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    • gpr109a inhibitor The exhibited efficacies of bone targeting

    2019-05-17

    The exhibited efficacies of bone targeting treatments, in phase III clinical trials, suggest significant progress in delaying skeletal-related events, with improvements having been seen in the direct comparisons between generations of drugs. These findings also lend clear support to the utility of bone targeted agents in comparison to treatment with placebo. An analysis of phase III trials attests to zoledronic acid’s increased benefits over previous generations of bisphosphonates. For this reason, it is the only bisphosphonate that has received US and European approval for treatment of bone metastases, independent of primary tumor type [6]. As treatment intent for patients with advanced cancer is to improve quality of life, it is important to consider the potential burden of debilitating SREs. Previous studies have found that after SREs, significant decline not limited to physical well-being, but also emotional and functional well-being is seen [11]. In addition, negative financial impact is also observed in patients who have an SRE; the estimated SRE-related cost per patient is USD 11,979 in one’s lifetime [11]. This cost, in addition to subsequent supportive care, totals approximately USD 28,000 per patient [12]. Of this, radiotherapy accounted for the greatest proportion of cost (61%) by SRE type, followed by bone surgery (21%) [11]. It is important to note that approximately 80% of the costs of treatment of SREs are incurred within 2 months of the first SRE-related claim. Therefore, proper management with bone targeted therapies are highly relevant in this population, and our study adds to growing evidence supporting the importance of therapy to help prevent or delay bone resorption. The fact that the SMR decreased in placebo arms over time hints that management of patients with bone metastases and awareness of the risk of SREs has improved. It is possible that, over time, due to improved understanding of bone biology, recognition of early symptoms of bone metastases, gpr109a inhibitor of an improving selection of anti-cancer therapeutic options, early introduction of treatment and better skeletal care education, SRE incidence has declined and will continue do so over time. In the past decade, improvements have been made to allow for early detection of spinal cord compression; magnetic resonance imaging (MRI) has been demonstrated to be the most reliable method, with 95% diagnostic accuracy [13]. Prophylactic stabilization and the use of prophylactic surgery for metastatic lesions have also been shown to provide a distinct survival advantage and are associated with relatively low perioperative risk [14]. These improvements in management could be reflected in the SMR decrease in the placebo arms over time. In a study of immediate or delayed treatment with zoledronic acid, immediate-start zoledronic acid was found to increase the prevention of bone loss, a factor that can contribute to SREs such as pain and fractures [15]. These results demonstrate the effect of timely treatment that could similarly be revealed in SMR data. A similar effect can be seen with denosumab studies, where better hazard ratio is seen among patients with no prior SRE, compared to those with prior SREs [16]; this indicates increased prevention ability with timely treatment. No data was collected with respect to the date of diagnosis or metastasis of patients, making it difficult to determine the state of the disease at which the patients were referred. But, perhaps this amelioration in management strategies in the latter time period, concurrent with increased bisphosphonate efficacy, could elucidate our SMR trend. It is also possible that primary therapies directed at the tumour might have had an effect on the time trend results. While the primary therapy practice has not changed; the proportion of patients receiving it has. For example, since the introduction of docetaxel in prostate cancer, across the studies, up to 82% of patients were on chemotherapy. In comparison, in a contemporary trial with the RANKL inhibitor denosumab performed by Fizazi et al. [10], the benefits of bone targeted agents were seen while one third of patients received docetaxel. It can also be seen that in the later studies examined 40% of breast cancer patients had been placed on chemotherapy [7]. While data on whether patients were on chemotherapy was limited, these discrepancies could account for the SMR trend. The proportion of patients on chemotherapy may also reflect a change in the need for primary therapy or changes in patient options. This change in chemotherapy use could account for the trends in SMR rates in the placebo arms of the studies.