2016 Management of Hormone Refractory Prostate Cancer

Abstract

SUMMARY P rostate cancer is a significant health concern for men worldwide. Adenocarcinoma of the prostate is currently the most frequent malignancy in men and is responsible for the second greatest number of cancer-related deaths after lung cancer. Prostate cancer is a major clinical problem, not only because of its high incidence and mortality, but also because of the severe morbidity associated with the advanced stages of this disease. The growth of prostate cancer is highly dependent on circulating androgens, in particular testosterone. During androgen-independent progression, prostate cancer cells depend on the androgen receptor as the primary mediator of growth and survival. Prostate cancer cells develop a. variety of cellular pathways to survive and flourish in an androgen-depleted environment. Postulated and documented mechanisms include androgen receptor (AR) gene amplification, AR gene mutations, involvement of ligand independent activation of the androgen receptor, and the Involvement of turner stem cells. The standard treatment for metastatic prostate cancer is hormone ablation, therapy either by surgical castration (orchiectomy) or medical Castration with lutenising hormone-releasing antagonists (LHRH) with or without anti-androgens. Androgen ablation therapy induces palliation of symptoms in many patients; however, over time the majority becomes refractory to hormone therapy with less than 50% alive at 5 years. Various groups have published practical recommendations that should be adhered to when defining HRPC. Some patients with progressive disease in the face of androgen ablation will still respond to secondary hormonal manipulations. Thus androgen-independent, but hormone-sensitive CaP, has to be differentiated from true HRPC from the outset. Whereas the first group still responds to secondary hormonal manipulations, such as antiandrogen Withdrawal, estrogens and corticosteroids, the latter is resistant to all hormonal measures. Patients with progressive prostate cancer despite a castrate testosterone-level (50ng/dl or less) have a distinct prognosis and set of therapeutic options. Prior to 1990, these patients typically presented with symptoms of pain or weight loss and multiple metastatic lesions. Today, in countries where PSA testing is readily available, virtually all CRPC patients are asymptomatic and manifest progression simply as a rising PSA. When assessing outcomes in CRPC, it is very important to differentiate patients with metastatic versus non metastatic disease. Two types of serum markers can be readily assessed in CRPC patients. The first category includes circulating markers directly derived from cancer cells such as PSA, prostatic acid phosphatase, and chromogranin A. In addition, markers can be derived from noncancerous tissues arid reflect the burden of the cancer on normal tissues (e.g., hemoglobin, alkaline phosphatase, acute phase reactants). Treatment options for HRPC remain unsatisfactory.