Hormone refractory prostate cancer

Indicated by increasing prostate specific antigen (PSA) levels despite androgen deprivation and castrate levels of testosterone(<50 ng/ml).

Also ref2241ed to as castration resistant prostate cancer.

Castrate resistant prostate cancer (CRPC) causes approximately 258,400 deaths annually, worldwide.

Castrate resistant prostate is almost always associated with increased PSA levels, suggesting the disease continues to be driven by androgen receptor signaling.

Mechanisms that are involved with the development of resistance to hormonal intervention focus on androgen receptor activity in addition to TMPRSS2/ERG fusion, PTEN,Nkx3.1, and EGR1.

A mutation in 3 beta-hydroxy steroid dehydrogenase-isoenzyme-1 (3BetaHSD1) results in a hyperactivated enzyme which converts precursor steroids to the most potent androgens, responsible for driving the disease in the setting of castration resistant prostate cancer.

Androgen receptor overexpression is sufficient to cause resistance to androgen deprivation and levels of intratumoral androgens are often increased in patients with progressive prostate cancer.

Dexamethasone is associated with a PSA response rate of approximately 50% and a median duration of response of approximately 12 months (Venkitaraman R et al).

Dexamethasone is superior to other corticosteroids in the setting of hormonally refractory prostate cancer.

Initial progression to hormone refractory state characterized by three consecutive rises in PSA, with the assays at least 2 weeks apart, resulting in two 50% increases over nadir or baseline.

The process by which prostate cancer cells become hormonally resistant is unclear and it is suggested that androgen ablation provides a selective advantage to androgen independent cells, which grow and repopulate the malignancy.

The prognosis for patients with castration sensitive prostate cancer is better than those with castration resistant prostate cancer with reduced survival times of the latter.

Survival for patients with castrate resistant prostate cancer is usually less than 3 years.

Fewer than 50% of patients with castrate resistant prostate cancer and bone metastasis are alive five years after diagnosis.

Death of patients with castrate resistant prostate cancer typically occurs within 24-48 months after the onset of hormonal resistance.

Even small successive PSA elevations as little as 0.1ng/ml are sufficient to suggest the presence of hormonally refractive prostate cancer.

Radiographic progression of disease rarely noted in the absence of PSA recurrence.

Majority of men that are started on androgen deprivation therapy do not have radiographic evidence of metastases, and when they reach the hormone refractory state most do not have evidence of metastases either.

Approximately 85 to 90% of patients with castrate resistant prostate cancer have evidence of bone metastases.

Increased levels of IL-6, chromogranin A, and VEGF.

In patients with nonmetastatic hormonally refractive prostate cancer the transition to metastases is determined by PSA doubling time and absolute PSA level, with a median bone metastasis-free survival of 30 months (Smith MR et al).

In a phase 3 study of patients with non metastatic castrate resistant prostate cancer the median time to progression to metastatic disease was approximately 22 months and the median overall survival for placebo treated patients was 46.1 months (Nelson JB et al). or

Median time to death when hormonally refractive prostate cancer is noted is 6 months for symptomatic patients and 18 months for those who are asymptomatic.

Androgen signaling, even at non-detectable androgen levels have an important role in the development of androgen deprivation therapy resistance.

An overexpression of the androgen receptor gene is found in hormone refractory disease.

The molecular mechanisms involved in androgen independence include: androgen receptor gene amplification, androgen receptor mutations that permit stimulation by weak androgens, androgen activation by autocrine products from tumor cells, altered coactivators, compressors, c-terminal splice variants, and acquired ability to synthesize or use androgen ice precursors: mechanisms indicate ongoing addiction to and dependence on androgen receptor for survival.

In castrate resistant prostate cancer up-regulation of androgen synthesis can lead to an increase in intratumoral androgen concentration, which can be levels measured in the bloodstream.

Overexpression of androgen receptors, and androgen-receptor mutations can lead to androgen-recepto binding by additional liglands that would not stimulate the wild type receptor.

Castrate resistant prostate cancer invariable fatal.

In locally recurrent hormone refractory disease intratumoral levels of testosterone and dihydrotestosterone can activate the androgen receptor.

Surgical and medical androgen deprivation abrogates gonadal testosterone production, but circulating testoserone of up to 10% of precastrate levels as a result of androgen production in the adrenal glands or the prostate cancer itself (Stanbrough M).

The duration of the course of metastatic hormonally refractive PC from the first documented metastasis until death may extend beyond 5 years.

TREATMENT

As of 2015 there are 5 life prolonging therapies for metastatic castration resistant prostate cancer:Abiratrone, enzalutamide, docetaxel,cabaztaxel and radium-223.

Most men with hormonally refractory prostate cancer should receive treatment with the above 5 agents, although the exact sequence and combinationsis not yet known.

Treatment strategies for patients with CRPC include secondary hormonal therapy with anti-androgens (nilutamide, flutamide, and bicalutamide), androgen suppressing agents (Ketocanazole, abiratone and estrogen), chemotherapy agents (docetaxel, mitoxanthone plus prednisone and estramustine), supportive measures such as bisphosphonates and erythropoietin.

Mitoxantrone plus prednisone is superior to prednisone alone for palliation of symptoms in CRPC, 29% versus 12% without a difference in overall survival (Tannock IF et al).

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