Official Title
A Multicentre Study Assessing 12-Weekly Intravenous Bisphosphonate Therapy in Women with Low Risk Bone Metastases from Breast Cancer Using Bone Resorption Markers
Summary:
You are being asked to consider taking part in a research study because you are a woman with breast cancer that has spread to bone (bone metastases). You are currently receiving a drug called pamidronate every 3 to 4 weeks. Pamidronate is a drug from the bisphosphonate group of drugs. This treatment can prevent and delay complications resulting from spread of breast cancer to bones. However, this treatment is associated with side effects and some of them, such as kidney failure and, jawbone necrosis (death of tissue), could be very serious. Currently, women with different levels of bone involvement receive the same dose of pamidronate on the same schedule (every 3-4 weeks). It is likely that women with low levels of bone involvement are being over treated and exposed to the potential side effects of these drugs unnecessarily. It may be that women with low levels of bone involvement are being over treated and treatment can occur less often.
Bone affected by cancer cells usually releases a number of chemicals into the blood stream. A number of these chemicals can be measured by simple blood tests. The studies show that one such test, called C-telopeptide (CTx) might show the level of bone involvement by cancer and the risk of developing complications from the bone cancer.
This study will look at biomarkers to see if women with low levels of bone involvement can have less treatment. Pamidronate is approved by Health Canada and the Food and Drug Administration (FDA, United States) for the treatment of bone metastases in breast cancer, however only in the standard 3-4 weekly regimen. Health Canada has allowed pamidronate to be given every 12 weeks in this clinical study. The usual treatment for your disease is pamidronate given once every 3-4 weeks.
Trial Description
Primary Objective
- To demonstrate that in women with biochemical evidence of lower risk bone metastases (defined as CTx levels <600 ng/L) following at least three months of regular 3-4 weekly pamidronate, the administration of pamidronate once every 12 weeks is sufficient to maintain this biochemical stability for one year. Biochemical failure in this trial will be defined as CTx levels >600 ng/L measured at predefined time points.
Secondary Objectives
- To evaluate the palliative benefit of 12-weekly intravenous pamidronate therapy as reflected by self-reported pain using the validated Brief Pain Inventory (BPI) [35] and Functional Assessment of Cancer Therapy-Bone Pain (FACT-BP) questionnaires [36].
- To assess the frequency of SREs in patients with lower risk bone metastases receiving 12 weekly intravenous pamidronate for one year. This will be compared with the frequency of SREs in those patients who were unable to enter the trial as their CTx levels were too high at baseline and therefore remained on their regular 3-4 weekly pamidronate schedule
Over 70% of women with metastatic breast cancer will have skeletal involvement, making it the most common site of metastatic disease. Metastatic bone disease is a major cause of morbidity and mortality for patients. In terms of morbidity, complications resulting from bone metastases include pain, reduced mobility and a reduced quality of life. In addition patients are at a considerable risk of skeletal related events (SREs) which are defined as; the requirement for surgery and/or radiotherapy to bone, pathological fractures, hypercalcemia, and spinal cord compression. It is important that a new approach is developed for optimal dosing of bisphosphonates based on an individual patient’s actual risk of SREs. The use of innovative markers of bone turnover such as urinary N-telopeptide (NTx), and serum C-telopeptide (CTx) have allowed for the collection of valuable prognostic and predictive information in patients with bone metastases and allow for improved ability to determine individual SRE risk. The question to be answered by the current proposal is whether patients with lower risk disease as defined through bone biomarkers can be satisfactorily managed with a reduced frequency of intravenous pamidronate therapy.
Assessment of sCTX can be done with a commercially available enzyme-linked immunosorbent assay which quantitates the level of sCTX in the serum or plasma. Reported reproducibility of the assay is good, with intra-assay and inter-assay coefficients of variation (CVs) of <10%. Since diurnal variation of the test can exist, a fasting morning sample is recommended. The lower and upper detection limits are 10 and 6000 ng/L respectively. Based on large prospective cohorts, 3 risk groups have been identified: a very low risk group with values of approximately <400ng/L, an intermediate group with values between 400-600 ng/L, and a high risk group with values >600ng/L.
Markers of bone resorption will likely guide more rational bisphosphonate treatment in the clinic, including optimal doses, frequency of administration, choice of bisphosphonate agent, and potential indications for switching or stopping a particular bisphosphonate.
This study is a single arm study. Potential candidates for this trial must have received pamidronate for no less than 3 months. Should eligible patients agree to participate, testing for sCTx, which is performed on a fasting morning blood sample, will be performed. Patients whose baseline sCTx is <600 ng/L will be initiated on the 12-weekly regimen. Patients continuing on study will be monitored for changes to their sCTx on weeks 6, 12, 24, 36 and 48, where baseline will be taken as the time of their previous pamidronate infusion prior to study entry. If the sCTx level in any subject rises above 600 ng/L while on the 12-weekly treatment arm, a repeat test will be carried out 4 weeks later to confirm the stability of the rise; once the rise is confirmed, the subject will be reverted back to a 3-4 weekly regimen. At all times when sCTx is evaluated, serum and urine will also be collected and stored for future correlative studies of bone turnover.
Data on pain, occurence of any SREs, analgesic use and resource utilization will be collected by use of validated questionnaires BPI and FACT-BP at the same time points noted above i.e. at baseline and weeks 6, 12, 24, 36 and 48. Use of analgesics administered over the study period will also be collected and converted into an oral Morphine-equivalent dose. This data will then used to adjust their potential effect on pain score assessment.
Optional blood and urine samples will also be collected (with patient’s consent) at baseline and weeks 6, 12, 24, 36, and 48. These samples will be stored and at the end of the study will be batch-tested for bone resorption markers including NTx and PN1P (n-terminal propeptide of type 1 procollagen).
