Tag Archives: active surveillance

No pain, no gain?


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One of my patients last week had a heartfelt discussion regarding the survival benefit of ADT vs his quality of life. He enjoys body building and showed me some pretty dramatic pictures of himself during his last ADT cycle (on intermittent therapy) versus now, when he had been off treatment for ~6-9 months. Added to his concern was his decline in libido and sexual function during ADT, a common complaint especially among younger patients. The question of quality vs quantity of life was,of course, utmost on his mind.

Starting from the initial diagnosis, every (maybe that should be every !!) prostate cancer patient will experience a decrement in quality of life. Those who elect “watchful waiting” will nevertheless experience anxiety regarding the shadow of CANCER following their footsteps. Sure, you can put it out of your mind, but turn around and there it is, like the neighbor’s unwanted cat stalking you. Then there is the anxiety over what the next PSA will be. And if on active surveillance, what will that next biopsy show?? These issues are both real, disturbing, and often under-appreciated in the discussions surrounding screening…”we should still be screening, but not treat the men who don’t need it…” Really? What about the 80% of men who die at age 90 with prostate cancer at autopsy who never had to deal with the shadow? (The inevitable counter-argument is, “yes, and what about those who had early detection of a high grade cancer whose life was saved?”)

We also tend to ignore the impact of competing mortality in our discussions. “Sure you had a stent placed last year, and you already survived that small colon cancer, so why wouldn’t we be aggressive in treating this new problem?” Dr. Sartor provided an elegant discussion of this in an editorial on the PIVOT trial you can read here. Whatever the flaws in that study, it remains clear that we are not very good at predicting the non-prostate cancer “future” for our patients, and the older you are, the thinner the ice gets regardless of how many marathons you run.

When patients choose one form of primary treatment vs another, they are weighing the different side effect profiles of surgery or radiation as much as which is “most effective”. I often give patients a copy of this article from NEJM and encourage them to spend some time looking at the graphics in Figure 1 to get some idea of what they will face in the way of side effects from treatment. As any honest physician would tell them, treatment will involve side effects, some permanent, in the best of circumstances.

In the setting of more advanced disease, for example a patient who presents with metastases outside the pelvis, the recent CHAARTED and STAMPEDE trials both suggest an advantage to the earlier use of docetaxel chemotherapy in combination with ADT as opposed to ADT alone. These data suggest that “pay me now or pay me later” analysis favors the “pay me now” approach in terms of overall survival. But at what price for quality of life? Fortunately most chemotherapy side effects are reversible, but distinctly unpleasant, potentially making the equation something like “4 months of misery to provide 14 months of longer life….not all of which will be great anyway”.

Even in the very advanced setting, there is some evidence that greater toxicity results in improved survival. A recent analysis of the TROPIC trial of cabazitaxel suggested that the patients who had the most “toxic response” in terms of dropping their neutrophil count benefited the most in terms of overall survival.

While all of this seems incredibly negative (for which I apologize), the history of oncology as a field has been the incremental improvement in survival AND the development of newer treatments that provide such advances with diminishing toxicity. Pediatric leukemia, as discussed extensively in “The Emperor of All Maladies” is a great example of how pioneering patients and physicians worked together to find cures and reduce side effects. We may only be at the beginning of such achievement in prostate cancer, but with the advent of the newer hormonal and imaging agents, increasingly sophisticated surgery and radiation, vaccines and immunotherapy, and even the chemotherapies now available, we have  no doubt reached the end of the beginning. Onward!

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Filed under General Prostate Cancer Issues, Prostate cancer therapy

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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Lengthen your telomeres this week


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For journal club last week, I selected an article that looks at length of telomeres as a prognostic variable for prostate cancer. Telomeres are DNA protein complexes that are added to the tips of chromosomes by an enzyme, telomerase, that carries its own little RNA unit and was involved in one of the authors (Elizabeth Blackburn) of the story below winning a Nobel prize. As you get older, the length of your telomeres shortens, eventually giving rise to loss of important chromosomal information that can lead to cancer. In the journal club article, it was found that men who had shorter and more variable telomere length in their prostate cancer or the surrounding tissue, had a higher chance of developing metastases or dying from their disease. Of course this is bad news, and you might think there is nothing you can do about it. Not so fast….

Blackburn and her colleagues at UCSF have been studying men with prostate cancer to see if exercise and diet can influence telomere length. In a 2008 study, they found that peripheral blood cells had increased telomerase after 3 months of improved diet and exercise intervention. In their most recent study, they find that the continuation of the diet/exercise program results in actual increases in the telomere length in the peripheral blood cells. Since these are men with low risk prostate cancer who are being followed on a study with active surveillance, we will also be learning how such improved life style affects other genetic changes in serial biopsies of the cancers.

For now, the bet is that (as usual) you will benefit from increasing your exercise program, dropping red meat from your diet, and probably watching less football and doing more hiking this week with your family as you celebrate Thanksgiving. I’m just saying….

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Shift work and PSA values


I just came across this article because the editors at Medscape send around interesting articles on prostate cancer when you sign up for them. It seems likely to me that this is not a red herring, but the accompanying editorial goes into the issues of more holistic prostate cancer screening – with the intent to try and figure out who might really benefit rather than just screening all men over age 50. If you could reduce the denominator in some way by eliminating men who have the “usual, non-threatening” “cancer” (with a nod to all the articles suggesting we should change the nomenclature for Gleason 3+3 disease), screening might make more sense and be of greater benefit. Until then, it’s still caveat emptor.

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Research and Movember


Since I actually grew a scraggly mustache and some of you contributed, I am dedicating this post to Movemeber. They just released a video you can watch here. I think the positive message is terrific, although I personally do not believe we will “put prostate cancer out of business” as Jonathan says. My reality is that cancer is a disease of aging and will always be with us. Prostate cancer is no exception. If we age, we accumulate DNA damage, although some studies suggest it is more the cellular response to DNA damage than the DNA damage itself that does us in. Our telomeres shorten, and our ability to whack the bad cells in us slowly gets weaker. 100 years ago, very few men lived long enough to get prostate cancer. Now, most men in developed countries will probably live long enough to do so as you can see from this table.

So, our goal is to leave the unimportant prostate cancers alone, and keep men who have the more aggressive ones alive and in good health for as long as possible. We have lots of new and developing tools to help us with this, and for the most part, I think prostate cancer is already a “chronic illness”, even though some of us, sure enough, will die from it. Fortunately, even now, that is only about 3/100 men. So keep exercising, don’t smoke, eat the right things, and die of something else if at all possible, and as late as your genes will let you.

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Active Surveillance – NIH draft statement


Not to put too many blogs up this week, but  a very well balanced article was just published and includes input from my friend Lori Klotz, whose articles have been at the forefront of doing active surveillance. He tried to get an international trial going that would provide some definitive evidence that this is a reasonable alternative. In the trial, men with low-volume Gleason 6 disease were asked if they would sign up to be randomized between immediate therapy versus going on an active surveillance program. We had the protocol open for about two years and could only find 1 or 2 men willing to participate. When you read THIS ARTICLE, you will see that the study was really important, since a significant portion of men go on to get treatment anyway, and that some studies suggest lower survival with this approach. On the other hand, those being watched do not suffer the side effects of definitive therapy. As with screening, there will be no “final answer”. However I really like this statement as an informational piece that I can give patients who are considering this approach. We also still offer targeted focal therapy at our institution as a possible “in between” treatment option – an interesting approach that is still very early in terms of knowing the long term consequences of this treatment. Mike Landess took this approach and has made a nice video blog of his experience. One of the major unanswered questions in all of this is what the optimal formula for followup should be. For example, PSA’s every 3 months, or should it be more often? Should you initiate treatment based on some absolute number, or a change in the doubling time? Should you biopsy every 2 years, or should it be 18 months? What about doing mapping biopsy on everyone who wants to consider active surveillance? So many questions and so little time !

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