Breast Cancer With Bone Metastasis
Conditions
Keywords
Breast cancer, Zoledronic acid, Skeletal related events (SRE)
Brief summary
The objective of this study is to assess the clinical benefit of two different dosing schedules of zoledronic acid in patients with metastatic bone lesions from breast cancer who have already been treated with zoledronic acid for about one year.
Interventions
DRUGZoledronic acid
Zoledronic acid as a 15-minute (at least) intravenous (i.v.) infusion. The dose of study drug will be the same administered before the study entry, that is 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female patients ≥ 18 years of age. * Written informed consent given. * Histologically confirmed Stage IV breast cancer with at least one bone metastasis radiologically confirmed. * Previous treatment with zoledronic acid every 3-4 weeks, for 9-12 infusions over no more than 15 months. * Eastern Cooperative Oncology Group (ECOG) performance status ≤2 . * Life expectancy ≥ 1 year.
Exclusion criteria
* More than 3 months since last infusion of Zoledronic Acid (Zometa®). * Treatments with other bisphosphonate than Zoledronic Acid (Zometa®) at any time prior to study entry. * Serum creatinine \> 3 mg/dL (265 μmol/L) or calculated (Cockcroft-Gault formula) creatinine clearance (CLCr) \< 30 mL/min CrCl = ({\[140-age (years)\] x weight(kg)}/ \[72 x serum creatinine (mg/dL)\])x 0.85 * Corrected (adjusted for serum albumin) serum calcium \< 8 mg/dl (2 mmol/L) or \> 12 mg/dL ( 3.0 mmol/L). * Current active dental problem including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a recurrent or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures. * Recent (within 6 weeks) or planned dental or jaw surgery (e.g. extraction, implants). * Pregnant patients (with a positive pregnancy test prior to study entry) or lactating patients. Women of childbearing potential not using effective methods of birth control (e.g. abstinence, oral contraceptives or implants, IUD, vaginal diaphragm or sponge, or condom with spermicide). * History of non-compliance to medical regimens or potential unreliable behavior. * Known sensitivity to study drug(s) or class of study drug(s). * Patients with severe medical condition(s) that in the view of the investigator prohibits participation in the study * Use of any other investigational agent in the last 30 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annual Overall Skeletal Morbidity Rate (SMR) | 12 months | The SMR was computed by summing all Skeletal Related Event(s) (SREs)which occurred during the observation period and dividing it by the ratio days of observation period / 365.25, for each participant. SRE was defined as: pathologic bone fracture, spinal cord compression, surgery to bone both curative and prophylactic, radiation therapy to bone, or hypercalcemia of malignancy. SMR (years) = 365.25 x SMR(days) where SMR (days) = total number of SREs / total SRE risk period (days). Risk period for SMR was computed as the days from randomization date to the date of last visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annual Incidence of Any Skeletal Related Events (SREs) | 12 months | Skeletal Related Events (SREs) are defined as a: * pathologic bone fracture such as non-vertebral and vertebral * spinal cord compression identified by X-rays evidence * surgery to bone both curative and prophylactic * radiation therapy to bone including palliative, therapeutic or prophylactic * hypercalcemia of malignancy, defined as a corrected serum calcium \> 12 mg/dl (3.00 mmol/l) or a lower level of hypercalcemia which is symptomatic and which requires active treatment other than rehydration. Annual incidence for each SRE was computed in the same way as annual overall SMR. |
| Median Time to First Skeletal Related Event(s) (SRE) | 12 month | Median Time to first skeletal related event (SRE) is defined as the time from randomization to the date of first occurrence of any SRE which includes at least one of the following: radiation therapy to bone, pathologic bone fracture, spinal cord compression, surgery to bone, and hypercalcemia of malignancy (HCM). Due to the few numbers of SRE, Kaplan-Meier estimate never reaches a failure probability \>=25%; so median time, 25th and 75th percentiles are not determined.For this reason only the estimated percentage of patient SRE free are reported at each time point. |
| Percentage of Participants Skeletal Related Event (SRE) Free | 12 months | Percentage of participants SRE free is defined as the Kaplan-Meier estimate of participants free of any Skeletal Related Events(SRE) at each time point. Skeletal Related Events (SREs) are: * pathologic bone fracture; non-vertebral and vertebral * spinal cord compression identified by X-rays * surgery to bone both curative and prophylactic * radiation therapy to bone (palliative, therapeutic or prophylactic) * hypercalcemia of malignancy, defined as a corrected serum calcium \> 12 mg/dl (3.00 mmol/l) or a lower level which is symptomatic and requires treatment other than rehydration. |
| Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | 12 month | Skeletal Related Events (SREs) are defined as a: * pathologic bone fracture such as non-vertebral and vertebral compression fractures * spinal cord compression identified by positive diagnosis documented by X-ray evidence * surgery to bone both curative and prophylactic * radiation therapy to bone including palliative, therapeutic or prophylactic * hypercalcemia of malignancy, defined as a corrected serum calcium \> 12 mg/dl (3.00 mmol/l) or a lower level of hypercalcemia which is symptomatic and which requires active treatment other than rehydration. |
| Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Baseline, Month 3, Month 6, Month 9 and Month 12 | Pain intensity at rest and on movement is rated by the patient by means of a validated 6-point Verbal Rating Scale (VRS) and refers to the pain which occurred during the last week before the assessment. Median score value is the median of all the observed scores (none=0, very mild=1, mild=2, moderate=3, severe=5 and very severe=6) at each time point. |
| Use Of Analgesic Medications According to the Analgesic Score Scale | At Baseline, Month 3, Month 6, Month 9 and Month 12 | The analgesic score used for this study is modified from the Radiation Therapy Oncology Group (RTOG) analgesic score scale. The scale represents type of medication administered from 0 to 4 where: 0 = None 1. = Minor analgesics (aspirin, NSAID, acetaminophen, propoxyphene, etc.) 2. = Tranquilisers, antidepressants, muscle relaxants, and steroids 3. = Mild narcotics (oxycodone, meperidine, codeine, etc.) 4. = Strong narcotics (morphine, hydromorphone, etc.) The outcome is given a the median score for the participants at Baseline and 3, 6, 9 and 12 months of treatment |
| Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | At Baseline, Month 3, Month 6, Month 9 and Month 12 | ECOG Performance Score has 4 grades. 0 = Fully active, able to carry out all pre-disease activities; 1 = Restricted in strenuous activity but ambulatory and able to carry out work of light or sedentary nature; 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Active about 50% of waking hours; 3 = Capable of limited self-care, confined to bed/chair more than 50% of waking hours; 4 = Completely disabled; cannot carry on self-care. Totally confined to bed/chair. Outcome is given as median score for participants at Baseline and 3, 6 , 9 and 12 months of treatment |
| Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | At Baseline, Month 3, Month 6, Month 9 and Month 12 | Bone pain was assessed by means of a pain score obtained using the Brief Pain Inventory (BPI) questionnaire. The BPI can produce three pain scores: worst pain, a composite pain score, and a pain interference score. The composite pain score, which is the average of questions 3, 4, 5 and 6 of the questionnaire was used in this study. Pain was rated on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). The outcome is given as the median score for participants at baseline, and 3, 6, 9 and 12 months of treatment |
Countries
Italy
Participant flow
Recruitment details
Total enrollment was 430; five participants were screened but not treated.
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid Every 3 Months Zoledronic acid given as a 15-minute (at least) i.v. infusion every three months. The dose of study drug was the same as administered before study entry; that is, 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Randomized participants received a maximum of 4 infusions in this group. | 209 |
| Zoledronic Acid Every 4 Weeks Zoledronic acid given as a 15-minute (at least) i.v. infusion every 4 weeks. The dose of study drug was the as same administered before study entry; that is, 4 mg or a reduced dose, i.e. 3.5 mg, or 3.3 mg or 3.0 mg. Participants randomized to this group received up to 12 infusions. | 216 |
| Total | 425 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 1 | 2 |
| Overall Study | Abnormal test procedure result(s) | 0 | 1 |
| Overall Study | Administrative reasons | 0 | 1 |
| Overall Study | Adverse Event | 21 | 27 |
| Overall Study | Death | 11 | 10 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Patient no longer requires study drug | 3 | 7 |
| Overall Study | Protocol Violation | 10 | 8 |
| Overall Study | Unsatisfactory therapeutic effect | 4 | 4 |
| Overall Study | Withdrawal by Subject | 9 | 13 |
Baseline characteristics
| Characteristic | Zoledronic Acid Every 3 Months | Zoledronic Acid Every 4 Weeks | Total |
|---|---|---|---|
| Age Continuous | 60.4 years STANDARD_DEVIATION 11.9 | 59.8 years STANDARD_DEVIATION 11.8 | 60.1 years STANDARD_DEVIATION 11.9 |
| Sex: Female, Male Female | 209 Participants | 216 Participants | 425 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 133 / 209 | 161 / 216 |
| serious Total, serious adverse events | 21 / 209 | 29 / 216 |
Outcome results
Primary
Annual Overall Skeletal Morbidity Rate (SMR)
The SMR was computed by summing all Skeletal Related Event(s) (SREs)which occurred during the observation period and dividing it by the ratio days of observation period / 365.25, for each participant. SRE was defined as: pathologic bone fracture, spinal cord compression, surgery to bone both curative and prophylactic, radiation therapy to bone, or hypercalcemia of malignancy. SMR (years) = 365.25 x SMR(days) where SMR (days) = total number of SREs / total SRE risk period (days). Risk period for SMR was computed as the days from randomization date to the date of last visit.
Time frame: 12 months
Population: Intent-to-treat (ITT) population will include all randomized patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid Every 3 Months | Annual Overall Skeletal Morbidity Rate (SMR) | 0.26 Number of Skeletal Events per Year | Standard Deviation 0.81 |
| Zoledronic Acid Every 4 Weeks | Annual Overall Skeletal Morbidity Rate (SMR) | 0.22 Number of Skeletal Events per Year | Standard Deviation 0.57 |
Secondary
Annual Incidence of Any Skeletal Related Events (SREs)
Skeletal Related Events (SREs) are defined as a: * pathologic bone fracture such as non-vertebral and vertebral * spinal cord compression identified by X-rays evidence * surgery to bone both curative and prophylactic * radiation therapy to bone including palliative, therapeutic or prophylactic * hypercalcemia of malignancy, defined as a corrected serum calcium \> 12 mg/dl (3.00 mmol/l) or a lower level of hypercalcemia which is symptomatic and which requires active treatment other than rehydration. Annual incidence for each SRE was computed in the same way as annual overall SMR.
Time frame: 12 months
Population: Intent-to-treat (ITT) population will include all randomized patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid Every 3 Months | Annual Incidence of Any Skeletal Related Events (SREs) | Vertebral pathological fracture rate | 0.02 Number of SRE per Year | Standard Deviation 0.19 |
| Zoledronic Acid Every 3 Months | Annual Incidence of Any Skeletal Related Events (SREs) | Non-vertebral pathological fracture rate | 0.08 Number of SRE per Year | Standard Deviation 0.58 |
| Zoledronic Acid Every 3 Months | Annual Incidence of Any Skeletal Related Events (SREs) | Spinal cord compression rate | 0.01 Number of SRE per Year | Standard Deviation 0.1 |
| Zoledronic Acid Every 3 Months | Annual Incidence of Any Skeletal Related Events (SREs) | Radiation to bone rate | 0.17 Number of SRE per Year | Standard Deviation 0.67 |
| Zoledronic Acid Every 3 Months | Annual Incidence of Any Skeletal Related Events (SREs) | Surgery to bone rate | 0.02 Number of SRE per Year | Standard Deviation 0.21 |
| Zoledronic Acid Every 3 Months | Annual Incidence of Any Skeletal Related Events (SREs) | Hypercalcemia of malignancy rate | 0.01 Number of SRE per Year | Standard Deviation 0.08 |
| Zoledronic Acid Every 4 Weeks | Annual Incidence of Any Skeletal Related Events (SREs) | Surgery to bone rate | 0.00 Number of SRE per Year | Standard Deviation 0.07 |
| Zoledronic Acid Every 4 Weeks | Annual Incidence of Any Skeletal Related Events (SREs) | Vertebral pathological fracture rate | 0.02 Number of SRE per Year | Standard Deviation 0.15 |
| Zoledronic Acid Every 4 Weeks | Annual Incidence of Any Skeletal Related Events (SREs) | Radiation to bone rate | 0.14 Number of SRE per Year | Standard Deviation 0.43 |
| Zoledronic Acid Every 4 Weeks | Annual Incidence of Any Skeletal Related Events (SREs) | Non-vertebral pathological fracture rate | 0.03 Number of SRE per Year | Standard Deviation 0.2 |
| Zoledronic Acid Every 4 Weeks | Annual Incidence of Any Skeletal Related Events (SREs) | Hypercalcemia of malignancy rate | 0.02 Number of SRE per Year | Standard Deviation 0.16 |
| Zoledronic Acid Every 4 Weeks | Annual Incidence of Any Skeletal Related Events (SREs) | Spinal cord compression rate | 0.00 Number of SRE per Year | Standard Deviation 0.07 |
Secondary
Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score
ECOG Performance Score has 4 grades. 0 = Fully active, able to carry out all pre-disease activities; 1 = Restricted in strenuous activity but ambulatory and able to carry out work of light or sedentary nature; 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Active about 50% of waking hours; 3 = Capable of limited self-care, confined to bed/chair more than 50% of waking hours; 4 = Completely disabled; cannot carry on self-care. Totally confined to bed/chair. Outcome is given as median score for participants at Baseline and 3, 6 , 9 and 12 months of treatment
Time frame: At Baseline, Month 3, Month 6, Month 9 and Month 12
Population: Intent-to-treat (ITT) population will include all randomized patients.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Zoledronic Acid Every 3 Months | Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | Baseline | 0 score on a scale |
| Zoledronic Acid Every 3 Months | Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | Month 3 | 0 score on a scale |
| Zoledronic Acid Every 3 Months | Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | Month 9 | 0 score on a scale |
| Zoledronic Acid Every 3 Months | Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | Month 12 | 0 score on a scale |
| Zoledronic Acid Every 3 Months | Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | Month 6 | 0 score on a scale |
| Zoledronic Acid Every 4 Weeks | Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | Month 9 | 0 score on a scale |
| Zoledronic Acid Every 4 Weeks | Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | Baseline | 0 score on a scale |
| Zoledronic Acid Every 4 Weeks | Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | Month 3 | 0 score on a scale |
| Zoledronic Acid Every 4 Weeks | Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | Month 6 | 0 score on a scale |
| Zoledronic Acid Every 4 Weeks | Assessment of the Eastern Cooperative Oncology Group (ECOG) Performance Score | Month 12 | 0 score on a scale |
Secondary
Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire
Bone pain was assessed by means of a pain score obtained using the Brief Pain Inventory (BPI) questionnaire. The BPI can produce three pain scores: worst pain, a composite pain score, and a pain interference score. The composite pain score, which is the average of questions 3, 4, 5 and 6 of the questionnaire was used in this study. Pain was rated on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). The outcome is given as the median score for participants at baseline, and 3, 6, 9 and 12 months of treatment
Time frame: At Baseline, Month 3, Month 6, Month 9 and Month 12
Population: Intent-to-treat (ITT) population will include all randomized patients. All ITT patients with BPI questionnaire filled up at baseline were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Zoledronic Acid Every 3 Months | Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | Month 3 (N= 156, 163) | 2.3 score on a scale | Standard Deviation 2 |
| Zoledronic Acid Every 3 Months | Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | Month 9 (N= 131, 130) | 2.3 score on a scale | Standard Deviation 2.2 |
| Zoledronic Acid Every 3 Months | Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | Month 6 (N= 143, 160) | 2.3 score on a scale | Standard Deviation 2.2 |
| Zoledronic Acid Every 3 Months | Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | Month 12 (N= 135, 124) | 2.4 score on a scale | Standard Deviation 2.3 |
| Zoledronic Acid Every 3 Months | Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | Baseline (N= 186, 185) | 2.0 score on a scale | Standard Deviation 1.8 |
| Zoledronic Acid Every 4 Weeks | Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | Month 12 (N= 135, 124) | 2.1 score on a scale | Standard Deviation 2 |
| Zoledronic Acid Every 4 Weeks | Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | Baseline (N= 186, 185) | 2.1 score on a scale | Standard Deviation 1.9 |
| Zoledronic Acid Every 4 Weeks | Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | Month 3 (N= 156, 163) | 2.2 score on a scale | Standard Deviation 1.9 |
| Zoledronic Acid Every 4 Weeks | Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | Month 6 (N= 143, 160) | 1.9 score on a scale | Standard Deviation 1.8 |
| Zoledronic Acid Every 4 Weeks | Composite Bone Pain Score According to the Brief Pain Inventory (BPI) Questionnaire | Month 9 (N= 131, 130) | 2.1 score on a scale | Standard Deviation 2 |
Secondary
Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value
Pain intensity at rest and on movement is rated by the patient by means of a validated 6-point Verbal Rating Scale (VRS) and refers to the pain which occurred during the last week before the assessment. Median score value is the median of all the observed scores (none=0, very mild=1, mild=2, moderate=3, severe=5 and very severe=6) at each time point.
Time frame: At Baseline, Month 3, Month 6, Month 9 and Month 12
Population: Intent-to-treat (ITT) population will include all randomized patients.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Zoledronic Acid Every 3 Months | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Rest: Baseline | 1 score on a scale |
| Zoledronic Acid Every 3 Months | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Rest: Month 3 | 2 score on a scale |
| Zoledronic Acid Every 3 Months | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Rest: Month 6 | 2 score on a scale |
| Zoledronic Acid Every 3 Months | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Rest: Month 9 | 1 score on a scale |
| Zoledronic Acid Every 3 Months | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Rest: Month 12 | 2 score on a scale |
| Zoledronic Acid Every 3 Months | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Movement : Baseline | 2 score on a scale |
| Zoledronic Acid Every 3 Months | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Movement : Month 3 | 2 score on a scale |
| Zoledronic Acid Every 3 Months | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Movement : Month 6 | 2 score on a scale |
| Zoledronic Acid Every 3 Months | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Movement : Month 9 | 2 score on a scale |
| Zoledronic Acid Every 3 Months | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Movement : Month 12 | 2.5 score on a scale |
| Zoledronic Acid Every 4 Weeks | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Movement : Month 6 | 2 score on a scale |
| Zoledronic Acid Every 4 Weeks | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Rest: Baseline | 1 score on a scale |
| Zoledronic Acid Every 4 Weeks | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Movement : Baseline | 2 score on a scale |
| Zoledronic Acid Every 4 Weeks | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Rest: Month 3 | 2 score on a scale |
| Zoledronic Acid Every 4 Weeks | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Movement : Month 12 | 2 score on a scale |
| Zoledronic Acid Every 4 Weeks | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Rest: Month 6 | 1 score on a scale |
| Zoledronic Acid Every 4 Weeks | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Movement : Month 3 | 2 score on a scale |
| Zoledronic Acid Every 4 Weeks | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Rest: Month 9 | 1 score on a scale |
| Zoledronic Acid Every 4 Weeks | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Movement : Month 9 | 2 score on a scale |
| Zoledronic Acid Every 4 Weeks | Evaluation of Pain According to Verbal Rating Scale (VRS) Based on Median Score Value | At Rest: Month 12 | 1 score on a scale |
Secondary
Median Time to First Skeletal Related Event(s) (SRE)
Median Time to first skeletal related event (SRE) is defined as the time from randomization to the date of first occurrence of any SRE which includes at least one of the following: radiation therapy to bone, pathologic bone fracture, spinal cord compression, surgery to bone, and hypercalcemia of malignancy (HCM). Due to the few numbers of SRE, Kaplan-Meier estimate never reaches a failure probability \>=25%; so median time, 25th and 75th percentiles are not determined.For this reason only the estimated percentage of patient SRE free are reported at each time point.
Time frame: 12 month
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid Every 3 Months | Median Time to First Skeletal Related Event(s) (SRE) | NA Day |
| Zoledronic Acid Every 4 Weeks | Median Time to First Skeletal Related Event(s) (SRE) | NA Day |
Secondary
Percentage of Participants Experiencing Skeletal Related Event(s) (SREs)
Skeletal Related Events (SREs) are defined as a: * pathologic bone fracture such as non-vertebral and vertebral compression fractures * spinal cord compression identified by positive diagnosis documented by X-ray evidence * surgery to bone both curative and prophylactic * radiation therapy to bone including palliative, therapeutic or prophylactic * hypercalcemia of malignancy, defined as a corrected serum calcium \> 12 mg/dl (3.00 mmol/l) or a lower level of hypercalcemia which is symptomatic and which requires active treatment other than rehydration.
Time frame: 12 month
Population: Intent-to-treat (ITT) population will include all randomized patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid Every 3 Months | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Non vertebral pathological fracture | 3.35 Percentage of Participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Radiation to bone | 10.53 Percentage of Participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Vertebral pathological fracture | 1.44 Percentage of Participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Hypercalcemia of malignancy | 0.48 Percentage of Participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Spinal cord compression | 0.96 Percentage of Participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Surgery to bone | 0.96 Percentage of Participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Patient with any SRE | 14.83 Percentage of Participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Surgery to bone | 0.46 Percentage of Participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Patient with any SRE | 15.28 Percentage of Participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Vertebral pathological fracture | 1.85 Percentage of Participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Non vertebral pathological fracture | 2.31 Percentage of Participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Spinal cord compression | 0.46 Percentage of Participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Radiation to bone | 11.11 Percentage of Participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Experiencing Skeletal Related Event(s) (SREs) | Hypercalcemia of malignancy | 1.85 Percentage of Participants |
Secondary
Percentage of Participants Skeletal Related Event (SRE) Free
Percentage of participants SRE free is defined as the Kaplan-Meier estimate of participants free of any Skeletal Related Events(SRE) at each time point. Skeletal Related Events (SREs) are: * pathologic bone fracture; non-vertebral and vertebral * spinal cord compression identified by X-rays * surgery to bone both curative and prophylactic * radiation therapy to bone (palliative, therapeutic or prophylactic) * hypercalcemia of malignancy, defined as a corrected serum calcium \> 12 mg/dl (3.00 mmol/l) or a lower level which is symptomatic and requires treatment other than rehydration.
Time frame: 12 months
Population: Intent-to-treat (ITT) population will include all randomized patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid Every 3 Months | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 5 | 94 Percentage of participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 11 | 83 Percentage of participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 8 | 86 Percentage of participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 12 | 78 Percentage of participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 3 | 96 Percentage of participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 9 | 85 Percentage of participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 4 | 94 Percentage of participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 2 | 98 Percentage of participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 6 | 93 Percentage of participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 10 | 84 Percentage of participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 7 | 88 Percentage of participants |
| Zoledronic Acid Every 3 Months | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 1 | 99 Percentage of participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 7 | 90 Percentage of participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 1 | 98 Percentage of participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 2 | 98 Percentage of participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 4 | 95 Percentage of participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 8 | 88 Percentage of participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 9 | 85 Percentage of participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 10 | 83 Percentage of participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 11 | 83 Percentage of participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 12 | 82 Percentage of participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 3 | 97 Percentage of participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 5 | 93 Percentage of participants |
| Zoledronic Acid Every 4 Weeks | Percentage of Participants Skeletal Related Event (SRE) Free | At Month 6 | 92 Percentage of participants |
Secondary
Use Of Analgesic Medications According to the Analgesic Score Scale
The analgesic score used for this study is modified from the Radiation Therapy Oncology Group (RTOG) analgesic score scale. The scale represents type of medication administered from 0 to 4 where: 0 = None 1. = Minor analgesics (aspirin, NSAID, acetaminophen, propoxyphene, etc.) 2. = Tranquilisers, antidepressants, muscle relaxants, and steroids 3. = Mild narcotics (oxycodone, meperidine, codeine, etc.) 4. = Strong narcotics (morphine, hydromorphone, etc.) The outcome is given a the median score for the participants at Baseline and 3, 6, 9 and 12 months of treatment
Time frame: At Baseline, Month 3, Month 6, Month 9 and Month 12
Population: Intent-to-treat (ITT) population will include all randomized patients.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Zoledronic Acid Every 3 Months | Use Of Analgesic Medications According to the Analgesic Score Scale | Baseline | 0 score on a scale |
| Zoledronic Acid Every 3 Months | Use Of Analgesic Medications According to the Analgesic Score Scale | Month 3 | 0 score on a scale |
| Zoledronic Acid Every 3 Months | Use Of Analgesic Medications According to the Analgesic Score Scale | Month 9 | 0 score on a scale |
| Zoledronic Acid Every 3 Months | Use Of Analgesic Medications According to the Analgesic Score Scale | Month 12 | 0 score on a scale |
| Zoledronic Acid Every 3 Months | Use Of Analgesic Medications According to the Analgesic Score Scale | Month 6 | 0 score on a scale |
| Zoledronic Acid Every 4 Weeks | Use Of Analgesic Medications According to the Analgesic Score Scale | Month 6 | 0 score on a scale |
| Zoledronic Acid Every 4 Weeks | Use Of Analgesic Medications According to the Analgesic Score Scale | Month 12 | 0 score on a scale |
| Zoledronic Acid Every 4 Weeks | Use Of Analgesic Medications According to the Analgesic Score Scale | Month 3 | 0 score on a scale |
| Zoledronic Acid Every 4 Weeks | Use Of Analgesic Medications According to the Analgesic Score Scale | Baseline | 0 score on a scale |
| Zoledronic Acid Every 4 Weeks | Use Of Analgesic Medications According to the Analgesic Score Scale | Month 9 | 0 score on a scale |