Showing posts with label TRT. Show all posts
Showing posts with label TRT. Show all posts

Wednesday, June 10, 2020

Testosterone Therapy Does Not Increase the Risks of Prostate Cancer Recurrence or Death After Definitive Treatment for Localized Disease

In the largest observational study so far, Sarkar et al. reported that men in the US Veterans Administration (VA) database who received surgery or radiation for localized prostate cancer and then received testosterone replacement therapy (TRT) for low testosterone were at no greater risk for recurrence than a matched sample of such men who received no TRT.

The VA database included 28,651 men treated with prostatectomy (RP) and 41,333 men treated with primary radiation (RT) between 2001-2015. Of those men:
  • 469 of the RP group received TRT
  • 543 of the RT group received TRT
  • Median follow-up was 7 years
Comparing the men who received TRT to a matched group of men who didn't, they found:
  • There was no difference in biochemical recurrence
  • There was no difference in prostate cancer mortality
  • There was no difference in overall mortality
The database did not include data on serum testosterone levels or duration of TRT.

This confirms a couple of smaller (sample size about 100) retrospective studies at Baylor College of Medicine on men who had received RP and RT.

Before treated men rush out to supplement testosterone, we should acknowledge that all of these studies are retrospective. Although the authors of the VA study made an effort to match the patient and disease characteristics of men who received TRT and those who did not, it is entirely possible that there were characteristics that were not included in the database. In other words, doctors may have been biased by other factors to select patients for treatment.

We should also acknowledge that in the Baylor studies and others, PSA did increase after TRT in both groups, although usually not to the extent that a biochemical recurrence was declared. This is expected in men who received RT because they still have intact prostates that may still secrete PSA from benign sources. However, it is more concerning in men who have had RP because benign prostate tissue should have been eliminated, and even Gleason score 6 prostate cancer may progress, albeit slowly (see this link).

Until we have a prospective randomized trial (like this one with results expected in 2024), patients and their doctors must make this decision based on available data and judgment. While it is undoubtedly true that castration levels of testosterone (below 50 ng/dl) discourage prostate cancer progression, Morgentaler's testosterone saturation theory says that above some minimal testosterone level (around 120 ng/dl), adding more testosterone does not further encourage prostate cancer progression. Many urologists now believe this. However, testosterone sold in the US is required to have a black box warning against its use in men who have had prostate cancer. Getting one's doctor to prescribe it may be challenging.

Also, see the following articles about the experimental use of high-dose testosterone for metastatic prostate cancer:





Monday, September 5, 2016

Testosterone to TREAT prostate cancer - are they crazy? No - it just may work. (mHSPC)

This is Part 2. In Part 1 we saw why bipolar androgen therapy (BAT) may be effective for men with metastatic castration-resistant prostate cancer (mCRPC), and the evidence so far in support of that. In this part, we'll look at what we know about BAT in men with metastases who are still hormone sensitive (mHSPC). As you recall, BAT is an experimental therapy for metastatic prostate cancer involving the administration of rapidly alternating treatments of androgen deprivation (ADT) with high-dose testosterone.

In theory, the high doses of testosterone will help the patient feel better and perhaps offset some of the symptoms of ADT (e.g., loss of libido, hot flashes, bone loss, lean muscle loss, mental symptoms).

In pilot trials so far, BAT was able to restore sensitivity to second-line hormone therapy, like Zytiga or Xtandi, in some men who had become resistant to their effects. If it can reverse castration resistance, can it also slow down the development of castration resistance? 

Schweizer et al. report on 29 patients:
  • None of the men in the study had started on androgen deprivation yet.
  • None had symptoms.
  • 10 had a low burden of metastases.
  • 19 had no detectable metastases, but had recurrent disease after an attempt at a cure (i.e., their cancer was micrometastatic)
  • They were all hormone sensitive. That means their PSA went down to less than 4 ng/ml after 6 months of ADT

They then received 3 months of testosterone injections, and then 3 months of ADT. Those cycles continued for a total of 18 months. 
  • They report that 17 men (59%) were still able to achieve their PSA goal (<4 ng/ml) at the end of 18 months. That is, they were still hormone sensitive.
  • Of the 10 patients with detectable metastases at the start, metastases had shrunk completely in 4, and partially in 4. So 8 in 10 (80%) had a positive radiographic response to BAT.
  • Six patients had metastatic progression. 
  • So, 13-15 of the 19 (68-79%) men with recurrent PC with no detectable metastases at the start still had no detectable metastases after 18 months of BAT.
  • Evaluations of quality of life improved.
Since the CHAARTED and STAMPEDE clinical trials, the new standard of care for mHSPC is the combination of ADT and docetaxel chemotherapy. Where would BAT fit in? We saw in Part 1 that BAT may work particularly well in conjunction with chemotherapy that targets the DNA responsible for cell replication. Docetaxel is usually administered in 6 three-week cycles. It may turn out that after an ADT induction period of 6 months, patients may be optimally treated by a high dose of testosterone and docetaxel concurrently. Testosterone would help the chemo patient feel better, and would also tend to raise his red blood cell counts, counteracting any chemo-induced anemia.

Another consideration is whether radiation ought to be included in the mix of early treatments. A few recent studies (see this link and this one) suggest that prostate radiation might still be beneficial to the metastatic patient. Moreover, a lab study suggests that radiation and BAT may be a particularly potent combination.

At this point, all of this is pure speculation. Future expanded clinical trials will have to determine whether BAT is useful for men with mHSPC, and what the optimal sequencing of therapies should be.

Sunday, September 4, 2016

Testosterone to TREAT prostate cancer - are they crazy? No - it just may work. (mCRPC)

Background

When prostate cancer metastasizes and becomes castration-resistant (mCRPC) after a period of androgen deprivation therapy (ADT), a number of biochemical changes to the androgen receptor (AR) take place within the cancer cell. Among those changes:
  • The androgen receptor (AR) multiplies on the cancer cell surface so that even the smallest amount of testosterone or other circulating androgens can activate it.
  • Even without an androgen ligand, the androgen receptor moves from the surface of the cell to the inside where it is protected. These internalized androgen receptors play a role in encouraging cell replication and in self-destruction (apoptosis) of cells in which the DNA  has become irreparably damaged.
  • The cell manufactures its own androgens internally. These activate the internalized androgen receptors.
  • The androgen receptor mutates into truncated versions that can be activated by a host of other molecules (other than testosterone), or don't require other molecules at all to activate it. Recently, researchers at Johns Hopkins identified a version called the "AR-V7 splice variant" that allows the cancer cell to multiply even when all androgens are completely eliminated. It is induced by long term androgen deprivation (see this link).
There may also be tissue-based effects. This means that, in a tumor, there are a variety of cell types. Castration resistance is not an all-or-none situation. Some cells within any given tumor will always remain hormone sensitive. Some cells, like cancer stem cells, have never been hormone sensitive. All of these cell types interact. Hormone-sensitive cells signal castration-resistant cells to become more like them. At the same time, castration-resistant cells signal hormone-sensitive cells to become more like them. Over time, the hormone-sensitive cells (being the ones that are killed by ADT)  lose the battle as the equilibrium shifts towards castration resistance.

How testosterone can help

Supraphysiologic doses, meaning serum levels greater than 1000 ng/dL, may help in several ways:
  • Testosterone prevents the androgen receptor from multiplying on the cell surface, and decreases the  number of androgen receptors already there, thereby increasing the cancer cell's sensitivity to subsequent androgen ablation (see this link). It also prevents the cell from becoming super-sensitized to androgens.
  • Inside the cell, high levels of testosterone prevent the internalized androgen receptors from encouraging cell replication - too much testosterone, as well as too little testosterone discourages cancer cell replication (see this link).
  • High levels of testosterone and other androgens may induce damage the cancer cell's DNA (see this link). One of the interesting hypotheses is that combining high testosterone with a chemotherapy that is known to cause DNA damage will be particularly effective (see below).
  • Testosterone may be able to reverse the AR-V7 splice variant that is known to cause resistance to even second-line hormonal therapies like Zytiga and Xtandi (see this link).
  • On the tumor tissue level, testosterone supports the growth of hormone-sensitive cells while destroying castration-resistant cells, as described. This shifts the equilibrium back towards androgen deprivation sensitivity.

Why can't we just give continuous high doses of testosterone?

It's been known for a while that testosterone plays a role in keeping healthy prostate cells healthy. We have observed that hypogonadal men (men who have low natural levels of testosterone) are more likely to have prostate cancer, and more virulent types. For a thorough recent review of this subject, see this link. In fact, one pilot study showed that men with mCRPC who had higher plasma testosterone levels (but still at castration levels) survived twice as long. They responded better  to chemotherapy as well (see this link).

In 2009, Robert Liebowitz et al. reported on 96 patients who received very high dose testosterone replacement therapy (TRT) after some kind of prostate cancer treatment. For 59 of those men, the only treatment had been androgen deprivation. 12% were detectably metastatic. 60% had PSA progression while on TRT, but few had metastatic progression in that time period. For most of those, discontinuing TRT reversed the PSA progression.

There was a small (12 man) safety trial at Memorial Sloan Kettering. None of the men achieved supraphysiological serum testosterone levels from the transdermal gel they used. One man had to discontinue when he experienced spinal pain, but there weren't any other major side effects. Of the 12 men, 7 had decreased PSA (one had a 50% decrease). The other 5 had increased PSA, 2 by more than 50%. There was no regression of metastases in any of the men.

Other small trials of TRT alone had mixed results (see this link and this one).

So TRT alone doesn't seem to work. Both effects are necessary: (1) the TRT re-establishes hormone sensitivity, and then (2) the ADT kills off the hormone-sensitive cancer cells. For disease stabilization or regression, it seems to be necessary to alternate TRT with ADT. This is called bipolar androgen therapy (BAT).

I'm on intermittent hormone therapy - doesn't that accomplish the same thing?

Unfortunately, no. It had been hoped that intermittent ADT would accomplish two benefits:
  1. Delay the development of castration resistance, and thereby prolong survival, and
  2. Give men a break during which quality of life would improve temporarily
In fact, it accomplishes neither for most men, although it may for some. At least we know that intermittent ADT is not usually inferior to continuous androgen ablation, although it may be for some (perhaps those with multiple metastases, especially). We are beginning to understand why it usually does not accomplish those twin goals.

After a long while on ADT, it takes a long time for a man's testicles to recover the ability to generate amounts of testosterone that are adequate to recover libido and help a man feel better. As far as the cancer is concerned, the cancer couldn't adapt if it were suddenly shocked by a large surge of testosterone. But during the "off-cycle,"as the amount of testosterone slowly increases, his cancer is able to adapt.  The cancer consequently thrives on the incremental increases rather than being killed by it. By the time the testosterone reaches a level that makes a measurable difference to his quality of life, the cancer has proliferated. His PSA has then gotten so high that the ADT "holiday" must be ended.

It sounds good in theory, but does it work in clinical practice?

Schweizer et al. conducted a pilot test at Johns Hopkins. They treated 16 asymptomatic men who were diagnosed a metastatic and castration-resistant. They were all still on ADT. They gave the men high doses of injected testosterone and treatment with the chemo drug etoposide (see above), which is normally ineffective in treating prostate cancer. After at least 3 cycles:
  • Half of them enjoyed a decline in PSA, most of those by more than a 50% decline
  • Half had a radiographic response, including 1 patient who had no discernable metastases
  • Half the patients did not respond at all, and PSA continued to rise
  • Responders had a higher pre-BAT PSA than non-responders
  • 10 of 10 patients (100%) responded to second-line ADT (Xtandi, Zytiga or Casodex) after BAT (some were resistant to those therapies before BAT)
  • 3 patients had severe toxicity attributable to etoposide.
It appears that BAT may at least delay progression in men with mCRPC. It seems to resensitize their cancers to hormonal agents, even when it didn't succeed in decreasing PSA or evident (radiographic) progression. We don't yet know if it increases survival. Importantly, the men periodically enjoyed enhanced quality of life from periodic high levels of testosterone. It's unclear whether etoposide chemotherapy added much to the response.

What's next?

In their next clinical trial, the researchers are investigating whether BAT can restore sensitivity to Zytiga and Xtandi to mCRPC men who have already progressed while using those. They are excluding those who have already had chemotherapy, and no chemo is used in this trial. (Update July 2020) The RESTORE trial found that BAT was able to restore responsiveness to Xtandi but much less to Zytiga.
  • After BAT, PSA declined by ≥50% in 68% on rechallenge with Xtandi
  • After BAT, PSA declined by ≥50% in 16% on rechallenge with Zytiga
(Update 6/2017) Denmeade's group reported on 30 minimally symptomatic mCRPC men who had progressed on Xtandi.
  • 30% saw PSA reduced by at least 50%
  • 43% saw PSA increase from baseline; in 17%, PSA more than doubled.
  • 36% had some regression of disease
  • Median 8.6 months of radiographic/clinical progression-free survival
  • 54% responded to re-challenge with Xtandi with a subsequent drop in PSA by at least 50% and progression-free survival of 4.8 months
  • A third of those with the resistant AR-V7 mutation responded to BAT, and had lowered AR-V7 levels
  • 2 converted from AR-V7 positive to AR-V7 negative
There were adverse side effects while on BAT. Transient pain flares was the most common, affecting 40%. A few men suffered very serious side effects: pulmonary embolism, heart attack, urinary obstruction, gallstones and fatal sepsis.

In a second clinical trial, chemo-naive mCRPC men who have failed therapy with Zytiga will be randomized to receive either BAT or Xtandi. This trial will be re-opened in July 2020.

In another clinical trial, men who are mCRPC and who have progressed on either Zytiga or Xtandi, will receive BAT and Nivolumab (an immune checkpoint inhibitor).

(Update 11/8/18) A new clinical trial at the University of Colorado, Denver will try transdermal testosterone instead of injections alternating with enzalutamide.

It will be important to determine, in future clinical trials, which men will respond to BAT and which men will not. It is also not yet clear if there is a survival benefit, although there is a quality of life benefit. Importantly, all clinical studies so far have only been pilot trials in very small groups of patients. Larger trials will be necessary to prove safety and efficacy. These determinations should only be made as part of a careful clinical trial.

There may be particular situations where BAT may be an effective therapy, but data are so far lacking: 
  • What, if any, is its benefit in men who are metastatic but still hormone responsive (mHSPC)? 
  • Does it have any benefit in men who have already had docetaxel chemotherapy? 
  • Considering that metastases shrank in many men on BAT, should it be tried in symptomatic men as well? 
  • What is its effect on AR-V7-positive or negative men? 
  • Should it be used in combination with other therapies, such as PARP1 inhibitors, immunotherapies, and radiological therapies? 
  • What is the optimal sequencing of therapies? 
  • Is there any benefit to BAT  used along with radiation therapy in high risk men (see this link)?

Tuesday, August 30, 2016

Androgen deprivation followed by androgen supplementation may increase the efficacy of radiotherapy


We have seen the ability of androgen deprivation to increase the efficacy of high dose IMRT in controlling prostate cancer (see this commentary). A new study from Johns Hopkins turns conventional logic on its head by demonstrating that sequential androgen deprivation and androgen repletion may be optimal for enhancing the therapeutic efficacy of radiation in prostate cancer… at least in mice.

I don’t often comment on lab studies because what works in the mouse world often does not work when tested in humans. Johns Hopkins has been a leader in exploring the possibility of androgen sequencing, and is currently conducting a trial of “bipolar androgen therapy (BAT)” in men undergoing lifelong ADT for advanced cancer (see this commentary).

Haffner et al. discovered that androgens, like testosterone or DHT, can activate an enzyme (TOP2B) that induces double-strand breaks (breaks on both sides of the double helix) in the DNA of prostate cancer cells that express the TMPRSS2:ERG fusion gene.  This gene has been implicated in prostate cancer development and has been detected in about half the cases of prostate cancer. Coincidentally, double-strand breaking is exactly how radiation kills cancer cells. They hypothesized that after androgen deprivation is used to kill off those cancer cells susceptible to it, that restoring androgens combined with ionizing radiation might increase the therapeutic potential over radiation alone. Hedayati et al. report that this is exactly what happened in mice.

This may or may not eventually translate into protocol changes in radiation therapy, but at the very least it gives us a healthy appreciation for the very complex biochemical machinery involved in cancer genesis and therapeutics.


Written February 4. 2016

Monday, August 29, 2016

Testosterone Replacement Therapy (TRT) after Radiation Therapy

Many urologists these days are fairly comfortable prescribing testosterone replacement therapy (TRT) for men who have had a radical prostatectomy and whose PSA has stayed at undetectable levels for some time. However, considerations may be somewhat different after radiation therapy.

Pastuszak et al. looked at the records of 98 men (median age 70) who were treated at 4 institutions with TRT after primary radiation therapy (brachytherapy or external beam). After a median follow up of 41 months, they found:
  • ·      Testosterone increased from 209 ng/dl to 420 ng/dl
  • ·      Median PSA was 0.08 ng/ml at baseline, and 0.09 ng/ml at end of follow-up (p=0.05)
  • ·      PSA of high-risk patients increased from 0.10 ng/ml to 0.36 ng/ml (p=0.02)
  • ·      Biochemical recurrence was found in 6.1 percent.

The authors note in an accompanying article that the biochemical recurrence rate was actually lower than expected based on historical data of men not given TRT after radiation therapy.

While it seems safe to give TRT after radiation, the authors caution:
Nevertheless, the safety of testosterone therapy in the setting of prostate cancer can only be truly demonstrated in the setting of a prospective, controlled trial, an effort that, to date, has been limited by difficulties with patient accrual. Until such a study is available, the burden remains on the physician to judiciously select men for testosterone therapy, and perhaps more importantly, to regularly monitor them with appropriate testing and examination.”

It is important to also note that the men selected for TRT in this study had a very low PSA at baseline, which is an appropriate selection criterion. An issue that can arise with TRT after radiation is that the testosterone might aggravate some incipient BPH that might cause PSA to rise even though the cancer is eradicated. In that case, monitoring PSA as an indicator of biochemical failure can become problematic.

Some studies have noted that for reasons that remain poorly understood, natural testosterone production may be depressed temporarily after radiation (Pickles et al.) It may be a better strategy to wait for a natural rebound in serum testosterone than to supplement immediately. Supplementing will stop the natural production of testosterone by the testes, and it may sometimes cease permanently as a result.

The other interesting issue raised by the lower than expected recurrence rate found by this study is the hypothesis that normal levels of testosterone are required to keep healthy prostate tissue healthy. Clinical trials are in place to test this hypothesis.