Wednesday, November 30, 2022

Androgen Deprivation Therapy In Prostate Cancer

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Effects On Men’s Sexuality

ADT and Its Consequences in the Treatment of Prostate Cancer

Normal male sexuality seems to depend upon very specific and complicated hormonal patterns that are not completely understood. One study suggests that ADT can alter the hormonal balance necessary for male sexual activity. As men age, testosterone levels decrease by about 1% a year after age 30 however, it is important to determine whether low testosterone is due to normal aging, or to a disease, such as hypogonadism. Testosterone plays a significant role in sexual functioning therefore, naturally declining levels of testosterone can lead to reduction in normal sexual functioning. Further decreases in serum testosterone can have a negative impact on normal sexual function, leading to a decline in quality of life.

Hormone Therapy For Prostate Cancer

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Hormone therapy is also called androgen suppression therapy. The goal of this treatment is to reduce levels of male hormones, called androgens, in the body, or to stop them from fueling prostate cancer cell growth.

Androgens stimulate prostate cancer cells to grow. The main androgens in the body are testosterone and dihydrotestosterone . Most androgens are made by the testicles, but the adrenal glands as well as the prostate cancer cells themselves, can also make androgens.

Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time. But hormone therapy alone does not cure prostate cancer.

Did Androgen Deprivation Therapy Cause Bone Loss For You

ADT long term ie 4 years has caused Osteopenia.

Interested in more discussions like this? Go to the Prostate Cancer group.

I had a Bone Scan before any treatment for my prostate cancer . It showedosteopenia. I am 75. Subsequent treatment over the next 8 mos included Radiation, Lupron, Zytiga. I assume the osteopenia is close to osteoporosis. No broken bones yet. Carpe Diem.

Welcome @tott123. Osteoporosis can be a complication of androgen deprivation therapy for prostate cancer. I’m glad that both you and @spryguy were being monitored and that the bone loss was discovered in the osteopenia phase before full blown osteoporosis.

What guidance did you get from your cancer team regarding lifestyle ways to avoid further bone loss, like diet, exercise, or treatments that help? Are you still taking ADT?

Welcome @tott123. Osteoporosis can be a complication of androgen deprivation therapy for prostate cancer. I’m glad that both you and @spryguy were being monitored and that the bone loss was discovered in the osteopenia phase before full blown osteoporosis.

What guidance did you get from your cancer team regarding lifestyle ways to avoid further bone loss, like diet, exercise, or treatments that help? Are you still taking ADT?

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Intermittent Versus Continuous Hormone Therapy

Most prostate cancers treated with hormone therapy become resistant to this treatment over a period of months or years. Some doctors believe that constant androgen suppression might not be needed, so they advise intermittent treatment. This can allow for a break from side effects like decreased energy, sexual problems, and hot flashes.

In one form of intermittent hormone therapy, treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy uses hormone therapy for fixed periods of time for example, 6 months on followed by 6 months off.

At this time, it isnt clear how this approach compares to continuous hormone therapy. Some studies have found that continuous therapy might help men live longer, but other studies have not found such a difference.

Reducing The Impact Of Adt

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For men who experience a PSA recurrence after radiation therapy for prostate cancer, hormone therapy given intermittently appears to be as effective as hormone therapy given continuously.14

Androgen deprivation therapy is designed to block testosterone from stimulating the growth of hormone-dependent types of prostate cancer. Because continuous androgen deprivation therapy produces side effects such as osteoporosis, hot flashes, and loss of libido, and because many prostate cancers eventually become resistant to hormonal therapy, researchers continue to explore alternatives. Intermittent androgen suppression is one such alternative. It involves the administration of hormonal therapy until a sufficient treatment response has been achieved, followed by a period of no treatment. The cycle is repeated as needed. IAS may reduce side effects and delay hormone resistance. In order to assess the effects of IAS among men who experience an increase in PSA after radiation therapy for prostate cancer, researchers evaluated 1,386 men. Half the patients were treated with continuous androgen deprivation and half were treated with IAS. IAS was delivered for eight months at a time, and was restarted if PSA levels off treatment exceeded 10 ng/ml. During follow-up, patients assigned to IAS were on treatment 27% of the time. The trial was stopped early when it became apparent that overall survival with IAS was no worse than with continuous androgen deprivation therapy.

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Early Versus Delayed Treatment

For men who need hormone therapy, such as men whose PSA levels are rising after surgery or radiation or men with advanced prostate cancer who dont yet have symptoms, its not always clear when it is best to start hormone treatment. Some doctors think that hormone therapy works better if its started as soon as possible, even if a man feels well and is not having any symptoms. Some studies have shown that hormone treatment may slow the disease down and perhaps even help men live longer.

But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the side effects of hormone therapy and the chance that the cancer could become resistant to therapy sooner, treatment shouldnt be started until a man has symptoms from the cancer. This issue is being studied.

What Is Androgen Deprivation Therapy

Most prostate cancers need testosterone to grow. Testosterone is a male sex hormone that is made by the testes and adrenal glands. One treatment for prostate cancer is to slow or stop the body from making testosterone or block it from working. By depriving your body of androgens, prostate tumors can shrink or grow more slowly. These medications are called androgen deprivation therapy, or ADT. ADT can sometimes be called androgen suppression therapy.

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Adt Helps Control Cancer Cells

Both normal and cancerous cells in the prostate gland rely on male hormones for growth. Hormones are chemical messages secreted by glands in the endocrine system. These hormones travel in the blood to affect cells in other organs.Male hormones encourage the growth of cancerous cells in the prostate gland. They also stimulate cancer cells that have migrated to other sites in the body.ADT controls cancer cells by reducing the levels of androgens in the body. This suppression has a direct effect on cancer cells themselves. It also affects new blood vessels that the cancer cells develop to support their growth.ADT is used increasingly to shrink prostate tumours before radiotherapy. For non-localised disease , ADT is also used to control the cancer after it has spread beyond the prostate. ADT is usually injected into muscle or delivered via implants under the skin. The most common form of ADT used today is a group of medicines called gonadotrophin-releasing-hormone agonists. These medicines stop the pituitary gland from making luteinising hormone . Without this ‘messenger’ hormone, the testicles produce less testosterone. Each injection is effective for one to four months.

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On-Off Therapy Works in Prostate Cancer
  • Both normal and cancerous cells in the prostate gland rely on male hormones such as testosterone.
  • The aim of ADT is to control cancer growth by reducing the level of male hormones. Potential side effects include impotence, reduced sex drive, fatigue and an increased risk of osteoporosis.
  • Men should take calcium and vitamin D while undergoing ADT to reduce the risk of osteoporosis.

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Prt And Physiological Adaptations

Muscle hypertrophy induced by PRT is the product of increased muscle fiber cross-sectional area and is accompanied by the enhancement of subcellular structures and increased substrate metabolism. This improvement in the metabolic capacity of skeletal muscle underlies a range of beneficial adaptations that may be particularly important to men treated with ADT.

Much of the current evidence regarding muscle adaptation in PRT is drawn from studies involving the elderly population with sarcopenia, a similar cohort to those on ADT . In sarcopenia, there is a reduction in the number of both slow-twitch type I and fast-twitch type II muscle fibers and specific type 2 muscle fiber atrophy , leading to a decline in muscle strength . PRT in this population has been shown to increase type IIa muscle fiber cross-sectional area . Thus, this physiological adaptation may improve physical function and contribute to improved glucose metabolism due to increased GLUT4 activity and enhanced insulin response via skeletal muscle . Furthermore, PRT also has beneficial effects on mitochondrial function and proteostasis, the loss of which is implicated in the pathophysiology of muscle loss in sarcopenia .

Changes In Gleason Criteria

Two of the Gleason criteria are altered by NADT. A decrease in gland size and an increase in stroma between glands occur. These findings can lead to a false upgrade of the Gleason score. The use of a modified Gleason system has been proposed to evaluate prostatectomy specimens from patients who have received NADT some physicians have suggested that no Gleason score should be allocated.

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Insulin Sensitivity And Obesity

Men with prostate cancer being treated with androgen deprivation therapy have an increased risk of osteoporosis and obesity.1-3

To gain more insight on the side effects caused by ADT, researchers from the University of Arizona compared data involving side effects of ADT. The study compared men with prostate cancer who were being treated with ADT and men not being treated with ADT . Obesity developed in 43% of men treated with ADT, compared to only 27% of men in the control group.1

The researchers concluded that patients with prostate cancer treated with ADT are at a higher risk for obesity. Appropriate preventive measures or close monitoring may help to prevent or reduce side effects.

Among men with locally advanced or recurrent prostate cancer, short-term treatment with Lupron Depot® and Casodex® increased body fat and decreased insulin sensitivity according to another study published in the Journal of Clinical Endocrinology and Metabolism.2

Metabolic changes such as insulin resistance could increase the risk of subsequent cardiovascular disease.

To explore whether androgen deprivation therapy reduces insulin sensitivity, researchers in the U.S. conducted a study among 25 men with locally advanced or recurrent prostate cancer. Average patient age was 68 years. The study excluded men who already had diabetes.

These changes also appear to increase the risk of diabetes and cardiovascular disease particularly in older men.

Who Should Receive Iad

prostate cancer treatments options

The commonest indication for iad in the Western world, where psa screening and early detection of prostate cancer are widespread, is biochemical recurrence after definitive therapy. Most such patients have no evidence of bone metastases. Based on the data reviewed here so far, iad should be used in most of them. Based on the swog study in metastatic disease, caution is warranted in men with bone metastases. As mentioned already, the interpretation of the swog study is controversial. Regardless, the benefit of iad in men with bone metastases is less because of decreased life expectancy and shortened off-treatment intervals. However, some of these patients demonstrate a robust and sustained response to adt. The nadir psa on treatment has been demonstrated to be a predictor for duration of response.

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British Columbia Specific Information

You are considered a low-risk patient if you have a PSA value that is equal or less than 10 nanograms per millilitre , a Gleason score that is equal or less than 6, and your cancer stage is T1c/T2a. PSA is your prostate specific antigen measured by a blood test, the Gleason score indicates how aggressive the cancer is by looking at tissue biopsy results, and the cancer stage describes how much the cancer has spread.

Active surveillance has been developed to allow for careful management of men with low-risk prostate cancer. For more information, visit BC Cancer Agency – Prostate.

When Is Hormone Therapy Used

Hormone therapy may be used:

  • If the cancer has spread too far to be cured by surgery or radiation, or if you cant have these treatments for some other reason
  • If the cancer remains or comes back after treatment with surgery or radiation therapy
  • Along with radiation therapy as the initial treatment, if you are at higher risk of the cancer coming back after treatment
  • Before radiation to try to shrink the cancer to make treatment more effective

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Improvement In Pathologic Variables

Treatment with neoadjuvant hormones has been shown to substantially improve local pathologic variables, such as organ-confined rates, pathologic down-staging, and rate of lymph node involvement. With regard to seminal vesical invasion, one study reported a decrease in seminal vesicle invasion rate with neoadjuvant therapy, whereas another study showed no difference.

The Role Of Ar Signaling In Crpc

Timing of ADT and Chemotherapy

The expression of PSA is mediated by androgen response elements. This suggests that the increasing PSA during ADT reflects activation of AR transcriptional activity. Consistent with this hypothesis, various recent findings have supported the notion that one of the most important mechanisms in CRPC development is the continuous activation of AR in prostate cancer cells. Several cellular and molecular alterations are related to this post-castration activation of the AR, including incomplete blockade of AR-ligand signaling, AR amplifications, AR mutations, aberrant AR co-regulator activities and AR splice-variant expression.

Enzalutamide is a novel AR antagonist that overcomes resistance to conventional anti-androgens by inhibiting nuclear localization and chromatin binding of AR. According to a recent phase I/II study in patients with mCRPC, the use of enzalutamide is safe, elicits PSA and radiographic response, and results in a median time to progression of 47 weeks. The superiority of enzalutamide over placebo was confirmed in a phase III clinical trial that showed increased overall survival and improvement in all secondary end points in patients with mCRPC after chemotherapy. Despite these encouraging results, after a period of remission that is characterized by significant variation in therapeutic response, these tumors eventually progress.

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Funding Support And Author Disclosures

Dr Narayan has received research support from Bristol-Myers Squibb, Merck, TMunity Therapeutics, Pfizer, and Janssen and consulting fees from Janssen, Pfizer, Myovant, Amgen, Regeneron, and Merck. Dr Ross has received consulting/speaker fees from Astellas, Bayer, Blue Earth, GenomeDx Biosciences, Janssen, Myovant, and Tempus. Dr Parikh has received grant support from Humana, the National Institutes of Health, the Prostate Cancer Foundation, the National Palliative Care Research Center, the Conquer Cancer Foundation, and the Veterans Administration received personal fees and equity from GNS Healthcare and Onc.AI received personal fees from the Cancer Study Group and Nanology and honorarium from Flatiron and Medscape and served on the board of the Coalition to Transform Advanced Care. Dr Nohria has received research support from Amgen and served as a consultant for AstraZeneca, Bantam Pharmaceuticals, Boehringer Ingelheim, and Takeda Oncology. Dr Morgans has received research support from Astellas, Seattle Genetics, Bayer, Sanofi, and Myovant and consulting fees from Astellas, AstraZeneca, AAA, Bayer, Clovis, Janssen, Dendreon, Myovant, Merck, Exelixis, Novartis, Pfizer, Blue Earth, Myriad, Sanofi, and Lantheus.

Clinical Predisposing Factors For Bone Loss And Osteoporosis

Considering factors that promote bone loss prior to ADT in PCa patients is important when initiating hormone therapy. The lifetime risk of bone fractures secondary to osteoporosis is 20%.14 Cheung et al.15 showed in an audit of 236 men that, at initiation of ADT, 11% had osteoporosis and 40% osteopenia. In addition, 61% of those with osteoporosis were unaware of it. These results reflect the need for a thorough screening of bone loss and its causes prior to initiation of ADT.

Osteoporosis promoted by other than age-related etiologies is referred to as secondary osteoporosis . These include alcohol or glucocorticoid excess, vitamin D deficiency and hypogonadism. Primary hypogonadism results from disease of the testes, as a distinction from secondary hypogonadism, which refers to anomalies of hormones secreted at the pituitary or the hypothalamic level. Some drugs may lead to secondary hypogonadism such as chronic glucocorticoid or opiates use, gonadal steroids and GnRH analogs, the drug of choice for ADT for prostate cancer. Although no threshold has been defined, testosterone levels < 150ngdl1 typically trigger hypogonadism-associated signs and symptoms.7

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How Can I Manage These Side Effects

It is important to manage any side effects you are having so that you can continue treatment. Listed below are tips on how to manage the side effects of androgen deprivation medications.

Sexual Dysfunction & Body Image Problems

ADT causes a loss of libido in most men. This tends to happen within the first few months of therapy, followed by erectile dysfunction . Libido often comes back a few months after androgen deprivation therapy has been finished. Depending on other cancer treatments and other medical problems, erectile function also can come back for many men.

Talk with your partner and your healthcare providers. Learn about ED. Ask for help from your urologist, who is trained in the treatment of ED. Finally, think about seeing a sex therapist, which can be helpful for couples facing these side effects.

Osteoporosis

Osteoporosis is when you have thinning of the bones that can lead to fractures . There are things you can do to lower your risk of a fracture and to strengthen your bones.

  • Take 1000 IU of vitamin D-3 daily.
  • Your healthcare provider may check blood levels of vitamin D with the 25-OH Vitamin D blood test.
  • Do not take more than 2000 IU of vitamin D3 a day unless directed by your healthcare provider.
  • Bone strengthening exercises.
  • Before you start an exercise program, check with your healthcare provider first. If you have cancer that has spread to your bones, a healthcare provider should help you see if weightlifting is safe for you.
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