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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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Today’s the day! Grow a Mo


Movember is here! I urge you to join our team and raise money for helping men fight prostate cancer.  We have, once again, organized a University of Colorado Cancer Center Team.  The MOVEMBER Foundation raises money to fund projects related to men’s health – specifically prostate cancer, testicular cancer, and mental health.  Since 2003, this grass roots project has gathered 5 million participants across 21 countries raising more than $710 million and funding over 1,200 projects.  We, The University of Colorado Cancer Center,  are actively involved in the Prostate Cancer projects which include translational research, clinical registries, and the Global True NTH program.  True NTH is aimed at catalyzing innovative health outcomes programs, through supportive care services, in an effort to improve the lived experience of men with prostate cancer, as well as their partners and caregivers.  

 Your action required is quite simple.

 1)      click HERE to register with the CU Cancer Center Team

2)    get your friends and family to join the conversation and support your efforts

3)    grow (or inspire others to grow) an incredible mustache for 30 days, starting TODAY

I cannot emphasize strongly enough the difference Movember has made in the fight against prostate cancer. Through multiple initiatives they are doing for this disease what Susan G Koman for the Cure has done for breast cancer research. I always used to say, “In breast cancer, they RACE for the cure, while in prostate cancer we CRAWL for the cure.” No longer! This an initiative by men and for men, although just as we have seen the NFL football players sporting pink shoelaces, there are a lot of women who support Movember as “Mo Sisters” as well. 

If you don’t want to join the team and “grow your own”, you can sponsor my feeble attempt at a moustache by clicking HERE.  Many thanks for your consideration. 

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Abiraterone (Zytiga™) earlier makes a big difference in outcomes


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The big news at the ASCO annual meeting this year included two “practice changing” presentations for prostate cancer that have been widely covered in the medical press. The basic finding is that adding abiraterone to ADT in the “up front” setting (i.e. when initially starting ADT for high risk disease, a rising psa or in someone who has newly diagnosed metastatic disease) results in markedly improved overall survival and time to progression of disease. I encourage you to read the link above which reviews the presentations and commentaries in detail. Reflecting our amazing digital age, the New England Journal published the detailed, peer-reviewed articles on the two studies simultaneously with the ASCO presentations.

In the Latitude trial, 1199 men who were newly diagnosed with metastatic disease and who “… were considered to have at least two high-risk prognostic features (e.g., a Gleason score of ≥8, the presence of ≥3 bone lesions, or the presence of measurable visceral metastasis)” were randomized to receive a GnRH analog plus abi/prednisone vs GnRH analog plus dual placebos. The science behind this is that with surgical (orchiectomy) or medical (GnRH analog) castration, testosterone synthesized by the testicles is mostly eliminated. But there is still stimulation of the prostate cancer androgen receptors (AR) by other testosterone, coming from the adrenal glands, the tumor cells making testosterone themselves,  other steroids, or even changes in the androgen receptor itself. Abiraterone or its metabolites can block most of these pathways. Thus the question is whether nearly complete shutdown of AR stimulation from the onset of treatment can achieve more than waiting to use Abi after resistance to AR directed treatment with a GnRH analog develops. The results were remarkable:

A second trial, from the STAMPEDE group used a similar approach in a different, more heterogeneous group of 1917 patients with high risk localized disease, metastatic disease, or PSA relapsing disease after local therapy. The randomization to standard ADT alone vs ADT plus Abi/prednisone was similar as were the remarkably positive outcomes.

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The P-values for some of the endpoints in this trial were eye-popping. “Time to failure improved by 71% in the abiraterone group (HR 0.29, 95% CI [0.25, 0.34]; p = 0.377×10-61)” The discussants at ASCO pointed out that future trials may need to consider comparison of abiraterone early addition to the early addition of chemotherapy as was done in the CHAARTED trial. Generally, however, the toxicities of docetaxel are certainly greater than abiraterone and such a trial would be complicated. It is even possible that one of the ways docetaxel works is “simply” blockade of AR translocation and that it is just a more toxic way of hitting the same pathway. In addition, the cost considerations of abiraterone, particularly when it must be taken for years, are a real concern, and in keeping with the very keen worries we have regarding new cancer drugs in general.

“Targeted therapies” along with the immune checkpoint blockade drugs are changing the landscape for cancer patients. To me, the somewhat surprising thing about these two studies is how great the advantage seems to be when you can truly effectively hit a target early and hard, in this case the AR signaling pathway. It is all the more remarkable that this is a pathway we have now been targeting for over 70 years and there is still more to come. If we can find the right combination of AR targeting and immune modulation, I see no reason why metastatic prostate cancer can’t be added to the “curable neoplasm” list in the near future. Then the question of whether, and how we need to screen will become even more complex. Good news !!

Disclaimer: I am a consultant for Janssen, the pharmaceutical company that sponsored the Latitude trial discussed above.

 

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