Prostate Cancer In UK And Therapy

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In the UK, prostate cancer is the most common cancer in men, with 47,500 men being diagnosed with prostate cancer every year leading to over 11,500 deaths per year. In Northern Ireland alone, over 1,000 men are diagnosed every year with prostate cancer with 250 dying from the disease (Prostate cancer UK, 2020). Androgen deprivation therapy (ADT) is the main go to treatment of this condition. It primarily works by suppressing the secretion of testicular androgens, as prostate cells are dependent on androgen for growth, function, and proliferation (Edcan.org.au., 2020). Therefore, if the supply of this hormone is halted, the prostate cells undergo apoptosis and limits the ability of the cancer growth. This can be achieved through the use of gonadotropin-releasing hormone (GnRH) antagonists such as Relugolix. This oral drug inhibits the release of luteinizing hormone from the pituitary gland, therefore, production of testosterone in Leydig cells in testes is inhibited. Due to the absence of testosterone, testosterone cannot be converted into dihydrotestosterone (DHT), subsequently DHT cannot be transported into target tissues- i.e. the prostate, so DHT cannot bind to the androgen receptor, stimulating the production of androgens. This drug Relugolix has a well-tolerated safety profile and is now going forward to stage 3 clinical trials (Dearnaley et al., 2020). It is preferred over previous GnRH antagonists as it is an oral drug therefore avoids injection site reactions and there is the option to stop the medication at any time (Kittai et al., 2018). However, benefits of this drug could be masked due to patient compliance as this is an oral medication.

Another potential target within ADT is the inhibition of 17-α-hydroxylase activity which also prevents testosterone production. Ketoconazole is a strategy used in ADT; it is classed as a CYP-17 inhibitor as it prevents androgen formation. It can block the production of cortisol, an important steroid hormone in the body, so men treated with this drug often need to take a corticosteroid (such as prednisone or hydrocortisone). Abiraterone, is another example of a CYP-17 inhibitor, however, is the preferred option as it has an increase on survival rates as opposed to no change with the use of ketoconazole. It is administered alongside prednisone which inhibits the production of androgens in the testes, adrenal glands, and most importantly prostate cancer cells, stunting their growth. It also has the ability to block intratumoural synthesis of androgens in prostate cancer cells. However, with this therapy liver function test monitored is recommended and dose decreasing may be needed, due to the risk of liver toxicity resulting in death (Colomba et al., 2020).

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Antiandrogens are another example of an oral agent for ADT. It blocks the action of testosterone as consequently blocks the action of DHT by competing for the specific binding site on the androgen receptor (Schroder., 2007). It is commonly used as an alternative to the traditional form of ADT, surgical castration. However, this process is rarely performed now due to the negative psychological impact it had on the men as well as the availability of other medical therapies.

However, this use of this therapy to treat prostate cancer has several adverse health effects, therefore more research needs to be done to prevent these from occurring or to develop a treatment with less side effects. It can cause side effects such as lowered libido, erectile dysfunction, hot flushes, breast swelling, bone thinning and hair loss. However, can also cause adverse effects more detrimental to health, including osteoporosis, liver problems, metabolic syndrome, and cardiovascular disease (Nguyena et al., 2015). Studies and trials have been conducted in order try and minimise these effects. For men receiving ADT, supplementation of Vitamin D and calcium is vital to maintain bone health to minimise incidences of osteoporosis leading to fractures. In 2013 a study concluded that a weekly oral alendronate significantly increased the spine and hip bone mineral density in men with prostate cancer receiving ADT, preventing bone loss, decreasing bone turnover, and increasing bone mass (Klotz et al., 2013).

ADT increases the risk of cardiovascular disease and diabetes and as a result, cardiovascular disease now causes almost as may death as the cancer itself in prostate cancer patients (Lu-Yao et al., 2004). Conditions such as coronary heart disease, myocardial infarction, sudden cardiac death, and new-onset diabetes have all been associated with the use of LHRH agonists in their ADT. The prevalence of these conditions is due to metabolic changes as a result of androgen suppression. It ultimately changes the man’s body composition by reducing lean mass, increasing fat mass, raising cholesterol and triglyceride levels, and increasing glucose and insulin (Haseen et al., 2010). To manage this an ABCD paradigm has been proposed to control cardiovascular risk factors in cancer survivors. This states aspirin is a potential drug for primary and secondary prevention of cardiovascular disease and possibly have the ability to reduce cancer related mortality. The use of angiotensin converting enzyme inhibitors to attain BP As mentioned above, the use of abiraterone is dose dependent due to the possibility of developing liver failure which ultimately could lead to death. Recent studies have researched the effects of using statins alongside abiraterone to increase the benefits and reduce the dose dependency. It presented data showing the positive effect the combination therapy had on the treatment outcomes, that it could lower all-cause and cancer-specific mortality in advanced prostate cancer patients (Yang et al., 2020). However, due to the small sample size further research is needed, to validate the efficacy of statins within ADT. As to date there is no drugs that are specially designed to treat liver dysfunction or hepatoxicity, however diuretics and pain medicine may be recommended.

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