Tag Archives: hormone therapy

February 28, 2021 · 10:23 pm

Return to Estrogen?


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Remarkably, estrogen was discovered to be a cancer driver for breast cancer by surgeons in the late 1800’s but it was 5 decades before the relationship of hormones to prostate cancer was discovered. George Beatson had considered performing oophorectomy for women with breast cancer because the procedure was successful in prolonging lactation in cattle. His first patient experienced a complete remission from soft tissue breast ca metastases and lived another 4 years. He later said that he thought this treatment would induce “fatty degeneration” of malignant cells.

The relationship of testosterone as a driver of prostate cancer is credited to Huggins and Hodges, who found that either surgical castration or administration of estrogen to men with prostate cancer could reduce what was then the only known marker of prostate cancer, acid phosphatase. Additionally, if they administered testosterone to these patients, the acid phosphatase would increase. This built on observations that the enzyme was present in the prostate gland and would go up in patients as they developed metastases, usually in the bones. For this work, Huggins was awarded the Nobel prize in 1966. The use of surgical castration or estrogen administration remained the mainstay of treating metastatic prostate cancer until the introduction of leuprolide in the early 1980’s. I had the extraordinary opportunity to participate in those trials, which we published in 1984. We compared leuprolide to DES, an oral form of estrogen that works on the same endocrine axis as leuprolide, causing the pituitary gland signaling hormone, LH to drop, and subsequently the testicles stop making testosterone. Leuprolide worked as well as DES, but oral estrogen is dangerous – leading to blood clots and increased risk for heart attacks or strokes. Thus, leuprolide (and other GnRH analogs…including the recently approved oral GnRH antagonist, relugolix) became the standard for ADT therapy of prostate cancer.

But estrogen still works. In fact, it may have some significant advantages over surgical castration or GnRH therapy. Our team found that DES could still produce meaningful responses in patients with rising PSA’s who had failed GnRH even though we did see blood clots. But, you can also give estrogen via transdermal patches which avoids many of the problems of oral DES. This week, the PATCH trial program in the UK reported the safety results of using estradiol patches (E) to treat prostate cancer patients compared to GnRH agonists. The ability to produce therapeutic (castrate level) testosterone was the same, but the E treated patients had lower cholesterols, lower blood pressure, less diabetic tendencies, and far fewer hot flushes. Previous study analyses have shown that E is better for bone health with no calcium loss. The only thing that was worse was breast enlargement (gynecomastia) which was seen in 86% of E patients compared to 38% in the GnRH agonist patients. To some extent, gynecomastia can be treated by radiating the breast tissue. The efficacy of E in treating the prostate cancer in these patients will be reported in 2023 and 2024. The cost of E treatment (4x .025mg/24h patches every 3.5 days) is about $62/week ($750/3 months) which is definitely less than any of the GnRH agonists or antagonists. It will be terrific if this “old fashioned” treatment can again join the treatment options for men with advanced prostate cancer. I think it would also be reasonable to try in patients who are failing the newer second generation agents before trying the more expensive/complicated/toxic alternatives like taxane chemotherapy or radionuclide agents (Radium 223, Lu177-PSMA, etc.) With PSA monitoring, it should be relatively easy to find patients who benefit from such treatment.

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January 13, 2021 · 7:08 pm

Pills vs Shots for Androgen Deprivation Therapy (ADT)


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My own interest in prostate cancer began with what, in retrospect, seems quaint and naive. When I arrived at the University of Colorado in 1978, as the first board certified medical oncologist, there were very few clinical trials underway. Having trained (at DFCI) with teams of researchers, my philosophy had evolved to the thought that “every patient should be treated on a protocol, and there should be a protocol for every patient”. This idea (in academic centers, at least) is how we make progress in treating cancer. I continue to urge every patient to participate in clinical research whenever possible, recognizing that for reasons of geography, convenience, or eligibility, it may not be possible. Clinicaltrials.gov lists all of the ongoing clinical research trials for patients and physicians, a dramatic advance in keeping everyone informed. You can learn how to use this tool in one of my previous blogs, here.

With few clinical trials going on at our cancer center, I wrote a naive letter to a number of pharmaceutical companies asking if they had any drug development trials that I might participate in. A single company, Abbott, wrote back inviting me to Chicago to discuss “Abbott 43-818”. This drug was an analog of gonadotropin releasing hormone, GnRH, a peptide (10 amino acids in this case) that looks like this: Pyr-{His}{Trp}{Ser}{Tyr}{Gly}{Leu}{Arg}{Pro}{Gly}-NH2. The 43-818 analog came to be known as leuprolide, and I had the opportunity to participate in taking it all the way from the first dose in men to a final clinical trial resulting in its approval as Lupron™. I’ve been caring for prostate cancer patients and doing clinical trials in prostate cancer ever since – fate!

The way Lupron™ works is shown in the figure below. Normally a part of your brain called the hypothalamus (1) releases a “pulse” of GnRH several times/hour. The peptide travels to the pituitary gland (2) and lands on cells called gonadotropins, causing them to release hormones LH and FSH that travel to the gonads (4) where the ovaries release estrogen or the testes release testosterone. Leuprolide interrupts this process by “over stimulating” its receptor on the pituitary cells and they turn off their LH/FSH production. Because of the small and relatively simple peptide sequence 100’s of other analogs have been made, and the molecular interactions with the receptor have been extensively studied. Some are agonists (like leuprolide/Lupron™/Eligard™, or goserelin/Zoladex™ and others are antagonists (degarelix/Firmagon™).

The hypothalamic-pituitary-gonadal axis

After a long research path, an oral antagonist (relugolix/Orgovix™) has now been synthesized, tested, and approved for treating prostate cancer. It is not a peptide, has the advantage of not having to be injected, and may be safer in patients with a cardiac history. The HERO trial evaluated 934 prostate cancer patients, 2/3 of whom received relugolix and 1/3 received leuprolide. As expected (based on the history of antagonists research), relugolix resulted in more rapid reduction in testosterone, faster recovery upon discontinuation, and faster reduction in PSA.

The frequency of the common bothersome side effects, hot flashes and fatigue, was similar. More patients on relugolix (12.2%) had diarrhea than those on leuprolide (6.8%). However, the leuprolide treated patients had more serious cardiovascular events (myocardial infarction, central nervous system hemorrhages and cerebrovascular conditions, or death from any cause), especially if they had a cardiac history. The incidence was 6.2% in the leuprolide group vs. 2.9% in the relugolix group.

All things being equal, use of relugolix would seem to be a superior choice for ADT in prostate cancer patients. However, as usual, “all things” may not be equal. First, while the biology above may seem to favor the antagonist, there are no data on whether this affects survival or time to progression of prostate cancer. The biology of reducing testosterone as the mainstay of treatment has not changed – we are attacking the same target: testosterone stimulation of prostate cancer cells. Indeed, the more rapid recovery of testosterone upon discontinuation of therapy (for example in a patient who receives several months of relugolix in combination with radiotherapy) might result in better quality of life with rapid recovery, but have a higher rate of recurrence due to the shorter overall duration of ADT treatment. Some patients will prefer pills to shots. On the other hand, insurance coverage for injections might be much better than that for an oral medication. The internet reported cost for a month of relugolix is reported to be $2313. The cost for a one month leuprolide dose is around $1700. However, the cost of a myocardial infarction is not insignificant, and thus comparison of one form of treatment vs another is always more complex than it initially seems.

I am writing this because I suspect there will be “news” articles and other advertising efforts for “Orgovyx™” in coming weeks/months and I hope to refer my patients to this article (and all the other ones I write). If a newly diagnosed patient has impending spinal cord compression, or major organ involvement or a history of cardiac disease, I would recommend the antagonist (relugolix/Orgovyx™) over the agonists (like leuprolide/Lupron™/Eligard™ or goserelin/Zoladex™). If a patient is already on one of those agonists, is doing well and has no cardiac history, there is probably no reason to change therapy. For a patient who is about to start therapy, I will discuss the options, and am happy to prescribe either an agonist or antagonist – it may well depend on insurance issues for a given patient. As with the Covid vaccine, the scientific progress in developing a non-peptide, oral agent is a testament to “our” (medical science) phenomenal scientific advances. The cost of such research (dating back at least to 2013 for relugolix) and what represents fair costs to patients or to Medicare and fair reimbursement to the pharma companies remain concerning to me.

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September 19, 2020 · 10:17 am

Why can’t we cure this???


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A frustration for patients and physicians alike is the incurability of metastatic prostate cancer in spite of the great response that many/most patients have to initial hormonal treatment. As most readers of this blog know, almost all prostate cancer cells depend on stimulation from testosterone to grow and to get outside the prostate, moving to lymph nodes or bones (the most common place for metastases in pca). Testosterone is normally made by the testes and adrenal gland, circulates in the blood stream, and enters the cancer cells where it binds to the AR (androgen receptor). The AR then translocates to the nucleus where it binds to specific locations “upstream” from various genes (including PSA, and interestingly TMPRSS2 which has implications for COVID-19) leading to the gene being “activated”. Many of the activated genes lead to cell division and invasion that characterize/lead to metastases we detect with bone, CT, or PET scans.

Normally, the way we detect that cancer cells are “turned off” or dying is by the PSA falling. PSA in general is far more sensitive than scans, but it really tells us about the “big picture”, not what is going on with individual collections of metastatic cancer cells. Measuring PSA every 3 months is a very common way to monitor the response to drugs that stop testosterone synthesis (abiraterone – Zytiga) or block testosterone from binding to the AR (bicalutamide-Casodex, enzalutamide-Xtandi, apalutamide-Erleda, darolutamide-Nubeqa)

Although much more expensive, monitoring response by repeating scans can begin to answer the question posed for the title of this blog. Why doesn’t hormone therapy lead to cures? The reason lies in a single word, heterogeneity. As I reviewed previously, when we look at different sites of cancer metastases, the tumor deposits in one area may have a very different genetic mutation profile than those in a different area. I was very struck by how well this is illustrated in a recent article using quantitative PET scans. In patients treated with enzalutamide, the different sensitivity is graphic as shown in this figure from the article:

Compare PET1 taken at the start of treatment with enzalutamide to PET3 when disease was progressing indicated by a rising PSA. Green spots indicate partial or complete response to the antiandrogen while red ones are new or progressive locations. This is a graphic example of the result of tumors having genetic changes that make them more or less sensitive to the drug. Finding a combination of chemotherapy or hormone therapy that can attack all of the genetically different deposits is impossible at this time. However, the immune system may be able to keep up with all the changes in some patients, and this provides hope for the expanding trials of immunotherapy in prostate cancer you can find here. Glass half full or half empty? You choose!

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March 15, 2020 · 10:17 am

(Love) Advice in the time of (Cholera) Coronavirus


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I wanted the title to look like this, but the software wouldn’t let me: Love Advice in the time of Cholera Coronavirus. In any case, if you are a patient or in the patient age range of prostate cancer you are automatically at some increased risk. There isn’t much evidence that cancer patients in general who aren’t on chemotherapy or an immunosuppressive agent have much increased risk. In fact, patients on ADT may actually do a little better based on reactivation of thymic function. Here is a quote from this complex article by James Gulley and colleagues:

Analyses of these data suggest that AR expressed by thymic epithelium play an important role in thymocyte development, and could explain why androgens induce apoptosis of thymocytes in vivo but not in vitro (31). In subsequent studies, androgen withdrawal led to increased thymopoiesis and reversal of thymic atrophy in post-pubertal male mice (32) and even in aged mice (33, 34). Furthermore, thymopoiesis decreased with the administration of testosterone (35, 36). Castration also results in increased T- cell export in aged mice and increased naive splenic T cells compared to aged controls (34).

Although persistent thymic function is evident in older individuals, it is decreased, as demonstrated by lower TREC [T-cell receptor rearrangement excision circles] levels (37). However, studies show that ADT can induce thymic renewal in older individuals (38). In one study, elderly prostate cancer patients given GnRH-A experienced a notable increase in TRECs in 6 out of 10 cases, indicating renewed thymopoiesis (34). These studies suggest that the effects of androgen ablation are not limited to the young, as evidenced by restoration of thymic function and export of naïve T cells after surgical (orchiectomy) or medical (GnRH-A) castration.

 

The enhanced thymopoiesis associated with ADT has important clinical implications for the treatment of immunocompromised patients and for immunotherapy for prostate cancer (see Figure 3 for a summary of ADT’s effects on the T-cell compartment). Thymic renewal in these patients may increase the diversity of the T-cell repertoire, increasing the pool of antigens recognized by the immune system. In the setting of vaccine therapy, an increased naïve T-cell compartment may enhance the response to immunotherapy.

 A few patients have asked me about whether to postpone surgery. In general, for patients with “average” (Gleason 3+4) tumors, this would probably be OK. It is a harder decision for those with Gleason 4+3, or any component of Gleason 5. It will have to be an individual decision (as are all decisions of this sort) with your doctor. The same would apply to radiation therapy treatment which can have some immunosuppressive effects, but certainly has never been studied in this situation.

In general, I would also recommend that you put aside your political biases and listen to the scientific experts. I was disturbed by a poll presented this morning on Face the Nation that indicated a significant difference in the perceptions of risk between Republicans and Democrats. This virus does not know or care about your party or politics. Practice the social isolation being recommended by Fauci and the other experts: “We should be over-reacting to this…” It would be just fine to look back and say we did that.

If you want to delve further into the science of this (which also dispels a lot of misinformation about where the virus comes from and how it arose), you should certainly look at this presentation: http://www.croiconference.org/

And in case you haven’t been thoroughly inundated with advice or just came out from under a rock, here is the succinct list of expert recommendations:

  • Social Distancing to flatten the curve of the pandemic (reduce infectivity rate from >2 to <1):
    • Wash/sanitize hands frequently
    • If sick, do not go to work
    • Work from home if at all possible
    • Maintain your personal space when around others
    • Eliminate travel (don’t be fooled by cheap flights or hotels)
    • Reduce exposure to groups of people
    • COVID-19 can persist on hard surfaces for several days so wipe down frequent contact surfaces repeatedly
    • Recognize that social distancing will have some mental health implications so be especially compassionate

Stay home. Stay well. Here is a list of things to do:  Fun Free Time Activities_

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September 8, 2019 · 5:53 pm

ADT and Alzheimer’s Disease: risk/benefit


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The July 3 issue of JAMA Network contained a disturbing article regarding the risk of developing Alzheimer’s disease or dementia following use of androgen deprivation therapy (ADT). Using the SEER-Medicare database, the authors identified a cohort of men aged 66 or older who were diagnosed with localized or advanced prostate cancer between 1996 and 2003. The data on what happened to them in the next 10 years were then analyzed according to whether they received ADT or not in the 2 years following their diagnosis.  These were older men (74-76) who mostly lived in metropolitan areas, and 3/4 were caucasians, 2/3 were married, with just over 1/3 coming from low socioeconomic backgrounds. There were 62,330 men who received ADT, and 91,759 who did not in the final groups analyzed.

With a mean followup of 8.3 years, the risk of developing Alzheimer’s disease among the control group was 9.4% but increased to 13.1% if the men received ADT (P<0.01). Similarly, a diagnosis of dementia increased from 15.8% to 21.6% with ADT exposure, and there was evidence that the longer the men were on ADT, the worse the risk. These data are disturbing to me on two levels. First, I was unaware that 75 year old men have such a high risk for developing Alzheimer’s disease or dementia in their next decade; and second, as a frequent prescriber of ADT for men with prostate cancer in general, and particularly for those receiving curative intent radiotherapy for high risk disease, it adds to the challenge of how long to recommend such therapy (if at all). The risk curve for Alzheimer’s is shown in this figure:

Screen Shot 2019-09-04 at 2.58.07 PM

The benefit of adding ADT to curative intent radiotherapy has been demonstrated in a large number of studies dating back to the 1990’s. For example one of the most cited studies compared the survival and prostate cancer specific survival of adding 3 or 6 months of hormone therapy to radiotherapy in patients with advanced local disease. The advantage of 6 months (compared to none or 3 months) of ADT is shown in this figure, and is about 10%, somewhat better than the increased risk of developing Alzheimer’s that is probably created.

Screen Shot 2019-09-08 at 6.19.23 PM

The details of these kinds of comparisons are quite complicated – for example trying to separate out various categories of “high risk” or “higher risk” prostate cancer, etc. as reflected in this editorial by Dr. D’Amico. Numerous other studies continue to support the use of ADT to improve outcomes of radiotherapy – the challenge being how long to continue it and weighing toxicities (cardiac, quality of life, dementia risk, etc.) vs the advantage in terms of prostate cancer control. Dr. D’Amico looks forward to better information in his final statement, “During the next few years, data that will shed light on whether more than 6 months of AST is needed to prolong survival in men treated with RT for localized high risk or locally advanced prostate cancer will be provided by the completed EORTC randomized study 22961.” Stay tuned, and if you are told to take ADT to improve the outcome of radiation to your high risk localized prostate cancer, discuss the details with your physicians! How old you are, what is in your family history, and your own thoughts regarding risks of prostate cancer recurrence/death or dementia are important issues.

 

 

 

 

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March 22, 2017 · 9:43 am

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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