Global update on defining and treating high-risk localized prostate cancer with leuprorelin: a Japanese perspective - the effect of primary androgen deprivation therapy on stage C prostate cancer
ABSTRACT Stage C prostate cancer, where the tumour has extended beyond the capsule of the prostate, is typically a high-risk disease. According to the National Cancer Institute Physician Data Query the treatments of choice for stage C disease comprise external beam radiation therapy (with or without the addition of adjuvant hormone therapy), androgen deprivation by either surgery or hormone therapy, radical prostatectomy, or careful observation. From 2001, the Japanese Urological Association initiated computer-based registration of all patients with prostate cancer in Japan. Data show that overall, 57% of all patients and 46% of those with T1c to T3 disease had primary androgen deprivation therapy (PADT). Similarly, the Japanese Prostate Cancer Group undertook a large-scale epidemiological surveillance study in Japan and found that the most commonly used hormone therapy is PADT, regardless of disease stage. To date, two randomized, controlled trials of the effect of PADT on stage C prostate cancer in elderly (> or =75 years old) patients have been undertaken in Japan. The results showed that patients with locally advanced prostate cancer treated with PADT are likely to have a life-expectancy similar to that of the normal population. In one study, combined androgen blockade (CAB) with leuprorelin plus chlormadinone appeared to prolong time to disease progression when compared with leuprorelin monotherapy, but there was no difference in survival between these treatment groups. In a second study CAB with an luteinizing hormone-releasing hormone (LHRH) agonist plus bicalutamide was found to prolong time to progression when compared with LHRH agonist monotherapy, but survival results for these regimens are still awaited.
- SourceAvailable from: Atsushi Mizokami
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ABSTRACT: One of the mechanisms through which advanced prostate cancer (PCa) usually relapses after androgen deprivation therapy (ADT) is the adaptation to residual androgens in PCa tissue. It has been observed that androgen biosynthesis in PCa tissue plays an important role in this adaptation. In the present study, we investigated how stromal cells affect adrenal androgen dehydroepiandrosterone (DHEA) metabolism in androgen-sensitive PCa LNCaP cells. DHEA alone had little effect on prostate-specific antigen (PSA) promoter activity and the proliferation of LNCaP cells. However, the addition of prostate stromal cells or PCa-derived stromal cells (PCaSC) increased DHEA-induced PSA promoter activity via androgen receptor activation in the LNCaP cells. Moreover, PCaSC stimulated the proliferation of LNCaP cells under physiological concentrations of DHEA. Biosynthesis of testosterone or dihydrotestosterone from DHEA in stromal cells and LNCaP cells was involved in this stimulation of LNCaP cell proliferation. Androgen biosynthesis from DHEA depended upon the activity of various steroidogenic enzymes present in stromal cells. Finally, the dual 5alpha-reductase inhibitor dutasteride appears to function not only as a 5alpha-reductase inhibitor but also as a 3beta-hydroxysteroid dehydrogenase inhibitor in LNCaP cells. Taken together, this coculture assay system provides new insights of coordinate androgen biosynthesis under the microenvironment of PCa cells before and after ADT, and offers a model system for the identification of important steroidogenic enzymes involved in PCa progression and for the development of the corresponding inhibitors of androgen biosynthesis.Endocrine Related Cancer 08/2009; 16(4):1139-55. DOI:10.1677/ERC-09-0070 · 4.91 Impact Factor
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ABSTRACT: In this review the current indications and the options for LHRH analogues are elucidated. For this purpose, a literature search in PubMed and the Cochrane-Database was performed. In addition, the EAU and AUA guidelines as well as actual meeting abstracts up to 2008 were taken into account. Since the first prospective study in 1991 showed the same effectivity for LHRH analogues and orchiectomy in metastasised prostate cancer patients, the use of LHRH analogues increased thereafter. Testosterone levels do not need to be checked regularly, but rather only when PSA rises again under treatment. After cessation of LHRH analogue treatment the time to testosterone level recovery is longer when the treatment time was longer. One must especially recognise the risks of diabetes and osteoporosis after more than 3 years of LHRH analogue treatment. In the case of neoadjuvant and adjuvant LHRH analogue treatment, several points have to be taken into consideration: LHRH analogues before radical prostatectomy lead to a lower positive margin rate and lower rate of lymph node metastasis, but tumour-specific survival is not improved. In contrast, neoadjuvant LHRH analogue treatment before radiation therapy leads to better tumour-specific and overall survival. An increased cardiovascular toxicity was not observed. Intermittent androgen ablation has been proved to be equivalent with a reduction of side effects. Hormonal salvage therapy should be initiated when the PSA doubling time is short or the PSA velocity is > 2 ng / mL / year. The benefit of early initiation (PSA < 10 ng / mL, PSA doubling time < 12 months) is that it can prolong the metastasis-free survival time.Aktuelle Urologie 03/2009; 40(2):100-8. DOI:10.1055/s-0028-1098746 · 0.28 Impact Factor