Tag Archives: leuprolide

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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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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Profiting from “YOUR” prostate


Medicine is a business. I get that. It is also a wonderful professional calling and being both at the frontiers of science like the genome project as well as holding the hand of a patient who is asking about whether he should try one more desperate treatment is a remarkable privilege. Since I started my medical practice 34 years ago, the changes in both business orientation and in the technologies of medicine are breathtaking. All of that said, I remember when the doctor in my home town of Chadron, Nebraska, made house calls, drove a Buick and lived a few blocks away in a very modest house. Making himself rich was really not part of the equation, although he did well enough to send his kids to fine colleges and eventually build a nicer home.

The skewing of medical practice towards being a “small business” and away from a profession bothers me. Even though I agree with my sister who married a wonderful cardiologist and has a remarkable estate that “once doctors could actually DO something, it became a transaction”, it simply bothers me. My introduction to this real world started when we participated in the development of leuprolide, giving the first patients small but increasing doses, assessing saftety, and eventually designing the trials that led to FDA approval. When the price for a 3 month injection was announced, I was astonished. When a “me too” drug came out called Zoladex, I thought that the competition between pharmaceutical companies would drop prices. It didn’t. Instead, companies competed on behind the scenes pricing schemas that began to corrupt the doctors prescribing the drugs. Eventually (though not soon enough to save billions of dollars to our Medicare system), there was a whistle blower who got enough attention to stop the practice.

Now we find that business and profit have become the (maybe that should be THE) driving force in medical decision making. Urologists who used to make large sums of money off of the drug markup schemes with lupron, changed over to doing more orchiectomies as soon as the profits fell off. The study documenting this found the following: “The use of medical castration increased from 2001 to 2003, whereas, over the same period, surgical castration decreased. Total allowed charges for medical castration peaked in 2003 at $1.23 billion. After the enactment of the MMA, surgical castration rates increased, and medical castration decreased. Total allowed charges for medical castration in 2005 dropped 65% from the 2003 peak.” In other words when the profits for giving Lupron fell, surgeons started doing more surgery and stopped giving leuprolide shots in their offices.

Now the focus has shifted to seeing if more money can be made doing radiation therapy than surgery. Medicare has decreased the compensation for doing prostate surgery.  Some large urology groups have formed and purchased their own radiation therapy equipment. .No problem with that if their practice of recommending surgery versus radiation for patients hasn’t changed. However the data for some of these groups suggests that is not the case. In a recent article from Bloomberg, the profit motive influences more and more urologist’s decision making. “one in five U.S. urologists add to their income by billing for the type of treatment in question, according to the journal Urology Times. Called intensity- modulated radiation therapy, or IMRT, it uses imaging software to focus multi-angled X-rays on tumors, aiming to deliver bigger doses with fewer side effects than prior technologies. This side business pays doctors up to $40,000 per patient from Medicare, or 645 times what a urologist gets for a standard office visit, and as much as 20 times what the federal insurance program pays a surgeon to remove a cancerous prostate gland, according to published studies. Reimbursement from private insurers for IMRT can be even higher, urologists say.”  Dr. Cooperberg, of UCSF is quoted as follows: ““Doctors do what they’re paid to do” Cooperberg said. “If you tell them they can earn $2,000 for surgery or $37,000 for IMRT, what do you think will happen?”

The article goes on to state: “When urologists have a financial stake in IMRT, the portion of patients referred for it roughly triples within about two years, according to preliminary data presented at a radiation oncology conference in Miami Beach last year by Jean Mitchell, a health-care economist at Georgetown University.”
I find all of this very sad. I know dozens of urologists who are absolutely terrific and would never let profit influence their decisions on a treatment recommendation. I also know radiation oncologists who are incensed that urologists are invading their own profit making world, and of course there is no shortage of medical oncologists who “struggle to make ends meet” by giving the most expensive chemotherapy when they should be referring patients to compassionate hospice care. My point is that I don’t think very many medical student applicants start off with making money as their motive for going into medicine. I am disappointed in what my profession seems to do to some of them. I love medicine as a profession, not as a business.

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