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    2019-04-11

    We have recently completed a prospective randomized feasibility study of de-escalated bisphosphonate treatment with intravenous pamidronate in patients with metastatic breast cancer to bone [7]. Here we report on an analysis utilizing data from this trial aimed at comparing BPI and FACT-BP and to correlate these with bone turnover markers.
    Methods We utilized data from a randomized, non-inferiority feasibility trial conducted in a single large cancer center [7]. The trial enrolled women with breast cancer and radiological or biopsy confirmed bone metastases with bone turnover marker C-telopeptide (CTx) levels in the low-risk range (defined as serum CTx levels in the lowest tertile [<600ng/L]). Eligible patients were stratified according to baseline serum CTx (<400ng/L and 400–600ng/L) and duration of prior bisphosphonate use (<6 months and >6 months) and were then randomly allocated to receive 90mg pamidronate intravenously every 3–4 weeks (control group) or every 12 weeks (de-escalated group). Serum was collected from enrolled patients following an overnight fast at baseline and weeks 12, 24, 36 and 48. Patients also completed the BPI and the 16-item version of FACT-BP at the same times at baseline, and weeks 12, 24, 36 and 48. Those remaining in the low-risk CTx group continued to receive their allocated treatment. Those whose CTx levels rose above 600ng/L remained on study, but thereafter received treatment every 3–4 weeks. Censoring was carried out for any patient receiving phenylephrine hydrochloride cost therapy to bone or a change in systemic therapy. The trial was approved by the respective institutional Research Ethic Board. Data on cumulative scores for both BPI and FACT-BP have been reported elsewhere [7]. Here, we also assessed item-level scores such as average pain over the past 7 days, worst pain over the past 7 days, and pain right now.
    Results A total of 38 patients were randomized with 19 patients in each arm, and 29 patients completed FACT-BP and BPI at baseline. At week 12, data was available for correlation of pain scores with bone turnover marker levels for 22 patients, 11 patients completed questionnaires at week 48 (Table 2).
    Conclusion Despite skeletal morbidity being associated with reduced quality of life and shortened survival, a reduction in the rate of skeletal related events (SREs) with bone-targeted agents has not shown any improvement in global quality of life scores or survival [8–12]. This raises a question regarding the sole use of SREs as clinically relevant endpoints. Bone pain is usually the earliest and most common symptom in patients developing skeletal metastases. Patient-reported bone pain reflects an individual patient\'s experience regarding pain severity and its impact on functioning and QoL. Bone pain is a logical candidate for evaluating treatment efficacy. Several groups have therefore been developing scores that are meaningful, valid, easy and fast to complete and assess. Matza and colleagues measured bone pain in oncology trials, and concluded that most approaches used simple assessment of general bodily pain, often with single items [2]. They recommended that bone pain assessment tools be validated within the target population (i.e., people with bone pain), and have sufficient content validity to represent the important concerns and specific impact of this unique pain experience. The Functional Assessment of Cancer Therapy-Bone Pain (FACT-BP) was developed in 2004 and published in 2009 [5], to provide such a tool. Similarly, others have tried to link biomarkers of bone turnover with a range of other pertinent surrogates [13]. The current results show that FACT-BP and BPI correlated well with each other over time. In addition, using either of these methods of assessment of pain, no differences were observed between the pain scores in the two study arms. While interestingly, we acknowledge the limitations of the current study. REFORM was a small randomized pilot study, thus it remains possible that the small number of patients analyzed presently could impact the present results. However, our findings support the use of FACT-BP in larger cohorts assessing bone targeted trials, particularly those focused on patients considered to be at low risk, as levels of the standard bone turnover biomarkers CTx and BSAP may not truly reflect the impact of the disease on a patient\'s well being. Our reasoning for this choice is that it correlates quite well with the most commonly-used pain instrument in prior bone pain trials, the BPI, and yet it introduces a wider variety of content which enhances the validity and applicability of the assessment to patients\' lives [2]. We thus plan to incorporate FACT-BP in larger bone-targeted trials for further evaluation of its validity.