Zoledronate in Preventing Osteoporosis and Bone Fractures in Patients With Locally Advanced Nonmetastatic Prostate Cancer Undergoing Radiation Therapy and Hormone Therapy

Prostate Cancer Clinical Trial

Official title:

A Phase III Randomized Study to Evaluate the Efficacy of Zometa® for the Prevention of Osteoporosis and Associated Fractures in Patients Receiving Radiation Therapy and Long Term LHRH Agonists for High-Grade and/or Locally Advanced Prostate Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00329797
• Other study ID #: RTOG 0518
• Secondary ID: CDR0000476469NCI
• Status: Completed
• Phase: Phase 3
• First received: May 23, 2006
• Last updated: October 23, 2017
• Start date: March 2006
• Est. completion date: November 2014

Study information

• Verified date: October 2017
• Source: Radiation Therapy Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Zoledronate may prevent bone loss in patients with prostate cancer undergoing radiation therapy and hormone therapy. It is not yet known whether zoledronate is more effective than calcium and vitamin D alone in preventing osteoporosis and bone fractures in patients with prostate cancer.

PURPOSE: This randomized phase III trial is studying zoledronate to see how well it works compared to calcium and vitamin D alone in preventing osteoporosis and bone fractures in patients with locally advanced nonmetastatic prostate cancer undergoing radiation therapy and hormone therapy.

Description:

OBJECTIVES:

Primary

• Compare the potential benefit of bisphosphonate therapy comprising zoledronate plus vitamin D and calcium supplement vs standard therapy with vitamin D and calcium supplement in the prevention of osteoporosis and associated bone fractures in patients with locally advanced nonmetastatic adenocarcinoma of the prostate undergoing radiotherapy and luteinizing hormone-releasing hormone (LHRH) agonist therapy.

Secondary

• Evaluate the potential benefit of these regimens on quality of life in these patients.

• Evaluate the potential benefit in bone mineral density over a period of 3 years for patients treated with these regimens.

OUTLINE: This is randomized multicenter study. Patients are stratified according to T score of the hip by dual x-ray absorptiometry (DXA) scan (< -1.0 but > -2.5 vs ≥ - 1.0) and planned duration of luteinizing hormone-releasing hormone (LHRH) agonist therapy (1-2½ years vs > 2½ years). Patients are randomized to 1 of 2 treatment arms.

Quality of life is assessed at baseline and every 6 months during treatment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 109
• Est. completion date: November 2014
• Est. primary completion date: November 2014
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Eligibility criteria:

• Pathologically (histologically or cytologically) proven diagnosis of adenocarcinoma of the prostate within 12 months of registration;

• Any one of the following clinical stages:

• T3 disease, any N stage, M0 with any Gleason score and any prostate-specific antigen (PSA); < T3 stage, any N stage, M0 with Gleason's score = 8 and any PSA; < T3 stage, any N stage, M0 with Gleason's score 7 and PSA = 15 nanograms/ml; < T3 stage, any N stage, M0 with Gleason score < 7 and PSA = 20 nanograms/ml.

• A negative bone scan for metastatic disease;

• It is mandatory that the treating physician determine the planned duration of LHRH therapy prior to the site registering the patient (minimum 1 year of therapy); If patient is receiving pre-treatment LHRH therapy, it must have begun = 6 months prior to registration. If pelvic radiation therapy (RT) has started, it must have begun = 8 weeks prior to registration;

• Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup to be done within 16 weeks prior to registration:

• History/physical examination;

• Dental evaluation, including history of dental surgery (e.g., extraction or implant);

• Bone scan;

• T and L spine films;

• DXA scan: To be eligible the patient must have a scan on Lunar, Hologic, or Norland equipment only and the T scores in both the L spine and total hip must be > negative 2.5;

• Zubrod Performance Status 0-1 within 16 weeks prior to registration; (8/16/07)

• Age = 18;

• Serum creatinine within 4 weeks prior to registration (8/16/07)

• Corrected serum calcium = 8.4 and = 10.6 mg/dl within 8 weeks prior to registration; note: for patients with an albumin of 4.0, corrected calcium=measured calcium. The formula for corrected calcium if serum albumin value is above or below 4.0 is as follows: Corrected calcium (mg/dl) = (4 - [patient's albumin (g/dl)] x 0.8) + patient's measured calcium (mg/dl)

• Patients who are sexually active must be willing/able to use medically acceptable forms of contraception, as the treatment involved in this study may be significantly teratogenic.

• Patient agrees to refrain from using all products listed in Section 9.2, "Non-permitted Supportive Therapy";

• Post-prostatectomy patients are eligible.

• Patient must sign study specific informed consent prior to study entry.

Ineligibility criteria:

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; e.g., carcinoma in situ of the breast or oral cavity are permissible;

• Patients with baseline T scores of = -2.5 are excluded.

• Patients with baseline calculated creatinine clearance < 30 mL/min (estimated by Cockcroft-Gault formula below) are excluded. creatinine clearance male = [(140 - age) x (wt in kg)] / [(serum creatinine) x (72)]

• Prior bisphosphonate therapy;

• Prior pelvic radiation (other than for current prostate cancer) or prior systemic radiotherapeutic agents, such as strontium or samarium;

• Patients receiving systemic chemotherapy, steroids, growth hormones, or calcitonin;

• Patients with a history of Paget's disease or with uncontrolled thyroid or parathyroid dysfunction or with other diseases that influence bone metabolism;

• Known hypersensitivity to zoledronic acid or other bisphosphonates;

• Active dental problems at study entry, including infection of the teeth or jawbone; dental or fixture trauma; or a current or prior diagnosis of osteonecrosis of the jaw, exposed bone in the mouth, or slow healing after dental procedures;

• Recent or planned

Related Conditions & MeSH terms

• Osteoporosis
• Prostate Cancer
• Prostatic Neoplasms

Intervention

Dietary Supplement:
• Calcium
A single dose of 500 mg of elemental calcium orally each day for 3 years.
• Zoledronic acid
Patients receive IV over 15 minutes once every 6 months for 3 years. The goal dose of zoledronic acid is 4 mg, but the selection of dose is determined based on calculated creatinine clearance at baseline.

Radiation:
• radiation therapy
Patients must receive external beam irradiation, brachytherapy (HDR or LDR), or a combination of external beam irradiation and brachytherapy at the discretion of the treating physician. Dose/duration also will be at the discretion of the treating physician; however, dose will not exceed 45 Gy to 100% of the proximal femur, and no proximal femur will receive = 60 Gy.

Drug:
• LHRH
LHRH therapy must take place for a minimum of one year. Choice of LHRH agonist, dose, and duration are at the discretion of the treating physician.

Dietary Supplement:
• Vitamin D
400 IU (10µg), orally each day for 3 years.

Locations

Country	Name	City	State
Canada	Margaret and Charles Juravinski Cancer Centre	Hamilton	Ontario
Canada	Maisonneuve-Rosemont Hospital	Montreal	Quebec
Canada	Centre Hospitalier Universitaire de Quebec	Quebec City	Quebec
Canada	Allan Blair Cancer Centre at Pasqua Hospital	Regina	Saskatchewan
Canada	CHUS-Hopital Fleurimont	Sherbrooke	Quebec
Canada	Doctor H. Bliss Murphy Cancer Centre	St. John's	Newfoundland and Labrador
Canada	Cancer Care Program at Thunder Bay Regional Health Sciences	Thunder Bay	Ontario
Canada	British Columbia Cancer Agency - Vancouver Island Centre	Victoria	British Columbia
United States	Rosenfeld Cancer Center at Abington Memorial Hospital	Abington	Pennsylvania
United States	McDowell Cancer Center at Akron General Medical Center	Akron	Ohio
United States	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio
United States	Saint Anthony's Hospital at Saint Anthony's Health Center	Alton	Illinois
United States	Theda Care Cancer Institute	Appleton	Wisconsin
United States	Northwest Community Hospital	Arlington Heights	Illinois
United States	Mission Hospitals - Memorial Campus	Asheville	North Carolina
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	St. Agnes Hospital Cancer Center	Baltimore	Maryland
United States	CCOP - Montana Cancer Consortium	Billings	Montana
United States	Northern Rockies Radiation Oncology Center	Billings	Montana
United States	Lourdes Regional Cancer Center	Binghamton	New York
United States	Veterans Affairs Medical Center - Brooklyn	Brooklyn	New York
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Cancer Institute of New Jersey at Cooper University Hospital - Camden	Camden	New Jersey
United States	Southeast Missouri Regional Cancer Center at Southeast Missouri Hospital	Cape Girardeau	Missouri
United States	Enloe Cancer Center at Enloe Medical Center	Chico	California
United States	Charles M. Barrett Cancer Center at University Hospital	Cincinnati	Ohio
United States	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan
United States	CCOP - Hematology-Oncology Associates of Central New York	East Syracuse	New York
United States	Northeast Georgia Medical Center	Gainesville	Georgia
United States	Adams Cancer Center	Gettysburg	Pennsylvania
United States	Wayne Radiation Oncology	Goldsboro	North Carolina
United States	Center for Cancer Care at Goshen General Hospital	Goshen	Indiana
United States	Great Falls Clinic - Main Facility	Great Falls	Montana
United States	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin
United States	Ingalls Cancer Care Center at Ingalls Memorial Hospital	Harvey	Illinois
United States	Methodist Cancer Center at Methodist Hospital	Indianapolis	Indiana
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	CCOP - Kansas City	Kansas City	Missouri
United States	Kingsbury Center for Cancer Care at Cheshire Medical Center	Keene	New Hampshire
United States	Christine LaGuardia Phillips Cancer Center at Wellmont Holston Valley Medical Center	Kingsport	Tennessee
United States	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky
United States	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California
United States	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin
United States	Community Memorial Hospital Cancer Care Center	Menomonee Falls	Wisconsin
United States	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin
United States	Veterans Affairs Medical Center - Milwaukee	Milwaukee	Wisconsin
United States	Vince Lombardi Cancer Clinic at Aurora St. Luke's Medical Center	Milwaukee	Wisconsin
United States	Jon and Karen Huntsman Cancer Center at Intermountain Medical Center	Murray	Utah
United States	Sentara Cancer Institute at Sentara Norfolk General Hospital	Norfolk	Virginia
United States	Val and Ann Browning Cancer Center at McKay-Dee Hospital Center	Ogden	Utah
United States	Saint James Hospital and Health Centers Comprehensive Cancer Institute - Olympia Fields	Olympia Fields	Illinois
United States	Cancer Center of Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania
United States	Robert and Beverly Lewis Family Cancer Care Center at Pomona Valley Hospital Medical Center	Pomona	California
United States	Naval Medical Center - Portsmouth	Portsmouth	Virginia
United States	Utah Valley Regional Medical Center - Provo	Provo	Utah
United States	St. Mary - Corwin Regional Medical Center	Pueblo	Colorado
United States	Cancer Centers of North Carolina - Raleigh	Raleigh	North Carolina
United States	Renown Institute for Cancer at Renown Regional Medical Center	Reno	Nevada
United States	Radiation Oncology Center - Roseville	Roseville	California
United States	Radiological Associates of Sacramento Medical Group, Incorporated	Sacramento	California
United States	CentraCare Clinic - River Campus	Saint Cloud	Minnesota
United States	Coborn Cancer Center	Saint Cloud	Minnesota
United States	Dixie Regional Medical Center - East Campus	Saint George	Utah
United States	Norris Cotton Cancer Center - North	Saint Johnsbury	Vermont
United States	CCOP - St. Louis-Cape Girardeau	Saint Louis	Missouri
United States	David C. Pratt Cancer Center at St. John's Mercy	Saint Louis	Missouri
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri
United States	Cancer Research UK Medical Oncology Unit at Churchill Hospital & Weatherall Institute of Molecular Medicine - Oxford	Salem	Ohio
United States	LDS Hospital	Salt Lake City	Utah
United States	Hulston Cancer Center at Cox Medical Center South	Springfield	Missouri
United States	St. John's Regional Health Center	Springfield	Missouri
United States	CCOP - Carle Cancer Center	Urbana	Illinois
United States	Franklin & Edith Scarpa Regional Cancer Center at South Jersey Healthcare	Vineland	New Jersey
United States	Cancer Institute of New Jersey at Cooper - Voorhees	Voorhees	New Jersey
United States	West Allis Memorial Hospital	West Allis	Wisconsin
United States	Precision Radiotherapy at University Pointe	West Chester	Ohio
United States	Wilmed Radiation Oncology Services	Wilson	North Carolina
United States	Cancer Treatment Center	Wooster	Ohio
United States	Lankenau Cancer Center at Lankenau Hospital	Wynnewood	Pennsylvania
United States	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington
United States	York Cancer Center at Apple Hill Medical Center	York	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Radiation Therapy Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Freedom From Any Bone Fracture (FABF) Rate at Three Years	The time of failure was measured from the date of randomization to the date of documented bone fractures, defined as any fracture of the bone. The three-year FABF rate will be estimated by the Kaplan-Meier method.	From randomization to 3 years
Secondary	Percent Change in Bone Mineral Density at 3 Years	Bone mineral density (BMD) was measured by DXA scan (Dual X-ray absorptiometry) for five locations: lumbar, right total hip, left total hip, right femoral neck, and left femoral neck. The percent change at 3 years was calculated for each location by the following formula: Percent Change BMD = (BMD_3 years - BMD_Baseline)/ BMD_Baseline * 100.	Baseline, 3 years from start of treatment
Secondary	Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years	The FACT-G is a validated, 27-item measure. In addition to a total QOL score, subscale scores for physical, functional, social and emotional well-being are produced. There are 5 responses options, with 0=Not a lot and 4=Very much. All items in a subscale are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Scores range from 0-108 for the FACT-G total score, 0-28 for the physical, social and functional subscales, and 0-24 for the emotional subscale. Certain items, identified on the FACT-G scoring guides, must be reversed before it is added by subtracting the response from 4. All subscale totals are added together to form the FACT-G total score. Each subscale requires at least 50% of the items to be completed while the overall response rate must be greater than 80%. If items are missing, the subscale scores can be prorated. A higher score indicates better QOL.	Baseline, 3 years from start of treatment
Secondary	Utility of the Use of Bisphosphonates as Assessed by Quality-adjusted Survival	The EQ-5D is a standardized instrument for measuring generic health status used to generate health utilities, used to derive quality adjusted survival. Quality adjusted survival is computed using the weighted sum of times in different health states added up to a total quality-adjusted survival time. The log-rank test is used to compare quality-adjusted survivals between the treatment arms.	From pre-treatment to 3 years from start of treatment