Category Archives: Prostate cancer therapy

March 15, 2020 · 10:17 am

(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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February 26, 2020 · 3:17 pm

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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October 5, 2019 · 12:20 pm

[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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September 8, 2019 · 5:53 pm

ADT and Alzheimer’s Disease: risk/benefit


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The July 3 issue of JAMA Network contained a disturbing article regarding the risk of developing Alzheimer’s disease or dementia following use of androgen deprivation therapy (ADT). Using the SEER-Medicare database, the authors identified a cohort of men aged 66 or older who were diagnosed with localized or advanced prostate cancer between 1996 and 2003. The data on what happened to them in the next 10 years were then analyzed according to whether they received ADT or not in the 2 years following their diagnosis.  These were older men (74-76) who mostly lived in metropolitan areas, and 3/4 were caucasians, 2/3 were married, with just over 1/3 coming from low socioeconomic backgrounds. There were 62,330 men who received ADT, and 91,759 who did not in the final groups analyzed.

With a mean followup of 8.3 years, the risk of developing Alzheimer’s disease among the control group was 9.4% but increased to 13.1% if the men received ADT (P<0.01). Similarly, a diagnosis of dementia increased from 15.8% to 21.6% with ADT exposure, and there was evidence that the longer the men were on ADT, the worse the risk. These data are disturbing to me on two levels. First, I was unaware that 75 year old men have such a high risk for developing Alzheimer’s disease or dementia in their next decade; and second, as a frequent prescriber of ADT for men with prostate cancer in general, and particularly for those receiving curative intent radiotherapy for high risk disease, it adds to the challenge of how long to recommend such therapy (if at all). The risk curve for Alzheimer’s is shown in this figure:

Screen Shot 2019-09-04 at 2.58.07 PM

The benefit of adding ADT to curative intent radiotherapy has been demonstrated in a large number of studies dating back to the 1990’s. For example one of the most cited studies compared the survival and prostate cancer specific survival of adding 3 or 6 months of hormone therapy to radiotherapy in patients with advanced local disease. The advantage of 6 months (compared to none or 3 months) of ADT is shown in this figure, and is about 10%, somewhat better than the increased risk of developing Alzheimer’s that is probably created.

Screen Shot 2019-09-08 at 6.19.23 PM

The details of these kinds of comparisons are quite complicated – for example trying to separate out various categories of “high risk” or “higher risk” prostate cancer, etc. as reflected in this editorial by Dr. D’Amico. Numerous other studies continue to support the use of ADT to improve outcomes of radiotherapy – the challenge being how long to continue it and weighing toxicities (cardiac, quality of life, dementia risk, etc.) vs the advantage in terms of prostate cancer control. Dr. D’Amico looks forward to better information in his final statement, “During the next few years, data that will shed light on whether more than 6 months of AST is needed to prolong survival in men treated with RT for localized high risk or locally advanced prostate cancer will be provided by the completed EORTC randomized study 22961.” Stay tuned, and if you are told to take ADT to improve the outcome of radiation to your high risk localized prostate cancer, discuss the details with your physicians! How old you are, what is in your family history, and your own thoughts regarding risks of prostate cancer recurrence/death or dementia are important issues.

 

 

 

 

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June 26, 2019 · 9:22 am

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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April 9, 2019 · 9:38 pm

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)

Screen Shot 2019-04-08 at 5.01.55 PM

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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March 9, 2019 · 10:56 am

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:

Screen Shot 2019-03-09 at 10.14.33 AM Screen Shot 2019-03-09 at 10.22.35 AM

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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February 18, 2019 · 3:02 pm

Tweet Storm from ASCO GU


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The American Society of Clinical Oncology (ASCO) along with other professional societies sponsors an annual symposium focused on GU cancers, with a day and a half devoted to prostate cancer. You can view all of the abstracts on screening, detection, and management of localized disease here. If you have an area of specific interest (for example, the use of MRI in detection) you can use the search function on your browser to find articles of interest. On the mac, it is “command+f” keys for both safari and chrome. You then type “MRI” into the box and use “command+g” to scroll through all of the abstracts. You come up with very interesting new information like an abstract on page 108, “MRI targeted biopsy dramatically increases detection of clinically significant prostate cancer while reducing the risk of indolent cancer detection.”

If your interest is more on the newest studies for advanced prostate cancer, you can go here, and do the same thing. What you will find, of course, is that the avalanche of information is pretty hard to digest. When we started ASCO OnLine in the early 90’s, the technology was limited, but now it overwhelms. We are left to hope that the experts who select the most important abstracts to be presented will have done a good job, but that presumes they know our individual interests, which of course they can’t. When tweeting became available, I decided I was too old. I did sign up for a handle, @ascotwit, that I used in a couple of meetings but in general, I haven’t found twitter to be very helpful, even though some of my younger colleagues tried to help me and we even wrote an an article about it. (…I certainly don’t think it is a good way to run a country…but I digress).

So to you, my loyal followers, and with no attempt to correct spelling (why should I if the leader of the free world doesn’t do it?), here are the tweets from the oral abstract presentations that I would have sent out if I was a twitter user:

Ipi + novolumab – “checkmate 650) therapy duration  only 2.1 or 1.4 months. Only 1/3 reached maintenance phase with ~1/2 of patients dropping out for toxicity. compared to patients in melanoma trial getting about 4 doses.“if you can’t get the drug in, you can’t see a response” 25% of patients had a response in cohort 1. They tend to respond early The subsets are those who had PD-1 positivity or high tumor mutation burden.

  • Scher assay. Getting to CTC 0 was useful in predicting better survival and was better than looking at a drop of 50% in PSA. The development of a show term outcome marker remains elusive. 46% of the patients who lived 13 weeks were not included because of not enough CTC’s
  • #140 ARAMIS study – efficacy and safety of darolutamide in nmcrpc.  Different structure than end and app and does not cross blood/brain barrier. men with no mets and psa dt <10 months. ADT + placebo vs dark. met free survival 18 months vs 40 months . overall survival 83% vs 73% placebo at 36 months. also improved time to pain, time to skeletal, time to cytotoxic chemo. Tolerance was excellent with no difference in AE rates. Fatigue 15.8% vs 11.4% (see nejm this week)
  • Final analysis of Phase III Latitude study. High risk met castrate naive pca newly diagnosed
    • High risk gleason >/= 8
    • Abi vs placebo + ADT. 
    • Final analysis showed hazard ratio of 0.66. OS 36.5 months vs 53.3 months. Time to pain progression was much longer (see slide). High volume patients clearly benefited most
  • #687 ARCHES trial ADT +/- Enz
    • included both low and high volume CHAARTED criteria, as well as could have had prior docetaxel or not. 2/3 had gleason 8-10; 18% had prior doce in the hormone sensitive setting
    • Primary endpoint was rPFS or death. secondary: time to spa progression, new rx, spa undetectable rate objective response rate
    • rPFS HR =0.39 across all subgroups including those who had previous doce Time to spa progression was 91% at 12 mo vs 63%. 68% got 0 psa vs 18%. 
    • Fatigue and hot flashes were worse but mostly grade 1/2. 93% of patients still alive. at 14.4 months
    • DISCUSSION
    • Is M0 crpc really important? New imaging techniques – does it even exist??. Inflection point of doubling time <6mo is important predictor (matt smith curve). Cost: for Enz 220k/year of life saved. PFS2 is the time to progression or death on the theft therapy. The Latitude trial suggests delay in time to next endpoint.  
    • Cost for abi/p is still 10k/mo but generic is now approved
    • discussion of which one to use. not strictly comparable patient populations. need cost effectiveness randomized trial?
  • # 2 Choline scan can replace conventional imaging, but has poor negative predictive value – identifies mets earlier but no way to say that the earlier management changes makes any difference.
  • #144 – small. initiation of apalutamide early may result in prolonged effect looking at psa2 See screen shot. Earlier treatment for non-metastatic disease is likely better than waiting for mets. There are 3 potential agents (enz, apa, dur). Delaying time to symptoms is also very important. Suggests that anything you add later still does not make up for starting early.
  • #365 – yu. Pembro + olaparib in doce pretreated patients with mCRPC. Needed disease progression after doce, randomized to cohort A Pembro + olap 68% had measurable disease. 41% with visceral disease. None of the patients had DDR mutations by biopsy or circ. dna. 12% response rate. 39% had some measurable disease response. they will expand from 42 to 100 patients. Continue randomizing to other cohorts.
  • #146 Chen Genetic drivers of poor prognosis and enz resistance in mcrpc. 86% patients had ar gain. Complete biallelic loss of RB1 median OS 14.1 months vs 42 months (not looked at in association with enz resistance -they didn’t look). WNT btea catenin pathway was highest abn asso with resistance. CTNNB1 mutation found only in enz resistant patients and was also associated with  poor prognosis similar to the RB1 
  • #147 – compared 3 arms. MDT upfront with SBRT. vs abi/ADT up front vs ADT up front. Assumed 10 years. Markov model. Looked at  cost effectiveness. ADT upfront low cost/low effective. Abi/ADT is not cost effective compared to MDT. Willingness to pay threshold of $100,000/qaly. Costs would need to decline by 90% to be the dominant strategy. MDT is a cost effective treatment. Did not look at MDT + upfront ADT with or without abi. Model assumed 1-3 extracranial metastases using data from STOMP and M1 Stampede.
  • #148 Doce +/- enz CHEIRON study. N=246. Combo arm more toxic with neutropenia. disease control 89% combo vs 73%. But no difference in overall survival but most patients did go on to receive 2nd gen adt.

Reading through them, with misspellings, poor wording, and probably containing some real errors (don’t rely on this “tweet” – go to the abstract to verify anything above) I realize how challenging it is to keep up these days. My best suggestion to ALL cancer patients is that they find a physician who is focused on their particular disease if at all possible. I fear the era of being a general medical oncologist is over (and certainly over for a 71-year-old like me). While any of us could use the NCCN guidelines (or other practice guidelines from organizations like ASCO or AUA) to care for patients, there is little that can replace the actual experience one gains by participating in the development of new agents that are rapidly coming into clinical use these days. If you can think of a solution, don’t tweet to me because I have no idea how to use it and don’t “follow” many people. However, I welcome your comments on this old fashioned blog, and can even throw in an emoji (of sorts):   😉  Have a great February and remember, the prostate is our only heart shaped organ.

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January 19, 2019 · 6:26 pm

Prostate Cancer and “the art of aging”


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As all of us septuagenarians (and probably octogenarians) know, and as Gilda Radner entitled her book, “It’s always something.” In it, she goes on to say, “I wanted a perfect ending. Now I’ve learned, the hard way, that some poems don’t rhyme, and some stories don’t have a clear beginning, middle, and end. Life is about not knowing, having to change, taking the moment and making the best of it, without knowing what’s going to happen next. Delicious Ambiguity.”

For most prostate cancer patients, the challenges presented by that diagnosis occur at a time of life when one is forced to admit that the sprained ankle doesn’t heal as fast, gray hairs are appearing, and/or your hairline is receding (or the bald patch growing), and there may indeed be as much life stretching out behind you in the rear view mirror as lies ahead. While one can choose to fight the cancer with every possible modern intervention, it is also true that there will be other challenges awaiting just around the corner, and it is impossible to handicap the inevitable threats to your health, of which prostate cancer is but one.

Recognizing this, and realizing that we spent two decades over-treating many patients, gave rise to the current option of “active surveillance” for men with low grade disease (Gleason 3+3, some 3+4). One of the most mature studies of this approach was published in the NEJM just last month. Peter Albertson, writing in F1000, nicely summarized the key findings from the article:

“First, the most powerful predictor of long-term outcome remains the Gleason score. Following surgery, men with Gleason 4+3 disease have an almost six times greater risk of dying from prostate cancer and men with Gleason 8 or 9 disease have an almost eleven times risk of dying from prostate cancer compared with men with lower grade Gleason 3+3 or 3+4 disease. Second, radical prostatectomy can provide improved outcomes, lowering the absolute risk of dying from prostate cancer by 11.7% and extending life by almost 3 years. Third, younger men less than 65 years of age at diagnosis are much more likely to benefit from surgery when compared to older men. Fourth, men with low grade cancer (Gleason 3+3 or 3+4) appear to have comparable outcomes and rarely died following surgery. The article was silent concerning the relative clinical outcomes of surgery and watchful waiting in this group of men. An important caveat to remember is that most men participating in this trial were diagnosed based upon clinical findings, not from testing for prostate-specific antigen. As suggested by data from the PROTECT trial, screen detected prostate cancer appears to introduce a lead time that could be as great as 10 years. This confounds estimates of the efficacy of surgical treatment especially among older men.”

I just submitted my own take on the active surveillance vs prostatectomy trial as follows:

“There is little to add to Dr. Albertsen’s excellent review although there are a few issues I would add as important perspectives in these kinds of long term followups. First, as a disease of aging, prostate cancer has many competitors in terms of cause of death. 261/347 (71.9%) men in the radical prostatectomy group and 292/348 (83.8%) men in the watchful waiting group have died from any cause. Of the 261 men in the prostatectomy group, 71(27.2%) died from prostate cancer while in the watchful waiting group, there were 110 deaths from prostate cancer (37.7%). From this perspective, prostate cancer is important, but far from the “most” important cause of death with ~2/3 of men dying from other causes regardless of what we do. Second, one needs to consider the quality of life (QOL), and this paper clearly indicates that many men develop metastases, requiring ADT with its side effects and this is reduced by prostatectomy, while the side effects of prostatectomy itself also take a very high toll on sexual function and a lesser, but significant risk of incontinence. If our goal is to “first do no harm”, the challenges of caring for men as they age remain with us, even as our technology for discovering earlier disease (in prostate cancer) and treating late disease (from any cause) advances.”

But there is something we can do to combat both prostate cancer and aging! Vigorous exercise. In a study performed at two hospitals in Canada and the UK, total and vigorous physical activity resulted in fewer men having worsening prostate cancer while on active surveillance. Further, retrospective studies demonstrate similar advantages even for men with metastatic disease. And if you don’t have prostate cancer, feel free to look at the 100’s of articles showing improved quality and length of life you can achieve with exercise (compared to minimal/no benefit from supplements). I’m also a fan of Fred Bartlit’s book, “Choosing the Strong Path” and his crusade to age gracefully by pumping iron. So the message is clear, even though “it’s always something” as we age or fight our cancers, we have it in our power to do something. Enjoy your time on the treadmill folks!!

 

 

 

 

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December 15, 2018 · 4:36 pm

Ho, Ho, Hox


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Fruit flies are a fascinating scientific resource to consider if you can get beyond your annoyance when they appear in one of those lovely boxes of ripe fruit you receive from a relative this time of year. (Just be thankful it wasn’t fruitCAKE!). For some great reading on the topic, I highly recommend a book, “Time, Love, and Memory“, the story of Seymour Benzer and how his graduate students figured out how different genes are involved in these creatures’ sense of time, or how they do their mating dance or remember whether they shouldn’t put their little leg down into a beaker and get a shock.

As with their behavior, there are wonderfully complex genes that also control how they develop from a single fertilized egg into an adult fly. These are called homeobox or “Hox” genes and it turns out their analogues are conserved throughout the animal kingdom. In this nice review of their functions, the following picture shows how the gene family controls development in the anterior – posterior development of the fly AND the mouse embryo.

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Screen Shot 2018-12-15 at 3.39.27 PMWhen things go wrong in the fruit fly (Drosophila), you can get a fascinating mutation that makes the fly look like this, with legs appearing where there should be antennae. In humans, analogous mutations can result in having extra fingers or malformations. You can read in more depth about how the Hox (a subset of the master homeotic regulator) genes are regulated at the Kahn academy in this article.

OK, you say, but what could this possibly have to do with prostate cancer? Ah, that’s what I find fascinating. Cancer is a superb example of dysregulation of the genetic programs that make cells behave. By the time you get to an animal developing a prostate gland, there are countless regulatory genes that must each turn on or off at the right time in embryogenesis. And just as “ontogeny recapitulates phylogeny“, oncology recapitulates ontogeny. One of these homeobox genes, HOXB13 was discovered to be mutated in studies of families with hereditary risk for prostate cancer by Johns Hopkins investigators several years ago. This gene interacts with the androgen receptor, so it makes some sense that the prostate gland would be affected by mutations. Further studies of families with this mutation indicate that if you inherit one copy of the G48E mutation, your risk of developing prostate cancer is 2.6 fold increased.

Whereas testing for such genetic mutations (and many others) used to be the provenance  of research labs, we are entering a time in medicine when genetic testing is becoming “mandatory” for best practice care. The following criteria are now used to help discern who might benefit from such testing:

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This table comes from a company, Myriad, that is now advertising for its own cancer risk gene panel, but there are several such companies and panels of genes. Although we (I) still don’t send off a genetic panel test to Myriad, Foundation Medicine, Invitae or the other companies in all patients, we are rapidly approaching the time when that will be standard. The challenges (as outlined in this article) are which genes should be tested, and what to do with the results. Some mutations such as those involving DNA damage repair, are already recognized as useful in directing therapy. For now, it is a topic best discussed with a genetics counsellor, and I fear, even more importantly one with an interest in prostate cancer if you can find one. Most of us physicians are struggling to keep up with which panel (if any) to order and when to order it.

So just remember when you see that little fly emerge from your fruit box this season, he/she/it has made immeasurable contributions to cancer research, and be thankful for all the science that is helping us to understand our amazing world.

 

 

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