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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Proscar/Avodart for prevention? The confusing tale of testosterone.

It has long been held that testosterone is the root of all evil – probably true for most wars, and possibly true for the development of prostate cancer. Oft times, lecturers on prostate cancer will cite  sketchy data on eunuchs not developing prostate cancer. When you try to actually find data supporting this statement, it is very difficult indeed. On the other hand, men born with a genetic defect in 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone do seem to be protected from developing prostate cancer (of course they don’t have prostates either !). Adding to the confusion surrounding this issue is the recurring finding that men with lower levels of testosterone who DO develop prostate cancer seem to have higher Gleason scores and in some cases more advance stage implying worse cancer outcomes.

So what would be the result of blocking the enzyme that converts T to DHT (which has 10 times the affinity for the androgen receptor) in preventing prostate cancer? This hypothesis was tested in two large randomized trials. I have reviewed the PCPT trial elsewhere in this blog. The REDUCE trial also looked at blocking the enzyme with dutasteride (Avodart, another 5 alpha-reductase inhibitor or 5-ARI) in men who had psa values of 2.5-10 and a previous negative biopsy. Both trials showed a reduction in the development of prostate cancer, but a disturbing increase in the few men with higher grade tumors. These findings led to an FDA warning about increased risk for high grade cancers that has been very controversial.

Another way to look at this controversy would be to simply evaluate what happens to men in terms of prostate cancer outcomes, not simply whether a certain grade or incidence of prostate cancer develops. In a current article in JAMA, Canadian investigators evaluated nearly 14,000 patients who were diagnosed with prostate cancer during the decade of 1999-2009 and compared the outcomes of men who were or were not taking a 5-ARI prior to their diagnosis. Using two separate mathematical models, they found no difference in prostate specific or overall mortality in the two groups.

In an accompanying editorial by Drs. Figg and Thompson (two highly regarded experts in this area), the question of whether one should consider using 5-ARI’s to prevent prostate cancer is further discussed. Their conclusion is as follows:

“The role of 5-ARIs as chemopreventive agents for prostate cancer remains uncertain. On the one hand, reduction of low-grade tumor incidence is unlikely to translate to a reduction in prostate cancer mortality; on the other hand, such a reduction could reduce disease overdetection and overtreatment, a serious concern that led the US Preventive Services Task Force to recommend against PSA screening.10 The study by Azoulay et al8 suggests that 5-ARI use is unlikely to increase prostate cancer mortality in men receiving them for BPH, reassuring those men on the symptom relief they may provide.”

Given these data and the discussion by the experts in the field, I would still recommend that sons of men with prostate cancer strongly consider taking 5-ARI’s, even though they may not reduce the chances of developing a lethal cancer. It seems reassuring that they will not have a worse outcome in all likelihood. Prevention of a low grade cancer and the morbidity from treatment seems a worthy goal to me (never mind the possibility of decreasing urinary obstructive -BPH- symptoms and reducing baldness). Whether it would help them not drive like idiots, attack their siblings at family gatherings, or say offensive things to their sisters is an entirely other matter. Happy Passover/Easter to those of you hosting such individuals!


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Prostate cancer advances – The Oscars are in…

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I have been attending the ASCO led GU oncology symposium for the last 48 hours. As usual, it is somewhat of a “firehose to take a drink” scenario with great presentations, more posters than you can possibly absorb, and lots of progress on many fronts. I remember when there were only about 50 “GU oncologists” 30 years ago, and about 300 attended this meeting when it first started. The attendance is 2900 from around the world. As one of my patients likes to put on his blog, “help is on the way”, which is really encouraging. There is more to report than I can possibly do in a blog, so I will just poach from existing internet info and highlight some of the existing posts.

Chemotherapy for newly diagnosed patients with many metastases is now the “standard of care” following the CHAARTED trial that I previously discussed. The French completed a smaller study that did NOT show an advantage for using docetaxel “up front”. There are a number of possible explanations that you can read about here. Not mentioned in that discussion is a moderately complex explanation that came up in the discussion period after the presentation. It turns out that ADT leads to changes in the way docetaxel is metabolized. Thus, the approval of the use of docetaxel in the setting of castrate resistant pca (which has been the usual situation) is different from using docetaxel when a patient hasn’t been on ADT for very long. The French study had more toxicity, and potentially more delays in treatment but the relationship of when the ADT started may have been different from the CHAARTED trial and could explain differences. Nevertheless, CHAARTED was larger and I think the trial still sets a new standard.

The optimal duration of ADT when given to enhance radiation was covered extensively by Anthony D’amico. The details are pretty complex, and if you want to wade into these weeds, you can start with his JCO article. Basically, the issue is this: ADT helps radiation therapy be more effective. But it is clearly “toxic” in terms of quality of life, and possibly increases cardiac events in men with a history of heart disease. Both of these factors make it questionable to use at all in men with “low intermediate risk” disease, and we would certainly like to use for as little time as necessary to get the benefit so that quality of life is preserved. In the higher risk patients there is no doubt that it should be used, but the duration is still up for discussion, with the existing “definitive” study showing 36 months is better than 6 months. Generally in such patients, I go over this, and then say, “let’s see how well you tolerate ADT before we reach any final decision on how long to continue”. Certainly a minimum of 4 months is required, and possibly the longer the better, but I suspect 36 months is too long. And really no one has taken into account the factor that a single 3 month leuprolide injection can result in quite variable overall duration of testosterone suppression with older men generally not recovering as quickly as the younger guys.

On the vaccine front, data were presented on Prostvac in combination with the immune checkpoint inhibitor, ipilumimab. The exciting findings in using checkpoint inhibitors (including the PD1 and PDL1 drugs in other diseases has lagged somewhat in prostate cancer because it isn’t clear that the ongoing immune response is very good. (For example ipi alone in prostate cancer didn’t work) However, given the promising data on using Prostvac in the phase II trials, the phase III trial has now accrued all of its patients and we await the result. Meanwhile, investigators have begun to look at whether adding a checkpoint inhibitor to a vaccine can make further headway. An abstract presented at the meeting reported on the early results of this approach. Dr. Singh from the NCI GU oncology team stated “In a Phase 1 combination study of 30 mCRPC patients with similar baseline characteristics (predicted median OS of 18.5 months), patients were treated with PROSTVAC plus escalating doses of ipilimumab. The observed median OS was 31.3 months for all dose cohorts and 37.2 months for patients treated at 10 mg/kg based on updated overall survival data. Furthermore, there appears to be a tail on the curve with approximately 20% of patients at 10 mg/kg alive at 80 months.” This certainly means that if the Phase III trial of Prostvac leads to approval by the FDA, there will quickly be more studies of how to make this vaccine even more effective.

Many of us have been talking at this meeting and other recent meetings about a “kitchen sink” approach combining all of the newer drugs to get a biochemical complete response in metastatic patients and then using a vaccine to “clean up” the microscopic disease that is clearly left behind. I’m looking forward to these trials which are probably a year or two away, but optimism abounds. Example: A new man with metastatic disease who had prostate radiation or surgery 5 years ago is found because of a rising PSA. We do fancy scans with C-11 acetate or choline, radiate the known disease, treat with second generation ADT plus docetaxel x 6, then use the vaccine with a checkpoint inhibitor. (read that link by the way – terrific) Given that prostate cancer is generally a “slow cancer”, there are many men alive today with lurking metastases that will only become apparent 5 or 10 years from now. These guys will almost certainly be able to take advantage of such an approach – never fast enough, but never more promising prospects, either.


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Predicting a cancer’s behavior – the cloudy crystal ball.

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In the past decade, a number of labs and companies have developed techniques to further define how a patient with prostate cancer, or suspected cancer is likely to do. There are at least a dozen tests that are in various stages of commercialization and it would be difficult to do justice to all of them here. However, I will at least describe the general approach and the potential utility and hazards of some of them.

First the mechanics: If you take a needle biopsy or a prostate that has been removed, you can microdissect the cancer out of the paraffin and extract RNA from the specimen. If you quantitate the amount of RNA for each gene you can get some idea of whether certain genes are being over-expressed or under-expressed in that specimen. Now let’s suppose you do that for 500 patients who have Gleason 7 cancer, a PSA between 3 and 10, and no lymph node involvement, negative margins, no extracapsular extension, etc. (We already have some idea of how this patient with intermediate risk will do using nomograms such as the CAPRA-S score (there is an app for this calculator) or Dr. Kattan’s at MSKI). If we look at all 500 patients who have a similar prognosis based on the nomograms, we can then ask whether a gene expression profile could further separate patient with similar a priori risk into “high intermediate” or “low intermediate” risk. (The same could be done for patients with low or high risk based on nomogram prediction of course). Now let us look at 50 patients who do much worse than expected and another 50 that do much better than expected. In these two groups, among the 30,000 genes tested suppose there are 500 that are overexpressed by 3-fold and another 500 that are underexpressed by 3-fold in the “bad outcome” group and similar findings for the “good outcome” group. Many of the genes will be telling us the same thing – for example that a certain characteristic like “rapid proliferation” is associated with a bad outcome and overexpression of those genes predicts a bad outcome. But, you don’t need all of the genes in that characteristic to tell you that. So you ask the computer to recalculate a prediction by leaving one of the genes out. If it makes no difference, then the remaining genes stay in until you reach a smaller subset of genes that are either over or under-expressed but suffice to make the prediction. You put those genes (from the “learning set”) on a chip that can quantitate expression and find another 500 patients from a different institution to see if the chip can accurately predict what happens to those 500 patients (the “validation set”) for whom you don’t know the outcome. If the chip performs well, you have a new test that could be a valuable clinical tool.

Examples of this sort of work that are now commercially available include the Prolaris™ and Decipher™ tests. As you might expect, the time/effort that has gone into making these tests has been considerable, and they are not inexpensive. Another such test, ConfirmMdx, evaluates gene hypermethylation (a way that genes are turned off) in prostate biopsy specimens and can help predict whether there was cancer NEAR a negative biopsy (a false negative biopsy result). Because the test might help avoid repeat biopsies, this is an example of the complexity in assessing cost. Saving cost/risk of further biopsies, if validated prospectively, could show that the test saves money. Similarly, using these kinds of tests to avoid overtreating a patient with “intermediate risk” who might actually have low risk based on a molecular analysis could save costs and morbidity.

What a purist would want to know is whether making a recommendation to an individual patient based on the outcome of one of these tests has been validated. In other words, how often when I tell a patient he has nothing to worry about in spite of having a Gleason 7 cancer on a biopsy, am I correct? Clearly no test is perfect, and patients themselves may differ in their risk tolerance. One patient who has a favorable genetic profile (say a test that says only 7% risk of metastases at 5 years) might be inclined to simply watch and do nothing more, while another would find that risk intolerable and opt for further treatment. Further, few doctors or patients are using the FREE analysis of overall health risk called the Charlson tool to put such risk into context (we wonder why not – no marketing is likely one answer). In this wonderful world of blogs and mobile devices, I am hoping someone will create an app for that! Meanwhile, the molecular testing of prostate cancer is a step forward, and hopefully how to use it will become clearer over time. We will, however, always have the challenge of heterogeneity and plasticity of the prostate genome to deal with. Such is the legacy of our good friend, Darwin.

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