Health and Prostate

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External beam radiation therapy (EBRT) and interstitial implantation (brachytherapy) are the two types of radiation therapy (RT) currently available for treatment of prostate cancer. The course for external beam radiation therapy is four to six weeks and is administered daily. A linear accelerator is used to direct gamma rays to the prostate with efforts made to avoid radiating healthy tissue. Problems associated with EBRT are impotence, diarrhea, bowel urgency, hemorrhoids, urinary urgency, urinary frequency, and pain. According to the Prostate Cancer Outcomes Study, men who underwent radical prostatectomy (RP) were more likely to be incontinent and impotent than men who underwent EBRT; however, men who received external beam radiation therapy had an increased incidence of bowel dysfunction. Brachytherapy involves implanting radioactive seeds into the prostate which will emit radiation over a given period of time. Brachytherapy is convenient because it requires one outpatient visit for implantation compared to external beam radiation therapy, which is administered daily. The procedure can cause prostate inflammation, which may lead to severe urinary retention. Long-term effects from brachytherapy include painful urination, urinary retention, bowel dysfunction, and rectal ulcers.

Hormone Therapy: Hormone therapy has a variety of roles in the treatment of prostate cancer. Diethylstilbestrol (DES) was one of the first hormonal treatments for prostate cancer. DES inhibits gonadotropin-releasing hormone (GnRH) from the hypothalamus, thus inhibiting testosterone release from the testes. Diethylstilbestrol had a number of undesirable toxicities associated with it, such as increased risk of cardiovascular death, thromboembolism, and significant gynecomastia. Diethylstilbestrol is no longer first-line hormone therapy since luteinizing hormone-releasing hormone (LH-RH) agonists have been introduced and have a better side effect profile. DES, which is no longer manufactured commercially, may be used as a second-line agent and may be obtained from a specialty compounding pharmacy. The LH-RH agonists available are goserelin, leuprolide, and triptorelin; all are as effective as a bilateral orchiectomy in reducing testosterone levels. Luteinizing hormone-releasing hormone agonists inhibit the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) through negative feedback by down-regulating the receptors on the pituitary. Testosterone levels are then decreased because there is a lack of LH to stimulate the testes to produce testosterone. Initially LH-RH agonists cause FSH and LH to surge with a concomitant surge in testosterone levels until receptor down-regulation occurs. This increase in testosterone can cause a “flare” of the disease, leading to an increased growth in the tumor, urinary symptoms, and bone pain, which usually lasts about two weeks. Other common adverse effects from luteinizing hormone-releasing hormone agonists include erectile dysfunction, hot flashes, and decreased libido. Giving the patient a short course of nonsteroidal antiandrogen therapy, which will block the androgen receptor at the cellular level, inhibiting the effects of testosterone, can prevent or minimize this effect. Antiandrogens (bicalutamide, flutamide, and nilutamide) competitively inhibit testosterone and dihydrotestosterone from binding to the androgen receptor. Adverse effects from antiandrogens are gynecomastia, hot flashes, diarrhea, constipation, and elevated liver function tests. Because antiandrogens do not provide as much androgen deprivation when compared to orchiectomy, it is not recommended that they be used as monotherapy in advanced or high-risk prostate cancer. For patients with low- and intermediate-risk early prostate cancer, there is a developing trend to treat with antiandrogens as monotherapy, especially in younger males who may want to decrease the incidence of impotence. In one study, the response rate of monotherapy with high-dose bicalutamide (>= 150 mg) in 31 patients with hormone-refractory disease was 22.5% overall and 43% in patients who were previously treated with flutamide. Combination therapy with luteinizing hormone-releasing hormone agonists and antiandrogens, otherwise known as combined androgen blockade (CAB), is mainly reserved for patients who have advanced disease and need to prevent the effects of the testosterone surge secondary to the LH-RH agonist by being on an antiandrogen for a period of two to four weeks. Because of the inconsistent data regarding the ability of CAB to significantly increase disease-free survival, overall survival, and quality of life, CAB is not recommended as standard therapy and should not be used as long-term maintenance therapy. Neoadjuvant hormone therapy is hormone therapy given before RP or RT to reduce the tumor size. The Lupron Depot Neoadjuvant Prostate Cancer Study Group has studied the use of hormone therapy prior to prostatectomy. Patients were to receive either leuprolide plus flutamide (ie, CAB) three months before RP or RP alone. There were significantly fewer positive tumor margins in patients who received hormone therapy, but biochemical recurrence (abnormal prostate-specific antigen value) rate was the same at five years as in those who received RP alone. There have been several other prospective trials that have failed to show improvement in survival or biochemical recurrence despite improved surgical outcomes. In patients with locally advanced prostate cancer, hormone therapy plus RT has been shown to improve survival, disease-free survival, and disease progression, but it did not have the same outcomes for men with prostate-confined disease.

Chemotherapy: Eventually almost all patients will develop hormone-resistant prostate cancer (HRPC); median survival in these patients is less than one year. The use of chemotherapy in HRPC historically has been limited to palliative care. The combination of mitoxantrone plus prednisone has been shown to improve pain in hormone-resistant prostate cancer and is a suitable choice for palliative treatment. Tannock et al randomized patients to either prednisone 10 mg daily plus mitoxantrone 12 mg/m every 21 days or to prednisone 10 mg daily. Pain was improved significantly, and the response duration was longer in the mitoxantrone group (29% vs 12% and 43 vs 18 weeks, respectively). The combination of estramustine and a taxane has shown the most promise with higher rates of biochemical and objective response in addition to a palliative response. Phase I studies with estramustine and a taxane failed to show any effect on survival. However, some phase II trials with estramustine and docetaxel revealed an increase in median survival time, implying there may be a positive effect on survival with this regimen. There is currently an ongoing study comparing estramustine and docetaxel with mitoxantrone and prednisone with the primary end point being survival. There are also studies comparing three-drug regimens of chemotherapy (eg, estramustine, carboplatin, and paclitaxel), which are considered experimental at this time.

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