Category Archives: Uncategorized

Here be Dragons


To read this on my blog site and find posts much more relevant to prostate cancer, please click here.

There are times in everyone’s life when it is worth pausing to consider larger issues than the conditions you find yourself facing every day. Big issues like the meaning of life, how we got here, what happens after we leave…, have been the topics of philosophers and kings with far more eloquence than I have. Nevertheless, I am compelled to pay homage to one of the most influential philosopher-teachers in my own life today, because failing to do so would be an injustice to my feelings about him, and this blog is my sole “public forum”.

Donald Seldin was the Chief of Medicine at UT Southwestern Medical School, better known to most people as “Parkland Hospital”, the place they took Kennedy. I went there as an intern in 1972 and was privileged to be under his spell for the two years of my training that represent, for most physicians, the most intense interval in all of their preparation to become “a doctor”. Unless you have lived through your first night on call, wondering whether and how your medical school has prepared you to actually make decisions about another human being who has, by choice or by chance, placed their life in your hands, it is hard to put those feelings into words. “Here be Dragons” is a myth about maps relating to what early cartographers would put on maps when they reached the edge of the known world. I always found that phrase evocative when it comes to facing the unknown. For thousands of physicians who trained under Dr. Seldin, he became the pilot who helped you edge out onto that unknown sea called MEDICINE and gave you the confidence to succeed.

Dr. Seldin died at the age of 97 last week. His life and contributions have been extolled by many of his admirers. The shortest version I can find is this obituary from the New York Times. For a more extensive version, and to meet the man himself, you can watch this video. When I was in mid-career in the 1980’s, we took a sabbatical in Helsinki, Finland. It gave me time to think about the larger issues and to write to some of my mentors, thanking them for taking me on as a student and sharing their wisdom with me. Dr. Seldin was one of the men to whom I corresponded. As I recall, in the letter I referred to the pop song, “To Sir with Love” because at an emotional level, the phrase “How do you thank someone who has taken you from crayons to perfume?”  best captured how I felt about his tutelage. He wrote back to the effect that he “had no idea that he cast such a long shadow”, which was surely not true, but his modesty was just another facet of his remarkable personality.

So, if you are in any sort of a contemplative mood at some point this year, take a bit of time to write to one of your mentors or a family member. Thank them for what they mean to you. When they are gone (or when you are gone), that letter will be worth your time as an emotional bond as you sail on into the unknown. Godspeed Dr. Seldin!

4 Comments

Filed under Uncategorized

Delaying metastatic disease – ASCO GU18


To view this blog on the website and sign up to be notified for future posts, click here.

Previously, we have discussed the conundrum of the rising PSA and when to start therapy. I also opined that for some men with a very slowly rising PSA, it might be best to just forget about it and enjoy life, comparing it to watching a clock, an opinion that understandably garnered negative comments from some. Of course the nuances surrounding PSA kinetics and their meaning are myriad. However, one graphic that helps understand this better is shown here.

Screen Shot 2018-02-12 at 2.49.27 PM

Smith, JCO 2013

This figure illustrates the fact that individuals with relatively long doubling times (>8-10 months) have a much lower risk of developing metastases or dying from prostate cancer than those with shorter doubling times. In a classic study published almost 2 decades ago, Pound et. al. followed a large number of patients who had rising PSAs following prostatectomy at Johns Hopkins. On average, men with rising PSA’s  who received no additional treatment, did not develop metastases for ~8 years. “In survival analysis, time to biochemical progression (P<.001), [i.e. the time from prostatectomy until PSA rise was detected] Gleason score (P<.001), and PSA doubling time (P<.001) were predictive of the probability and time to the development of metastatic disease.”

With these findings as a background, two studies were presented at the ASCO GU18 meeting, both involving use of improved analogues of bicalutamide (Casodex): enzalutamide (Xtandi) or apalutamide (Erleada). These drugs block the androgen receptor, thus preventing stimulation of prostate cancer growth, but are more potent than bicalutamide. Patients with rising PSA’s in spite of having low levels of testosterone from surgical (orchiectomy) or medical (GnRH agonists/antatgonists) castration, short doubling times (<10 months), but no metastases were treated either with apalutamide/placebo (SPARTAN trial) or enzalutamide/placebo (PROSPER trial). The trials were both remarkably positive in delaying the time to development of metastatic disease.

Screen Shot 2018-02-19 at 8.44.28 AM

SPARTAN TRIAL (Apalutamide)

Screen Shot 2018-02-12 at 2.42.37 PM

PROSPER TRIAL (Enzalutamide)

These are remarkable findings and great news for patients with the most aggressive forms of prostate cancer. However, there are (as usual) numerous questions raised by the trials, as was nicely discussed by Dr. Kantoff after the data were presented. These included a more careful analysis of the side effects and clinical benefits. Obviously patients are psychologically better off when they don’t have a rising PSA or metastases, but neither study reached statistical significance when it came to improved survival (both are trending in this direction). What are the side effects of being on such drugs for longer periods of time? In the enzalutamide study, there were more deaths from “other causes” – not pca within 3 months of progression. Why? In the apalutamide study there were more falls and fractures compared to placebo. Why? To these, I would add the issue of “pay me now or pay me later” – how much time/quality of life do you really lose by waiting until the first metastasis shows up, never mind the extraordinary costs (to patients, insurers, medicare, etc.) of remaining on these drugs for years. Further, neither study compared the outcome to using bicalutamide, the generic and much cheaper alternative anti-androgen, instead of placebo. And what about using the newer scans? All of the patients have metastatic disease, we just can’t see it until there are enough cells in one spot to turn a scan (e.g. fluciclovine or PSMA PET) positive. We can possibly gain advantages in staying off ADT of any sort in some patients by radiating oligometastatic disease. Nevertheless, these studies are great progress and landmarks in the fight against prostate cancer. Apalutamide became the first drug to be approved by the FDA for use in this setting with a “snap approval“. And I need to disclose that I am a paid advisor to J&J, although I have no personal stock in their company, and did not treat patients on either trial.

6 Comments

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

Today’s the day! Grow a Mo


Movember is here! I urge you to join our team and raise money for helping men fight prostate cancer.  We have, once again, organized a University of Colorado Cancer Center Team.  The MOVEMBER Foundation raises money to fund projects related to men’s health – specifically prostate cancer, testicular cancer, and mental health.  Since 2003, this grass roots project has gathered 5 million participants across 21 countries raising more than $710 million and funding over 1,200 projects.  We, The University of Colorado Cancer Center,  are actively involved in the Prostate Cancer projects which include translational research, clinical registries, and the Global True NTH program.  True NTH is aimed at catalyzing innovative health outcomes programs, through supportive care services, in an effort to improve the lived experience of men with prostate cancer, as well as their partners and caregivers.  

 Your action required is quite simple.

 1)      click HERE to register with the CU Cancer Center Team

2)    get your friends and family to join the conversation and support your efforts

3)    grow (or inspire others to grow) an incredible mustache for 30 days, starting TODAY

I cannot emphasize strongly enough the difference Movember has made in the fight against prostate cancer. Through multiple initiatives they are doing for this disease what Susan G Koman for the Cure has done for breast cancer research. I always used to say, “In breast cancer, they RACE for the cure, while in prostate cancer we CRAWL for the cure.” No longer! This an initiative by men and for men, although just as we have seen the NFL football players sporting pink shoelaces, there are a lot of women who support Movember as “Mo Sisters” as well. 

If you don’t want to join the team and “grow your own”, you can sponsor my feeble attempt at a moustache by clicking HERE.  Many thanks for your consideration. 

Leave a comment

Filed under Uncategorized

Abiraterone (Zytiga™) earlier makes a big difference in outcomes


To view this on my blog site and subscribe to future posts, click here.

The big news at the ASCO annual meeting this year included two “practice changing” presentations for prostate cancer that have been widely covered in the medical press. The basic finding is that adding abiraterone to ADT in the “up front” setting (i.e. when initially starting ADT for high risk disease, a rising psa or in someone who has newly diagnosed metastatic disease) results in markedly improved overall survival and time to progression of disease. I encourage you to read the link above which reviews the presentations and commentaries in detail. Reflecting our amazing digital age, the New England Journal published the detailed, peer-reviewed articles on the two studies simultaneously with the ASCO presentations.

In the Latitude trial, 1199 men who were newly diagnosed with metastatic disease and who “… were considered to have at least two high-risk prognostic features (e.g., a Gleason score of ≥8, the presence of ≥3 bone lesions, or the presence of measurable visceral metastasis)” were randomized to receive a GnRH analog plus abi/prednisone vs GnRH analog plus dual placebos. The science behind this is that with surgical (orchiectomy) or medical (GnRH analog) castration, testosterone synthesized by the testicles is mostly eliminated. But there is still stimulation of the prostate cancer androgen receptors (AR) by other testosterone, coming from the adrenal glands, the tumor cells making testosterone themselves,  other steroids, or even changes in the androgen receptor itself. Abiraterone or its metabolites can block most of these pathways. Thus the question is whether nearly complete shutdown of AR stimulation from the onset of treatment can achieve more than waiting to use Abi after resistance to AR directed treatment with a GnRH analog develops. The results were remarkable:

A second trial, from the STAMPEDE group used a similar approach in a different, more heterogeneous group of 1917 patients with high risk localized disease, metastatic disease, or PSA relapsing disease after local therapy. The randomization to standard ADT alone vs ADT plus Abi/prednisone was similar as were the remarkably positive outcomes.

Screen Shot 2017-06-05 at 10.16.58 AM

The P-values for some of the endpoints in this trial were eye-popping. “Time to failure improved by 71% in the abiraterone group (HR 0.29, 95% CI [0.25, 0.34]; p = 0.377×10-61)” The discussants at ASCO pointed out that future trials may need to consider comparison of abiraterone early addition to the early addition of chemotherapy as was done in the CHAARTED trial. Generally, however, the toxicities of docetaxel are certainly greater than abiraterone and such a trial would be complicated. It is even possible that one of the ways docetaxel works is “simply” blockade of AR translocation and that it is just a more toxic way of hitting the same pathway. In addition, the cost considerations of abiraterone, particularly when it must be taken for years, are a real concern, and in keeping with the very keen worries we have regarding new cancer drugs in general.

“Targeted therapies” along with the immune checkpoint blockade drugs are changing the landscape for cancer patients. To me, the somewhat surprising thing about these two studies is how great the advantage seems to be when you can truly effectively hit a target early and hard, in this case the AR signaling pathway. It is all the more remarkable that this is a pathway we have now been targeting for over 70 years and there is still more to come. If we can find the right combination of AR targeting and immune modulation, I see no reason why metastatic prostate cancer can’t be added to the “curable neoplasm” list in the near future. Then the question of whether, and how we need to screen will become even more complex. Good news !!

Disclaimer: I am a consultant for Janssen, the pharmaceutical company that sponsored the Latitude trial discussed above.

 

8 Comments

Filed under Uncategorized

To Watch or Not to Watch


To read this blog on my blog site, comment, and subscribe to notifications for future posts, click here.

Active surveillance (active monitoring, watch and wait, etc. – each with slightly different definitions) means you know you have a low risk prostate cancer (typically defined by a small amount of cancer in only a few of the biopsy cores and usually with a Gleason 3+3 score (some studies also include low volume Gleason 3+4 patients). Knowing this, you decide to not have treatment but just “keep an eye on things”. It all sounds so simple until you try to project what that means for YOU, and here is where the decision making becomes complex. Risk tolerance and rewards of decisions are psychological issues, not so much medical ones. Some people feel the thrill of jumping out of an airplane or off a bridge with a bungee cord more than compensates for the relatively small risk. Others don’t. For some men, ANY decrease in their sexual function or chance of incontinence is not worth the risks of treatment. For others, ANY risk of dying from prostate cancer is unthinkable. And, I would add – having counseled many couples – that the spouse’s feelings about sexual intimacy and survival vary considerably. For the record, the most common comment I hear from the wife is “We don’t care so much about sex, I just want George to be here” or similar, sometimes paired with the comment (regarding surgery vs. radiation) “I just want it out of him.”

With that background, Anthony D’Amico, one of the most prolific researchers and best analytic minds in our field, has written an editorial worth reading. In it he posits the question of whether the development of metastases, not death from prostate cancer, should be the better way of evaluating active surveillance. His primary analysis comes from looking at the ProtecT study, published last year in the NEJM. In that study, “82,429 men had a PSA test; 2664 received a diagnosis of localized prostate cancer (including 146 men from the feasibility study), and 1643 agreed to undergo randomization to active monitoring, radical prostatectomy, or radiotherapy.” There were about 550 men in each arm of the study and at the end of 10 years, there was no difference in the death rates from prostate cancer. 291/545 of the men in the surveillance arm had gone on to receive treatment within 10 years. However, as D’Amico points out, “the occurrence of metastasis, defined as the spread of PC to bone, viscera, or lymph nodes or a PSA level > 100 ng/mL, occurred in 62 men and was more than two-fold higher in men randomly assigned to [active surveillance] versus a treatment protocol.” In absolute terms, this meant that 32/545 surveillance vs 13/553 surgically treated vs 16/545 radiotherapy patients developed metastases and would need to suffer the side effects of hormonal treatment during their last decade or so of life. D’Amico argues that these men with metastases should be a better measure of the outcome for the active surveillance approach. What he does not deal with, however, is the benefit the men without metastases experienced by taking the approach. By 10 years, nearly half of the surveillance group had not had the side effects of definitive treatment, and even those who “fell off the wagon” and were treated enjoyed some additional time without side effects.

In a companion article to the ProtecT cancer outcomes article, we learn more about the side effects of treatment. These graphics from that article show that surgery (red line) and radiation therapy (gold line) produce significantly more side effects than the slower problems that develop over time with both urinary and sexual function in the surveillance (and all aging men) group (blue line). The PIVOT trial (also worth reading to gain perspective on the relative advantages of treatment or not) demonstrated that virtually all patients who receive treatment experience some decrement in sexual function.

Not shown, but an important part of the overall picture, is that the surveillance protocols involve biopsies every 1-2 years, or MRI exams (or increasingly both), following the PSA values which can and does produce anxiety (see my blog on the “PSA Clock”), and the psychologic burden of “knowing you have cancer”. These side effects of surveillance are often under-appreciated, and some men who elect for surveillance eventually change their mind and opt for treatment because of them.

Finally, age makes a big difference in psychology. Older men are generally less sexually active and focused than younger. There is good evidence that it is just as safe to do active surveillance in younger men, if sexual function is an overriding consideration. In the end, the decisions about what to do if you have been diagnosed with a low grade prostate cancer are not easy, and highly personal – just like sky-diving and bungee jumping!

9 Comments

Filed under Uncategorized

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

Build your own bunker


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

In the New Yorker last week, there is an interesting article about current ultra-wealthy survivalists who are spending all sorts of money buying up property in New Zealand, or outfitting old missile silos in Kansas in preparation for the dissolution of society. The tone is definitely post-apocalyptic, much like the book/movie, The Road, and causes me to ponder, “What would life be like in an underground silo for the last years of my life?”

Personally, I’m not going there! But the matter of personal choices is a very real one in dealing with prostate cancer. I am reminded of the exploding genre of molecular tests that assist in prognosticating about prostate cancer outcomes – whether that is the likelihood of developing metastatic cancer if you have an elevated PSA with the OPKO 4K test, or the chances you have a cancer that was missed on an initial biopsy with ConfirmDx, or the predicted behavior of a cancer with OncotypeDx. All of these tests have been validated using 1000’s of patients for whom the outcome of their cancer is known. None have been validated in terms of how often using such a test prospectively led to a patient/physician making the “right” decision. Nevertheless, they are the way “personalized medicine” is playing  out in the management of prostate cancer, and I discuss them with my patients.

So, back to the bunker. Do you build one if the chances of the stock market crashing, governmental chaos and nuclear war is 2%? What if it is 50%? And in the case of prostate cancer, what does “meltdown” look like? To start with, we too often ignore our inevitable mortality and the competing causes of death. The Charlson comorbidity index is a great place to start and should be used far more often in prostate cancer counseling. There are a variety of online calculators, including this one that you can use to peer into the future. A 60 year old man with none of the diseases listed has a 90% chance of 10 year survival. If you are over 71 and have had a heart attack, it drops to 21%. Overall, my impression is that patients do better than this in the current era, but it is nevertheless true that competing causes of death play an increasing role in decision making, and that age plays the dominant role. Given that we can control prostate cancer fairly well for 5-10 years in most patients, even if they have metastatic disease, what should a 78 year old otherwise healthy man do with his elevated PSA? Biopsy? Molecular test? The range of answers is broad indeed. Before ordering any of the more sophisticated tests, it is worth sitting down and looking at the way the results will be reported and asking “what if” the test comes back in one way versus another – will that change my mind or help me make a decision?

The bunker all of us geezers should  be building, however, is our own physical one. In a great review article by my colleague, Mark Moyad, he notes the following:

Kenfield et al17 studied a population of 2,705 male health care professionals (mean age at prostate cancer diagnosis about 70 years) with nonmetastatic prostate cancer and found that those participating in vigorous physical activity (metabolic equivalent task [MET] value21 ≥6) for a duration ≥3 hours/week demonstrated a 49% lower risk of all-cause mortality and a 61% lower risk of death specifically from prostate cancer, compared with men who did <1 hour/week of vigorous activity.

It is hard to imagine ANY fancy test, supplement, or other intervention that could have a greater impact on your prognosis. Therefore, hard as it is, and whether you have prostate cancer or not, your bunker awaits at the local gym. The Psalmist said we are given 3 score and 10 years or with strength, 4 score, but he had a morbid view of the last of them. 2000+ years later it may not have changed that much. But if you look out the window, the world still looks like a pretty nice place to me and I say make the most of it!

5 Comments

Filed under Uncategorized