Hormone Ablation Therapy, Doxorubicin, and Zoledronate With or Without Strontium 89 in Treating Patients With Androgen-Dependent Prostate Cancer and Bone Metastases

RATIONALE: Androgens can stimulate the growth of prostate cancer cells. Drugs such as goserelin and leuprolide may fight prostate cancer by stopping the adrenal glands from producing androgens. Drugs used in chemotherapy such as doxorubicin work in different ways to stop tumor cells from dividing so they stop growing or die. Zoledronate may prevent bone loss and stop the growth of tumor cells in bone. Radioactive substances such as strontium-89 may relieve bone pain associated with prostate cancer. It is not yet known whether hormone (androgen) ablation therapy and chemotherapy combined with zoledronate is more effective with or without strontium-89 in treating prostate cancer and bone metastases.

PURPOSE: This randomized phase II trial is studying giving hormone ablation therapy, doxorubicin, and zoledronate together with strontium-89 to see how well it works compared to hormone ablation therapy, doxorubicin, and zoledronate alone in treating patients with androgen-dependent prostate cancer and bone metastases.

OBJECTIVES:

Primary

• Compare the clinical efficacy of hormonal ablative therapy combined with doxorubicin and zoledronate with or without strontium chloride Sr 89, in terms of progression-free survival, in patients with androgen-dependent prostate cancer and bone metastases.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to the number of bony metastases (≤ 6 versus > 6). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive hormonal ablative therapy comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy. Patients also receive doxorubicin intravenously (IV) on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses; and a single dose of strontium chloride Sr 89 IV over 1-2 minutes on day 1.
• Arm II: Patients receive hormonal ablative therapy, doxorubicin, and zoledronate as in arm I.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 80 patients (40 per treatment arm) will be accrued for this study within 20 months.

• Metastatic Cancer
• Prostate Cancer

• Drug: Doxorubicin hydrochloride
  Doxorubicin 20 mg/m^2 is administered intravenously either over 15 to 30 minutes via a peripheral line or over 24 hours via a central line on days 1, 8, and 15 every 28 days for 2 cycles.
  Other Names:

  • Adriamycin PFS
  • Adriamycin RDF
  • Adriamycin
  • Rubex
• Drug: Goserelin acetate
  Other Name: Zoladex
• Drug: Leuprolide acetate
  Other Name: Lupron Depot
• Drug: Zoledronic acid
  4 mg given intravenously over 15 minutes every 28 days for a total of 6 doses.
  Other Names:

  • Zoledronate
  • Zometa
• Procedure: orchiectomy
• Radiation: strontium chloride Sr
  1 dose of strontium-89 (4 millicurie (mCi) total dose) administered intravenously on the first day of treatment
  Other Names:

  • Sr-89
  • Strontium-89
  • Mestastron

• Experimental: HAT, Doxorubicin, Zoledronate + Strontium chloride
  Arm I: Hormonal ablative therapy (HAT) comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses; and a single dose of strontium chloride Sr 89 IV over 1-2 minutes on day 1.
  Interventions:

  • Drug: Doxorubicin hydrochloride
  • Drug: Goserelin acetate
  • Drug: Leuprolide acetate
  • Drug: Zoledronic acid
  • Procedure: orchiectomy
  • Radiation: strontium chloride Sr
• Experimental: HAT, Doxorubicin + Zoledronate
  Arm II: HAT, doxorubicin, and zoledronate as in arm I. HAT comprising luteinizing hormone-releasing hormone agonist (e.g., leuprolide or goserelin) continuously during study treatment OR bilateral orchiectomy; doxorubicin IV on days 1, 8, and 15 every 28 days for 2 courses; zoledronate IV over 15 minutes on day 1 every 28 days for 6 courses.
  Interventions:

  • Drug: Doxorubicin hydrochloride
  • Drug: Goserelin acetate
  • Drug: Leuprolide acetate
  • Drug: Zoledronic acid
  • Procedure: orchiectomy

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed prostate cancer

  • Osteoblastic metastases on bone scan or computed tomography (CT) scan

• Androgen-dependent disease

  • Previously treated with neoadjuvant or intermittent hormonal ablative therapy* at least 3 years ago AND has reinitiated hormonal ablative therapy within 3 months before study entry NOTE: *Therapy was less than 3 years in duration
• No symptomatic bulky lymphadenopathy causing scrotal or pedal edema
• No significant local invasive disease with bladder invasion
• No evidence or suspicion of myelodysplastic syndromes by complete blood count and bone marrow biopsy
• No small cell carcinoma, purely lytic bone metastasis, or bulky (i.e., ≥ 5 cm) visceral or nodal disease in the absence of bone involvement by biopsy
• No known brain metastases

PATIENT CHARACTERISTICS:

Age

• Not specified

Performance status

• Eastern Cooperative Oncology Group (ECOG) 0-3 OR
• Karnofsky 40-100%

Life expectancy

• More than 3 months

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• White Blood Count (WBC) ≥ 3,000/mm^3

Hepatic

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal
• Bilirubin normal

Renal

• Creatinine ≤ 3.0 mg/dL
• Calcium level ≥ 8 mg/dL

Cardiovascular

• Left Ventricular Ejection Fraction (LVEF) ≥ 45%
• No history of congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other

• Fertile patients must use effective contraception
• No prior allergic reaction attributed to compounds of similar chemical or biological composition to zoledronate or other study drugs
• No other malignancy within the past 5 years except nonmelanoma skin cancer
• No active or ongoing infection
• No psychiatric illness or social situation that would preclude study compliance
• No untreated symptomatic spinal cord compressions
• No other concurrent uncontrolled illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Prior doxorubicin allowed provided the cumulative dosage was ≤ 250 mg/m^2
• No more than 1 prior chemotherapy regimen

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• No prior strontium chloride Sr 89 or samarium Sm 153 lexidronam pentasodium

Surgery

• Not specified

Other

• Prior zoledronate allowed provided treatment was no more than 3 months in duration
• Other prior bisphosphonates allowed
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No other concurrent anticancer therapy