Tag Archives: cancer research

3 Articles and a forth


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OK, I admit to a sleazy, seemingly misspelled word to attract attention. At least I didn’t tweet it at 3AM. So what about the “forth”? I’m using it to remind you to sally forth in your search for information about prostate cancer. I previously wrote a blog giving some practical instructions on how to find the latest research publications on prostate cancer that you can find here. Another possibility, if you want to be overwhelmed is to subscribe to the Prostate Cancer Daily, published by Uro Today. So far as I can tell it is open to all, presents the original abstracts, and links via PubMed to the article itself. I now realize that the prediction of patients knowing more than their doctors about a given condition is glaringly obvious, something I discussed when I first wrote about the Internet and Oncology two decades ago.

So, on to the 3 articles: Typically, the most important articles in medicine are published in high profile journals. The premier one for medical oncology is the Journal of Clinical Oncology, JCO. The editors recently published a “best of genitourinary cancer, 2017” edition in coordination with what we medical oncologists call “GU ASCO” (actually co-sponsored by ASCO, ASTRO, and SUO). I thought it would be of interest to briefly re-cap the 3 prostate articles chosen for that edition.

ARTICLE 1: Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial. This study compared the more potent anti-androgen, enzalutamide (Xtandi™) to the older drug, bicalutamide (Casodex™) in patients who had become resistant to initial hormonal therapy. About 2/3 of the men had positive scans, while in 1/3 the resistance was detected only by a rising PSA without a positive scan. As we might have expected from the way enzalutamide was developed, it was clearly superior, with progression free survival of 19 months for enzalutamide vs. 6 months for bicalutamide. In an ideal world, we would use enzalutamide instead of bicalutamide in almost all cases where an antiandrogen is indicated. However, the increased cost of this drug is dramatic, and there may be other options or confounding issues with interpretation of the study.

ARTICLE 2: Randomized Phase III Noninferiority Study Comparing Two Radiotherapy Fractionation Schedules in Patients With Low-Risk Prostate Cancer. This article reports on one of many studies looking at whether radiation therapy treatment times can be safely shortened by increasing the dose of radiation given with each treatment and giving fewer treatments (fractions). The underlying principles are that tumor cells cannot repair DNA damage from radiation as quickly as normal cells, so giving radiation in small fractions daily allows killing of the tumor while normal cells repair most of the damage. Giving all of the radiation at once would kill every cell (and the patient).  Experimentally, prostate cancer cells may be more susceptible to larger fractions, and this study demonstrated that a radiation therapy course could be safely shortened from 41 sessions to 28 sessions with similar “cure” rates at 5.8 years of followup. This is a general trend in radiation therapy for prostate cancer. Using newer radiation focusing technologies (IMRT, IGRT, Stereotactic radiosurgery, etc.) it is possible to treat prostate cancer with as few as 5 treatments, although the long term efficacy is still unknown, and the addition of androgen deprivation to radiation treatment at any dose also improves efficacy. How to combine these approaches, the optimal duration of ADT, and which patients should stay with the older methods is still uncertain.

ARTICLE 3: Improved Survival With Prostate Radiation in Addition to Androgen Deprivation Therapy for Men With Newly Diagnosed Metastatic Prostate Cancer. Proudly, many of the authors on this article are from the University of Colorado Cancer Center. The authors used the National Cancer Database to determine whether patients with metastatic prostate cancer, traditionally treated with hormone therapy (ADT) only (although more recently with hormone therapy plus chemotherapy) benefit from also radiatiScreen Shot 2015-10-30 at 11.02.16 AMng the prostate itself. The analogy would be burning down the barn after the horse has left (with apologies to my radiation therapy colleagues who never like to compare radiation
treatments to burning). The patients who had their prostates radiated
had a 5 year survival of 49% compared to 33% for those receiving ADT alone. Removing the prostate surgically also worked. The prostate may also be a site where metastatic cells from another location return, as illustrated in this picture and discussed here. The take home message is that the cancerous prostate may continue to “seed” cancer cells to the rest of the body, or be a home for circulating tumor cells and getting rid of it, even though not curative, may be a good idea (toxicities and costs aside).

Consider yourselves updated! (sort of…)

 

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No pain, no gain?


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One of my patients last week had a heartfelt discussion regarding the survival benefit of ADT vs his quality of life. He enjoys body building and showed me some pretty dramatic pictures of himself during his last ADT cycle (on intermittent therapy) versus now, when he had been off treatment for ~6-9 months. Added to his concern was his decline in libido and sexual function during ADT, a common complaint especially among younger patients. The question of quality vs quantity of life was,of course, utmost on his mind.

Starting from the initial diagnosis, every (maybe that should be every !!) prostate cancer patient will experience a decrement in quality of life. Those who elect “watchful waiting” will nevertheless experience anxiety regarding the shadow of CANCER following their footsteps. Sure, you can put it out of your mind, but turn around and there it is, like the neighbor’s unwanted cat stalking you. Then there is the anxiety over what the next PSA will be. And if on active surveillance, what will that next biopsy show?? These issues are both real, disturbing, and often under-appreciated in the discussions surrounding screening…”we should still be screening, but not treat the men who don’t need it…” Really? What about the 80% of men who die at age 90 with prostate cancer at autopsy who never had to deal with the shadow? (The inevitable counter-argument is, “yes, and what about those who had early detection of a high grade cancer whose life was saved?”)

We also tend to ignore the impact of competing mortality in our discussions. “Sure you had a stent placed last year, and you already survived that small colon cancer, so why wouldn’t we be aggressive in treating this new problem?” Dr. Sartor provided an elegant discussion of this in an editorial on the PIVOT trial you can read here. Whatever the flaws in that study, it remains clear that we are not very good at predicting the non-prostate cancer “future” for our patients, and the older you are, the thinner the ice gets regardless of how many marathons you run.

When patients choose one form of primary treatment vs another, they are weighing the different side effect profiles of surgery or radiation as much as which is “most effective”. I often give patients a copy of this article from NEJM and encourage them to spend some time looking at the graphics in Figure 1 to get some idea of what they will face in the way of side effects from treatment. As any honest physician would tell them, treatment will involve side effects, some permanent, in the best of circumstances.

In the setting of more advanced disease, for example a patient who presents with metastases outside the pelvis, the recent CHAARTED and STAMPEDE trials both suggest an advantage to the earlier use of docetaxel chemotherapy in combination with ADT as opposed to ADT alone. These data suggest that “pay me now or pay me later” analysis favors the “pay me now” approach in terms of overall survival. But at what price for quality of life? Fortunately most chemotherapy side effects are reversible, but distinctly unpleasant, potentially making the equation something like “4 months of misery to provide 14 months of longer life….not all of which will be great anyway”.

Even in the very advanced setting, there is some evidence that greater toxicity results in improved survival. A recent analysis of the TROPIC trial of cabazitaxel suggested that the patients who had the most “toxic response” in terms of dropping their neutrophil count benefited the most in terms of overall survival.

While all of this seems incredibly negative (for which I apologize), the history of oncology as a field has been the incremental improvement in survival AND the development of newer treatments that provide such advances with diminishing toxicity. Pediatric leukemia, as discussed extensively in “The Emperor of All Maladies” is a great example of how pioneering patients and physicians worked together to find cures and reduce side effects. We may only be at the beginning of such achievement in prostate cancer, but with the advent of the newer hormonal and imaging agents, increasingly sophisticated surgery and radiation, vaccines and immunotherapy, and even the chemotherapies now available, we have  no doubt reached the end of the beginning. Onward!

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Olaparib for resistant prostate cancer


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In what is the first (and hopefully one of many) example of using modern genomic methods to match treatments to the molecular defects in prostate cancer, the FDA has just granted “breakthrough designation” to olaparib, a drug made by AstraZeneca. This followed a publication in the NEJM with nearly as many authors as patients, illustrating the power of team science and international collaboration.

Cancer cells develop numerous mutations that provide them with the ability to divide, metastasize, escape immune surveillance and so forth. One of the drivers of this mutation cascade is genetic instability, in part due to the accumulation of mutations that keep the cells from correcting DNA alterations. These mutations in DNA-repair enzymes can leave the cancer susceptible to additional inhibitors of DNA repair, one of which is PARP, an enzyme found in the nucleus that detects DNA strand breaks and initiates repair. When olaparib interferes with this enzyme, cells can become so genetically unstable they die.

In the TOPARP-A trial, 50 patients who had castrate resistant prostate cancer and had progressed on second generation anti-androgen treatment and docetaxel were given olaparib. 16 of 49 evaluable patients responded, however the exciting finding was that because these patients participated in the clinical trial and allowed the investigators to biopsy their tumors, it was possible to relate response to the presence of defects in the DNA repair genes. For this subgroup, 14 of 16 responded, indicating that using the repair defects as a biomarker you could predict high response rates, while at the same time, patients without such genetic defects had a much lower response rate (2/33). There is an excellent video that illustrates the results accompanying the publication that you can find by clicking here.

Although this is terrific news for prostate cancer patients, it brings a number of challenges. Testing for genetic mutations is a growing (and somewhat expensive) process. When compared to giving patients a drug that predictably won’t work, however, it can be very cost effective. Second, when you biopsy a tumor, the results can vary depending on where you biopsy as I discussed in this previous blog. “Liquid biopsies” of circulating DNA or tumor cells may provide some help in meeting this challenge.  Third, responses to targeted therapies such as olaparib tend to be rather short-lived, as the cancer cells continue to mutate to find ways around the new agent. The hope would be that combining a targeted treatment like olaparib with an immune approach might bring more prolonged responses. Finally, we must find a way to deal with the extraordinary costs of the new oncology drugs. The actual cost of olaparib is $13,440/month according to this article in the ASCO post. I have previously opined on this issue and invite you to join the discussion by clicking here.

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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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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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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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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:

Screen Shot 2014-12-10 at 10.23.28 PM

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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