Download The Treatment of Advanced Prostate Cancer

Treatment of Advanced Prostate Cancer Gregory F. Byrd Prostate cancer is a confounding disease. It demonstrates a remarkable spectrum of behavior. Low risk cancer may be indolent and take 20 years to cause death. Advanced prostate cancer grows rapidly, causing local symptoms of urinary obstruction and hematuria, then distant symptoms from enlarging pelvic and retroperotoneal lymphadenopathy, painful bony metastases, and diffuse systemic metastatases. Patients with advanced disease typically suffer from difficult‐to‐relieve symptoms before succumbing to the disease. Prostate cancer remains the most common non‐skin cancer for men in this country and is persistently the second leading cause of cancer death. According to the CDC, the actual number of men diagnosed with prostate cancer was 206,640 and 28,088 men died from prostate cancer in 2009, the most recent reported year. With PSA screening, most men present with early stage disease. In fact only 4% of men present with distant disease. Prior to the PSA era, up to 30% of men presented with advanced disease. If PSA screening is abandoned, models predict that we will see more men presenting with advanced prostate cancer again. Men with early stage prostate cancer treated with prostatectomy or radiation generally achieve high cure rates. However, more than 10% of men eventually recur. When cancer relapses or presents with advanced stage disease, the treatment strategy is markedly different. Unfortunately, advanced prostate cancer is lethal. Discoveries over the past decade are now able to extend life expectancy. Prostate cancer growth is primarily regulated by androgens. Androgen deprivation therapy (ADT) can either induce apoptosis or cause arrest of the cell cycle at G1 phase. Therefore, ADT is the backbone of treatment for advanced prostate cancer. Tragically, prior to 2004, the most important discovery in the management of advanced prostate cancer was reported in 1941, when Huggins and Hodges described that orchiectomy prolonged life expectancy and decreased pain in metastatic prostate cancer. Currently, ADT is most commonly achieved by administering injections of luteinizing hormone releasing hormone (LHRH) agonists or antagonists, although surgical castration is another option. Regardless, ADT does not cure prostate cancer. It improves survival, decreases symptoms, and decreases the burden of disease, but this is only temporary. On average, men are on ADT for 18‐24 months before progressing to castrate resistant prostate cancer (CRPC). Once CRPC has developed, the average survival is 9‐22 months. Traditionally, the treatment of CRPC has consisted of continuing ADT and adding androgen receptor blockers, estrogens, or inhibition of adrenal androgen synthesis via ketaconazole, with most patients not responding to treatment. In the early 2000s, it was found that docetaxol based chemotherapy prolonged life by 3 months. However, not all patients can tolerate systemic chemotherapy. Sipuleucel‐T (Provenge) is a therapeutic cancer vaccine that was approved in 2010 for the treatment of metastatic minimally symptomatic CRPC. A patients own antigen presenting cells (APCs) are harvested via leukopheresis, incubated with prostatic acid phosphatase (PAP) , then infused intravenously. PAP is present in most prostate cancer cells. The vaccine stimulates the patient’s immune system against prostate cancer cells containing PAP. The IMPACT trial served as the basis of FDA approval and showed a 4.1 month survival advantage. This trial was analyzed on an intent‐to‐treat basis, with a cross over for patients in the placebo arm that had disease progression. If we consider the results for patients who never received the medication compared to those who received it initially, the survival advantage is 8‐9 months. The next two new treatments challenge our understanding of how CRPC develops. It has previously been thought that CRPC grew independent of androgens; however advanced prostate cancer cells can synthesis androgens themselves, overexpress androgen receptors (AR), and demonstrate altered androgen receptor signaling. Abiraterone acetate (Zytiga) is an oral medication that potently inhibits the steroidogenesis pathway by inhibiting CYP17‐hydroxylase and C17,20‐lyase, effectively reducing the production of sex hormones throughout the body. Zytiga was first approved in 2011 for CRPC that progressed after docetaxol based chemotherapy after showing a 4 month survival advantage. In January 2013 it was subsequently approved for use in metastatic HRPC prior to chemotherapy. It is also well tolerated, with the most common side effects of hypertension, hypokalemia, or edema in less than a third of patients. Enzalutamide (Xtandi) is potent second generation oral AR antagonist. It works on the AR through three distinct mechanisms: irreversible competitive binding to AR, inhibition of AR nuclear translocation, and AR interaction with nuclear DNA. It was approved for use in metastatic HRPC after chemotherapy in August 2012 after demonstrating a 5 month survival advantage (18 versus 13 months). Studies are maturing regarding its use prior to chemotherapy and will likely be approved in the near future. The multiple treatments approved for CRPC within the past 3 years are providing hope and extending quality and quantity of life in men who had few options. There are additional medications in the various phases of clinical trials. The outlook for advanced prostate cancer has never been more promising.