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3 Articles and a forth


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OK, I admit to a sleazy, seemingly misspelled word to attract attention. At least I didn’t tweet it at 3AM. So what about the “forth”? I’m using it to remind you to sally forth in your search for information about prostate cancer. I previously wrote a blog giving some practical instructions on how to find the latest research publications on prostate cancer that you can find here. Another possibility, if you want to be overwhelmed is to subscribe to the Prostate Cancer Daily, published by Uro Today. So far as I can tell it is open to all, presents the original abstracts, and links via PubMed to the article itself. I now realize that the prediction of patients knowing more than their doctors about a given condition is glaringly obvious, something I discussed when I first wrote about the Internet and Oncology two decades ago.

So, on to the 3 articles: Typically, the most important articles in medicine are published in high profile journals. The premier one for medical oncology is the Journal of Clinical Oncology, JCO. The editors recently published a “best of genitourinary cancer, 2017” edition in coordination with what we medical oncologists call “GU ASCO” (actually co-sponsored by ASCO, ASTRO, and SUO). I thought it would be of interest to briefly re-cap the 3 prostate articles chosen for that edition.

ARTICLE 1: Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. This study compared the more potent anti-androgen, enzalutamide (Xtandi™) to the older drug, bicalutamide (Casodex™) in patients who had become resistant to initial hormonal therapy. About 2/3 of the men had positive scans, while in 1/3 the resistance was detected only by a rising PSA without a positive scan. As we might have expected from the way enzalutamide was developed, it was clearly superior, with progression free survival of 19 months for enzalutamide vs. 6 months for bicalutamide. In an ideal world, we would use enzalutamide instead of bicalutamide in almost all cases where an antiandrogen is indicated. However, the increased cost of this drug is dramatic, and there may be other options or confounding issues with interpretation of the study.

ARTICLE 2: Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer. This article reports on one of many studies looking at whether radiation therapy treatment times can be safely shortened by increasing the dose of radiation given with each treatment and giving fewer treatments (fractions). The underlying principles are that tumor cells cannot repair DNA damage from radiation as quickly as normal cells, so giving radiation in small fractions daily allows killing of the tumor while normal cells repair most of the damage. Giving all of the radiation at once would kill every cell (and the patient).  Experimentally, prostate cancer cells may be more susceptible to larger fractions, and this study demonstrated that a radiation therapy course could be safely shortened from 41 sessions to 28 sessions with similar “cure” rates at 5.8 years of followup. This is a general trend in radiation therapy for prostate cancer. Using newer radiation focusing technologies (IMRT, IGRT, Stereotactic radiosurgery, etc.) it is possible to treat prostate cancer with as few as 5 treatments, although the long term efficacy is still unknown, and the addition of androgen deprivation to radiation treatment at any dose also improves efficacy. How to combine these approaches, the optimal duration of ADT, and which patients should stay with the older methods is still uncertain.

ARTICLE 3: Improved Survival With Prostate Radiation in Addition to Androgen Deprivation Therapy for Men With Newly Diagnosed Metastatic Prostate Cancer. Proudly, many of the authors on this article are from the University of Colorado Cancer Center. The authors used the National Cancer Database to determine whether patients with metastatic prostate cancer, traditionally treated with hormone therapy (ADT) only (although more recently with hormone therapy plus chemotherapy) benefit from also radiatiScreen Shot 2015-10-30 at 11.02.16 AMng the prostate itself. The analogy would be burning down the barn after the horse has left (with apologies to my radiation therapy colleagues who never like to compare radiation
treatments to burning). The patients who had their prostates radiated
had a 5 year survival of 49% compared to 33% for those receiving ADT alone. Removing the prostate surgically also worked. The prostate may also be a site where metastatic cells from another location return, as illustrated in this picture and discussed here. The take home message is that the cancerous prostate may continue to “seed” cancer cells to the rest of the body, or be a home for circulating tumor cells and getting rid of it, even though not curative, may be a good idea (toxicities and costs aside).

Consider yourselves updated! (sort of…)

 

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Build your own bunker


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In the New Yorker last week, there is an interesting article about current ultra-wealthy survivalists who are spending all sorts of money buying up property in New Zealand, or outfitting old missile silos in Kansas in preparation for the dissolution of society. The tone is definitely post-apocalyptic, much like the book/movie, The Road, and causes me to ponder, “What would life be like in an underground silo for the last years of my life?”

Personally, I’m not going there! But the matter of personal choices is a very real one in dealing with prostate cancer. I am reminded of the exploding genre of molecular tests that assist in prognosticating about prostate cancer outcomes – whether that is the likelihood of developing metastatic cancer if you have an elevated PSA with the OPKO 4K test, or the chances you have a cancer that was missed on an initial biopsy with ConfirmDx, or the predicted behavior of a cancer with OncotypeDx. All of these tests have been validated using 1000’s of patients for whom the outcome of their cancer is known. None have been validated in terms of how often using such a test prospectively led to a patient/physician making the “right” decision. Nevertheless, they are the way “personalized medicine” is playing  out in the management of prostate cancer, and I discuss them with my patients.

So, back to the bunker. Do you build one if the chances of the stock market crashing, governmental chaos and nuclear war is 2%? What if it is 50%? And in the case of prostate cancer, what does “meltdown” look like? To start with, we too often ignore our inevitable mortality and the competing causes of death. The Charlson comorbidity index is a great place to start and should be used far more often in prostate cancer counseling. There are a variety of online calculators, including this one that you can use to peer into the future. A 60 year old man with none of the diseases listed has a 90% chance of 10 year survival. If you are over 71 and have had a heart attack, it drops to 21%. Overall, my impression is that patients do better than this in the current era, but it is nevertheless true that competing causes of death play an increasing role in decision making, and that age plays the dominant role. Given that we can control prostate cancer fairly well for 5-10 years in most patients, even if they have metastatic disease, what should a 78 year old otherwise healthy man do with his elevated PSA? Biopsy? Molecular test? The range of answers is broad indeed. Before ordering any of the more sophisticated tests, it is worth sitting down and looking at the way the results will be reported and asking “what if” the test comes back in one way versus another – will that change my mind or help me make a decision?

The bunker all of us geezers should  be building, however, is our own physical one. In a great review article by my colleague, Mark Moyad, he notes the following:

Kenfield et al17 studied a population of 2,705 male health care professionals (mean age at prostate cancer diagnosis about 70 years) with nonmetastatic prostate cancer and found that those participating in vigorous physical activity (metabolic equivalent task [MET] value21 ≥6) for a duration ≥3 hours/week demonstrated a 49% lower risk of all-cause mortality and a 61% lower risk of death specifically from prostate cancer, compared with men who did <1 hour/week of vigorous activity.

It is hard to imagine ANY fancy test, supplement, or other intervention that could have a greater impact on your prognosis. Therefore, hard as it is, and whether you have prostate cancer or not, your bunker awaits at the local gym. The Psalmist said we are given 3 score and 10 years or with strength, 4 score, but he had a morbid view of the last of them. 2000+ years later it may not have changed that much. But if you look out the window, the world still looks like a pretty nice place to me and I say make the most of it!

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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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