Intermittent Androgen Castration: A Biological Reality during Intermittent Treatment in Metastatic Prostate Cancer?

Abstract

Introduction: To assess the effects of intermittent maximal androgen blockade (IMAB) on testosterone (T) levels during on- and off-treatment periods. Materials and Methods: A total of 51 patients with metastatic prostate cancer underwent a 6-months period of continuous maximal androgen blockade (MAB) consisting of leuprorelin (3.75 mg at monthly intervals) plus flutamide (250 mg t.i.d.) followed by IMAB. During each cycle, the cut-off prostate-specific antigen (PSA) levels to stop and resume treatment were 4 and 10 ng/ml, respectively. IMAB continued until progression under treatment occurred. Monthly PSA and T measurements were performed in central laboratories. Results: From the 51 patients included (mean age 67.6 years), 27, 16, 12, 8 and 5 underwent a second, third, fourth, fifth and sixth cycle, respectively (mean follow up: 17 months). Before treatment, 4 patients had a T lower than normal laboratory value but these recovered all to a normal T value at the end of the first cycle. During the 6 cycles, only 8 patients did not recover a normal T at least once during the off-treatment periods (OTP). The mean T values at the end of each OTP did not change during these 6 cycles (Anova test, p = 0.621) with a mean stable recovery delay of 32–43 days (Anova test, p = 0.722). Conclusion: IMAB protocol with an initial 6-month treatment period can result in an intermittent castration with the recovery of normal T levels in most patients during six consecutive cycles of treatment.

Intermittent Androgen Deprivation Therapy with Antagonist: Really New Information?

“…This is not so different from data obtained with other compounds [7,8]. It must be remembered that the minimum testosterone level required to avoid castration side effects is still unclear.…”

Androgen Deprivation Therapy for the Treatment of Prostate Cancer: Consider Both Benefits and Risks

“…Intermittent ADT, for example, was associated with recovery of BMD in the off-treatment phase [87], a beneficial effect on cognitive function and depression [88,89], and an overall increase in general health-related QoL [90]. This is based on the fact that testosterone levels recover during off-treatment phases [91]. Because the majority of these studies are limited by relatively small sample sizes, it is currently unclear whether intermittent ADT may also reduce the incidence of severe side effects such as diabetes and cardiovascular morbidity.…”

Bifurcation analysis on a hybrid systems model of intermittent hormonal therapy for prostate cancer

“…The main concern of these studies is to understand the mechanism of treatment-resistant tumor growth, or a cancer relapse, after a remission period induced by hormone deprivation therapy. A possible strategy to delay or prevent the progression to hormone-resistance caused by prolonged hormone suppression is to incorporate treatment interruption, which is known as intermittent hormonal therapy repeating cycles of on-treatment and off-treatment periods [8][9][10][11][12][13][14][15]. In this paper, we deal with nonlinear dynamics and bifurcations in a mathematical model of intermittent hormonal therapy for prostate cancer.…”

“…Many efforts have been made to understand the properties of androgen receptors and signal-transduction pathways leading to a hormone-refractory prostate cancer [20][21][22][23]. Intermittent androgen suppression (IAS) is an alternative approach to maintain tumor sensitivity to androgen deprivation with the possibility to prolong a relapse [8][9][10][11][12][13][14][15]. Although clinical trials are still in progress for establishing the clinical efficacy of IAS therapy [11,14,15], it has already been confirmed that side effects and economic costs are at least reduced in comparison with continued androgen suppression.…”

“…Intermittent androgen suppression (IAS) is an alternative approach to maintain tumor sensitivity to androgen deprivation with the possibility to prolong a relapse [8][9][10][11][12][13][14][15]. Although clinical trials are still in progress for establishing the clinical efficacy of IAS therapy [11,14,15], it has already been confirmed that side effects and economic costs are at least reduced in comparison with continued androgen suppression. Following these advances in experimental and clinical studies of IAS, a mathematical model of IAS therapy for prostate cancer was presented [24][25][26].…”