Osteoporosis, Prostate Cancer
Conditions
Keywords
osteoporosis, adenocarcinoma of the prostate, stage IIB prostate cancer, stage IIA prostate cancer, stage III prostate cancer, stage IV prostate cancer
Brief 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.
Detailed 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.
Interventions
A single dose of 500 mg of elemental calcium orally each day for 3 years.
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.
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.
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.
400 IU (10μg), orally each day for 3 years.
Sponsors
Study design
Eligibility
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Freedom From Any Bone Fracture (FABF) Rate at Three Years | From randomization to 3 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Bone Mineral Density at 3 Years | Baseline, 3 years from start of treatment | 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. |
| Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years | Baseline, 3 years from start of treatment | 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. |
| Utility of the Use of Bisphosphonates as Assessed by Quality-adjusted Survival | From pre-treatment to 3 years from start of treatment | 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. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy. | 50 |
| Control Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy. | 46 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 6 |
Baseline characteristics
| Characteristic | Zoledronic Acid | Control | Total |
|---|---|---|---|
| Age, Continuous | 70 years | 71 years | 71 years |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 50 Participants | 46 Participants | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 45 / 50 | 38 / 46 |
| serious Total, serious adverse events | 8 / 50 | 5 / 46 |
Outcome results
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.
Time frame: From randomization to 3 years
Population: Eligible patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Freedom From Any Bone Fracture (FABF) Rate at Three Years | 98.0 percentage of participants |
| Control | Freedom From Any Bone Fracture (FABF) Rate at Three Years | 97.4 percentage of participants |
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.
Time frame: Baseline, 3 years from start of treatment
Population: Eligible patients with baseline and 3-year FACT-G data
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Zoledronic Acid | Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years | Social Subscale | -0.69 units on a scale |
| Zoledronic Acid | Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years | Functional Subscale | -1.10 units on a scale |
| Zoledronic Acid | Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years | Emotional Subscale | 1.83 units on a scale |
| Zoledronic Acid | Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years | Total | -1.00 units on a scale |
| Zoledronic Acid | Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years | Physical Subscale | -1.03 units on a scale |
| Control | Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years | Total | -2.77 units on a scale |
| Control | Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years | Physical Subscale | 0.06 units on a scale |
| Control | Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years | Social Subscale | -1.13 units on a scale |
| Control | Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years | Emotional Subscale | 1.15 units on a scale |
| Control | Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years | Functional Subscale | -2.76 units on a scale |
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.
Time frame: Baseline, 3 years from start of treatment
Population: Eligible patients with baseline and 3-year BMD data at respective location
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Zoledronic Acid | Percent Change in Bone Mineral Density at 3 Years | Hip - Right | -2 percentage of baseline value |
| Zoledronic Acid | Percent Change in Bone Mineral Density at 3 Years | Femoral - Right | 1 percentage of baseline value |
| Zoledronic Acid | Percent Change in Bone Mineral Density at 3 Years | Hip - Left | 1 percentage of baseline value |
| Zoledronic Acid | Percent Change in Bone Mineral Density at 3 Years | Femoral - Left | 3 percentage of baseline value |
| Zoledronic Acid | Percent Change in Bone Mineral Density at 3 Years | Lumbar | 6 percentage of baseline value |
| Control | Percent Change in Bone Mineral Density at 3 Years | Femoral - Left | -8 percentage of baseline value |
| Control | Percent Change in Bone Mineral Density at 3 Years | Hip - Right | -5 percentage of baseline value |
| Control | Percent Change in Bone Mineral Density at 3 Years | Hip - Left | -8 percentage of baseline value |
| Control | Percent Change in Bone Mineral Density at 3 Years | Femoral - Right | -6 percentage of baseline value |
| Control | Percent Change in Bone Mineral Density at 3 Years | Lumbar | -5 percentage of baseline value |
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.
Time frame: From pre-treatment to 3 years from start of treatment
Population: Eligible patients with baseline and follow-up EQ-5D scores, resulting in only 59 patients (no deaths), less than half of enrolled patients (and less than 5% of planned enrollment), which is extremely problematic as it can lead to selection bias, especially with even fewer patients with follow-up scores. Therefore analysis was not conducted.