Addressing Physical, Cognitive Effects of ADT in Prostate Cancer Patients

In this interview ahead of ASCO 2017 we discuss the physical and cognitive effects of androgen deprivation therapy in older men treated for prostate cancer.

The 2017 American Society of Clinical Oncology (ASCO) Annual Meeting is taking place June 2–6 in Chicago. As part of this year’s coverage, we are speaking with Alicia K. Morgans, MD, assistant professor of medicine in the division of hematology/oncology at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. At this year’s meeting, she will be speaking at an education session about the physical and cognitive effects of systemic therapy in older men with prostate cancer.

-Interviewed by Leah Lawrence 

Cancer Network: For the purpose of this discussion, how do you define older men?

Dr. Morgans: Usually in geriatric oncology “older” is considered over 65. Since the average age of diagnosis of prostate cancer in the United States is 66, this includes the majority of men diagnosed with prostate cancer. Though, of course, there are younger men afflicted with this disease.

Cancer Network: What is the most commonly used systemic therapy to treat prostate cancer in older men?

Dr. Morgans: The backbone of therapy for anyone who has metastatic disease or high-risk localized disease-or even recurrent disease in certain situations-is androgen deprivation therapy (ADT), which lowers testosterone through several hormonal feedback loops in the system. In lowering testosterone, this treatment really alters the hormonal milieu in this patient population. Lowering testosterone causes multiple side effects, and also consequently, lowering estrogen levels, which causes a number of other side effects. The biggest player in all of this in terms of side effects is ADT and other prostate cancer treatments that often act through the testosterone pathway in limiting testosterone signaling.

Cancer Network: Let’s start first with the physical side, what are some of the most commonly seen physical effects of systemic therapy in this patient population?

Dr. Morgans: The most commonly complained of symptom in my clinic is fatigue. Altering testosterone levels can take someone’s energy level down pretty significantly. In addition, men often have aches and pains because altering testosterone also seems to uncover arthritis that may not have been such a problem before, but after we lower testosterone all of these aches and pains, especially in big joints, seem to come out.

Men definitely have a loss of libido with ADT, and erectile dysfunction is often a problem. However, in this patient population, because of treatments that they may have gotten previously, erectile dysfunction may have been something that they have lived with for some time, even before we start ADT.

I would say fatigue, aches and pains, loss of libido, and erectile dysfunction are the biggest physical effects that we see in this patient population.

Cancer Network: What are some of the cognitive effects of these treatments?

Dr. Morgans: Unfortunately, ADT has been associated with things like depression, which is a psychological and cognitive effect. It has also been associated with dementia of many types, including Alzheimer disease-though this is a bit controversial. Some of the more recent literature has been retrospective population-based data, which has found an association between duration of exposure to ADT and the development of dementia. Although this is compelling, it is more hypothesis generating than a prospective study.

Interestingly, a recent prospective study with a fairly large population, followed men who were treated with ADT and found that there was development of cognitive impairment over time. The difference between those men treated with ADT and those not treated with ADT in proportion of cognitive impairment became statistically significantly at about 1 year after ADT treatment.

Cognitive impairment is certainly different than a full-blown diagnosis of dementia, but it is certainly something that can impact daily life. This development of cognitive impairment or the question of whether ADT is associated with cognitive impairment is one of the most important complications, in my mind, in this population.

Cancer Network: Are these effects, both physical and cognitive, long-lasting or permanent?

Dr. Morgans: I would say a little bit of both. I talked earlier about the physical side effects that patients feel most. There are other side effects that I should mention, particularly the development of osteoporosis, which one wouldn’t feel, and the higher risk of fracture that is associated with the development of osteoporosis. Fracture is a physical side effect that if one experiences, one might have residual pain for years to come. Hopefully, we could resolve or relieve that pain with surgical treatment, radiation treatments, or with pain medicine, but it is something that can affect people for years, as can any skeletal-related event that can happen in the prostate cancer population.

We do hope that some of the effects that men experience-like fatigue or cognitive change-might be reversible, such that when we stop treatment with hormonal therapy and their bodies start to produce testosterone again, some of these symptoms may resolve. For example, there are certain situations where we are able to stop ADT. Most of the patients that I take care of who end up having recovery of testosterone levels are noticeably more energetic, and believe that they have fewer aches and pains from arthritis. Some feel a little more sharp, as if their cognitive function may have turned around.

We do believe that though that some of these effects may be longer lasting. Others, we hope, are reversible if we have the opportunity to stop ADT.

When we don’t stop ADT-and for a majority of patients, especially with advanced prostate cancer, we are not able to stop ADT-these side effects are ongoing because they are still on treatment. In some men we stop ADT, but their bodies are not able to recover testosterone levels. Those patients would continue to feel side effects of therapy because they are all associated with low testosterone and low estrogen levels.

Cancer Network: How can clinicians work to prevent some of these more commonly occurring effects of therapy?

Dr. Morgans: That is a key question for the whole field and something we have been working on for years. It is still a work in progress.

At this point, one of the most important things is to avoid a treatment like ADT, a systemic therapy that lowers testosterone, in any situation that we can. If there is not a clear indication for treatment and a clear benefit from treatment, we should not give it people. There are some areas where there is a clear benefit to treating with ADT, like high-risk localized disease concurrent with radiation therapy, and metastatic cancer. In situations where there is some discretion about using ADT, the most important thing we can do is to not treat someone who does not have clear reason to benefit. Avoiding the therapy is the most effective way to avoid the side effects.

In situations where we are treating our patients we need to be diligent as physicians to recognize when an individual is developing osteoporosis, for example, because if someone is developing osteoporosis due to long-term exposure to ADT there are treatments like bisphosphonates and denosumab that can increase bone density and reduce the risk of fracture.

I also always recommend to my patients that they remain physically active. This can prevent the weight gain that we sometimes see with ADT and can prevent loss of muscle mass, which is another physical effect that we see associated with ADT. The more active someone is, the more energy they have, the less weight gain they experience, the more muscle mass they maintain, the closer to normal they are going to feel.

Certainly if an individual is developing depression or seems to have some cognitive impairment, it is important to connect that person with a psycho-oncologist or psychologist who may be able to help with effective treatment for depression. Even a neurologist or someone who is trained in neurocognitive training may be able to help slow the decline of cognitive dysfunction or teach an individual how to compensate for changes in cognitive function.

I would say that the most important thing is to avoid treatment in anyone who does not need ADT, and for those who need to be on ADT, to be very cognizant and aware of the physical and cognitive changes that one can develop-to meet them head on and proactively engage in ways to prevent complications and resolve complications in any setting in which we can.

Cancer Network: What are the most important takeaway points for our readers about this topic?

Dr. Morgans: To me, the most important point about ADT is that although it is not chemotherapy, it does cause these changes in an individual that can dramatically affect their quality of life, can be morbid, and can increase the risk of mortality-particularly if an individual is developing osteoporosis and fracture or if they are having cardiac complications or other complications from their therapy that can put them at increased risk of death. This treatment is not benign, so avoid it in any situation where it is not clearly benefiting the patient.

The second thing is to make sure we are cognizant of these changes that these patients are experiencing. Not all of them are clearly recognized by objective measures or by vital signs, and we do need to ask our patients, “How are you feeling?” and gauge their mood, assess their cognitive function, assess their ability to do the things they need to do physically, and determine whether there are ways that we can intervene to mitigate some of the changes and dysfunction that ADT can cause.