A Urologist’s tale

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The response to my recent blog entitled the PSA Clock has been highly gratifying. There seem to be many new subscribers to this blog and I welcome you and your comments. I have just attended a prostate cancer meeting (IPCU 2017) where a lot of great science was presented. I will share some of that in a future blog, and plan to do the same after the ASCO GU conference next month. However, I wanted to make you aware of a remarkable article (please click on that link and read it NOW) by one of the real leaders in prostate cancer research, Paul Schellhammer. Paul and I even shared authorship of an article…it’s a small world! Interestingly, in his article he used the same metaphor I used in that previous blog. He says, “I was entering the universe of the ticking PSA clock. The second PSA failure confirmed that I was in the story for the long haul.”

I don’t think I have ever read a more up-to-date, thoughtful, yet personal and empathetic scientific article about prostate cancer, or maybe even cancer in general. A possible exception is “When Breath Becomes Air” which I previously reviewed and still highly recommend. In Paul’s article, he describes in detail, with the latest advances carefully referenced, his approach to his own prostate cancer. He used the PSA clock to make decisions all along the way (as I do with my patients, and as many of you do). However, he also makes this observation: “War is energy depleting, resource consuming, and long wars all the more so. Prostate cancer is a disease of long natural history. Patients who enter into a daily battle with the disease forfeit the state of living well with their cancer. Mukherjee, in his biography of cancer, the Emperor of all Maladies, discussed his concern with the cancer war metaphor. He suggested that the war on cancer may have to be won by redefining the meaning of victory. For prostate cancer patients this may involve a state of negotiation whereby they learn to live well and hopefully long with their disease.”

Some of the great commentators on my “PSA Clock” blog felt that I may have been advocating not looking at the PSA or not fighting the war. As I responded, that is a highly personal decision and the patient and doctor should discuss things like how often to look at the PSA and what difference it might make to check in monthly versus annually, or not at all, depending on where in the “war” they are, and what the options are. What I hoped could be worthwhile thinking about was turning off the clock either temporarily or permanently in some situations – and that clearly is a psychological decision, not a medical one. As one commentator pointed out, we do the vital signs every time we see a patient because knowing that someone’s heart is beating and their blood pressure is OK is “vital”.

Another friend Dr. Aroop Mangalik has just published a book on dealing with your doctor regarding end-of-life choices. “Dealing with Doctors, Denial, and Death.” Hopefully that is not where you are at present, but if so, Aroop is another of those very thoughtful physicians who has much to offer. You can get a discount on his book here. Use a promotion code: RLFANDF30 at checkout. From Dr. Schellhammer, “For prostate cancer patients this may involve a state of negotiation whereby they learn to live well and hopefully long with their disease. The emphasis is on thrival as well as survival. This mindset has been described by others as when there are clouds on the horizon one learns to dance in the rain, or those patients do best who learn to dance with their disease. Again, as stated earlier, the appreciation of “today” is affirming and healing.”

It’s a lovely sunny day here in Colorado, and time to go skiing! Find your own groove and have a great time this weekend.


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The PSA Clock

In our journey around the sun, we have reached the shortest day of the year, which, although my brother-in-law informs me is not to be feared…”the sun shall return”… is still not a bad time for reflection. This was a year when I said goodbye to one of my oldest patients, a retired physician with whom I had coffee or breakfast every Wednesday for over 20 years. He came to my lab or office, and in the last years, I went to his home. We measured our lives to some extent by those intervals, sharing stories of our families, our medical training, and of course solving the world’s problems. One thing we did not do was obsess about his PSA. Indeed, for the most part we ignored it.

I cannot count the number of times I have thought to myself (and occasionally commented aloud) “If it were not for the PSA, you would no doubt be out there playing golf, skiing, biking, taking a grandchild to the park, or just enjoying life.” Far too many of my patients let their PSA control their lives. Living from one PSA to the next is a bad way to mark the passing of time.

In a lovely essay in this week’s New Yorker, Alan Burdick discusses “how time became psychological.” He quotes Plato: “The instant, this strange nature, is something inserted between motion and rest, and it is in no time at all.” And he proposes that Augustine, writing in the year 397, “plucked time from the realm of physics and placed it squarely in what we now call psychology. ‘In you, my mind, I measure time’…To consider this present is to glimpse the soul, Augustine argued.”

The PSA clock, for many physicians and patients, is dehumanizing. It is a technical artifact of modern medicine, one so sensitive that it provides a second hand when we should be looking at the hour hand, the calendar, or the seasons. Imagine if your cardiologist could measure the thickening of your coronary artery year by year in microns as plaque builds up. Would you want that test? Would it change how you lived if you knew for certain that you will die from a stroke in 8 years?

This is not to say that we can’t use the PSA to guide treatment or make decisions. A younger person with aggressive prostate cancer who must fight with every tool available may well benefit from close observation of the PSA. On the other hand, in Dr. Walsh’s series of men (reported by Pound) who had rising PSA after surgery, it was 8 years on average before anything was revealed on a bone scan or CT scan, and another 5 years before they died. Did these men benefit from the PSA’s? To be sure, treatment options have changed in the 17 years since that series was reported, but we need perspective. Another of my physician patients (a thoracic surgeon) had his prostate removed and never checked his PSA again. About 9 years later, he presented with bone metastases, and is now doing well on androgen ablation. He doesn’t come in for PSA’s. He is in his early 80’s and enjoying his life. I suspect I will see him when he develops new symptoms, and then we can discuss his alternatives. I hope that won’t be for many years, and indeed, that is entirely possible.

So on this winter solstice you might pause to consider all of your blessings and turn off the PSA clock in your mind. 47 years ago today (on the longest night of the year), I got married. Two careers, three kids, four grandchildren later, I don’t look at my PSA. Rather, I try to enjoy my Time in a Bottle. If you are in a contemplative mood as this year ends, click on that link and enjoy the holidays! Good wishes and glad tidings to you and yours in the coming year.



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Happy Thanksgiving/Movember

It is half way through Movember, and my moustache is scratchy. I hope you are growing your own, but if not, feel free to support mine here: http://mobro.co/michaelglode

I apologize for not having posted more commentary in the last few months. I am taking a bit of a hiatus to celebrate retirement, but I have a list of topics queued up for blogging that I can share with you. Here are a few, hypertexted so you can think about them:

Ethics of expensive treatments, Earlier salvage radiation therapy, Randomized trial of monitoring, surgery, or radiation, and the patient side effects of each, and what to do about metformin.

Feel free to suggest your own topics that I can research for you and add my thoughts, or vote for one of the above. I hope you and your family have a very peaceful and Happy Thanksgiving!


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Immune therapy for PCa?

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Earlier in this blog, I attempted to explain the excitement surrounding the use of the checkpoint inhibitors and activated T-cells to fight cancer. Now the New York Times has done an excellent series on this approach which is worth reading, and no doubt more comprehensive and comprehensible than my effort. I encourage you to read it here.

For prostate cancer, there are both challenges and some early positive results that remain intriguing. An excellent review article published in April reviews the completed and ongoing efforts to harness the immune system in prostate cancer specifically. As the authors note, there have been variable results. One of the key challenges is to identify those patients who will benefit from the treatment and to date, using antibodies to stain the cancer cells that are making the PD-1 ligand that turns off the immune system has been challenging, since there are no accepted reproducible tests yet. Nevertheless, as demonstrated in this article, some patients do seem to have remarkable responses that offer real hope if the science continues to advance. If you read that abstract, pay attention to the issue of auto-immune side effects: “One had grade 2 myositis, one had grade 3 hypothyroidism, and one had grade 2 hypothyroidism. None of these patients had a response.” What this means is that the immune system was activated, but instead of attacking the prostate cancer, it attacked their muscle or thyroid, and apparently ignored the evil cancer cells. This has been a general problem in the entire field. Yet, in melanoma, where the greatest progress has been made, we are learning to walk the line between killing tumor cells and damaging the normal tissue with immune therapy.

My bias is that with continued progress in the vaccine field in prostate cancer (where we have one of the only vaccines approved for treating cancer, Sipuleucel-T), combining a vaccine with an immune booster type of treatment will ultimately provide the best results. Various trials of this sort are already underway.

Edited January, 2017: Another article just appeared in the JCO evaluating ipilimumab, the antibody that shuts down CTLA-4 T-cells (these are cells that suppress an immune response) in patients with metastatic, castrate resistant prostate cancer before they received chemotherapy. Although there was some hint of activity with a higher PSA response (23% vs 8% with placebo) and slightly longer time to progression, the overall survival was not changed (28.7 months in 399 patients treated with ipilimumab vs. 29.7 months in 199 patients receiving placebo). I’m still awaiting a larger trial like this with an immune checkpoint treatment combined with a vaccine. One such trial started in August 2016 at UCSF. A similar trial with promising results was published 4 years ago by the NCI group. Progress…but slower than we would like.



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Precision medicine and AR-V7

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Much of the news this week in prostate cancer will be generated by the annual ASCO Meeting in Chicago where VP Joe Biden will be speaking tomorrow about the moon shot. It will be hard to miss the excitement – perhaps even eclipsing (for a day or so) the ongoing circus that is our presidential politics at the moment.

In prostate cancer, there are likely to be considerable news releases regarding precision medicine, and especially AR-V7, so I thought I would explain this a bit. Precision medicine is the broad terminology that (in oncology) refers to looking at the individual patient’s tumor genetic profile. In the broadest sense, it can also refer to all of our genetic makeup that can influence, for example, how we metabolize drugs. The optimal dose for you might be different from that for me based on our inheritance of slightly different enzymes that are involved in breaking down a certain drug. In oncology, it is now possible to perform whole exome sequencing (WES) on circulating tumor cells that give a nearly complete picture of an individual’s cancer – what is driving it, and what it might be susceptible to. In metastatic prostate cancer, as you know from my previous post, the tumor cells circulating in the blood stream could be coming from a variety of places, and likely each individual cell might have slightly different genetics – creating a considerable challenge in the long run for picking out “the” drug that is best for that patient, even with this high-tech approach. Nevertheless, WES has already demonstrated exceptional ability to find targetable mutations in cancer cells, often with several different pathways of potential susceptibility in each patient. Two challenges arise: 1) the drugs that target each “driver pathway” are often frightfully expensive, and 2) which one or ones would be the best to target?

So what about AR-V7? 14 of the 214 prostate cancer abstracts (keep that in mind when you ask your doctor, “Hey doc, is there anything new out there?”) deal with this biomarker. AR-V7 stands for Androgen Receptor – Splice Varient 7. I know…”too complicated for me to understand”. Think of it this way: The AR is the energizer bunny, and testosterone is the battery. Put the battery in the bunny, and he hops into the nucleus of the cancer cell and turns on all sorts of genes (including psa) that drive the cancer cell to do bad things (divide, invade surrounding tissue, metastasize, etc.). Now suppose the bunny becomes autonomous – no need for a battery – he can hop in and do his thing whether or not testosterone is present. This means that all of the new treatments that target testosterone (abiraterone/Zytiga™, enzalutamide/Xtandi™, etc.) really won’t do much. We call this resistance. Castrate resistant prostate cancer (CRPC) used to mean “simply” tumor progressing in spite of very low levels of testosterone (achieved with drugs like leuprolide/Lupron™, goserelin/Zoladex™, etc) or T-blockers like bicalutamide/Casodex™. What we now know is that patients whose cancers are expressing the AR-V7 form of the AR will not respond well to any of these drugs. This means that it could make more sense to proceed directly to treating with chemotherapy with a drug like docetaxel/Taxotere™. Dr. Scher and colleagues at MSKI report in this weeks JAMA Oncology and at the ASCO meeting on the utility of looking for AR-V7 in circulating tumor cells to guide therapy. Screen Shot 2016-06-05 at 8.21.17 AMUsing special immunofluorescent stains, they can identify the “bunny” (shown in white on this photograph from their publication) in the nucleus of some cells in some patients, and these patients are better treated with chemotherapy than with approaches targeting the AR. The implications of this are that we may be able to use such tests to avoid the expense and wasted time of trying to use AR directed therapies in some patients. As often happens, the science is far ahead of the insurance companies however. The Hopkins group have commercialized the test and in an abstract show that it can be cost effective in populations of patients where AR-V7 is likely to be >5% prevalent. Better yet, these insights are now in clinical trial to hopefully develop new treatments for these patients such as galeterone, which may be able to degrade (“kill”) the bunny as described in this abstract from the ASCO meeting.

So YES, we are making progress, and there is a LOT that is new “out there”. Scan the abstracts for yourself – it really isn’t that hard – and kudos to the prostate cancer researchers who are moving this fight forward so quickly.


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What does it feel like to die from this?

I have been asked some version of that question a number of times. Quite obviously, it is as uncomfortable to ask as it is to answer. Medical oncologists (myself included) deal with some version of this on a weekly basis and for the most part, answer as honestly and sincerely as they can – but necessarily at a superficial level. “We will do everything we can to keep you comfortable.” “When that time comes, I will be there for you and your family.” “That is a question I think we should address with our palliative care team or hospice – would you like me to get them involved?”

Yet the reality is much more complicated and if there is one word for the experience, I would pick “sadness”. For all of us, there is both personal and corporate/family sadness. We don’t want to say goodbye, and neither do our friends and family. I want to share some thoughts about that in a minute, but first I can deal with the physical/medical experience of death, which is one aspect of answering the question.

Whether you are a religious person or not, you are immortal. The carbon, oxygen, hydrogen, nitrogen, phosphorus and other atoms that make “you” will never be changed, or if they are, it will be in some sort of nuclear reaction that changes them into another element and involves incredible energy. After all, as Carl Sagan liked to point out, we are all stardust – made (or created if you would rather), from the stuff that happens when stars collapse. That is the root meaning of “disaster”. Beyond that, I happen to think that the energy you have put back into our universe in the form of words spoken, deeds done, mountains climbed, and so forth are immortal as well. “For every action, there is an equal and opposite reaction” is a physical principle we all learned in grade school science class. Thus, the butterfly wing that flaps in the mountains of Mexico and results in a cyclone half way around the world is not completely inconceivable in my view. You, or YOU… have made a difference in the cosmos by being alive. You have utilized chemical bonds that hold matter or elements together into energy and imparted that into your surroundings. When black holes collapse, millions of years later, we detect gravitational energy waves. When you breathed, your breath had more energy than the air you took in as you exhaled. It was warmer, had more CO2 and less O2, and velocity that forced the air around it to move. With a sensitive enough detector, there might be a way to detect that in a million years as some femtochange in some aspect of the cosmos.

When all of this melts down, the function we call “life” ends. The physicochemical reactions going on in your heart muscle, liver, and brain stop. Your consciousness is gone, and with it, what we know as “you” are gone, which brings us to the metaphysical aspects of life and death. Describing the end of “life”, if we are honest, is far more than the cessation of physical and chemical reactions. If it were not so, I cannot imagine my feeling that “sadness” is what describes the experience best. Within our conscious experience of life, “love” is what we cherish most, in all of its meanings. My favorite author, Pat Conroy, died a few weeks ago, and in looking at some of his quotes, I was most deeply moved by this one: “I do not have any other way of saying it. I think it happens but once and only to the very young when it feels like your skin could ignite at the mere touch of another person. You get to love like that but once.”

Certainly that captures a universal experience of one kind of love. But of course, all kinds of love (eros, philia, agape, pragma, philautia) are part of a pretty mysterious collection of our existential experiences, and all end with our personal demise. The result is sadness. Promises of immortality, however comforting, cannot remove the sting of death. Were it not so, the famous two line verse from the bible, “Jesus wept” [John 11:35] at the death of his friend, would not be there to ponder 2000 years later.

Dying from cancer involves all of this. It is a journey. For some, it ends unexpectedly with a sudden chest pain and unconsciousness as the heart fibrillates and oxygen is no longer delivered to the brain. However, for most, it is a series of attempts to beat back the cancer with increasingly toxic and or ineffective treatments, ultimately resulting in an admission by both the patient and physician that focusing on comfort through medication and family/support is the better option. Both the patient and the family must cross the threshold of giving the patient “permission” to die, and face the sadness. What physically comes with this is variable, depending on what organs are involved – bone pain (reasonably easily treated, although with well-known side effects of opiate administration or radiation) is common with prostate cancer, as is fatigue (not so easily treated). What is untrue is that the PSA can predict any of this. I have had patients who went elk hunting and enjoyed themselves with a PSA of 6000, and others who crossed the bar when their PSA was less than 10. Too much focus on the PSA can ruin whatever time a patient has been given either by the genetics of his own disease or by the ministrations of modern medicine.

But this sequence, to be traveled in one way or another by all of us, can also be beautiful in its own way. Life has meaning. Death has meaning beyond sadness. Immortality, in the way I have thought of it, is undeniable. Religion can (for some) be incredibly comforting as one faces the reality of death itself. Rather than try to go further in this (hopefully honest, yet inexorably sad) essay on the topic, I would strongly urge you to read a recently published book, “When Breath Becomes Air”, that I think captures a death from cancer with far more sensitivity and meaning than I am able to impart. Paul Kalanithi’s death from lung cancer in his late 30’s one year ago was a journey he captured as perhaps only a philosopher/neurosurgeon/husband/father and brilliant writer could accomplish. It was his gift to all of us, and by referring you to his writing, I hope I have extended that gift to you on a topic that we too often avoid.


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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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