Prostate Cancer Patients Benefit Greatly From Exercise, but For Many it is Difficult to Commit to Exercising in The Long Term

This will be a short blog entry. That’s because the main story is told in the title of the paper by Houben et al. cited below.

That paper focuses on 78 patients on ADT who participated in a 20-week supervised resistance exercise training program. The program worked in that the patients had more muscle mass and more strength at the end of 20 weeks compared to when they started in the program.

The researchers, however, also looked at whether the benefit of the exercise was retained one year after it started. That was more than a half year after the research program had ended and the men were on their own. The authors are very honest about the fact that the benefits of exercise at 20 weeks were largely NOT sustained when the patients were re-assessed at the one-year mark.

When we pair that paper with the other paper listed below (i.e., Western et al. 2024), we get some insights into factors that lead to cancer patients not staying with exercise even after they have started it. Western et al. looked at dropout rates during exercise research studies while still underway. It is important to note that that the Western et al. study was not specific to prostate cancer. The majority of participants were in fact women with breast cancer. However, it was a large study with over 300 participants treated for male genitourinary cancers, which would have been predominantly prostate cancer.

Of those 300+ participants, just over 10% dropped out.

Being overweight or obese was the major correlated to men dropping out of the study. They were also more likely to drop out if part of the exercise program was not strictly supervised. Lastly, individuals with a low to medium level of education were more likely to drop out than individuals with higher levels of education.  

The author conclude that more effort needs to be taken to retain cancer patients in exercise programs, who fit the profile outlined above whether in a formal research study or on their own. To that we add that patients are more likely to stay with exercise if they start early…and preferrable before they are challenged by the side effects of their cancer treatments. That surely fits for patients treated with ADT.

References:

Western B, Ivarsson A, Vistad I, Demmelmaier I, Aaronson NK, Radcliffe G, … & Buffart LM. Dropout from exercise trials among cancer survivors-An individual patient data meta-analysis from the POLARIS study. Scand J Med Sci Sports. 2024 Feb;34(2):e14575. doi: 10.1111/sms.14575. PMID: 38339809.

Houben, L. H., Overkamp, M., Senden, J. M., van Roermund, J. G., de Vries, P., de Laet, K., ... & Beijer, S. (2024). Benefits of resistance training are not preserved after cessation of supervised training in prostate cancer patients on androgen deprivation therapy. European Journal of Sport Science, 24(1), 116-126.

Yet Again, We Explore the Topic of the Impact of ADT on Cognitive Function

When it comes to the quality of life of patients on ADT one major area of research is the impact of ADT on cognition. Patients usually discuss this in terms of brain fog, problems with memory, or just problems in finding common things around their home. Despite a huge number of studies on the topic, there's not been a solid consensus about how ADT, either alone or combined with ARTAs, impacts patients’ cognitive abilities.

We now have a new comprehensive review and meta-analysis of the research that is more rigorous than any so far. Twenty studies are included in the systematic review built upon data from 1440 patients. Fifteen of those 20 had enough data to be used in a meta-analysis.

In the ADT book, we reference a 2014 meta-analysis, which was the most comprehensive meta-analysis previous analysis. That paper concluded that the best evidence for cognitive impairment was in the visuo-spatial domain. However, this new analysis questions that conclusion. The authors are careful to distinguish different types of trials, such as whether patients were compared to their baseline data only or whether there was a control group.

What the authors found in their new meta-analysis is that consistent evidence for objective cognitive impairment from ADT is still lacking. The authors offer some suggestions for why they got this result. For example, they noted that some 20 to 50% prostate cancer patients show some sign of objective cognitive decline even before they are exposed to ADT. This could be due to depression or anxiety directly or indirectly related to the stress of having advancing cancer.

The authors even found some evidence of cognitive improvement (!) when they compared patients tested at baseline and re-tested at a later date. They suggested that this could be the result of the participants learning how to take the tests from their previous exposure to the tests. 

What is probably the most surprising and relevant take-away for patients from this paper is that  authors found evidence of subjective cognitive decline with ADT.  Objective cognition is measured with standardized tests whereas subjective cognition is documented by simply asking the patients various questions about whether they feel like they are having a harder time thinking, remembering, and finding things, whether they are words or objects in the world they live in.

From a patient's perspective what matters most is subjective sense of cognitive decline versus the objectivemeasures. It is that subjective impression of cognitive impairment that would be associated with distress in patients. It could be tied to fatigue, insomnia, and depression, which are common in cancer patients. One study that the authors cite, for example, shows that patients reporting subjective cognitive impairment showed insomnia as a mediating factor.

In the real-world objective cognitive impairment is worth assessing and finding ways to limit it  for the safety of the patient. At the same time in the real world, it is subjective sense of brain fog and cognitive impairment that stresses out patients. If stressed out patients have poor sleep quality, that can lead to fatigue and depression. Patients in that situation may report a high level of brain fog which in turn can lead to problems with sleeping in a feedback loop fashion.

This may seem scary, but there is a somewhat positive side to the story. There are interventions that can help with sleep quality and depression, and perhaps help with the subjective sense of cognitive impairment. This can include various medications, but exercise alone has been shown to help with managing insomnia, daytime fatigue, and depression.

In contrast, it is harder to treat objective cognitive decline of the sort associated with aging.

This paper is superb not only in its thoroughness, but in pointing out that clinicians treating patients with ADT need to take seriously the patients’ concerns about brain fog and cognitive impairment…even if they’re not documented in standardized tests.

Reference:

Boué A, Joly F, Lequesne J, Lange M. Does hormone therapy impact cognition in patients with prostate cancer? A systematic review and meta-analysis. Cancer. 2024 Feb 2. doi: 10.1002/cncr.35210.

More on ADT and Depression

The incidence of depression for men over the age of 65 in the general population is about 9.5%. In contrast, various studies suggested that men diagnosed with prostate cancer have an overall incidence of depression of 10 to 40%. A new review article and meta-analysis of 38 studies by Qazi et al. (2024), which collectively included data from over 350,000 men, arrived at a pooled estimate of depression of 20.9% of men treated with ADT. That is substantial.

Another new study by Mandel et al. (2024) extracted data from a global database (i.e., TriNetX) of almost 80,000 men on ADT who were subsequently prescribed anti-depressant medication. It confirmed that ADT increases the risk of depression in men diagnosed with prostate cancer.

What particularly stands out in Mandel et al. study is the difference between the White and Black population. To quote the authors, “After starting ADT, White patients had 30% greater odds of being diagnosed with the depression, compared to Black patients.” Mandel  also found that White patients were at greater odds of getting treated with anti-depressants than the Black patients.

This is not to say that the Black population is less likely to experience depression. The data do not show that. The problem appears to be that depression is being under diagnosing for Black prostate cancer patients and subsequently inadequately treated in that population.

This is just one more example of racial disparities in healthcare for White and Black men in the USA.

References:

Mandel AL, Simhal RK, Shah YB, Wang KR, Lallas CD, Shah MS. Racial disparities in diagnosis and treatment of depression Associated with androgen deprivation therapy for prostate cancer. Urology. 2024 Feb 21:S0090-4295(24)00094-3. doi: 10.1016/j.urology.2024.01.021.

Qazi SU, Altaf Z, Zafar M, Tariq MA, Khalid A, Kaleem A, Saad E, Qazi S. Development of depression in patients using androgen deprivation therapy: A systemic review and meta-analysis. Prostate. 2024 Feb 19. doi: 10.1002/pros.24676.

So, What Exactly Are the Cardiovascular Risks Associated with Intensifying Standard ADT with an ARTA/ARPI?

Let’s start with some definitions. ARTAs and ARPIs are just two names for the same thing. The abbreviations stand for “androgen receptor targeting agents” and “androgen receptor pathway inhibitors,” respectively. The drugs go by other names as well, such as “next-generation hormonal agents”.

Right now, there are four drugs in the group: abiraterone (Zytiga, Yonsa) plus the newer anti-androgens; i.e., enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa). One can expect more on the market in the next few years.

These drugs are getting a lot of attention because they have been shown to slow the progression of prostate cancer when use in combination with the standard ADT agents.

However…with more drugs come more side effects. In the case of the ARTAs, this includes some serious cardiovascular effects. Researchers have now reviewed 21 randomized control trials involving these drugs and almost 20,000 patients for data on the relative risks of various cardiovascular disease.

The results show that abiraterone and enzalutamide can lead to a significantly higher hypertension rates (high blood pressure) compared with placebo. This was not seen with apalutamide or darolutamide.

There were no significant differences between the four agents when compared to placebo for the incidence of ischemic heart disease (i.e., angina and heart attacks). The overall conclusion though is these drugs carry some increased risk of cardiotoxicity compared to placebo.

How much of a concern is this for patents? One study showed that enzalutamide is associated with a 10% increased risk of hypertension and that may be the highest cardiovascular risk in terms of percentages. But it is not necessarily the most serious as it can generally be medical managed. Heart attacks with these drugs are far less common but can be fatal and the risk of fatal cardiovascular disease goes up with unmanaged hypertension.

The authors conclude that it is “crucial to carefully monitor and manage patients treated with abiraterone or enzalutamide.” Patients offered any ARTA along with ADT should have a cardiac assessment when starting the drugs…and commit to a heart healthy lifestyle!

Reference:

Liang Zhen, Wang Juan, Feng Tianrui, Chen Yuliang, Zhou Zhien, Zhou Yi, Yan Weigang and Cao Fenghong, A net-work metaanalysis of the cardiac safety for next-generation hormonal agents in treating castration-resistant prostate cancer: how to choose drugs appropriately? Critical Reviews in Oncology / Hematology, (2024) doi: https://doi.org/10.1016/j.critrevonc.2024.104273

On getting testosterone down, and getting it up again: Either way you've got to get it measured.

The primary medications for ADT suppress testosterone production from the testes. Historically the goal has been to drive the serum testosterone levels down to below 50 ng/dL, which was considered “castrate levels” that could stop or slow the growth of prostate cancer (PCa) cells. That level is well below the serum level of 280 ng/dL, which is considered normal for men around the average age of those starting ADT. However, in the last decade or so it has been shown that an even lower level of T,  of <20 ng/dL, proved better cancer control.

A new paper by Klotz and Tat looked a variety of studies done with one particular ADT agent, triptorelin, which is similar to Lupron, Eligard, and Zoladex, but used more commonly outside North America. The overall sample was 592 men with PCa and the study showed that the overall survival was better in the men, who achieved an even lower  T serum level of <10 ng/dL. Simple conclusion—the lower the T, the better the control of systemic PCa.

But some PCa patients go on ADT short term to increase the effectiveness of radiotherapy. Many of them feel better when their T levels are back in the normal range, and they are off androgen suppressing medications. That raised the question of how well T serum levels recovery after stopping ADT and does it matter for the patients’ health, if not full recovery is achieved.

A second new paper looked at the reverse question to the Klotz and Tat study. The authors of this second paper had data from 1553 men, who had their T levels measured within 12 months of discontinuing ADT. In that first year, 75% of the men did not achieve normal T levels.

It was already known that most men do not fully recover T levels after extended ADT, but what is new here is that the authors also showed that those men, who showed poor T recovery, were also more likely to start to develop type 2 diabetes.

Whether one is going on ADT or coming off it, these two studies suggest that patients should request that the physicians,  who manage their PCa, request not just regular PSA tests,  but samples to track their T levels.

References:

Klotz, L., & Tat, T. (2023). Testosterone nadir and clinical outcomes in patients with advanced prostate cancer: Post hoc analysis of triptorelin pamoate Phase III studies. BJUI Compass.

Preston, M. A., Hong, A., Dufour, R., Marden, J. R., Kirson, N. Y., Gatoulis, S. C., ... & Morgans, A. K. (2024). Implications of Delayed Testosterone Recovery in Patients with Prostate Cancer. European Urology Open Science, 60, 32-35.

So, What is the Best Exercise Program for Men on ADT?

That question comes up often. Although there have been dozens of papers published on the value of exercise for men on ADT, you would think we would know by now the best way to exercise. We still don’t have a simple answer, but a couple of new papers help refine the question.

One paper, which is a review from the Netherlands, looked at the value of resistance training for men on ADT. It endorsed what we already knew; i.e., that resistance training helps maintain muscle strength for men on ADT. The paper ends with a firm conclusion that exercise programs involving resistance training should be part of healthcare for any patients going out ADT for any length of time. That paper, however, does not address the question of how to fund such programs on an on-going basis, which is something of a concern since good resistance training programs typically require access to a gym and staff that can show men how to do the exercises safely.

That leads to the second paper, which is from Canada. The researchers there compared individual home-based versus supervised group exercises programs for prostate cancer patients on ADT. That study was a randomized control trial to see whether an individual home-based program was inferior to a group exercise program.

By way of background, there are already several studies showing that group exercise programs provide a social environment that helps encourage cancer patients to stay with the activity even after the research is completed. That typically favors group exercise programs over individual home programs.

The Canadian study had 13 co-authors that included some of the top kinesiology researchers in Canada who work with cancer patients as well as some of the top physicians that study the quality of life of prostate cancer patients. They found that there was a 30% probability that a home program was not inferior to a group program…at least in terms of helping reduce fatigue for men and maintaining good function. The study included a cost analysis that showed that a home program was more cost effective than a group program since patients exercising at home did not have to spend time or money traveling to a gym.

However, this study had some major problems that are common to many studies that involve lifestyle intervention for prostate cancer patients. One is that it is hard to accrue patients to such studies when they are randomized trials. As result, the sample size was only 20 men in the one group and 18 in the other.  That is simply too small a sample to draw any strong conclusions.

There are also some sociological issues that were not addressed. Typically, patients who are willing to join an exercise research study, can afford a membership in a gym, where they can exercise with others. Although a home program may be cheaper, patients who have fewer financial resources rarely participate in lifestyle research studies. The authors present no evidence that saving money is an effective incentive to get more prostate cancer patients to exercise.

References:

Houben LHP, Overkamp M, VAN Kraaij P, Trommelen J, VAN Roermund JGH, DE Vries P, DE Laet K, VAN DER Meer S, Mikkelsen UR, Verdijk LB, VAN Loon LJC, Beijer S, Beelen M. Resistance Exercise Training Increases Muscle Mass and Strength in Prostate Cancer Patients on Androgen Deprivation Therapy. Med Sci Sports Exerc. 2023 Apr 1;55(4):614-624. doi: 10.1249/MSS.0000000000003095. Epub 2022 Dec 14. PMID: 36534950; PMCID: PMC9997646.

Alibhai SMH, Papadopoulos E, Mina DS, Ritvo P, Tomlinson G, Sabiston CM, Durbano S, Bremner KE, Chiarotto J, Matthew A, Warde P, O'Neill M, Culos-Reed SN. Home-based versus supervised group exercise in men with prostate cancer on androgen deprivation therapy: A randomized controlled trial and economic analysis. J Geriatr Oncol. 2024 Jan;15(1):101646. doi: 10.1016/j.jgo.2023.101646. Epub 2023 Nov 15. PMID: 37976654.

ADT’s impact on Muscle and Fat

Standard ADT with either LHRH agonist or antagonist drugs (like Lupron or Firmagon, respectively) cause a loss of lean muscle mass and weight gained as fat. Those are among the most common side effects of ADT. Patients experience this as fatigue for they have more weight to move and less muscle to do it with. It is also part of a suite of features associated with an increased risk of diabetes and heart disease.

So, how does the situation change when one adds either Zytiga (abiraterone ) or Xtandi (enzalutamide) to standard ADT? This is an important question since patients are increasingly being offered doublet therapy to control prostate cancer. Doublet therapy typically entails adding either a second-generation anti-androgen, like enzalutamide, or abiraterone (Zytiga) to a standard LHRH treatment. Do these combined therapies improve the situation or make it worse?

According to a new paper that asks these very questions the combinations typically, but not always, make matters worse. The data come from 229 patients, with 120 on an LHRH drugs alone, and just over 50 patients on either enzalutamide or abiraterone.

In terms of muscle loss, there was greater loss with the doublet therapies particularly after 18 months when enzalutamide was the secondary agent. This is consistent with a common complaint for patients of a lot of fatigue when enzalutamide is added to the LHRH drugs.

As for the amount of fat gained, the authors distinguished between subcutaneous fat and the deeper fat packed in the body around the viscera. The LHRH drugs alone show minimal change in the visceral fat. In fact, there can even be a loss of visceral fat, but insignificantly so. Adding in abiraterone, however, significantly increased the visceral fat after just six months by an average almost 5%.

The situation is quite different when it comes to the subcutaneous fat. Here the increase is substantial; i.e., a 8.6% at six months with the LHRH drugs alone, although that can decrease over the following year to an average increase of 4.7% at 18 months.

This increase in subcutaneous fat is consistent with the extra belly roll of fat that men at ADT typically acquire—unless they aggressively commit to burning off more calories than they are ingesting.

In that regard, the authors do not say anything about how lifestyle may influence the results related to fat distribution and weight gain. One suggestion we have is that patients, who find the weight gain, belly roll, and fatigue bothersome, make lifestyle changes to slow down the progressive loss of muscle and gain in fat. There is no evidence though that the authors of the paper collected data on how exercise or diet might have influenced their findings.

Perhaps what's most interesting in this paper is the differences between these drugs affects on visceral versus subcutaneous fat, and how this is associated with a different level of diabetic risk with the different doublet combinations. It turns out that adding abiraterone to standard ADT increases the diabetic risk slightly, while adding enzalutamide reduces that risk for some men on ADT. This can be partly understood by changes in the androgen receptor, which is targeted by enzalutamide. Those receptors are indeed more prominent in visceral than subcutaneous fat.

From the patients’ perspective this has important implications to personalized oncological care and diabetic risk. If a patient is already overweight and diabetic, the paper suggests that, of the two options, they may be better treated with an anti-androgen, like enzalutamide, then with abiraterone. The authors also acknowledged that since abiraterone must be taken with a steroid, the steroid can also affect the body’s composition.

So, what is the bottom line? In general, for patients, who need to be on hormonal therapy, adding in these new agents can improve cancer control. But overall, they increase the risk of loss of muscle mass, and they have complicated and disparate effects on the body’s fat distribution. Overall, they're more likely to increase serious side effects, which need to be managed. That can be done in part with appropriate lifestyle interventions.

 

Reference:

Blow, T. A., Murthy, A., Grover, R., Schwitzer, E., Nanus, D. M., Halpenny, D., ... & Goncalves, M. D. (2023). Profiling of Skeletal Muscle and Adipose Tissue Depots in Men with Advanced Prostate Cancer Receiving Different Forms of Androgen Deprivation Therapy. European Urology Open Science, 57, 1-7.

Is the Embr Wave a Winner When it Comes to Hot Flashes?

The Embr Wave is a battery-operated device that one wears like a wristwatch on one’s wrist. It is marketed as a product that can help manage hot flashes. If one senses that they're starting to have a hot flash, they can push a button on the Embr Wave and its surface in contact with the skin starts to cool.

The Embr Wave was initially marketed for women with hot flashes, but it was inevitable that the company would explore marketing it to men, who are experiencing hot flashes from androgen suppressing therapies. Thus, we now have the first paper with some data on the products effectiveness for prostate cancer patients.

The data are posted on Research Square, which is not a medical journal, but a repository for manuscripts that have been submitted for publication, but still have to go through peer review. The publishers of Research Square acknowledge that what they post there “should not be considered conclusive.”

So, what did the researchers report? Based on a modest sample of 39 prostate cancer patients, who experienced what the researchers called “hot flash interference” both during the day and night, they found a statistically significant improvement. Specifically, some 69% of the participants in the study felt that “the thermal device was effective at helping them manage hot flashes.”

A 69% positive response rate is a long way from a definitive cure for hot flashes. One can get that level of an effect from placebos for certain medical interventions. That is why one needs randomized control trial data from men on ADT bothered by hot flashes, and data of that sort have yet to be published for the Embr Wave. Since the product has been on the market for some time for menopausal women, one can look up hundreds of posted reviews at sites, like Amazon and Costco. The reviews to date are quite mixed and with a fair number of negative reviews consistent with the finding from this paper.

We noted that the lead author on the paper is an employee of a company that makes the Embr Wave. In addition, the device is not cheap. Its online price from Costco in the USA is $400USD and it can sell for over $600CAN when bought online in Canada.

Reference:

Peeke, P. et al. 2023 Feasibility of a novel wearable thermal device for management of bothersome hot flashes in patients with prostate cancer Research Square https://doi.org/10.21203/rs.3.rs-3367438/v1

ADT and Our Gut Microbiota Interact, But What Does that Mean Clinically?

There has been an explosion of interest in the last decade in the interaction of the microorganisms in our gut with our bodies and overall health. More than half the cells in our body are not our own cells. They are instead the single cell microbes that reside in our gut, and there has been an explosion of interest in the last decade in they interact with our bodies and overall health.

We have a crucial symbiotic relationship with these microbes. We provide them with food, a safe home where they can multiply. They, in turn help us digest our food. In order for this relationship to be mutually beneficial, we have to have a biochemical “amnesty agreement” with them. When things are going well, we all remain healthy. When things are not going well gastrointestinal diseases, such as cholera or irritable bowel disease, emerge.

Over 300 different types of microbes have been found in the human gut, but 30 or so are more common there and part of a normal healthy gut ecosystem. Maintaining this as a mutual beneficial system requires a constant negotiation with our immune system. That, however, can be kicked off balance by what we ingest and whether it's contaminated with pathogens that take up residence in our guts solely for their own benefit and not ours.

All sorts of things can disrupt this internal ecosystem. This includes not only the normal foods we eat, but the microorganisms we ingested with them along with any medications we might be taking. It is well known that some foods and drugs can alter digestion causing constipation or diarrhea.

What has become clear in the last decade is that many drugs can interact with the gut microbial system through our immune system. That is where ADT comes in. In the last few years, it has been suggested that patients on ADT show some shift in the types and ratio of gut microbes. A study with mice suggested that one such microbe can enhance ADT’s effectiveness and possibly slow cancer progression. This has inspired a lot more interest in the relationship between ADT and our gut microbes.

A researcher has now examined how quickly the initiation of ADT leads to shifts in our gut microbial community. The author found that the shift was not immediate, but took more than a year to occur and stabilize.

So, what does this mean overall to the health of the patients on ADT, particularly in terms of cancer control?

Supposedly one might look at the gut microbes that are most common in patients on ADT, who have good cancer control and try to encourage the growth of those specific microbes in other patients on ADT.

There are at least two problems with that idea. First it assumes that the relationship between ADT’s effectiveness and the gut microbes is a simple and direct relationship. But we can't be sure of that. For instance, we know that ADT can change patients’ diabetic risk. Diabetes is a disease of the pancreas, which not only produces the hormone insulin (to help us process sugar in the body), but it also produces important chemicals that are injected into the gut to help aid digestion. As such, ADT might indirectly interact with the gut ecosystem through the function of the pancreas, changing the chemical environment of the gut ecosystem. That could, in turn, favors certain microbes over others.

If we find that certain microbes are beneficial for helping ADT control prostate cancer, the “best” microbes still have to work well in terms of our digestion. That means we must keep the complex ecosystem healthy, which involves a wealth of different species.

In sum, the evidence continues to grow that there is a relationship between the symbiotes in our gut, our immune system, and how well ADT works in controlling prostate cancer. But we don’t know if the relationship is directly causal or just some indirect correlative association involving all sorts of other variables that can be affecting our health overall.

Not just our own cells, but the community of other organisms that live in our guts, can impede, or enhance the effectiveness of medical treatments. However, we don’t know how to alter and then sustain the microbial community in a reproducible way that improves cancer control and concurrently keeps our gut microbial community our allies and not our enemies.

Reference:

Wang L. Changes in the gut microbial profile during long-term androgen deprivation therapy for prostate cancer.   2023 Sep 11. doi: 10.1038/s41391-023-00723-w. Epub ahead of print. PMID: 37696986.