Hormone Therapy Plus Radiation Therapy With or Without Combination Chemotherapy in Treating Patients With Prostate Cancer

A Phase III Protocol of Androgen Suppression (AS) and Radiation Therapy (RT) vs AS and RT Followed by Chemotherapy With Paclitaxel, Estramustine, and Etoposide (TEE) for Localized, High-Risk, Prostate Cancer

RATIONALE: Hormones can stimulate the production of prostate cancer cells. Hormone therapy may fight prostate cancer by reducing the production of androgens. Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether hormone therapy plus radiation therapy is more effective with or without combination chemotherapy for prostate cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of hormone therapy plus radiation therapy with or without combination chemotherapy in treating patients who have prostate cancer.

Study Overview

• Status: Completed
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: bicalutamide; Drug: flutamide; Drug: Luteinizing hormone releasing hormone [LHRH] agonist; Radiation: Radiation therapy; Drug: estramustine phosphate sodium; Drug: etoposide; Drug: paclitaxel; Drug: warfarin

Detailed Description

OBJECTIVES:

• Compare the efficacy of androgen suppression and radiotherapy with or without subsequent paclitaxel, estramustine, and etoposide, in terms of overall and disease-free survival, biochemical and local control, and freedom from distant metastasis, in patients with localized high-risk prostate cancer.
• Compare the toxic effects of these regimens in these patients.

OUTLINE: This is a randomized study. Patients are stratified according to prostate-specific antigen level (≤ 10 ng/mL vs 11-100 ng/mL), tumor stage (T1-2 vs T3-4), Gleason score (7 vs 8-10), and prior hormone use (yes vs no). Patients are randomized to one of two treatment arms.

All patients receive androgen suppression comprising a luteinizing hormone-releasing hormone (LHRH) agonist AND bicalutamide OR flutamide for 4 months. Beginning 8 weeks after the initiation of androgen suppression, all patients undergo radiotherapy once daily, 5 days a week, for 7-8 weeks. Patients who received prior androgen suppression therapy count time to radiotherapy from start date of prior hormonal therapy.

• Arm I: Patients continue androgen suppression therapy (LHRH agonist only) for approximately 20 more months after radiotherapy is completed.
• Arm II: Patients continue therapy as in arm I and receive chemotherapy beginning 28 days after completing radiotherapy. Chemotherapy comprises oral estramustine 3 times daily and oral etoposide twice daily on days 1-14 and paclitaxel IV over 1 hour on day 2. Chemotherapy repeats every 21 days for 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 1,440 patients will be accrued for this study within 6 years.

• Study Type: Interventional
• Enrollment (Actual): 397
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • New Brunswick
    • Saint John, New Brunswick, Canada, E2L 4L2
      • Saint John Regional Hospital
  • Ontario
    • London, Ontario, Canada, N6A 4L6
      • Cancer Care Ontario-London Regional Cancer Centre
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3300
      • University of Alabama at Birmingham Comprehensive Cancer Center
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Foundation for Cancer Research and Education
  • California
    • Concord, California, United States, 94524-4110
      • Mount Diablo Medical Center
    • Greenbrae, California, United States, 94904
      • Sutter Health Western Division Cancer Research Group
    • Santa Rosa, California, United States, 95403
      • CCOP - Santa Rosa Memorial Hospital
  • Colorado
    • Denver, Colorado, United States, 80010
      • University of Colorado Cancer Center at University of Colorado Health Sciences Center
  • Florida
    • Miami, Florida, United States, 33176-2197
      • Baptist Hospital of Miami
  • Illinois
    • Park Ridge, Illinois, United States, 60068
      • Lutheran General Cancer Care Center
  • Indiana
    • Indianapolis, Indiana, United States, 46206-1367
      • Methodist Cancer Center at Methodist Hospital
    • Muncie, Indiana, United States, 47303-3499
      • Ball Memorial Hospital Cancer Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0293
      • Markey Cancer Center at University of Kentucky Chandler Medical Center
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Mary Bird Perkins Cancer Center
    • New Orleans, Louisiana, United States, 70121
      • CCOP - Ochsner
  • Maryland
    • Annapolis, Maryland, United States, 21401
      • Anne Arundel Oncology Center
    • Baltimore, Maryland, United States, 21204
      • Greater Baltimore Medical Center and Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0010
      • University of Michigan Comprehensive Cancer Center
    • Kalamazoo, Michigan, United States, 49007
      • West Michigan Cancer Center
    • Marquette, Michigan, United States, 49855
      • Marquette General Hospital
  • Minnesota
    • Saint Louis Park, Minnesota, United States, 55416
      • CCOP - Metro-Minnesota
  • Missouri
    • Columbia, Missouri, United States, 65203
      • Ellis Fischel Cancer Center at University of Missouri - Columbia
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • CCOP - Southern Nevada Cancer Research Foundation
  • New Jersey
    • East Orange, New Jersey, United States, 07019
      • Veterans Affairs Medical Center - East Orange
    • Long Branch, New Jersey, United States, 07740-6395
      • Monmouth Medical Center
    • Millville, New Jersey, United States, 08332
      • South Jersey Regional Cancer Center
    • Pomona, New Jersey, United States, 08240
      • Atlantic City Medical Center
    • Trenton, New Jersey, United States, 08629
      • Fox Chase Cancer Center at St. Francis Medical Center
  • New York
    • Manhasset, New York, United States, 11030
      • CCOP - North Shore University Hospital
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University
  • Ohio
    • Akron, Ohio, United States, 44302
      • Akron General Medical Center
    • Akron, Ohio, United States, 44304
      • Akron City Hospital
    • Columbus, Ohio, United States, 43210-1240
      • Arthur G. James Cancer Hospital - Ohio State University
    • Columbus, Ohio, United States, 43206
      • CCOP - Columbus
    • Dayton, Ohio, United States, 45429
      • CCOP - Dayton
    • Toledo, Ohio, United States, 43623-3456
      • CCOP - Toledo Community Hospital
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18105
      • John and Dorothy Morgan Cancer Center at Lehigh Valley Hospital
    • Bethlehem, Pennsylvania, United States, 18015
      • St. Luke's Hospital Cancer Center
    • Drexel Hill, Pennsylvania, United States, 19026
      • Delaware County Memorial Hospital
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19107-5541
      • Kimmel Cancer Center at Thomas Jefferson University - Philadelphia
    • Philadelphia, Pennsylvania, United States, 19141-3098
      • Albert Einstein Cancer Center
    • Wynnewood, Pennsylvania, United States, 19096
      • CCOP - MainLine Health
    • York, Pennsylvania, United States, 17403
      • Wellspan Health - York Cancer Center
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas - MD Anderson Cancer Center
  • Utah
    • Saint George, Utah, United States, 84770
      • Dixie Regional Medical Center
    • Salt Lake City, Utah, United States, 84143
      • LDS Hospital
  • Washington
    • Seattle, Washington, United States, 98195-6043
      • University Cancer Center at University of Washington Medical Center
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54301
      • CCOP - St. Vincent Hospital Cancer Center, Green Bay
    • Green Bay, Wisconsin, United States, 54307-3508
      • St. Vincent Hospital
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center
    • Milwaukee, Wisconsin, United States, 53215
      • St. Luke's Medical Center
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin Cancer Center
    • Racine, Wisconsin, United States, 53405
      • All Saints Cancer Center at All Saints Healthcare

Participation Criteria

Eligibility Criteria

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

Description

DISEASE CHARACTERISTICS:

• Histologically proven prostate cancer at high risk for relapse as determined by either of the following:

  • Prostate-specific antigen (PSA) 20-100 ng/mL and Gleason score at least 7 (any T stage)
  • Clinical stage at least T2, Gleason score at least 8, and PSA no greater than 100 ng/mL
• Negative lymph nodes
• No metastatic disease

PATIENT CHARACTERISTICS:

Age:

• Over 18

Performance status:

• Zubrod 0 or 1

Life expectancy:

• Not specified

Hematopoietic:

• White blood cell (WBC) count of at least 3,000/mm^3
• Platelet count at least 130,000/mm^3
• Hemoglobin at least 11.4 g/dL

Hepatic:

• Aspartate aminotransferase (AST) no greater than 2 times upper limit of normal

Renal:

• Creatinine no greater than 2.5 mg/dL

Other:

• No other invasive cancer within the past 5 years except superficial nonmelanomatous skin cancer
• No major medical or psychiatric illness that would preclude study participation
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• At least 5 years since prior chemotherapy

Endocrine therapy:

• At least 60 days since prior finasteride for prostatic hypertrophy
• At least 90 days since prior testosterone
• No more than 30 days since initiation of prior pharmacologic androgen ablation for prostate cancer

Radiotherapy:

• No prior pelvic radiotherapy
• No concurrent intensity-modulated radiotherapy

Surgery:

• No prior radical prostatectomy
• No prior cryosurgery for prostate cancer
• No prior orchiectomy

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: Hormones and RT; Androgen suppression (AS) (Luteinizing hormone releasing hormone agonist and bicalutamide [Casodex] or flutamide [Eulexin]) x 8 weeks followed by RT to 70.2 Gy with concurrent AS (LHRH agonist and bicalutamide [Casodex] or flutamide [Eulexin]). AS will continue for a total of 24 months from initiation of all treatment. Oral anti-androgen will be discontinued at the end of radiation therapy (RT).	Drug: bicalutamide; Administered orally at a dose of one 50mg tablet per day. Begins 8 weeks prior to radiotherapy and continues throughout radiotherapy.; Other Names: Casodex; Drug: flutamide; Administered orally at a dose of two 125 mg capsules three times a day for a total daily dose of 750 mg. Begins 8 weeks prior to radiotherapy and continues throughout radiotherapy.; Other Names: Eulexin; Drug: Luteinizing hormone releasing hormone [LHRH] agonist; Releasing hormone agonists (such as leuprolide, goserelin, buserelin, triptorelin) will be given for 4 months; Radiation: Radiation therapy; Radiation will begin 8 weeks following the initiation of hormone administration: 46.8 Gy to the regional lymphatics followed by a 23.4 Gy boost to the prostate to bring the total dose to the prostate to 70.2 Gy. Daily tumor doses will be 1.8 Gy per day, 5 days per week x 7-8 weeks.
Experimental: Hormones and RT plus Chemotherapy; AS (LHRH agonist and bicalutamide [Casodex] or flutamide [Eulexin]) x 8 weeks followed by RT to 70.2 Gy with concurrent AS (LHRH agonist and bicalutamide [Casodex] or flutamide [Eulexin]) and estramustine phosphate sodium, etoposide, paclitaxel, and warfarin [Coumadin®]. AS will continue for a total of 24 months from initiation all treatment. Oral antiandrogen will be discontinued at the end of RT.	Drug: bicalutamide; Administered orally at a dose of one 50mg tablet per day. Begins 8 weeks prior to radiotherapy and continues throughout radiotherapy.; Other Names: Casodex; Drug: flutamide; Administered orally at a dose of two 125 mg capsules three times a day for a total daily dose of 750 mg. Begins 8 weeks prior to radiotherapy and continues throughout radiotherapy.; Other Names: Eulexin; Radiation: Radiation therapy; Radiation will begin 8 weeks following the initiation of hormone administration: 46.8 Gy to the regional lymphatics followed by a 23.4 Gy boost to the prostate to bring the total dose to the prostate to 70.2 Gy. Daily tumor doses will be 1.8 Gy per day, 5 days per week x 7-8 weeks.; Drug: estramustine phosphate sodium; 280 mg three times a day for 14 days and repeated every 3 weeks for 4 cycles; Drug: etoposide; 50 mg/m^2 in divided doses b.i.d. for 14 days and repeated every 3 weeks for 4 cycles; Drug: paclitaxel; 135 mg/m^2 given as a 1-hour infusion (on day 2 of each cycle) and repeated every 3 weeks for 4 cycles; Drug: warfarin; To keep international normalized ratio (INR) > 1.5 and < 2.5; begins with the start of chemotherapy and will be given continuously until 4 weeks after the end of the fourth cycle of chemotherapy; Other Names: Coumadin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (5-year Rate Reported)	Survival time is defined as time from randomization to date of death from any cause and is estimated by the Kaplan-Meier method. Patients last known to be alive are censored at date of last contact. This analysis was planned to occur when all patients had been potentially followed for 5 years.	From the date of randomization to the date of death or last follow-up. Analysis occurs after all patients have been potentially followed for 5 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Biochemical Failure at 5 Years	Biochemical failure uses the American Society for Radiation Oncology (ASTRO) definition of prostate-specific antigen (PSA) rises on three consecutive occasions, with biochemical failure date being midway between the last non-rising PSA and the first rise in PSA. Time to biochemical failure is defined as time from randomization to biochemical failure, last known follow-up (censored), or death (competing risk). Biochemical failure rates are estimated using the cumulative incidence method.	From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years.
Rate of Local Progression at 5 Years	Local progression is defined as documented clinical local and/or regional progression. Time to local progression is defined as time from randomization to local progression, last known follow-up (censored), or death (competing risk). Local progression rates are estimated using the cumulative incidence method.	From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years.
Rate of Distant Metastasis at Five Years	Distant metastasis (DM) is defined as documented metastatic disease. Time to distant metastasis is defined as time from randomization to distant metastatic disease, last known follow-up (censored), or death (competing risk). Distant metastasis rates are estimated using the cumulative incidence method.	From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years.
Disease-free Survival Rate at 5 Years	Disease-free survival (DFS) was measured from the date of randomization to the date of documentation of progression (local, distant, biochemical failure), death, or last follow-up (censored). The Kaplan-Meier method was used to estimate DFS rates.	From randomization to last follow-up. Analysis occurs after all patients have been potentially followed for 5 years. Maximum follow-up at time of analysis was 13.3 years.

Collaborators and Investigators

• Sponsor: Radiation Therapy Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Howard M. Sandler, MD, University of Michigan Rogel Cancer Center

Publications and helpful links

General Publications

• Rosenthal SA, Bae K, Pienta KJ, Sobczak ML, Asbell SO, Rajan R, Kerlin KJ, Michalski JM, Sandler HM; Radiation Therapy Oncology Group Trial 9902. Phase III multi-institutional trial of adjuvant chemotherapy with paclitaxel, estramustine, and oral etoposide combined with long-term androgen suppression therapy and radiotherapy versus long-term androgen suppression plus radiotherapy alone for high-risk prostate cancer: preliminary toxicity analysis of RTOG 99-02. Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):672-8. doi: 10.1016/j.ijrobp.2008.05.020. Epub 2008 Nov 5.
• Rosenthal SA, Hunt D, Sartor AO, Pienta KJ, Gomella L, Grignon D, Rajan R, Kerlin KJ, Jones CU, Dobelbower M, Shipley WU, Zeitzer K, Hamstra DA, Donavanik V, Rotman M, Hartford AC, Michalski J, Seider M, Kim H, Kuban DA, Moughan J, Sandler H. A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902. Int J Radiat Oncol Biol Phys. 2015 Oct 1;93(2):294-302. doi: 10.1016/j.ijrobp.2015.05.024. Epub 2015 Jul 21.

Helpful Links

• Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive.

Study record dates

Study Major Dates

• Study Start: January 1, 2000
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: December 10, 1999
• 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 19, 2020
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: stage III prostate cancer; stage IV prostate cancer; 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; 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; Hormone Antagonists; Anticoagulants; Androgen Antagonists; Etoposide; Paclitaxel; Hormones; Bicalutamide; Warfarin; Estramustine; Flutamide; Prolactin Release-Inhibiting Factors
• Other Study ID Numbers: RTOG-9902; CDR0000067250