Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases

PURPOSE: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning. METHODS: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. RESULTS: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. CONCLUSIONS: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning

Utilities associated with subcutaneous injections and intravenous infusions for treatment of patients with bone metastases

Introduction: Although cost−utility models are often used to estimate the value of treatments for metastatic cancer, limited information is available on the utility of common treatment modalities. Bisphosphonate treatment for bone metastases is frequently administered via intravenous infusion, while a newer treatment is administered as a subcutaneous injection. This study estimated the impact of these treatment modalities on health state preference. Methods: Participants from the UK general population completed time trade-off interviews to assess the utility of health state vignettes. Respondents first rated a health state representing cancer with bone metastases. Subsequent health states added descriptions of treatment modalities (ie, injection or infusion) to this basic health state. The two treatment modalities were presented with and without chemotherapy, and infusion characteristics were varied by duration (30 minutes or 2 hours) and renal monitoring. Results: A total of 121 participants completed the interviews (52.1% female, 76.9% white). Cancer with bone metastases had a mean utility of 0.40 on a standard utility scale (1 = full health; 0 = dead). The injection, 30-minute infusion, and 2-hour infusion had mean disutilities of −0.004, −0.02, and −0.04, respectively. The mean disutility of the 30-minute infusion was greater with renal monitoring than without. Chemotherapy was associated with substantial disutility (−0.17). When added to health states with chemotherapy, the mean disutilities of injection, 30-minute infusion, and 2-hour infusion were −0.02, −0.03, and −0.04, respectively. The disutility associated with injection was significantly lower than the disutility of the 30-minute and 2-hour infusions (P , 0.05), regardless of chemotherapy status. Conclusion: Respondents perceived an inconvenience with each type of treatment modality, but injections were preferred over infusions. The resulting utilities may be used in cost−utility models examining the value of treatments for the prevention of skeletal-related events in patients with bone metastases

Reduction of circulating cholesterol and apolipoprotein levels during sepsis

Sepsis with multiple organ failure is frequently associated with a substantial decrease of cholesterol levels. This decrease of cholesterol is strongly associated with mortality suggesting a direct relation between inflammatory conditions and altered cholesterol homeostasis. The host response during sepsis is mediated by cytokines and growth factors, which are capable of influencing lipid metabolism. Conversely lipoproteins are also capable of modulating cytokine production during the inflammatory response. Therefore the decrease in circulating cholesterol levels seems to play a crucial role in the pathophysiology of sepsis. In this review the interaction between cytokines and lipid metabolism and its clinical consequences will be discussed

Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases

PURPOSE: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning. METHODS: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. RESULTS: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. CONCLUSIONS: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning

Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease

Changes in Bone Turnover Marker Levels and Clinical Outcomes in Patients With Advanced Cancer and Bone Metastases Treated With Bone Antiresorptive Agents

Purpose: Bone antiresorptive agents can significantly reduce bone turnover markers (BTMs) in patients with advanced cancer. We evaluated association of changes in BTMs with overall survival (OS), disease progression (DP), and disease progression in bone (DPB) in patients with advanced cancer and bone metastases following denosumab or zoledronic acid treatment. Experimental Design: This is an integrated analysis of patient-level data from three identically designed, blinded, phase III trials with patients randomized to subcutaneous denosumab or intravenous zoledronic acid. Levels of the BTMs urinary N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBSAP) measured at study entry and month 3 were analyzed. OS, DP, and DPB were compared in patients with BTMs {greater than or equal to} median vs < median based on month 3 assessments. Results: uNTx levels {greater than or equal to} the median of 10.0 nmol/mmol at month 3 were associated with significantly reduced OS compared with levels < median (HR for death 1.85, P<0.0001). sBSAP levels {greater than or equal to} median of 12.6 ng/mL were associated with significantly reduced OS compared with levels < median (HR 2.44, P<0.0001). uNTx and sBSAP levels {greater than or equal to} median at month 3 were associated with significantly greater risk of DP (HR 1.31, P<0.0001 and HR 1.71, P<0.0001, respectively) and DPB (HR 1.11, P=0.0407 and HR 1.27, P<0.0001, respectively). Conclusions: BTM levels {greater than or equal to} median after 3 months of bone antiresorptive treatment were associated with reduced OS and increased risk of DP and DPB. Assessment of uNTx and sBSAP levels after bone antiresorptive therapy may add to identification of patients at risk for worse clinical outcomes

Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer

Purpose: Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials. Methods: Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years. Results: Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9 %) and 31 (1.2 %) in the denosumab and ZA groups, respectively. In total, 32 (6.9 %) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1 %, in patients continuing and switching to denosumab, respectively. Conclusion: These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports

Role of denosumab in the management of skeletal complications in patients with bone metastases from solid tumors

Skeletal-related events (SREs) including pain, fractures, and hypercalcemia are a major source of morbidity for cancer patients with bone metastases. The receptor activator of NF-κB ligand (RANKL) is a key mediator of osteoclast formation and activity in normal bone physiology as well as cancer-induced bone resorption. The first commercially available drug that specifically targets and inhibits the RANKL pathway is denosumab, a fully human monoclonal antibody that binds and neutralizes RANKL, thereby inhibiting osteoclast function. In this review, we summarize the major studies leading to the US Food and Drug Administration-approval of denosumab for the prevention of SREs in patients with bone metastases from solid tumors. Further, we discuss the role of denosumab in the prevention and treatment of SREs and bone loss in cancer patients. As a monoclonal antibody, denosumab has several advantages over bisphosphonates, including improved efficacy, better tolerability, and the convenience of administration by subcutaneous injection. In addition, as denosumab has no known renal toxicity, it may be the preferred choice over bisphosphonates in patients with baseline renal insufficiency or receiving nephrotoxic therapies. However, other toxicities, including osteonecrosis of the jaw and hypocalcemia, appear to be class effects of agents that potently inhibit osteoclast activity and are associated with both denosumab and bisphosphonate use. The data presented highlight the differences associated with intravenous bisphosphonate and denosumab use as well as confirm the essential role bone-modifying agents play in maintaining the quality of life for patients with bone metastases

Denosumab treatment for fibrous dysplasia

Fibrous dysplasia (FD) is a skeletal disease caused by somatic activating mutations of the cyclic adenosine monophosphate (cAMP)‐regulating protein, α‐subunit of the Gs stimulatory protein (G s α). These mutations lead to replacement of normal bone by proliferative osteogenic precursors, resulting in deformity, fracture, and pain. Medical treatment has been ineffective in altering the disease course. Receptor activator of NF‐κB ligand (RANKL) is a cell‐surface protein involved in many cellular processes, including osteoclastogenesis, and is reported to be overexpressed in FD‐like bone cells. Denosumab is a humanized monoclonal antibody to RANKL approved for treatment of osteoporosis and prevention of skeletal‐related events from bone metastases. We present the case of a 9‐year‐old boy with severe FD who was treated with denosumab for a rapidly expanding femoral lesion. Immunohistochemical staining on a pretreatment bone biopsy specimen revealed marked RANKL expression. He was started on monthly denosumab, with an initial starting dose of 1 mg/kg and planned 0.25 mg/kg dose escalations every 3 months. Over 7 months of treatment he showed marked reduction in pain, bone turnover markers (BTMs), and tumor growth rate. Denosumab did not appear to impair healing of a femoral fracture that occurred while on treatment. With initiation of treatment he developed hypophosphatemia and secondary hyperparathyroidism, necessitating supplementation with phosphorus, calcium, and calcitriol. BTMs showed rapid and sustained suppression. With discontinuation there was rapid and dramatic rebound of BTMs with cross‐linked C‐telopeptide (reflecting osteoclast activity) exceeding pretreatment levels, accompanied by severe hypercalcemia. In this child, denosumab lead to dramatic reduction of FD expansion and FD‐related bone pain. Denosumab was associated with clinically significant disturbances of mineral metabolism both while on treatment and after discontinuation. Denosumab treatment of FD warrants further study to confirm efficacy and determine potential morbidity, as well as to determine the mechanism of RANKL in the pathogenesis of FD and related bone marrow stromal cell diseases. © 2012 American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92121/1/1603_ftp.pd

Bone Tumor Environment as a Potential Therapeutic Target in Ewing Sarcoma

Ewing sarcoma is the second most common pediatric bone tumor, with three cases per million worldwide. In clinical terms, Ewing sarcoma is an aggressive, rapidly fatal malignancy that mainly develops not only in osseous sites (85%) but also in extra-skeletal soft tissue. It spreads naturally to the lungs, bones, and bone marrow with poor prognosis in the two latter cases. Bone lesions from primary or secondary (metastases) tumors are characterized by extensive bone remodeling, more often due to osteolysis. Osteoclast activation and subsequent bone resorption are responsible for the clinical features of bone tumors, including pain, vertebral collapse, and spinal cord compression. Based on the "vicious cycle" concept of tumor cells and bone resorbing cells, drugs, which target osteoclasts, may be promising agents as adjuvant setting for treating bone tumors, including Ewing sarcoma. There is also increasing evidence that cellular and molecular protagonists present in the bone microenvironment play a part in establishing a favorable "niche" for tumor initiation and progression. The purpose of this review is to discuss the potential therapeutic value of drugs targeting the bone tumor microenvironment in Ewing sarcoma. The first part of the review will focus on targeting the bone resorbing function of osteoclasts by means of bisphosphonates or drugs blocking the pro-resorbing cytokine receptor activator of NF-kappa B ligand. Second, the role of this peculiar hypoxic microenvironment will be discussed in the context of resistance to chemotherapy, escape from the immune system, or neo-angiogenesis. Therapeutic interventions based on these specificities could be then proposed in the context of Ewing sarcoma