Tag Archives: medicine

It’s MO time – please help!


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In my career fighting for the cure of prostate cancer, two organizations (besides the National Cancer Institute) have been outstanding partners. Movember was started by a couple of friends in a bar in Australia. This became the answer to a long standing jealousy of mine for something as popular and effective as the Susan G. Koman Foundation and Race for the Cure. I often refer to our prostate cancer journey when I lecture by noting how we “crawl for the cure” while our sisters are racing. In 2016, the NCI budget for breast cancer research was $519.9 million, more than twice as much as that for prostate cancer at $241 million. This, in spite of the fact that prostate cancer deaths this year are 3/4 as common (29,430) as breast cancer deaths (40,920). It’s not a contest really, since all cancer research is moving the field forward rapidly, but Movember has been incredibly helpful in sponsoring research and advocating for us.

The other organization, Prostate Cancer Foundation, shows how much a single individual with great connections and personal motivation can do. Michael Milken deserves enormous credit for his vision and leadership. I personally benefited from grants given out by the foundation, and even more from their amazing annual meeting that draws together prostate cancer researchers from around the world to share data and ideas. Dr. Howard Soule is a key factor in PCF’s incredible success and his name should be as well known as Susan G. Koman in my view.

I hope you will join with all of us in fighting for the cure in prostate cancer. Grow one, or support someone who is growing, and tell your friends. The progress and future has never been brighter, and our hairy upper lips should show it!

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Money, Medicine, and Me


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In an article appearing on Medscape on September 13, a Reuters correspondent cited a recent study published in the Lancet looking at doctors who tweet. Although tweeting is a form of social media I have not embraced, I did participate in an attempt to study its use in the ASCO meetings in this article. However, the Medscape and Lancet articles did cause me to think about transparency in this blog.

I began blogging at the invitation of an internet company looking for physicians who would provide content they could use. When they were successful enough, they began using pharmaceutical advertising, and I left them, choosing to pay for my own web presence on wordpress.com. However, I now realize that I should also disclose my other relationships with pharmaceutical companies. In the Medscape article, there is a reference to a government website where you can look up the payments and transactions I have with pharmaceutical companies. What it does not reveal is the nature of those transactions which I will herewith share.

In doing drug development, pharmaceutical companies rely on [mostly] academic physicians to perform clinical trials. These activities may involve grants to study drugs in the laboratory, grants to their institutions to offset the cost of data managers, IRB costs, and reimbursement for travel to discuss the ongoing trial or its publication with other physician/researchers. In the past, I have had support in all of these categories, most notably (in terms of career influences) in the development of leuprolide, the first new drug approved for treating prostate cancer in many decades back in ~1985. It was an amazing opportunity for a young faculty member to treat the first patients in the world with a new drug, eventually present the findings to the FDA, publish the results, and then participate in teaching the medical community about its use.

Since then, the landscape of disclosure has changed for the better. Now when my colleagues and I give presentations or publish articles we sign disclosure agreements revealing which companies we consult for, and there are annual reporting requirements to our academic institutions. In my case, the current companies I have consulting relationships with include Janssen (abiraterone, apalutamide), Bayer (rogaratinib), and Seattle Genetics (enfortumab vedotin). I also have founded (and have ownership interests in) Aurora Oncology, ProTechSure, and Gonex/Cedus, three startup companies attempting to move drugs we have worked on in my laboratory to the clinic. None of these relationships involve giving promotional talks, using company slides in education, or advocating for the drugs on this blog or elsewhere. For the large commercial companies they involve insuring patient safety in ongoing trials as an independent monitor.

I have expressed my concerns about the rapid increase in medical costs for cancer care here and here. I do not have a solution for this intrinsically difficult challenge in our capitalistic system, and I realize that my own consulting and entrepreneurial activities ultimately add to those costs. Indeed, the costs of prostate cancer detection and treatment in men over 70 is 1.2 Billion dollars every 3 years. The newest targeted agents and immuno-oncology agents are phenomenally expensive, often in the $8-10,000/month range which can result in severe economic distress even for those patients who have co-pay supplemental insurance. Eventually, American medicine, with all of its amazing basic science and translational science (bench to bedside research) will need to find a balance between the profit motives that drive innovation and the altruistic care that medicine embodies in its most noble applications. What is an extra 3 months of life worth, and what toxicities (economic or clinical) are acceptable to pay for that? We need to have honest discussions as a society, and importantly, with our own families about these questions, especially when we are facing the diminishing benefits of aggressive/expensive care in terminal illnesses.

 

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

A perfect death


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This week in which the country will come together to mourn the passing of a true American original, John McCain, it might be worth considering our (your) own mortality. Even as the ongoing progress toward controlling prostate cancer is underway, it remains clear that “something else” will get us. As an example, in a study I was privileged to lead among patients with high risk prostate cancer, other cancers (many of which were caused by our adjuvant mitoxantrone treatment) were as likely to lead to death and prostate cancer was the cause of dying only ~20% of the time

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As oncologists, we face the “end of life” issues more frequently than most physicians, and certainly deal with the reality of death more than folks in most other professions. I distinctly remember one lovely woman in her 50’s who was very open in discussing her wishes. She wanted to die while lying on her favorite beach in Florida watching the sunlight sparkling on the ocean – not an easy thing to arrange (and it didn’t happen). My own fantasy would be to have a lovely vacation in Hawaii (without this week’s rain) with my entire family, say my good-byes as I put them all on the plane, and stay over an extra day to pay for the hotel and be sure all of my financial affairs were up to date – then die of a heart attack on the way home the next day. Perfect. The airline would be carrying my carcass home for the mere cost of a coach seat and I wouldn’t even have to suffer that long in the crunched position with no leg room.

Short of these fantasies, however, I recently undertook an exercise that anyone could do and I herewith commend to you as well. My wife and I were lucky enough to score tickets to the London production of Hamilton last February. In it, there were two numbers that grabbed me by the heart. First was Washington’s “teach ’em how to say goodbye” song, “One Last Time”. As with John McCain’s final commentaries over the past few months, Hamilton’s farewell speech written for Washington was masterful (as is Lin-Manuel Miranda’s reprise).

But the song that most moved me to tears (and action) was “Who Lives, Who Dies, Who Tells Your Story”. After listening to it about a dozen times, I realized that we all have a story. It may not be as honest/noble as John McCain’s, or as consequential as Hamilton’s or Washington’s, but for some small group of your relatives or children or grandchildren, your story will have special meaning. If you don’t write it, your memories of your father, your grandfather, your family in general will die with you. In my case, I read a couple of autobiographies, self-published, from friends/acquaintances and decided that their stories were highly personal, and not terribly interesting. But when I started writing the story of my own grandfather and father, and my story, it was a joyful experience of reliving many happy memories, and a way of reconnecting with my first love affair, our children’s births, and the many blessings that have come my way. The result is not a literary masterpiece, but I am going to have it bound and give a copy to each of my kids to gather dust on their bookshelves.

In the arc of history, some things have not changed. “Our days may come to seventy years, or eighty, if our strength endures; yet the best of them are but trouble and sorrow, for they quickly pass, and we fly away.” (Psalm 90:10). Although trouble and sorrow are a part of life (and of dying), there can be real joy in pausing to appreciate all life has given you. Carpe diem!

 

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Filed under General Prostate Cancer Issues, Prostate cancer therapy

The Hits Just Keep on Coming


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I have a hiking companion who loves math, computers, and to a large extent, eugenics. He posits that we will eventually understand the human genome so well that we will be able to make all humans “smart” or “better” through genetic engineering. I argue back endlessly, with little success, that his definition of “smart” and “better” may not be shared  by everyone (he counters that these definitions will be left to the parents…) and that there will be unintended consequences of diving into our DNA with CRISPR/Cas9 technology.

The wonderful complexity of humankind is, of course, reflected in every single cell in our bodies and in all of our cancer cells as well. The debate over the number of synapses (or permutations) in our brains versus atoms (or stars etc.) in the observable universe is well beyond my comprehension. Unfortunately the “much simpler” question of how many things go wrong in cancer cells is also mind boggling. Hence, the phenomenal work of one of the West Coast Dream Team’s recent publications is not surprising. A reductionist view is shown in this diagram from their paper published last month:

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The scientific team, using funds from PCF, SU2C, and Movember (among others), did a whole genome analysis of metastatic tumor specimens from 101 men with castration resistant (hormone insensitive) prostate cancer. There is an excellent report on this work from the UCSF News Center here. Lest you believe that the results have resulted in an “aha moment” that will lead to “A prostate cancer cure”, you might do as I had to do and Google the word I had not heard of in the above figure, “chromothripsis“. Rather, the research leads to some very important insights that will doubtless contribute towards more effective therapy for 1000’s of patients eventually. By looking at the structural variants in the DNA that occurs outside of expressed genes, a much more complex picture of what drives castration resistant prostate cancer (CRPC) becomes evident. For example the androgen receptor (AR) is over-expressed in the majority of metastases and this study found a region of the “junk DNA” (non-coding for genes) that lies 66.94 million base pairs upstream of the AR that was amplified in 81% of the cases. This was 11% more common than the amplification of AR itself – an indication of how important the DNA controlling a gene like AR is, compared to the gene itself. So much for calling the DNA that doesn’t code for a protein “junk”!

A second example is the insight into patients who have alterations in a gene called CDK12 that may render them more sensitive to one of the “hottest” areas of cancer research, the use of checkpoint inhibitors of the PD-1 pathway I described in my last post.  This abnormality results in the cancer cells having an increased number of “neoantigens” (targets) for the immune system to attack as shown in this illustration from another recent exceptional paper.

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The ongoing research from the many scientific teams focused on prostate cancer is awe-inspiring when you consider the complexities involved in the two figures in this post alone. Even getting a complete picture from a single patient is impossible, given the genetic instability and the variable mutations found in different metastases. Remember, this team looked at the DNA from only one (or a few) of the many metastatic sites found in each patient. Other studies have shown lots of different mutations depending on which site is evaluated as I reviewed here.  In spite of all of this complexity, the ability to at least begin to understand what is going on “underneath the hood” is the way forward, and just as we can recognize Fords vs Chevys vs Toyotas, “brands” that emerge from such studies will lead to treatments that are more appropriate for certain classes of patients. As we have known for a very long time, the most common feature is the “gasoline” of testosterone, and how it fuels the amplified AR has remained an effective target for the newer drugs like abiraterone, enzalutamide, and apalutamide. Perhaps studies such as this one will lead to a way of kinking the hose upstream of the gasoline nozzle, or throwing sand (immunotherapy) into the engine itself. But… to admit that we will never understand it all (or design the “perfect human”) still seems an appropriate expression of humility to me.

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Of Prostates and Teslas


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

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

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

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

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

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

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

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

The billionaire cancer researcher


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Several patients/friends told me this week about the 60 Minutes piece highlighting the ongoing efforts of Patrick Soon-Shiong, a surgeon who was involved in the development of abraxane and has become worth $11B as a result. So I did my duty and watched on the Internet tonight and will share my thoughts with you loyal followers. Let it first be said that the optimism in this video is compelling, and for the most part based on science that has been going on for the past decade or so in labs all over the country. The 60 Minutes team working with Dr. Soon-Shiong highlighted in a visually compelling, and mostly understandable way, the progress that is being made using the latest technology and understanding of cancer biology. I will highlight this as follows: 1) massive computer technology and sequencing advances allow “all” of the mutations that characterize a cancer cell to be displayed. 2) Drug development to attack vulnerable biologic pathways within cancer cells is accelerating. 3) The possibility of finding the gene mutations driving these cells by looking at circulating tumor cells portends a [mostly] promising way of sampling what is going on within a patient, yet not having to biopsy the tumors. 4) The recent breakthroughs in enhancing immune responses to tumors by shutting down the innate immune checkpoint controls appears to offer great promise for “wiping out” residual/resistant tumor cells.

With that summary, let me urge anyone who watches/watched the video to pay close attention to my good friend, Derek Raghavan’s commentary. Derek is one of the most insightful and honest translational medical scientists I know. In essence, he points out that although Dr Soon-Shhiong is applying an “all of the above” approach to the attack on cancer, there will still be enormous amounts of work to be done and thereby hints at the problem I have  with the video – overselling hype/hope is a specialty of the media. Presenting the single patient with pancreatic cancer who is doing well is an example of this focus on the “sizzle and not the steak” approach. I take nothing away from what a billion dollars can do to pull the existing technologies together and applaud Dr. Soon-Shiong’s efforts. As a matter of fact, one of the techniques he touches on, using low continuous doses of chemotherapy, is something we may have been the first to try in prostate cancer several years ago and published here.

So what are the cautionary issues? 1) The sheer number of mutations found in most cancers (and perhaps especially prostate cancer where the term “shredding of the genome” has been used, make attacking ALL of the pathways at once nearly impossible.  If even one cell can further mutate in the face of having, say 6 or 7 drugs being given to shut down the mutations, it will survive to become the dominant and lethal metastatic problem. This is layered onto the challenge of using “all 6 drugs” together, which will more than likely compound the toxicities to the host when compared to using one of them at the optimal dose. 2) Tumor heterogeneity. In an incredible tour-de-force, a team of scientists at the Cancer Research UK London Research Institute  did whole genome analysis of the original kidney cancer in four patients as well as in their metastases. The graphic of how the research was done is shown here:

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Each spot in the original tumor as well as each metastasis had a somewhat unique set of mutations. Thus “personalized medicine”, the favorite buzzword of the moment in medicine, has a huge challenge in cancer, since there might be different combinations of drugs required for each metastatic site in some patients. The same might apply even for the evaluation of individual circulating tumor cells of course, which is now possible. A cell coming into the research syringe at one time might reflect a tumor deposit in one area, while the next cell isolated could be coming from somewhere else. 3) The excitement over using the most clever of the immune approaches, including the checkpoint inhibitors and the CART cell approach have significant challenges, either because of unleashing autoimmunity, or the very high costs of manipulating each individual patient’s T-cells in order to come up with the autologous cancer-fighting cell treatment.

So, here’s to the optimism and billionaire strategies, and we all hope it moves forward quickly and successfully. And here’s to 60 Minutes for highlighting the amazing biology and progress that is being made. Hope is one of the keystones of human progress, whether it is landing on Mars or repairing a broken relationship. Love and hope are what make life worth living. May your holiday celebrations be filled with both!

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Is medicine a profession or a business?


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I have been thinking about writing a blog like this for some time. So first let me make some disclosures: ONE: I am generally a “liberal” and would favor a single payor health care system. TWO: I grew up in a small town in Nebraska where the local doctors were beloved, cared for the families in our town, and drove Buicks (BMWs, Teslas, Lexi, etc. were unknown – the two bankers drove Cadillacs) THREE: Medicine was much less complex, much cheaper, and much less effective. FOUR: I have had a wonderful career in academics where I received a paycheck from the State of Colorado and was usually required to earn >90% of my salary through grants or clinical earnings – I could talk more about “tenure” if anyone is interested. Academic salaries are generally less than private practice, but the advantages of no/minimal night call and working with residents and students and exploring new treatments in the lab and clinic are great rewards that can’t be measured in dollar terms.

With that out of the way, I remain saddened by what has happened to my profession. For all kinds of reasons, many physicians now consider themselves as much “small businessmen” as they do physicians. As the business of medicine has become more and more complex, they provide jobs for increasing numbers of staff, pay higher malpractice premiums than they used to, and look for ways increase their incomes. But few if any are missing any meals, and many are privileged to be in the top 1% of wage earners. Nothing wrong with that.

BUT… This week’s New England Journal article exposes a very disturbing issue that I happen to know a lot about. Some urologists, who only a decade ago were constantly arguing with their radiation therapy counterparts on how much better surgery is for treating prostate cancer, have been buying radiation therapy equipment and hiring “their own” radiation oncologist to run the equipment, then self-referring. The reason is obvious and it has nothing to do with what is best for patients. It is to increase their already very substantial incomes, which (to be fair) have been decreased somewhat by lesser reimbursement for surgery, less for giving lupron, and no doubt other cuts. The outcome of radiation and surgery treatment in terms of cure is the same. The side effects are somewhat different and deserving of discussion with each man who chooses treatment. The figure shows the magnitude of this trend.

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There are many examples of similar trends when doctors stand to make money by ordering tests, buying their own equipment, setting up their own “surgicenters”, or in my own subspecialty, giving one chemotherapy that has a higher reimbursement than another that is equally efficacious. Other articles have dealt with how hospitals maximize their profits with the “chargemaster”. And still others have dealt with the practice of pharmaceutical companies charging huge amounts for novel drugs – expensive to develop for sure, but also hugely profitable.

So the answer to my question seems to be that medicine is both a profession and a business. My view is that the patient should always come first, not the pursuit of profit. Thus there is a built-in conflict if the goal of business is to make as much money as possible. Herein lies the challenge for our health care system. I don’t have any idea if the ACA will help, but I do know that the current system is in dire need of reform, and that the entering medical students who say they want to be doctors “because they love science and love people” will have a long ways to go in realizing that dream if there aren’t changes.

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October 27, 2013 · 5:29 pm