Bisphosphonate Use in Patients with Lung Cancer and Bone Metastases: Recommendations of a European Expert Panel Filippo De Marinis, MD, Wilfried Eberhardt,

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Bisphosphonate Use in Patients with Lung Cancer and Bone Metastases: Recommendations of a European Expert Panel Filippo De Marinis, MD, Wilfried Eberhardt, MD, Peter G. Harper, MD, Bartomeu Massuti Sureda, MD, Kristiaan Nackaerts, MD, PhD, Jens Benn Soerensen, MD, PhD, Kostas Syrigos, MD, PhD, Jean Trédaniel, MD, PhD Journal of Thoracic Oncology Volume 4, Issue 10, Pages 1280-1288 (October 2009) DOI: 10.1097/JTO.0b013e3181b68e5a Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Graph of data from Rosen et al.76 describing the total percentage of patients experiencing skeletal-related events (SREs; green). Also indicated is the percentage of patients suffering pathologic fracture (pink), requiring radiotherapy (dark blue), undergoing surgical intervention (light blue), or experiencing spinal cord compression (gray). Journal of Thoracic Oncology 2009 4, 1280-1288DOI: (10.1097/JTO.0b013e3181b68e5a) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Treatment algorithm for advanced non-small cell lung cancer (NSCLC). The treatment scheme was developed by the authors based on current treatment recommendations and their own clinical experience. Patients in performance status 0 to 2 should undergo chemotherapy as 1st line treatment. Chemotherapy should be supported by the use of bisphosphonates. Also for 2nd and 3rd line therapy, a combination of chemotherapeutics or the tyrosine kinase inhibitor erlotinib with bisphosphonates is recommended. In the performance status 3 to 4, patients with lung cancer may be treated with bisphosphonates on an individual basis. Journal of Thoracic Oncology 2009 4, 1280-1288DOI: (10.1097/JTO.0b013e3181b68e5a) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Cellular mechanisms of osteoclast-mediated bone resorption: cancer cells produce factors that stimulate both osteoclast and osteoblast activity. Overproduction of cytokines with osteoclast activation function results from interaction between cancer cells and stromal cells. Interleukin (IL)-6, IL-11, IL-1β, tumor necrosis factor (TNF)α, and macrophage colony-stimulating factor (M-CSF) are produced predominantly by stromal cells, whereas hepatocyte growth factor (HGF), macrophage inflammatory protein (MIP)-1α, MIP-1β, IL-1, osteopontin (OPN), IL-6, and parathyroid hormone-related protein are primarily produced by myeloma cells. Receptor activator of NF-kappaB (RANK) ligand (RANKL), a potent activator of osteoclasts, is expressed and secreted by stimulated stromal cells. RANKL binds to RANK on the surface of precursor and mature osteoclasts, activating bone resorption. When the ratio of RANKL/osteoprotegerin (OPG) is skewed in favor of RANKL, the normal regulatory effect of OPG is bypassed. This results in increased osteoclastogenesis and osteoclast function. The disruption of this RANK/RANKL/OPG axis is regarded as the main cause of the progression of bone metastases. Journal of Thoracic Oncology 2009 4, 1280-1288DOI: (10.1097/JTO.0b013e3181b68e5a) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Graph based on data from Rosen et al.76 shows that zoledronic acid reduced the proportion of patients with a skeletal-related events (SRE) across all types of SRE. Journal of Thoracic Oncology 2009 4, 1280-1288DOI: (10.1097/JTO.0b013e3181b68e5a) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Graph of data from Rosen et al. demonstrates that zoledronic acid increased the median time to the first skeletal-related event (SRE).29 Journal of Thoracic Oncology 2009 4, 1280-1288DOI: (10.1097/JTO.0b013e3181b68e5a) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 6 Survival patterns of patients with non-small cell lung cancer (NSCLC) based on NTX levels at baseline. Graphs are adapted with permission from J Thorac Oncol Copyright 2008.15 NTX, amino-terminal crosslinking telopeptide of collagen. Journal of Thoracic Oncology 2009 4, 1280-1288DOI: (10.1097/JTO.0b013e3181b68e5a) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 7 Kaplan Meier estimated cumulative costs of skeletal-related event (SRE)- and non SRE-related care. Graphs are adapted with permission from J Thorac Oncol Copyright 2006.57 Journal of Thoracic Oncology 2009 4, 1280-1288DOI: (10.1097/JTO.0b013e3181b68e5a) Copyright © 2009 International Association for the Study of Lung Cancer Terms and Conditions