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    • In patients who develop bone metastases these are

    2019-06-18

    In patients who develop bone metastases, these are commonly diagnosed at the time of their initial work up for their metastatic disease (∼80%) [7], although others can develop skeletal metastases at any time during the disease course. The consequences of bone metastases include pain (∼80%) [3,6,8] and skeletal-related events (SRE\'s). SREs are defined as: pathological fractures; spinal cord or nerve root compression; the requirement for surgery or radiotherapy to bone; or hypercalcemia of malignancy. SREs occur in approximately half of lung cancer patients with bone BMS 470539 dihydrochloride [3,9,10]. Not surprisingly, these events negatively impact quality of life, performance status, and independent functioning. In addition, patients who experience one SRE are then at significant risk for developing additional SRE\'s and may possibly have a shorter survival [3,9]. It is not surprising therefore that the diagnosis of bone metastases and the occurrence of SREs frequently require therapeutic intervention, with an associated impact on increased health care costs [11,12]. The exact mechanism of bone breakdown is not fully understood in lung cancer. However, it is likely similar to what has been observed in bone metastases arising from other tumour types. Bone breakdown, or osteolysis, results from a disruption of the normal balance of bone resorption and formation controlled by opposing functions of the osteoclast and the osteoblast. As osteoclast activity is responsible for bone degradation, it has become an important target for drug intervention leading to the development of bisphosphonates and more recently the antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL), denosumab. A number of trials have shown that treatment with osteoclast inhibiting agents is associated with a reduction in both the risk of, and time to development of SREs [13–17]. Bone-targeted therapies appear to be less commonly used in patients with bone metastases arising from lung cancer (6–50%) as compared with those from breast (80%) and prostate cancers(23%–70%) [3,7,18–20]. The reasons for this discrepancy are unknown, however may reflect the belief that patients with bone metastases from advanced lung cancer already have such a poor outcome that bone-targeted therapies are unlikely to significantly help as there is insufficient time for significant bone re-modelling. To further evaluate whether this is true we decided to review the literature in order to evaluate the frequency, consequences, and outcome of patients with lung cancer and bone metastases. We further examined literature describing the impact of bone-targeted therapy in both clinical trial and non-trial populations. This review could help determine whether or not the use of these agents may be warranted.
    Methods
    Results
    Discussion There is clearly much more to learn regarding the use of bone-targeted agents in these patients. Although the data from clinical trial cohorts compared to the general lung cancer population are similar (particularly the incidence of SREs and survival) there are a few notable differences between the datasets, such as the performance status being slightly worse in the non-trial versus trial populations [62]. There is also increasing evidence regarding the role of EGFR TKIs, such as gefitinib and erlotinib, in the treatment of bone metastases. In a Japanese series of 127 NSCLC patients with bone metastases, of whom 50% had activating EGFR mutations, the time to SRE was significantly longer in mutation positive patients treated with EGFR TKI than mutation negative patients (13 vs. 6 months, p<0.05) [40]. It would be interesting to investigate the impact on bone metastases in the numerous clinical trials that have randomized patients to chemotherapy versus erlotinib or gefitinib in EGFR mutation positive patients [63–66]. Finally, bone metastases and SREs contribute to the high economic burden of the treatment of patients with metastatic lung cancer [12]. The overall prognosis of metastatic lung cancer patients is poor, however, given the high incidence of symptomatic SREs, pain emerging in the first few months from diagnosis, and the costs associated with treatment of their SREs, it seems that these patients may significantly benefit from more routine use of bone-targeted agents. We do however need better predictive markers for the development of bone metastasis and SRE\'s in lung cancer patients to guide clinicians in the more appropriate use of bone targeted therapy for these patients. Some retrospective analyses suggest that high NTX levels, male sex, multiple bone metastases, and poor performance status may be predictors of SRE\'s, however these should be further validated in additional prospective cohorts.