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

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

Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics

Background: Analyses of phase III trials showed that denosumab was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) irrespective of age, history of SREs, or baseline pain status. This analysis assessed the risk of SREs across additional baseline characteristics. Patients and Methods: Patients (N Z 5543) from three phase III trials who had breast cancer, prostate cancer, or other solid tumours and one or more bone metastasis were included. Superiority of denosumab versus ZA in reducing risk of first SRE and first and subsequent SREs was assessed in subgroups defined by the Eastern Cooperative Oncology Group performance status (ECOG PS), bone metastasis location, bone metastasis number, visceral metastasis presence/absence, and urinary N-telopeptide (uNTx) level using Cox proportional hazards and AndersoneGill models. Subgroups except bone metastasis location were also assessed for each solid tumour type. Results: Compared with ZA, denosumab significantly reduced the risk of first SRE across all subgroups (hazard ratio [HR] ranges: ECOG PS, 0.79e0.84; bone metastasis location, 0.78e0.83; bone metastasis number, 0.78e0.84; visceral metastasis presence/absence, 0.80e0.82; uNTx level, 0.73e0.86) and reduced the risk of first and subsequent SREs in all subgroups (HR ranges: ECOG PS, 0.76e0.83; bone metastasis location, 0.78e0.84; bone metastasis number, 0.79e0.81; visceral metastasis presence/absence, 0.79e0.81; uNTx level, 0.74e0.83). Similar results were observed in subgroups across tumour types. Conclusion: Denosumab was superior to ZA in preventing SREs in patients with bone metastases from advanced cancer, regardless of ECOG PS, bone metastasis number, baseline visceral metastasis presence/absence, and uNTx leve

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

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 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

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

A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points

SU5416 (Z-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone; semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR)2. A Phase I dose escalation study was performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic assessment tool. In all, 27 patients were recruited. SU5416 was administered twice weekly by fixed rate intravenous infusion. Patients were treated in sequential cohorts of three patients at 48, 65, 85 110 and 145 mg m−2. A further dose level of 190 mg m−2 after a 2-week lead in period at a lower dose was completed; thereafter, the cohort at 145 mg m−2 was expanded. SU5416 showed linear pharmacokinetics to 145 mg m−2 with a large volume of distribution and rapid clearance. A significant degree of interpatient variability was seen. SU5416 was well tolerated, by definition a maximum-tolerated dose was not defined. No reproducible changes were seen in DCE-MRI end points. Serial assessments of VEGF in a cohort of patients treated at 145 mg m−2 did not show a statistically significant treatment-related change. Parallel assessments of the impact of SU5416 on coagulation profiles in six patients showed a transient effect within the fibrinolytic pathway. Clinical experience showed that patients who had breaks of therapy longer than a week could not have treatment reinitiated at a dose of 190 mg m−2 without unacceptable toxicity. The 145 mg m−2 dose level is thus the recommended dose for future study

Angiogenesis inhibitors in clinical development; where are we now and where are we going?

Angiogenesis is crucial for tumour growth and the formation of metastases. Various classes of angiogenesis inhibitors that are each able to inhibit one of the various steps of this complex process can be distinguished. Results from clinical studies with these agents are summarised. In general, it has been shown that most angiogenesis inhibitors can be safely administered, but that tumour regressions are rare. Combining angiogenesis inhibitors with cytotoxic chemotherapy can enhance anticancer activity. Recently, some promising data with regard to clinical efficacy have been presented. While performing clinical studies with angiogenesis inhibitors, defining biological activity is crucial, but thus far no validated techniques are available. It is conceivable that in the near future various classes of angiogenesis inhibitors will be combined in an attempt to further improve antiangiogenic and anticancer activity