Of Prostates and Teslas


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If you thought this might be an article about how your urologist shops for his/her newest fancy car, you are mistaken (sadly…). Nikola Tesla was a fascinating inventor and ultimately “mad scientist” at the turn of the last century. Every time you plug your cuisinart into the wall to chop something up, you are the beneficiary of his contributions to the alternating current coming to your kitchen and the motor driving the chopper. My favorite story (because of the local connection) was his laboratory in Colorado Springs, where he attempted to develop a method of transmitting power without wires. By creating YUUUGE electromagnetic fields, he could make lots of electrical things happen at considerable distances, including knocking out the power station for the city. Here’s a quote from the Wikipedia article:

He produced artificial lightning, with discharges consisting of millions of volts and up to 135 feet (41 m) long.[11] Thunder from the released energy was heard 15 miles (24 km) away in Cripple Creek, Colorado. People walking along the street observed sparks jumping between their feet and the ground. Sparks sprang from water line taps when touched. Light bulbs within 100 feet (30 m) of the lab glowed even when turned off. Horses in a livery stable bolted from their stalls after receiving shocks through their metal shoes. Butterflies were electrified, swirling in circles with blue halos of St. Elmo’s fire around their wings.[12]

Of course, for purposes of this blog, the key thing is that the strength of magnetic fields was named after him. When you get an MRI of your prostate, brain, or anything else, you are put into a machine with a superconducting magnet that produces 1.5 or 3 “T” of strength. At the risk of being completely wrong and oversimplifying, what happens in the MRI machine is that a strong magnetic field temporarily lines up the hydrogen atoms in the water that is 70% of “you”, and when these atoms “relax” they give off radio signals that can be converted to images. Details and images are here. Early on, my colleagues and I were fascinated by the possibility of using MR to investigate the prostate gland and published an article (completely ignored – cited only 3 times, so must not have been that important…) showing changes in MR that occurred after testosterone administration to castrated rats.

Now there are complex MRI protocols to image the prostate using techniques I don’t fully understand (multiparametric imaging) that give us remarkable pictures of the prostate gland. Here is one:

Screen Shot 2018-01-10 at 1.53.20 PM

Prostate gland with red arrow indicating a suspicious lesion that could be biopsied or followed closely.

As with any radiologic imaging technique, the skill of the radiologist as well as the equipment being used determine the accuracy of the MRI to diagnose a cancer.

While most of us learned how to “read X-rays” in medical school, it is beyond most clinicians to read MRI’s of the prostate. Fortunately, the radiologists have developed a system that helps us think about “how abnormal” some area of the gland is, called PI-RADS.  This can be very useful in thinking about what area to concentrate on when biopsying a patient, or in trying to determine whether surgery or radiation therapy should be altered if there is concern that the cancer is outside of the gland. An interesting question that is still controversial is whether the MRI could replace repetitive biopsies in a man who has chosen active surveillance. Particularly when combined with molecular techniques (see my previous blog here) to characterize biopsies, it may be that Tesla will be helping to do more than get you from one place to another or run your electric shaver. (Rock on, Elon Musk) To me, that is a pretty interesting outcome from knocking out all of the lights in Colorado Springs!

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PCa Immunotherapy (for people in a hurry)


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I just finished reading Niel deGrasse Tyson’s book on astrophysics that was pretty understandable. Although I am no immunology expert, and certainly not at the academic achievement level of Dr. Tyson, I have made monoclonal antibodies in my lab and participated in several prostate cancer immunotherapy trials, so I’ll give this a try. My inspiration comes from a truly excellent and comprehensive review on the topic by Laccetti and Subudhi that appeared in Current Opinion in Urology. I will follow their outline with my own “layman’s view” and comments.

Provenge (Sipuleucel-T) was the first immunotherapy ever approved for treating Pca, and has been available since 2010. To be eligible, you have to have failed standard androgen deprivation therapy (though not necessarily the newer agents) and have metastases that can be detected on bone or CT scans. While the treatment works, has been shown to slow the rate of PSA increase and prolong survival, it is complex to administer. You need to donate your own immune cells for “activation” in a treatment facility, following which you receive them back as a transfusion. The process is repeated 3 times and costs in the range of $100K. Many of us wish it was even more effective given the costs and inconvenience, and of course all patients want to see their PSA go down with ANY treatment, which doesn’t happen often with this treatment. Efforts to improve the efficacy have included earlier use when patients are still hormone sensitive and combining SipT with ipilimumab, an antibody that enhances immune responses.

A number of [somewhat] more traditional vaccines are in trials. In a phase II trial, Prostvac, utilized a pox virus approach to deliver PSA (as the antigen) along with co-stimulatory molecules to help the immune system recognize and kill PSA producing cells. Although the phase II data looked very promising, the phase III trial was closed in September when the data did not support continuing to treat patients. Given this disappointment, it is not surprising that the immunologists/clinicians pursuing the goal of a successful prostate cancer vaccine would turn to the “checkpoint therapies” as a possible way to induce the body to fight prostate cancer.

Perhaps the best known of these approaches (due in part to intense advertising on the evening news channels) are nivolumab (Opdivo™) and pembrolizumab (Keytruda). The general idea here is that the immune system would potentially constantly be fighting our own body parts if there wasn’t a way to turn it off. Examples include diabetes (immune system attacks the insulin secreting cells of the pancreas) or rheumatoid arthritis (immune system attacks your joints). The checkpoint system, known as PD-1 (programmed cell death protein 1) is a shutdown system whereby the attacking T-cells are turned off by the PD-l1 ligand, a protein that can also be secreted (unfortunately) by the cancer cells. Thus the cancer cells can turn off our own immune system which is trying to attack and kill the cancer. The checkpoint antibodies effectively throw a monkey wrench into this system, allowing the immune cells to do their thing (and of course, as you would predict, the side effects can include attack of other “self” organs like the lung or colon or pituitary gland). This approach has shown real promise in melanoma, lung cancer, head and neck cancer, bladder cancer, and in some patients with colorectal cancer. Another checkpoint player is ipilimumab, which was first approved for melanoma and also releases “blunted” T-cells to go on the attack. Unfortunately, none of these checkpoint inhibitors have been promising by themselves in early tests in advanced prostate cancer, but there is optimism that by combining them with some of the vaccines in trial, or, perhaps by timing their use with androgen deprivation or radiation therapy when lots of pca cells are dying we will see improved responses. There are 19 actively recruiting studies at clinicaltrials.gov with the terms “vaccine, prostate cancer, recruiting”.  As with many of the challenges in prostate cancer, the best time to use an immune approach is likely early on, when the disease burden is low (for example, a Gleason 9 patient with NO evident metastases). These trials are challenging because such patients are fortunately uncommon, and because these men also can live for many years with current treatments, making the evaluation of a new treatment modality difficult.

2017 was a year when we lost one of the most inspiring teacher/researchers in prostate cancer, Dr. Donald Coffey. The good news is that his legacy lives on in the large number of researchers who continue to push the frontiers of prostate cancer diagnosis and treatment. We owe him a great debt of gratitude for his tireless efforts to advance this field of medicine. I predict it won’t be long until we have the kinds of exciting pca immunotherapies that have made such a remarkable difference in melanoma and other cancers.

 

 

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23 & You – Genetic tests for pca


The genetics of prostate cancer are daunting, but there are now a range of tests available that could be used at almost every stage of the disease IF you can deal with the answers you are likely to receive. Generally these tests are the product of science that goes something like this: A complete molecular picture is taken of all the mutations or all the genes expressed in a series of prostate cancer patients diagnosed years ago. For these patients “all you need to do” is go back to the paraffin blocks that were saved for each patient, extract the DNA/RNA and quantify gene expression and any mutations that can be detected. A decade ago, the technology for doing this was daunting, but now it is relatively easy. Once you have the gene expression profile, you can ask a computer to look for gene expressions that correlate with a certain outcome. For example, you take 500 patients from one center for whom the outcome is known…50 patients are dead, 32 from prostate cancer…70 patients developed metastases by 5 years…these 315 patients are alive and well with no evidence of recurrence…etc. Let’s say there are 50 genes that show changes in expression or mutation. Do we need all 50 to forecast what happened to the patients in that group? No. A computer algorithm can keep testing combinations and permutations of genes and reduce the 50 to a smaller number. We can either let the computer pick the final genes, or we could start with genes we think are related to tumor progression and then do the reduction. In the end, we have a small number of genes with characteristics that accurately separate the patients into “good” and “bad” groups and everything in between. We now take our gene panel, reduced to something like a computer chip and apply the test to 500 patients at another institution blinded from what actually happened to those patients. If our algorithm works, we should be able to accurately predict what happened to those patients in the next 5 or 10 years. If it works, our testing system has been validated, and we can begin offering the test to newly diagnosed patients at some stage of illness. For example, a Gleason 3+4=7 patient might fall into a group where surgery produced a 90% chance of being cured at 10 years, or a 40% chance depending on the gene expression. BUT…and this is key…what to do about the result is still a complex decision for both patient and physician. If you are a Gleason 3+3=6 patient and with no treatment at all you have an 85% chance of “cure” at ten years, is that good enough? What if it is a 95% chance? Will that make you more comfortable choosing no treatment, or do you want to be cured at any cost (impotence, incontinence, other side effects of radiation or surgery)?

As none of these tests has been proven in a prospective study – that is, using the tests to do something like even more aggressive therapy in a group of high risk patients, we are still in the early stages of understanding how and when to use them. Fortunately, my colleague, Dave Crawford and some colleagues have put together an excellent website to help patients/doctors understand the tests. http://www.pcmarkers.com has a list of most of the available tests and you can see what results might look like before you and your physician decide to send one off. This is a rapidly evolving field however, and not every test that is being commercialized is listed, and at big centers, there are always new tests being developed.

Finally, as with all of medicine, the payment systems/insurance coverage is crazily complex. Only today, I received an email with the “news” that a cardiologist/congressman, Rep. Buchson has introduced a bill called the “Prostate Cancer Misdiagnosis Elimination Act of 2017” that uses DNA profiling to make sure the tissue being tested is yours. You could theoretically apply this test to ANY cancer biopsy of course, so why prostate cancer? Then there is the motivation…call me cynical, but I suspected that the good congressman, meddling in medicine, might have a local connection, and sure enough, the company that markets the test is from his home state, Indiana. Not to say it isn’t important to know that tissue being tested comes from the correct patient or that the test isn’t a nice application of the kind of technology that identified OJ’s blood, just that we live in interesting times where medical technology is rapidly consuming more and more of our tax/insurance/personal dollars. Personalized medicine will depend totally on this type of technology and can be incredibly expensive. Whether it saves money or consumes it may depend on how many “worthless” (for that patient…and is a treatment with only a 5% chance of working really worthless??…not if you are in the 5% group) treatments are avoided and at what cost. I don’t have the answers. Hopefully this blog at least helps you begin to understand the current molecular diagnostic landscape.

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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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A statin a day??


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I remember when the statins first came out in the late 1980’s. I had a mildly elevated cholesterol that didn’t respond much to the dietary changes (admittedly few) I was willing to make, so taking a statin seemed like a great step forward. But… were they safe? Of course the same could be asked of aspirin, bike riding, eating meat, or skiing. It’s really about risk/benefit in the end. In the years that followed, I ended up taking statins with the permission of my doctor and they work far better than dietary manipulation for my cholesterol and I combine their use with exercise for all of the other benefits (read here). I previously posted about statin use here, but there are new data all the time worth keeping up with.

In a recent JCO article, a large group (31,790) of Danish men were evaluated for prostate cancer specific and overall mortality depending on their use of statins. Even though there was a higher mortality from prostate cancer than is usually seen in such studies (23% – potentially because there is lower use of screening in Denmark), the prostate cancer specific death rate and overall death rate was 15-20% lower in the men who took statins after diagnosis. This was regardless of their treatment (surgery, radiation, hormones). Since I mentioned aspirin, other studies have suggested that men with high Gleason scores (≥8) may benefit from aspirin use as well. Statins have also been shown to inhibit a long list of other cancer causes of death that you can read about in Wikipedia, so the benefits to prostate cancer patients, who often die of other cancers or cardiovascular disease is not limited to their concerns about prostate cancer itself.

In an editorial accompanying the JCO article by Mucci and Kantoff, there is a thoughtful review of whether statins should be recommended for all men with prostate cancer. The article also discusses how they might work to slow down prostate cancer, so be sure to read it for the excellent summary. They conclude that the evidence is still not there, although certainly the large number of studies and meta-analyses they provide make a strong case. My question would be “what is the risk?”, and it seems to be minimal. Statins are cheap and widely available. They provide risk-lowering effects on cholesterol/heart disease, and the only side effect that is a problem in general is the muscle pain that occurs in some patients, which almost always goes away when you stop the drug. I can’t disagree with the thought that a prospective randomized trial in a subgroup of prostate cancer patients is desirable, but in the absence of such a trial to invite patients’ participation, I personally encourage patients to take statins unless their primary care physician disagrees. For that matter, I would almost encourage their presence in the water supply like fluorides given all their other benefits (just kidding, but they really do have a long list of benefits and very favorable risk profile in my view).

An apple a day is a good idea. Statins should maybe join that, and keep exercising!

 

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Rising PSA – When to start therapy


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One of the most frequent situations I encounter in my small “prostate cancer only” practice is a man who has had treatment (usually surgery or radiation) several years ago and now has a rising PSA. He feels absolutely fine, may be exercising daily, and his PSA is often so low that a routine scan won’t show anything. What to do?

The options in this situation are changing. Treating oligometastatic disease (few metastases) is somewhat of a new frontier in this situation. In the “old days” when I wrote about this subject, we reviewed the non-randomized data that suggested no advantage to starting ADT earlier. More recently, the idea of treating some men with radiation or surgery directed at the mets if they have only a few has become more popular. Added to this is the increased sensitivity of the newer PET scans (choline, acetate, PSMA targeted) that may reveal metastases even with PSA values less than 1.0. While it is hoped that some men could be cured by this approach, it is also possible that one could delay the implementation of ADT and its side effects. There are multiple ongoing clinical trials looking at this issue. With such rapidly changing technology, it will be difficult to come up with a “right choice” in every situation. What may have been considered “non-metastatic rising PSA” last year could become “oligometastatic” simply by the implementation of the new scans.

Beyond this is the issue of treatment-related side effects. In an article this week in Lancet Oncology, the side effects of treating men with asymptomatic, non-curable prostate cancer (TOAD and TROG studies) was reported. This study is one of the few randomized studies in this setting. The men were about 70 years old with rising PSA’s, most having been previously treated. They were randomized 1:1 to starting ADT immediately or waiting until at least 2 years later unless “symptoms or metastases developed or PSA doubling times decreased to 6 months or less”. Earlier, the investigators published the survival data in this study, indicating some advantage to starting earlier, as shown in this graph. Screen Shot 2017-09-12 at 9.14.48 PM

However, keep in mind that the men who were in the immediate ADT arm also experienced the ADT side effects sooner according to the new report. The most important areas of symptoms were the hot flashes and decreases in sexual activity (reported only in the men who were sexually active) which were significantly worse with the immediate treatment, as might be expected. In a “global quality of life” measurement there was also worse quality of life, although it was not significant (the score number was 72.39 for delayed therapy vs. 70.83 for the immediate group). Further, the type of ADT used varied, and included both intermittent and continuous therapy (usually intermittent therapy has at least some improvement in quality of life). Finally, none of the men in these studies received the newer (and vastly more expensive -but probably more effective) ADT agents, abiraterone or enzalutamide which have been shown to improve survival when used “up front” in the metastatic setting.

Thus, a rising PSA is obviously a reason for concern, but choosing a management strategy is quite complicated at the present time. The best news to come out of this study is that prostate cancer is a slow disease. “Overall, 18 (6%) men died from prostate cancer, 12 (8%) in the delayed treatment arm and six (4%) in the immediate arm…” This is not to say that as time goes on there will not be more prostate cancer deaths, and there was earlier metastatic progression in the delayed group, but it is equally important to realize that at age 70 there will be significant competing causes of mortality. Something will get us eventually, so the key is to not let prostate cancer (or the PSA) dominate our thinking. What other things can you work on? Stop smoking. Exercise. Improve your diet. And most of all, enjoy each day as a gift and live it to the fullest regardless of how you decide to deal with a rising PSA.

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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.

Screen Shot 2017-06-05 at 10.16.58 AM

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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