Discussion
Here we presented 4 heavily pretreated (including RRP, EBRT, metastasectomy, and Radium chloride) CRPC patients successfully treated with supra-physiological doses of T. Although it is widely accepted that T promotes prostate cancer growth, it was hypothesized that rapid cycling of T levels from high supra-physiological to castration levels result in clinical improvement. It has been shown that in a xenograft mice model androgen caused growth suppression of androgen-independent tumors. Furthermore, these tumors became androgen-sensitive by androgen stimulation and the growth of androgen-stimulated tumors could be restrained by androgen ablation(1). In mice experiments, it was also demonstrated that that low T levels stimulated and higher T levels inhibited PCa cell growth. Castrate T levels are not sufficient to support PCa cell growth(8). Androgen suppressed the growth of androgen-independent LNCaP subline by inducing cell cycle arrest(11).
Several clinical trials using BAT have been reported (3, 4). In phase II study enrolling asymptomatic mCRPC BAT was shown to be a safe therapy that resulted in responses in asymptomatic men with mCRPC and also resulted in re-sensitization to enzalutamide in most patients(10). In phase II study enrolling asymptomatic mCRPC patients, BAT showed clinical activity in mCRPC patients and was effective in resensitizing to ARAT (4). A randomized phase II study comparing BAT versus enzalutamide demonstrated clinical activity and safety of BAT and confirmed that BAT can sensitize CRPC to subsequent antiandrogen therapy (3).
Although precise molecular mechanisms driving responses to high doses of T are needed to be determined, the following possible mechanisms have been proposed. BAT led to a decrease in AR copy number and mutations presumably due to transcriptional repression of AR including AR variants. BAT also induced alterations in DNA repair genes (7). Ligand-driven activation of AR by supraphysiological doses of T may result in growth inhibition due to cell cycle arrest and apoptosis(5). These are most likely caused by DNA double-strand breaks, DNA dysfunction, and mitotic distress(5). Another proposed mechanism includes the disruption of AR-mediated DNA licensing(5). Thus, the mechanism of BAT-induced inhibition of PCa cell growth and death is multimodal.
The patients in this series had been heavily pretreated and had a poor prognosis. The first patient was re-challenged with bicalutamide which resulted in a drastic PSA decrease that lasts for more than 3 years. Enzalutamide and abiraterone re-challenge after T treatment have been reported. This is the first report of a successful bicalutamide re-challenge after T treatment. Also, this is the first report on T treatment in a CRPC patient with CRF on hemodialysis. The second patient progressed on docetaxel and cabazitaxel resulted in PSA stabilization only. A steeper decline in PSA was observed after T injections. The third patient is being successfully treated with gemcitabine and carboplatin after T injections, although he previously has failed to respond to estramustine, docetaxel, and cabazitaxel. In the fourth patient one-fifth fold decrease in PSA levels was observed.
The limitation of this case series report is a short duration of BAT in cases 2-4. Adverse events (AE) of T injections include musculoskeletal pain, impaired liver function, increased hemoglobin, hypertension, breast tenderness, nausea, pruritus, edema, urinary obstruction, myocardial infarction, pulmonary embolism. In our cases, no such AEs have occurred.