BERKELEY, CA (UroToday.com) - Androgens and the androgen receptor (AR) have been implicated in the aggressiveness of prostate cancer. In 1941, Huggins and Hodges demonstrated that bilateral orchiectomy or estrogen treatment was an effective treatment for prostate cancer. Based upon their findings, androgen deprivation therapy (ADT) has remained the main therapeutic option for patients with advanced prostate cancer for nearly the past 70 years.
|"The use of androgen deprivation therapy with higher doses of radiotherapy (RT) or newer RT modalities must still be properly assessed."|
Patients with prostate cancer with high Gleason scores have low DHT levels in the prostatic tissue. Biologically aggressive prostate cancer can occur under a low DHT-level environment where prostate cancer of a low malignancy with high DHT dependency cannot easily occur. Serum testosterone levels in men being treated with ADT have never been categorically established. After ADT with castration and flutamide, DHT levels in the prostatic tissue remained at approximately 25% of the amount measured before ADT in the same patients. Conventional ADTs that we have used cannot decrease DHT levels in the prostate sufficiently to restrain the growth of the cancer in patients with aggressive prostate cancer. Androgen levels in blood were low; however, it became clear that AR signals play important roles for progress of the cancers from the studies of prostate cancers that became exacerbated after ADT.
The androgen milieu in men with high Gleason score prostate cancer is probably less affected by conventional ADT than that in men with low Gleason score cancer, which was suggested to be associated with adrenal androgen levels. In patients treated with ADT, the pituitary-adrenal axis, mediated by adrenocorticotropic hormone, has a central role in the regulation of androgen synthesis. Several experimental studies have confirmed the potential benefits from the combination of ADT with radiotherapy (RT). Based on the results of phase III randomized trials, a combination of external RT with short-term ADT is recommended. In contrast, the combination of RT plus 6 months of ADT provides inferior survival as compared with RT plus 3 years of ADT in the treatment of locally advanced PCa. Notably, randomized trials included patients from diverse risk groups treated with older RT modalities, a variety of ADT scheduling and duration, and, importantly, suboptimal RT doses. Also importantly, the suboptimal suppression of androgen activity in prostate cancer may account for the heterogeneity in treatment effect observed across individual patients, and, moreover, may contribute to the outgrowth of resistant prostate cancer clones adapted to survive in a low androgen environment, suggesting that more effective methods for suppressing the androgen axis in the tumoral microenvironment are required.
The use of ADT with higher doses of RT or newer RT modalities has to be properly assessed.
Tsutomu Nishiyama, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Division of Urology, Department of Regenerative and Transplant Medicine, Department of Molecular and Cellular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan