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To Watch or Not to Watch


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Active surveillance (active monitoring, watch and wait, etc. – each with slightly different definitions) means you know you have a low risk prostate cancer (typically defined by a small amount of cancer in only a few of the biopsy cores and usually with a Gleason 3+3 score (some studies also include low volume Gleason 3+4 patients). Knowing this, you decide to not have treatment but just “keep an eye on things”. It all sounds so simple until you try to project what that means for YOU, and here is where the decision making becomes complex. Risk tolerance and rewards of decisions are psychological issues, not so much medical ones. Some people feel the thrill of jumping out of an airplane or off a bridge with a bungee cord more than compensates for the relatively small risk. Others don’t. For some men, ANY decrease in their sexual function or chance of incontinence is not worth the risks of treatment. For others, ANY risk of dying from prostate cancer is unthinkable. And, I would add – having counseled many couples – that the spouse’s feelings about sexual intimacy and survival vary considerably. For the record, the most common comment I hear from the wife is “We don’t care so much about sex, I just want George to be here” or similar, sometimes paired with the comment (regarding surgery vs. radiation) “I just want it out of him.”

With that background, Anthony D’Amico, one of the most prolific researchers and best analytic minds in our field, has written an editorial worth reading. In it he posits the question of whether the development of metastases, not death from prostate cancer, should be the better way of evaluating active surveillance. His primary analysis comes from looking at the ProtecT study, published last year in the NEJM. In that study, “82,429 men had a PSA test; 2664 received a diagnosis of localized prostate cancer (including 146 men from the feasibility study), and 1643 agreed to undergo randomization to active monitoring, radical prostatectomy, or radiotherapy.” There were about 550 men in each arm of the study and at the end of 10 years, there was no difference in the death rates from prostate cancer. 291/545 of the men in the surveillance arm had gone on to receive treatment within 10 years. However, as D’Amico points out, “the occurrence of metastasis, defined as the spread of PC to bone, viscera, or lymph nodes or a PSA level > 100 ng/mL, occurred in 62 men and was more than two-fold higher in men randomly assigned to [active surveillance] versus a treatment protocol.” In absolute terms, this meant that 32/545 surveillance vs 13/553 surgically treated vs 16/545 radiotherapy patients developed metastases and would need to suffer the side effects of hormonal treatment during their last decade or so of life. D’Amico argues that these men with metastases should be a better measure of the outcome for the active surveillance approach. What he does not deal with, however, is the benefit the men without metastases experienced by taking the approach. By 10 years, nearly half of the surveillance group had not had the side effects of definitive treatment, and even those who “fell off the wagon” and were treated enjoyed some additional time without side effects.

In a companion article to the ProtecT cancer outcomes article, we learn more about the side effects of treatment. These graphics from that article show that surgery (red line) and radiation therapy (gold line) produce significantly more side effects than the slower problems that develop over time with both urinary and sexual function in the surveillance (and all aging men) group (blue line). The PIVOT trial (also worth reading to gain perspective on the relative advantages of treatment or not) demonstrated that virtually all patients who receive treatment experience some decrement in sexual function.

Not shown, but an important part of the overall picture, is that the surveillance protocols involve biopsies every 1-2 years, or MRI exams (or increasingly both), following the PSA values which can and does produce anxiety (see my blog on the “PSA Clock”), and the psychologic burden of “knowing you have cancer”. These side effects of surveillance are often under-appreciated, and some men who elect for surveillance eventually change their mind and opt for treatment because of them.

Finally, age makes a big difference in psychology. Older men are generally less sexually active and focused than younger. There is good evidence that it is just as safe to do active surveillance in younger men, if sexual function is an overriding consideration. In the end, the decisions about what to do if you have been diagnosed with a low grade prostate cancer are not easy, and highly personal – just like sky-diving and bungee jumping!

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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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