When it comes to cancer we often see that what seems to be logical isn’t necessarily the way it works! In a surprising study result, it was shown that the use of intermittent androgen-deprivation therapy (IADT) for prostate cancer is not associated with fewer long-term adverse events than continuous ADT! Who would have guessed?
Hormone therapy (ADT) comes with a guarantee of an array of adverse events, including sexual dysfunction, bone de-mineralization, cardiovascular disease, metabolic complications, cognitive changes, and a diminished quality of life. We thought that going on an intermittent schedule would minimize these events, but based on a recent study this it isn’t necessarily true!
In this study of men with advanced metastatic prostate cancer it was shown that for one category of complications, ischemic and thrombotic events, there was an increased incidence in men on an intermittent ADT schedule. Yes, an increase, not a decrease and in a serious side effect . This is a stunning find; we might be safer having continuous ADT!
According to lead author Dawn Hershman, MD, from the Columbia University Medical Center in New York City, "We were all surprised that our analyses found an increase in the cumulative incidence of ischemic and thrombotic events in men randomized to the intermittent ADT."
Hershman’s finding comes from an exploratory analysis of data from the Southwest Oncology Group randomized trial, known as S9346, which compared the two schedules of ADT administration in men with metastatic prostate cancer. The primary outcome of the trial was overall survival, but the trial failed to demonstrate non-inferiority of intermittent ADT compared with continuous ADT. To translate this, intermittent and continuous ADT schedules are equal in overall survival.
Hershman’s study looked at data from 636 men enrolled in the S9346 trial using their Medicare claims to investigate differences in long-term adverse events. The researchers grouped adverse events into five categories: endocrine events, sexual dysfunction, dementia and depression, acute kidney injury, and ischemia and thrombosis.
There was no significant difference between the study groups for the first four categories. But, the great surprise was that the 10-year cumulative incidence of ischemic and thrombotic events differed significantly between the two groups with 24% in the continuous group and 33% in the intermittent group (hazard ratio, 0.69; P = .02).
Hershman did say that overall, the men, who had a median age of 71 years, had a lot of health issues. "The reality is that long-term, health-related events were high in both arms." She also found that the most common long-term events experienced by the men were hypercholesterolemia (31%) and osteoporosis (19%).
In peer review comments to the study it was pointed out that the study findings are weakened by "methodological limitations." According to the reviewer’s comments, Saroj Niraula, MBBS, MD, from the University of Manitoba in Winnipeg, and Ian F. Tannock, MD, PhD, from the University of Toronto, "Neither the primary SWOG study nor the current one was powered adequately to examine differences in occurrence of toxic effects between the two strategies."
They felt that the study does not prove the statistical superiority of continuous ADT in terms of thromboembolic and ischemic events. However, the pair acknowledge that, given the direction of this trend, "it is highly unlikely that a larger cohort would find [the events] to be reduced with intermittent ADT."
Given how counter-intuitive this finding is, we need to examine the conclusion. Both the peer reviewers and the study authors have speculated as to why there were more ischemic and thrombotic events with intermittent ADT.
Among other thoughts, the reviewers said: "Multiple insults to the coagulation system with decrease and increase in testosterone levels during IADT might therefore be responsible for the observations coming from this study."
The study authors touched on that same idea: "Changes in the coagulation cascade have been reported with lowering of testosterone during ADT as well as with increasing estrogen (after stopping ADT)."
Hershman has also report that results from a phase 2 study showed that men treated with intermittent ADT had a higher incidence of myocardial infarction during their off-treatment period than during their on-treatment period (4.6% vs 2.8%), but the difference was not significant (Clin Genitourin Cancer. 2008;6:46-52).
Hersman has cautioned that intermittent ADT is something that clinicians should be "cautious" about using in elderly men with metastatic prostate cancer. This is, of course, a twist in what is our current thinking.
All of these findings, especially given the finding of non-inferiority in survival terms, about an intermittent schedule still doesn’t dissuade me from factoring in the very important reality, IADT does have a major positive effect on a man’s quality of life, an important factor that needs to be factored into the very personal decision each of us need to be making.
This touches on a subject where I have been at odds with Richard Wassersug. A dozen years back, when I was plowing through PubMed, I could see no case against testosterone [T] as a PCa initiator. In fact, there was emerging evidence that estradiol [E2] had more of a role.
A new estrogen receptor (ERbeta) had been discovered a few years earlier. Lots of interest amongst breast cancer researchers; very little PCa interest. Ultimately, it became clear - the traditional ER (now renamed ERalpha) was largely confined to the stroma, whereas the "new" ERbeta was found in the epithelium (where PCa emerges). An early event in PCa is the loss of ERbeta in affected cells & the emergence of ERalpha.
It is now recognized that ERalpha & ERbeta oppose each other. ERalpha is pro-growth, while ER-beta is anti-growth. Interestingly, the natural ligand for ERbeta is a metabolite of dihydrotestosterone [DHT]. The natural cycle of growth stimulation doesn't end (how could it) when T is converted to DHT. This is not an endocrine event contolled from afar, it is an intracrine event, confined to the cell. After a while, the presence of DHT causes its clearance. The metabolite that binds to ERbeta then puts the breaks on growth stimulation. It's very neat, but dependent on functional ERbeta.
The removal of ERbeta messes that up, & the appearance of ERalpha adds insult to injury.
For me, studies suggest that estrogen dominance is a dangerous state in PCa. That is because T is required for E2-induced growth. At low levels, T cannot oppose E2. I came up with the idea that the E2:T ratio is important. In 2015 I looked for PubMed references to the ratio. There were plenty, but not for PCa.
Steve Freedland has warned that intermittent ADT [IADT] is not a case of alternating between castration & normal T levels. In the off-phase, castration continues. It can take 6 months or more for T to plateau, & it never reaches the previous high - which is often close to the hypogonadal cut-off anyway.
The danger of slow-rising T with E2 recovering at a faster rate is (a) a stimulus to PCa growth, & (b) a profound effect on coagulation factors. With high-normal T, E2 cannot cause blood clots.
My feeling is that IADT for most men should involve T restoration in the off-phase. Not just to > 350 ng/dL but to at least 650. The aim would be to do this rapidly to minimize the estrogen dominant transition period.
With some types of androgen receptor mutations, T restoration would not be a good idea. In fact, IADT would not be a good idea. The benefit of the IADT vacation period is based on the idea that the return of T does not result in rampant growth in most men. Dr. Myers has said that as T rises above 350, there is no additional growth impetus. This is in line with Morgenthaler's saturation model.
"Among cases .., compared to controls .., median testosterone levels were significantly lower in males (4.4 vs 5.4 ng/mL ...). Median estradiol levels were higher in male (68 vs 52 pg/mL ...)"
"The T/E ratio was significantly lower in male cases"
I could find more, but it's perhaps enough to indicate that the transition from castrate involves a period where there may be increased risk. & this could be avoided by rapid T restoration, IMO.
Since I am mentioned here (I just joined the group), I will offer a brief response...
Patrick, I do not object to most of what you say. And your approach is obviously working for you as you seem to be able to keep your PSA doubling time stable at 3 months for what (I am guessing) is now years.
I notice that you down play the idea of a cellular mechanism for measuring the "testosterone:estradiol ratio", which makes me feel like you heard my concern that such a mechanism was simply unknown.
Two points though...
1) You say " the natural ligand for ERbeta is a metabolite of dihydrotestosterone [DHT]." I believe that most endrocrinologists would argue that the natural ligand to that receptor is estradiol (E2), which is a metabolite of testosterone, not DHT.
2) The situation is more complex than what you present because E2 can regulate the density of its own receptors. Granted, ERalpha domination (and activation) is bad news when one is dealing with advance PCa, as you are. As such, I, like you, would want to avoid E2.
However before one gets to where you are, activation of the beta receptor appears important for a lots of bodily functions in males and can thus help maintain QoL...particularly for males who are androgen-deprived. It can help maintain bone mineral density. Data, which we have in press, indicated that estrogens can help maintain sexual interest and (if we can extrapolate form data from women) cognitive function. Our preclinical data (already published) with a rodent model show that E2 can reduce fatigue and improve sleep quality in androgen-deprived males. Estradiol is natures way of avoiding hot flashes. I acknowledge though that more data are needed in this area from actual PCa patients.
What is worth watching are the results from the PATCH study in the UK, which so far show that high dose transdermal estradiol may have advantages over LHRH agonist drugs for prostate cancer control.
The natural ligand for ERbeta (the beta estrogen receptor) in the prostate is not estradiol [E2], but 3beta-Adiol, a metabolite of DHT.
"As the intraprostatic levels of 3beta-Adiol in vivo are about 100-folds higher than those of estradiol, this steroid is considered the natural ligand of ERbeta in the gland."
"Prostate cancer (PC) progression from androgen-dependent (AD) to castration-resistant (CR) disease is a process caused by modifications of different signal transduction pathways within tumor microenvironment. Reducing cell proliferation, estrogen receptor beta (ERbeta) is emerging as a potential target in PC chemoprevention. Among the known selective ERbeta ligands, 3beta-Adiol, the endogenous ligand in the prostate, has been proved to counteract PC progression. This study compares the effects of chronic exposure (1–12 weeks) to different ERbeta selective ligands (DPN, 8beta-VE2, 3beta-Adiol) on proliferation of human androgen-responsive CWR22Rv1 cells, representing an intermediate phenotype between the AD- and CR-PC. 3beta-Adiol (10 nM) is the sole ligand decreasing cell proliferation and increasing p21 levels."
Incidentally, I believe that 3beta-Adiol cannot be converted back to an androgen.
The E2:T ratio is a convenient expression & has been used as such in a number of non-PCa studies. My interpretation of the studies that associate lower levels of testosterone [T] with higher grade PCa, is that T (which is required for growth) is growth-permissive at low levels, but resists growth at higher levels. The stimulus for PCa growth being estradiol, operating through ERalpha. So there is not, as you know, a receptor that measures the ratio.
It's a matter of balance. Estrogen dominance needs to be avoided in early PCa, IMO. With PCa where ADT has been employed, a variety of changes can occur to the androgen receptor. T might no longer exert a regulatory effect in some men, & T restoration might promote growth. But Dr. Myers has discussed two patients (in his vblog) who had T restored without it triggering out-of-control growth. PSA rose at T increased through the hypogonadal range, but plateaued.
Regarding E2 & male health, I think that LEF is correct in warning against E2 > 30 pg/dL & E2 < 20 pg/dL.
From what I recall of studies involving bone health in elderly men, <12 pg/dL is a dangerous place to be. If castration takes one lower, the lowest dose Vivelle-Dot estradiol patch can be used (not every day necessarily) to get E2 to ~20 pg/dL. A more natural therapy for osteoporosis than bisphosphonates, & without the risk of osteonecrosis of the jaw.
E2 should be monitored at both ends of the spectrum, I think. I use Arimidex to keep E2 at ~20 pg/dL. It is an aromatase inhibitor. Aromatase is the enzyme that converts T to E2, & is often upregulated in PCa.
I appreciate the conversations above. Unfortunately, for the average person it is pretty much Greek. We are about to get results of E2 test at LEF.
We are also about to go back on ADT after being off for 1 year. What scared us was the rapid loss of muscle. Yes, we've taken risks. We were on estrogen patches for 3 1/2 years. I will never look back at that move since my husband had a great 3 1/2 years.
So, my question is, we are thinking of doing the ADT monthly to get stable again and add one estrogen patch for bone strength. We will try Lupron first and then if needed move to Zoladex. With Lupron he never did lose much muscle, with Zoladex it was rapid loss and extreme.
Without saying what we 'should' do, can you offer any guidelines to what to look for in testing that would counter this.
We don't know his exact T at this point. After so much ADT for so many years, I believe the last T was only at 66.
(adding T in his situation, at this point is too risky)
The E2 was could only be measured at a cut off range of 20. So he was below that.
The E2 test yesterday at LEF will show anything above 7.9, so it will be a better indicator.
What a mine field for the average person. Thanks very much for all your work and conversations. You both, Richard and Patrick, have always been a support for me personally. It's beyond appreciated- many wishes for continued goodness in your lives..
The loss if muscle mass is directly related to the lack of testosterone. The best way to combat it ( actually slow it down) is with weight bearing exercise.
If his T level is 60 then he is not technically castrate. He will have to get the T level, ideally, below 20 when he goes back on ADT. This can mean more need for more exercise to skow down muscle mass loss.
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