rates between open retropubic radical prostatectomy (ORRP) and robotic assisted laparoscopic surgery (RALRP).

This is an important finding because 85% of prostatectomies in the United States are undertaken using robotic-assisted techniques, yet there has been little published data to show that this technique improves functional outcomes.

At the European Association of Urology (EAU) annual congress last year in Vienna some of the challenges and opportunies with robotic surgery were raised:

  • lack of data on improved functional outcome
  • need for licensing of robotic surgeons
  • high learning curve – it takes 250 patients to become proficient

In reality, we see hospitals marketing their robotic surgery to patients in shopping malls and with advertisements on the side of buses.  You can read Gary Schwitzer’s thoughts on some of the recent marketing claims & “gizmo idolatry.”

This is why a survey comparing the results of open to robotic assisted prostate removal surgery is important evidence based medicine. Published online first in the Journal of Clinical Oncology, Barry and colleagues randomly surveyed 800 men who filed Medicare claims between August and December 2008.  685 completed surveys were returned, and information on adverse events was obtained.

The data highlights the dramatic effect on quality of life that prostate cancer surgery can have, irrespective of the surgical technique. The men rated themselves:

31.1% – moderate or big problem with continence  (95% CI 27.5 to 34.8%)

88.0% – moderate or big problem with sexual function (95% CI 85.4% to 90.6%)

Breaking this down by technique (robotic surgery versus open prostatectomy):

Continence: 27.1% of men (Open) versus 33.3% (Robotic) – not significant (P=0.113)

Sexual Function: 89.0% of men (Open) versus 87.5% (Robotic) – not significant (P=0.57)

The authors conclude in their JCO paper:

Our results do not demonstrate a lower risk of problems with incontinence or sexual function after RALRP compared with ORRP.

In fact, after adjusting for potential confounders, there was at least a strong trend toward a higher risk of patient-reported moderate or big problems with incontinence following RALRP.

The authors in their discussion do raise the interesting question as to whether patients were led to believe that they would have fewer side effects with robotic surgery, which may have impacted the survey findings.  This merits further investigation.

There is clearly a need for patients to give informed consent, and be aware of the risks and complications of prostate cancer surgery, particularly with regards fundamental quality of life issues such as continence or sexual function.

The accompanying JCO editorial by Matthew Cooperberg and colleagues from UCSF is well worth reading and raises the question as to whether men with prostate cancer should expect better outcomes than those reported in the survey?

What the survey by Barry et al did not do is look at the volume of procedures and experience level of the surgeon, both of which are associated with outcomes.

Cooperberg noted that “surgeons performing fewer than 5 prostatectomies per year account for approximately half the national volume.

A chilling statistic, and if you factor in the learning curve of more than 200 procedures to be competent at robotic surgery, it is perhaps not surprising that some men experience higher complication rates than others.

Which brings me back to the importance of the PIVOT (Prostate Cancer Intervention versus Observation Trial) data presented in the plenary session at the 2011 annual meeting of the American Urological Association (AUA) in May last year.

Why has this practice changing data not been published in a peer-reviewed journal yet?

The fact that the updated PIVOT study results presented at AUA 2011 have not been published (to the best of my knowledge) is a disservice not only to the medical and scientific community, but to men with prostate cancer whose treatment should be guided by evidence-based medicine.

The long-term results of the PIVOT trial presented by Professor Wilt showed no benefit of radical prostatectomy over watchful waiting, except for high-risk patients.  Yet, the reality is that many men end up having surgery. This may be considered overtreatment and an exposure of more men than is necessary to the complications of prostatectomy, irrespective of whether this is robotic or open surgery.

The decision to undergo radical prostatectomy should be an informed one, not only as to the risks and benefits of the surgical technique, but also whether the surgery should be performed in the first place as compared to “watchful waiting.”

I hope the paper and editorial published in the JCO this month will generate some debate. Next month I will be at the European Urology Association annual congress in Paris.

References

ResearchBlogging.orgBarry, M., Gallagher, P., Skinner, J., & Fowler, F. (2012). Adverse Effects of Robotic-Assisted Laparoscopic Versus Open Retropubic Radical Prostatectomy Among a Nationwide Random Sample of Medicare-Age Men Journal of Clinical Oncology DOI: 10.1200/JCO.2011.36.8621

Cooperberg, M., Odisho, A., & Carroll, P. (2012). Outcomes for Radical Prostatectomy: Is It the Singer, the Song, or Both? Journal of Clinical Oncology DOI: 10.1200/JCO.2011.38.9593

Update August 12, 2012 – Paper published in European Urology shows lower incontinence and greater rate of erection recovery with robot-assisted radical prostatectomy

A paper published online (July 20, 2012) in the journal, European Urology by Franceso Porpiglia provides some evidence that robot-assisted radical prostatectomy offers functional benefits to patients. I have not read the full paper only the freely available abstract.

The clinical trial evaluated the functional outcomes of 120 men in a randomized clinical trial where half (n=60) received radical prostatectomy (RARP) that was robot-assisted and the other half (n=60) who had the operation laparoscopically without robot assistance (LRP).

Following the surgery performed by Dr Porpiglia, the functional outcomes between the two groups were compared. Those men operated on with robot assistance showed:

  • Lower incontinence. “Continence after 3 mo was 80% in the RARP group and 61.6% in the LRP group (p = 0.044), and after 1 yr, the continence rate was 95.0% and 83.3%, respectively (p = 0.042)”
  • Better erection recovery. “Among preoperative potent patients treated with nerve-sparing techniques, the rate of erection recovery was 80.0% and 54.2%, respectively (p = 0.020).”

The challenge of this study is that although it was randomized, it reflects the results of only one surgeon with a small number of patients.

Dr Matthew Cooperberg (@cooperberg_ucsf) was quoted by Reuters saying that this was likely the best study we were going to get showing the benefits of RARP over LRP. On twitter he said the real question was now between radical prostatectomy and external radiation therapy (XRT).

https://twitter.com/cooperberg_ucsf/status/233427660708126721

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