Maximal testosterone suppression in the management of recurrent and metastatic prostate cancer

Abstract

Introduction: Testosterone suppression, or androgen-deprivation therapy (ADT), is an established treatment for recurrent and metastatic prostate cancer (PCa). Based on the accuracy and sensitivity of early assays (c. 1960-1970), the castrate testosterone level was set at ≤1.7 nmol/l. Improved sensitivity of testosterone assays shows that both surgical and medical castration can achieve levels <0.7 nmol/l. However, the clinical implications and importance of maximum testosterone suppression remains a subject of controversy. This evidence-based review assesses prospective and retrospective clinical data, linking maximum suppression of testosterone with improved outcomes from ADT. Methods: PubMed and conference proceedings were searched for studies assessing the impact of low testosterone on clinical outcomes from ADT. The key search terms included combinations of prostate cancer and testosterone, predictive/prognostic, and androgen deprivation. Results were limited to studies investigating the relationship between testosterone levels and clinical outcomes. Results: Both prospective and retrospective data support a relationship between testosterone levels below the historical standard of 1.7 nmol/l and improved outcomes. Eight studies showed significant improvements in survival-related outcomes, with the majority of data supporting a testosterone level cutoff of ≤0.7 nmol/l. Conclusions: Tracking both testosterone and prostate-specific antigen (PSA) levels has significant clinical benefits, and the serum testosterone threshold of ≤0.7 nmol/l is a practical goal. The relative levels of testosterone and PSA may indicate continued hormone responsiveness or progression toward castration-resistant prostate cancer (CRPC) and should, therefore, inform treatment strategy. Standardization of assay methods and clinical coordination to facilitate widespread access to state-of the art laboratory equipment is necessary to ensure accurate decision-making.

Interleukin-6 and Lymphocyte Count Associated and Predicted the Progression of Frailty Syndrome in Prostate Cancer Patients Undergoing Antiandrogen Therapy

“…To date, no studies have evaluated if ADT in PCa patients associates with the progression of frailty syndrome over time, taking into account that ADT in PCa greatly reduce the levels of circulating testosterone sometimes achieving undetectable levels, in order to limit cancer relapses and disease progression [18][19][20] and could accelerate the progression of frailty syndrome. There is a consistent body of evidence that relate testosterone deficiency to systemic inflammatory responses e.g., both animal studies and human studies showed that testosterone deficiency is associated with an increase in pro-inflammatory cytokines and testosterone substitution reduced pro-inflammatory cytokines in patients with coronary artery disease, prostate cancer and diabetes mellitus through the decrease in pro-inflammatory cytokines (IL-1β, IL-6, and TNF-alpha) [21,22].…”

Discordance between testosterone measurement methods in castrated prostate cancer patients

“…Our findings are relevant to previous studies that have demonstrated that testosterone levels <0.7 nM correlate with a longer time to CRPC progression (4, 5). Patients with nadir testosterone levels during the first year of ADT ≤0.7 nM had a longer time to CRPC compared to those with levels either between 0.7 and 1.7 nM or >1.7 nM (10.0 vs 7.21 vs 3.62 years respectively; P = 0.015) (14, 24). In addition, testosterone breakthroughs above 1.1 and 1.7 nM have been found to be predictors of progression to CRPC when compared to patients without breakthrough (88 vs 137 months; P < 0.03) (5, 6, 7, 8).…”

“…The most important consequence would be to not recognize a patient as being CRPC rather than suboptimally castrated. Based on IA testosterone level determination, prostate-specific antigen (PSA) levels and metastatic status, it is now recommended to either change the ADT drug, or add bicalutamide, enzalutamide or abiraterone acetate (Canadian guidelines) (10, 24). Herein, we propose an updated clinical decision algorithm based on the one by Klotz et al .…”

Insulin resistance in prostate cancer patients and predisposing them to acute ischemic heart disease

“…In some instances, it has been reported that higher degree of testosterone somehow might be the causative agent in prostate malignancy, though the exact mechanism was speculative [40]. From our previous experiment, we reported that in the presence of testosterone (male androgen hormone), aggregation of platelets was higher compared with control, whereas only ADP-induced platelet aggregation is a normal phenomenon [41]; so, prostate cancer patients are prone to AIHD in such cases.…”