Treating Advanced, Metastatic, Hormone-Resistant Prostate Cancer

Advanced or Metastatic Prostate Cancer

In advanced prostate cancer limited to local spread, androgen-deprivation therapy (ADT) in combination with radiation therapy are the standard measures. ADT offers a 10-year survival in 80% of men with microscopic lymph node spread. This therapy is also used for low, intermediate and high-risk prostate cancer and is discussed further under Prostate Cancer Treatments and Prostate Cancer Treatment Options.

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ADT is the mainstay of treatment in the newly diagnosed metastatic prostate cancer patients. It can result in symptomatic improvement and disease regression in the majority of patients. The method adopted to produce androgen deprivation can vary between various centers. It can be achieved by surgical removal of testes (orchiectomy),  medically with luteinizing hormone releasing hormone LHRH agonists, or use of anti-androgens.

LHRH agonists can temporarily increase testosterone levels in early days of therapy and cause an initial worsening of signs and symptoms. Usually an anti-androgen is also given in the first few days of LHRH therapy to prevent tumor exacerbation. The LHRH treatment can produce medical castration within 4 weeks. Most patients prefer sustained release LHRH-based treatments over the surgical approach. The high-risk localized, lymph node positive or recurrent prostate cancers remain sensitive to hormones for 5 to 10 years. The duration for which metastatic cancers remain hormone sensitive is usually short and lasts for about 2 years.

In some patients anti-androgens, like flutamide, are used alone or in combination with a 5-alpha reductase inhibitor, like finasteride. A close monitoring of PSA levels (refer to Prostate Cancer Diagnosis) after commencing with hormone therapy identify the patients at high risk for hormone-refractory prostate cancer.

Hormone-Resistant Prostate Cancer

Hormone-resistant prostate cancer (HRPC) is also called castration-resistant prostate cancer (CRPC) or androgen-independent prostate cancer (AIPC). Most patients with HRPC develop metastases to the bone which are detected on scans. The bone lesions are mostly osteoblastic (bone forming) lesions rather than osteolytic lesions. Bone lesions can be found in more than 80% of the HRPC patients and lymph node spread is found in 20 to 40% of HRPC patients.

The earliest indication of resistance to ADT is rising levels of PSA despite testosterone being in the range of castration levels (50 ng/dL or less). The patients are followed up with serial PSA levels. PSA decline and alkaline phosphatase levels are commonly used to assess response to treatment.

Patients having disease progression despite being on LHRH agonists and with castration level testosteron should continue with LHRH agonist treatment and additional secondary hormonal manipulation or chemotherapy should be considered. Secondary hormonal manipulation includes withdrawal of anti-androgen treatment (if present), suppression of adrenocortical secretions, glucocorticoids, or estrogens. In patients with bone metastases, bisphosphonates or radioisotopes concentrating in bone lesions may be useful in decreasing the rates of bone related events.

Patients on treatment with anti-androgens who developing HRPC should be evaluated for anti-androgen withdrawal response. Withdrawal responses for drugs like diethylstilbestrol, estramustine, megesterol and so on can also be evaluated in addition to androgen receptor blockers. If withdrawal responses are to develop, it usually takes 3-4 weeks (6-8 weeks for bicalutamide) after discontinuation of the medication. If no satisfactory response, additional treatments measures can be undertaken.

  • Glucocorticoids have been shown to improve symptoms are produce PSA responses in HRPC patients. Prednisone or dexamethasone is commonly used for this.
  • Estrogens have known palliative effects in HRPC patients, but its extensive use is limited by the high risk for thromboembolism. Diethylstilbesterol or premarin is now used only for palliative purposes. Estramustine which has estrogenic actions is also useful in HRPC for the same reasons.
  • Drugs that suppress the adrenal steroid synthesis like ketoconazole can also be used in HRPC patients. Ketoconazole is often combined with low doses of glucocorticoids as the drug also reduces glucocorticoid levels. Ketoconazole is known to cause several drug interactions and hence the drug is used with caution with other drugs known to be involved in drug interactions.
  • Zoledronate is the only bisphosphonate that is approved by FDA for HRPC with bone metastases. The drug effectively reduces the fractures related to bone metastases.
  • Chemotherapy for non-metastatic HRPC is controversial. Chemotherapy regimens useful in metastatic HRPC are estramustine-docetaxel, docetaxel-prednisone or mitoxantrone-prednisone. Docetaxel based treatment is the only treatment that has shown improvement in the overall survival. Docetaxel-prednisone is now considered standard care for HRPC. Mitoxantrone has significant palliative effects as a single agent or in combination.

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