Tag Archives: prostate cancer

PSMA PET-CT scans for Prostate Cancer


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PSMA stands for Prostate Specific Membrane Antigen, which is a protein (enzyme) that is expressed on the surface of prostate cancer cells (and on a few other cell types). As with many cell surface proteins, you can find ligands that will bind to the protein, and then label these with radioactive isotopes that allow imaging. PET stands for Positron Emission Tomography, and of course, CT stands for Computerized Tomography. When you put these technologies together, you obtain a powerful way to look for prostate cancer that has spread outside the prostate gland. The physics of this (how a positron interacts with an electron, releasing gamma photons at 180 degrees) is very cool, but probably of interest only to the most nerdy. (I made a cloud chamber for my 7th grade science project and my hiking buddy is a nuclear medicine doc who wrote a definitive text on the math/science of his craft…so go figure).

Prior to developing PET agents for prostate cancer, we had standard CT scans and bone scans and we used these to determine whether someone with, for example, a very high PSA or high Gleason score had cancer deposits that had escaped (metastasized) from the prostate. If so, it was felt that putting them through surgery or radiation treatments in an attempt to cure was fruitless and exposed the patient to the unnecessary toxicity risks (impotence, incontinence, rectal damage, etc.) Especially if they had symptoms (e.g. bone pain), hormone treatment reducing testosterone was the best approach. If you had a rising PSA several years after local treatment, the question was always, “Where is the cancer?” but the sensitivity of routine bone and CT scans was quite limited not showing anything until the PSA reached 10 or so at which time ~1/2 of scans would be positive. Screen Shot 2020-04-26 at 7.26.14 AMThis figure illustrates the difference in sensitivity. A normal sized lymph node on CT scan (left) is revealed to  contain prostate cancer with the PET isotope technique (right). At present, the only approved PET scan in the U.S. is fluciclovine, the “Axumin” scan, which the FDA approved for detecting cancer in patients with rising PSA, but not in newly diagnosed patients. In several studies PSMA-PET CT scans are even more sensitive (about 3x) than Axumin. At the risk of calling up an overused phrase, “this changes everything”.

First, it is clear that many high risk patients we would previously have treated with surgery or radiation to the prostate hoping to cure them might now be found to have prostate cancer deposits outside of the treatment target (prostate or prostate + pelvic lymph nodes). A superb study in this month’s Lancet found that PSMA PET-CT scans provided higher sensitivity (85% vs 38%) and specificity (98% vs 91%) than routine bone and CT scans in high risk patients (PSA >20, Gleason 4+3 or worse). Does this mean we shouldn’t treat the prostate in high risk patients with positive scans? In the study, conventional imaging changed the management in 15% of men, while PSMA PET-CT imaging changed the plans in 28% (p=0.008). Should all high risk patients have a PSMA PET-CT before deciding on treatment? Should the FDA approve this scan quickly? (It is currently available only in research centers and not covered by insurance…read my blog on how to search for such studies or click here).

Second, what about treating a small number of prostate metastases (oligometastatic prostate cancer) in a patient who was treated years ago and now has a rising PSA? Ongoing investigations suggest this might delay the need for hormone therapy in such patients or potentially even cure some of them. But the PSMA PET-CT isn’t perfect. How high do you let the PSA go up before ordering such a scan? – the farther it rises, the more likely the scan will show something, but that gives the cancer more time to spread. A negative scan is no guarantee there aren’t many more foci of a few prostate cancer cells that will eventually show up elsewhere in the body. Is this some version of Whack-a-mole? And how do we define “cure” anyway?? (My personal definition is that you die from something else, regardless of your PSA or scan results).

Finally, since even at research centers the PSMA PET-CT scan may cost you $3,000 or so, is it worth it? It is “free” in the European health care systems, but we all know nothing is free – even if Medicare pays for something it costs society and ultimately must be accounted for in terms of value. Medicare covered PSMA PET-CT’s vs fixing pot holes and bridges? How about finding a treatment for SARS Co-V2 instead? No easy answers, but if you are like me, homebound as a “high risk” senior citizen, plenty to think about. Wash your hands, wear your mask, and enjoy your grandkids on Zoom!

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Filed under General Prostate Cancer Issues, Oligometastatic prostate cancer, Prostate cancer therapy, Targeted treatment

COVID-19, ADT and Prostate Cancer


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Spoiler alert: As I start to write this, my intent is to delve into some basic science readers may find too detailed/complex and some speculation that has limited/no support and should NOT be taken as anything other than hypothesis generating. I fell in love with biology in about the 8th grade and with thinking about how to answer biology questions in medical school, so this is more self-indulgent writing rather than being written to inform.

Starting with the COVID-19 story, there have been so many excellent articles that if you haven’t read too many already, you can get a one minute overview from this video. Now for some more Screen Shot 2020-03-29 at 8.47.20 AMdetailed science. This figure from an excellent article in Science shows the real details of how the virus works and some of the drugs that might be useful in stopping or slowing it down at the cellular level. If you use your best “Where’s Waldo” approach, (and if you are an avid follower of prostate cancer biology) you may find a very familiar protein hiding in the membrane where the virus binds to the exterior of the cell, TMPRSS2. This protein is an enzyme in the family of serine proteases, proteins that can cut peptide bonds at the site of the amino acid serine. Trypsin is another example of this category of enzymes we use in the lab to release cells from petri dishes, and you use various enzymes every day in your dishwasher to digest proteins stuck to your dishes. As shown in the figure, TMPRSS2 plays a crucial role in the entry of the SARS-CoV-2 virus into the respiratory epithelial cells leading to COVID-19 disease.

I first heard of TMPRSS2 several years ago in a lecture at the PCF annual scientific meeting. Investigators at the University of Michigan found that in a large percentage of prostate cancer, the androgen response elements in DNA that control the expression of TMPRSS2 have become fused to an oncogene, ERG. Every gene in our DNA is controlled by “upstream” segments of DNA called promoters or enhancers that regulate the expression of the gene. In the case of prostate cancer the androgen receptor, AR, binds to testosterone (or DHT) and then the is translocated to the nucleus where it binds to DNA at the sites of androgen response elements, leading to transcription and expression of the “downstream” genes. A reasonable analogy is to think of testosterone flipping a light switch to “on” and the AR being the wire going to the light bulb, TMPRSS2, in our case. You are familiar with this if you know about drugs like Lupron, Zytiga, or Xtandi that block testosterone signaling in various ways. Although taking any of these drugs turns off many genes related to prostate cancer development and progression, one of these genes is clearly ERG (if you have the TMPRSS2:ERG fusion), and of course you probably turn down expression of TMPRSS2 in normal cells.

So what does this have to do with COVID-19? As you may have seen, men have approximately twice the mortality of women from infection with SARS-CoV-2. There are no doubt many possible reasons. Men smoke more. Men may not practice social distancing as much. Men have more heart disease. But what if one reason is that they express higher levels of TMPRSS2 in their respiratory epithelium? The exact mechanism of TMPRSS2 in the infection can be found in this article.  A cartoon from the article illustrates the several points in the viral infection cycle where TMPRSS2 (and other serine proteases) acts to facilitate the entry, replication and budding of the virion from a cell.

Screen Shot 2020-03-29 at 10.19.32 AM

The article discusses several drugs that are being investigated to inhibit TMPRSS2 that could hopefully be effective in fighting COVID-19. One of them, camostat (seen in the first figure in this post), is already scheduled to begin clinical trial at the end of this month.

However, there is already a very interesting global “clinical trial” underway if you have followed the above (and necessarily complex …sorry!) story about TMPRSS2. If ADT, familiar to all men with metastatic or high risk prostate cancer, turns down the expression not only of ERG and other oncogenic pathways, but also the expression of TMPRSS2, it might reduce the infection rate or morbidity/mortality from COVID-19. Looking at large global databases, it may be possible to see whether men with a diagnosis of both “prostate cancer” and “COVID-19”  can be extracted from the data, and then whether within this grouping, those men on ADT have a better outcome than those not on ADT. It would be complex, of course, since some of the men not on ADT might be on chemotherapy, or more sick in general, and thus more susceptible to dying from the infection. It might also be possible to see what the expression levels of TMPRSS2 in the pulmonary epithelium of men versus women are as a potential partial explanation of the differences in mortality. Finally, and this would be the most intriguing possibility of all, a clinical trial that combined some partially effective “drug X” from the list of drugs in the first figure with or without ADT could determine whether short term use of ADT could enhance the treatment. Proof that no one ever has a “unique” idea (and of the speed with which you can share ideas in today’s internet environment), in doing a minimal amount of literature research on this topic, I came across a preprint of a beautiful article looking at exactly the hypotheses I laid out above. It was submitted only 5 days ago! The authors have found very significant differences in the levels of expression of TMPRSS2 among adults using published databases and hypothesize that this could explain why some individuals may be more susceptible to bad outcomes. They also evaluate the potential of down regulation of the gene with ADT drugs like enzalutamide or estrogens and they conclude, “Together, these results identify existing drug compounds that can potentially be repurposed to transcriptionally inhibit TMPRSS2 expression, and suggest that the activation of estrogen pathways or inhibition of androgen pathways can be a promising modality for clinical intervention in SARS-CoV-2 infection.”

In summary, if you have prostate cancer and are on ADT, the well known side effects you put up with are unpleasant to say the least. But there is a “not-zero” possibility that your ADT is also protecting you. The best advice is still to practice social distancing, wash your hands, and be vigilant regarding your health, but maybe there is a silver lining in this story. I hope so, and there are already clinical and basic scientists exploring the hypotheses discussed above. Be well and my best wishes during these trying times!

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Filed under General Prostate Cancer Issues, Prostate cancer therapy

(Love) Advice in the time of (Cholera) Coronavirus


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I wanted the title to look like this, but the software wouldn’t let me: Love Advice in the time of Cholera Coronavirus. In any case, if you are a patient or in the patient age range of prostate cancer you are automatically at some increased risk. There isn’t much evidence that cancer patients in general who aren’t on chemotherapy or an immunosuppressive agent have much increased risk. In fact, patients on ADT may actually do a little better based on reactivation of thymic function. Here is a quote from this complex article by James Gulley and colleagues:

Analyses of these data suggest that AR expressed by thymic epithelium play an important role in thymocyte development, and could explain why androgens induce apoptosis of thymocytes in vivo but not in vitro (31). In subsequent studies, androgen withdrawal led to increased thymopoiesis and reversal of thymic atrophy in post-pubertal male mice (32) and even in aged mice (33, 34). Furthermore, thymopoiesis decreased with the administration of testosterone (35, 36). Castration also results in increased T- cell export in aged mice and increased naive splenic T cells compared to aged controls (34).

Although persistent thymic function is evident in older individuals, it is decreased, as demonstrated by lower TREC [T-cell receptor rearrangement excision circles] levels (37). However, studies show that ADT can induce thymic renewal in older individuals (38). In one study, elderly prostate cancer patients given GnRH-A experienced a notable increase in TRECs in 6 out of 10 cases, indicating renewed thymopoiesis (34). These studies suggest that the effects of androgen ablation are not limited to the young, as evidenced by restoration of thymic function and export of naïve T cells after surgical (orchiectomy) or medical (GnRH-A) castration.

 

The enhanced thymopoiesis associated with ADT has important clinical implications for the treatment of immunocompromised patients and for immunotherapy for prostate cancer (see Figure 3 for a summary of ADT’s effects on the T-cell compartment). Thymic renewal in these patients may increase the diversity of the T-cell repertoire, increasing the pool of antigens recognized by the immune system. In the setting of vaccine therapy, an increased naïve T-cell compartment may enhance the response to immunotherapy.

 A few patients have asked me about whether to postpone surgery. In general, for patients with “average” (Gleason 3+4) tumors, this would probably be OK. It is a harder decision for those with Gleason 4+3, or any component of Gleason 5. It will have to be an individual decision (as are all decisions of this sort) with your doctor. The same would apply to radiation therapy treatment which can have some immunosuppressive effects, but certainly has never been studied in this situation.

In general, I would also recommend that you put aside your political biases and listen to the scientific experts. I was disturbed by a poll presented this morning on Face the Nation that indicated a significant difference in the perceptions of risk between Republicans and Democrats. This virus does not know or care about your party or politics. Practice the social isolation being recommended by Fauci and the other experts: “We should be over-reacting to this…” It would be just fine to look back and say we did that.

If you want to delve further into the science of this (which also dispels a lot of misinformation about where the virus comes from and how it arose), you should certainly look at this presentation: http://www.croiconference.org/

And in case you haven’t been thoroughly inundated with advice or just came out from under a rock, here is the succinct list of expert recommendations:

  • Social Distancing to flatten the curve of the pandemic (reduce infectivity rate from >2 to <1):
    • Wash/sanitize hands frequently
    • If sick, do not go to work
    • Work from home if at all possible
    • Maintain your personal space when around others
    • Eliminate travel (don’t be fooled by cheap flights or hotels)
    • Reduce exposure to groups of people
    • COVID-19 can persist on hard surfaces for several days so wipe down frequent contact surfaces repeatedly
    • Recognize that social distancing will have some mental health implications so be especially compassionate

Stay home. Stay well. Here is a list of things to do:  Fun Free Time Activities_

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Filed under General Prostate Cancer Issues, Prostate cancer therapy

New findings from clinical trials 2020


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There are a number of ongoing trials or completed trials that represent attempts to develop new approaches to prostate cancer. I am sometimes asked what I know or think about them (often not as much as I would like) from various investment consultants, so I thought rather than respond to a recent list, I would just use it to explain the trials for readers of this blog. Perhaps when your friends ask you whether there is “anything new out there”, you can point them to some of these.

The PROFOUND, TALAPRO-1, TRITON-2 studies are all designed to evaluate the efficacy of small molecule drugs that inhibit “PARP” which stands for an enzyme (Poly ADP-ribose polymerase) that is involved in DNA repair. It turns out that patients who inherit a damaged/mutated version of any of several enzymes that help cells maintain their DNA integrity (BRCA1/2 being an example you may have heard of – when mutated it leads to the development of breast and ovarian cancers as well) are more likely to get prostate cancer, and often it is of the more aggressive variety. It is also a frequent condition of prostate cancer metastases in patients who no longer respond to hormone therapies (leuprolide, abiraterone, enzalutamide, etc). These patients appear to be uniquely sensitive to PARP inhibitors and several pharmaceutical companies are developing them. Olaparib and rucaparib received breakthrough designation from the FDA for accelerated development. In the PROfound trial, patients who had progressed on either enzalutamide (Xtandi) or abiraterone (Zytiga) were randomized to receive the “other” new hormonal agent or the PARP targeted drug olaparib (Lynparza). As reported by my friend/colleague Maha Hussain, the olaparib treated patients fared significantly better than the patients who received the “other hormone”. The take-home message from these trials is that we now have ways to look at the molecular underpinnings of resistant prostate cancer. If you have metastatic prostate cancer, ask your physician about the genomic tests that can be done to see if you might benefit from one of these new drugs.

In a somewhat similar design, the CARD trial evaluated treating patients who had had been treated with docetaxel (Taxotere) and then progressed while on enzalutamide or abiraterone with cabazitaxel (Jevtana) rather than the alternate hormone targeted drug. Chemotherapy with cabazitaxel was the better approach. This was similar to a previous trial called FIRSTANA that looked at alternatives of mitoxantrone or cabazitaxel in progressing docetaxel treated patients. The take-home message here is that chemotherapy with cabazitaxel may be a good choice if you don’t fit the PARP profile above, and studies have shown that cabazitaxel is preferred in terms of side effects compared to docetaxel.

Finally, I will comment on the VISION trial. PSMA stands for prostate specific membrane antigen and it is expressed on prostate cancer cells. It can be used to direct pet-scanning agents to metastatic cancer deposits and these scans are currently the most sensitive ones we have for detecting prostate cancer. These scans are available at several centers in the U.S. and are now routinely used in Europe. By linking a more radioactive isotope, Lu177 to the PSMA, you can also treat prostate cancer and early results in patients with progressive hormone refractory disease have been encouraging with more than half of patients responding. The VISION trial compares this approach with cabazitaxel to see which might be the best, but in the long run, it may be possible to use both agents, and potentially to use them even earlier before resistant disease has developed.

We have entered an era when there are numerous promising options for treatment, and the key is to get as many men  as possible to participate so we can finish the trials and get these new agents approved. We also have drugs like cabazitaxel that have been approved for some time and a better idea of when to use them. Working with a team that has the expertise to guide a patient and offer the right choices at the right time is essential for the best outcomes.

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Filed under Prostate cancer therapy, Targeted treatment

Thanksgiving for an oncologist


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First, I want to thank those readers who generously helped me reach my goal of fundraising for the annual Movember effort to increase awareness and support research into prostate cancer and men’s health. If you are so inclined and want to make a last minute contribution, you may do so here: https://mobro.co/michaelglode?mc=1 My itchy, scraggly moustache is destined to come off tomorrow!

Second, it has been an incredible journey since my internship to watch the evolution of our understanding of cancer. In 1972, when my mother called to tell me (a young medical intern) she “had a little lump in her breast” – it turned out to be not-so-little, and she fought the disease for another 4 years before succumbing – we had little we could do other than surgery and in some cases radiation. Even adjuvant chemotherapy (the CMF treatment) had not been published yet. During the next decade, remarkable strides were made in finding new drugs, most notably cisplatin, that allowed cures of previously lethal diseases – especially testis cancer.

Then, while on sabbatical in Helsinki in 1986, I found an article to present at our journal club that I thought would revolutionize medicine. The PCR reaction opened the door to rapid DNA sequencing. When I returned to my lab in Denver, my PhD colleague, Ian Maxwell had already started to use the technique with his own jury-rigged thermal cycler, but it would be 3 or 4 more years until a medical student in his/her 3rd year clinical rotation would be able to tell me what PCR stood for. Recognizing there would be a generation of physicians who “missed out” on what would be the revolution, I was able to help start a catch-up course in Aspen, Molecular Biology in Clinical Oncology, that is still ongoing. As a “fly on the wall” I was able to listen to the world leaders in molecular oncology (including this year’s Nobel Prize winner, Bill Kaelin) describe their research that unlocked the mysteries of how cancer works. Fly-fishing with some of them on the Frying Pan was a bonus to be cherished!

As the cancer story unfolded, I was able to participate in many clinical trials, bringing new treatments that emerged to my patients. Thanks to the brilliant writing of Siddhartha Mukherjee, author of “The Emperor of all Maladies“, it became possible for my patients to begin to understand the nagging question, “how did this happen to me?” And now, this week, a brilliant article summarizing all we know about the genes and mutations that cause cancer has appeared in the New England Journal. I invite you to read that (it’s free online) if you want to join me in peering over the horizon to the future of cancer medicine. It is both overwhelming and humbling.

The privilege of living through the last half of the 20th century and into the 21st is one of the most amazing journeys one could ask of a human lifetime. As I ponder it, looking out on the snow I will get to ski on next week and enjoying my grandchildren and family, I am truly thankful to have been here. Happy Thanksgiving to all!

 

 

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Filed under General Prostate Cancer Issues, Movember

Immuno-Fighting Cancer Like Wildfires


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I live in what is now known as the urban wildland interface west of Denver, the kind of area prone to the devastating fires that have been scorching California. Our firewise community efforts have taught us a lot about how a single windblown ember from miles away can destroy your house, and many of us have done a lot of mitigation. But, if the “big one” comes, our best hope is to grab the family albums and head down the hill.

Cancer can be very similar. If someone walks in with widespread disease, unless it is one of the highly treatable ones like testis cancer, flying over the patient with flame retardant (chemotherapy) may delay things for a while, but often the home is lost. The earliest realization of how to do better may have come from breast cancer. William Halstead realized in 1894 that putting out the fire effectively might include getting the surrounding “embers” (lymph nodes) at the time of removing the primary breast tumor (campfire in this analogy). A century later, it had become clear that in many instances the embers had spread too far for more radical surgical approaches, but that in some cases the embers could be extinguished (adjuvant chemotherapy) before the fire got out of control.

But what if the fire could be self-extinguishing? What if there was a boy scout at the campfire with a fire extinguisher? Better yet, what if you had smoke jumpers who could parachute in and help the boy by putting out the small fires elsewhere started by the embers? Immunotherapy offers just such hope. In the 1980’s we learned that giving high dose IL-2 to some patients with particularly sensitive tumors (kidney, melanoma) could produce cures in some cases. I liken this to sending in a group of non-specialist firemen/women in huge numbers to fight the forest fire doing the best they can.

Sending these individuals to more specialized training resulted in Provenge (sipuleucel-T), the first “vaccine” approved for treating any cancer, prostate being the target, and I was fortunate to participate in some of the first trials of this approach. But what was needed was both more effective equipment (in this case the PD-1 inhibitors that can “extinguish” the cancer’s ability to turn off the immune response) and more highly trained firefighters (potentially think of CAR-T cells) who have advanced skills, graduate degrees from a university, and can be deployed to go in search of the embers.

Now to torture this analogy just a bit further, let’s imagine that rather than sending the firefighters to universities for advanced generalized training, we could send them to CIA camps where they would receive the most specialized training possible right at the site where the fire started. In cancer, this may be the idea of using cryotherapy or irreversible electroporation to kill the local tumor, then injecting some cocktail of immune stimulatory molecules that enhance the body’s ability to create very effective T-cells that can go out as smoke jumpers looking for the embers (metastases), without the need for the university training outside the body (Sip-T or CAR-T).

Screen Shot 2019-11-11 at 8.13.35 AM

Already there are clinical trials underway with this technique that show promise. Gary Onik has demonstrated some remarkable responses in metastatic prostate cancer patients. Diwakar Davar just presented similarly exciting data in high risk melanoma patients who received intratumoral CMP-001 and systemic nivolumab before resection of the primary tumors. 62% of the patients had no tumor left in their surgical specimens! So  the cancer/firefighters are out there and although there will always be wildfires we simply can’t extinguish, the prospects for controlling them before or soon after they have spread have never looked better.

 

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Here’s your prognosis…


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Bill Farwinkle (a fictional patient) and his wife Judy are seated in two chairs in the exam room as I enter, introduce myself, and take a seat in front of the evil, glowing screen that often dominates physician/patient interactions these days. I have read through the urologist’s excellent intake notes as well as those from the radiation oncologist he saw earlier in the week. It is clear that he has been told most, if not all, of the information about his options for treating a Gleason 4+3 cancer found in 6/12 cores, plus the suspicion of a solitary metastasis in his left ilium. So, I start by asking him to tell me about his goals for today’s visit. As soon as it is convenient in the visit, I move the conversation to what he enjoyed about his import business and what he is doing with his retirement, and from there, just let them ask the questions he or Judy are most concerned about. It takes an hour more or less.

These intimate encounters are the raison d’être of my 4 decades of medical practice. Trying desperately to keep up with the molecular biology of how a loss of PTEN or the presence of a mutation in one of the many DNA damage repair genes, never mind any of the multigene panels that could be ordered, hovers over each encounter as I ponder my role in helping an individual navigate a frightening diagnosis or a change in his clinical picture. Before reading any further in this post, I hereby assign you (as is my duty, being a professor after all…) this reading assignment: “Don’t Tell Me When I’m Going to Die” (You need to click on that title and read the short article before continuing).

The promise of “precision medicine” is all the rage currently. For example, in this week’s NEJM there is an article on re-adding the clinical risk parameters to the 21-gene recurrence score now in standard use for certain breast cancer patients. In the accompanying editorial, Hunter and Longo (discussing the complexities imposed by combining clinical and genomic attributes) state, “Within these groups, both physicians and patients will have to face substantial uncertainty, and ‘educated guesses’ informed by multiple sources of evidence as well as by clinical acumen will continue to be necessary even in the age of precision medicine…”

And so, when “Mr. Farwinkle” looks me in the eye at the end of our hour and says, “I suppose you know what I’m going to ask next…” I’m fully prepared to do my best, but in my heart I realize that medicine remains an art. Does he realize that his parents’ longevity, his smoking history, his cholesterol and blood pressure, and his willingness to exercise may play as much a role as the Gleason score or any genomic tests? “How long have I got, doc?” The question hangs there as I ponder how to answer.

We all share the same prognosis: Our time is fleeting, “threescore and ten, I remember well” as Shakespeare quotes in Macbeth. How to factor in the possibility that enzalutamide or abiraterone, a PARP inhibitor, or even an immuno-oncology agent that blocks the PD-1 pathway may affect this truth by a few months or even a year or two is on the one hand hopeful, and on the other, probably irrelevant. If only I could be as eloquent as Paul Kalanithi, the author of “When Breath Becomes Air“. In his original submission to the NY Times, when he was discussing coming to grips with his own cancer diagnosis, he stated, “What patients seek is not scientific knowledge doctors hide, but existential authenticity each must find on her own. Getting too deep into statistics is like trying to quench a thirst with salty water. The angst of facing mortality has no remedy in probability.”

And so I answer the Farwinkles. “I think you are going to be fine. Regardless of your decision as to what therapy we choose, you are likely to have a good outcome initially for several years, and I will be here for you. We can get through this together and we will take great care of you. But just as I have to remind myself, every day is a gift and we should live it like there won’t be unlimited tomorrows.”

Nothing has really changed for him. Or for me. I look forward to getting to know this family better…

 

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Is it OK if I drink?


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I’m not sure exactly how one could do a prospective study on the question of drinking and cancer, but I am sure you can find thousands of articles on the topic. As I have written in the past, if you wish to do literature searches that are somewhat better than just Google, use PubMed or Google Scholar. Both of these will take you to peer-reviewed articles on anything, as opposed to “just googling” it. My search today for “drinking + cancer” on PubMed found 16,377 articles. By contrast, a standard Google search for the same two words found 295 million hits. Narrowing the view to drinking and prostate cancer at PubMed gets us to 523 articles, and “drinking alcohol prostate cancer” finds 317.

My impetus for writing this post is two-fold. First, I think that the question itself is one of the most common I am asked in my regular clinic, so it seems to be of some interest to many men. If the woman/wife who accompanies the patient asks, I am usually alerted to this being an ongoing “issue” for the man with prostate cancer. Second, I was reminded to think about the topic by yet another article that appeared in one of the journals I follow. This most recent publication was from the Health Professionals Follow-Up Study that evaluated 47,568 cancer free men from 1986-2012 during which time 5,182 (10.9%) developed prostate cancer. They started off 90% caucasian at an average age of 55, and not exercising much. (~9-12 MET-h/week which is the equivalent of walking for 3-4 hours 3 times a week at 3 miles/hr). The results of the study as stated in the abstract are:

Total alcohol intake among patients with prostate cancer was not associated with progression to lethal prostate cancer (any v none: HR, 0.99 [95% CI, 0.57 to 1.72]), whereas moderate red wine intake was associated with a lower risk (any v none: HR, 0.50 [95% CI, 0.29 to 0.86]; Ptrend = .05). Compared with none, 15 to 30 g/d of total alcohol after prostate cancer diagnosis was associated with a lower risk of death (HR, 0.71 [95% CI, 0.50 to 1.00]), as was red wine (any v none: HR, 0.74 [95% CI, 0.57 to 0.97]; P trend = .007).

A quick look at some of the other articles in the PubMed search seems to support this conclusion. For example a study in Finnish twins found similar protection from light alcohol intake while heavy drinking increased risk. A meta-analysis of 27 studies also reported a slight protective effect of an occasional drink:

Screen Shot 2019-05-17 at 8.40.07 AM

Note that a glass of wine or 12 oz of beer contains 14 g of EtOH. so that the “occasional” drinker in the above graph has a drink every 1-2 weeks.

Feel free to do you own research on the other articles, but my recommendation is that it is OK to have one drink a week (maybe even good for you) and probably red wine would be the best choice. But you should incorporate exercise into the formula and only let yourself have this if you have done 50+ minutes of vigorous exercise at least 3 times during the week. Otherwise, you are kidding yourself about “doing everything you can” to stave off the grim reaper.

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What we see and what YOU get.


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Will Rogers is said to have stated, “When the Oakies left Oklahoma and moved to California, it raised the IQ of both states.” This story has given rise to the concept of the “Will Rogers phenomenon” in medicine that is very well explained in this essay. Basically, it provides a cautionary message when evaluating new therapies in cancer medicine, because if a new study has taken advantage of newer diagnostic techniques to eliminate some of the patients with higher risk (say those with metastases), then it could easily be that an improved result is not from the new therapy, but from the ability to throw out the higher risk patients from a study cohort.

We are certainly at risk of this now in prostate cancer. In the last 5-10 years, a number of more sensitive scans have been introduced that can reveal metastatic deposits previously missed by standard technetium-99m bone scans or CT scans. Most of these rely on the technology known as PET (positron emission tomography) scanning. The first clinical PET scans mostly utilized glucose to which a positron emitter, Fluorine-18, was attached. For bone metastases, it is easy to see how much more sensitive F-18 scans are as shown in this image: (Same patient – A. “Regular” Tc-99m bone scan  B. NaF-18 PET scan)

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Suppose you have a new treatment that is for patients “with 10 or fewer” bone metastases. If you are comparing the new treatment with one that was used in the past, and you now use the PET scan (on the right), this patient would not be eligible, whereas in the past (old scanning technique) he would have been. He clearly has a higher tumor burden than 10 metastases. Hence, he is now eliminated from the new study, and therefore the new study will automatically look better in terms of outcome than previous treatments. This is called “stage migration” or the “Will Rogers phenomenon”.

For “soft tissue” metastases (lymph nodes, liver, lung, etc.) the regular Fluorodeoxyglucose FDG-PET scans were approved decades ago for lung cancer, colon cancer, lymphomas and breast cancer but they never worked well for prostate cancer. A simplistic explanation may have to do with the different metabolism of prostate cancer which tends to utilize lipid rather than glucose for energy. (see our study here). Therefore researchers looked for other metabolites that would light up prostate cancer. Acetate and choline could be labelled with Carbon-11 and worked well. However, C-11 has a half life of only 20 minutes, so making the label in a cyclotron had to be done essentially in the room next door to the scanner and injected immediately into the patient. Another metabolite taken up by prostate cancer, an artificial amino acid (fluciclovine), could be labeled with F-18, worked well and has now been approved, called the Axumin scan.  Potentially even better will be the PSMA scan, now in research mode.

The net result of these new scans is to allow physicians to answer the frequent question patients ask, “Where is the PSA coming from?” The problem then becomes the title of this essay – What we see and what You get. There are numerous scenarios. For example, a patient who comes in with a very aggressive Gleason 9 cancer and a PSA of 12.3. Should we go immediately to a routine bone and CT scan, or just order an Axumin scan? And if we find 2 positive spots, one in a rib and the other in a lymph node, does that mean the patient can’t be cured?? Five years ago, we would have never known about the metastases and we would have operated or used radiation therapy in a curative attempt. Screen Shot 2019-04-09 at 9.56.43 PMWhat about the patient with a rising PSA 5 years after he had surgery. We do a PSMA scan and find a solitary node near the left iliac artery. Should we irradiate the node? What about operating and removing it – remember, it may not look any different from all the other nodes to the surgeon. Which one should he/she take out? And what is accomplished by these efforts? Should the PSA go down (yes if that’s the only metastasis) and what to do if it doesn’t go down. Are we playing “whack a node”? How many times do we go after spots that keep showing up, versus starting some sort of hormone therapy?

There is an excellent article addressing some of these questions written by my good friend Chris Sweeney and colleagues that you can read here. A summary quote from their article states, “Given the current limited understanding of how reliable these scans are in predicting the need for appropriate management change, data-driven guidelines and standardized consensus approaches are more critical than ever.” A review of some of the early attempts to treat a small number of metastases (called oligometastatic disease) has just appeared here. One example of a paper reporting interesting results is summarized as follows: “Of the retrospective reports, the largest includes 119 treatment‐naive patients who had ≤3 sites of oligorecurrence and received SBRT to all involved sites, with 92 of 119 (77%) undergoing pretreatment choline PET. The 3‐year distant PFS [progression free survival] rate of 31% and the 3‐year OS rate of 95% are favorable and suggest a subset of patients likely benefitted from aggressive local therapy; however, conclusions from these data are limited in the absence of a comparative control arm.”

Maybe we simply have to refer back to another quote from Will Rogers, “America is a nation that conceives many odd inventions for getting somewhere but it can think of nothing to do once it gets there.” Stay tuned…

 

 

 

 

 

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Filed under General Prostate Cancer Issues, Oligometastatic prostate cancer, Prostate cancer therapy, Targeted treatment

Black holes and genetic laws


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I just finished reading Stephen Hawking’s last book, Brief Answers to the Big Questions, which I found more accessible than A Brief History of Time, written more than 30 years ago. Hawking’s abilities to explain the very (for me) abstract concepts of how no information can flow out of black holes and that the amount in there is somehow directly related to the cross sectional area of the hole was satisfying. As a very math challenged individual, I’m also a fan of Heisenberg and the perplexing issue that in the quantum/wave world of particle physics, you just can’t be certain about position and momentum. Yet, there are certain laws, like the speed of light, that are never violated, at least in the universe we live in.

So what does this have to do with genetics and prostate (or other) cancers? Here is a law: A always pairs with T, and C always pairs with G. In our biologic universe, without this law, no life as we know it could exist (prions may be an exception, but that gets too far into the definition of “life”). Yet, just as with the uncertainty of Heisenberg, the base pairing in DNA/RNA is not completely inviolable. Mistakes are made…and this can result in cancer. Cancer is a genetic disease and for anyone who hasn’t read it, I still recommend you avail yourself of the incredibly well written book, The Emperor of All Maladies. In the short time since that book was written, the explosion in our understanding of how genetic errors and cancer are related has been difficult to keep up with. The Cancer Genome Atlas (clever name, eh?) is but one example, and its use by scientists skilled in math (ugh) continues to help classify cancers based on how their mutations drive them rather than just how they look under the microscope or which organ they started in. Here is the math and the results one such analysis has on predicting survival for stomach cancer:

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As you can see, the prognosis and potentially the treatment for one subtype of “stomach cancer” might be very different for one patient than for another. Bringing this technology to prostate cancer, we already know the mutational landscape is vast. For example, this article looked at 1,013 different prostate cancers and found 97 significantly mutated genes, including 70 not previously recognized, and many present in <3% of cases. There is hidden good news in this story, in that the same mutational uncertainties that can give rise to cancer (breaking the law of AT-CG) also allows our immune systems to react to the novel mutated proteins that cancers now display. For an interview from this week’s NEJM on gene editing, click here.

Keeping up with this world of laws, broken laws, and “black holes” will be a remarkable challenge for patients and oncologists alike. My final recommendation for reading about this is a terrific article you can find here by George Sledge, one of the outstanding leaders in our field. He notes that even the most skilled oncologist, paired with the smartest of patients, will be unable to keep up. But remember this, you can’t go faster than the speed of light. That’s the law!

 

 

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Filed under General Prostate Cancer Issues, Prostate cancer therapy, Targeted treatment