Docetaxel, Androgen Ablation, and External-Beam Radiation Therapy in Patients With High-Risk Localized Prostate Cancer

OBJECTIVES:

Primary

• Determine the dose-limiting toxicity and maximum tolerated dose of docetaxel when administered in combination with androgen ablation therapy and adaptive external-beam radiotherapy in patients with high-risk localized adenocarcinoma of the prostate.

Secondary

• Determine the 2-year biochemical progression-free survival of patients treated with this regimen.

OUTLINE: This is a multicenter, open-label, dose-escalation study of docetaxel.

• Androgen ablation therapy: Patients receive leuprolide acetate or other luteinizing hormone-releasing hormone agonist beginning 2-3 months prior to the start of chemoradiotherapy and continuing for up to 2 years.
• Chemoradiotherapy: Patients receive docetaxel IV over 1 hour on day 1 and high-dose external-beam radiotherapy on days 1-5. Treatment repeats every 7 days for 8 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of docetaxel until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

After completion of study treatment, patients are followed every 3 months.

Inclusion criteria

• Histologically confirmed adenocarcinoma of the prostate with any of following clinical features:

A) T3 or T4 B) T1-2 + Gleason Score 8-10 C) T1-2 + Gleason Score 7 + Prostate Specific Antigen (PSA) >10 ng/mL D) T1-2 + Any Gleason Score + PSA >20 ng/mL

• No evidence of metastatic disease on chest x-ray, bone scan or CT scan of abdomen/pelvis.
• Age > 18
• The Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
• Peripheral neuropathy: must be < grade 1
• Hematologic parameters A) Absolute neutrophil count > 1,500/mm3 B) Hemoglobin > 8.0 g/dL C) Platelet count > 100,000/mm3.
• Hepatic parameters / Renal function A) Total Bilirubin must be ≤ 1.2 mg/dL B) Transaminases (AST and ALT) must be < 1.5 x upper limit of normal (ULN) C) Alkaline phosphatase must be < 2.5 x ULN D) Creatinine < 1.5 x ULN ( < 2.1 mg/dL)
• No prior pelvic or prostate radiation or chemotherapy for prostate cancer. Androgen ablation therapy with one of the luteinizing hormone-releasing hormone (LH-RH) agonists prior to enrollment is acceptable as long as protocol treatment with radiotherapy and chemotherapy is started within 3 months of the initiation of androgen ablation.
• Patient must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter.

Exclusion criteria

• Documented metastases on staging studies
• Life expectancy <10 years secondary to co-morbid illness
• Myocardial infarction or significant change in anginal pattern within one year prior to study entry or current congestive heart failure (New York Heart Association Class 2 or higher)
• Patients with a history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80
• History of invasive malignancy within the last five years prior to study entry except for carcinoma in situ or nonmelanoma skin cancer.
• Psychiatric conditions which would prevent compliance with treatment or adequate informed consent.
• Patients receiving another investigational agent during chemo- and radiotherapy
• Uncontrolled intercurrent illness or other conditions that limit compliance with protocol treatment