Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Prostate Cancer Screening’

Dr Benjamin J. Davies, an academic urologist at the University of Pittsburgh today castrated the media over their coverage of the Prostate Cancer Intervention versus Observation Trial (PIVOT).

Pivot Prostate Cancer Trial Conclusion

In an article titled “Prostate Cancer: Lessons from PIVOT lost in media hype” published in the News and Views section of Nature Reviews Urology, Dr Davies states, “we must be careful to ensure the less-newsworthy facts and limitations of high-profile trials, such as PIVOT, are not lost in the media hype.

Davies goes on to say,

“an odious meme is circulating in the medical media, suggesting that prostate cancer is universally diagnosed, that PSA screening causes more harm than help, and that urologists should disregard basic epidemiologic data.”

Strong words perhaps, but those who follow Davies on twitter (@daviesbj) will know that he does not mince words and is not lost for an opinion.

However, in writing for a publication such as Nature Reviews Urology, which is probably not on the reading list of the private practice urologist or member of the mass media, he is preaching to the converted, namely academic-orientated physicians like Davies himself.

All clinical trials have their limitations, and Davies makes valid points that the PIVOT trial has a number of noticeable weaknesses.  Attention was also drawn to this in the accompanying editorial when the data was recently published in the New England Journal of Medicine.  I encourage you to read his review.

I reported the presentations of the PIVOT data from the plenary sessions at the 2011 annual meeting of the American Urological Association (AUA) and the 2012 congress of the European Association of Urology (EAU) on this blog and do take exception to Davies’ implied assertion that ALL the media coverage of the PIVOT trial was “hype.”

Experienced Healthcare journalists such as Scott Hensley (@scotthensley) provided fair and evenly balanced coverage on NPR Shots, for example.

If the media coverage of the PIVOT trial data was not as balanced or did not contain the message that Davies wanted to hear, then rather than shoot the media messenger the urology community should ask themselves why they did not obtain it?

Interestingly, at AUA 2011 and EAU 2012 there were no press conferences on the PIVOT trial data, yet it was an important topic and a plenary presentation.  Press conferences allow the media to ask questions of a panel of speakers and the opportunity to gain a variety of perspectives.  Why did the leading urologists who organize these major medical congresses not provide this access?

It is the responsibility of the urology community to reach out and educate the media if you think we don’t understand the nuances of the data.

Davies singles out the PIVOT trial for critical review, but in so doing he touches upon the wider issue of the lack of quality clinical trial data to support treatment and practice in urology.  It is for this reason that those clinical trials that are published, whatever their limitations, have disproportionate impact.

As I wrote from EAU 2012, why is there no level 1 evidence-based medicine that shows the benefits of robot assisted radical prostatectomy?  Are academic physicians unable to do high quality and robust clinical trials that justify their practice?

In his article, Davies goes beyond criticizing the PIVOT trial to castigating the media over their coverage of PSA screening, for which he is an ardent proponent.

Unfortunately, he ignores the reality that mass media don’t generate the data, they only report what organizations such as the United States Preventative Services Task Force (USPSTF) recommend.  If academic urologists believe the USPSTF got it wrong, then the failure is theirs in their inability to generate compelling data or influence the recommendations.

Finally, when Davies says, “no doubt urologists have not helped themselves by overscreening and overtreating” he touches on what I believe is the underlying cause of much of the problem associated with PSA screening.

Academic urologists need to educate their community colleagues.  Influencing everyday practice and treatment decisions will do more to help patients in the long run than being critical of the media, however justified that may be in some cases.

1 Comment

Vitamins on Shelf

Despite promising preclinical data suggesting that selenium and vitamin E may reduce prostate cancer risk, a randomized trial started in 2001 with over 35,000 men now suggests otherwise.

Given the prevalence of people taking vitamin supplements, these findings have important public health implications.

The results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) reported in the October 12, 2011 issue of the Journal of the American Medical Association (JAMA) show that dietary supplementation with Vitamin E significantly increased the risk of prostate cancer in healthy men.

Over 35,000 men were randomized into 4 groups: selenium (200 mg/d from L-selenomethionine) with matching placebo, vitamin E (400IU/d of all rac-a-tocopherol acetate) with matching placebo, both agents, or placebo.  The study was stopped in September 2008 as a result of an interim analysis that showed lack of efficacy for risk reduction and futility analysis showed a lack of future benefit.

The data in 2008 with a median follow-up of 5.5 years suggested an increased risk of prostate cancer observed with vitamin E.  That finding has now reached statistical significance in the latest analysis of the trial data, 7 years after the last patient was randomized.

Participants were healthy men at average risk of prostate cancer. They were monitored every 6 months and recommended to undergo prostate-specific antigen (PSA) and digital rectal examination (DRE) based on the standard of care in their community.  The primary end point was prostate cancer incidence resulting from routine community care.

The updated results from the SELECT trial are published in JAMA by lead author Eric Klein from the Cleveland Clinic and colleagues.  The data shows that the incidence of prostate cancer was greater in all treatment groups compared to placebo, but statistically significant only in the vitamin E group alone (P=0.008, HR: 1.17; 99% CI, 1.004-1.36).

The authors note this data means:

 “The risk of prostate cancer at 7 years of median follow-up was increased by 17% in men randomized to supplementation with vitamin E alone, a difference that started to appear about 3 years after randomization.”

Why does Vitamin E supplementation cause this increased risk? The authors in their JAMA paper make no suggestion.

The data from this trial has important implications for all men who take multivitamin supplements.  The authors note that more than 50% of all individuals over 60 take a vitamin supplement and 23% of them take a 400 IU/d or greater dose of Vitamin E, a dose that now has been shown to increase the risk of prostate cancer.

All too often we associate taking vitamins as healthy living.  The conclusion of the authors is one that we should all take note of:

“The observed 17% increase in prostate cancer incidence demonstrates the potential for seemingly innocuous yet biologically active substances such as vitamins to cause harm.”

Only by doing clinical trials such as SELECT, can we assess the true harms and benefits of unregulated over-the-counter products such as vitamins.

ResearchBlogging.orgEric A. Klein, MD, Ian M. Thompson Jr, MD, Catherine M. Tangen, DrPH, John J. Crowley, PhD, M. Scott Lucia, MD, Phyllis J. Goodman, MS, Lori M. Minasian, MD, Leslie G. Ford, MD, Howard L. Parnes, MD, J. Michael Gaziano, MD, MPH, Daniel D. Karp, MD, Michael M. Lieber, MD, Philip J. Walther, MD, PhD, Laurence Klotz, MD, J. Kellogg Parsons, MD, MHS, Joseph L. Chin, MD, Amy K. Darke, MS, Scott M. Lippman, MD, Gary E. Goodman, MD, Frank L. Meyskens Jr, MD, & Laurence H. Baker, DO (2011). Vitamin E and the Risk of Prostate Cancer, The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA: The Journal of the American Medical Association, 306 (14), 1549-1556


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)

Launch of Zytiga (abiraterone acetate) at 2011 annual meeting of American Urological Association (AUA) in Washington DCThe market for prostate cancer therapies is set to expand from $1 billion currently to $5 billion by 2015, according to analysts reported by this morning’s Washington Post/Bloomberg news.  This is perhaps no surprise given the recent approval of abiraterone acetate (Zytiga®) from Ortho Biotech (JNJ).

New clinical data on prostate cancer clinical trial results is expected at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago this weekend from many of the prostate cancer therapies in development such as MDV3100, TAK700, ARN-509, cabozantinib (XL184), ipilimumab, custirsen (OGX-11), BPX-101, alpharadin, denosumab (Xgeva®) and Prostvac-VF.

Indeed, one could argue that prostate cancer is becoming a competitive marketplace.  Any emerging biotechnology company that is not already developing a prostate cancer drug is likely to find it a hard market in which to create a blockbuster.  By the time any drug comes to market, there will be incumbents with effective products who have captured market share.

Prostate cancer is an exciting market to watch from a marketing strategy and patient perspective, as several companies potentially bring new products to market over the next few years.

However, the bottom line is that patients will live longer as a result of all the innovation that is taking place.  Not only that but physician education and awareness of how to treat this disease is also likely to improve as they seek out knowledge on new therapies and treatments.  This to many will make a major difference.  At the recent American Urological Association (AUA) annual meeting, the sessions on treatment of prostate cancer were standing room only.  There is clearly a demand for knowledge out there as the treatment paradigms change.

At the other end of the spectrum, there is also innovation taking place in terms of improved diagnosis and treatment of prostate cancer.  Whether we should screen all men for PSA remains a controversial topic, although use of risk calculators do appear to offer less false positives.  Indeed, calculating risk is going to be one of the key areas that primary care physicians and urologists need to focus on, particularly in the light of the PIVOT trial data that was presented at AUA, showing radical prostatectomy (with risks including incontinence and erectile dysfunction) was not better than watchful waiting in low-risk, early stage disease.

However, a presentation I am looking forward to at ASCO 2011 is on circulating tumor cells (CTC) and whether these can be a prognostic or even a predictive biomarker.   Both the phase III MDV3100 and abiraterone acetate clinical trials captured CTC data.  It will be exciting news at ASCO 2011 if circulating tumor cells that require only a blood sample offer an improvement over PSA not only for detection of prostate cancer, but in monitoring the disease over time.

I will be at ASCO 2011 this weekend, and look forward to writing more on prostate cancer from the conference!

One of the ongoing debates in prostate cancer and urology is the value of routine screening of all men in a certain age group.  There was a difference of opinion amongst the experts at the recent European Association of Urology (EAU) Congress in Vienna.

Prof Schroder from Rotterdam outlines potential benefit and harm from prostate cancer screeningProfessor Schröder from Rotterdam summarized what he tells a man who is considering prostate cancer screening:

Benefit: If your prostate cancer is detected by screening, your chance of dying within 10 years is reduced by at least 20%

Harm: Screening may detect cancer which would never harm you and you may undergo treatment for no good reason.

Research published in the British Medical Journal (BMJ) on March 31, 2011 adds weight to the body of data that suggests general prostate cancer screening is of little or no benefit.

In an open access BMJ paper, Gabriel Sandblom and colleagues showed that prostate cancer screening did not reduce death rate in a randomly selected population of men between 50-69 who were followed for 20 years.

The study methodology is worth noting.

Take a city in Sweden and randomly select every sixth man aged between 50-69 and screen them for prostate cancer every 3 years. That’s what happened in 1987 in the City of Norrköping in Sweden.

1497 men received four screenings from 1987 to 1996, with the first two being digital rectal examinations (DRE), and the final two screenings combining this with measurement of prostate specific antigen (PSA).

The conclusion from the results published in the BMJ is that :

“After 20 years of follow-up the rate of death from prostate cancer did not differ significantly between men in the screening group and those in the control group.”

There is an ongoing debate on the value of population based screening for prostate cancer, a disease that may affect 1 in 6 men.  Like mammography, the benefits of prostate specific antigen (PSA) screening are hotly debated given the potential for overdiagnosis and overtreatment.

The results from the Norrköping study clearly show that where there is no assessment of risk factors or focus of screening on those who might be at risk, there is no significant difference in mortality between those screened and those who are not screened.  The study results:

“did not show a significantly longer prostate cancer survival (P=0.065) or overall survival (P=0.14) for men with prostate cancer diagnosed in the screening groups.”

This study of a large group of men over a long-period of time suggests that the risks of screening the general population may not outweigh the potential benefits.

The authors note that in the ERPSC prostate cancer screening trial published in the New England Journal of Medicine in 2009 it was estimated that “to prevent one death from cancer, 1410 would need to be screened and 48 treated.”

While there are advantages if you are the lucky man whose death is prevented, the 47 who have to be treated to “save” you are not so lucky since they undergo treatment risks such as erectile dysfunction, urinary incontinence and bowel problems, not to mention the discomfort associated with prostate cancer biopsy and psychological effects of receiving a false positive result.

This study of 1497 men in a Swedish city over 20 years does not definitively answer the question of whether screening should be done or not.  As we have seen in the debate around breast cancer mammograms, emotion can drive health policy decisions as much as scientific data.

However, it does suggest that indiscriminate prostate screening may not be the way to go until more sensitive biomarkers of the disease other than PSA are developed or as the authors in their paper suggest screening is better able to discriminate “indolent tumours from high risk tumours.”

ResearchBlogging.orgSandblom, G., Varenhorst, E., Rosell, J., Lofman, O., & Carlsson, P. (2011). Randomised prostate cancer screening trial: 20 year follow-up BMJ, 342 (mar31 1) DOI: 10.1136/bmj.d1539

Free Email Updates
Subscribe to new post alerts, offers, and additional content!
We respect your privacy and do not sell emails. Unsubscribe at any time.
error: Content is protected !!