Tag Archives: prostate cancer

3 Articles and a forth


To read this post on my blog site, see other blogs, and sign up for future posts, click here.

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…)

 

4 Comments

Filed under General Prostate Cancer Issues, Prostate cancer therapy, Uncategorized

No pain, no gain?


To view this blog at my blog’s website where you can sign up to be notified and read other posts relevant to prostate cancer, click here.

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!

5 Comments

Filed under General Prostate Cancer Issues, Prostate cancer therapy

Olaparib for resistant prostate cancer


To view this blog at my blog’s website where you can sign up to be notified and read other posts relevant to prostate cancer, click here.

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.

1 Comment

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

Prostate Drug Costs


To read this on my blog site and sign up for future notifications, please click here.

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??

6 Comments

Filed under Uncategorized

Gentlemen, Start your Moustaches !


To read this on my blog site where you can read previous blogs and sign up for future notifications, click here.

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.

1 Comment

Filed under Uncategorized

Support the petition for reasonable drug prices.


To view this blog at my blog’s website where you can sign up to be notified and read other posts relevant to prostate cancer, click here.

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.

2 Comments

Filed under Uncategorized

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


To subscribe to this blog, view it on the blog website, and receive email notifications, click here.

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 ClinicalTrials.gov.

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????….”

3 Comments

Filed under Uncategorized