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.