Hormone Therapy Plus Chemotherapy in Treating Patients With Prostate Cancer

A Phase III Randomized Study of Patients With High Risk, Hormone-Naive Prostate Cancer: Androgen Blockade With 4 Cycles of Immediate Chemotherapy Versus Androgen Blockade With Delayed Chemotherapy

RATIONALE: Androgens can stimulate the growth of prostate cancer cells. Drugs such as luteinizing hormone-releasing hormone agonist, flutamide, and bicalutamide may stop the adrenal glands from producing androgens. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Combining hormone therapy with chemotherapy may kill more tumor cells. It is not yet known whether chemotherapy given at the same time as hormone therapy is more effective than chemotherapy given after hormone therapy in treating prostate cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of chemotherapy given at the same time as hormone therapy with that of chemotherapy given after hormone therapy in treating patients who have prostate cancer.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: docetaxel; Drug: ketoconazole; Drug: doxorubicin hydrochloride; Drug: paclitaxel; Drug: vinblastine sulfate; Drug: flutamide; Drug: estramustine phosphate sodium; Drug: bicalutamide; Drug: releasing hormone agonist therapy

Detailed Description

OBJECTIVES:

Primary

• Compare the survival of patients with high-risk hormone-naive prostate cancer treated with androgen blockade with concurrent chemotherapy vs delayed chemotherapy.

Secondary

• Compare biochemical control in patients treated with these regimens.
• Determine the toxicity of these regimens in these patients.
• Compare the time to clinical failure, as measured by progression on bone scan or CT scan or a prostate-specific antigen (PSA) doubling time of ≤ 32 weeks, in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior therapy (surgery vs radiotherapy and/or brachytherapy vs both), original combined Gleason score (6 vs 7 vs 8-10), and prior vaccine therapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive androgen blockade (AB) comprising a luteinizing-hormone releasing-hormone agonist continuously and oral flutamide or oral bicalutamide once daily for at least 1 month. Within 4 weeks of initiation of AB, patients begin chemotherapy. Patients receive 1, and only 1, of the following chemotherapy regimens:

  • Regimen A: Patients receive oral estramustine 3 times daily on days 1-5 and docetaxel IV on day 3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
  • Regimen B: Patients receive oral estramustine 3 times daily on days 1-5 and paclitaxel IV on days 3, 10, 17, 24, 31, and 38. Treatment repeats every 56 days for 4 courses in the absence of disease progression or unacceptable toxicity.
  • Regimen C: Patients receive oral ketoconazole 3 times daily on days 1-7, 15-21, and 29-35; doxorubicin IV on days 1, 15, and 29; vinblastine IV on days 8, 22, and 36; and oral estramustine 3 times daily on days 8-14, 22-28, and 36-42. Treatment repeats every 56 days for 4 courses in the absence of disease progression or unacceptable toxicity.
  • Regimen D: Patients receive oral estramustine 3 times daily on days 1-4 and docetaxel IV over 1 hour on days 3, 10, and 17. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
  • Regimen E: Patients receive docetaxel IV on day 1. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
  • Regimen F: Patients receive docetaxel IV on days 1, 8, and 15. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
  • Regimen G: With approval from the protocol chair, patients may receive a regimen that has been demonstrated in a published phase II study to have at least a 50% response rate as measured by PSA decrease from baseline over 2 measurements 28 days apart or a decrease in measurable soft tissue disease by 50% in 2 dimensions.
• Arm II: Patients receive AB as in arm I. Patients continue with AB until clinical failure, at which time patients receive chemotherapy as in arm I. Patients who have a response may continue to receive chemotherapy beyond 4 courses.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 1,050 patients will be accrued for this study within 4-6 years.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
• Peru
  • Lima, Peru, 34
    • Instituto De Enfermedades Neoplasicas
• Puerto Rico
  • San Juan, Puerto Rico, 00936-7344
    • San Juan City Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Foundation for Cancer Research and Education
    • Tucson, Arizona, United States, 85723
      • Veterans Affairs Medical Center - Tucson
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Veterans Affairs Medical Center - Little Rock
  • California
    • Martinez, California, United States, 94553
      • Veterans Affairs Outpatient Clinic - Martinez
  • Colorado
    • Aurora, Colorado, United States, 80012-0000
      • Medical Center of Aurora - South Campus
    • Boulder, Colorado, United States, 80301-9019
      • Boulder Community Hospital
    • Colorado Springs, Colorado, United States, 80909
      • Memorial Hospital Cancer Center
    • Colorado Springs, Colorado, United States, 80933
      • Penrose Cancer Center at Penrose Hospital
    • Denver, Colorado, United States, 80210
      • Porter Adventist Hospital
    • Denver, Colorado, United States, 80218
      • Presbyterian - St. Luke's Medical Center
    • Denver, Colorado, United States, 80224
      • CCOP - Colorado Cancer Research Program, Incorporated
    • Denver, Colorado, United States, 80218-1191
      • St. Joseph Hospital
    • Denver, Colorado, United States, 80220
      • Rocky Mountain Cancer Centers - Denver Rose
    • Englewood, Colorado, United States, 80112
      • Swedish Medical Center
    • Lone Tree, Colorado, United States, 80124
      • Sky Ridge Medical Center
    • Longmont, Colorado, United States, 80501
      • Hope Cancer Care Center at Longmont United Hospital
    • Pueblo, Colorado, United States, 81004
      • St. Mary-Corwin Regional Medical Center
    • Thornton, Colorado, United States, 80221
      • Rocky Mountain Cancer Centers - Thornton
  • Florida
    • Gainesville, Florida, United States, 32610-0385
      • Shands Cancer Center at the University of Florida Health Science Center
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center
    • Panama City, Florida, United States, 32405-4587
      • Gulf Coast Cancer Treatment Center
    • Tallahassee, Florida, United States, 32308
      • Tallahassee Memorial Hospital
    • Tampa, Florida, United States, 33612
      • Veterans Affairs Medical Center - Tampa (Haley)
  • Idaho
    • Boise, Idaho, United States, 83706
      • Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center
  • Illinois
    • Hines, Illinois, United States, 60141
      • Veterans Affairs Medical Center - Hines
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • John Stoddard Cancer Center at Iowa Methodist Medical Center
    • Des Moines, Iowa, United States, 50314
      • Mercy Cancer Center at Mercy Medical Center - Des Moines
    • Des Moines, Iowa, United States, 50316-2301
      • John Stoddard Cancer Center at Iowa Lutheran Hospital
    • Dubuque, Iowa, United States, 52001
      • Wendt Regional Cancer Center at Finley Hospital
  • Kansas
    • Wichita, Kansas, United States, 67218
      • Veterans Affairs Medical Center - Wichita
  • Kentucky
    • Lexington, Kentucky, United States, 40502-2236
      • Veterans Affairs Medical Center - Lexington
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Veterans Affairs Medical Center - New Orleans
    • Shreveport, Louisiana, United States, 71101-4295
      • Veterans Affairs Medical Center - Shreveport
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0010
      • University of Michigan Comprehensive Cancer Center
    • Detroit, Michigan, United States, 48201-1932
      • Veterans Affairs Medical Center - Detroit
    • Kalamazoo, Michigan, United States, 49007
      • West Michigan Cancer Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • Veterans Affairs Medical Center - Jackson
  • Missouri
    • Springfield, Missouri, United States, 65807
      • Cancer Research for the Ozarks
  • Nebraska
    • Papillion, Nebraska, United States, 68128-4157
      • Midlands Cancer Center at Midlands Community Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87108-5138
      • Veterans Affairs Medical Center - Albuquerque
    • Albuquerque, New Mexico, United States, 87131
      • MBCCOP - University of New Mexico HSC
  • New York
    • New York, New York, United States, 10016
      • NYU School of Medicine's Kaplan Comprehensive Cancer Center
    • Rochester, New York, United States, 14621
      • Lipson Cancer and Blood Center at Rochester General Hospital
  • North Carolina
    • Goldsboro, North Carolina, United States, 27534-9479
      • CCOP - Southeast Cancer Control Consortium
  • Ohio
    • Akron, Ohio, United States, 44304
      • Akron City Hospital at Summa Health System
    • Akron, Ohio, United States, 44302
      • Akron General's McDowell Cancer Center
    • Cincinnati, Ohio, United States, 45220-2288
      • Veterans Affairs Medical Center - Cincinnati
    • Dayton, Ohio, United States, 45428-1002
      • Veterans Affairs Medical Center - Dayton
    • Salem, Ohio, United States, 44460
      • Cancer Care Center, Incorporated
    • Wooster, Ohio, United States, 44691
      • Cancer Treatment Center
  • Oregon
    • Portland, Oregon, United States, 97207
      • Veterans Affairs Medical Center - Portland
  • Pennsylvania
    • Darby, Pennsylvania, United States, 19023
      • Mercy Fitzgerald Hospital
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Scranton, Pennsylvania, United States, 18501
      • Mercy Hospital Cancer Center - Scranton
  • South Carolina
    • Charleston, South Carolina, United States, 29401-5799
      • Veterans Affairs Medical Center - Charleston
    • Greenville, South Carolina, United States, 29615
      • CCOP - Greenville
  • South Dakota
    • Rapid City, South Dakota, United States, 57709
      • Rapid City Regional Hospital
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • Erlanger Cancer Center
    • Memphis, Tennessee, United States, 38104
      • Veterans Affairs Medical Center - Memphis
    • Nashville, Tennessee, United States, 37232-5671
      • Vanderbilt-Ingram Cancer Center at Vanderbilt Medical Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • Veterans Affairs Medical Center - Amarillo
    • Galveston, Texas, United States, 77555-0209
      • University of Texas Medical Branch
    • San Antonio, Texas, United States, 78229
      • Veterans Affairs Medical Center - San Antonio (Murphy)
    • Temple, Texas, United States, 76504
      • Veterans Affairs Medical Center - Temple
  • Utah
    • Murray, Utah, United States, 84107
      • Cottonwood Hospital Medical Center
    • Ogden, Utah, United States, 84403
      • McKay-Dee Hospital Center
    • Provo, Utah, United States, 84604
      • Utah Valley Regional Medical Center - Provo
    • Saint George, Utah, United States, 84770
      • Dixie Regional Medical Center
    • Salt Lake City, Utah, United States, 84148
      • Veterans Affairs Medical Center - Salt Lake City
  • Washington
    • Seattle, Washington, United States, 98108
      • Veterans Affairs Medical Center - Seattle
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301
      • CCOP - St. Vincent Hospital Cancer Center, Green Bay
    • Marshfield, Wisconsin, United States, 54449
      • CCOP - Marshfield Clinic Research Foundation
    • Racine, Wisconsin, United States, 53405
      • All Saints Cancer Center at All Saints Healthcare

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

DISEASE CHARACTERISTICS:

• Diagnosis of adenocarcinoma of the prostate

  • Failed local treatments (surgery and/or radiotherapy and/or brachytherapy) as defined by a rising prostate-specific antigen level of at least 2.0 ng/mL (confirmed by 2 measurements at least 2 weeks apart) and a doubling time of 32 weeks or less
  • No clinical or radiographic evidence of disease
  • Original Gleason score of at least 7 OR Gleason score of 6 with capsular penetration or positive seminal vesicles or lymph nodes
• No metastases

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Zubrod 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Absolute granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 10 g/dL
• No history of bleeding disorders that would contraindicate warfarin, including clotting factor defects

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• AST/ALT no greater than 1.5 times upper limit of normal

Renal:

• Creatinine no greater than 1.5 mg/dL
• Blood Urea Nitrogen (BUN) no greater than 1.2 times normal

Cardiovascular:

• No symptomatic heart disease
• No history of myocardial infarction
• No history of thromboembolic events (e.g., deep vein thrombosis, symptomatic cerebrovascular events, or pulmonary embolism)

Other:

• No other major medical or psychiatric illness that would preclude study entry
• No other prior or concurrent invasive malignancy within the past 5 years except superficial skin cancer
• No history of esophageal varices
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 6 weeks since prior vaccine therapy

Chemotherapy:

• At least 5 years since prior chemotherapy

Endocrine therapy:

• Prior adjuvant or neoadjuvant hormonal therapy of less than 8 months duration allowed
• At least 1 year since prior androgen therapy

Radiotherapy:

• See Disease Characteristics
• At least 5 years since prior radiotherapy to sites other than prostate

Surgery:

• See Disease Characteristics

Other:

• Concurrent warfarin allowed
• Concurrent bisphosphonate therapy initiated prior to or after randomization allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Androgen blockade + immediate chemotherapy; Androgen blockade with immediate chemotherapy	Drug: docetaxel; Drug: ketoconazole; Drug: doxorubicin hydrochloride; Drug: paclitaxel; Drug: vinblastine sulfate; Drug: flutamide; Drug: estramustine phosphate sodium; Drug: bicalutamide; Drug: releasing hormone agonist therapy
Experimental: Androgen blockade + delayed chemotherapy; Androgen blockade with delayed chemotherapy	Drug: docetaxel; Drug: ketoconazole; Drug: doxorubicin hydrochloride; Drug: paclitaxel; Drug: vinblastine sulfate; Drug: flutamide; Drug: estramustine phosphate sodium; Drug: bicalutamide; Drug: releasing hormone agonist therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall Survival	From date of randomization to the date of death due to any cause

Secondary Outcome Measures

Outcome Measure	Time Frame
Biochemical control	From date of randomization to the date of first PSA failure defined as a PSA doubling time <= 32 weeks
Time to Clinical Failure	Time from study entry to positive scan or positive disease evaluation of the pelvis or chest or a PSA doubling time ≤ 32 weeks
Frequency of non-hematologic (>= grade 3), hematologic (grade >=4) and fatal (grade 5) toxicities	From the beginning of treatment to 90 days post treatment

Collaborators and Investigators

• Sponsor: Radiation Therapy Oncology Group
• Collaborators: National Cancer Institute (NCI); NRG Oncology; Eastern Cooperative Oncology Group; Southwest Oncology Group; Cancer and Leukemia Group B
• Investigators: Study Chair: Naomi S. Balzer-Haas, MD, Fox Chase Cancer Center; Study Chair: Arif Hussain, MD, University of Maryland Greenebaum Cancer Center; Study Chair: Gregory P. Swanson, MD, Deaconess Medical Center, Spokane, Washington; Study Chair: Kenneth J. Pienta, MD, FACP, University of Michigan Rogel Cancer Center

Publications and helpful links

General Publications

• Sandler HM, Pienta KJ. Rationale for the Radiation Therapy Oncology Group Study RTOG P-0014. Rev Urol. 2003;5 Suppl 2(Suppl 2):S28-34.

Study record dates

Study Major Dates

• Study Start: October 1, 2002
• Primary Completion (Actual): February 4, 2005
• Study Completion (Actual): February 4, 2005

Study Registration Dates

• First Submitted: February 14, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Actual): October 22, 2020
• Last Update Submitted That Met QC Criteria: October 21, 2020
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: stage III prostate cancer; stage IV prostate cancer; recurrent prostate cancer; adenocarcinoma of the prostate; stage IIB prostate cancer; stage IIA prostate cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antibiotics, Antineoplastic; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Androgen Antagonists; 14-alpha Demethylase Inhibitors; Docetaxel; Doxorubicin; Liposomal doxorubicin; Hormones; Bicalutamide; Ketoconazole; Estramustine; Vinblastine; Flutamide
• Other Study ID Numbers: RTOG-P-0014; CDR0000069186; ECOG-RTOG-P-0014; CALGB-RTOG-P-0014; SWOG-RTOG-P-0014