Clinical Conditions

Management of Advanced Prostate Cancer

For patients who have hormone-resistant prostate cancer growth, several options including investigational treatments are available. Most patients who are treated with hormone-resistant prostate cancer have symptomatic disease. This is true because there are no treatment options available with high effectiveness for cure of patients in this situation. Palliative therapy generally involves management of pain from bony metastases as well as diversionary treatment of obstructive uropathy either from local prostate cancer growth into the bladder base obstructing the ureters or retroperitoneal lymph node enlargement from metastatic disease.

Spinal cord compression

Spinal cord compression is a serious emergency for patients with advanced metastatic prostate cancer. For patients with evidence of spinal cord compression, immediate hormonal therapy should be instituted, preferably with ketoconazole 400 mg p.o. q.8 hours. Immediate orchiectomy is an alternative treatment. Patients who have previously received hormonal therapy should be treated with high dose steroids and subsequently receive neurosurgical consultation and consideration of emergent radiation therapy. Spinal cord compression may occur secondary to vertebral collapse from metastatic prostate cancer or epidural metastases. These can be effectively evaluated with MRI scans.

Palliative radiation therapy

Patients with isolated bony metastases that are symptomatic typically present with unrelenting, continuous localized pain. They may be effectively treated with localized radiation therapy of 3,000 cGy in 10 divided fractions (Porter et al., 1998). Patients should also be evaluated by an orthopedic surgeon. If a pathologic fracture has occurred in a weight-bearing region, surgical fixation is required for pain control and to allow healing. Post-operative irradiation may then be provided.

Systemic radionuclide therapy

For patients with extensive bony metastases that are symptomatic, systemic radionuclide therapy may be administered with good results. Strontium89 is quickly taken up in the mineral matrix of bone. The proportion of Strontium89 retained is directly related to the metastatic tumor burden and varies between 20 to 80 percent of the administered dose. Preferential accumulation occurs in and around metastatic bone deposits, where Strontium releases beta energy directly to the tumor. Elimination occurs through the kidneys, so careful disposal of urine is required for seven to 10 days after treatment. Patients who receive Strontium89 typically have myelosuppression with platelet counts decreasing 20 to 50 percent starting approximately three weeks after treatment. Strontium89 significantly delays the appearance of new, painful bony sites and also prolongs the time to the requirement of additional radiotherapy, compared to patients who received control treatments (Porter et al., 1993). Treatment may be repeated after three months. Buchali (1988) suggested a median survival advantage of more than eight months in patients who are treated with strontium89. Mertens et al. (1992) noted an eight month improvement in survival for patients treated with strontium89 in low dose cis-platin. However, a survival advantage for Strontium-treated patients has not been definitively demonstrated. Controlled trials are required to determine whether systemic radionuclide therapy provides any survival advantage over supportive care alone.

Medical management of hormone-refactory disease

Management of hormone refractory prostate cancer involves a difficult problem in management of the prostate cancer patient. Unfortunately, almost 40,000 men will die of prostate cancer per year, the second leading cause of cancer mortality in men in the United States. Previous trials for treatment of men with hormone refractory prostate cancer have been limited in their ability to demonstrate benefits.

Four steps may be considered in the management of hormone refractory prostate to decrease tumor growth. First, the maintenance of testicular androgen suppression should be confirmed. Castrate levels of testosterone should be reliably less than 50 ng/ml. Unfortunately, many patients who are on long-term GnRH-agonist therapy may have "acute on chronic" effects of GnRH agonist leading to biochemical flare of testosterone and PSA levels with recurrent treatment. If symptomatic disease is demonstrated in patients, or biochemical evidence of disease progression occurs related to repeat GnRH-depot treatments, then steps should be taken such as orchiectomy or shortening the interval of depot injections to confirm adequate androgen suppression. Secondly, antiandrogen therapy should be discontinued if it is in place. Antiandrogen withdrawal may result in clinical and PSA responses in up to 21 percent of men previously treated with the antiandrogens flutamide, bicalutamide, and megesterol acetate (Kelly and Scher, 1993). The phenomenon occurs within days of stopping flutamide, but may take up to six weeks after cessation of treatment with bicalutamide. The apparent agonist activity of flutamide has been suggested to occur as an activation of certain mutant androgen receptors present in prostate cancer cells (Fenton et al., 1997; Culig et al., 1997). Thirdly, second line hormonal therapy should be considered. For patients who have not previously received antiandrogens, antiandrogen therapy may be provided. Treatment of androgen-independent prostate cancer may respond to 150 to 200 mg of bicalutamide per day for about 25 percent of patients, after previously receiving flutamide therapy. Megesterol acetate has progestational activity that results in objective response rates of zero to nine percent and significant PSA declines in 12 to 14 percent of patients. Side effects may include thrombophlebitis and fluid retention. Adrenal androgen inhibitors such as aminoglutethamide or ketoconazole may also be applied in these patients with a low, partial response rate. Patients who are maintained on ketoconazole or aminoglutethamide should also receive hydrocortisone to prevent symptomatic systemic adrenal insufficiency. Estrogens and antiestrogens have also been applied to patients with hormone refractory prostate cancer. Up to three-quarters of patients treated with high-dose estrogen had effective pain relief, and approximately one-third had PSA declines of greater than 50 percent. This may be related to a direct mitotic arrest or cytotoxic effects on prostate cancer cells (Robertson et al., 1996).

An additional step is to consider chemotherapy for patients with hormone refractory prostate cancer. Unfortunately, even recent chemotherapy trials in hormone refractory prostate cancer have noted resulted in dramatic measurable responses for most patients. However, subjective responses can be noted. Apparently active agents can include estramustine, cyclophosphamide, etoposide, platinum, paclitaxel or adriamycin or vinblastine. The results of recent trials are summarized in Table (Oh and Kantoff, 1998). Adjunctive therapies with the use of systemic radiation have been previously discussed. In addition, investigational targets for therapy include growth-factor inhibitors, differentiation agents, cdk inhibitors, activators of apoptosis, antiangiogenesis agents, and immunotherapy including vaccines (Oh and Kantoff, 1998).

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The challenge of the future for treatment of prostate cancer will involve development and application of effective treatments for systemic disease. It is fortunate that prostate cancer is so hormonally sensitive in its growth pattern, as this allows effective palliation for advanced disease. Chemotherapy currently offers palliative benefits to a small subset of patients; however, multi-drug combinations may offer some potential for curative treatment. Despite the promise of local therapies in decreasing the death rate from prostate cancer, management of advanced hormone refractory prostate cancer will remain an important issue for treatment of patients with this genitourinary disease.