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Pills vs Shots for Androgen Deprivation Therapy (ADT)


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My own interest in prostate cancer began with what, in retrospect, seems quaint and naive. When I arrived at the University of Colorado in 1978, as the first board certified medical oncologist, there were very few clinical trials underway. Having trained (at DFCI) with teams of researchers, my philosophy had evolved to the thought that “every patient should be treated on a protocol, and there should be a protocol for every patient”. This idea (in academic centers, at least) is how we make progress in treating cancer. I continue to urge every patient to participate in clinical research whenever possible, recognizing that for reasons of geography, convenience, or eligibility, it may not be possible. Clinicaltrials.gov lists all of the ongoing clinical research trials for patients and physicians, a dramatic advance in keeping everyone informed. You can learn how to use this tool in one of my previous blogs, here.

With few clinical trials going on at our cancer center, I wrote a naive letter to a number of pharmaceutical companies asking if they had any drug development trials that I might participate in. A single company, Abbott, wrote back inviting me to Chicago to discuss “Abbott 43-818”. This drug was an analog of gonadotropin releasing hormone, GnRH, a peptide (10 amino acids in this case) that looks like this: Pyr-{His}{Trp}{Ser}{Tyr}{Gly}{Leu}{Arg}{Pro}{Gly}-NH2. The 43-818 analog came to be known as leuprolide, and I had the opportunity to participate in taking it all the way from the first dose in men to a final clinical trial resulting in its approval as Lupron™. I’ve been caring for prostate cancer patients and doing clinical trials in prostate cancer ever since – fate!

The way Lupron™ works is shown in the figure below. Normally a part of your brain called the hypothalamus (1) releases a “pulse” of GnRH several times/hour. The peptide travels to the pituitary gland (2) and lands on cells called gonadotropins, causing them to release hormones LH and FSH that travel to the gonads (4) where the ovaries release estrogen or the testes release testosterone. Leuprolide interrupts this process by “over stimulating” its receptor on the pituitary cells and they turn off their LH/FSH production. Because of the small and relatively simple peptide sequence 100’s of other analogs have been made, and the molecular interactions with the receptor have been extensively studied. Some are agonists (like leuprolide/Lupron™/Eligard™, or goserelin/Zoladex™ and others are antagonists (degarelix/Firmagon™).

The hypothalamic-pituitary-gonadal axis

After a long research path, an oral antagonist (relugolix/Orgovix™) has now been synthesized, tested, and approved for treating prostate cancer. It is not a peptide, has the advantage of not having to be injected, and may be safer in patients with a cardiac history. The HERO trial evaluated 934 prostate cancer patients, 2/3 of whom received relugolix and 1/3 received leuprolide. As expected (based on the history of antagonists research), relugolix resulted in more rapid reduction in testosterone, faster recovery upon discontinuation, and faster reduction in PSA.

The frequency of the common bothersome side effects, hot flashes and fatigue, was similar. More patients on relugolix (12.2%) had diarrhea than those on leuprolide (6.8%). However, the leuprolide treated patients had more serious cardiovascular events (myocardial infarction, central nervous system hemorrhages and cerebrovascular conditions, or death from any cause), especially if they had a cardiac history. The incidence was 6.2% in the leuprolide group vs. 2.9% in the relugolix group.

All things being equal, use of relugolix would seem to be a superior choice for ADT in prostate cancer patients. However, as usual, “all things” may not be equal. First, while the biology above may seem to favor the antagonist, there are no data on whether this affects survival or time to progression of prostate cancer. The biology of reducing testosterone as the mainstay of treatment has not changed – we are attacking the same target: testosterone stimulation of prostate cancer cells. Indeed, the more rapid recovery of testosterone upon discontinuation of therapy (for example in a patient who receives several months of relugolix in combination with radiotherapy) might result in better quality of life with rapid recovery, but have a higher rate of recurrence due to the shorter overall duration of ADT treatment. Some patients will prefer pills to shots. On the other hand, insurance coverage for injections might be much better than that for an oral medication. The internet reported cost for a month of relugolix is reported to be $2313. The cost for a one month leuprolide dose is around $1700. However, the cost of a myocardial infarction is not insignificant, and thus comparison of one form of treatment vs another is always more complex than it initially seems.

I am writing this because I suspect there will be “news” articles and other advertising efforts for “Orgovyx™” in coming weeks/months and I hope to refer my patients to this article (and all the other ones I write). If a newly diagnosed patient has impending spinal cord compression, or major organ involvement or a history of cardiac disease, I would recommend the antagonist (relugolix/Orgovyx™) over the agonists (like leuprolide/Lupron™/Eligard™ or goserelin/Zoladex™). If a patient is already on one of those agonists, is doing well and has no cardiac history, there is probably no reason to change therapy. For a patient who is about to start therapy, I will discuss the options, and am happy to prescribe either an agonist or antagonist – it may well depend on insurance issues for a given patient. As with the Covid vaccine, the scientific progress in developing a non-peptide, oral agent is a testament to “our” (medical science) phenomenal scientific advances. The cost of such research (dating back at least to 2013 for relugolix) and what represents fair costs to patients or to Medicare and fair reimbursement to the pharma companies remain concerning to me.

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Holiday greetings and philosophy


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I want to wish all of you a very Merry Christmas, happy holiday (whichever ones you celebrate or just celebrated) and a safe and vaccinated New Year. And most of all, THANK YOU to the many folks who contributed to my annual Movember Moustache. We again blew the top off my goal, and it makes me abundantly happy to join you in supporting the research into prostate cancer survival and cure.

Second, I urge you to hang in there, wear your masks, and limit the Christmas interactions. We only have a couple of months to go before we are vaccinated if you are in my age bracket, so stay the course!

Finally, I will share the thoughts of my Department of Medicine Chairman, David Schwartz who has put as fine a summary on where we have been and where we need to go as I have seen. I hope you will find it encouraging:

“A number of months ago, I wrote that ‘Science will lead our way out of this crisis.  Basic modeling and infectious disease epidemiology has helped us understand what’s coming, the science of social distancing, clinical trials have identified remdesivir as a promising agent, novel serologic assays will identify the extent of disease in our communities, and vaccine development will provide the cure.  All of this takes investment, and now is not the time to back away from our scientists or our scientific infrastructure.  In fact, now’s the time to double down.  We still have to get through this crisis but rest assured there will be human health challenges in the future, and we need to be ready.’  

Now with the demonstrated importance of social distancing, the improved care of patients with Covid, and the FDA emergency use approvals of the Pfizer and Moderna vaccines, it’s time that we recognize and celebrate the truly remarkable advances in our fight against Covid that have been made since the initial transmission of SARS-CoV-2 in the Huanan Seafood Wholesale Market only one year ago.

·         Social distancing:  The past few weeks have demonstrated the profound effect that social distancing has had on the transmission of the virus.  The story of the coronavirus in America is a compartmentalized one, with different places experiencing different spikes for different reasons at different times.  Fortunately, over the past week in Colorado, there’s been an average of about 3,100 cases per day, a decrease of 28% from the average 2 weeks earlier.  This decrease in cases per day in Colorado is reflected in the census data in our hospitals, and the state-wide hospitalization data with both peaking and slowly going down since the beginning of December.  In contrast, over the past week in the entire U.S., there’s been an average of about 220,000 new cases per day, an increase of 19% from the average 2 weeks earlier.  Continue to wear a mask, practice social distancing, and don’t travel over the holidays.

·         Clinical trials:  Over the past year, well-conducted clinical trials (by many of our investigators) have identified what works and what doesn’t.  Our improved ability to take care of patients with SARS-CoV-2 infection is reflected in the decreased percent of patients requiring ICU care (55% last spring – 40% now) and a decrease in the number of patients in the ICU requiring intubation (90% last spring – 67% now).  Moreover, the survival and re-admission rates continue to improve among our Covid patients.

·         Vaccines:  One year ago, very few people would have predicted that we would be embarking on a vaccination program with two extremely effective vaccines with minimal side effects.  This was not a miracle.  The development of these vaccines were enabled by many scientific accomplishments (bat virology, DNA sequencing, computational biology, and basic science of RNA, proteins and lymphocyte biology to name a few) that have been supported by the federal government, industry, academia, and public-private partnerships.  Investments in science are essential to our future.

I think there are other take home-messages that will continue to strengthen the scientific programs on our campus:

·         Team science and scientific partnerships are critical to combining clinical insights with cutting–edge research.  Collaborations and social networking will improve the efficiency of research.  We need to foster these interactions.

·         Public-private partnerships (like the one between the NIH and Moderna) can lead to powerful advances and need to be nurtured.

·         Our nation has to place a higher value on science.  Part of this involves public education and we’ve got some real opportunities with our patients.  However, we should also do everything possible to help Congress recognize the sad lessons learned from the ways science has been pushed aside during the pandemic, and strongly advocate to substantially increase the federal research budget.”

To all of you who subscribe to this blog, I thank you for your interest, ideas for topics, and your support for the physicians, nurses, staffs and researchers who have made it possible for all of us to live longer and healthier lives than any generation in history. It has been an incredible journey for most of us and in spite of the 2020 “downer” we have much to be thankful for. Keep exercising and my best wishes for the New Year!

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Epigenetics


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One of our faithful readers suggested this topic. My first introduction to the concept of epigenetics may have been in a lecture that the late Don Coffey gave at a course I helped organize at the Given Institute in Aspen which still goes on today. Don was a pied piper to hundreds of students at all levels at Johns Hopkins, and on his first visit to the course told them about arriving late at the Denver airport, driving his rental car too fast over Vail pass, then exiting and hiding under a bridge while a State Patrol car zoomed over him, and getting back on the road to make it to Aspen just in time. Not a bad way to endear yourself to some younger physicians in training!

His signature illustrative story was that of the fertilized hen’s egg. There it sits, with all the information needed to make a full chicken encoded in the DNA, but nothing happens until it is put in an incubator and the temperature rises. Only then does the machinery kick in to go from a single cell to billions of cells with everything from feathers to an intestinal tract. “How does that happen?”, he would ask, and then proceed to talk about how the DNA is wrapped around histones as shown in the following illustration:

Dr. Coffey would then show pictures of DNA in prostate cancer cells, some of which was compactly wound around the histone proteins (and therefore inactive) and some of which was “open for business” with long loops of DNA strands sticking out from a chromosome. I love the simplicity of this illustration, because it demonstrates how not only temperature can influence the long string of base pairs that otherwise are the deceptively simple ATCGTCCATA… code, but also begins to explain how environmental factors, drugs, aging, and diet can change gene expression. My hiking friend, who is somewhat of a eugenics devotee, thinks mankind will evolve to [his view of] perfection by using CRISPR to modify just the DNA sequence and change everything from physiognomy to behavior. I, of course, disagree based on epigenetics. A woman in her first trimester who eats too much broccoli one evening might well affect her child’s math score by 1/10 of a point…

But back to prostate cancer! As shown in the above figure, one of the common ways genes and their expression is modified is through methylation. The chemistry is shown in this figure and a complete article on DNA methylation from Wikipedia is here.

This image shows a DNA molecule that is methylated on both strands on the center cytosine. DNA methylation plays an important role for epigenetic gene regulation in development and cancer. [Details: The picture shows the crystal structure of a short DNA helix with sequence “accgcCGgcgcc”, which is methylated on both strands at the center cytosine. 

These methylation changes are frequently found in what are known as CpG islands, or areas of the genome that are rich in Cytosine Guanine base pairs, and particularly in the so called “promoter regions” upstream from the gene itself that control whether the gene is “active” or not. In prostate cancer, methylation of an enzyme called GSTP1 was one of the first methylation markers that became useful in detecting prostate cancer. If a man with a highly suspicious rise in PSA was biopsied and there was no cancer found, if the biopsy of the “normal” tissue next to true cancer was analyzed and methylation of GSTP1 was found, it was highly predictive that real cancer was present but just missed. As time went on, many other genes with hypermethylation changes were found, and panels of such genes could be used to detect prostate cancer cells in the urine, potentially replacing invasive biopsies. More recently, utilizing advanced techniques to search for methylation patterns in the whole genome, it has been possible to find markers (probes) for genes (see this article) which are differentially methylated in prostate cancer and have dramatic prognostic significance. Here is one such example showing that depending on which form (allele) of a gene called ATP2A3 (that can be methylated or not) you inherit, it can affect your survival.

The homozygous alternative genotype of a haplotype on chromosome 17, associated with methylation of ATP2A3, gives a survival advantage. HR and P values are from the CoxPH model.

Although much of the article from which I copied that figure is way (WAY) over my head, the point of understanding epigenetics is that prostate cancer is much more complicated than just a mutation or two in some cancer causing genes. The expression of a myriad of other genes that can be controlled by methylation or other epigenetic processes can play a major role in what happens to us. As it turns out, this week’s NEJM has an article specifically related to the epigenetics of prostate cancer as it evolves from localized to metastatic. Here is the key illustrative figure and accompanying explanation.

Figure 2. Epigenetic Regression with Clinical Progression of Prostate Cancer. Pomerantz and colleagues4 describe epigenomic patterns that occur in the transitions from the normal human prostate gland to organ-confined prostate cancer to metastatic castration-resistant prostate cancer, with their findings regarding metastasis relying largely on patient-derived tumor xenograft models. Sites of androgen-receptor binding in the genome have been associated with this transition from normal prostate gland to metastatic disease. Such binding sites are “premarked” by the transcription factors HOXB13 and FOXA1. Also, the researchers found that sites that are specific to metastatic castration-resistant prostate cancer correspond with sites in the open chromatin state in the normal prostate gland and in organ-confined prostate cancer, which indicates a lower barrier to reprogramming to a metastatic state. The epigenome (H3K27 acetylation) pattern in prostate cancer metastasis was similar to that in fetal (but not adult) prostate cells. A limitation of the study is that it does not include an analysis of circulating tumor cells or metastatic castration-sensitive prostate cancers.

As this story unfolds, “precision medicine” will become a way to individualize prostate cancer treatment. However… the heterogeneity of prostate cancer metastases will remain a major challenge in the practical application of such knowledge. Meanwhile, if you haven’t already supported prostate cancer research through my Movember effort, feel free to wander over to my website and make a contribution – and THANKS to all of you who helped me reach my goal!

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Yay – Voting is over and it’s Movember y’all


Every year, in honor of the guys I care for and the progress Movember has made in supporting research for prostate cancer, I join in the effort to raise funds from my faithful readers. This year is no exception. 2020 has been such a downer, we all need to do something positive to make ourselves feel better. So, if you can spare some change, I humbly ask you to support my annual scraggly moustache, and I can assure you the funds are well spent. For example, new tests are coming out of labs Movember supports. They constantly update the priorities as you can see in this article, and support ongoing clinical trials like this one. And for men isolated in our COVID times, there is the kind of support you need when facing tough questions at “Men Like Me“. In short, I hope you will help me with a donation to my Movember effort by clicking here:

Mike’s Movember Website

  • Then click the DONATE BAR under my picture: (not the one at top right)

For donors of >$50, I have ordered some Movember Moustache masks and will send you one. And for all participants, let’s plan on a zoom celebration in December – maybe I can answer questions sent in on chat or similar. If you are more savvy than me, scan the following image on your smart phone to be taken to my Movember webpage. And THANKS for your consideration and help!!!

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Nex Gen Diagnostics and Treatment


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When I was a fellow in Dr. David Livingston’s lab 40+ years ago, DNA sequencing had just become “widely” available, developed by Maxam and Gilbert. There was a brilliant MIT student, 16 years old as I recall, who visited the lab that summer and brought his TI calculator to the lab, assigning a number (1,2,3,4) to each of the bases and would go into David’s office with a string of numbers to look at. The evolution of that technology to what goes on today when you send in a saliva sample to 23 and Me is shown in the following video:

This video explains next generation DNA sequencing

With what seems (to an old guy like me) shocking speed, the human genome was unraveled and with it, all (most?) of the genes that control cellular processes including cancer. As I have recommended before in this blog, for a fabulous review of the story, I recommend you read “The Emperor of All Maladies” by Siddhartha Mukherjee.

Due to the power of DNA sequencing it is now possible to obtain DNA that originates in tumors and do sequencing of cancer causing genes directly from the blood stream or from the urine or other body fluids. This is a so-called “liquid biopsy“.

The entry of this technology into caring for cancer patients has also been incredibly rapid. At the present time, for prostate cancer, the NCCN patient guidelines are a great place to start learning about pca in general if you are new to the topic, but the physician NCCN guidelines are much more specific regarding what you need to know about your genetics. Here are the recommendations for “germline” testing, i.e. what you have inherited that may have pre-disposed you to develop prostate cancer and what might affect other members of your family including children or siblings:

The guidelines are also very informative about this testing being done with the help of professional genetic counsellors:

Genetic testing in the absence of family history or clinical features (eg, high- or very-high-risk prostate cancer) may be of low yield.
• The prevalence of inherited (germline) DNA repair gene mutations in men with metastatic prostate cancer, unselected for family history (n = 692), was found to be 11.8% (BRCA2 5.3%, ATM 1.6%, CHEK2 1.9%, BRCA1 0.9%, RAD51D 0.4%, and PALB2 0.4%). The prevalence was 6% in the localized high-risk population in the TCGA cohort (Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 2015;163:1011-1025; Pritchard CC,Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016;375:443- 453).

• Genetic counseling resources and support is critical and pre-test counseling is preferred when feasible, especially if family history is positive.

• Post-test genetic counseling is recommended if a germline mutation (pathogenic variant) is identified. Cascade testing for relatives is critical to inform the risk for familial cancers in male and female relatives.

https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

However, as noted above, we can also sequence the tumor itself or look for mutations in tumor DNA that is circulating. The most important thing that may show up in these analyses is a mutation that can be specifically targeted with one of the newer drugs. Examples include the finding of a DNA repair gene mutation such as BRCA1 or BRCA2 in which case the use of a category of drugs called PARP inhibitors or platinum based chemotherapy might be an important consideration for patients who have failed hormone therapy. Thus, we now utilize DNA sequencing both in patients who have family histories for certain cancers, patients with metastatic disease, high risk disease, and again when there is progression of the cancer after hormone treatment stops working. Beyond these impacts of DNA sequencing are the many gene-based tests that have evolved that can help determine risk for finding prostate cancer on a biopsy, or predicting whether someone is at high or low risk for metastatic disease after a positive biopsy and Gleason score is known.

I tried to help understand the complexities of integrating all of these new tests and therapies in this blog. Although it may be difficult to keep up with this rapidly evolving landscape for both patients and physicians, there is no doubt that we have entered the “next gen” era of prostate cancer management. Finding an expert who focuses on pca and discussing some of the issues raised in this blog is key to taking advantage of what is being learned. Hopefully this blog will help you become a better informed member of your team in terms of the underlying technology. For a more erudite discussion of cancer precision medicine, you might read this newly posted discussion.

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Why can’t we cure this???


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A frustration for patients and physicians alike is the incurability of metastatic prostate cancer in spite of the great response that many/most patients have to initial hormonal treatment. As most readers of this blog know, almost all prostate cancer cells depend on stimulation from testosterone to grow and to get outside the prostate, moving to lymph nodes or bones (the most common place for metastases in pca). Testosterone is normally made by the testes and adrenal gland, circulates in the blood stream, and enters the cancer cells where it binds to the AR (androgen receptor). The AR then translocates to the nucleus where it binds to specific locations “upstream” from various genes (including PSA, and interestingly TMPRSS2 which has implications for COVID-19) leading to the gene being “activated”. Many of the activated genes lead to cell division and invasion that characterize/lead to metastases we detect with bone, CT, or PET scans.

Normally, the way we detect that cancer cells are “turned off” or dying is by the PSA falling. PSA in general is far more sensitive than scans, but it really tells us about the “big picture”, not what is going on with individual collections of metastatic cancer cells. Measuring PSA every 3 months is a very common way to monitor the response to drugs that stop testosterone synthesis (abiraterone – Zytiga) or block testosterone from binding to the AR (bicalutamide-Casodex, enzalutamide-Xtandi, apalutamide-Erleda, darolutamide-Nubeqa)

Although much more expensive, monitoring response by repeating scans can begin to answer the question posed for the title of this blog. Why doesn’t hormone therapy lead to cures? The reason lies in a single word, heterogeneity. As I reviewed previously, when we look at different sites of cancer metastases, the tumor deposits in one area may have a very different genetic mutation profile than those in a different area. I was very struck by how well this is illustrated in a recent article using quantitative PET scans. In patients treated with enzalutamide, the different sensitivity is graphic as shown in this figure from the article:

Compare PET1 taken at the start of treatment with enzalutamide to PET3 when disease was progressing indicated by a rising PSA. Green spots indicate partial or complete response to the antiandrogen while red ones are new or progressive locations. This is a graphic example of the result of tumors having genetic changes that make them more or less sensitive to the drug. Finding a combination of chemotherapy or hormone therapy that can attack all of the genetically different deposits is impossible at this time. However, the immune system may be able to keep up with all the changes in some patients, and this provides hope for the expanding trials of immunotherapy in prostate cancer you can find here. Glass half full or half empty? You choose!

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Prostate Theranostics


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Sometimes a great new word evokes curiosity, so I have used it to title this post and see if a few of you thought it would be worth looking at rather than sending to your “junk” email. You can’t find it in the dictionary, interestingly enough, but it’s related in derivation to Theranos, the bizarre company started by Elizabeth Holmes and if you haven’t read “Bad Blood” or seen the video you can find that story here:

For us prostate cancer followers, however, theranostics represent a “new” field in which the same/similar drugs can potentially be used for both diagnosis and therapy. There is a nice review of an ASCO educational presentation on the topic here. The main idea is that a radioisotope can be specifically directed to a target for either diagnosis or therapy. One of the oldest examples of this is radioiodine which is taken up by the thyroid gland. If you have thyroid cancer, the metastases will also take up the radioactive iodine and with nuclear medicine detectors you can see them, or if you inject even more, it will be “hot” enough to kill them.

223Ra is an isotope that seeks bone, just like calcium, and where there is more bone turnover/remodeling, more of it accumulates. As a drug, it was given the name Xofigo, and was approved for treating prostate cancer in men with bone dominant disease in 2013. It emits alpha particles, which are known as “high Linear Energy Transfer” radiation because they go only a very short distance before interacting with cancer cells and killing them. This is important since you would not want the radiation to kill the normal bone marrow cells that live in the same neighborhood. In the study leading to approval of 223Ra, men with symptomatic bone metastases and no visceral (e.g. liver or lung) metastases who received the isotope as a monthly injection for 6 months lived 14.9 months as compared to 11.3 months for placebo (P<0.001) and had fewer skeletal events and less bone pain. I always loved alpha emitters because I had the fun of making a cloud chamber for a science fair when I was in 6th grade. You might want to help a grandchild do that!

177Lutetium (177Lu) is an isotope that allows both diagnosis and therapy because it emits gamma radiation for detection, and high energy beta radiation that can kill cancer cells. When bound to PSMA (see these posts)

177Lu becomes a theranostic that shows considerable promise for treating prostate cancer. There are a number of completed trials of 177Lu-PSMA that have been summarized in this table:

For more details on 177Lu-PSMA treatment, this is an excellent recent review from the European Society of Radiology:

https://epos.myesr.org/poster/esr/ecr2020/C-00307

There are a number of ongoing trials of 177Lu-PSMA that you can find here.

Keep wearing your masks to protect your fellow prostate cancer groupies, be patriotic, and if you want to pay homage to one of the great scientists whose research led to these advances, look no farther than Radioactive, the recent Amazon Prime movie about Marie Curie. As one of the commentators on the trailer posted, “In a world full of Kardashian’s… be Madam Curie.”

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COVID-19 and “the news”


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This won’t be a long blog, but since I anticipate lots of news this week regarding an article that was published a few days ago, I thought I would provide a “heads up” to my prostate cancer “groupies”. What makes the news and becomes “viral” is interesting and I haven’t had the opportunity to watch the sequence up close personally before. My wife is a pediatric infectious disease expert with specific interest in Kawasaki Disease. As you most likely have seen in the news over the past few days, SARS CoV2 now seems to trigger a KD type of illness in children. This became apparent a little over a week ago with calls flying back and forth from around the world among her friends, notably because Michael Levin, from London had seen some cases and sounded the alarm among the international colleagues. So, from “insider info” to public alarm seems to take about a week.

As you know from faithfully reading this blog, I predicted that men on androgen deprivation therapy might be protected from SARS CoV2 about 6 weeks ago and that physicians/scientists with access to large databases would be able to show this. And, true to the prediction, this past week an article appeared showing just that. I have summarized the data for you on this slide:

Screen Shot 2020-05-10 at 8.33.47 AM

It will be interesting to see this get picked up and “sensationalized” by the media over the coming days. And it is already underway. I am aware of a conference call with the CDC and another being hosted by the Prostate Cancer Foundation this coming week. So consider yourselves forewarned! CNN, FOX, ABC, etc. etc. will be all over it…

Now, as I also predicted, I would bet that there will be prospective studies looking at ADT as a form of therapy for COVID19 starting soon (if not already underway). My favorite design would be with the approved agent, remdesivir in a randomized prosepective trial. Male patients sick enough to be admitted to a hospital would all receive remdesivir, and 1/2 would receive ADT in the form of an anti-androgen (e.g. enzalutamide, apalutamide or darolutamide) or a single injection of a month of a GnRH analog like degarelix (Firmagon), or the androgen synthesis blocker abiraterone/prednisone (Zytiga). I would hope that this kind of approach could help men (and maybe even women) fight the virus by blocking TMPRSS2 as I previously showed you in the graphic on the original blog. Now YOU are the insiders!

PS, I think that another approach could be starting everyone in a nursing home “under attack” could be starting all the occupants on finasteride. Blocks DHT production from T and is very well tolerated in the  pcpt trial. Lower DHT -> lower TMPRSS2 -> lower viral replication.

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Tools for planning ahead


I am currently at the ASCO GU 2020 meeting (abstracts here ) with lots of great information being presented. (Actually drowning in great info, but that is an aging thing…). I promise to post something in the next week or so from the notes I’m taking.

Meanwhile, before I forget it (yes, another aging issue), I wanted to make available to subscribers a remarkable website that I recommend for planning. If you follow this blog, you may remember I was surprised and concerned regarding data that showed an increase in Alzheimer’s and dementia from ADT therapy. The most surprising issue was that among 74 year old men with prostate cancer diagnosis and NO ADT, the incidence of Alzheimer’s was 9% at 10 years and rose to 13% if they had been treated with ADT.

So here’s the thing. There is something you can do about planning in advance. Compassion and Choices has put together a great tool that takes you through a number of scenarios and lets you decide what you would want done in advance of you becoming impaired. I strongly recommend you take a look and consider this important issue:

Click here.

There are other tools you may also find useful, but I think we all owe it to our families to go through the dementia tool given the challenges we seem to face as we age. Best wishes for a Happy Valentine’s Day with your loved ones.

 

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[How to] Choose Your Own Adventure


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Back when Al Gore and I invented the internet (just kidding…but it does seem like a long time ago – before twitter, instagram, and all the rest), I had the privilege of helping my professional society create its first website, ASCO Online. As part of that effort, I wrote an introductory article to assist my colleagues in understanding what I felt lay in the future. In addition to trying to explain how browsers and the internet worked (as an amateur early adopter), I stated, “Oncologists will increasingly act as information guides rather than information resources for patients and their families with cancer.”

Herein, I will attempt to make that easier for you if you have a personal interest in prostate cancer. There are now more than 103 million “hits” in a google search for “prostate cancer”. Therefore, first understand your condition. If you are thinking about screening, put that in your search term, or read this article I selected for you.

Next, be familiar with the myriad of terms that have evolved to describe different situations (“states”, “stages”, “conditions” etc.) to describe the disease. “Localized” means you have prostate cancer that is felt to be (or even proven to be after surgery) confined to the prostate. If localized, is it high risk, intermediate risk, or low risk? Your physician should be able to help you understand this based on the Gleason score, pathology findings, and PSA, but there are now multiple molecular tests that can be done to help further characterize what has been found. There is an excellent article to help you understand these here. If you haven’t had surgery or radiation, and are just deciding what to do, some of these tests can be done on your biopsy. I once wrote a blog about the challenging decision of choosing a method of primary treatment that is still relevant here.

However to be really up to date, you may wish to look at the research going on for any of the more advanced prostate cancer conditions. For this, you should become familiar with and use the NIH website, Clinicaltrials.gov. To help you with this, I have done some preliminary searches for different conditions, but recognize that the terms you enter change what you see, so regard this as just a start. Pick your condition, and click on it and you will find some trials that are ongoing (I preselected “recruiting”) for some common situations. If you don’t see your situation, play with the search terms yourself.

High risk after surgery based on pathology
Rising PSA (biochemical failure) after surgery or radiation
Known metastatic disease (spread to bones or nodes on scans) never previously treated
Rising PSA or new metastases on scans while on hormone therapy

Now, taking the last example which gave links to 160 studies, you can narrow the search results by using the pull down menu on the search screen, starting with country. Note that limiting to the U.S. drops the available trials from 160 to 93. Adding the state, Colorado, drops it to 14 studies, etc. Maybe you have a relative in a certain city or state you could visit if a trial fits your situation. If you would like to look only at immunotherapy trials, try entering the term, “immunotherapy”.

Next, let’s go further into one trial. Let’s say we are interested in the NIH immunotherapy trial being conducted at the NCI. If you scroll down, you can see what will be involved:

Screen Shot 2019-10-05 at 12.48.14 PM

Next, since the devil is in the details, you need to know if you are eligible for this trial. Continue to scroll down to the Eligibility Criteria section. Here you find what clinical conditions you MUST have (Inclusion Criteria) or MUST NOT have (Exclusion Criteria).

At this point, you should understand how it would be almost impossible for your physician to stay up on all of the trials. YOU are now the “information guide” and if you are interested in whether a certain trial (or even an approach you have found that might be something you could do outside of a trial) could be useful in your case, you should make an appointment to speak with your doctor about the trial/approach. Recognize that this will probably take more time than your “usual visit” and notify the clinic you will want extra time to discuss this. Print out the relative parts of the trial so you can show it to her/him, and ideally have your meeting in an exam room with an internet-connected computer so you can search through details together. If there are questions, each trial has the phone number for a contact person (typically a research nurse), and since your physician may be able to answer questions you would have trouble finding in your record, this phone call is best made together from the exam room.

In our fast-moving, internet-enabled era of medicine, this is how I think medicine should be practiced. The shared burden of “keeping up” means the patient has to do his (no women have prostate cancer) or her (if you are a supportive spouse or similar) own research, help the doctor, and work on approaches as a team. Being respectful of the time involved is critical, but it CAN work. And it is much more rewarding than keeping up with tweet storms!! And if this is “not for you”, find a grandchild and choose some different adventures here. (disclaimer: I have never done this, but looks like it could be fun)

 

 

 

 

 

 

 

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Filed under General Prostate Cancer Issues, Prostate cancer therapy, Uncategorized