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

Sponsor

NCIC Clinical Trials Group (Other)

Overall Status

Completed

CT.gov ID

NCT00002633

Collaborator

National Cancer Institute (NCI) (NIH), Eastern Cooperative Oncology Group (Other), Southwest Oncology Group (Other), Medical Research Council (Other)

361

Enrollment

Locations

Arms

202.9

Actual Duration (Months)

24.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: bicalutamide Drug: buserelin Drug: flutamide Drug: goserelin Drug: leuprolide acetate Drug: nilutamide Procedure: orchiectomy Radiation: radiation therapy	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

361 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase III Randomized Trial Comparing Total Androgen Blockade Versus Total Androgen Blockade Plus Pelvic Irradiation in Clinical Stage T3-4, N0, M0 Adenocarcinoma of the Prostate

Actual Study Start Date :

Feb 8, 1995

Actual Primary Completion Date :

Sep 23, 2011

Actual Study Completion Date :

Jan 6, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Total Androgen Blockade	Drug: 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 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 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 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 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 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 Procedure: orchiectomy Optional orchiectomy
Active Comparator: Total Androgen Blockade Vs TA Blockade Plus Pelvic Irradiation	Drug: 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 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 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 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 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 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 Procedure: orchiectomy Optional orchiectomy Radiation: radiation therapy Radical Radiation Therapy - (65-69 Gy; 35-37 treatments)

Arm

Intervention/Treatment

Active Comparator: Total Androgen Blockade

Drug: 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

Drug: buserelin

Drug: flutamide

Drug: goserelin

Drug: leuprolide acetate

Drug: nilutamide

Procedure: orchiectomy

Optional orchiectomy

Active Comparator: Total Androgen Blockade Vs TA Blockade Plus Pelvic Irradiation

Drug: bicalutamide

Drug: buserelin

Drug: flutamide

Drug: goserelin

Drug: leuprolide acetate

Drug: nilutamide

Procedure: orchiectomy

Optional orchiectomy

Radiation: radiation therapy

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

Outcome Measures

Primary Outcome Measures

Overall survival [10 years]

Secondary Outcome Measures

Disease specific survival [10 years]
Time to disease progression [10 years]
Symptomatic local control measured by surgical intervention rate [10 years]
Quality of life assessed by EORTC-QLQ-C30 + 3 and a trial-specific checklist (PR17) or the FACT-P questionnaire [10 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 79 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
2	BCCA - Fraser Valley Cancer Centre	Surrey	British Columbia	Canada	V3V 1Z2
3	BCCA - Vancouver Cancer Centre	Vancouver	British Columbia	Canada	V5Z 4E6
4	QEII Health Sciences Center	Halifax	Nova Scotia	Canada	B3H 1V7
5	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8V 5C2
6	Cancer Centre of Southeastern Ontario at Kingston	Kingston	Ontario	Canada	K7L 5P9
7	London Regional Cancer Program	London	Ontario	Canada	N6A 4L6
8	Ottawa Health Research Institute - General Division	Ottawa	Ontario	Canada	K1H 8L6
9	Regional Cancer Program of the Hopital Regional	Sudbury	Ontario	Canada	P3E 5J1
10	Thunder Bay Regional Health Science Centre	Thunder Bay	Ontario	Canada	P7B 6V4
11	Univ. Health Network-Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
12	Windsor Regional Cancer Centre	Windsor	Ontario	Canada	N8W 2X3
13	CHUM - Hopital Notre-Dame	Montreal	Quebec	Canada	H2L 4M1
14	McGill University - Dept. Oncology	Montreal	Quebec	Canada	H2W 1S6
15	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4

Sponsors and Collaborators

NCIC Clinical Trials Group
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
Southwest Oncology Group
Medical Research Council

Investigators

Study Chair: Padraig R. Warde, MB, MRCPI, FRCPC, Princess Margaret Hospital, Canada
Study Chair: Richard R. Whittington, MD, Abramson Cancer Center of the University of Pennsylvania
Study Chair: Srinivasan Vijayakumar, MD, Michael Reese Hospital and Medical Center
Study Chair: Patricia Lillis-Hearne, MD, Brooke Army Medical Center
Study Chair: Malcolm D. Mason, MD, Velindre NHS Trust