Sexual Dysfunction And Gynecomastia
Several studies have shown that treatment for clinically localized prostate cancer involving either radical prostatectomy, brachytherapy, or external beam radiotherapy can result in long-term erectile dysfunction. Patients receiving neoadjuvant ADT with EBRT were found to have decreased frequency of erection, decreased overall sexual function, and an increase in frequency of hot flushes. In addition, loss of libido is a major consequence of ADT. The degree of erectile dysfunction for patients on ADT is impacted by pretreatment sexual function, as well as by changes in libido in patients previously able to attain an erection, phosphodiesterase 5 inhibitors, intracavernosal injection therapy, vacuum-assisted devices, or other topical agents may be used. Given the complex interplay between physiology, psychology, stress, and emotion involved in sexual function, a referral to a psychology or counseling service with a focus on sexual health is recommended for interested patients and their partners.
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.
Metabolic Syndrome And Cardiovascular Disease
Metabolic syndrome is a set of symptoms that increase the risk of stroke, cardiovascular disease, and type II diabetes mellitus . There is an increased risk of developing DM in prostate cancer patients treated with ADT than patients not treated with ADT .103 ADT was also associated with higher risk of complications in patients previously diagnosed with DM. Patients on ADT had a 17% increased risk of developing diabetic retinopathy, 14% higher risk for diabetic neuropathy, and twice as likely to have diabetic amputations.104
In longitudinal cohort study of 190 men undergoing ADT, mean triglycerides , HDL cholesterol , and waist circumference were significantly increased 6 months and 12 months after initiating ADT.105 Although HDL cholesterol is known to improve cardiovascular Health, an increase in overall cholesterol and triglycerides have negative effects as shown in the next two studies. Patients on ADT were at a higher risk of coronary heart disease and myocardial infarctions .106 ADT also increased the risk for ischemic stroke when compared to non ADT users.107
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Lhrh/gnrh Agonists And Antagonists
LHRH/GnRH agonists, such as leuprorelin/leuprolide, goserelin, and triptorelin, are by far the most commonly utilized forms of ADT in clinical practice in the treatment of PCa, targeting the LHRH/GnRH receptor in the anterior pituitary gland and administered as an intramuscular or subcutaneous injection. They stimulate the receptor, creating a temporary surge in LH and testosterone levels followed by downregulation of the receptor over the next 23 weeks with a subsequent reduction in LH and suppression of testosterone production by the testes.19 They achieve serum testosterone levels below castration within 46 weeks with a subsequent reduction in the PSA level.20 The most common adverse effects associated with treatment are hot flashes, fatigue, sexual/erectile dysfunction, testicular atrophy, cognitive decline, increased risk of diabetes and cardiovascular events, and decreased bone mineral density associated with joint disorders and/or osteoporosis that needs to be monitored periodically with bone density scanning.21
Hormone Starvation For Prostate Health
Hormone therapy may not be the first treatment people think of after hearing their prostate cancer diagnosis. Typically, the “C” word elicits images of exhausting radiation exposure or heavily invasive surgical procedures to remove cancerous cells.
But the success of these treatment options for prostate cancer can be bolstered, or somewhat supplemented, by ADT. It starves the cancerous cells of what they need to prosper and self-propagate.
“You know, humans, we need food and water to survive,” said Brian K. McNeil, M.D., the chief of urology at the University Hospital of Brooklyn in New York City. “And prostate cancer cells actually feed on testosterone, the hormone itself. So when we talk about androgen deprivation therapy or hormone therapy, the goal is to disrupt either the production or delivery of testosterone to the prostate cancer cell.”
McNeil said physicians have different ways of performing ADT, and theoretically, they can starve the prostate cancer cells. The goal is to inhibit their growth, shrink them or prevent progression.
Is this starvation approach a potential first line of defense against prostate cancer and an aid in recovery? Or is it more of a last-ditch, everything-but-the-kitchen-sink tactic?
The answer is complicated and generally determined on an individual basis. There are guidelines in place for doctors, despite challenges to those guidelines.
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Alternatives To Adt For Prostate Cancer
Several other techniques can reduce the level of male hormones in the body, including:
- orchidectomy the surgical removal of the testicles. About 95 per cent of male hormones are made by the testicles. Their removal causes testosterone levels to plummet, so that medications to block hormone production are not necessary. The scrotum itself is not removed
- subcapsularorchidectomy in this surgical procedure, only the parts of the testicles that make testosterone are removed, leaving the exterior skin and the scrotum
- anti-androgen medication called anti-androgens, are often used in low doses to treat distressing symptoms such as hot flushes, which result from the injections or surgical removal of the testicles. They may also be used with other treatments to stop the production of male hormones. They may affect liver function and cause other adverse effects, so liver function tests are monitored closely during treatment.
There are different types of anti-androgens in use such as flutamide and bicalutamide these are often used in low doses. Enzalutamide and abiraterone have recently become available in Australia and may be offered to some men. They have a very strong anti-androgen action that improves survival and quality of life.
Details Of The Combined Analysis
For their study, Spratt and colleagues carried out the first combined individual patient analysis of two phase 3 randomized trials to determine the optimal timing of ADT with radiotherapy for patients with localized prostate cancer. In the neoadjuvant group, ADT was initiated a few months prior to starting radiotherapy, and it was continued during radiotherapy in the adjuvant group, ADT was given after radiotherapy or was initiated during it.
Data from 1065 patients were analyzed. The neoadjuvant and the adjuvant groups had the same number of patients. The two cohorts were extremely well matched, Spratt commented: more than 50% of both groups had Gleason 7 disease the majority had palpable disease and baseline prostate-specific antigen levels were greater than 10 ng/mL in the majority of patients.
The primary endpoint was progression-free survival median follow-up was 14.9 years.
For all oncologic outcomes with the exception of prostate cancerspecific survival and overall survival, adjuvant ADT was statistically superior to neoadjuvant ADT, Spratt reported. There was a 25% relative improvement in PFS with adjuvant ADT compared with neoadjuvant ADT, which translated into a 7% absolute improvement at 15 years’ follow-up.
“Biochemical recurrence was significantly lower with adjuvant ADT, with a 37% relative improvement over neoadjuvant ADT and a 10% absolute improvement again at 15 years,” Spratt observed.
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Complications Of Androgen Deprivation Therapy In Men With Prostate Cancer
This article summarizes the key side effects associated with ADT for the treatment of prostate cancer and discusses strategies to optimize management.
The standard treatment for men with metastatic prostate cancer is androgen deprivation therapy . This therapy is associated with a multitude of side effects that can impact quality of life. These include vasomotor complications , sexual dysfunction and gynecomastia, osteoporosis, metabolic syndrome, and depression. Additionally, ADT has been associated with neurocognitive deficits, thromboembolic disease, and cardiovascular disease, although the data regarding the latter associations are mixed. This article summarizes the key side effects associated with ADT and discusses strategies to optimize management.
How Does Hormone Therapy Work Against Prostate Cancer
Early in their development, prostate cancers need androgens to grow. Hormone therapies, which are treatments that decrease androgen levels or block androgen action, can inhibit the growth of such prostate cancers, which are therefore called castration sensitive, androgen dependent, or androgen sensitive.
Most prostate cancers eventually stop responding to hormone therapy and become castration resistant. That is, they continue to grow even when androgen levels in the body are extremely low or undetectable. In the past, these tumors were also called hormone resistant, androgen independent, or hormone refractory however, these terms are rarely used now because the tumors are not truly independent of androgens for their growth. In fact, some newer hormone therapies have become available that can be used to treat tumors that have become castration resistant.
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What Are The Side Effects Of Hormone Therapy For Prostate Cancer
Because androgens affect many other organs besides the prostate, ADT can have a wide range of side effects , including:
- loss of interest in sex
Studer UE, Whelan P, Albrecht W, et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer Trial 30891. Journal of Clinical Oncology 2006 24:18681876.
Zelefsky MJ, Eastham JA, Sartor AO. Castration-Resistant Prostate Cancer. In: Vincent T. DeVita J, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology, 9e. Philadelphia, PA: Lippincott Williams & Wilkins 2011.
Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer. European Urology 2021 79:150158.
Chapter : Early Vs Delayed Adt
The timing of androgen deprivation therapy in the management of recurrent and advanced prostate cancer has been controversial for many years. This is mainly due to a lack of adequate randomized clinical trials comparing early vs delayed ADT in patients with recurrent PSA following failure of local curative treatment. To date the available studies and current guidelines are stating that early use of ADT to be only beneficial in symptomatic patients with recurrent or metastatic disease. The EAU recommends ADT only in symptomatic patients requiring palliative treatment.53 In the following we summarize the current practice guidelines on timing of ADT in patients with recurrent prostate cancer after failing local curative treatment.
Van den Bergh and colleagues performed a systematic literature review to assess the effectiveness of ADT in patients with PSA recurrence following local curative treatment. This meta-analysis found that the benefit of early/immediate ADT for nonmetastatic prostate cancer recurrence remains unproven. The conclusion was that early ADT should be reserved for patients with the highest risk of progression based on PSADT or Gleason Score, but having a long life expectancy. This falls in line with the current standard of care recommendations of the EAU/ESTRO/SIOG and AUA/ASTRO/SUO.58
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Androgen Deprivation Therapy Strategies
For advanced prostate cancer, the most appropriate time to initiate hormonal therapy remains controversial.7 One study showed that immediate treatment of men with locally advanced asymptomatic disease who were ineligible for local therapy improved progression-free survival but not overall survival or quality of life.27 Patients with an initial PSA > 50 ng/mL and/or a PSA doubling time of < 12 months had a high risk of dying from their disease and, therefore, might be good candidates for immediate ADT, with the goal of preventing or delaying complications.28
An analysis of four randomized controlled studies in patients with advanced prostate cancer who had received early vs. deferred ADT as primary therapy showed that early androgen suppression significantly reduced disease progression and complication rates due to progression, but did not improve cancer-specific survival. The small benefit in overall survival was not evident until after 10 years.29 According to ASCO, a moderate decrease in relative risk for prostate cancer-specific mortality and a moderate increase in relative risk for non-prostate cancer-specific mortality has been reported, and no overall survival advantage has been found when ADT is instituted immediately vs. waiting until symptom onset.14
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.
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When Adt Fails To Successfully Treat Prostate Cancer
Prostate cancer recurs within 12 months of ADT in around 20 per cent of men. Other treatment options then include:
- radiotherapy precisely targeted x-rays are used to control the symptoms of secondary cancers in other parts of the body
- other forms of ADT using types of ADT other than gonadotrophin-releasing-hormone agonists may slow cancer growth for a limited time
- chemotherapy recent evidence indicates some men respond to chemotherapy. The chemotherapy medicines docetaxel or cabazitaxel can improve survival and quality of life
- corticosteroids shrink the cancer and help manage pain
- pain-relieving medication includes morphine
- lifestyle changes improved diet, regular exercise and stress management have been shown to improve quality of life and even prolong survival of men on ADT
- palliative care is used to manage pain and discomfort, including treatments to prevent bone fracture and bone pain.
Dr Nabid On A Shorter Duration Of Adt In Prostate Cancer
Abdenour Nabid, MD, from the Centre Hospitalier de Universitaire de Sherbrooke in Sherbrooke, Canada, discusses results of a phase III randomized study that compared 18 months of ADT to 36 in men with high-risk, localized prostate cancer.
Abdenour Nabid, MD, associate professor at Centre Hospitalier de Universitaire de Sherbrooke in Sherbrooke, Canada, discusses results of a phase III randomized study that compared 18 months of androgen-deprivation therapy to 36 months in men with high-risk, localized prostate cancer.
In the study, 630 patients were evenly randomized to 36 or 18 months of pelvic radiotherapy plus bicalutamide and goserelin. At a median follow-up of 77 months, the study found that both overall survival and disease-specific survival were not statistically different between the two arms.
Treatment with ADT may result in serious adverse events that make a patient’s life miserable, Nabid points out. Shortening the duration of treatment could help alleviate some of these side effects and improve quality of life.
A more thorough analysis of quality of life is currently underway looking at patient-reported data from 9638 questionnaires. This analysis will provide further information on the impact of treatment duration on quality of life for men in this study.
What Are The Symptoms Of Prostate Cancer Metastasis
Cancer of the prostate may spread to the lymph nodes in the groin or to other organs. Most prevalent symptoms are swelling and discomfort in the region where the disease has progressed. Cancer cells may prevent lymph fluid drainage. This may result in leg edema owing to fluid retention in that location.
Ep 3a: Androgen Deprivation Therapy Failure And Second
is really the backbone of systemic therapy for advanced prostate cancer, and it has been for decades. Importantly, we now know that in many situations of advanced prostate cancer, it’s ADT intensification or ADT combinations that are really now standard of care.
When ADT or a combination therapy starts to fail the patient, and the is rising, and the disease looks like it may be spreading or growing on scans, we absolutely need to think about next steps. And, in most cases, I try to think about next steps in our treatment journey before we get to that point, just to make sure I understand what our options are so that I’m ready to move forward, especially if it’s an emergent situation. Some of that preplanning, of course, requires that we do additional testing. And particularly for things like PARP inhibitors, where we need to do genetic germline or somatic testing, that is going to need to happen in advance of when we need that treatment.
I think that the next few years are going to be incredibly rich when it comes to prostate cancer clinical trials, and the advances are going to be coming fast and furious. It’s been only 6 months or even less since we learned the results of the VISION trial. I do expect that the ongoing trials investigating lutetium PSMA are going to probably move it forward, and we will be able to see its benefits be even more pronounced as we move it earlier in the disease spectrum.
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How Will I Know That My Hormone Therapy Is Working
Doctors cannot predict how long hormone therapy will be effective in suppressing the growth of any individual mans prostate cancer. Therefore, men who take hormone therapy for more than a few months are regularly tested to determine the level of PSA in their blood. An increase in PSA level may indicate that a mans cancer has started growing again. A PSA level that continues to increase while hormone therapy is successfully keeping androgen levels extremely low is an indicator that a mans prostate cancer has become resistant to the hormone therapy that is currently being used.