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Blood tests and stopping medications


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I have been struck by how many patients ask me to measure their lipid panels as we work our way through the management for their prostate cancer. To be sure, it is important to know about cholesterol, triglycerides, and cardiac risks for both men and women. If you have never had a fasting lipid panel, you should get one. If you are not on a statin, you might consider that and read about the benefits for prostate cancer patients in one of my previous posts here or here. Knowing about cardiac risks for the general population is a terrific public health idea, and you can check out your own risks here. (If you are otherwise healthy, with good blood pressure and a non-smoker, it is sobering to play with that calculator and watch what happens to your risk with increasing age…the one thing you can’t do much about!)

But why continue to worry about heart disease once you have prostate cancer, especially if you have metastases and become resistant to hormonal manipulation? Do you need to continue to take your statin? There is a reasonable literature looking at the downside of polypharmacy in patients as they age, and the potential cost savings, and even improvement in quality of life by stopping some medications. Read this brief article for a good discussion on the topic.

Expanding this thinking to what blood tests we should worry about and how often to do them is an important exercise. In particular, I think we are all addicted (often too addicted) to the PSA test as I discussed in the PSA clock blog. There were many  comments pointing out the necessity of following PSA to know the efficacy of changing treatments, and I agree with that. On the other hand, obsessing about PSA can definitely be a negative for your mental health and enjoyment of life. Don’t fall for the idea of daily measurements if someone comes out with a finger stick blood test for PSA!

Testosterone measurements, on the other hand, may be too infrequently measured in caring for prostate cancer patients, and compared to the costs of the newer ADT agents, or even the GnRH injections, they can be highly cost effective. A quick search suggests that measuring your T could be as little as $50 or probably 2-3x that in a hospital. If you have metastatic prostate cancer it is key to have the T level as low as possible. Some cancer cells become hypersensitive to even low levels of circulating T by over expressing the androgen receptor, and of course this led to the research on further blocking testosterone synthesis  by drugs like abiraterone or the receptor by the “lutamides” (bicalutamide, enzalutamide, apalutamide, duralutamide). These drugs can cost in the range of $10K/month, so measuring T levels has minimal impact on the overall cost of care. However, in two abstracts presented at the recent ASCO meeting, the possibility of stopping GnRH injections in patients on abiraterone was studied. It makes sense that if abi completely blocks T synthesis in the testis, adrenal gland, and cancer cells, you might not need the injections. There is a good review of one of the abstracts here. I had always wondered about this, and it was nice to see it studied. The cost savings if this became a standard could be in the millions. (caution however – would need to be studied more carefully, and if someone missed abi doses, very rapid T increases would be seen due to high LH levels no longer suppressed by GnRH analog injections).

I realize this is far into the weeds for most patients, but maybe a take home message could be to discuss measuring your T levels once in a while with your physician, rather than just the PSA. And maybe you could go over what meds you might consider stopping at this point in your care. We doctors are too often pill pushers and as I try to say to every patient at every visit, [Please CLICK ON THIS ONE:] there is nothing more effective in general than increasing your exercise – often as effective as ANY additional pill or blood test!

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Prostate Cancer and “the art of aging”


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As all of us septuagenarians (and probably octogenarians) know, and as Gilda Radner entitled her book, “It’s always something.” In it, she goes on to say, “I wanted a perfect ending. Now I’ve learned, the hard way, that some poems don’t rhyme, and some stories don’t have a clear beginning, middle, and end. Life is about not knowing, having to change, taking the moment and making the best of it, without knowing what’s going to happen next. Delicious Ambiguity.”

For most prostate cancer patients, the challenges presented by that diagnosis occur at a time of life when one is forced to admit that the sprained ankle doesn’t heal as fast, gray hairs are appearing, and/or your hairline is receding (or the bald patch growing), and there may indeed be as much life stretching out behind you in the rear view mirror as lies ahead. While one can choose to fight the cancer with every possible modern intervention, it is also true that there will be other challenges awaiting just around the corner, and it is impossible to handicap the inevitable threats to your health, of which prostate cancer is but one.

Recognizing this, and realizing that we spent two decades over-treating many patients, gave rise to the current option of “active surveillance” for men with low grade disease (Gleason 3+3, some 3+4). One of the most mature studies of this approach was published in the NEJM just last month. Peter Albertson, writing in F1000, nicely summarized the key findings from the article:

“First, the most powerful predictor of long-term outcome remains the Gleason score. Following surgery, men with Gleason 4+3 disease have an almost six times greater risk of dying from prostate cancer and men with Gleason 8 or 9 disease have an almost eleven times risk of dying from prostate cancer compared with men with lower grade Gleason 3+3 or 3+4 disease. Second, radical prostatectomy can provide improved outcomes, lowering the absolute risk of dying from prostate cancer by 11.7% and extending life by almost 3 years. Third, younger men less than 65 years of age at diagnosis are much more likely to benefit from surgery when compared to older men. Fourth, men with low grade cancer (Gleason 3+3 or 3+4) appear to have comparable outcomes and rarely died following surgery. The article was silent concerning the relative clinical outcomes of surgery and watchful waiting in this group of men. An important caveat to remember is that most men participating in this trial were diagnosed based upon clinical findings, not from testing for prostate-specific antigen. As suggested by data from the PROTECT trial, screen detected prostate cancer appears to introduce a lead time that could be as great as 10 years. This confounds estimates of the efficacy of surgical treatment especially among older men.”

I just submitted my own take on the active surveillance vs prostatectomy trial as follows:

“There is little to add to Dr. Albertsen’s excellent review although there are a few issues I would add as important perspectives in these kinds of long term followups. First, as a disease of aging, prostate cancer has many competitors in terms of cause of death. 261/347 (71.9%) men in the radical prostatectomy group and 292/348 (83.8%) men in the watchful waiting group have died from any cause. Of the 261 men in the prostatectomy group, 71(27.2%) died from prostate cancer while in the watchful waiting group, there were 110 deaths from prostate cancer (37.7%). From this perspective, prostate cancer is important, but far from the “most” important cause of death with ~2/3 of men dying from other causes regardless of what we do. Second, one needs to consider the quality of life (QOL), and this paper clearly indicates that many men develop metastases, requiring ADT with its side effects and this is reduced by prostatectomy, while the side effects of prostatectomy itself also take a very high toll on sexual function and a lesser, but significant risk of incontinence. If our goal is to “first do no harm”, the challenges of caring for men as they age remain with us, even as our technology for discovering earlier disease (in prostate cancer) and treating late disease (from any cause) advances.”

But there is something we can do to combat both prostate cancer and aging! Vigorous exercise. In a study performed at two hospitals in Canada and the UK, total and vigorous physical activity resulted in fewer men having worsening prostate cancer while on active surveillance. Further, retrospective studies demonstrate similar advantages even for men with metastatic disease. And if you don’t have prostate cancer, feel free to look at the 100’s of articles showing improved quality and length of life you can achieve with exercise (compared to minimal/no benefit from supplements). I’m also a fan of Fred Bartlit’s book, “Choosing the Strong Path” and his crusade to age gracefully by pumping iron. So the message is clear, even though “it’s always something” as we age or fight our cancers, we have it in our power to do something. Enjoy your time on the treadmill folks!!

 

 

 

 

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Buddy, can you spare a …


Sorry for the intrusion, and I promise to write another blog after December 1 (my commitment for one/month). I’m thinking about discussing the HOX gene system which is fascinating – stay tuned. But for today, I’m shamelessly begging for 9 folks to contribute $25 to help me reach my Movember goal. If you can “spare the change”, please head on over to my website <https://mobro.co/michaelglode?mc=1&gt; and join in.

Many thanks to all of you who contributed this year and even encouraged your friends and family. Know that it makes a difference and we are on our way to beating prostate cancer!

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Lest we forget…


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Screen Shot 2018-11-12 at 11.28.18 AMOn this Veteran’s Day, we would be remiss not to thank the thousands of men and women who serve and remember those who have died in the cause of freedom. My parents used to take me to our local cemetery where the American Legion guys would solemnly fire a 21 gun salute at exactly 11AM and we would lay some flowers on the graves. Those were simpler times, before Viet Nam and all that has followed, but we still need them and I honor their service.

That said, I have wondered over the years how many thousands of men (and women) might have died from cancer caused by smoking that started when they joined the military. In searching for some information on this, I came across this article, actually from a “pro-smoking” magazine, that is a reasonably balanced history of tobacco in the military and admits to the relationship.

Focusing on prostate cancer, there is NO doubt that smoking increases your risk for developing the disease, and if you have prostate cancer, you definitely reduce your length of survival by smoking. I doubt there are many smokers who read this blog, but if you know someone who is fighting prostate cancer be sure to make them aware of this. It is probably one thing they could do (besides EXERCISE, EXERCISE, EXERCISE…) that could increase their survival… more than any supplement which we all continue to put false hopes in. In one (of many) articles evaluating the risk of biochemical relapse (rising PSA) after radical prostatectomy (N=6538) former (N=2086) and current smokers  (N=2214) were 1.5 times more likely to have relapse than never smokers (N=2238). If the men had quit > 10 years, their risk returned to the same as the never smokers.

So, if you know a vet (or non-vet) who is still smoking, thank them for their service, but give them a hug to encourage their smoking cessation.

 

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Rorshach and biomarkers


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Psychology, or for that matter being able to read others’ personalities, has never been a strong suit for me. Neither was art – I still am at the stick figure stage when drawing. It turns out that Hermann Rorshach was probably good at both. The question of what you see when looking at an ink blot seems relevant to the current status of biomarkers in prostate (and others) cancer. On the one hand, some biomarkers are fabulous – for example the Philadelphia chromosome, described in 1959, was the first unique cancer marker that ultimately resulted in a specific targeted treatment, imatinib (Gleevec), dramatically improving survival for patients with chronic myelogenous leukemia. PSA, on the other hand (our “favorite”) is not so great, and as I previously noted, may give rise to the “PSA Clock” effect in which patients ruin their lives by clock watching. But, as we know, it is remarkably useful as a weather vane. When a prostate cancer patient is being followed on any sort of therapy, going down is good and going up is bad.

Thus, there have been thousands of articles attempting to either make PSA interpretation  better, or to replace it with more sensitive or more accurate predictors of prostate cancer behavior. I reviewed some of these, and the challenges here. Today, yet another article on a rather “simple” biomarker, PTEN loss, showed up among the >20 prostate related emails I receive each day. Writing in European Urology, a group of well-known prostate cancer investigators looked at immunohistochemistry (using special stains to highlight a protein in cells under a microscope slide) to evaluate loss of PTEN, a tumor suppressor gene, in prostatectomy specimens. This simple test (in this particular experiment) was as good as the commercial Prolaris test that evaluates a panel of genes related to how fast cells are dividing in predicting biochemical recurrence (PSA relapse) or prostate cancer specific mortality. With PTEN loss, the chances of having a biochemical relapse (rising PSA) or developing metastases or dying in a 10 year followup period were significantly greater than if you did not have PTEN loss. A simple, inexpensive test might replace a more complicated one.

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Here’s where Dr. Rorshach’s psychological construct comes into play at so many levels. If you are the scientist looking through the microscope, do you score a loss when there is only faint staining? Are you sure you are looking at a cancer cell and not a normal cell or  a stromal cell, or maybe even an immune cell? If you decide on giving a score to each cell, say “1+, 2+, or 3+” staining, how do you add all those up?  How many cells should you examine? All parts of the tumor, or only the most aggressive (Gleason pattern ≥ 4) And if you can figure all that out, can you teach your colleagues to look at the same specimen(s) and come up with the same answer? These are the challenges we face when we move a lab experiment into the clinic (and they are well recognized by the authors).

But…there is more! Look at the graphs. Obviously you would rather be on the upper curve with PTEN present, but how bad is it really? At 10 years, only ~10% of the men had developed metastases or died in this study. Recognize that these men were a cross section of patients, median age 59, median PSA 5.9, 64% Gleason 3+3 and another 23% Gleason 3+4 with pretty low a priori risk (did we need the PTEN test to tell us?). So the real issue is whether you would want anything different done to you if you were one of the few patients with Gleason 3+3 and PTEN loss, just because you have this new information? And what would that be?? Radiation? Hormone therapy? How much and how long? -all in the psychology of looking at those curves. Some men might want nothing more done, while others would want “the kitchen sink” thrown at them, even if they had relatively little (and unproven) to gain.

So, medicine remains as much an art as it is a science (with no offense to my mathematical statistical colleagues). As the father of American Internal Medicine, William Osler, told his students, “Common sense in matters medical is rare, and is usually in inverse ratio to the degree of education.”

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Here be Dragons


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There are times in everyone’s life when it is worth pausing to consider larger issues than the conditions you find yourself facing every day. Big issues like the meaning of life, how we got here, what happens after we leave…, have been the topics of philosophers and kings with far more eloquence than I have. Nevertheless, I am compelled to pay homage to one of the most influential philosopher-teachers in my own life today, because failing to do so would be an injustice to my feelings about him, and this blog is my sole “public forum”.

Donald Seldin was the Chief of Medicine at UT Southwestern Medical School, better known to most people as “Parkland Hospital”, the place they took Kennedy. I went there as an intern in 1972 and was privileged to be under his spell for the two years of my training that represent, for most physicians, the most intense interval in all of their preparation to become “a doctor”. Unless you have lived through your first night on call, wondering whether and how your medical school has prepared you to actually make decisions about another human being who has, by choice or by chance, placed their life in your hands, it is hard to put those feelings into words. “Here be Dragons” is a myth about maps relating to what early cartographers would put on maps when they reached the edge of the known world. I always found that phrase evocative when it comes to facing the unknown. For thousands of physicians who trained under Dr. Seldin, he became the pilot who helped you edge out onto that unknown sea called MEDICINE and gave you the confidence to succeed.

Dr. Seldin died at the age of 97 last week. His life and contributions have been extolled by many of his admirers. The shortest version I can find is this obituary from the New York Times. For a more extensive version, and to meet the man himself, you can watch this video. When I was in mid-career in the 1980’s, we took a sabbatical in Helsinki, Finland. It gave me time to think about the larger issues and to write to some of my mentors, thanking them for taking me on as a student and sharing their wisdom with me. Dr. Seldin was one of the men to whom I corresponded. As I recall, in the letter I referred to the pop song, “To Sir with Love” because at an emotional level, the phrase “How do you thank someone who has taken you from crayons to perfume?”  best captured how I felt about his tutelage. He wrote back to the effect that he “had no idea that he cast such a long shadow”, which was surely not true, but his modesty was just another facet of his remarkable personality.

So, if you are in any sort of a contemplative mood at some point this year, take a bit of time to write to one of your mentors or a family member. Thank them for what they mean to you. When they are gone (or when you are gone), that letter will be worth your time as an emotional bond as you sail on into the unknown. Godspeed Dr. Seldin!

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Delaying metastatic disease – ASCO GU18


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Previously, we have discussed the conundrum of the rising PSA and when to start therapy. I also opined that for some men with a very slowly rising PSA, it might be best to just forget about it and enjoy life, comparing it to watching a clock, an opinion that understandably garnered negative comments from some. Of course the nuances surrounding PSA kinetics and their meaning are myriad. However, one graphic that helps understand this better is shown here.

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Smith, JCO 2013

This figure illustrates the fact that individuals with relatively long doubling times (>8-10 months) have a much lower risk of developing metastases or dying from prostate cancer than those with shorter doubling times. In a classic study published almost 2 decades ago, Pound et. al. followed a large number of patients who had rising PSAs following prostatectomy at Johns Hopkins. On average, men with rising PSA’s  who received no additional treatment, did not develop metastases for ~8 years. “In survival analysis, time to biochemical progression (P<.001), [i.e. the time from prostatectomy until PSA rise was detected] Gleason score (P<.001), and PSA doubling time (P<.001) were predictive of the probability and time to the development of metastatic disease.”

With these findings as a background, two studies were presented at the ASCO GU18 meeting, both involving use of improved analogues of bicalutamide (Casodex): enzalutamide (Xtandi) or apalutamide (Erleada). These drugs block the androgen receptor, thus preventing stimulation of prostate cancer growth, but are more potent than bicalutamide. Patients with rising PSA’s in spite of having low levels of testosterone from surgical (orchiectomy) or medical (GnRH agonists/antatgonists) castration, short doubling times (<10 months), but no metastases were treated either with apalutamide/placebo (SPARTAN trial) or enzalutamide/placebo (PROSPER trial). The trials were both remarkably positive in delaying the time to development of metastatic disease.

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SPARTAN TRIAL (Apalutamide)

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PROSPER TRIAL (Enzalutamide)

These are remarkable findings and great news for patients with the most aggressive forms of prostate cancer. However, there are (as usual) numerous questions raised by the trials, as was nicely discussed by Dr. Kantoff after the data were presented. These included a more careful analysis of the side effects and clinical benefits. Obviously patients are psychologically better off when they don’t have a rising PSA or metastases, but neither study reached statistical significance when it came to improved survival (both are trending in this direction). What are the side effects of being on such drugs for longer periods of time? In the enzalutamide study, there were more deaths from “other causes” – not pca within 3 months of progression. Why? In the apalutamide study there were more falls and fractures compared to placebo. Why? To these, I would add the issue of “pay me now or pay me later” – how much time/quality of life do you really lose by waiting until the first metastasis shows up, never mind the extraordinary costs (to patients, insurers, medicare, etc.) of remaining on these drugs for years. Further, neither study compared the outcome to using bicalutamide, the generic and much cheaper alternative anti-androgen, instead of placebo. And what about using the newer scans? All of the patients have metastatic disease, we just can’t see it until there are enough cells in one spot to turn a scan (e.g. fluciclovine or PSMA PET) positive. We can possibly gain advantages in staying off ADT of any sort in some patients by radiating oligometastatic disease. Nevertheless, these studies are great progress and landmarks in the fight against prostate cancer. Apalutamide became the first drug to be approved by the FDA for use in this setting with a “snap approval“. And I need to disclose that I am a paid advisor to J&J, although I have no personal stock in their company, and did not treat patients on either trial.

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