Hormone Therapy With or Without Surgery or Radiation Therapy in Treating Patients With Prostate Cancer

NCT ID: NCT00002633

Last Updated: 2020-04-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 361 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1995-02-08
• Study Completion Date: 2012-01-06

Brief Summary

RATIONALE: Hormones can stimulate the growth 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. It is not yet known whether hormone therapy plus surgery is more effective than hormone therapy plus radiation therapy for prostate cancer.

PURPOSE: This randomized phase III trial is studying giving hormone therapy alone to see how well it works compared to giving hormone therapy together with bilateral orchiectomy or radiation therapy in treating patients with stage III or stage IV prostate cancer.

Detailed Description

OBJECTIVES:

• Compare the overall survival, disease specific survival, and time to progression in patients with locally advanced adenocarcinoma of the prostate treated with total androgen suppression with or without pelvic irradiation.
• Compare the symptomatic control as measured by the rates of surgical interventions needed for control of local disease (e.g., transurethral resections, stent insertions, nephrostomies, and colostomies) in patients treated with these regimens.
• Compare the quality of life of patients treated with these regimens.
• Compare the sensitivity of the EORTC-QLQ-C30+3 and a trial-specific checklist (PR17) with the FACT-P questionnaire in measuring changes in quality of life of patients treated with these regimens.

OUTLINE: This a randomized, multicenter study. Patients are stratified according to center, initial PSA level (less than 20 vs 20-50 vs greater than 50 ng/mL), method of node staging (clinical [no CT scan] vs radiological [CT scan negative] vs surgical), Gleason score (less than 8 vs 8-10), prior hormonal therapy (excluding orchiectomy) (yes vs no), and choice of hormonal therapy (bilateral orchiectomy with or without antiandrogen vs luteinizing hormone-releasing hormone [LHRH] with antiandrogen). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive antiandrogen therapy comprising oral flutamide every 8 hours, oral nilutamide every 8 hours for 1 month and then once daily, or oral bicalutamide once daily. Patients also choose to undergo bilateral orchiectomy or LHRH agonist therapy comprising goserelin subcutaneously (SC) every 4 weeks (short-acting formulation) or every 3 months (long-acting formulation), leuprolide intramuscularly every 4 weeks (short-acting formulation) or every 3 months (long-acting formulation), or buserelin SC every 8 weeks or every 12 weeks. Patients choosing orchiectomy may receive an antiandrogen for at least 6 weeks before surgery to counter any flare phenomenon and may continue the antiandrogen after surgery (at the physician's discretion).
• Arm II: Patients undergo total androgen ablation as in arm I. Patients with node-negative dissection undergo radiotherapy 5 days a week for 6.5-7 weeks. All other patients undergo radiotherapy 5 days a week for 5 weeks, followed by boost radiotherapy 5 days a week for 2-2.4 weeks.

Hormonal therapy on both arms continues in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, on the last day of radiotherapy, at 6 months, and then every 6 months thereafter.

Patients are followed at 1, 2, and 6 months and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 1,200 patients will be accrued for this study within 7.5 years.

Conditions

Prostate Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Total Androgen Blockade

Group Type: ACTIVE_COMPARATOR

bicalutamide

Intervention Type: DRUG

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

buserelin

Intervention Type: DRUG

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

flutamide

Intervention Type: DRUG

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

goserelin

Intervention Type: DRUG

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

leuprolide acetate

Intervention Type: DRUG

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

nilutamide

Intervention Type: DRUG

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

orchiectomy

Intervention Type: PROCEDURE

Optional orchiectomy

Total Androgen Blockade Vs TA Blockade Plus Pelvic Irradiation

Group Type: ACTIVE_COMPARATOR

bicalutamide

Intervention Type: DRUG

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

buserelin

Intervention Type: DRUG

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

flutamide

Intervention Type: DRUG

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

goserelin

Intervention Type: DRUG

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

leuprolide acetate

Intervention Type: DRUG

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

nilutamide

Intervention Type: DRUG

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

orchiectomy

Intervention Type: PROCEDURE

Optional orchiectomy

radiation therapy

Intervention Type: RADIATION

Radical Radiation Therapy - (65-69 Gy; 35-37 treatments)

Interventions

bicalutamide

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

Intervention Type: DRUG

buserelin

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

Intervention Type: DRUG

flutamide

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

Intervention Type: DRUG

goserelin

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

Intervention Type: DRUG

leuprolide acetate

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

Intervention Type: DRUG

nilutamide

Antiandrogen (optional with orchiectomy) Flutamide 250 mg po TID or Nilutamide 100 mg po TID x 1 mo; then 150 mg po QD or Bicalutamide 50 mg po QD PLUS (patient's choice) Bilateral orchiectomy or LHRH agonist Goserelin 3.6 mg SC (abd) q28d or 10.8 mg SC (abd) Q3mos or Leuprolide 7.5 mg IM q28d (Leuprorelin 3.75 mg) or 22.5 mg IM Q3mos (Leuprorelin 11.25 mg) or 30 mg IM Q4mos or Buserelin 6.3mg SC (abd) Q8wk or 9.45mg SC (abd) Q12wk

Intervention Type: DRUG

orchiectomy

Optional orchiectomy

Intervention Type: PROCEDURE

radiation therapy

Radical Radiation Therapy - (65-69 Gy; 35-37 treatments)

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

DISEASE CHARACTERISTICS:

• Histologically proven locally advanced adenocarcinoma of the prostate, defined as 1 of the following:

• T3-4, N0 or NX, M0
• T2, PSA greater than 40 µg/L
• T2, PSA greater than 20 µg/L AND Gleason score at least 8
• Diagnosis made within the past 6 months
• Gleason score and PSA known
• Pelvic lymph nodes must be clinically negative

• Lymph nodes no more than 1.5 cm in greatest diameter by CT scan or MRI of the pelvis
• Negative needle aspirate required for any lymph node more than 1.5 cm
• If a lymph node dissection was performed, it must be histologically negative
• No small cell or transitional cell carcinoma by biopsy
• No bony metastases by bone scan

PATIENT CHARACTERISTICS:

Age:

• Under 80

Performance status:

• ECOG 0-2

Life expectancy:

• At least 5 years excluding malignancy

Hematopoietic:

• Hemoglobin at least 10.0 g/dL
• WBC at least 2,000/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin less than 2 times upper limit of normal (ULN)
• SGOT and SGPT less than 2 times ULN
• Alkaline phosphatase less than 2 times ULN
• No history of chronic liver disease

Renal:

• Creatinine less than 2 times ULN

Other:

• No contraindication to wide-field pelvic irradiation (e.g., inflammatory bowel disease or severe bladder irritability)
• No other malignancy within the past 5 years except nonmelanoma skin cancer
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• Not specified

Endocrine therapy:

• Prior hormonal therapy within the past 12 weeks allowed provided the following conditions are met:

• Negative bone scan before beginning any hormonal therapy
• Extracapsular extension remains palpable on rectal re-exam
• Baseline PSA known before beginning any hormonal therapy
• At least 4-6 weeks since prior 5-alpha-reductase inhibitor (e.g., finasteride) for benign prostatic hypertrophy

Radiotherapy:

• No prior pelvic irradiation

Surgery:

• No prior radical prostatectomy
• Prior transurethral resection of the prostate allowed

Other:

• No prior cytotoxic anticancer therapy
• No other prior treatment for prostate cancer
• No other concurrent anticancer therapy unless documented disease progression

• Maximum Eligible Age: 79 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Eastern Cooperative Oncology Group

NETWORK

Sponsor Role: collaborator

SWOG Cancer Research Network

NETWORK

Sponsor Role: collaborator

Medical Research Council

OTHER_GOV

Sponsor Role: collaborator

NCIC Clinical Trials Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Padraig R. Warde, MB, MRCPI, FRCPC

Role: STUDY_CHAIR

Princess Margaret Hospital, Canada

Richard R. Whittington, MD

Role: STUDY_CHAIR

Abramson Cancer Center at Penn Medicine

Srinivasan Vijayakumar, MD

Role: STUDY_CHAIR

Michael Reese Hospital and Medical Center

Patricia Lillis-Hearne, MD

Role: STUDY_CHAIR

Brooke Army Medical Center

Malcolm D. Mason, MD

Role: STUDY_CHAIR

Velindre NHS Trust

Locations

Cross Cancer Institute

Edmonton, Alberta, Canada

BCCA - Fraser Valley Cancer Centre

Surrey, British Columbia, Canada

BCCA - Vancouver Cancer Centre

Vancouver, British Columbia, Canada

QEII Health Sciences Center

Halifax, Nova Scotia, Canada

Regional Cancer Program of the Hopital Regional

Greater Sudbury, Ontario, Canada

Juravinski Cancer Centre at Hamilton Health Sciences

Hamilton, Ontario, Canada

Cancer Centre of Southeastern Ontario at Kingston

Kingston, Ontario, Canada

London Regional Cancer Program

London, Ontario, Canada

Ottawa Health Research Institute - General Division

Ottawa, Ontario, Canada

Thunder Bay Regional Health Science Centre

Thunder Bay, Ontario, Canada

Univ. Health Network-Princess Margaret Hospital

Toronto, Ontario, Canada

Windsor Regional Cancer Centre

Windsor, Ontario, Canada

CHUM - Hopital Notre-Dame

Montreal, Quebec, Canada

McGill University - Dept. Oncology

Montreal, Quebec, Canada

Saskatoon Cancer Centre

Saskatoon, Saskatchewan, Canada

Countries

Canada

References

Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, Gospodarowicz M, Sanders K, Kostashuk E, Swanson G, Barber J, Hiltz A, Parmar MK, Sathya J, Anderson J, Hayter C, Hetherington J, Sydes MR, Parulekar W; NCIC CTG PR.3/MRC UK PR07 investigators. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011 Dec 17;378(9809):2104-11. doi: 10.1016/S0140-6736(11)61095-7. Epub 2011 Nov 2.

Reference Type: RESULT

PMID: 22056152 (View on PubMed)

Brundage M, Sydes MR, Parulekar WR, Warde P, Cowan R, Bezjak A, Kirkbride P, Parliament M, Moynihan C, Bahary JP, Parmar MK, Sanders K, Chen BE, Mason MD. Impact of Radiotherapy When Added to Androgen-Deprivation Therapy for Locally Advanced Prostate Cancer: Long-Term Quality-of-Life Outcomes From the NCIC CTG PR3/MRC PR07 Randomized Trial. J Clin Oncol. 2015 Jul 1;33(19):2151-7. doi: 10.1200/JCO.2014.57.8724. Epub 2015 May 26.

Reference Type: DERIVED

PMID: 26014295 (View on PubMed)

Mason MD, Parulekar WR, Sydes MR, Brundage M, Kirkbride P, Gospodarowicz M, Cowan R, Kostashuk EC, Anderson J, Swanson G, Parmar MK, Hayter C, Jovic G, Hiltz A, Hetherington J, Sathya J, Barber JB, McKenzie M, El-Sharkawi S, Souhami L, Hardman PD, Chen BE, Warde P. Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer. J Clin Oncol. 2015 Jul 1;33(19):2143-50. doi: 10.1200/JCO.2014.57.7510. Epub 2015 Feb 17.

Reference Type: DERIVED

PMID: 25691677 (View on PubMed)

Other Identifiers

CAN-NCIC-PR3

Identifier Type: REGISTRY

Identifier Source: secondary_id

ECOG-JPR03

Identifier Type: OTHER

Identifier Source: secondary_id

MRC-PR07

Identifier Type: OTHER

Identifier Source: secondary_id

SWOG-JPR3

Identifier Type: OTHER

Identifier Source: secondary_id

EU-99013

Identifier Type: OTHER

Identifier Source: secondary_id

NCI-T94-0110O

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

ISRCTN24991896

Identifier Type: REGISTRY

Identifier Source: secondary_id

CDR0000064065

Identifier Type: OTHER

Identifier Source: secondary_id

PR3

Identifier Type: -

Identifier Source: org_study_id