The robot vs the surgeon.


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I have previously blogged on the issues surrounding robotic prostatectomy. Recently I was asked by my professional society, ASCO (the American Society of Clinical Oncology) to provide commentary on two experts “debating” the pros and cons of open (tradiational) prostatectomy vs. the robotically assisted laproscopic approach. Rather than give a long, repetitive blog to you, I am just going to have you click on THIS LINK to read the post.

The issue is largely going away because of the dominance of the robot in clinical practice, but I thought that the experts did a great job explaining their positions.

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Statins and prostate cancer


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The use of statins to control dyslipidemia is now over 20 years old and supported for patients with coronary artery disease by the landmark Scandanavian Simvastatin Survival Study published in 1994. That study demonstrated a significant reduction in the rate of myocardial infarction and death among treated patients and remarkable safety. Subsequently numerous trials demonstrated their efficacy and safety in the cardiovascular arena even among patients with relatively normal lipid profiles and found a wide variety of other “off target” effects of statins which were originally designed to inhibit HMG-CoA reductase, a key enzyme in the regulation of cholesterol. For example the JUPITER trial highlighted the importance of CRP, a marker of inflammation as a possible additional mechanism of action.

Fortunately, many of the “off target effects” of the statins also have the ability to suppress cancer development, some of which may relate to the evolving understanding of insulin resistance and insulin as a growth factor for prostate cancer. Dozens of articles have been published on the efficacy of statins to reduce the incidence of a wider variety of cancers, including (but not limited to) colon, breast, esophageal, gastric, and melanoma because their use is so common in the population and both cancer and heart disease are common to the aging process. The studies are often confounded by “what else” patients might have been doing (exercise, low fat diets, taking NSAIDS, finasteride, dutasteride, etc), but in general it is likely that statin use is beneficial in prevention and perhaps in prolongation of survival among patients with prostate cancer. In one of the larger articles demonstrating this effect, Yu et. al. studied 11,772 men from the UK who were newly diagnosed with non-metastatic prostate cancer between 1998 and 2009. They published these conclusions in the Journal of Clinical Oncology last year:

“During a mean follow-up time of 4.4 years (standard deviation, 2.9 years), 3,499 deaths occurred, including 1,791 from prostate cancer. Postdiagnostic use of statins was associated with a decreased risk of prostate cancer mortality (HR, 0.76; 95% CI, 0.66 to 0.88) and all-cause mortality (HR, 0.86; 95% CI, 0.78 to 0.95). These decreased risks of prostate cancer mortality and all-cause mortality were more pronounced in patients who also used statins before diagnosis (HR, 0.55; 95% CI, 0.41 to 0.74; and HR, 0.66; 95% CI, 0.53 to 0.81, respectively), with weaker effects in patients who initiated the treatment only after diagnosis (HR, 0.82; 95% CI, 0.71 to 0.96; and HR, 0.91; 95% CI, 0.82 to 1.01, respectively).”

A very balanced editorial accompanied this publication reviewing the many similar articles and came to the cautious conclusion that “the current data may be sufficient to sway some clinical decisions toward statin use for men who are on the borderline for cardiovascular disease prevention.” I would certainly concur with this opinion, and if you have family members at risk for prostate cancer, it would seem prudent for them to have their lipid profiles tested and (given the other potential benefits and low risks for statin use) have them discuss starting statins if they have not already done so. Adding statin “therapy” after prostate cancer is diagnosed is probably of little harm, but as with metformin, much less proven as an interventional strategy.

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What is going to kill me? – the cloudy crystal ball


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With an intense focus on prostate cancer, it is easy to overlook the reality of other causes of death or disability in making decisions about therapy. An example of this issue is the proliferation of molecular tests that have been validated to separate patients with “intermediate risk”, or “low risk” into “even lower” or “even higher” risk disease categories using a number of different gene expression profiles on the tumor or biopsy material. For example, Genomic Health offers the Oncotype Dx test that provides a “Genomic Prostate Score” that gives a patient who (based on clinical criteria such as PSA and number of biopsy cores positive) falls into a low or intermediate risk category another lab value (GPS) that can potentially be useful in making a decision about treatment. GenomeDx has a test that can evaluate high risk men after prostatectomy to more accurately predict metastatic disease at 5 years. There is a very balanced article on the challenges of using these tests (which are a potential step forward to be sure) in the real world of the clinic here.

However, in all of the excitement and marketing of these and other tests, a couple of key facts are often overlooked (and may be much more important in decision making). Prostate cancer is generally a slow disease anyway. Competing mortality looms large as patients get older. And most importantly, there are validated ways to put the “whole patient” into the picture before ordering these tests, whether they be a PSA, biopsy, or molecular analysis. The Charlson comorbidity index can be extremely useful in predicting survival and is barely ever mentioned in the molecular analysis literature/reports. It is a simple yes/no answer to whether a patient has any of these 12 conditions: diabetes, bleeding gastrointestinal ulcer, chronic lung disease, congestive heart failure, stroke, myocardial infarction, angina or chest pain, cirrhosis or liver disease, arthritis, inflammatory bowel disease, hypertension, and depression. In a lovely article published last year, the use of this analysis in relationship to prostate cancer mortality gave a vivid picture of prostate cancer mortality in the larger setting of 3533 men with prostate cancer. A snapshot of their data looks like this:

Screen Shot 2014-06-19 at 9.15.54 AM

Very often, the comorbid conditions lead to death from another cause. In my opinion (and in my practice), we too often ignore our ability to quantify the risk of dying from “something else” when we focus so intensely on the PSA or other tests in counseling patients about what to do. It is also true that patient perception of test results can vary dramatically. One patient with a “GPS score” of 10 might be reassured, while another will perceive it as “not low enough” and opt for aggressive treatment rather than observation. To some extent this exposes the fallacy of “we need to separate the issue of treatment from that of diagnosis” thinking. Until the crystal ball becomes crystal clear, management of prostate cancer will remain challenging and requires the kind of wholistic thinking that is often better done by primary care physicians or public health professionals than by prostate cancer docs, or their patients.

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Practice changing results….chemotherapy up front.


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Adding 6 cycles of docetaxel at the outset of hormonal therapy for prostate cancer has been shown to improve survival, especially in men with a high burden of disease. The much anticipated report was presented in detail today at the ASCO annual meeting. Those of you who have followed this blog will remember that I previously highlighted the CHAARTED trial when the trial was stopped prematurely because of the positive result.

The first author, Chris Sweeney, is a good friend and led the study in which several of our patients here in Denver were participants. Thanks guys !

This study randomized 790 men who presented with metastatic prostate cancer and who had never received hormone therapy (ADT) to receive ADT alone (393) vs ADT plus chemothrapy with docetaxel (397) starting up front at the time the ADT was started.  In patients with high volume disease, defined as those men with visceral metastases or >3 skeletal mets including one beyond the pelvis and spine, there was an improvement of 17 months in overall survival from 33 months to 49 months with a p value of <.0006 for significance between the two arms of the trial. The men with lower volume of metastases are also doing better, but the curves for the two treatment arms have not met significance. There was reasonable balance in age, race, psa values, etcetera between the arms. A key point is that 3/4 of the men initially treated with ADT alone went on to receive docetaxel at the time of progressive disease, meaning that this trial can reasonably be considered to reflect a “pay me now or pay me later” with docetaxel toxicity, and the men who were on the “pay me now” arm had the most benefit from the toxicity of the chemotherapy. There was good balance between the arms in terms of the number of men who received others of the newer treatments (abiraterone, enzalutamide, sipuleucel-T).

For prostate cancer, this is akin to the studies of using chemotherapy “up front” in the adjuvant setting that really got medical oncology going in the early 1970’s in women with breast cancer. It opens the door to the study of using aggressive multimodality treatment including the newer hormonal agents, and possibly vaccines, in men with high risk disease at the very outset of their therapy, which should be the next studies. The problems with designing such studies is the very long period of time it takes to get answers. CHAARTED was opened in 2006 and only now, 8 years later, do we have a result. The time could be dramatically shortened if more men would be placed on clinical trials. 1000’s of men were treated with same old same old treatment during the time we worked on CHAARTED. If 50% of them would have been put on this trial in the first two years, we could have had this result about 4 years earlier. Since that takes a major change in how medicine is practiced in the US, don’t hold your breath.

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Measles Virus – ’tis the season for sensational news


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As a practicing physician, it is always interesting to capture the pulse of what cancer patients, at least my cancer patients (95% of whom are dealing with prostate cancer), are finding in what Rush Limbaugh would call the “drive by media”. I would love to go on and make political comments about Rush, but will stay away from that one! For the past two weeks, the questions have all been about the story that a patient was cured by the measles virus. This is a story published online from investigators at the Mayo Clinic. In casting about for the background to the story, I could not possibly improve on this article which puts the findings in context: Could measles cure cancer? Uh, not exactly… If you want to know the details about that particular newsworthy story, click and read it for yourself. (Parenthetically, Cancer Research UK’s website seems remarkably well designed and useful for promoting cancer clinical trials that move the ball forward for prostate and other cancers.)

This post is meant to help you do a little background research for yourself. The news media loves to write articles that attract attention to hopeful cancer research breakthroughs. Next weekend, the ASCO annual meeting will give them a remarkable amount of grist for writing articles. If you search for prostate, you will find that there are forty pages of abstracts to read through, describing the ongoing research. The presentation I am most looking forward to is Chris Sweeney’s presentation on the results from a large phase III clinical trial that evaluated the use of docetaxel “up front” in patients starting ADT. This will be a plenary session presentation, but we already know that the trial was stopped early because patients who received the chemotherapy in addition to hormonal treatment alone seem to live longer. The question/answer session for this should be interesting. Is the toxicity worth it? Was there balance in the number of patients who received any of the newer second line hormonal treatments? How many patients received a vaccine?

In general, when you see news articles and want to dig just a bit deeper, my favorite method is to go to Google Scholar. In the case of the measles virus stories, use “Scholar” to hunt for this search term: “measles virus cancer”. It will take you to this page, where sure enough, people ARE working on using measles virus to treat prostate cancer.  Otherwise, try to find the meeting where the “new breakthrough” the news writer is discussing was published, and look at the abstract for yourself. People like to write and read about promising cancer research. But, as we all know, it is a very long way from mouse to man, and the clinical trials take a long time to complete, especially in a slowly moving disease like prostate cancer. Remember that large phase III clinical trials are the ones that change practice and become widely available, whereas phase I and phase II trials are often available only at some locations and the drugs discussed may never make it to the clinic. Not the kind of thing you want to hear if your own disease has become more aggressive, but it is great that so much prostate cancer research is going on to help the next generations. It is a vastly different landscape than 30 years ago when it seemed that all of the exciting progress was in lymphoma and breast cancer. And as I predicted almost 20 years ago, patients and their families now have as much information as the doctors caring for them.

 

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Oh, no! My PSA is going up….do something….


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One of the most frustrating and frightening things that can happen to a prostate cancer patient is for there to be a recurrence of the PSA after he thought he had been cured by surgery, radiation therapy, or both. This is entirely understandable. It is no picnic to go through those treatments in the first place, and when the PSA is clearly going up, it can only mean (with very rare exception) that there are still cancer cells lurking somewhere in the body. The rate of the PSA rise can predict how long it will be until something shows up on a scan, and on average, this is about EIGHT years. The median time to death from prostate cancer after a PSA recurrence is 16 years.

For >95% of patients there is something that CAN be done to stem the rise in PSA. That is to go on hormonal therapy (androgen deprivation, ADT) which will drop the PSA, often all the way to undetectable levels, in over 95% of patients. Voila! Both patient and physician feel much better emotionally. But for the patient, there is a significant price to pay. Namely the hot flashes, loss of energy, weight gain, bone calcium loss, lack of libido and further decrease in sexual function to name a few. The question is whether this is “worth it”.

A study to be presented in the next few weeks at ASCO’s annual meeting, suggests it won’t make much difference if you start ADT early versus waiting until metastases, or perhaps even symptoms occur. Utilizing the CaPSURE database, the investigators evaluated over 2000 men who had PSA relapse. The estimated 5 year overall survival (87% vs 85%) and 10 year overall survival (72% vs 72%) were the same regardless of whether the men received immediate or delayed ADT. The same was true for death from prostate cancer…no significant difference. There are of course other considerations that may come into play like treating those patients who have highly aggressive disease earlier because one knows that there will be metastases within a year, or the patient simply can’t live with himself knowing his PSA is going up.

In my experience, it is the exceptional patient who is willing to go play golf or travel or enjoy his grandchildren and forgo PSA testing on a regular basis. I have trouble even convincing my patients to extend their PSA testing to 6 months from 3 months. The question is, does it make any sense to watch this “number”, any more than it would to have cardiac catheterization every 3 months to follow the slow but inexorable accumulation of calcium in your coronary artery? Or what about the 0.01 mm increase in your abdominal aortic aneurysm? Or the accumulation of two more tangles in the Alzheimer plaque in your brain. Just because we CAN measure PSA so easily certainly doesn’t mean we SHOULD, and I have seen far too many men let this number ruin their otherwise healthy lives.

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Vitamin D – Two new studies


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Here is a sad confession: I often think about topics on which I blog when a news article appears or, even more often, when one of the many medical websites that fill my email box each day with targeted posts (and ads) sends something new. For a really hilarious read on the email scene, if you are a subscriber to the New Yorker, click here for an outstanding Shouts and Murmers article regarding “walk-in bathtubs” by Calvin Trillin. But I digress…

With thanks to the good folks at Medscape, two articles worth knowing about suggest that in spite of my general anti-supplement stance, you really SHOULD consider vitamin D supplementation, or at the least know your levels and think about it. Vitamin D (cholecalciferol, D3) is actually a member of the steroid superfamily. (called secosteroids) Thus, there can be interactions between various forms of Vitamin D and other steroid receptors in all likelihood if certain mutations occur. This could be good or bad, but provides a plausible explanation for why Vitamin D (and other non-androgen types of molecules) might play a role in prostate cancer.

In one article, Chinese investigators did a review of 25 studies that evaluated the Vitamin D levels in over 17,000 patients with various cancers and found that those patients with the highest levels lived significantly longer than those with the lowest levels.  A similar study appeared in the British Medical Journal last month, evaluating >800,000 patients from 73 studies and reached a similar conclusion: “Evidence from observational studies indicates inverse associations of circulating 25-hydroxyvitamin D with risks of death due to cardiovascular disease, cancer, and other causes. Supplementation with vitamin D3 significantly reduces overall mortality among older adults; however, before any widespread supplementation, further investigations will be required to establish the optimal dose and duration and whether vitamin D3 and D2 have different effects on mortality risk.”

In the other article highlighted by Medscape, baseline 25-OH Vitamin D levels were evaluated in men undergoing prostate biopsies. Among both African American and European American men, severe deficiency (<12 ng/ml) was associated with higher Gleason scores and more advanced stage disease. In the AA population, <20 ng/ml had a significant association with a positive biopsy.

The problem, of course, is that when experts review these and similar articles, they really cannot come to a strong consensus on what to do for the general population, let alone for the cancer population. In this review, the authors point out all of the pitfalls in taking publications like the two Medscape articles as “gospel”. Quoting their abstract, “vitamin D use and cancer may not have correctly addressed the question, and that new randomized trials should be organized. The reasons are due to several unsolved issues including selection of the effective dose, varying baseline levels of subjects before randomization, compliance with the intervention, contamination of the placebo group (i.e., intake of vitamin D supplements by subjects allocated to the placebo group) and unknown effective lag time between start of the intervention and disease onset.”

“So what would you do, doctor?” Ah, the piercing question… What I did was measure my 25-OH Vitamin D level and found that it was very low. I’m now taking 2-4000 U/day of D3, and I plan to remeasure my level in a couple of months. So there! (BUT – I’m still slathering on the sunscreen that probably got me deficient in the first place)

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