[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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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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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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Blood tests and stopping medications


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I have been struck by how many patients ask me to measure their lipid panels as we work our way through the management for their prostate cancer. To be sure, it is important to know about cholesterol, triglycerides, and cardiac risks for both men and women. If you have never had a fasting lipid panel, you should get one. If you are not on a statin, you might consider that and read about the benefits for prostate cancer patients in one of my previous posts here or here. Knowing about cardiac risks for the general population is a terrific public health idea, and you can check out your own risks here. (If you are otherwise healthy, with good blood pressure and a non-smoker, it is sobering to play with that calculator and watch what happens to your risk with increasing age…the one thing you can’t do much about!)

But why continue to worry about heart disease once you have prostate cancer, especially if you have metastases and become resistant to hormonal manipulation? Do you need to continue to take your statin? There is a reasonable literature looking at the downside of polypharmacy in patients as they age, and the potential cost savings, and even improvement in quality of life by stopping some medications. Read this brief article for a good discussion on the topic.

Expanding this thinking to what blood tests we should worry about and how often to do them is an important exercise. In particular, I think we are all addicted (often too addicted) to the PSA test as I discussed in the PSA clock blog. There were many  comments pointing out the necessity of following PSA to know the efficacy of changing treatments, and I agree with that. On the other hand, obsessing about PSA can definitely be a negative for your mental health and enjoyment of life. Don’t fall for the idea of daily measurements if someone comes out with a finger stick blood test for PSA!

Testosterone measurements, on the other hand, may be too infrequently measured in caring for prostate cancer patients, and compared to the costs of the newer ADT agents, or even the GnRH injections, they can be highly cost effective. A quick search suggests that measuring your T could be as little as $50 or probably 2-3x that in a hospital. If you have metastatic prostate cancer it is key to have the T level as low as possible. Some cancer cells become hypersensitive to even low levels of circulating T by over expressing the androgen receptor, and of course this led to the research on further blocking testosterone synthesis  by drugs like abiraterone or the receptor by the “lutamides” (bicalutamide, enzalutamide, apalutamide, duralutamide). These drugs can cost in the range of $10K/month, so measuring T levels has minimal impact on the overall cost of care. However, in two abstracts presented at the recent ASCO meeting, the possibility of stopping GnRH injections in patients on abiraterone was studied. It makes sense that if abi completely blocks T synthesis in the testis, adrenal gland, and cancer cells, you might not need the injections. There is a good review of one of the abstracts here. I had always wondered about this, and it was nice to see it studied. The cost savings if this became a standard could be in the millions. (caution however – would need to be studied more carefully, and if someone missed abi doses, very rapid T increases would be seen due to high LH levels no longer suppressed by GnRH analog injections).

I realize this is far into the weeds for most patients, but maybe a take home message could be to discuss measuring your T levels once in a while with your physician, rather than just the PSA. And maybe you could go over what meds you might consider stopping at this point in your care. We doctors are too often pill pushers and as I try to say to every patient at every visit, [Please CLICK ON THIS ONE:] there is nothing more effective in general than increasing your exercise – often as effective as ANY additional pill or blood test!

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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)

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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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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