PSA and the US Preventive Services Task Force


I heard on the news tonight a well known urologist expressing “outrage” at the findings of the task force. No doubt it is in other newscasts as well, but I can only stand to listen to so many… Let’s start by giving you the link to their recommendation which is here. My personal view is that the better recommendation would have been to have men read the document before deciding about being screened, and then make their own decision. I can’t tell you how many times I have had men read a clinical trial (which must explain in 8th grade language, the risks and benefits) consent form and then decline to participate because of the long list of side effects that accompany every drug imaginable. However in the case of PSA testing, these side effect considerations are outweighed by 2 decades of “promoting” screening by well-meaning (and some not-so-well meaning) physicians, often urologists. It is likely these doctors are biased, not because of any personal gain, but because they are on the front line of watching men die from prostate cancer and our long-standing belief is that early detection is the way to cure cancer. We all grew up in the era when Pap smears helped eliminate cervical cancer, and now we have a vaccine that can do even better.

In addition, I have virtually never met a man in my clinic or in our support group who didn’t feel either that 1) screening and treatment saved his life, or 2) that earlier detection/screening WOULD HAVE saved his life. The reality is that neither of these feelings is accurate. Some men who are screened will be treated, suffer the side effects, and never would have needed to know they had cancer. Others will be found “early” yet succumb to cancer that had escaped their prostate long before they were detected by the best techniques. And remember that those of us who have lived through the treatment have a built in emotional bias to think “we did the right thing” as a balm for the side effects we endure. In any event, this won’t be the last of this controversy, so we all have time to ponder the challenges of our “favorite” disease. Personally I applaud the USPSTF for taking a hard look at the evidence and putting it together in a document for all to see, and perhaps that document provides the best way to try and help men be better informed than having a political figure, war hero, or movie star stand before the general public and urge everyone to “get screened”.

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The eye of the beholder.


Since I have previously written blogs on both the vaccine and the issue of screening (several blogs actually), I will simply pass these on with minimal commentary that follows. In the screening controversy, Europe updated their data showing that screening reduces death from prostate cancer but not overall mortality. My view is that 1) men with some high risk factor (African American, affected first-degree relative, BRCA-2 mutation family, etc) should be screened 2) others should be careful what they are asking for. And my corollary is that there are no screened/treated men who don’t feel either that screening saved their life or WOULD HAVE saved their life if it had been done earlier. But as a public health issue, since the vast majority of men will develop prostate cancer, current screening falls far short of the test we are looking for, and finding “more sensitive” tests is certainly not the answer. We need more SPECIFIC tests for the lethal phenotype.

As for the vaccine, there is a nice review of an alternative interpretation of the data that led to the approval of Provenge. It is worth knowing about, as is the intense interest in this vaccine from the financial community as well as patient advocacy groups. Be sure to read the whole article to get a balanced perspective. If you have the time, I also recommend reading a companion article that is linked on the Reuters page. Negative scientific studies are never published, nor do news writers bother making the few that are published into headlines. Companies like Amgen who have to put their resources where their “beliefs” lie do us a favor when they look into sensational claims.

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Psychology and science


In my view, the ideal physician is one who combines caring, compassion, empathy and introspection with hard core science. It is all too easy to become fascinated by the “mind over matter” paradigm and delude one’s self into thinking that a positive attitude will solve some very basic problem (like a mutation in DNA…). That said, I have little doubt that patients with a positive attitude generally enjoy their lives and whatever time they have left with friends and families more than those who become obsessed with one disease or another and launch on an endless search for an answer that probably doesn’t exist. My own experience with cancer in my parents, siblings and self has taught me that equanimity is one of the most essential characteristics of the cancer survivor. We all survive (with luck) various insults in our genomes or our environments for only so long, and then we move on. I will turn 65 this summer, and it is hard for me to internalize the reality that (again with luck) I may have only about 20 or so more years to enjoy this wonderful planet. Like everyone else, my mind tells me I will go on forever, but the harsh reality of 20 years is just plain difficult to internalize. Are you kidding me? 1992 seems like only yesterday!

Today I received an email from a colleague with a link to this website that is written by a psychologist. It seems to have lots of good resources, and I recommend it on your journey. Perhaps Dr. Pope will have helped winnow down the avalanche of information out there for you as well. Good luck!

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Reality check – why a simple answer won’t work…


This week’s New England Journal of Medicine has an article that everyone who asks the question, “How close are we to a cure?” should read. Let’s start with the reality that our genes have been around for a very VERY long time. I don’t want to get into the creation/evolution debate, so if you don’t agree with the premise that our genes have been in the process of adapting to change and that is why/how we got here, you can stop reading this and I sincerely wish you well. On the other hand, if you accept the fact that, for example, bacteria mutate all the time and that is why penicillin doesn’t work so well any more, or that our continued use of levofloxacin prior to prostate biopsies is now leading to increased septic complications with biopsy due to resistant organisms, then read on.

A group of 30 investigators, (yes, that’s what it takes these days to do BIG SCIENCE) studied 4 consecutive patients with metastatic renal-cell carcinoma. They looked at mutations before removing the kidney, then treated with everolimus, a marginally effective kidney cancer treatment, then looked at mutations in different areas of the tumor when it was taken out. They also looked at the mutations in metastases. The take home message is that different regions of the tumor give rise to different metastases and have different genetic mutations. The picture (not really as good as the 1000 words by the way) looks like this:

While you see the VHL mutation is a common starting place, all of those other mutations give the tumors or regions of tumor unique survival and growth characteristics. This is not new information and there have been similar studies around for years. But what it DOES indicate is how naive it is to beat the drum for “personalized medicine” by doing an expensive analysis of a single tumor biopsy. There is no doubt that our genetic abilities are awesome, but they pale in comparison to the intelligence built into the genome we all carry.

For prostate cancer, the good news is that if we take the advances of the last 18 months, they would all attack where “VHL” shows up in the figure above. But the letters would change to “AR”, the androgen receptor. It is spectacular that we can continue to attack this choke point even late in the disease with drugs like abiraterone and get good mileage in our fight. The news releases in the last 48 hours on use of abiraterone earlier in the disease are great news. As chair of the committee that advised J&J to stop the study, I can tell you that when the full data become public in about 2 months, everyone will be cheering on behalf of our patients with metastatic prostate cancer who now have increasing options. I’ll also point out the speed with which science moves. The committee completed its analysis just over a week ago, and the public is already aware of our recommendations. You can read elsewhere in this blog about TAK700, MDV3100, and ARN509, all of which give us further ammunition against the AR target and will likely continue our path, not to a cure, but to a chronic disease we can control.

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Androgen Receptor Addiction


The term oncogene addiction, or “driver mutation” is pretty central to most of the exciting progress being made in drug development for prostate cancer. At the outset, unlike breast cancer, ~95% of men with prostate cancer achieve some sort of remission with simple androgen ablation. This can take the form of surgical castration (orchiectomy), or the same thing can be achieved (lowering the T level in the blood) through administration of gonadotropin hormone releasing hormone analogs. The best known of these is probably leuprolide, but the same thing happens with other analogs, be they agonists, or the more recently marketed antagonist, degarelix. Overall, there is probably little difference which one is used.

The newer drugs are all designed to further inhibit testosterone stimulation in other ways. Examples include the better androgen receptor blockers (AR) like MDV-3100 or ARN-509 which are improvements on the small molecule blockers initially developed like flutamide or the more commonly used bicalutamide. Still in the laboratory phase are potentially even better blockers like a small molecule called EPI-001 that exerts its action not through blocking androgen binding to its receptor, rather blocking the receptor itself from interacting with DNA in the nucleus or with other proteins. Clearly there are many other approaches to the AR that will eventually lead to newer and better drugs. Blocking the cancer cells from making their own testosterone as is done with abiraterone or TAK-700 is a good example.  However, as Peter Nelson outlines in a lovely review article in the Journal of Clinical Oncology this week, additional mechanisms of resistance emerge. He has characterized this as different “states” of prostate cancer cell existence as shown in this figure from his publication:

States of the Androgen Receptor

Of  course it is important to understand that even this level of complexity is far too simple. The feedback loops that are activated when AR is blocked, or when it is no longer active are many and varied and will require a great deal of further work. Already, trials are evaluating mtor inhibitors like temsirolimus in blocking some of these feedback loops.  Nevertheless, it is great to see the increasing knowledge that will lead to suppression of prostate cancer in patients, and as I have often said, in this field if we can keep patients alive long enough to die of a heart attack or some other malady, we can claim it as a “cure”.

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News from ASCO GU


This will be a “quick hit” post, as I am not at the symposium this year. If I am not mistaken, there is nothing I haven’t covered before that has been released yet, but just to be sure everyone is getting the same info, you can go here to read whatever you like. The basics are that (as reported in the press several months ago), MDV 3100 trial is positive but I didn’t see anything about the timing to approval which several readers have asked about. Similarly I already covered Radium-223 which Ollie Sartor presented and the data have been known for more than a year. Again, I don’t have any inside info on availability, but both will be welcome additions to the armamentarium.

It is interesting to speculate on whether we could gin up a “curative” regimen at this point. My own view is that the answer depends on your definition of “cure”. If by that you mean that every detectable prostate cancer cell in the body is gone forever, then I don’t think this is likely to occur. However, if you mean that more patients with metastatic disease, starting from the time of metastases, might well live 10-20 years and die of something else, then very definitely we are on the right track. If cost/availability were no problems right now, I would imagine a scenario something like this:

A man who had radiation/surgery 10 years ago comes in with rising psa and a new painless bone metastasis on scan. He might start on a GnRH antagonist for a month, switching to a one year agonist implant and following the testosterone/psa monthly. In addition, we would add one of the new, more effective antiandrogens like MDV 3100 or ARN-509 and keep him on that for at least that first year. We would give him a dose of Radium 223 to handle the known met to the bone (and maybe prevent others). We would also add in one of the inhibitors of T synthesis like abiraterone or TAK 700. There would be little harm in adding one of the 5-alpha reductase inhibitors (finasteride or dutasteride), but probably not that much to be gained either. I’m not sure about adding an immunologic approach, but if cost were no object, certainly there would seem to be little harm in either sipuleucel-T or prostvac being added somewhere in there,  possibly with a sprinkling of ipilumimab. And this is just the list of “available or soon to be” drugs. There are several more of some interest that we don’t know enough about, like cabozantinib.

Of course there are lots of unknowns here. What is the right sequence? Would it be better to do different treatments one after the other or all at once?. What about giving Radium 223 at the start along with an agonist (raising the T and PSA temporarily, thus stimulating the bone mets to take up more isotope leading to their death) rather than the antagonist? And at the end of a year, where would we go? And how can we pay for this kind of treatment in the current environment, never mind getting the companies to cooperate and provide free treatment until it is proven to be a “cure”. Remember, their patents run out long before our “cured” patients die and they spent millions getting these drugs to market. Is there room for reduced costs to men who agree to participate in a trial, and if so, how much? Finally, what would you propose as the “control arm”? (leave one out? continue therapy for 2 years in one arm and stop at one year in the other?)  Are you willing to sign up?  Given all the challenges, this treatment will likely not happen anytime soon, but it should!

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2011 in review


The WordPress.com stats helper monkeys prepared a 2011 annual report for this blog. It is somewhat interesting to look at what topics generated the most interest as well as where visitors came from. To all of you who took the time to comment, I thank you for adding to the discussion and look forward to continuing to find topics of interest to bring to your attention in 2012. I sincerely welcome suggestions for topics that you would like to see covered. Just add them as comments to this post and I will try to get through them in coming weeks . Happy New Year!

Here’s an excerpt:

A New York City subway train holds 1,200 people. This blog was viewed about 4,600 times in 2011. If it were a NYC subway train, it would take about 4 trips to carry that many people.

Click here to see the complete report.

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