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.

ADT Vacation or Intensification? What Do We Know About Which Way To Go?

It is standard care to offer ADT to prostate cancer (PCa) patients experiencing a rising PSA after localizing prostate cancer with curative intent. Because of the many side effects of ADT, patients in consult with their oncologist need to consider not just their risk of dying from prostate cancer, but their overall health and quality of life in deciding to start on ADT.

Once they elect to go on ADT, many patients want to know how long they need to stay on that treatment. Here the decision gets more complicated, for patients are increasingly advised that for cancer control they would do better on not just basic ADT, but on an intensified ADT protocol. Those are ones where other treatments are added in, such as chemotherapy and/or an ARTA (e.g., drugs like Xtandi, Erleada or Zytiga).

Many patients on ADT are so bothered by the side effects of basic ADT that they seek intermittent therapy where they take a vacation from ADT and cycle on and off it. Indeed, several studies have shown that many patients can have comparably long-term cancer control on intermittent ADT as good as on continuous ADT. For more advanced patients, however, such intermittent treatment may not be the best strategy and intensified ADT protocols may be a better way to go.

In terms of the options, the literature can sound conflicting. For example, a recent review and meta-analysis of intermittent versus continuous ADT by Becker et al. (2023) concluded that intermittent ADT is “less likely to yield adverse side effects [and that] future treatment guidelines should consider these advantages over continuous androgen deprivation therapy.”

In contrast, a series of papers in the last six months in prestigious journals like Lancet Oncology, Journal of Clinical Oncology (example citations below) support ADT intensification.

So, what is the better way to go? Take a vacation or intensification?

To be clear, adding additional drugs to ADT, does not reduce the side effects burden. Instead, it often increases the intensity of the ADT side effects and can add in new side effects. So, as noted above, the patient’s overall health and quality of life need to be taken into consideration when on ADT. With a broad range of options—from intermittent to intensified ADT—it become increasingly important that patients on ADT monitor not just their PSA, but other measures of their health, such as their energy levels and diabetic risk. 

What has been surprisingly missing in the studies that have shown a benefit to intermittent therapy, is the impact of intermittent therapy on not just the patient, but also their partners. We have known for decades that the side effects of ADT on patients can indirectly lower the quality of life of the partners of patients. What we have not seen is studies of the how the partners of PCa patients, who cycling on and off ADT, are doing with each cycle. Do they also benefit? We just don’t know.

With PCa patients living longer with ADT—and with the broadened range of ADT treatment options—it is time to not just study the impact of the various treatment protocols on the patients, but also on their intimate partners.

References:

Becker, B., Stroever, S., Reddy, A., & de Riese, W. T. W. (2023). Comparison of Intermittent and Continuous Androgen Deprivation Therapy in Prostate Cancer Patients: An Up-to-Date Meta-analysis for Urologists and Medical Providers. Urology practice, 10(5), 424–434. https://doi.org/10.1097/UPJ.0000000000000424

Sayyid R & Z. Klaassen (2023) Prostate Radiotherapy for De Novo, Low Volume Metastatic Hormone Sensitive Prostate Cancer: Is There Benefit? UroToday

https://www.urotoday.com/library-resources/mhspc/145327-prostate-radiotherapy-for-de-novo-low-volume-metastatic-hormone-sensitive-prostate-cancer-is-there-benefit.html

Jeremiah Wala, Paul Nguyen, and Mark Pomerantz (2023) Early Treatment Intensification in Metastatic Hormone-Sensitive Prostate Cancer Journal of Clinical Oncology 2023 41:20, 3584-3590.

Vale, C. L., Fisher, D. J., Godolphin, P. J., Rydzewska, L. H., Boher, J. M., Burdett, S., ... & Tierney, J. F. (2023). Which patients with metastatic hormone-sensitive prostate cancer benefit from docetaxel: a systematic review and meta-analysis of individual participant data from randomised trials. The Lancet Oncology, 24(7), 783-797.

Sometimes in Science the Story is in the Missing Data

There’s a new paper out of Finland that may seem unrelated to ADT, but tells an interesting story relevant to men challenged by ADT side effects. The paper is specifically about a questionnaire called the Expanded Prostate Cancer Index (EPIC) used to collect data on the impact of cancer treatments on prostate cancer patients’ quality of life (QoL). A separate study from our own research team (Mainwaring et al. 2023) showed that the EPIC is the second most common survey instrument used to collect QoL data from prostate cancer patients. Indeed, the EPIC has been cited in over 4000 papers over the last 23 years!

The researchers surveyed 625 prostate cancer patients where 12% of the men were on ADT.

What is unusual about this study is the authors not only looked at the questions that the patients answered, but also examined the ones that the patients elected to leave unanswered. The researchers noticed that patients on ADT were more likely than chance to skip answering questions in two areas; those that related to sexual function as well as questions categorized as hormone related. Questions in those two areas ask specifically about things like hot flash bother, frequency of erections, and ability to reach orgasm.

Questions in these areas are particularly problematic for patients on ADT. Many men on ADT are greatly bothered by loss of sexual function and hormonal effects, such as hot flashes. However, others are not, and it can depend on factors such as their age and how adapted they are to the changes in their lives brought on by ADT.

What the authors found is that men, who are not in a sexual relationship, were more likely to leave questions on sexual function unanswered compared to other questions. Note that the question asks “Overall, how big a problem has your sexual function or lack of sexual function been for you during the last four weeks?” Trying to answer that question can be difficult for any man whose sex drive is depressed by ADT, but is also unpartnered. As the authors noted, it is not clear how men on ADT should answer that question or how researchers should interpret their answers. It’s not surprising that so many men on ADT elected to simply pass on the question. 

Another issue with the EPIC is that it only explores the concerns of the patients, yet we already know that prostate cancer treatments affect not only patients, but indirectly their intimate partners. Regrettably, very few studies have looked at any correlation between the answers that the patients gave on QoL questionnaires, like the EPIC, and what answers their partners might give.

There’s been a great push lately for survey instruments that can collect data from patients on questionnaires that can be filled out on a tablet by patients in the waiting room. Such questionnaires are collectively called “patient reported outcome measures”, or PROMs. The EPIC is a PROM which seems to get used a lot simply because it is easy to fill in and has been used by so many past studies. But it may not help us understand what is really bothering patients the most, what is affecting their partners, or what to do about that.

It is often hard for us patients to describe how ADT is affecting our lives. It’s to the credit of the Finnish authors that they recognized weaknesses in the EPIC questionnaire based the questions there that many of the men on ADT decline to answer.

Reference:

Talvitie, A. M., Helminen, M., Ojala, H., Tammela, T., Auvinen, A., & Pietilä, I. (2023). Missingness in the expanded prostate cancer index short form (EPIC-26) — prevalence, patterns, and explanatory factors. Health and quality of life outcomes, 21(1), 89. https://doi.org/10.1186/s12955-023-02175-1

Mainwaring, J. M., Lee, T. K., Wassersug, R. J., & Wibowo, E. (2023). Scales for assessing male sexual function are not entirely applicable to gay and bisexual men with prostate cancer. Urologic Clinics [in press]

A New Meta-Analysis Concludes that ADT is Associated with a Significant Increase in the Risk of Dementia, Parkinson’s Disease, and Depression…but the Interesting Stuff is in the Details

Here we have a new meta-analysis of research on the neurocognitive risk associated with ADT. The study has not been published yet in the peer reviewed literature, but it is available online, and an abstract was published in the spring in the Journal of Urology.

The data was extracted from large retrospective data sets that identify correlations between ADT and select psychological problems for prostate cancer patients. The sample size is impressive; twenty-seven studies are pooled, which collective compare data from over 900,000 prostate cancer patients, who received ADT, with over 1.2 million patients, who did not receive ADT, as well as another 330,000+ patients with neither prostate cancer nor treatment with ADT.

If one only reads the Abstract, the conclusions seem scary. But there are some interesting points buried in the body of the paper not mentioned there.

Granted, the paper documents an increased risk of dementia and depression in prostate cancer patients on ADT, but that has been reported many times before. However, this study goes further and distinguishes Alzheimer’s disease from vascular dementia and also reports an increased risk of Parkinson's disease. Although that was only documented in three of the 27 studies included in the meta-analysis.

Before we dig into the details, one should understand that researchers can most easily find significance differences between populations when the sample sizes are very large, as they are here. Retrospective studies like this can only find correlations, which is not the same as identifying causal links. All the data in this study are presented as hazard ratios, where a significant hazard ratio of 1.66 indicates a likelihood of a 66% increase of the incidence of the condition at the population level. That, by the way, is the highest hazard ratio reported in this study and it’s for depression, which is the best studies neurocognitive disorder assessed with ADT. From other studies, we already know that depression is common with ADT, but not invariable and not demonstrable in the majority of men on ADT.

So, let's get into some of the new findings…

1.There is some hint that the specific form of androgen suppression (i.e., the “treatment modality”) may correlate with the risk of Alzheimer disease, but this warrants further research 

2. Age appears to be a factor with no increased risk for men on ADT younger than 65 but greater risk for men over 65.

3. In comparable studies from around the world, “only cohorts from America showed an increased risk of dementia with ADT.” Since this increased risk was not seen in studies from Europe or Asian, the authors pointed out that “genetic and environmental factors may play a role in modifying the risk of cognitive decline in patients with prostate cancer”.

On this last point, dementia is progressive and not something that can be cured. However, lifestyle interventions—e.g., maintaining a heart healthy diet, controlling one’s weight, and getting a good amount of physical exercise—can all limit the risk of depression and cognitive impairment as we age regardless of whether we are starting on ADT or not.

Reference:

Hinojosa-Gonzalez, D., Zafar, A., Saffati, G., Kronstedt, S., Zlatev, D., & Khera, M. (2023). Androgen Deprivation Therapy for Prostate Cancer and Neurocognitive Disorders: A Systematic Review and Meta-Analysis. https://doi.org/10.21203/rs.3.rs-3221041/v1

Note: A preprint that has been posted on Research Square, but not yet published in a peer-reviewed journal.

When it Comes to ADT, some Patient Reported Outcomes (PROs) Miss the Mark

It is increasingly popular for researchers to use patient reported outcome measures (PROMs) to capture data on the Quality of Life (QoL) of cancer patients. For many of us, who are patients, when one hears of “patient reported outcomes”, we envision a doctor or nurse asking us about how we're feeling, what side effects we're experiencing, and what is the greatest concern to us. In the clinical setting, however, PROMs tend to be captured using questionnaires that patients fill in rather than information gathered through direct conversation with healthcare providers.

In the world of prostate cancer, one of the most popular and commonly used PROMs is the Expanded Prostate Cancer Index Composite; i.e., the EPIC. The EPIC has been around for over 20 years and has been used in over 700 studies. As more researchers use the EPIC, more may assume it’s use is appropriate. However, from our perspective the EPIC has serious limitations when used to assess the QoL of men on ADT.

The EPIC has several separate domains. One is labelled “sexual function.” The questions there don’t actually ask about sexual function, but rather about “how big a problem,” the patient perceives to be having related to their sexual desire, ability to have erections, and ability to reach orgasm over the past 4 weeks.

ADT limits men’s ability to have erections and to reach orgasms, but it also affects sexual desire.

Patients, who are sexually active at the time they start ADT, may either find ways to continue to be sexually active … or they may abandon having sexual activity altogether. Reasons for this differ but may include expectations about the kind of the sexual activity they have, or their partner’s interest in sex. The loss of erections and orgasm may be greatly bothersome, not only to the patient but also the partner if they both have high desire for sex. Alternatively, the same changes may be of little bother for either of them, yet they may have a good, strong, co-supportive, dyadic bond built upon other factors than sex. Aging may also contribute to changes in sexual activity and interest. 

The EPIC questionnaire fails to sort this out. This is because the sexual domain in the questionnaire asks about bother, not function. Both patients and partners may have no sexual function, but also little or no bother from that because they have little sexual desire. Or they may be greatly bothered. There’s no way of telling based on the wording in the EPIC.

What concerns us here is a new study by Movsas et al. (2023), which used the EPIC questionnaire to look at QoL for prostate cancer patients with intermediate risk disease, who either used androgen deprivation therapy short term to support radiotherapy (RT) or got RT without ADT. The participants were surveyed with the EPIC at baseline, at the end of their RT treatments, six months later, a year later, and then five years later.

The EPIC revealed that the patients were greatly bothered by the impact of ADT on their sexual desire, erections, and ability to have orgasms at the end of their RT sessions. However, as time went by, the overall EPIC score for the sexual domain improved in the ADT group. The scores became less extreme and less clinically meaningful.

Had the patients returned to baseline and recovered from the ADT’s impact in the sexual domain? Or had they adapted to (or resigned to) a sex-free life without erections and orgasms secondary to reduced sexual desire? The paper doesn’t say. Furthermore, the researchers did not survey the partners to find out how they were doing. Nothing is said about sexual interests or bother for the partners of the men who had been on ADT.

The paper also reports on another EPIC QoL domain that collected data on whether the patients have experienced in the last four weeks hot flashes, loss of body hair, depression, a lack of energy, and any change in body weight. The results showed major changes in most of these variables at the six-month mark, but less so at the year mark.

Often hot flashes simply diminish overtime, loss of body hair typically occurs within six months and doesn’t change after that. Changes in body weight may be substantial in the first six months, but patients may be taking action to stabilize that so they’re no longer experiencing changes in their weight after months to a few years go by. Once again, one cannot tell whether these QoL features have returned to baseline or stabilized overtime.

This study involved approximately 400 patients. It is not clear though what to make of the authors statement that “PRO differences were relatively short-lived, with no clinically meaningful differences between patients getting ADT or not with RT, by one year after initiating treatment.” That could easily be interpreted to mean that ADT effects are transient and disappear after one year. The paper concludes by saying that instruments like the EPIC “provide added value to help individuals make fully informed decisions among the treatment options.”

When patients are offered ADT, they might like to know what changes might occur that can be easily reversed, and which ones are more permanent. As sexual function impacts both the partner and the patient, to help them make “fully informed decisions among treatment options,” they should both be informed about the changes they’re going to experience that may be difficult to reverse upon completion of short-term ADT. This can include the health and stability of their intimate partnership.

Reference:

Movsas, B., Rodgers, J., Elshaikh, M., Martinez, A., Morton, G. , Krauss, D., Yan, D., Citrin, D., Hershatter, B., Michalski, J., Ellis, R., Kavadi, V., Gore, E., Gustafson, G., Schulz, C., Velker, V., Olson, A., Cury, F., Papagikos, M., Karrison, T., Sandler, H., and Bruner, D. (2023). Dose-Escalated Radiation Alone or in Combination With Short-Term Total Androgen Suppression for Intermediate-Risk Prostate Cancer: Patient-Reported Outcomes From NRG/Radiation Therapy Oncology Group 0815 Randomized Trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 41(17), 3217–3224. https://doi.org/10.1200/JCO.22.02389