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Posts tagged ‘AUA 2011’

The recent announcement from the United States Preventative Services Task Force (USPSTF) on prostate cancer screening has stimulated a lot of debate.  “Dr Len’s Cancer Blog” from the American Cancer Society has a thoughtful piece about the “to screen or not to screen” dilemma. It is reminiscent of the breast cancer mammography debate.

Scott Hensley’s post on “Shots”, the NPR health blog also provides a good overview of the debate and issues. I confess I was surprised by the vehemence of the response from some practising urologists on twitter such as Dr Benjamin J. Davies (@daviesbj), Assistant Professor of Urology at the University of Pittsburgh School of Medicine:

What do the US Preventative Task Force authors say? In the findings published in the October 7, 2011 issue of the Annals of Internal Medicine, the conclusion from their peer-review of the literature is that:

“screening based on PSA identifies additional prostate cancers, but most trials found no statistically significant effect on prostate cancer–specific mortality.”

This is nothing new – the evidence in favor of Prostate-Specific Antigen (PSA) screening for prostate cancer has for sometime been inconclusive at best. Research published in the British Medical Journal earlier this year suggested that indiscriminate screening for prostate cancer may not be of value until we obtain more sensitive biomarkers.

All the USPSTF have done is a retrospective literature review that confirms our current state of knowledge.

Despite the amount of $$$ that have been spent on PSA clinical studies, no convincing data in support of it as a screening tool for all men has been developed. That’s not to say that it has no utility or benefit.

If PSA screening does detect some prostate cancers and early treatment may save lives particularly in those with an aggressive form of the disease, then it’s hard not ask:

  • What is the alternative if PSA screening is now discouraged?
  • Will this mean more men will not be screened, even those at high risk, with a consequent increase in prostate cancer mortality or lower overall survival?
  • Will insurers refuse to cover PSA testing moving forwards?
  • Will family physicians actively discourage PSA testing?

One limitation of the USPSTF report that struck me while reading through the analysis and recommendations, was the absence of data from the Prostate Cancer Intervention versus Observation (PIVOT) trial that was presented in the plenary session at the American Urological Association (AUA) annual meeting earlier this year.

I wrote in a previous blog post about the PIVOT data presented at AUA 2011 by Dr Wilt. This VA/NCI/AHRQ randomized clinical trial showed in a 12 year follow-up of over 5000 men with localized prostate cancer, no benefit from radical prostatectomy in low risk early stage patients.

In my opinion it is practice changing data that sadly has not yet been published in a peer-reviewed journal which is why it was not included in the USPSTF analysis. A few photographs that I took at the presentation of the PIVOT data are shown below:

The 12 year survival data showed that in those patients with PSA <=10 ng/ml there was no significant difference in survival over observation versus RP.

However in those patients with PSA > 10ng/ml there was a significant difference in mortality (p=0.03 HR=0.36) suggesting that in the small sub-group of patients with high PSA, RP did provide a benefit over “watchful waiting.” PSA measurements may therefore help in the treatment and ongoing management of patients.

If one of the challenges of PSA screening is the issue of the harms from treatment, then the PIVOT data that showed no difference in mortality through watchful waiting over radical prostatectomy (RP) except for high risk patients is important.

Roger Chou and his colleagues in their Annals paper did note this:

“When available, results from the Prostate Cancer Intervention Versus Observation Trial, which compared prostatectomy with watchful waiting for screening-detected cancer, may help clarify which patients would benefit from prostatectomy or other active treatments, potentially reducing harms from unnecessary treatment.”

The issue may, therefore, not be one that PSA screening per-se is the problem, but that in too many men, a raised PSA results in unnecessary surgery or overtreatment with its consequent risks and harms.

As reported by Alemozaffar and colleagues in the September 21, 2011 issue of the Journal of the American Medical Association (JAMA), 2 years after RP only 35% of men could maintain a functional erection.

“At 2 years after treatment, erectile dysfunction was reported by 619 of 987 (63% [95% CI, 60%-66%]) men (334/511 [65% {95% CI, 61%- 69%}] in the prostatectomy group”

That’s depressing news when coupled with other side-effects from RP or other interventions such as incontinence or problems with bowel function.

It adds further support to the idea that the potential risks versus benefits from prostate cancer surgery and deciding who should actually have surgery or other intervention, is where there’s also a need for more debate.

Men need to be able to make an informed decision. Some urologists may not be unbiased in their treatment recommendations given they have a vested interest in earning money from surgery or maintaining utilization rates of expensive robotics. Data from the PIVOT trial, when published, is evidence-based medicine that will impact their practice.

Use of prostate cancer risk calculators to assess those patients at high risk who might benefit from RP or other intervention could also help lower the harms that currently impact the utility of PSA screening.

How will men approach the PSA screening debate? Despite the USPSTF recommendations I will still be asking my physician for an annual PSA test, so long as it remains covered by my health insurance. The PSA test and digital rectal exam remain the main ways we have to detect prostate cancer early.

Psychologically I value the risk of picking up a disease early higher than the downside of a false positive. I would, however, not rush into any surgery or radiotherapy absent a clear finding that the benefits of intervention outweighed the potential harm.

My approach towards prostate cancer PSA screening again reminds me of the debate over mammography.  We all want to discover cancer early, and have the best possible treatment options as a result.

Hopefully, as our understanding of the biology of prostate cancers and associated biomarkers develop we may be able to generate new screening tests that have fewer false positives than PSA and provide for more accurate early diagnosis.

ResearchBlogging.orgAlemozaffar, M., Regan, M., Cooperberg, M., Wei, J., Michalski, J., Sandler, H., Hembroff, L., Sadetsky, N., Saigal, C., Litwin, M., Klein, E., Kibel, A., Hamstra, D., Pisters, L., Kuban, D., Kaplan, I., Wood, D., Ciezki, J., Dunn, R., Carroll, P., & Sanda, M. (2011). Prediction of Erectile Function Following Treatment for Prostate Cancer JAMA: The Journal of the American Medical Association, 306 (11), 1205-1214 DOI: 10.1001/jama.2011.1333

Roger Chou, MD, Jennifer M. Croswell, MD, MPH, Tracy Dana, MLS, Christina Bougatsos, BS, Ian Blazina, MPH, Rongwei Fu, PhD, Ken Gleitsmann, MD, MPH, Helen C. Koenig, MD, MPH, Clarence Lam, MD, MPH, Ashley Maltz, MD, MPH, J. Bruin Rugge, MD, MPH, & Kenneth Lin, MD (2011). Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force Annals of Internal Medicine, E-375 (October 7)

As many of you know, I previously wrote up on this blog the results from the Prostate Cancer Intervention versus Observation trial (PIVOT) that were presented during the plenary session at the recent American Urological Association (AUA) 2011 annual meeting.

Other science bloggers who were at the meeting also wrote about the presentation (see Scott Hensley’s excellent post on NPR’s health blog).

In fact anyone in the press room at AUA (I had a media pass as a science blogger) could have reviewed a copy of Dr Wilt’s presentation immediately afterwards and written about it.

However, what surprises me is that the data from this trial, which to many was the highlight of the AUA meeting and may be practice changing for urologists, has had relatively little or no pick-up by the mainstream news media.  The only reason I can think for this is due to the fact there is no abstract available, press release or other information for the media to use as reference.  Why is this?

As a scientist it makes no sense to me to present the results of a landmark study in the plenary session of a major scientific congress and not to share the data, especially when the data could have a major impact for men diagnosed with early prostate cancer and the practice of evidence based medicine.  Are urologists seriously supposed to rely on the notes they made from a rushed presentation or blog posts to guide them?

While it is common for abstracts to be delayed till the day of the presentation for groundbreaking or late-breaking research, there is no reason why an abstract with the main findings from the PIVOT trial should not have been released.

A cooperative study sponsored by government institutions such as the VA/NCI/AHRQ should be prepared to disseminate data, or else why present it at AUA?

Instead, the problem may be more due the fact that Dr Wilt, as Scott Hensley pointed out in his NPR blog post, has not submitted a manuscript of the data he presented at AUA for publication, so may be trying not to fall foul of the so-called “Ingelfinger rule” that medical journals insist upon.

This rule was named after the New England Journal of Medicine editor who established it.  In its simplicity, it states that data will not be accepted for publication if it has been published elsewhere.

However, with no disrespect to a full Professor of Medicine at a major medical school who has published numerous papers, it’s unfair to the scientific community to want to have your cake and eat it  i.e. have the glory of a plenary presentation without allowing the scientific community to use the data until you get round to writing a paper.  Clearly, it would have made more sense to have a manuscript in press before agreeing to present at the AUA plenary.

I am also troubled by the fact that what constitutes publication of the data does not include presentation at the plenary session of a major scientific congress.  If this isn’t publication, what is?  While technically a plenary presentation is not a peer-reviewed publication in the sense of having been through the rigors of a journal’s peer-review process (the value of which may not be as much as we believe), there is some implied peer review of scientific merit, or else why would it be given a plenary?

According to the Journal of the American Medical Association (JAMA) policy on dissemination of information, it’s OK to make a presentation at a scientific meeting, but not to disseminate further information to the media or the press.  I’m sorry but this makes no sense to me.  In other words it appears it’s OK for Dr Wilt to present the data, but not share it, but if you were at the meeting you can report it.  However, if you were not at the meeting, then you can’t obtain a copy of what was presented?

You can read the tangled logic of the JAMA policy below, and each journal is slightly different in how it views this:

Presentation of research findings during, or publication of an abstract for, an open scientific or clinical meeting does not preclude consideration of the study for publication in JAMA.

News media reports based on coverage that occurs during the usual course of presentation of a scientific or clinical paper does not preempt a manuscript from consideration for publication.

However, authors presenting papers at such meetings are advised to refrain from providing additional information beyond that covered during the course of their presentation and exchange with meeting attendees.

Yet, here we have the results of a major 12 year study which for the first time establishes evidence based medicine on the use of radical prostatectomy in early stage prostate cancer patients, and nobody wants to share the data with the public?

In the light of the presentation that was made at the AUA plenary and the lack of any further information while we wait for Dr Wilt to submit a manuscript through the peer-review process of a major journal, which can take several months, I think it’s important for this data to be shared.

Since media reports of data presented at meetings appear to not to forego the opportunity of publishing the results, at least according to the JAMA policy, I hope that we will see further news reports about Dr Wilt’s AUA plenary presentation.

The results from the PIVOT study are important to scientists, urologists and men talking to their doctor about prostate cancer.  This data may help them better judge whether they should undertake watchful waiting or undergo radical prostatectomy surgery.  The data slides and Dr Wilt’s conclusions speak for themselves, as you can see in my earlier post.  I look forward to reading the full scientific paper when it is eventually published.

Update May 23, 2011

A webcast with audio and slides of Dr Wilt’s plenary presentation of the PIVOT data is now available on the AUA website.


Data from the Prostate Cancer Intervention versus Observation Study (PIVOT) presented today in the plenary session of the 2011 annual meeting of American Urological Association (AUA) will have a major impact on the practice of Urology.

The VA/NCI/AHRQ cooperative study, initiated in 1994, was designed to assess the effect of radical prostatectomy (RP) compared to observation only or “watchful waiting” in men with localized prostate cancer.

What makes the PIVOT study so important is that it is the first randomized trial in the United States to look at RP versus “watchful waiting.”  In all, 13,022 men were screened at 52 US centers, from which 5023 men were deemed eligible.  Surprisingly, 4292 declined randomization and 731 men were enrolled in the trial.

The primary endpoint was all-cause mortality and the secondary endpoint, Prostate Cancer (PCa) mortality.  The two groups of patients were comparable between the observation and RP groups (mean age 66.8, 67.0 years); PSA Mean (10.2, 10.1), Gleason Score < 6 (70.1%, 69.8%).

Timothy Wilt (Minnesota) presented the results today at AUA 2011 (Abstract#407)

All-Cause Mortality

  • Absolute Risk Reduction (ARR) between Observation & RP = 2.9%,
  • Hazard Ratio = 0.88 (95% 0.71-1.08), P=0.22



Prostate Cancer Mortality – all patients

  • AR = 2.7%  (95% CI -1.3 to 6.2)
  • Hazard Ratio=0.63 (95% CI 0.36-1.09), p=0.09

In other words looking at the groups as a whole there was no benefit of RP on survival.  Wilt presented further analysis on subgroups with low-risk local pathology, intermediate risk-local pathology and high risk PSA>10.

Only in the high-risk groups (PSA>10) was there a significant benefit to RP, in terms of lowering Prostate Cancer Mortality.

  • HR= 0.36 (0.15 to 0.89); p=0.03
  • ARR = 7.2% (0 to 14.8)

Wilt’s conclusion from the data was that compared to observation, RP produced

“reductions in all-cause and prostate cancer mortality that were not significant and less than 3% in absolute terms over 12 years.”

He added that:

“Surgery did not reduce mortality more than observation in men with low PSA or low risk from Prostate Cancer”

However, these “results suggest a benefit from surgery in men with higher PSA or higher risk of disease.”

The PIVOT trial provides evidence-based medicine results that will directly influence how urologists treat early stage prostate cancer.  Several urologists and others at AUA tweeted about the PIVOT data.  Using Storify, these provide some sentiments and perspective from practicing urologists in the live audience.

The conclusion from this data is that low risk, early stage prostate cancer patients should be observed by “watchful waiting” rather than undergo radical prostatectomy (RP).  This may have a financial impact on urologists who previously may have favored RP in low risk patients.

Update May 23, 2011

A webcast with audio and slides of Dr Wilt’s plenary presentation of the PIVOT data is now available on the AUA website.

Update March 6, 2012

Dr Wilt presented an update on the PIVOT trial at the 2012 European Association of Urology (EAU) Congress in Paris. You can read my blog post from the meeting:

PIVOT data continues to show no survival benefit for prostatectomy over watchful waiting in men with low to medium risk early prostate cancer.”

 Update July 18, 2012

The data from the PIVOT trial presented in the plenary sessions at AUA 2011 and EAU 2012 has finally been published online first (July 18, 2012) in The New England Journal of Medicine.NEJM PIVOT trial prostate cancer


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.

There is a lot of focus at the annual meeting of the American Urological Association (AUA) here in Washington DC on metastatic castrate resistant Prostate Cancer (mCRPC), and the recently FDA approved adrenal steroid inhibitor, abiraterone acetate (Zytiga®).

Drugs in development that target the androgen receptor, such as MDV3100, are also generating a lot of interest from urologists.

However, Oliver Sartor (Tulane) in the Saturday morning satellite symposia that I attended, focused on emerging therapies in CRPC, beyond the androgen axis. His hypothesis:

“Cancers are devious and some of the mechanisms of AR activation appear to be ligand-independent and resistant to all current androgen-axis targeted therapies.”

What this means is that focusing on adrenal steroid inhibition or blocking the androgen receptor may not be sufficient to prevent disease progression. If we are looking for a Prostate Cancer cure, then will it take multiple drugs, including those that target various stromal sites? That is the intriguing question that Sartor raised.

Indeed, if there is one take home from this meeting, it is that the “desert” of prostate cancer therapies has now blossomed into a multiplicity of potential new therapies and development, which will mean that urologists and oncologists will soon be spoilt for choice as abiraterone and MDV3100 are not the end of the story.

Sartor highlighted some interesting ones on the horizon to watch out for:

Alpharadin: This is a bone targeted therapy that uses radioactive Radium 223 to kill cancer cells. It is being developed by Norwegian company, Algeta in partnership with Bayer Schering Pharma AG. The 900 patient phase III trial completed accrual earlier this year in Jan 2011. Phase II data was published in the Lancet in 2007 by Nilsson et al. Data from alpharadin will be “coming soon” according to Sartor.

XL-184 (cabozantinib): Activated MET is highly expressed in prostate bone metastases. Exelixis XL-184 is a small molecule tyrosine kinase inhibitor that specifically inhibits both MET and VEGFR2.

Data from a phase 2 study of XL-184 in castrate resistance patients was presented last year at the EORTC-AACR-NCI Symposium on Molecular Targets and Cancer Therapeutics in Berlin by David Smith et al (Abstract 406).

Both XL-184 and alpharadin would be potential competitors to Amgen’s denosumab (Xgeva®).

Other new products in development “Beyond the Androgen Axis” that Dr. Sartor mentioned included Prostvac-VF, BPX-101 and ipilimumab. A phase III trial of ipilimumab, both pre- and post- docetaxel is now underway in mCRPC. A phase III trial of Prostvac-VF will start later this year with 1200 patients in a placebo controlled study with minimally symptomatic, castration-resistant metastatic prostate cancer patients.

Over the next few years a lot of data may emerge on exciting new treatment options. Coupled with the basic research that is going on, tremendous progress in the treatment of Prostate Cancer is already taking place.

According to Sartor “multiple drugs will be necessary to cure mCRPC and that is our greatest challenge today.” Major progress is now being made towards this.

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I am off to Washington DC tomorrow for the annual meeting of the American Urological Association (AUA).

If you are not able to attend, then you can follow the Twitter coverage on Pharma Strategy Blog where Sally Church (@MaverickNY) will be aggregating the tweets.  The conference hashtag is #AUA2011.  I also expect to be live-tweeting from the conference.

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Like many medical conferences in the United States, the AUA meeting kicks off with independent continuing medical education (CME) satellite symposia on topics of interest.

As a lawyer who has to pay for his own continuing legal education (CLE) credits, I have to confess that I am somewhat cynical that other professionals such as physicians expect to have their CME paid for through free industry-sponsored events.  These symposia are certainly not cheap to run.

However, compared with Europe, CME events in the United States are usually well-produced and fair balanced, albeit with a topical theme that obviously relates to the sponsor’s interest.

The two satellite symposia that I will be attending at AUA are Friday evening’s Amgen supported “Managing Skeletal-Related Events in Patients with Prostate Cancer” and the Saturday morning Astellas/Medivation supported “Reason for Hope: Key Advances in the Management of Castration-Resistant Prostate Cancer.”

While at Quintiles, I was lead CRA/European Project Manager for the phase III trial trial of risedronate in elderly women at risk of hip fracture, so I am interested in bone related treatments, and am looking forward to hearing more about denosumab (Xgeva®) and its impact on skeletal related events (SRE).

Oliver Sartor (Tulane) raises some excellent questions in a recent paper published in the Asian Journal of Andrology, “if a patient has a SRE, does it affect the way a patient feels, functions or survives?”

Sartor argues that a better definition of the benefit a drug has on SRE’s would be “a reduction in pain, analgesic consumption or improvement in quality of life (QoL)” instead of the current “feel, function or survive” standard.

He notes that patients with bone-metastatic castrate resistant prostate cancer (CRPC) have a limited life expectancy, so that QoL is a key issue. “An asymptomatic event linked to a future adverse event is less meaningful in a patient with metastatic CRPC.

Sartor concluded his paper by saying:

“The lack of effect of bisphosphonates or denosumab on patient-reported outcomes including QoL, pain or analgesic consumption continues to be a disappointment for this entire field.”

When we talk about a reduction in SRE’s what does this really mean for the patient?  I look forward to hearing what the expert panel at Friday evening’s symposia on this topic and hope it will be addressed.

Moving on to the other satellite symposium, supported by Medivation/Astellas, that I will be attending early on Saturday morning.  I expect this symposium will focus on new drugs in the pipeline such as MDV3011 and ARN-509 that target the androgen receptor. Hopefully they will also discuss other therapeutics, such as the recently approved abiraterone acetate (Zytiga®), as well TAK-700, which has a similar mechanism of action to abiraterone, i.e. they both inhibit CYP17 and testosterone production.

I’m looking forward to hearing what the expert panel has to say about the need to take prednisone with abiraterone, and whether there are any issues surrounding long-term usage if abiraterone ends up being used earlier in the pre-chemotherapy setting.  Updated data from the COU-AA-301 trial will be presented at AUA on Monday, and I expect a lot of interest from urologists in this.

The satellite symposia are set to be a good warm up act to the start of the main AUA meeting that runs from May 14 to 19 in Washington DC.  I’ll be writing more from the AUA 2011 over the next few days.

ResearchBlogging.orgSartor, O. (2011). Denosumab in bone-metastatic prostate cancer: known effects on skeletal-related events but unknown effects on quality of life Asian Journal of Andrology DOI: 10.1038/aja.2011.33

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