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Case for Monotherapy

Posted by admin on June 21st, 2011 No Comments

TxNxMl: the Case for Monotherapy There has been a substantial increase in the incidence of prostate cancer recently, particularly in the proportion of patients presenting with early stages of the disease. Despite this shift toward early diagnosis, prostate cancer remains the second most common cause of death from cancer, with approximately 25% of all prostate cancer patients ultimately dying from metastatic disease. In contrast to organ-confined disease, there is still no curative treatment for metastatic prostate cancer. Moreover, in spite of better understanding of the clinical and biologic aspects of this disease, the median survival of patients with metastatic prostate cancer has not changed in the last five decades and ranges from 24 to 36 months. The first line of treatment for metastatic prostate cancer relies primarily on the suppression of gonadal androgens. While androgen deprivation represents an extremely effective palliative treatment for patients with metastatic disease, a survival benefit for this treatment has never been properly demonstrated in randomized trials. Current methods Read more [...]

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Overview of Clinical Trials

Posted by admin on June 21st, 2011 No Comments

Twenty-seven randomized controlled trials involving 7987 patients compared the outcome of surgical or medical castration alone (monotherapy) to almost every possible combination of castration and antiandrogens (17 of the trials are shown in Table Large Randomized Trials Comparing Combined Androgen Blockade to Monotherapy). The majority of trials used the nonsteroidal antiandrogen flutamide, along with nilutamide in the combination arm. Only seven trials used the steroidal antiandrogen cyproterone acetate. This review is organized to evaluate trials according to methods of gonadal ablation and class of antiandrogen (steroidal versus nonsteroidal). The vast majority of patients had metastatic disease, largely stage D2, but several trials included patients with nonmetastatic disease. Many trials included small numbers of patients and insufficient follow-up, resulting in a lack of statistical power to appropriately test the primary hypothesis. Relative efficacy was assessed by comparing treatment arms with respect to survival, disease progression, and response. Overall survival (death from any Read more [...]

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Observations in Patient Subsets (Minimal Disease)

Posted by admin on June 21st, 2011 No Comments

Preliminary results of the INT-0036 trial suggested that the Combined androgen blockade effect could be more prominent in patients with minimal disease and good performance status. Minimal metastatic disease was defined as axial skeleton involvement (pelvis and spine) and/or nodal involvement whereas the extensive disease subset included patients with appendicular skeleton (extremities, skull, ribs) and/or visceral involvement. With a median follow-up of > 60 months, the median progression-free survival was 19 months for the leuprolide plus placebo arm and 48 months for the combination arm. The median survival was 42 and 61 months, respectively. Multivariate analysis of the INT-0036 data indicated that extent of disease represents an important prognostic factor in metastatic prostate cancer. The subset analysis on INT-0036 included only a limited number of patients and therefore should be reviewed as a hypothesis requiring confirmation in specifically designed prospective randomized trials. Data from EORTC 30853 also suggest that patients with good performance status and minimal disease Read more [...]

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Adverse Effects and Quality of Life

Posted by admin on June 21st, 2011 No Comments

Because hormonal treatment is primarily a palliative therapy and has not been shown to significantly affect survival in metastatic prostate cancer, it is important to evaluate quality-of-life issues associated with Combined androgen blockade. Among the most common adverse reactions of androgen deprivation are hot flashes, gynecomastia (sometimes painful), anemia, diarrhea, and changes in liver function tests. Anemia and diarrhea, however, were significantly more prevalent in patients treated by castration combined with flutamide.'' Nilutamide has been associated with side effects such as pneumonitis, alcohol intolerance, and impaired adaptation to the dark. Bicalutamide as a single agent and in Combined androgen blockade was reported to cause breast tenderness and other adverse effects similar to flutamide although with lower incidence. Another way to evaluate treatment-related toxicity is to compare patient dropout from clinical trials. The INT-0105 trial reported that 33 patients with Combined androgen blockade were removed from the study because of drug toxicity, compared to only 10 patients Read more [...]

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Response to androgen blockade

Posted by admin on June 28th, 2010 No Comments

After the initiation of androgen deprivation therapy (ADT), most patients with prostate cancer will show some evidence of clinical response; the magnitude and rapidity of that response remain the best predictors of its durability. Assuming that ADT effectively targets the androgen-sensitive population of prostate cancer cells, an incomplete or sluggish response is evidence of a significant androgen-refractory population. Early in the clinical use of prostate specific antigen (PSA) as a biomarker of prostate cancer, it was recognized that decline of PSA level could predict response. For example, patients who had more than an 80% drop of PSA level within 1 month of initiation of androgen deprivation therapy had significantly longer disease-free progression rate. Likewise, the nadir PSA predicted the progression-free interval, as did pretreatment testosterone levels. A rise in prostate specific antigen level, evidence of the emergence of androgen-refractory disease, preceded bone metastatic progression by several months, with a mean lead time of 7.3 months. More recent studies Read more [...]

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Mechanisms of androgen axis blockade

Posted by admin on June 25th, 2010 No Comments

There are four therapeutic approaches for androgen axis blockade in current clinical use: ablation of androgen sources, inhibition of androgen synthesis, antiandrogens, and inhibition of luteinizing hormone–releasing hormone (LHRH) or luteinizing hormone (LH) release ( Table: Therapeutic Approaches to Androgen Deprivation Therapy ). Table: Therapeutic Approaches to Androgen Deprivation Therapy[*] Ablation of Androgen Sources Inhibition of Androgen Synthesis Antiandrogens Inhibition of LHRH or LH Orchiectomy Aminoglutethimide Cyproterone acetate DES Ketoconazole Leuprolide Flutamide Goserelin Bicalutamide Triptorelin Nilutamide Histrelin Cetrorelix Abarelix DES, diethylstilbestrol; LH, luteinizing hormone; LHRH, luteinizing hormone–releasing hormone. * Several agents have multiple mechanisms of action. Ablation of Androgen Sources Bilateral orchiectomy quickly reduces circulating testosterone levels to less than 50 ng/dL, which, on the basis of this procedure, is considered the castrate Read more [...]

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Sources of androgen

Posted by admin on June 21st, 2010 No Comments

Testosterone is the major circulating androgen, with 90% produced by the testes. More than half of testosterone is bound to sex-binding globulin and 40% is bound to albumin. Only 3% of testosterone remains unbound, and this is the functionally active form of the hormone. After passive diffusion through the cell membrane into the cytoplasm, testosterone undergoes conversion to dihydrotestosterone (DHT) through the action of the enzyme 5α-reductase. Although the relative potencies of testosterone and DHT are similar (as defined by the ability to cause half-maximal response in a prostate regrowth model), if the conversion of testosterone to dihydrotestosterone is blocked by the 5α-reductase inhibitor finasteride, 13-fold more testosterone is required for the same effect. Both testosterone and DHT exert their biologic effects by binding to the androgen receptor in the cytoplasm, promoting the association of androgen receptor co-regulators. The complex then translocates to the nucleus and binds to androgen response elements in the promoter regions of target genes. Molecular biology of androgen axis Androgen Read more [...]

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General complications of androgen ablation

Posted by admin on June 15th, 2010 No Comments

Osteoporosis The increased number of men being prescribed androgen ablation therapy much earlier in the course of their disease allows the chronic manifestations of the hypogonadal state to emerge. Widespread androgen ablation therapy applied to an increasingly aging population, already predisposed to loss of bone mineral density, has created an epidemic of osteopenia and osteoporosis. Fragile bones increase the risk of skeletal fracture. More than half of men meet the bone mineral density criteria for osteopenia or osteoporosis — defined as more than 2.5 standard deviations below an age-specific reference mean — before the initiation of androgen deprivation therapy (ADT). The longer a man receives ADT, the greater the risk of fracture. After 5 years of androgen deprivation therapy, 19.4% of men experienced fractures compared with 12.6% of controls; with more than 15 years, cumulative incidence of fractures was 40% compared with 19% of non-castrate controls. It has been estimated that 4 years of ADT will place the average man in the osteopenia range. Rarely discussed even 10 years ago, skeletal Read more [...]

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Liarozole: the Treatment of Recurrent Prostate Cancer

Posted by admin on January 30th, 2010 No Comments

Each year in the United States, 317,000 cases of prostate cancer are reported, with 41,400 men dying from it. About 50% of patients suffer from metastatic disease when they are diagnosed. These patients are treated with medical or surgical castration that may or may not involve antiandrogens. This first-line therapy has no effect on progression for 20% to 30% of patients. The remaining 70% to 80% experience relapse within the next three years and may qualify for second-line therapy options, which include cyproterone acetate, a synthetic antiandrogen steroid, and liarozole, the first retinoic acid metabolism-blocking agent. Liarozole, a novel imidazole derivative, is the first retinoic acid metabolism-blocking agent (RAMBA) to be developed as differentiation therapy for human solid tumors. Most importantly, the drug has been shown to demonstrate anticarcinogenic and antitumor effects. Preclinical studies of liarozole have shown that it inhibits the growth of androgen-independent tumors, along with others, by inhibiting 4-hydroxylase, a cytochrome P450-dependent enzyme that is involved in retinoic Read more [...]

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Herbal Help for Prostate Problems

Posted by admin on January 19th, 2010 No Comments

Saw palmetto berry extract helps to shrink swollen tissue, herbalists say When a 50-plus man starts to have trouble when he urinates, most doctors will have a check for an enlarged prostate, properly called benign prostate hyperplasia. And saw palmetto berry extract, listed by Consumer Reports in the US as a potentially helpful herb, could be just what the doctor ordered. As many as a third of all men over 50 may suffer from benign prostate hyperplasia, experts estimate. The condition is not cancerous and simply means that the tissue of the prostate is inflamed and swollen. Saw palmetto berry extract can help the tissue to shrink, allowing for more regular urination patterns - and with few side effects, as long as you use it with a doctor's help, experts say. How does it work? No one is exactly sure, but herbalists have an idea. "It seems to affect the hormone levels in the genital area," says Kara Dinda, director of education for the American Botanical Council in Austin, Texas. And while the effects of the herb on men's prostates seem fairly well documented, its effect on women Read more [...]

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