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Posts tagged ‘radical prostatectomy’

PIVOT-prostate-cancer-intervention-versus-observation-trial-dataTimothy J. Wilt MD, MPH presented an update on the VA, NCI, AHRQ Prostate cancer Intervention Versus Observation Trial (PIVOT) on the final day of the 2012 European Association of Urology (EAU) Congress in Paris.

I previously wrote on this blog about the PIVOT data presented by Professor Wilt in the plenary session at the 2011 American Urological Association Annual meeting.

The PIVOT trial objective according to Dr Wilt, was to answer the following question:

Among men with clinically localized prostate cancer detected during the early PSA era, does the intent to treat with radical prostectomy reduce all-cause & prostate cancer mortality compared to observation?

PIVOT enrolled 731 men from 1994 to 2002 who were randomized to either receive radical prostatectomy or undergo just observation.

The results from the trial provide level 1 evidence based medicine (highest standard) concerning the survival benefits conferred by radical prostactectomy (with the potential for quality of life impacts such as incontinence & erectile dysfunction), as compared to not undertaking surgery, but instead doing observation only in the form of watchful waiting or active monitoring.

Dr Wilt told the urologists in the EAU 2012 Congress plenary session, that after a median follow-up of 10 years (interquartile range = 7.3 to 12.6), the median survival was 12.7 years. Wilt told the audience that:

“Prostate cancer mortality was uncommon occurring in only 7.1% of men, it did not vary considerably by patient age, race, comorbidities or health status, but did vary considerably by tumor risk status ranging from 3 % in men with low risk disease to 13 % in men with high risk disease.”

PIVOT Prostate Cancer Mortality Results

No of Deaths: 52/731 (7.1%)

    • Low risk  (3.4%)
    • High risk (8.4%)
    • High risk (13.3%)

In the men who had death judged to be due to prostate cancer, absolute differences between treatments were less than 1%,” Wilt said.

As far as I could determine, the data presented at EAU 2012 was no different from the PIVOT data presented at AUA 2011 other than being another year mature.

A subgroup analysis showed that surgery conferred no survival benefit over watchful waiting except for high-risk patients.  In his EAU 2012 presentation, Dr Wilt described the subgroup findings in more detail (emphasis added):

Low Risk Prostate Cancer

“In men with low risk prostate cancer, disease mortality occurred in less than 3% and did not differ between radical prostatectomy and observation”  (HR=1.48; ARR=1.4, P=0.54). This favored observation.”

High Risk Prostate Cancer

“Among men with high risk tumors, prostate cancer mortality occurred in approximately 13%. Radical prostatectomy produced a 60% relative risk reduction  (HR = 0.4, ARR = 8.4) of borderline significance (P=0.04).

Intermediate Risk Prostate Cancer

“Among men with intermediate risk prostate cancer, we found a non-significant reduction of 4.6%.”

PSA <= 10ng/ml

“In men with PSA <= 10ng/ml there was no significant difference between radical prostatectomy and watchful waiting.” (HR = 0.92, ARR=0.3%, P=0.82).  The findings were virtually identical throughout the course of the study. The lines are essentially superimposable for prostate cancer mortality in men treated with observation or with radical prostatectomy.”

PSA > 10ng/ml

“Among men with baseline PSA > 10ng/ml, radical prostatectomy reduced prostate cancer death by a relative 64% and an absolute difference of 7.2%. You can see the curves begin to separate at approximately 7 years.” (HR=0.36, ARR= 7.2%, P=0.03)

PIVOT-Prostatectomy-versus-observation-data-conclusion-2012Dr Wilt’s conclusion based on the latest study data was that:

“In men with localized prostate cancer detected during the early PSA era, radical prostatectomy compared to observation did not significantly reduce all-cause and prostate cancer mortality. Absolute differences through at least 12 years were less than 3%” 

These results are important findings that should impact the treatment of men diagnosed with early stage, low risk prostate cancer.

The fact that the survival curves do not diverge except for high-risk patients presenting with a PSA > 10ng/mL, may also have an impact on the ongoing PSA prostate screening debate.

If the PIVOT data results in more men being put on watchful waiting/active monitoring, then it should lower the overtreatment that screening currently produces.  Urologists will, however, need to be prepared to counsel their patients accordingly and forego the economic benefits that undertaking surgery affords many of them.

Urologists at the EAU in Paris greeted the PIVOT trial data in silence and an absence of social media interaction (I did not see any urologists tweet enthusiastically about it).

Many urologists who have trained many years to perform complex surgical techniques may find the idea of watchful waiting an anathema.

Adopting a policy of watchful waiting in many prostate cancer patients may also place economic pressures placed on those urologists who need a throughput of patients to recover or amortize the cost of expensive technology such as the da Vinci robotic system.

The PIVOT trial data is, however, level 1 evidence based medicine that cannot be ignored.

Hopefully, this analysis of the PIVOT trial data will be published in a peer-reviewed journal in the not too distant future so that it can reach a wider audience than those urologists who attended the AUA 2011 and EAU 2012 plenary sessions.

Update July 18, 2012

The results of the PIVOT trial presented at AUA 2011 and EAU 2012 have been published in the New England Journal of Medicine (online first, July 18, 2012).

NEJM PIVOT prostate cancer

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

One of the sessions that I attended at the 2011 annual meeting of the American Urological Association (AUA) focused on research into advanced prostate cancer.  A particularly thought provoking presentation was:

Time trends of biochemical recurrence (BCR) following radical prostatectomy (RP) among 1574 BCR patients (Abstract #639)

Presented by Alex Haese from Hamburg, Germany, this paper was a retrospective analysis of 1,574 patients who had a biochemical recurrence (PSA > 0.2 mg/dl) following RP. Researchers looked at clinical progression and cancer specific survival rates and compared their findings to published United States data.

The results appeared to be somewhat depressing for European patients who experience a BCR, with a time to BCR of 1.8 years, compared to 2.1 years in the US research by Pound from Johns Hopkins and 2.4 years in the data published by Hull, at Memorial Sloan Kettering Cancer Center (MSKCC).

Once a BCR is experienced, the time to metastases is faster in Europe, 4.7 years in the research presented by Haese at AUA, as compared to 8 years in US research by Pound. Risk factors for metastasis free survival include time to BCR i.e.

“The longer the interval between RP and BCR, the greater the probability of being met-free.”

In other words delaying time to progression is associated with longer survival.

Following BCR, time to Prostate Cancer death was 6.0 years in the 1,574 European patients, compared to 13 years in the US Pound research.  Again, the data presented showed that,

“The longer the interval between RP and BCR, the greater the probability of being alive.”

This research must be put into context, as metastasis and death in BCR patients are rare (92% of the 1,574 patients with BCR were free of metastases at 5 years, 81% at 10 years).  However, for those patients who did progress, the results appear significantly different between the US and Europe.

What could explain this?

The presentation left this question unanswered, although in Q&A it was briefly touched upon. One person raised the question of whether differences in screening could be the difference in Europe vs. US?

Other questions that come to mind are whether the subject populations in the Hull and Pound data were comparable.  The German data also had more patients (1574) compared to 304 in the Pound research and 147 (Hull) raising the question that the larger sample size may be more accurate data?

Other factors that might possibly explain the difference include:

  • Androgen deprivation therapy (ADT)
  • Radiotherapy
  • Supportive care (eg bisphosphonates)

All of which tend to be more aggressively pursued as treatment options in the USA.

Overall, this presentation raised the interesting question of US/European differences in Prostate Cancer progression that hopefully will be answered by future research.

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