238 CHAPTER 6 Urological neoplasia
Management of advanced prostate cancer: hormone therapy III
Monitoring treatment
Typically, patients with advanced prostate cancer will have baseline PSA, full blood count, renal and liver function tests, imaging (renal ultrasound or CT), and a bone scan. The PSA is repeated after 3 months, with long-term follow-up every 3–6 months along with periodic serum testosterone to assure castrate levels (< 50 ng/mL).
Liver function is checked every 3 months if antiandrogen monotherapy is used. Renal function should be checked on disease progression, and bone imaging used if clinically indicated.
While PSA is very useful as a marker for response and progression, 5–10% of patients can show clinical progression without PSA rise. This may occur in anaplastic tumors that fail to express PSA.
Advice on exercise, diet, and treatment of erectile dysfunction is often sought by patients during treatment.
Early versus delayed hormone therapy
Traditionally, hormone therapy was reserved for patients with symptomatic metastatic disease. Arguments against early hormone therapy revolve around its side effects and cost. However, studies of patients with locally advanced and metastatic disease have demonstrated slower disease progression and reduced morbidity when treated with androgen deprivation early (i.e., before the onset of symptoms).
Improved survival has also been reported in patients without bone metastases but including node-positive disease, when treated immediately.
Intermittent hormone therapy
The potential advantages of stopping hormone therapy when the disease has remitted, then restarting it when the PSA has risen again, are the reduced side effects and cost. Small series have suggested disease control equivalent to that with continuous hormonal ablation with reduced side effects.1 However, large randomized trials are lacking and none of the agents is FDA approved for intermittent use.
Regardless, this approach is becoming increasingly popular among clinicians and patients. It can take up to 6 months after stopping treatment for the serum testosterone to recover, hence side effects may persist into off-treatment periods.
Additional therapies
Androgen blockade can cause osteopenia/osteoporosis; bisphosphonate therapy can limit reductions in bone mineral density. Bisphosphonates inhibit osteoclast bone resorption. Patients should receive calcium (1200 mg/d) and vitamin D (800–1000 IU/day) supplements and be encouraged to exercise and stop smoking and drink in moderation.
1 HYPERLINK “/pubmed/19683858” Potential benefits of intermittent androgen suppression therapy in the treatment of prostate cancer: a systematic review of the literature.
Abrahamsson PA. Eur Urol. 2010 Jan;57(1):49–59. Epub 2009 Aug 7. Review
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With androgen ablation, consider bisphosphonates (e.g., zoledronic acid 4 mg IV yearly or alendronate 70 mg PO/week.) Adjust zoledronic acid on the basis of creatinine level.
Osteonecrosis of the jaw can result from any bisphosphonates, so patients should avoid major dental work while on this treatment.
In castration-resistant prostate cancer, zoledronic acid 4 mg (the most widely studied agent) adjusted to renal function every 3–4 weeks IV to prevent skeletal-related events (SREs). SREs are defined as pathological fracture, spinal compression/vertebral body collapse, radiation or surgery to bone, or change in antineoplastic therapy.
240 CHAPTER 6 Urological neoplasia
Management of advanced prostate cancer: androgen-independent/ castration-resistant disease
Second-line hormone therapy
When the PSA rises from its lowest (nadir) value, or if symptomatic progression occurs despite a favorable biochemical response to first-line hormone therapy, the disease has entered its androgen-independent phase. It is essential to verify that the current androgen ablation regimen is resulting in castrate levels of testosterone (<50 ng/dL), as there are some cases of LHRH analogue therapy that do not develop an adequate response to the ablation therapy.
If the patient is confirmed to be in the castrate testosterone range, further treatment is usually considered. If there is relapse during androgen ablation, up to 25% of patients respond by adding an antiandrogen (e.g., bicalutamide 50 mg daily) to establish maximal androgen blockade (MAB). The addition of an antiandrogen will result in PSA declines of 50% in 15–54% of patients (median duration 4–6 months).
If MAB was used from initiation of hormone therapy, withdrawal of the antiandrogen paradoxically elicits a favorable PSA response in 5–25% of patients; unfortunately this “anti-androgen withdrawal phenomenon” is rarely durable.
A further rise in PSA may require other hormonal manipulations such as the use of ketoconazole or the addition of estrogens. No secondary hormonal manipulation has been shown to extend survival in any trial.
The prognostic factors for survival with androgen-independent disease are identical to the factors predicting response to hormone therapy (see p. 233), plus time from initiation of hormone therapy to initiation of chemotherapy and visceral metastasis status.
Cytotoxic chemotherapy
Systemic chemotherapy is offered to appropriate patients with androgenindependent metastatic disease and disease progression. LHRH agonists are continued during therapy to prevent escape from androgen blockade.
Currently FDA-approved agents include docetaxel, mitoxantrone, and estramustine. Estramustine has limited utility due to cardiovascular and thromboembolic toxicity. Mitoxantrone at a dose of 12 mg/m2 with prednisone 5 mg PO bid every 3 weeks palliates bone pain in 30%. Improved survival was not seen when mitoxantrone with prednisone was compared to prednisone alone.
Two major trials (TAX 327/SWOG 99–16) showed that docetaxel 60–70 mg/m2 every 3 weeks with estramustine 280 mg PO tid for 5 days or docetaxel 75 mg/m2 every 3 weeks with prednisone had a 20–24 % improvement in survival compared to mitoxantrone 12–14 mg/m2 and prednisone. Palliation of bone pain was superior in those treated with docetaxel compared with those treated with mitoxantrone (TAX 327 study). Many consider docetaxel to be the current standard of care in this setting.
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Clinical trials are under way to evaluate docetaxel combined with other agents (e.g., targeting angiogenesis [bevacizumab], and bone-targeted agents [atrasentan].) There is no standard therapy for patients who fail docetaxel; mitoxantrone in this setting has PSA decline rates of 50%, in 10%–20% of men treated.
Clinical trials are evaluating novel immunotherapeutic, cytotoxic, and antiangiogenic agents. In men with prostate cancer exhibiting neuroendocrine features, androgen blockade should be initiated along with immediate chemotherapy using cisplatin/etoposide or carboplatin/etoposide or a docetaxel-based regimen.
Newer agents for castration-resistant prostate caner
Abiraterone acetate is an inhibitor of the enzyme CYP17 that is critical to the generation of androgens and estrogens. It is 10 times more potent than ketoconazole in this activity and has shown promise in castrationresistant prostate cancer (CRPC).
ZD4054 is an endothelin receptor antagonist that appears to extend survival in men with CRPC and is in phase III trials. A variety of agents in late-stage clinical testing rely on immune modulation of the prostate cancer cell. Sipuleucel-T (Provenge, Dendreon Seattle, WA) was approved by the FDA in 2010. A patient’s own ex vivo processed dendritic cells expressing a key tumor antigen (prostate acid phosphatase), are reinfused for 3 cycles. In patients with minimally symptomatic, castrate resistant metastatic prostate a statistically significant survival extension of at least 4 months at an overall survival of about 20 months has been shown1.
1 Bot, Adrian (2010) The Landmark Approval of Provenge®, What It Means to Immunology and “In This Issue”: The Complex Relation Between Vaccines and Autoimmunity International Reviews of Immunology Vol. 29, No. 3, 235–238.