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  • We are aware that physician

    2019-05-14

    We are aware that physician surveys have been previously used to assess; bisphosphonate use for bone pain [14], bisphosphonate use in metastatic breast cancer patients [15] and radiotherapy use for painful bone metastases [16] but are not aware of physician surveys being used to help design trials of bone-targeted agents. Given the need for larger definitive studies this survey was designed to develop a greater understanding of the current clinical practice at Canadian centers in terms of frequency of use of bone-targeted agents and preferred choice of agent and frequency of administration. It was also designed to explore the degree of clinical equipoise which would underlie potential future trials of de-escalated bone-targeted therapy in breast and prostate cancer patients. Input on core methodological considerations for such trials was also explored. The results from this survey tell several important aspects of current clinical practice that can be explored in trials. The first component was devised to collect pertinent demographic information of the population of respondents, as well as to determine what proportion amongst them that use bone-targeted agents to treat their patients. Firstly, it is evident that bone-targeted agents are commonly used for both breast and prostate patients with metastatic bone disease. It is also clear that the rationale for starting these agents are indeed based on practice guidelines [18,19]. The second component was designed to gain an understanding of current Canadian clinical practice by collecting information from those respondents who prescribe bone-targeted agents. Specifically we sought to collect information with regard to intended benefits from bone-targeted agent use, scenarios in which they prescribe bone-targeted agents and their choice of agent for their patients. From this part of the study it was clear that the rationale for starting these agents was based on practice guidelines [18,19]. Respondents primarily provide bone-targeted agents to reduce the risk of skeletal related events and improve pain control. Few felt that these agents had any effect on either progression-free or overall survival. The choice of bone-targeted agent reflected funding and therefore more agents were used in breast cancer patients (pamidronate, clodronate, zoledronic Talabostat mesylate or denosumab) than in prostate cancer patients (zoledronic acid or denosumab). Treatments are usually given every 3–4 weeks and once started clinicians rarely stopped therapy. Also of interest was the fact that few clinicians use biomarkers of bone turnover to assess response to therapy. With respect to discontinuation of bone-targeted therapy clinicians did not feel that worsening of bone pain, the presence of radiographic evidence of progression or the occurrence of an SRE while on a bone-targeted agent was an indication to stop this therapy. Indeed, the most common reasons for treatment cessation was a marked deterioration in patient performance status. In the third component, respondents were presented with a series of questions related to the design of a future clinical trial geared toward studying the clinical benefits of de-escalated therapy, with topics of interest including outcome selection and patient inclusion criteria. With respect to potential future trials, given that once started these agents are rarely stopped, it would appear that initiating a study of effect of drug cessation would be extremely difficult to do from a practical standpoint. It is also evident that there is more variability in the choice of bone-targeted agent in Talabostat mesylate the treatment of breast cancer patients than in prostate cancer, which is likely a reflection of differential funding for these agents. This means that for a de-escalation trial to be performed in breast cancer patients the design would need to incorporate the use of different bone-targeted agents. The results do however confirm that physicians are very interested in de-escalation trials and that they would consider de-escalating therapy from every 3–4 weeks to 3 monthly therapy and entering patients on such a study at anytime from 3 months to 2 years after starting treatment. However, physicians do want the primary study endpoint to be SRE [11] and not biomarker studies using biomarkers of bone turnover as a surrogate for skeletal related event risk [12]. Ultimately the results from our survey confirms that trials exploring de-escalated use of bone targeted agents are wanted for both breast and prostate cancer and that ultimately there will remain a need for further very large randomised trials with skeletal related events as the primary endpoint.