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What does it feel like to die from this?

I have been asked some version of that question a number of times. Quite obviously, it is as uncomfortable to ask as it is to answer. Medical oncologists (myself included) deal with some version of this on a weekly basis and for the most part, answer as honestly and sincerely as they can – but necessarily at a superficial level. “We will do everything we can to keep you comfortable.” “When that time comes, I will be there for you and your family.” “That is a question I think we should address with our palliative care team or hospice – would you like me to get them involved?”

Yet the reality is much more complicated and if there is one word for the experience, I would pick “sadness”. For all of us, there is both personal and corporate/family sadness. We don’t want to say goodbye, and neither do our friends and family. I want to share some thoughts about that in a minute, but first I can deal with the physical/medical experience of death, which is one aspect of answering the question.

Whether you are a religious person or not, you are immortal. The carbon, oxygen, hydrogen, nitrogen, phosphorus and other atoms that make “you” will never be changed, or if they are, it will be in some sort of nuclear reaction that changes them into another element and involves incredible energy. After all, as Carl Sagan liked to point out, we are all stardust – made (or created if you would rather), from the stuff that happens when stars collapse. That is the root meaning of “disaster”. Beyond that, I happen to think that the energy you have put back into our universe in the form of words spoken, deeds done, mountains climbed, and so forth are immortal as well. “For every action, there is an equal and opposite reaction” is a physical principle we all learned in grade school science class. Thus, the butterfly wing that flaps in the mountains of Mexico and results in a cyclone half way around the world is not completely inconceivable in my view. You, or YOU… have made a difference in the cosmos by being alive. You have utilized chemical bonds that hold matter or elements together into energy and imparted that into your surroundings. When black holes collapse, millions of years later, we detect gravitational energy waves. When you breathed, your breath had more energy than the air you took in as you exhaled. It was warmer, had more CO2 and less O2, and velocity that forced the air around it to move. With a sensitive enough detector, there might be a way to detect that in a million years as some femtochange in some aspect of the cosmos.

When all of this melts down, the function we call “life” ends. The physicochemical reactions going on in your heart muscle, liver, and brain stop. Your consciousness is gone, and with it, what we know as “you” are gone, which brings us to the metaphysical aspects of life and death. Describing the end of “life”, if we are honest, is far more than the cessation of physical and chemical reactions. If it were not so, I cannot imagine my feeling that “sadness” is what describes the experience best. Within our conscious experience of life, “love” is what we cherish most, in all of its meanings. My favorite author, Pat Conroy, died a few weeks ago, and in looking at some of his quotes, I was most deeply moved by this one: “I do not have any other way of saying it. I think it happens but once and only to the very young when it feels like your skin could ignite at the mere touch of another person. You get to love like that but once.”

Certainly that captures a universal experience of one kind of love. But of course, all kinds of love (eros, philia, agape, pragma, philautia) are part of a pretty mysterious collection of our existential experiences, and all end with our personal demise. The result is sadness. Promises of immortality, however comforting, cannot remove the sting of death. Were it not so, the famous two line verse from the bible, “Jesus wept” [John 11:35] at the death of his friend, would not be there to ponder 2000 years later.

Dying from cancer involves all of this. It is a journey. For some, it ends unexpectedly with a sudden chest pain and unconsciousness as the heart fibrillates and oxygen is no longer delivered to the brain. However, for most, it is a series of attempts to beat back the cancer with increasingly toxic and or ineffective treatments, ultimately resulting in an admission by both the patient and physician that focusing on comfort through medication and family/support is the better option. Both the patient and the family must cross the threshold of giving the patient “permission” to die, and face the sadness. What physically comes with this is variable, depending on what organs are involved – bone pain (reasonably easily treated, although with well-known side effects of opiate administration or radiation) is common with prostate cancer, as is fatigue (not so easily treated). What is untrue is that the PSA can predict any of this. I have had patients who went elk hunting and enjoyed themselves with a PSA of 6000, and others who crossed the bar when their PSA was less than 10. Too much focus on the PSA can ruin whatever time a patient has been given either by the genetics of his own disease or by the ministrations of modern medicine.

But this sequence, to be traveled in one way or another by all of us, can also be beautiful in its own way. Life has meaning. Death has meaning beyond sadness. Immortality, in the way I have thought of it, is undeniable. Religion can (for some) be incredibly comforting as one faces the reality of death itself. Rather than try to go further in this (hopefully honest, yet inexorably sad) essay on the topic, I would strongly urge you to read a recently published book, “When Breath Becomes Air”, that I think captures a death from cancer with far more sensitivity and meaning than I am able to impart. Paul Kalanithi’s death from lung cancer in his late 30’s one year ago was a journey he captured as perhaps only a philosopher/neurosurgeon/husband/father and brilliant writer could accomplish. It was his gift to all of us, and by referring you to his writing, I hope I have extended that gift to you on a topic that we too often avoid.


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2015’s Major Advances

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One of the most frequent questions I hear in my clinic is “are we making any progress?” or “is there anything new out there?” The answer is always “yes” or more properly YES!

To keep up on the latest information on prostate cancer I have a few suggestions for places to search on the Internet. First, you can search for prostate cancer every single day if you want and get overwhelmed using the NCBI website, PubMed. Next, you can do a search on Google Scholar which will also include abstracts and patents, as well as citations that list something like prostate cancer. (I modified the clickable link to look at “prostate cancer” for 2015). Finally, you should keep track of new treatments that are being evaluated via clinical trials by looking at (link again modified to look for “prostate cancer” but you can modify to look for trials with specific agents or available in specific locations)

By posting these blogs and in other ways, many of us try to help our patients keep up on the various news alerts that circulate as well. Subscribe to this blog and you will get about one email/month from me that reflects the most pressing topic(s) I have heard about from my patients. I also highly recommend the Prostate Cancer Foundation website, which for today’s post “2015’s major advances” has an excellent list of the 2015 advances that I am hard pressed to improve upon, including video presentations. I hope that helps and wish you all a healthy 2016 which I guarantee is going to have an avalanche of progress, beginning with the upcoming ASCO GU symposium. I’ll try to post some of the highlights from there next month.


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Alzheimer’s and ADT…some perspectives

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Several of you asked for my perspective on the article that appeared last week in JCO and was widely picked up by the media. The NYT covered it with this headline: “Prostate Cancer Treatment Tied to Alzheimer’s Risk.”  NBC News said, “Common Prostate Cancer Treatment May Double Risk for Alzheimer’s”, then did a reasonable job of placing some perspective on the article in spite of the scary headline.

First, I would point out that this article is representative of the way medical investigators will be able to use BIG DATA in intriguing and effective ways. This team started off with a total of 5.5 million electronic medical records at Stanford and Mt. Sinai and used sophisticated computer algorithms to find 16,888 patients with prostate cancer and then looked further to find new onset Alzheimer’s disease among the 2,397 who received ADT therapy. They were able to control for known Alzheimer’s risk factors such as age and cardiovascular disease in doing their analyses. The statistical methods and mathematics for the study are certainly beyond anything I could understand or effectively comment on, but my congratulations to the investigators on their study!

To compare the risks of developing Alzheimer’s disease from ADT, one needs to know the benefit (if any) from taking ADT. There should be little doubt that a man who presents with painful boney metastases benefits far beyond any risk. Such an individual might expect to live 44 months with ADT alone (and might improve his prognosis to a median survival of 58 months by taking 6 cycles of docetaxel at the onset of ADT (CHAARTED trial). To give a graphical comparison of the Alzheimer’s risk compared to this man’s life expectancy from prostate cancer, I superimposed the Alzheimer’s risk onto the CHAARTED trial survival graph:

Screen Shot 2015-12-15 at 12.48.58 PM


What about someone with local disease but high risk based on PSA >20? In one of the larger trials comparing the addition of ADT to radiation vs. radiation alone in such patients, even as short as 4 months ADT resulted in cutting the disease specific mortality at 10 years from 8% to 4% (and improving overall survival from 57% to 62%) Again, this seems like a favorable equation in favor of using ADT, considering the risk of Alzheimer’s disease at 10 years in the new article is 5% with ADT and 4% without ADT. Moreover, the Alzheimer study found that shorter duration of ADT didn’t represent as much risk (< 12 months treatment resulted in an insignificant increase in risk when all the known other risks for Alzheimer’s disease were accounted for).

Thus in the larger context, I think for the majority of men who must consider ADT therapy, the risk of Alzheimer’s disease is small and for most would not be much of a factor to consider. The 5 leading causes of death for men in the United States are heart disease, cancer, unintentional injuries, respiratory disease and stroke (in that order). Alzheimer’s disease comes in at 9th place, representing just 2% of deaths, less than suicide which places 7th at 2.5%. I am currently reading one of the O’Reilly books, “Killing Patton,” which is full of quotes from the famous general. Death, he said, “in time comes to all men.” As a professional soldier, he wanted to die from “the last bullet of the last battle of the last war.” Most of us don’t imagine such glorious endings and would settle for a peaceful death in our sleep after a fine meal with our family, or perhaps, as one of my patients managed, walking back from a river with his fly rod in hand and his hip waders still on. Prostate cancer is terrible, and Alzheimer’s even worse, but most of us are destined to die of something else, and the real message is to live each day honorably and hopefully in the service of a greater cause.




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Prostate Drug Costs

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Most readers will have seen something in the popular press over the last 6 months regarding the increasing awareness of oncology drug costs. For example, there have been very nice commentaries in the New England Journal of Medicine like this one, that deals with the cost of nivolumab, a PD-1 pathway inhibitor that is approved for treating melanoma and may show promise in a number of other cancers like kidney cancer. The final paragraph is telling:

Hand clapping for science is now inextricably linked to hand wringing over affordability. Drug prices are increasing more rapidly than their benefits, and the growth in spending on drugs has started to outstrip growth in other areas of health care. Addressing this problem requires realizing that cost-effectiveness assessment — a step that we are not even ready for in the United States — has limitations when one considers the price of the comparator and the impact on overall budgets.

I have opined elsewhere in this blog site on the excitement over the new immune-stimulating drugs that show promise. Indeed, some may be able to improve the response to prostate vaccine approaches. The question is whether we can afford all of these drugs, who decides, how they decide, and what methods they use. In the past, a QALY (quality adjusted life year) has been used to benchmark some of the things we do in medicine. In a nice NEJM perspective article, the classic “$50,000/QALY” benchmark was reviewed, but the authors suggested that given medical progress and inflation, a more realistic number might be as high as $100,000 or $150,000. The costs of the newer prostate cancer drugs such as abiraterone, enzalutamide, sipuleucel-T, cabazitaxel etc. have not escaped attention. Medscape had an article on this over 2 years ago. I am no expert on Markov models, differing ways to evaluate cost-effectiveness, and the economics of medicine. But as a simple way of explaining the challenge, how much is cisplatin, a cornerstone of curative treatment for testis cancer, the number one cancer of young men in their 20’s worth? If you can answer that, then how much would it be worth if you were using the same drug as a third line to treat prostate cancer, where responses are rare except in the case of the small cell variant, but no one is cured? In the case of the young testis cancer patient, many years (or QALY’s) are achieved while in the case of even the “sensitive” form of prostate cancer, the benefit would be in months at best. Should testis cancer patients have to pay huge sums because it works so well for them and prostate cancer patients less? And how do we figure in the drug development costs in a fair way that retains a financial incentive for the pharmaceutical companies and researchers to keep working for new discoveries?

Added to this is my own experience when I have described using a highly expensive (sometimes toxic) drug to a patient with well-known, very limited (but measurable, approved, and “covered” by Medicare or insurance) benefit. Often when I am honest and say, “this may help for a while, but is not a cure,” to a patient who may have very few symptoms at all but is progressing based on a rising PSA, the reply will be “what choice do I have”? That is a great question. If someone else is paying for some very expensive drug, why not try it? Although I know that the ethicists feel “my wishful answer” is unethical, I would like to be able to say something like this: “Well Mr. Smitherton, Medicare has decided that if you would rather take the money and apply it to your grandchild’s college fund, they will be willing to divert the costs (or some proportion of them) to that cause because ‘we’ [society] feel that should be your choice, rather than having us pay for a relatively ineffective, expensive drug if you don’t think it is worth it, or if you value his/her education over a few months of additional life span.” If wishes were horses, beggars would ride. And if I was qualified in ethics, I would probably not be writing this. That’s my 2¢ – or maybe it should be my $20,000??


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Gentlemen, Start your Moustaches !

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Movember is both a month and a cause, the latter being one you should commit to supporting. Adam Gerone described his journey starting this remarkable movement in a TED talk that you should watch, just for it’s inspirational value if nothing else. This year, Movember has morphed ahead and is challenging all of us to not only support the research into men’s health (and especially prostate and testicular cancers), but to get off the couch and MOVE, with the tagline “30 MOVEs in 30 days“. As my faithful readers will know, exercise is an incredible way to fight both cancer and the side effects of androgen deprivation.

So here’s the deal: I think you should sign up with Movember to raise money for our cause AND you should commit to exercising more this month. If you don’t have a team to join or don’t want to grow your own moustache to remind your friends of how important our health is, you can support my scraggly moustache by clicking on THIS LINK, but in any case, enjoy this fabulous month and get off the couch! That’s it for today – I’m off to the gym.

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The PCF Meeting and Heterogeneity

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Let me just say again that the Prostate Cancer Foundation Annual Retreat is overwhelmingly my favorite meeting of the year. The organizers bring in the very best researchers, both clinical and basic science oriented for a two day intense update. Trying to take notes during the sessions leaves you with writer’s cramp and brain ache, but each year brings incredible progress. You can get some idea of the progress for this year from an excellent overview lecture given by Jonathan Simons. Thanks to PCF for getting this up on the web quickly! If you are a patient or family member, please spend 30 minutes viewing Jonathan’s talk and you will definitely not need to ask your physician, “is there anything new?”. (But try not to embarrass him/her with your new insights, either!)

I think the facet of cancer most commonly misunderstood by non-scientists (patients/families) is heterogeneity. While there were several presentations that touched on this, Steven Bova’s talk, reviewing the Nature paper he and his colleagues published this year, probably illustrates the phenomenon best. This international group was able to do whole genome sequencing on cancer metastases (and primary tumors) in 10 patients who had just died from prostate cancer. You can think of this as looking at a fingerprint of different small pieces of tumor found in the prostate, a lymph node in the pelvis, another in the neck area, and maybe two more from some spots you identified on a bone scan. When you look at your fingerprint, there are lines that divide, curve, end, and so forth in patterns that are completely unique to you. Thus each individual tumor metastasis could be identified by the unique set of mutations found at that site and you could look back at the primary tumor to see how many of the mutations and other genetic alterations (deletions, amplifications, etc.) were present in the original tumor or were shared (or not) by another metastasis. What emerges from such investigation is a phenomenal picture of genetic instability starting even in the primary tumor (about which we simply say, “all right, you have a Gleason 3+4 cancer in 3 out of 12 biopsy cores” – an incredible oversimplification of what is really there under the microscope) You can also think of it as tree trunk with multiple branches, then leaves. Here is an illustration from the paper for two patients.

Screen Shot 2015-10-30 at 11.00.13 AMThis is the trunk and tree illustration of genetic alterations found in a patient’s metastases. As you can see in the trunk (site of the original tumor) there are already a host of changes, each of which might be related to tumor suppressor genes or oncogenes that drive the tumor. You can appreciate how much more complex this is than simply saying “Gleason pattern 3+4”, and if you look in the same tumor, just a few millimeters away, you might find different alterations. Indeed, in some studies like this, it was the “not dangerous” Gleason 6 pattern tumor from one area of the prostate that spread and led to metastases, not the “more dangerous” Gleason 7 pattern tumor found somewhere else in the patient’s prostate. This gives you some notion of why it may be challenging to send off a bit of tumor for genetic analysis, then make a clinical decision based on just looking at “the worst” area for predicting what to do in terms of treatment. In the figure, you can also appreciate that if you spent millions of dollars finding a drug that worked for the “CTNNB1” amplification, it would only be part of the story. However, it might be a better drug to develop for this patient than one for MYC amplification shown at the lower right, since that target is only present in one branch of the tree. Also note that androgen receptor amplification (AR amp) is found in the “leaves” , illustrating that the tumors in sites D and E have figured out a way to get around hormone treatment by increasing the number of receptors for the tiny amount of testosterone that might not be suppressed by drugs like leuprolide/goserelin/abiraterone or blocked by drugs like bicalutamide/enzalutamide.

Screen Shot 2015-10-30 at 11.02.16 AM

In this figure, we can see the incredible picture of how the cancer has spread from the prostate to different sites, but also from one site to another, and even from a metastatic site back to the prostate itself. During the conference, there were numerous similar examples of heterogeneity shown. As one example, using the most modern of imaging techniques (such as PET scanning), patients who were initially treated with hormone therapy, and who had “complete remission” as determined by dramatic drops in PSA and disappearance of all metastases on routine bone scans, were in fact shown to have mixed responses with the more sensitive scans. While most of the spots on the sensitive scan went away, a few got worse, and actually new ones appeared elsewhere – all the while, we clinicians are telling patients that “everything looks great” because the regular bone scans and PSA have responded so nicely.

I think all of this leads to the conclusion that no one will ever walk out of a lab with a single new drug that represents “the cure” for all patients with prostate cancer. Instead, we should be able to figure out how to better  attack the trunk of the trees for individual patients, rather than just picking off a leaf. For now, the trunk target most tractable relates to the androgen signaling pathway, and the good news is that with the newer drugs available, we seem to be making real progress in turning prostate cancer into more of a chronic disease like diabetes, even if “cure” remains elusive. For many men, the remissions that are available with existing drugs are “good enough” to extend life for many years, sometimes decades. And as I sometimes joke with my patients (in my black humor sort of way… but there is truth here, none-the-less) “If you die of a heart attack at age 90, I’m going to count that as a cure!”


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Support the petition for reasonable drug prices.

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I hereby confess that when it comes to healthcare, I am somewhat of a socialist. I feel healthcare should be a right, not a privilege. However, I would draw some sort of line for certain conditions, even including cancer. For example, there is little evidence that 3rd or 4th line therapies for many cancers have any significant impact on survival, yet we often prescribe them for patients who are healthy enough to try them with the rationale that “even a 5% chance” is worth taking. Weighing that 5% chance against a 25% chance of causing further toxicity and NOT improving someone’s quality of life requires sensitive counseling and is part of the “art” of practicing medical oncology. We already don’t pay for cosmetic surgery when it comes to face-lifts, but breast cancer patients enjoy coverage for breast reconstruction, while men with erectile dysfunction following surgery or radiation don’t have coverage in most instances for ED drugs or other treatments. Thus, there is a lot of room for improvement in our health care system. The ACA is not the best answer, but it may provide at least a start through inclusion of coverage for end-of-life counseling and funding of the Patient-Centered Outcomes Research Institute. We should not tolerate having the most expensive health care system on the planet that delivers care that ranks dead last in the developed world.

One of the most disturbing trends in our broken health care system has been the introduction of numerous new cancer drugs that have (in some cases) remarkable activity but are priced beyond any reasonable value consideration. Trying to decide about “value” itself is an extremely challenging undertaking. Numerous articles like this one have proposed guidelines through which value might be better quantified. Now a group of oncology physicians have published a position statement regarding cancer drug costs that deserves your attention. They propose a number of solutions that could help the cancer community move toward the kind of progress made by the AIDS community when they were faced with similar challenges of highly expensive drugs. You should read the whole article to see the context, but their enumerated suggestions are as follows:

If you agree that these actions should become a part of our national discussion, please join me in signing the petition these thoughtful oncology leaders have started. You can click on this link to sign up, and please invite your friends to join you.


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STAMPEDE-ing for New Approaches to Prostate Cancer

It is difficult (but not impossible) to reflect on the fact that one of the key reasons I went into medical oncology was the seminal study by Bonadonna published in 1976 showing a dramatic reduction in cancer recurrence among women with breast cancer and positive axillary nodes who received CMF chemotherapy. Subsequently, tens of thousands of women participated in clinical trials to further refine which drugs (including many new ones), which clinical presentations (e.g. node positive or node negative, hormone and growth factor receptor status, menopausal status…) benefited most from different treatments in randomized controlled trials. Medical oncologists, surgeons, and radiation oncologists collaborated in advancing our understanding of how best to treat these patients, resulting in multidisciplinary clinics that are now a standard of care in most medically advanced countries.

What went wrong with prostate cancer? Certainly, there were some efforts to replicate the breast cancer experience. Indeed, The National Prostate Cancer Project studied single agents in the late 1970’s with hints of improvement in progression free survival. Yet, it was 17 YEARS (!) before the CMF regimen (“combination chemotherapy”) was found to have minimal activity in advanced prostate cancer in a small clinical trial. Following this, mitoxantrone as a single agent, was found to improve quality of life in metastatic prostate cancer and my colleagues and I started a study to evaluate it in combination with two years of ADT in high risk post-surgery patients. However, it wasn’t until a truly active chemotherapy class, the taxanes became available that real progress could be forecast. Never-the-less, the numbers of patients being placed on trials remained abysmal compared to breast cancer. Cooperation between medical, surgical (urologic), and radiation oncologists has lagged in the U.S. as physicians debated “who really knows this disease best?” rather than relying on collaborative improvement in care.

Potentially, we are finally at the end of this dark tunnel. The ASCO/ASTRO/SUO annual GU cancer symposium started off with a few hundred participants and now attracts thousands of physicians and scientists from around the world. Moreover, we are seeing the fruits of improved collaboration in the form of the CHAARTED trial, as well as the new data emerging from the STAMPEDE trial. This European trial has multiple arms and in a pre-ASCO meeting press conference, chemotherapy with docetaxel  has again been shown to improve survival for men with metastatic disease compared to ADT alone. Moreover, the study will soon have mature data on the use of such treatment in the adjuvant setting following surgery/radiation and we look forward to the results. My colleague, Dr. Garnick has urged caution in rushing to establish early use of docetaxel as a new standard of care, pointing out the potential benefit of adding the newer second line hormones (abiraterone, enzalutamide, TAK 007, etc.) which have fewer side effects. This seems like sound advice, particularly since one of the mechanisms of action of docetaxel may indeed be inhibition of translocation of the androgen receptor to the nucleus of cancer cells – in other words, docetaxel might be just a more toxic way of inhibiting the AR signaling pathway.

The good news is that after watching Koman and women “race for the cure” we are no longer “crawling for the cure” in prostate cancer. Men of good will (including all of you who support Movember) and their physicians are newly energized to make progress. It is an altogether satisfying situation to observe as I near the end of my oncology career!

Published Abstract from the ASCO meeting:

Background: STAMPEDE is a randomised controlled trial using a novel multi-arm multi-stage design. It recruits men (pts) with high-risk locally advanced or metastatic prostate cancer (PCa) starting long-term hormone therapy (HT) for the first time. The trial initially assessed adding 1 or 2 of 3 treatment approaches to standard of care (SOC). We report primary survival results for 3 research comparisons that recruited through all their intermediate analyses: docetaxel (D), zoledronic acid (ZA) & the combination (D+ZA). Methods: SOC was hormone therapy for > = 3yrs; RT was encouraged for N0M0 pts up to Nov-2011, then mandated; RT was optional for N+M0 pts. Stratified randomisation allocated pts 2:1:1:1 to SOC (control), SOC+D, SOC+ZA or SOC+D+ZA. 4mg ZA was given for six 3-weekly cycles then 4-weekly until 2yrs. D was given as 75mg/m2 for six 3-weekly cycles with prednisolone 10mg daily. The primary outcome measure was survival (time from randomisation to death from any cause). Pairwise comparisons to control on survival for each research arm had 90% power at 2.5% 1-sided alpha for a hazard ratio of 0.75 requiring ~400 control arm deaths, accounting for 3 intermediate lack-of-benefit analyses on failure-free survival. Analyses used the Cox model of the logrank test, adjusted for stratification factors. Results: From Oct-2005 to Mar-2013, 2,962 pts were randomised to the 4 arms. The groups were balanced with median age 65yrs; 61% metastatic, 14% N+/XM0, 22% N0M0; 93% diagnosed within 6m of randomisation; median PSA 65ng/ml. Median follow-up was 42m. Grade 3-5 toxicity was reported for 31% SOC, 50% SOC+D, 32% SOC+ZA and 52% SOC+D+ZA.There were 405 deaths on the control arm (84% from PCa). The hazard ratio was 0.76 (95% CI 0.63, 0.91; p = 0.003) for SOC+D vs SOC; 0.93 (95% CI 0.79, 1.11; p = 0.437) for SOC+ZA vs SOC; and 0.81 (95% CI 0.68, 0.97; p = 0.020) for SOC+D+ZA vs SOC. Median survival was increased by 10m from 67m on SOC to 77m on SOC+D. Results in M0 and M1 disease will be shown. Conclusions: Survival data from STAMPEDE show a clinically and statistically significant improvement in survival from adding docetaxel but not from adding zoledronic acid in men starting long-term hormone therapy for the first time. Clinical trial information: NCT00268476


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Earlier use of docetaxel – ready or not…

This year I “attended” the ASCO Annual Meeting via the Internet. ASCO was one of the first professional societies to have a virtual meeting, and I had the opportunity to help organize that event. In those days, speakers used 35mm cardboard slides to make their presentations, and a small team of us sat in the basement of a convention hall and manually “synched” the slides that had been digitized by some sort of gizmo called “the soapbox” to the audio that had been recorded. Ah, technology…

In any case, the following post was originally published on ASCO Connection during the meeting and contains a few thoughts about one of the interesting controversies regarding the earlier use of docetaxel in prostate cancer:

As someone who is interested in prostate cancer almost exclusively in my practice, listening to Dr. Nicholas James present the data from the STAMPEDE trial was of high interest. The trial showed a highly significant improvement in failure-free survival as well as overall survival for men with newly diagnosed metastatic disease, confirming the findings of the CHAARTED trial presented at last year’s ASCO Annual Meeting. Further encouraging news came from Dr. Howard Sandler’s presentation of RTOG 0521 that demonstrated improvement in overall survival among patients receiving androgen deprivation therapy (ADT) with docetaxel compared to those who did not receive chemotherapy as part of curative-intent treatment for high-risk localized disease.

Ian Tannock, another outstanding investigator in our field, then made a presentation regarding clinical trial design and chemotherapy—an excellent overview of the past decade of clinical trials using docetaxel earlier in the disease.

He pointed out the similarities of the three trials (including the negative GETUG-15 trial reported earlier) and noted that in spite of lack of statistical significance of GETUG-15, it favored docetaxel and that combining the data from all three trials leads to a highly significant test for overall effect of p = 0.003, leading him to recommend that men with high-risk metastatic disease at presentation should receive six cycles of chemotherapy as a new standard of care.

Turning to the early use of docetaxel in combination with radiotherapy and ADT in the initial curative-intent treatment as was done in RTOG 0521, he pointed to several potential pitfalls in accepting this as a standard of care. He again combined the other studies (GETUG-12 and STAMPEDE) looking at similar patients and noted that only the RTOG trial showed a difference in overall survival in spite of all three showing improvement in failure-free survival. Given the RTOG trial used a one-sided statistical analysis for finding a marginally significant (p = 0.04) improvement in overall survival, he concluded that “chemo delayed is toxicity delayed” and feels that at present adding docetaxel up front to ADT/radiation curative-intent treatment is not warranted. Perhaps the most remarkable slide he presented, however, was a look at his own institution’s experience with using docetaxel in a trial setting as opposed to routine practice. Toxicity increased and efficacy diminished, highlighting the challenges of extrapolating from the generally healthier, better staged and more closely followed patients who enter clinical trials compared to day to day experience.

Ian is truly a sage who helps my own field better understand the status of clinical management of prostate cancer and being able to hear his voice and share his insights on the Virtual Meeting website was most rewarding!


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Sensational results, 4-MU, Viruses, and “the drive-by media”

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An intriguing part of writing this blog is how much I learn from my patients. It also turns out that I learn ABOUT my patients. I suppose nothing should surprise me about this in the digital age, where presumably all of you can find my address, social security number and probably what brand of oatmeal I like ! (I’ll save you some time there, try McCanns Steel Cut Irish Oatmeal, it’s terrific…). For the past month or so, one after another has come in with the question, “So, what do you think about 4-MU?” or “Did you hear about poliovirus killing cancer?” Actually, I have heard next to nothing about either, but of course I was intrigued as to where my patients get their information.

Starting with the 4-MU story, it seems it was featured on that bastion of “fair and balanced news,” FOX. I sincerely hope that is not the primary source for your news, and that you don’t subscribe exclusively to a certain talk show host who calls everybody but himself the “drive-by media”. If you want serious journalism, I’d suggest the NYT, WSJ, and NPR for a pretty good balance of real news. None of them carried the two stories I’m going to go over here. Further, if you ever hear of a story with interest in medicine, I suggest you go immediately to Google Scholar, which is absolutely wonderful at finding abstracts, patents, and journal articles on almost anything in medicine. And if you want to know if a novel treatment in development is available in your area or anywhere else, for that matter, do your search at

Well, using combinations of all of the above to learn about 4-MU, (which stands for 4-methylumbelliferone) I found that FOX decided to sensationalize a mouse study published by some University of Miami investigators. 4-MU turns out to inhibit synthesis of hyaluronic acid, a major component of synovial fluid and the “goo” or intracellular matrix. It has been studied in the past to inhibit some bacterial and viral replication, and indeed there is even a clinical trial with 4-MU listed as going on in chronic hepatitis. The Miami researchers found that in mouse models 4-MU inhibited prostate cancer metastases, which gained excitement because it is supposedly a non-toxic supplement. While I try to keep an open mind, there is a long history of various natural products working in mouse models that then have little or no activity in the real world of human cancer. We, ourselves, discovered that acai juice and the milk thistle derived molecule, silibinin, had minimal/no activity in prostate cancer, in spite of promising results in animals. My judgment regarding 4-MU is that it would indeed be of interest to study in human prostate cancer, and hopefully it would work, but until such a trial is done, I would not recommend taking it if you find a supplier somewhere on the Internet or similar.

The poliovirus story is a bit more complicated. It gained patient attention via a 60 minutes presentation.  Many tumors, including the highly lethal glioblastoma brain tumors, have receptors on their cell surface for the virus. Through very elegant and complex recombinant DNA technology, investigators at Duke University engineered a novel virus that could induce death in the brain tumors after direct injection. In an ongoing Phase I clinical trial, they are seeing dramatic responses after direct injection of the tumors in the brain, in part because of a “violent” immune response. The key here, however, is direct injection. It may be possible to build on this, but direct injection of oncolytic viruses into head and neck cancers, lung cancers, and even prostate cancers in the past have not had the desired results. Moreover, what we really want, is some sort of virus that a) can seek out every metastatic cell in the body [brain tumors seldom metastasize, but kill people by local growth], and b) produce that immune response after infection. I have written elsewhere about the promise of the immune checkpoint inhibitors, and I encourage you to go to my blog site and read about those ongoing efforts. Meanwhile, I hope that the search strategies I have outlined in this blog will help you do your own research to answer the question, “Doc, have you ever heard????….”


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