47Treatment of Metastatic Cancer: Hormonal Agents, Chemotherapy, Immune Modulation, and Radiopharmaceuticals
Management of metastatic prostate cancer involves the sequential or combined use of multiple kinds of therapies. The goals are prolonging survival with reasonable side effect morbidity, and maintenance or improvement of the patient’s quality of life. In this chapter, we focus on the effective disease-modifying therapies available. We mostly focus on adenocarcinoma histology, with brief mention of small cell cancer of the prostate.
CASTRATION SENSITIVE DISEASE
Androgen deprivation therapy (ADT), with the goal of lowering serum testosterone to castrate levels (<50 ng/dL), is the mainstay treatment for metastatic prostate cancer (1). For men whose only evidence of disease is an elevated PSA or for patients with asymptomatic low-volume metastases, the optimal timing of initiation of therapy is controversial, and will be discussed further in the controversies in management chapter. Although the duration of response to ADT is highly variable, initial objective tumor responses are around 80% to 90% with a median failure-free survival duration of 20 months and median overall survival (OS) of 42 months (2). There are several ways to prescribe ADT, and since they are considered equivalent in terms of effectiveness, choosing one of these 48therapies is primarily based on patient preference, cost, and treatment availability. The typical antiandrogenic side effects of ADT include (3):
• Hot flashes, decreased body hair, and sexual dysfunction.
• Loss of lean body mass, increased body fat, and decreased muscle strength.
• Decreased bone mineral density.
• Gynecomastia and breast tenderness.
• Cardiovascular disease and insulin resistance.
• Emotional changes and cognitive impairment, although some of these could be accounted for by comorbidities, cancer stage, and other diseases that occur with aging.
The most currently used ADT are described below:
• Surgical Orchiectomy (1,3): Relatively simple and cost-effective with a rapid decline in testosterone. Useful when rapid response is a priority or when costs and adherence to therapy are a concern. The psychological effect is an important factor in patient preference and it may be ameliorated with placement of testicular prostheses or by performing a subcapsular orchiectomy.
▪ Gonadotropin releasing hormone (GnRH) agonists (e.g., leuprolide, goserelin, triptorelin): They bind to the GnRH receptors in the pituitary and cause an initial release of luteinizing hormone (LH), causing an early increase in testosterone, followed 1 week later by downregulation of GnRH receptors and decline in LH. Castration levels are reached within 3 to 4 weeks. The initial increase in testosterone can cause a “tumor flare,” which might contribute to bone pain, urinary obstruction, or spinal cord compression. This can be prevented by bridging with antiandrogen therapy.
▪ GnRH antagonists (Degarelix): They do not cause the initial testosterone level increase that GnRH agonists do and can achieve suppression of testosterone level within 3 days. However, injections have to be done monthly and local injection site reactions are reported more frequently.
49• Chemohormonal therapy (1,2): Refers to the combination of ADT plus docetaxel. Traditionally docetaxel was reserved for the castration resistant setting. However, it might be beneficial in the castration sensitive patient. In the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation for Drug Efficacy (STAMPEDE) trial, 1,184 patients with castration sensitive metastatic or high-risk locally-advanced disease were randomized to ADT plus 6 cycles of docetaxel and 10 mg prednisone daily or ADT alone. 61% of patients had metastatic disease. Docetaxel showed an OS benefit of 77 versus 67 months (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.63–0.91), and the benefit was seen particularly in metastatic disease (65 vs. 43 months). In the Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) study, 790 patients with castration sensitive metastatic prostate cancer were randomized to 6 cycles of docetaxel and ADT or ADT alone. Chemohormonal therapy showed a benefit in median time to progression (20 vs. 12 months) and an OS benefit of 58 versus 44 months (HR 0.61, 95% CI 0.47–0.80). The benefit was particularly significant in the patients with high-volume disease (defined by visceral metastases and/or four or more bone metastases), with median survival of 49 versus 32 months (HR 0.61, 95% CI 0.52–0.72). Although there was a trend toward benefit, not enough events were seen in the low-volume disease group to reach a conclusion. An important limitation of this trial is that only 47% of patients in the ADT alone group received docetaxel at the time of castration resistance.
KEY POINTS FOR CASTRATION SENSITIVE METASTATIC PROSTATE CANCER
• The initial treatment for metastatic prostate cancer with low-volume disease (defined as no visceral metastases and <4 bone metastases) is ADT (Figure 8.1).
• Chemohormonal therapy combining ADT with docetaxel should be considered as initial treatment for high-volume disease.
Figure 8.1 Treatment options for metastatic prostate cancer.
ADT, androgen deprivation therapy; PSA, prostate-specific antigen.
51CASTRATION RESISTANT DISEASE
Eventually, prostate cancer progresses after administration of ADT, in spite of adequately depressed testosterone. This is labeled as castration resistant disease. Despite lack of randomized trial evidence, ADT is generally continued with subsequent therapies, due to the concern that discontinuation could result in a rise in testosterone and contribute to progression (3). Additional therapeutic options for castration resistant disease includes the following (see Figure 8.1):
• First-generation antiandrogens (e.g., bicalutamide, nilutamide, flutamide)