Ask the Experts - Therapy for Hormone-Refractory Prostate Cancer?
Ask the Experts - Therapy for Hormone-Refractory Prostate Cancer?
In a 67-year-old patient with bone spread of prostate cancer who is treated with a luteinizing hormone-releasing hormone (LHRH) agonist but then develops resistance, which are the possible forms of therapy? In particular, which chemotherapy protocols, if any, should be considered?
David Young, MD, FRCP
The first step in such patients is to exhaust all hormonal options. This approach includes checking serum testosterone levels to ensure that the patient's testosterone level is below 50 ng/dL. If the testosterone level is elevated and the patient is on an LHRH agonist, an orchiectomy is appropriate. Secondary hormonal manipulations, particularly ketoconazole and hydrocortisone, can yield a prostate serum antigen (PSA) response in up to 62% of the patients. Unfortunately, the median duration of secondary hormonal manipulations is short, usually 4-6 months.
Right now, there is no standard chemotherapeutic treatment for hormone-refractory prostate cancer that has been proven to prolong survival in phase III studies. The standard of care is considered by many to be mitoxantrone and a corticosteroid, which in 2 randomly assigned trials have demonstrated a palliative benefit but not a survival benefit when compared with steroids alone.
A Canadian group led by Ian Tannock randomly assigned 161 men with hormone-refractory prostate cancer to receive either prednisone 10 mg PO daily, or mitoxantrone 12 mg/m every 3 weeks combined with prednisone. A significant improvement in palliation of bone pain (29% vs 10%, P = 0.011) was observed in patients who received the combination, when compared with those who received prednisone as a single agent. The duration of this pain response in patients treated with the combination was also significantly longer (43 weeks vs 18 weeks, P < .0001). The objective response rate was not reported.
A Cancer and Leukemia Group B (CALGB) study compared the combination of hydrocortisone 40 mg plus mitoxantrone 14 mg/m every 3 weeks with hydrocortisone alone. No difference in survival was seen between the 2 arms, with patients surviving a median of 12.6 and 12.3 months for hydrocortisone and the combination of mitoxantrone and hydrocortisone, respectively. Of note, a similar median survival was reported in the Tannock study. Only 7% of patients treated with mitoxantrone and hydrocortisone manifested an objective response.
Estramustine, an estrogen linked to a nor-nitrogen mustard, is approved by the FDA for the treatment of hormone-refractory prostate cancer. The combination of estramustine with vinblastine or oral etoposide is commonly used in clinical practice. PSA declines 50% or more in 45% and 52% of patients, and objective responses in 26% and 33% of patients have been observed when estramustine is combined with vinblastine or etoposide, respectively.
A recent study randomly assigned 201 patients to receive either the combination of estramustine 600 mg/m PO plus vinblastine 4 mg/m IV once a week for 6 weeks or vinblastine 4 mg/m IV as a single agent for 6 weeks. Treatment in each arm was repeated after a 2-week break. The results demonstrated a trend toward improved survival in the estramustine/vinblastine arm (11.9 months vs 9.2 months for vinblastine alone) and a small, yet statistically significant, improvement in time to progression for the combination-therapy arm. Unfortunately, this trial was powered to detect a 6-month survival difference, and thus, smaller improvements may have been missed.
Taxane-based therapy seems to hold considerable promise for the treatment of this disease, when administered either as a single agent or in combination with estramustine. Hudes evaluated the combination of estramustine 120 mg/m plus paclitaxel by continuous infusion over 96 hours in 33 evaluable patients with hormone-refractory prostate cancer and found that 52% of the patients treated had a greater than 50% PSA decline. Objective responses were observed in 44% of patients with measurable soft-tissue lesions. The median survival reported in this study was 17 months.
In a phase I study, Petrylak and colleagues combined estramustine 280 mg 3 times a day for the first 5 days with docetaxel 40 mg/m to 80 mg/m on day 2 every 21 days in 34 men with hormone-refractory prostate cancer. Overall, 62% of patients treated with docetaxel had a PSA decline of 50% or more; objective responses were observed in 28% of patients. Of 15 patients with symptomatic bone pain requiring narcotic analgesia, 53% discontinued all pain medications for a median of 6 weeks. The median survival reported was approximately 23 months.
The Southwest Oncology Group has an active trial comparing the combination of docetaxel 60 mg/m every 3 weeks plus estramustine 280 mg 3 times daily on days 1 to 5 with mitoxantrone 12 mg/m every 3 weeks plus prednisone 5 mg twice daily. This trial is powered to detect a 3-month survival difference and will accrue 620 patients over the next 3 years.
In a 67-year-old patient with bone spread of prostate cancer who is treated with a luteinizing hormone-releasing hormone (LHRH) agonist but then develops resistance, which are the possible forms of therapy? In particular, which chemotherapy protocols, if any, should be considered?
David Young, MD, FRCP
The first step in such patients is to exhaust all hormonal options. This approach includes checking serum testosterone levels to ensure that the patient's testosterone level is below 50 ng/dL. If the testosterone level is elevated and the patient is on an LHRH agonist, an orchiectomy is appropriate. Secondary hormonal manipulations, particularly ketoconazole and hydrocortisone, can yield a prostate serum antigen (PSA) response in up to 62% of the patients. Unfortunately, the median duration of secondary hormonal manipulations is short, usually 4-6 months.
Right now, there is no standard chemotherapeutic treatment for hormone-refractory prostate cancer that has been proven to prolong survival in phase III studies. The standard of care is considered by many to be mitoxantrone and a corticosteroid, which in 2 randomly assigned trials have demonstrated a palliative benefit but not a survival benefit when compared with steroids alone.
A Canadian group led by Ian Tannock randomly assigned 161 men with hormone-refractory prostate cancer to receive either prednisone 10 mg PO daily, or mitoxantrone 12 mg/m every 3 weeks combined with prednisone. A significant improvement in palliation of bone pain (29% vs 10%, P = 0.011) was observed in patients who received the combination, when compared with those who received prednisone as a single agent. The duration of this pain response in patients treated with the combination was also significantly longer (43 weeks vs 18 weeks, P < .0001). The objective response rate was not reported.
A Cancer and Leukemia Group B (CALGB) study compared the combination of hydrocortisone 40 mg plus mitoxantrone 14 mg/m every 3 weeks with hydrocortisone alone. No difference in survival was seen between the 2 arms, with patients surviving a median of 12.6 and 12.3 months for hydrocortisone and the combination of mitoxantrone and hydrocortisone, respectively. Of note, a similar median survival was reported in the Tannock study. Only 7% of patients treated with mitoxantrone and hydrocortisone manifested an objective response.
Estramustine, an estrogen linked to a nor-nitrogen mustard, is approved by the FDA for the treatment of hormone-refractory prostate cancer. The combination of estramustine with vinblastine or oral etoposide is commonly used in clinical practice. PSA declines 50% or more in 45% and 52% of patients, and objective responses in 26% and 33% of patients have been observed when estramustine is combined with vinblastine or etoposide, respectively.
A recent study randomly assigned 201 patients to receive either the combination of estramustine 600 mg/m PO plus vinblastine 4 mg/m IV once a week for 6 weeks or vinblastine 4 mg/m IV as a single agent for 6 weeks. Treatment in each arm was repeated after a 2-week break. The results demonstrated a trend toward improved survival in the estramustine/vinblastine arm (11.9 months vs 9.2 months for vinblastine alone) and a small, yet statistically significant, improvement in time to progression for the combination-therapy arm. Unfortunately, this trial was powered to detect a 6-month survival difference, and thus, smaller improvements may have been missed.
Taxane-based therapy seems to hold considerable promise for the treatment of this disease, when administered either as a single agent or in combination with estramustine. Hudes evaluated the combination of estramustine 120 mg/m plus paclitaxel by continuous infusion over 96 hours in 33 evaluable patients with hormone-refractory prostate cancer and found that 52% of the patients treated had a greater than 50% PSA decline. Objective responses were observed in 44% of patients with measurable soft-tissue lesions. The median survival reported in this study was 17 months.
In a phase I study, Petrylak and colleagues combined estramustine 280 mg 3 times a day for the first 5 days with docetaxel 40 mg/m to 80 mg/m on day 2 every 21 days in 34 men with hormone-refractory prostate cancer. Overall, 62% of patients treated with docetaxel had a PSA decline of 50% or more; objective responses were observed in 28% of patients. Of 15 patients with symptomatic bone pain requiring narcotic analgesia, 53% discontinued all pain medications for a median of 6 weeks. The median survival reported was approximately 23 months.
The Southwest Oncology Group has an active trial comparing the combination of docetaxel 60 mg/m every 3 weeks plus estramustine 280 mg 3 times daily on days 1 to 5 with mitoxantrone 12 mg/m every 3 weeks plus prednisone 5 mg twice daily. This trial is powered to detect a 3-month survival difference and will accrue 620 patients over the next 3 years.
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