Mortality in older adults following a fragility fracture: real-world retrospective matched-cohort study in Ontario.

BACKGROUND: Recent studies are lacking reports on mortality after non-hip fractures in adults aged > 65. METHODS: This retrospective, matched-cohort study used de-identified health services data from the publicly funded healthcare system in Ontario, Canada, contained in the ICES Data Repository. Patients aged 66 years and older with an index fragility fracture occurring at any osteoporotic site between 2011 and 2015 were identified from acute hospital admissions, emergency and ambulatory care using International Classification of Diseases (ICD)-10 codes and data were analyzed until 2017. Thus, follow-up ranged from 2 years to 6 years. Patients were excluded if they presented with an index fracture occurring at a non-osteoporotic fracture site, their index fracture was associated with a trauma code, or they experienced a previous fracture within 5 years prior to their index fracture. This fracture cohort was matched 1:1 to controls within a non-fracture cohort by date, sex, age, geography and comorbidities. All-cause mortality risk was assessed. RESULTS: The survival probability for up to 6 years post-fracture was significantly reduced for the fracture cohort vs matched non-fracture controls (p < 0.0001; n = 101,773 per cohort), with the sharpest decline occurring within the first-year post-fracture. Crude relative risk of mortality (95% confidence interval) within 1-year post-fracture was 2.47 (2.38-2.56) in women and 3.22 (3.06-3.40) in men. In the fracture vs non-fracture cohort, the absolute mortality risk within one year after a fragility fracture occurring at any site was 12.5% vs 5.1% in women and 19.5% vs 6.0% in men. The absolute mortality risk within one year after a fragility fracture occurring at a non-hip vs hip site was 9.4% vs 21.5% in women and 14.4% vs 32.3% in men. CONCLUSIONS: In this real-world cohort aged > 65 years, a fragility fracture occurring at any site was associated with reduced survival for up to 6 years post-fracture. The greatest reduction in survival occurred within the first-year post-fracture, where mortality risk more than doubled and deaths were observed in 1 in 11 women and 1 in 7 men following a non-hip fracture and in 1 in 5 women and 1 in 3 men following a hip fracture.

Fragility fracture identifies patients at imminent risk for subsequent fracture: real-world retrospective database study in Ontario, Canada.

BACKGROUND: The secondary fracture prevention gap in the osteoporosis field has been previously described as a 'crisis'. Closing this gap is increasingly important in the context of accumulating evidence showing that an incident fragility fracture is associated with an increased risk of subsequent fracture within 1-2 years, known as imminent fracture risk. The objective of this study was to use health services data to characterize the time between index fragility fractures occurring at different osteoporotic sites and subsequent fractures. METHODS: This retrospective observational study used de-identified health services data from the publicly funded healthcare system in Ontario, the largest province of Canada. Patients aged > 65 with an index fragility fracture occurring between 2011 and 2015 were identified from the ICES Data Repository using International Classification of Diseases (ICD)-10 codes. We examined median time to subsequent fragility fractures for osteoporotic fracture sites until the end of follow-up (2017). BMD assessment and use of osteoporosis therapies following index fracture were also characterized. RESULTS: Among 115,776 patients with an index fragility fracture, 17.8% incurred a second fragility fracture. Median time between index and second fracture occurring at any site was 555 days (interquartile range: 236-955). For each index fracture site examined, median time from index to second fracture was < 2 years. The proportion of patients with BMD assessment was 10.3% ≤1 year prior to and 16.4% ≤1 year post index fracture. The proportion of patients receiving osteoporosis therapy was 29.8% ≤1 year prior, 34.6% ≤1 year post, and 25.9% > 3 years post index fracture. CONCLUSIONS: This cohort of Canadian patients aged > 65 years who experienced a fragility fracture at any site are at imminent risk of experiencing subsequent fracture within the next 2 years and should be proactively assessed and treated.

A systematic literature review of the efficacy, effectiveness, and safety of filgrastim.

PURPOSE: Filgrastim (NEUPOGEN®) is the originator recombinant human granulocyte colony-stimulating factor widely used for preventing neutropenia-related infections and mobilizing hematopoietic stem cells. This report presents findings of a systematic literature review and meta-analysis of efficacy and safety of originator filgrastim to update previous reports. METHODS: A literature search of electronic databases, congress abstracts, and bibliographies of recent reviews was conducted to identify English-language reports of clinical trials and observational studies evaluating filgrastim in its US-approved indications up to February 2015. Two independent reviewers assessed titles/abstracts and full texts of publications, and extracted data from studies that compared originator filgrastim vs placebo or no treatment. For outcomes with sufficient homogeneous data reported across studies, meta-analysis was performed and relative risk (RR) determined. Data were summarized descriptively for all other evaluated outcomes. RESULTS: A total of 1194 unique articles evaluating originator filgrastim were identified, with 25 meeting eligibility criteria for data extraction: 18 randomized controlled trials, 2 nonrandomized clinical trials, and 5 observational studies. In chemotherapy-induced neutropenia (CIN), filgrastim vs placebo or no treatment significantly reduced febrile neutropenia incidence (RR 0.63, 95% CI 0.53-0.75) and grade 3 or 4 neutropenia incidence (RR 0.50, 95% CI 0.37-0.68). The most commonly reported adverse event (AE) with filgrastim was bone pain (RR 2.61, 95% CI 1.29-5.27 in CIN). Additional efficacy and safety outcomes are described within indications. CONCLUSIONS: This systematic literature review and meta-analysis confirms and updates previous reports on the efficacy and safety of originator filgrastim. Bone pain was the commonly reported AE associated with filgrastim use.

NOLAN: a randomized, phase 2 study to estimate the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on bone pain in patients with early-stage breast cancer receiving chemotherapy and pegfilgrastim.

PURPOSE: Mild-to-moderate bone pain is a commonly reported adverse event (AE) associated with pegfilgrastim. We evaluated the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on pegfilgrastim-associated bone pain. METHODS: In this open-label study (NCT01712009), women ≥ 18 years of age with newly diagnosed stage I-III breast cancer and an ECOG performance status ≤ 2 who were planning ≥ 4 cycles of adjuvant or neoadjuvant chemotherapy with pegfilgrastim support starting in cycle 1 were randomized 1:1:1 to receive naproxen, loratadine, or no treatment to prevent pegfilgrastim-associated bone pain. The primary endpoint was all-grade bone pain in cycle 1 from AE reporting. Secondary endpoints included bone pain in cycles 2-4 and across all cycles from AE reporting and patient-reported bone pain by cycle and across all cycles. RESULTS: Six hundred patients were enrolled. Most patients (83.0%) were white, and mean (SD) age was 54.2 (11.1) years. The percentage of patients with all-grade bone pain in cycle 1 from AE reporting in the naproxen, loratadine, and no prophylaxis groups was 40.3, 42.5, and 46.6%, respectively; differences between the treatment groups were not statistically significant. Maximum, mean, and area under the curve for patient-reported bone pain were consistently lower in the naproxen and loratadine groups than in the no prophylaxis group; some of these differences were significant. Loratadine was associated with fewer treatment-related AEs and discontinuations than naproxen. CONCLUSIONS: Given its tolerability, its ease of administration, and its potential benefit, treatment with loratadine should be considered to help prevent bone pain in patients receiving chemotherapy and pegfilgrastim. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ; NCT01712009.

A Randomized, Single-Blind Study Evaluating the Effect of a Bone Pain Education Video on Reported Bone Pain in Patients with Breast Cancer Receiving Chemotherapy and Pegfilgrastim.

BACKGROUND: Mild-to-moderate bone pain is the most commonly reported adverse event associated with pegfilgrastim. AIMS: To investigate the effect of bone pain education on pegfilgrastim-related bone pain in patients with breast cancer receiving chemotherapy and pegfilgrastim. DESIGN: Randomized, single-blind study. SETTINGS: Forty-eight community oncology clinics throughout the United States. PARTICIPANTS: Three hundred women ≥18 years of age with newly diagnosed stage I -III breast cancer, who were planning ≥4 cycles of neoadjuvant or adjuvant chemotherapy with pegfilgrastim support starting in cycle 1. METHODS: Patients were randomized 1:1 to view a general education DVD on chemotherapy side effects (GE-DVD) or a DVD on bone pain following chemotherapy and pegfilgrastim (BP-DVD). Patients recorded severity of bone pain on a scale of 0-10, location of pain, and use of bone pain medications (i.e., analgesics, antihistamines, and nonsteroidal anti-inflammatory drugs) for 5 days, beginning on the day of pegfilgrastim administration, in each of the first four chemotherapy cycles. RESULTS: Patient-reported maximum bone pain was similar in the two groups (GE-DVD vs BP-DVD: cycle 1, 3.2 vs. 3.5, p = .3479; across all cycles, 4.1 vs. 4.6, p = .2196). Other measures of bone pain were also similar between the groups. Bone pain was highest in cycle 1 but decreased and then remained stable in subsequent cycles. Bone pain medication use was similar in both groups and was highest in cycle 1. CONCLUSIONS: The bone pain-specific education evaluated here did not improve perceptions of bone pain reported in this patient population.

The effectiveness and safety of same-day versus next-day administration of long-acting granulocyte colony-stimulating factors for the prophylaxis of chemotherapy-induced neutropenia: a systematic review.

PURPOSE: Granulocyte colony-stimulating factors (G-CSF) are commonly used in clinical practice to prevent febrile neutropenia (FN). US and EU prescribing information and treatment guidelines from the NCCN, ASCO, and EORTC specify that pegfilgrastim, a long-acting (LA) G-CSF, should be administered at least 24 h after myelosuppressive chemotherapy. Nevertheless, many patients receive LA G-CSFs on the same day as chemotherapy. This systematic literature review evaluated the relative merits of same-day versus next-day dosing of LA G-CSFs. METHODS: A broad Ovid MEDLINE® and Embase® literature search was conducted that examined all publications indexed before May 9, 2016 that compared same-day versus next-day LA G-CSF administration. A congress abstract literature search included congresses from January 1, 2011 to April 6, 2016. The parameters for this review were prospectively delineated in a research protocol and adhered to the PRISMA Guidelines. RESULTS: The first part of the systematic literature search identified 1736 publications. After elimination of duplicates, title/abstract screening was conducted on 1440 records, and full text review was conducted on 449 publications. Eleven publications met all criteria and are included in this systematic review; of these, four included data from randomized or single arm prospective studies, and seven were retrospective studies. In most studies included in this review and across a variety of tumor types, administration of pegfilgrastim at least 24 h after myelosuppressive chemotherapy resulted in improved patient outcomes. CONCLUSIONS: Data from multiple publications support administration of pegfilgrastim at least 1 day after chemotherapy.

Burden of Chemotherapy-Induced Febrile Neutropenia Hospitalizations in US Clinical Practice, by Use and Patterns of Prophylaxis with Colony-Stimulating Factor.

INTRODUCTION: Evidence suggests that many cancer chemotherapy patients who are candidates for colony-stimulating factor (CSF) prophylaxis do not receive it or receive it inconsistent with guidelines, and that such patients have a higher risk of febrile neutropenia hospitalization (FNH). Little is known about the number and consequences of FNH by use/patterns of CSF prophylaxis in US clinical practice. METHODS: A retrospective cohort design and private healthcare claims data were employed. Study population comprised adults who received a chemotherapy course with a high-risk regimen, or an intermediate-risk regimen (if ≥1 FN risk factor present), for non-metastatic breast cancer or non-Hodgkin's lymphoma (NHL); each chemotherapy cycle within the course and each FNH episode within the cycles were identified. Consequences included mortality, inpatient days, and costs (US$2013) during FNH. Use (yes/no) and patterns (agent, administration day/duration) of CSF prophylaxis were evaluated within cycles in which FNH episodes occurred. RESULTS: Among all FNH episodes (n=6,355; 109 episodes per 1,000 patients), 41.3% (95% CI: 40.1-42.5) occurred among patients who did not receive CSF prophylaxis in that cycle, and 8.8% (8.1-9.5) occurred among those who received CSF prophylaxis on the same day as chemotherapy. Among FNH episodes occurring in patients who received daily CSF agents (2% of CSF use), 56.1% (44.1-68.0) received prophylaxis <7 days during the cycle. Results for FNH consequences were comparable. CONCLUSIONS: In this retrospective evaluation, one-half of FNH episodes, outcomes, and costs among cancer chemotherapy patients who were candidates for CSF prophylaxis occurred in those who either did not receive it or received it inconsistent with guidelines.

Relationship between severity and duration of chemotherapy-induced neutropenia and risk of infection among patients with nonmyeloid malignancies.

PURPOSE: Chemotherapy-induced neutropenia (CIN) may increase infection risk for cancer patients; however, there is limited understanding on the quantitative relationships between severity and duration of CIN and infection risk. METHODS: This study combined individual data from adult cancer patients receiving no granulocyte colony-stimulating factor during the first chemotherapy cycle in six trials. We used area over the curve (AOC) of absolute neutrophil count (ANC) time-response curve (below different thresholds) to measure the combined effect of severity and duration of CIN. Time-dependent Cox proportional hazards models quantified the hazard of first infection associated with duration of grade 4 or grade 3/4 CIN and the hazard associated with AOC. RESULTS: We analyzed data from 271 patients who had small cell lung cancer, non-Hodgkin's lymphoma, head and neck cancer, or breast cancer; 63.8 % of the patients had advanced cancer, and 77.5 % received chemotherapy regimens with high risk of febrile neutropenia. In the first cycle, 18.8 % of the patients had infection-related hospitalizations. Each additional day patients had grade 3/4 or grade 4 CIN was associated with 28 % (95 % CI 7, 51 %) and 30 % (95 % CI 10, 54 %) increased risk of infection-related hospitalization, respectively. Each unit increase in AOC (day × 10(9)/L ANC), with threshold of ANC < 0.5 × 10(9)/L, was associated with a significantly increased risk of infection-related hospitalization (hazard ratio 1.98; 95 % CI 1.35, 2.90). CONCLUSIONS: Infection risk increases dramatically with each additional day of grade 3 or 4 CIN. Interventions limiting CIN severity and duration are of critical importance to reduce infection risk in cancer patients receiving chemotherapy.

Risk of chemotherapy-induced febrile neutropenia with early discontinuation of pegfilgrastim prophylaxis in US clinical practice.

PURPOSE: Accumulating evidence suggests that not all cancer chemotherapy patients who receive first-cycle pegfilgrastim prophylaxis continue to receive it in subsequent cycles and that these patients may be subsequently at higher risk of febrile neutropenia (FN). Additional evidence from US clinical practice is warranted. METHODS: Data from two US private healthcare claims repositories were employed. The source population comprised adults who received "intermediate-risk" or "high-risk" chemotherapy regimens for solid cancers or non-Hodgkin's lymphoma and first-cycle pegfilgrastim prophylaxis. From the source population, all patients who did not receive second-cycle pegfilgrastim prophylaxis ("comparison patients") were matched (1:1) to those who received it ("pegfilgrastim patients") based on cancer, regimen, and propensity score. Odds ratios (OR) for FN-broad and narrow definitions-during the second chemotherapy cycle were estimated for comparison patients versus pegfilgrastim patients using generalized estimating equations. RESULTS: A total of 2245 comparison patients (5.3 % of source population) were matched to pegfilgrastim patients; cohorts were well-balanced on baseline characteristics. Second-cycle FN incidence proportions for comparison and pegfilgrastim patients were 3.8 versus 2.2 % based on broad definition and 2.6 versus 0.8 % based on narrow definition; corresponding OR were 1.7 (95 % CI 1.2-2.5, p = 0.002) and 3.5 (95 % CI 2.0-6.0, p < 0.001). Results were similar within cancer/regimen-subgroups and were robust when using alternative methods for confounding adjustment. CONCLUSIONS: In this retrospective evaluation of cancer chemotherapy patients who received first-cycle pegfilgrastim prophylaxis in US clinical practice, a clinically relevant minority did not receive second-cycle prophylaxis. Second-cycle FN odds among this subset were significantly higher than they were among those who continued prophylaxis.

Comorbidities among patients with cancer who do and do not develop febrile neutropenia during the first chemotherapy cycle.

Patients receiving myelosuppressive chemotherapy with certain comorbidities are at increased risk of febrile neutropenia. A comprehensive evaluation of febrile neutropenia-related comorbidities across cancers is needed. This study compared comorbidity prevalence among patients with cancer who did and did not develop febrile neutropenia during the first chemotherapy cycle. This case-control study used administrative claims from adult patients with non-Hodgkin lymphoma or breast, lung, colorectal, ovarian, or gastric cancer who received chemotherapy between 2007 and 2012. Each patient who developed febrile neutropenia (case) was matched with up to four patients without febrile neutropenia (controls) by cancer type, metastasis, chemotherapy regimen, age group, and sex. For each comorbidity (identified in the year before chemotherapy began), the adjusted odds ratio (aOR) for febrile neutropenia by cancer type was evaluated using conditional logistic regression models adjusted for potential confounding factors. Of 31,331 eligible patients, 672 developed febrile neutropenia in the first chemotherapy cycle. A total of 3312 febrile neutropenia cases and matched controls were analyzed. Across tumor types, comorbidity prevalence was higher in patients who developed febrile neutropenia than in those without febrile neutropenia. Among patients with breast cancer, osteoarthritis was more prevalent in patients with febrile neutropenia (aOR, 1.85; 95% CI, 1.07 to 3.18). Among patients with non-Hodgkin lymphoma, renal disease was more prevalent in patients with febrile neutropenia (aOR, 2.25; 95% CI, 1.23 to 4.11). Patients who developed febrile neutropenia in the first chemotherapy cycle presented with comorbidities more often than otherwise similar patients who did not develop febrile neutropenia. These findings warrant further investigation and support the inclusion of comorbidities into febrile neutropenia risk models.

Importance of Risk Factors for Febrile Neutropenia Among Patients Receiving Chemotherapy Regimens Not Classified as High-Risk in Guidelines for Myeloid Growth Factor Use.

BACKGROUND: Clinical practice guidelines recommend prophylaxis in patients with cancer receiving a colony-stimulating factor (CSF) when the risk of febrile neutropenia (FN) is high (>20%). For patients receiving chemotherapy regimens not documented as high-risk, the decision regarding CSF prophylaxis use can be challenging, because some patients may be at high risk based on a combination of the regimen and individual risk factors. METHODS: A retrospective cohort design and US private health care claims data were used. Study subjects received chemotherapy regimens classified as "low" or "intermediate," or unclassified, in terms of FN risk, and were stratified by cancer and regimen. For each subject, the first chemotherapy course, and each cycle and FN episode within the course, were identified. FN incidence proportions were estimated by the presence and number of risk factors and chronic comorbidities. RESULTS: Across the 17 tumor/regimen combinations considered (n=160,304 in total), 74% to 98% of patients had 1 or more risk factor for FN and 41% to 89% had 2 or more. Among patients with 1 or more risk factor, FN incidence ranged from 7.2% to 29.0% across regimens, and the relative risk of FN (vs those without risk factors) ranged from 1.1 (95% CI, 0.8-1.3) to 2.2 (95% CI, 1.5-3.0). FN incidence increased in a graded and monotonic fashion with the number of risk factors and comorbidities. CONCLUSIONS: In this retrospective evaluation of patients with cancer receiving chemotherapy regimens not classified as high-risk for FN in US clinical practice, most patients had 1 or more FN risk factor and many had 2 or more. FN incidence was found to be elevated in these patients, especially those with multiple risk factors.

Protocol adherence and the progression of cardiovascular calcification in the ADVANCE study.

BACKGROUND: The ADVANCE study assessed the progression of vascular and cardiac valve calcification in 360 hemodialysis patients with secondary hyperparathyroidism (sHPT) assigned randomly to treatment either with cinacalcet plus low-dose vitamin D (≤ 6 µg/week of intravenous paricalcitol equivalent) or with varying doses of vitamin D alone for 52 weeks. The primary efficacy endpoint was progression of coronary artery calcification (CAC). METHODS: In this post-hoc analysis, we compared CAC progression among 70 protocol-adherent subjects given cinacalcet and low doses of vitamin D (CPA) as specified in the study protocol and 120 control subjects given vitamin D sterols. RESULTS: Baseline patient characteristics did not differ between CPA and control subjects. The mean (standard error of the mean, SEM) doses of vitamin D at week 2 were 4.7 (0.3) and 12.8 (1.0) µg/week in CPA and control subjects, respectively, and the corresponding mean cumulative doses of vitamin D over 52 weeks in each group were 225 (22) and 671 (47) µg. The median change in Agatston CAC score after 52 weeks was less in CPA subjects than in controls (17.8% versus 31.3%, P = 0.02). The median increase in calcification scores in the aortic valve also was less in CPA subjects than in controls (6.0% versus 51.5% P = 0.02). Reductions in serum parathyroid hormone, calcium and phosphorus levels were significantly greater in CPA subjects than in controls (P < 0.05). CONCLUSIONS: The progression of cardiovascular calcification was attenuated among cinacalcet-treated subjects with sHPT given low doses of vitamin D per protocol compared with control subjects in whom sHPT was treated with higher doses of vitamin D sterols alone.

Presence of valvular calcification predicts the response to cinacalcet: data from the ADVANCE study.

BACKGROUND AND AIM OF THE STUDY: Cardiac valve calcification (CVC) and coronary artery calcification (CAC) appear to be linked pathogenetically, and both are associated with a poor prognosis among patients with chronic kidney disease on dialysis (CKD-5D). Little is known, however, about factors that affect the progression of CVC and CAC. METHODS: A post-hoc analysis was performed of the ADVANCE study to assess whether patients with CVC are more prone to CAC progression, and whether CVC predicts the response to different treatments for secondary hyperparathyroidism. RESULTS: Subjects were randomized to treatment with either cinacalcet and low doses of vitamin D analogs or larger, varying doses of vitamin D. Among 235 subjects, aortic valve or mitral valve calcification was detected in 108 (46%) and 118 (50%), respectively; 69 subjects (29%) had calcification of both valves. CVC was associated both with baseline CAC and CAC progression (p < 0.05). Subjects with aortic valve calcification who were treated with cinacalcet and low doses of vitamin D experienced less progression of CAC than subjects given larger, varying doses of vitamin D (adjusted OR: 0.26; 95% CI: 0.10, 0.64). This effect was greater in subjects with larger CAC burden at baseline. CONCLUSION: The study findings suggest that CVC is a predictor of CAC progression and, potentially, of greater cardiovascular vulnerability. Treatment with cinacalcet combined with low doses of vitamin D slowed the progression of CAC compared to therapy using larger, varying doses of vitamin D.

A retrospective observational study of osteoporosis management after a fragility fracture in primary care.

In many countries, osteoporosis is predominantly managed by primary care physicians; however, management after a fragility fracture has not been widely investigated. We describe osteoporosis care gaps in a real-world patient cohort. Our findings help inform initiatives to identify and overcome obstacles to effective management of patients after fragility fracture. PURPOSE: A fragility fracture is a major risk factor for subsequent fracture in adults aged ≥ 50 years. This retrospective observational study aimed to characterize post-fracture management in Canadian primary care. METHODS: A total of 778 patients with an index fragility fracture (low-trauma, excluding small bones) occurring between 2014 and 2016 were identified from medical records at 76 primary care centers in Canada, with follow-up until January 2018. RESULTS: Of 778 patients (80.5% female, median age [IQR] 73 [64-80]), 215 were on osteoporosis treatment and 269 had osteoporosis diagnosis recorded prior to their index fracture. The median follow-up was 363 (IQR 91-808) days. Of patients not on osteoporosis treatment at their index fracture, 60.2% (n = 339/563) remained untreated after their index fracture and 62.2% (n = 23/37) continued untreated after their subsequent fracture. After their index fracture, fracture risk assessment (FRAX or CAROC) was not performed in 83.2% (n = 647/778) of patients, and 59.9% (n = 466/778) of patients did not receive bone mineral density testing. Of patients without osteoporosis diagnosis recorded prior to their index date, 61.3% (n = 300/489) remained undiagnosed after their index fracture. At least one subsequent fracture occurred in 11.5% (n = 86/778) of patients. CONCLUSION: In the primary care setting, fragility fracture infrequently resulted in osteoporosis treatment or fracture risk assessment, even after multiple fragility fractures. These results suggest a fragility fracture is not recognized as a major risk factor for subsequent fracture and its occurrence does not prompt primary care physicians to intervene. These data urge initiatives to identify and overcome obstacles to primary care physicians' effective management of patients after fragility fractures.

Real-World Insights Into Evolocumab Use in Patients With Hyperlipidemia: Canadian Analysis From the ZERBINI Study.

Background: The 2021 Canadian Cardiovascular Society guidelines recommend proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor therapy in patients with atherosclerotic cardiovascular disease whose low-density lipoprotein cholesterol (LDL-C) concentration remains ≥ 1.8 mmol/L despite maximally tolerated statin therapy. This retrospective and prospective observational study characterizes Canadian patients treated with evolocumab and describes its effectiveness and safety. Methods: Between August 2017 and July 2019, a total of 131 patients initiated on evolocumab therapy were enrolled at 15 sites in Canada. Data were extracted from medical records every 3 months between 6 months prior to, and for 12 months following evolocumab therapy initiation, until July 6, 2020. Baseline and prospectively collected data are reported as available. Results: A total of 131 patients were enrolled (59.5% male; mean age [standard deviation (SD)] 64.7 ± 10.6 years), most with a diagnosis of atherosclerotic cardiovascular disease and/or familial hypercholesterolemia (93.4%). Mean (± SD) LDL-C concentration at baseline was 3.7 (± 1.7) mmol/L (n = 119), with 58.0% of patients receiving a statin (36.6% high intensity). Mean (± SD) LDL-C concentration after evolocumab treatment was 1.6 (± 1.0) mmol/L (n = 120), representing a 58.7% decrease from baseline (n = 109). This level remained stable over 12 months. An LDL-C concentration < 1.8 mmol/L was achieved by 77.5% of patients. Persistence was 92%, and no serious treatment-emergent adverse events were reported. Conclusions: These findings provide real-world evidence of guideline-recommended initiation of evolocumab therapy, as well as confirmation of its effectiveness and safety in a Canadian population. Evolocumab therapy can address a healthcare gap in the management of dyslipidemia, by increasing the proportion of patients achieving LDL-C goals recommended to lower cardiovascular risk.

Introduction: Les lignes directrices de la Société canadienne de cardiologie de 2021 recommandent un traitement par les inhibiteurs de proprotéine convertase subtilisine-kexine de type 9 (PCSK9) aux patients atteints de la maladie cardiovasculaire athérosclérotique chez lesquels les concentrations de cholestérol à lipoprotéines de faible densité (cholestérol LDL) demeurent ≥ 1,8 mmol/l malgré le traitement maximalement toléré par statines. La présente étude observationnelle rétrospective et prospective donne les caractéristiques des patients canadiens traités par évolocumab, et décrit l'efficacité et l'innocuité de ce médicament. Méthodes: Entre août 2017 et juillet 2019, nous avons inscrit un total de 131 patients qui avaient amorcé le traitement d'évolocumab dans 15 établissements du Canada. Nous avons extrait les données des dossiers médicaux tous les trois mois de six mois avant et jusqu'à 12 mois après le début du traitement par évolocumab, et ce, jusqu'au 6 juillet 2020. Les données initiales et les données collectées de façon prospective sont déclarées selon leur disponibilité. Résultats: Nous avons inscrit un total de 131 patients (59,5 % d'hommes; âge moyen [écart type (ET)] 64,7 ± 10,6 ans); la plupart avaient un diagnostic de maladie cardiovasculaire athérosclérotique et/ou d'hypercholestérolémie familiale (93,4 %). Les concentrations initiales moyennes (± ET) de cholestérol LDL étaient de 3,7 (± 1,7) mmol/l (n = 119), et 58,0 % des patients recevaient une statine (36,6 % d'intensité élevée). Les concentrations moyennes (± ET) de cholestérol LDL après le traitement par évolocumab étaient de 1,6 (± 1,0) mmol/l (n = 120), soit une diminution de 58,7 % par rapport aux concentrations initiales (n = 109). Ces concentrations sont demeurées stables durant 12 mois. Des concentrations de cholestérol LDL < 1,8 mmol/l ont été atteintes par 77,5 % des patients. La persistance a été de 92 %, et aucun événement défavorable sérieux associé au traitement n'a été déclaré. Conclusions: Ces résultats fournissent des données probantes du monde réel sur l'amorce du traitement par évolocumab conformément aux recommandations des lignes directrices, ainsi qu'une confirmation de son efficacité et de son innocuité au sein d'une population canadienne. Le traitement par évolocumab peut permettre de remédier aux lacunes des soins de santé dans la prise en charge de la dyslipidémie par l'augmentation de la proportion de patients atteignant les objectifs recommandés en matière de cholestérol LDL pour réduire le risque de maladies cardiovasculaires.

Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone.

BACKGROUND: Identifying predictive biomarkers is important to optimally treat patients. This analysis evaluated the association of K-ras, BRAF, and PIK3CA gene mutations with tumor resistance to panitumumab alone. PATIENTS AND METHODS: From 3 phase II panitumumab metastatic colorectal cancer (mCRC) studies, 62 of 533 patient samples were available. Mutations were identified from genomic DNA by sequencing. RESULTS: Of the 62 samples, 24 (38.7%) harbored a K-ras mutation, and 38 (61.3%) were wild type. In the wild-type K-ras group, 11% of patients had a partial response (PR), 53% had stable disease (SD), and 37% had progressive disease (PD). In the mutant K-ras group, 21% of patients had SD, and 79% of patients had PD; there were no responses. The absence of a K-ras mutation was associated with response to panitumumab (PR vs. SD vs. PD; P = .0028). The hazard ratio for wild-type versus mutant K-ras was 0.4 (95% CI, 0.2-0.7) for progression-free survival and 0.5 (95% CI, 0.3-0.9) for overall survival. Four patients had a V600E BRAF mutation, and 2 patients had a PIK3CA mutation. CONCLUSION: These data suggest that patients with mCRC with activating K-ras mutations are less likely to respond to panitumumab alone. The small sample size limits us from defining a predictive role of PIK3CA and BRAF mutations for panitumumab treatment.

Performance of the pegfilgrastim on-body injector as studied with placebo buffer in healthy volunteers.

OBJECTIVE: The pegfilgrastim on-body injector (OBI) is a single-use, disposable, battery-powered injector that is designed to automatically deliver a single subcutaneous dose of pegfilgrastim beginning approximately 27 hours after activation and continuing over approximately 45 minutes. In this open-label study, we assessed performance of the OBI delivering placebo buffer in healthy volunteers. RESEARCH DESIGN AND METHODS: Healthy men and women aged 18-55 years, with a body mass index of 18-35 kg/m2, were enrolled. OBIs were activated by filling them with placebo buffer, and two injectors were applied concurrently to each subject: one to the abdomen and one to the back of the upper arm. Subjects were monitored for substantial leakage during and after administration. MAIN OUTCOME MEASURES: The primary endpoint of the study was successful delivery of placebo buffer based on a composite of the following: no substantial leakage during or after administration, green status light indicator on the injector during and after administration, and fill indicator bar at the empty position after administration. The secondary endpoint was the incidence of treatment-emergent adverse events (AEs). RESULTS: Of the 150 subjects enrolled, 149 (99.3%) completed the study. Study subjects were 48.0% men, and 52.0% women; 47.3% were white, 35.3% black or African American, 12.7% Asian, and 4.7% other. Mean (SD) age was 35.9 (10.8) years. Of the 297 total deliveries, 292 (98.3%) were considered successful: 147/149 (98.7%; 95% confidence interval [CI]: 95.2%-99.6%) to the abdomen and 145/148 (98.0%; 95% CI: 94.2%-99.3%) to the back of the upper arm. Five deliveries were considered unsuccessful: two due to hazard alarms, and three due to substantial leakage. The most common treatment-emergent AEs (in >2% of subjects overall) by preferred term were medical device site reaction (20.7%), catheter-site hemorrhage (8.7%), and headache (3.3%). No serious AEs were reported. CONCLUSIONS: The pegfilgrastim OBI was well tolerated, and deliveries of placebo buffer were successful 98.3% of the time. The generalizability of these results may be limited by the conduct of this study in healthy subjects in a controlled environment.

A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pegfilgrastim in Patients Receiving First-Line FOLFOX/Bevacizumab or FOLFIRI/Bevacizumab for Locally Advanced or Metastatic Colorectal Cancer: Final Results of the Pegfilgrastim and Anti-VEGF Evaluation Study (PAVES).

BACKGROUND: Pegfilgrastim's role in reducing the risk of febrile neutropenia (FN) in patients with colorectal cancer (CRC) receiving chemotherapy plus bevacizumab was not previously evaluated in a prospective study. The present phase III, double-blind trial evaluated the efficacy of pegfilgrastim versus placebo in reducing the incidence of grade 3/4 FN in patients with advanced CRC receiving bevacizumab combined with first-line chemotherapy (FOLFOX [leucovorin, 5-fluorouracil, oxaliplatin] or FOLFIRI [leucovorin, 5-fluorouracil, irinotecan]). PATIENTS AND METHODS: Patients aged ≥ 18 years with locally advanced or metastatic CRC were randomized 1:1 to placebo or 6 mg of pegfilgrastim ∼24 hours after receiving chemotherapy plus bevacizumab every 14 days. The study treatment period included 4 cycles, but patients could continue treatment for ≤ 60 months. The primary endpoint was incidence of grade 3/4 FN in the first 4 cycles. The secondary endpoints included the objective response rate (ORR), overall survival, and progression-free survival, analyzed at the end of the long-term follow-up period. RESULTS: A total of 845 patients were randomized from November 2009 to January 2012 (422, pegfilgrastim; 423, placebo). Pegfilgrastim significantly reduced the incidence of grade 3/4 FN in the first 4 treatment cycles (pegfilgrastim, 2.4%; 95% confidence interval [CI], 1.1%-4.3%; placebo, 5.7%; 95% CI, 3.7%-8.3%; odds ratio [OR], 0.41; P = .014). No significant differences were observed between the 2 arms in ORR (OR, 1.15; P = .330), overall survival (hazard ratio, 0.94; P = .440), and progression-free survival (hazard ratio, 0.93; P = .300). CONCLUSION: Pegfilgrastim reduced the FN incidence in patients with advanced CRC receiving chemotherapy and bevacizumab. Administration of pegfilgrastim was tolerable and did not negatively affect the tumor response or survival in this patient population.

Metaplastic breast cancer: clinical significance.

BACKGROUND: Metaplastic breast carcinoma (MBC) is a rare poorly differentiated breast cancer characterized by coexistence of ductal carcinoma with areas of matrix producing, spindle-cell, sarcomatous, or squamous differentiation; ER/PR/HER2 negativity; and a reputation for poor outcome. METHODS: The Swedish Cancer Institute prospective breast cancer database (> 6500 patients; 1990-2005) has 24 MBC cases that were compared with typical breast cancer cases matched for age, date of diagnosis, stage, and ER/PR/HER2 status. RESULTS: The mean metaplastic primary tumor diameter was 2.5 cm. The histological/nuclear grade was high in 21 of 24 cases. No patient had distant metastasis. ER and/or PR receptor status was negative in all cases. HER2 was negative in 10 of 11 cases tested. EGFR (HER1) was positive in 7 of 7 cases tested. All patients had sentinel and/or axillary lymph node dissection and surgical resection; 18 received chemotherapy and 22 had radiation therapy. Four patients had distant recurrences 5 to 88 months from diagnosis. Five-year survival was 83% (95% confidence interval, 66-100%). Comparison with matched typical breast cancer cases revealed no major significant difference in multidisciplinary treatment patterns, recurrence, or survival. CONCLUSION: MBC is associated with poor prognostic indicators, but outcomes comparable with matched typical breast cancer cases can be achieved with routine aggressive multidisciplinary care. Increased, expression of EGFR (HER1) provides an opportunity for targeted tumor therapy.

Annual patient and caregiver burden of oncology clinic visits for granulocyte-colony stimulating factor therapy in the US.

OBJECTIVE: Prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs) is indicated for chemotherapy patients with a significant risk of febrile neutropenia. This study estimates the annual economic burden on patients and caregivers of clinic visits for prophylactic G-CSF injections in the US. METHODS: Annual clinic visits for prophylactic G-CSF injections (all cancers) were estimated from national cancer incidence, chemotherapy treatment and G-CSF utilization data, and G-CSF sales and pricing information. Patient travel times, plus time spent in the clinic, were estimated from patient survey responses collected during a large prospective cohort study (the Prospective Study of the Relationship between Chemotherapy Dose Intensity and Mortality in Early-Stage (I-III) Breast Cancer Patients). Economic models were created to estimate travel costs, patient co-pays and the economic value of time spent by patients and caregivers in G-CSF clinic visits. RESULTS: Estimated total clinic visits for prophylactic G-CSF injections in the US were 1.713 million for 2015. Mean (SD) travel time per visit was 62 (50) min; mean (SD) time in the clinic was 41 (68) min. Total annual time for travel to and from the clinic, plus time at the clinic, is estimated at 4.9 million hours, with patient and caregiver time valued at $91.8 million ($228 per patient). The estimated cumulative annual travel distance for G-CSF visits is 60.2 million miles, with a total transportation cost of $28.9 million ($72 per patient). Estimated patient co-pays were $61.1 million, ∼$36 per visit, $152 per patient. The total yearly economic impact on patients and caregivers is $182 million, ∼$450 per patient. LIMITATIONS: Data to support model parameters were limited. Study estimates are sensitive to the assumptions used. CONCLUSIONS: The burden of clinic visits for G-CSF therapy is a significant addition to the total economic burden borne by cancer patients and their families.