Predictors of imminent risk of fracture in Medicare-enrolled men and women.

Advancing age, female sex, recent prior fracture and falls, and specific comorbidities and medications contribute to imminent (within 1-2 years) risk of fracture in Medicare enrollees. Clinician awareness of these risk factors and their dynamic nature may lead to improved osteoporosis care for elderly patients. PURPOSE: The burden of osteoporotic fracture disproportionately affects the elderly. Growing awareness that fracture risk can change substantially over time underscores the need to understand risk factors for imminent (within 1-2 years) fracture. This study assessed predictors of imminent risk of fracture in the US Medicare population. METHODS: Administrative claims data from a random sample of Medicare beneficiaries were analyzed for patients aged ≥ 67 years on January 1, 2011 (index date), with continuous coverage between January 1, 2009 and March 31, 2011, excluding patients with non-melanoma cancer or Paget's disease. Incident osteoporotic fractures were identified during 12 and 24 months post-index. Potential predictors were age, sex, race, history of fracture, history of falls, presence of osteoporosis, cardiovascular diseases, chronic obstructive pulmonary disorder (COPD), mood/anxiety disorders, polyinflammatory conditions, difficulty walking, use of durable medical equipment, ambulance/life support, and pre-index use of osteoporosis medications, steroids, or central nervous system medications. Cox proportional hazards models were used to evaluate predictors of fracture risk in the two follow-up intervals. RESULTS: Among 1,780,451 individuals included (mean age 77.7 years, 66% female), 8.3% had prior fracture and 6.1% had a history of falls. During the 12- and 24-month follow-up periods, 3.0% and 5.4% of patients had an incident osteoporotic fracture, respectively. Imminent risk of fracture increased with older age (double/triple), female sex (> 80%), recent prior fracture (> double) and falls, and specific comorbidities and medications. CONCLUSIONS: Demographics and factors including fall/fracture history, comorbidities, and medications contribute to imminent risk of fracture in elderly patients.

Validated prediction of imminent risk of fracture for older adults.

OBJECTIVES: To develop and validate predictive models for imminent fracture risk in a Medicare population. STUDY DESIGN: This retrospective administrative claims (Humana Research Database) study assessed imminent risk in Humana's Medicare Advantage and Prescription Drug plan members. METHODS: Individuals (aged 67-87 years on January 1, 2015 [index]) with 1 year or more of history were followed for 3 months to up to 2 years, with censoring at death/disenrollment. The cohort was split into training and validation samples (1:1). Cox regression models assessed demographics, fracture history, medically significant falls, osteoporosis-related factors, frailty markers, and selected medications and comorbidities for independent predictors (P <.001) of incident nontraumatic clinical fractures in 12 and 24 months. A 6-variable model of 12-month risk used a published method for the risk-scoring point system. RESULTS: Of 1,287,354 individuals (mean age, 74.3 years; 56% female; 84% white), 3.8% had at least 1 fragility fracture at 12-month follow-up; 6.6% experienced fracture at 24 months (women vs men: 12 months, 4.8% vs 2.5%; 24 months, 8.3% vs 4.4%; both P <.01). At 12 months, recent fracture conferred approximately 3-fold-higher fracture risk (vs no recent fracture). Older age, white race, female sex, osteoporosis-related screening/diagnosis/medication, antidepressant/antipsychotic/sedative hypnotic/muscle relaxant medications, history of falls, fracture history, and respiratory conditions also increased risk (all P <.0001). The simplified model (recent fracture, age, sex, race, falls, antidepressant/antipsychotic/sedative hypnotic/muscle relaxant medications) performed well (C statistic = 0.71). CONCLUSIONS: Recent fracture, older age, female sex, white race, falls, and antidepressant/antipsychotic/sedative hypnotic/muscle relaxant medications predict imminent fracture risk in an older-adult Medicare Advantage population. Imminent fracture risk can be assessed using 6 easily quantified factors.

Relative dose intensity of first-line chemotherapy and overall survival in patients with advanced non-small-cell lung cancer.

PURPOSE: The effects of chemotherapy dose intensity on survival in patients with advanced non-small-cell lung cancer (NSCLC) are poorly understood. We retrospectively analyzed dose delays/reduction, relative dose intensity (RDI), and the association between chemotherapy intensity and survival in advanced NSCLC. METHODS: This retrospective cohort study included adults with advanced lung cancer who received first-line myelosuppressive platinum-based chemotherapy (January 2007-December 2010) in ~ 230 US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. Overall survival (OS) was measured using Kaplan-Meier and Cox proportional hazard (PH) models. RESULTS: Among 3866 patients with advanced NSCLC, 32.4% experienced dose delays ≥ 7 days, 50.1% experienced dose reductions ≥ 15%, and 40.4% had RDI < 85%. Reduced RDI was also common regardless of baseline ECOG PS (ECOG PS ≥ 2, 56.2%; ECOG PS 0, 33.6%) and tumor subgroup (squamous cell carcinoma, 52.2%; adenocarcinoma, 36.0%). When stratified by chemotherapy intensity measures, significant OS differences were observed only for dose delays. Median (95% CI) OS was 1.02 years (0.96-1.12) for dose delays ≥ 7 days and 0.71 years (0.66-0.77) for dose delays < 7 days. In multivariable Cox PH analysis, dose delays ≥ 7 days (HR = 0.71; 95% CI = 0.63-0.80) and RDI ≥ 85% (HR = 1.18; 95% CI = 1.05-1.32) were significantly associated with decreased mortality. CONCLUSIONS: Dose delays, dose reductions, and reduced RDI were common, and dose delays ≥ 7 days and high RDI were significantly associated with decreased mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.

Designing effective capstone experiences and projects for entry-level doctoral students in occupational therapy: One program's approaches and lessons learned.

Entry-level doctoral occupational therapy programs require students to complete a capstone experience and project that supports advanced skills through an in-depth learning experience with a student-selected mentor. Strong curriculum design and mentorship are vital aspects of successful capstone experiences and projects. Through the application of these key components, students are supported, in collaboration with mentors, to achieve mutually beneficial projects allowing advancement of the profession through dissemination of capstone work.

Predictors of Imminent Risk of Nonvertebral Fracture in Older, High-Risk Women: The Framingham Osteoporosis Study.

Osteoporosis treatment decisions are often based solely on BMD or on 10-year fracture risk; little is known about factors increasing imminent fracture risk. Understanding factors contributing to imminent risk of fracture is potentially useful for personalizing therapy, especially among those at high risk. Our aim was to identify predictors of nonvertebral fracture for 1- and 2-year periods in women at high risk for fracture. The Framingham Osteoporosis Study cohort included 1470 women (contributing 2778 observations), aged ≥65 years with BMD hip T-score ≤ -1.0, or history of fragility fracture (irrespective of T-score). Nonvertebral fractures were ascertained prospectively over 1 year and 2 years following a baseline BMD scan. Potential risk factors included age, anthropometric variables, comorbidities/medical history, cognitive function, medications, history of fracture, self-rated health, falls in the past year, smoking, physical performance, hip BMD T-score, Activities of Daily Living (ADL) score, and caffeine and alcohol intakes. Predictive factors with p value ≤ 0.10 in bivariate Cox proportional hazards regression models were subsequently considered in multivariable models. Mean baseline age was 75 years (SD 6.0). During 1-year follow-up, 89 nonvertebral fractures occurred; during 2-year follow-up, 176 fractures occurred. Of the variables considered in the bivariate models, significant predictors of nonvertebral fractures included age, history of fracture, self-rated health, falls in the prior year, BMD T-score, ADL, renal disease, dementia, and current use of nitrates, beta-blockers, calcium channel blockers, or antidepressants. In multivariable models, significant independent risk factors were history of fracture, self-rated health, hip BMD T-score, and use of nitrates. Significant 1-year results were attenuated at the 2-year follow-up. In addition to the traditional factors of BMD and fracture history, self-rated health and use of nitrates were independently associated with imminent risk of fracture in older, high-risk women. These specific risk factors thus may be useful in identifying which women to target for therapy.

Medical Costs for Osteoporosis-Related Fractures in High-Risk Medicare Beneficiaries.

OBJECTIVES: To estimate the incremental direct medical care costs associated with first fracture observable in high-risk older adults. DESIGN: Retrospective analysis of claims and survey data over a 3-year period from the Health and Retirement Study (HRS), a nationally representative biennial study of individuals aged 50 and older. SETTING: United States. PARTICIPANTS: Participants were HRS respondents who consented to have their Medicare claims data linked to the HRS data, were aged 65 or older, had at least 1 risk factor for fracture observable in the data, and experienced a fracture between 1996 and 2008 (n = 689) and their propensity score-matched controls (n = 689). MEASUREMENTS: Total Medicare, inpatient, outpatient, emergency department, physician office visit, and prescription drug care expenditures were primary outcomes. Two-staged generalized linear models were estimated using a difference-in-differences model. RESULTS: Fracture cases' total Medicare expenditures increased by $13,929 (95% confidence interval (CI)=$11,920-15,938, p <.001) more than those of matched controls from the year before the index or fracture date to 1 year after the index date. Inpatient expenditures of $12,751 (95% CI=$10,790-14,7111, p < .001) more for fracture cases than comparison cases primarily drove this increase. Two and 3 years after fracture, there were no significant differences in growth in expenditures between the two groups. Results did not vary according to whether the fracture was at the hip or other site. CONCLUSION: Fractures impose a significant economic burden, especially in the first year after the fracture, in Medicare beneficiaries with at least 1 risk factor for fracture. Our sample was limited to community-dwelling individuals, and we are unable to control for fracture history before the study period. Costs may be greater for those in skilled nursing and similar facilities and for those who have had a previous fracture. J Am Geriatr Soc 66:2298-2304, 2018.

Chemotherapy Dose Intensity and Overall Survival Among Patients With Advanced Breast or Ovarian Cancer.

BACKGROUND: The effects of chemotherapy dose intensity on patient outcomes in advanced cancer are not well understood. We studied the association between chemotherapy relative dose intensity (RDI) and overall survival (OS) among patients with advanced breast or ovarian cancer. PATIENTS AND METHODS: This retrospective cohort study included adults with advanced breast or ovarian cancer who received first-line myelosuppressive chemotherapy (January 2007 to December 2010) in US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. OS was measured by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Among 874 patients with advanced breast cancer, 33.2% experienced dose delays ≥ 7 days, 48.7% experienced dose reductions ≥ 15%, and 38.9% had RDI < 85%. In the multivariable Cox proportional hazards model, Eastern Cooperative Oncology Group performance status 1/2 versus 0 (hazard ratio [HR] = 1.45; 95% confidence interval [CI], 1.15-1.82) and triple-negative status (HR = 3.14; 95% CI, 1.15-8.62) were significantly associated with mortality. Among 170 patients with advanced ovarian cancer, 43.5% experienced dose delays ≥ 7 days, 48.2% experienced dose reductions ≥ 15%, and 46.5% had RDI < 85%. In the multivariable Cox proportional hazards model, dose reductions ≥ 15% (HR = 1.94; 95% CI, 1.09-3.46) and other tumor histology (vs. nonserous adenocarcinoma; HR = 3.55; 95% CI, 1.38-9.09) were significantly associated with mortality. CONCLUSION: Dose delays, dose reductions, and reduced RDI were common. In advanced breast cancer, health status and triple-negative disease were significantly associated with mortality. In advanced ovarian cancer, dose reductions and tumor histology were significantly associated with mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.

A Model for Assessing the Clinical and Economic Benefits of Bone-forming Agents for Reducing Fractures in Postmenopausal Women at High, Near-term Risk of Osteoporotic Fracture.

PURPOSE: The goal of this study was to assess and compare the potential clinical and economic value of emerging bone-forming agents using the only currently available agent, teriparatide, as a reference case in patients at high, near-term (imminent, 1- to 2-year) risk of osteoporotic fractures, extending to a lifetime horizon with sequenced antiresorptive agents for maintenance treatment. METHODS: Analyses were performed by using a Markov cohort model accounting for time-specific fracture protection effects of bone-forming agents followed by antiresorptive treatment with denosumab. The alternative bone-forming agent profiles were defined by using assumptions regarding the onset and total magnitude of protection against fractures with teriparatide. The model cohort comprised 70-year-old female patients with T scores below -2.5 and a previous vertebral fracture. Outcomes included clinical fractures, direct costs, and quality-adjusted life years. The simulated treatment strategies were compared by calculating their incremental "value" (net monetary benefit). FINDINGS: Improvements in the onset and magnitude of fracture protection (vs the teriparatide reference case) produced a net monetary benefit of $17,000,000 per 10,000 treated patients during the (1.5-year) bone-forming agent treatment period and $80,000,000 over a lifetime horizon that included 3.5 years of maintenance treatment with denosumab. IMPLICATIONS: Incorporating time-specific fracture effects in the Markov cohort model allowed for estimation of a range of cost savings, quality-adjusted life years gained, and clinical fractures avoided at different levels of fracture protection onset and magnitude. Results provide a first estimate of the potential "value" new bone-forming agents (romosozumab and abaloparatide) may confer relative to teriparatide.

Hospitalizations, outcomes, and management costs of febrile neutropenia in patients from a managed care population.

PURPOSE: The study objective was to evaluate chemotherapy treatment patterns and incidence, cost, and resource utilization of febrile neutropenia-related hospitalization (FNH) in patients with breast cancer, lung cancer, and non-Hodgkin's lymphoma (NHL) from Kaiser Permanente Southern California (KPSC), a large integrated delivery system. METHODS: Adults ≥18 years with any stage breast cancer, lung cancer, or NHL who initiated myelosuppressive chemotherapy from 01/01/2006 to 12/31/2009 were included. Chemotherapy dose delays ≥7 days, relative dose intensity (RDI), regimen switching, FNH and all-cause mortality, granulocyte colony-stimulating factor (G-CSF) and antibiotic use, and healthcare utilization/cost were evaluated by cancer type, regimen, and/or cycle. RESULTS: Among 3314 breast cancer patients, 25.3% received an RDI ≤85%, 13.9% experienced FNH with an all-cause mortality rate of 2.0%, and 20.2% received primary prophylaxis with G-CSF. Among those with FNH, mean hospital length of stay (LOS) was 4.1 days, and mean total costs were $20,462. Among 1443 lung cancer patients, 17.9% had an RDI ≤85%, 8.0% experienced FNH with an all-cause mortality rate of 25.2%, and 4.5% received primary prophylaxis with G-CSF. Among those with FNH, mean LOS was 6.8 days, and mean total costs were $32,964. Among 581 NHL patients, 27.9% had an RDI ≤85% and 22.4% experienced FNH with an all-cause mortality rate of 13%. Among those with FNH, mean LOS was 7.9 days, and mean total costs were $37,555. CONCLUSIONS: Marked variability was observed among different cancer types and chemotherapy regimens. Given the variability, detailed insight into incidence, management, and burden of FN can help inform clinical decision making.

Two-year persistence and compliance with osteoporosis therapies among postmenopausal women in a commercially insured population in the United States.

This retrospective, observational study assessed 2-year persistence and compliance by treatment, route of administration, and dosing frequency in postmenopausal women initiating a new osteoporosis therapy. Two-year persistence and compliance rates were higher in women receiving injectables compared with oral agents. PURPOSE: This study extends previous studies limited to 1-year follow-up by examining persistence with osteoporosis therapies over a 2-year period and compares short- and long-term trends in persistence and compliance among postmenopausal women with commercial or Medicare supplemental insurance in the USA. METHODS: This retrospective, observational cohort study enrolled women ≥50 years newly initiating osteoporosis therapy between January 1 and December 31, 2012 (i.e., the index date), with continuous enrollment ≥14 months before and ≥24 months after their index date. Persistence (continuous therapy without a >60-day gap) and compliance with the index therapy were evaluated at 2 years of follow-up. Multivariable logistic regression was used to compare the odds of persistence and compliance across treatment and dosing regimens. RESULTS: This study included 43,543 patients with mean (standard deviation) age 65 (10) years. At 2 years of follow-up, persistence and compliance were higher for patients treated with injectable agents (ranging from 34 to 41%, excluding an every-3-month injection) than those treated with oral agents (ranging from 20 to 31%). Additionally, patients initiating oral bisphosphonates (except risedronate once daily), raloxifene (daily), or zoledronic acid (annually) had significantly lower odds of persistence compared with denosumab (every 6 months). CONCLUSIONS: Patients initiating injectable therapies had greater persistence and compliance at 2 years than those initiating oral therapies. Patients initiating an every-6-month injection had significantly higher persistence compared with those initiating more frequently dosed (e.g., daily and weekly) oral or injectable agents.

Cost-Effectiveness Analysis of Prophylaxis Treatment Strategies to Reduce the Incidence of Febrile Neutropenia in Patients with Early-Stage Breast Cancer or Non-Hodgkin Lymphoma.

OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of no prophylaxis, primary prophylaxis (PP), or secondary prophylaxis (SP) with granulocyte colony-stimulating factors (G-CSFs), i.e., pegfilgrastim, lipegfilgrastim, filgrastim (6- and 11-day), or lenograstim (6- and 11-day), to reduce the incidence of febrile neutropenia (FN) in patients with stage II breast cancer receiving TC (docetaxel, cyclophosphamide) and in patients with non-Hodgkin lymphoma (NHL) receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) over a lifetime horizon from a Belgian payer perspective. METHODS: A Markov cycle tree tracked FN events during chemotherapy (3-week cycles) and long-term survival (1-year cycles). Model inputs, including the efficacy of each strategy, risk of reduced relative dose intensity (RDI), and the impact of RDI on mortality, utilities, and costs (in €; 2014 values) were estimated from public sources and the published literature. Incremental cost-effectiveness ratios (ICERs) were assessed for each strategy for costs per FN event avoided, life-year (LY) saved, and quality-adjusted LY (QALY) saved. LYs and QALYs saved were discounted at 1.5% annually. Deterministic and probabilistic sensitivity analyses (DSAs and PSAs) were conducted. RESULTS: Base-case ICERs for PP with pegfilgrastim relative to SP with pegfilgrastim were €15,500 per QALY and €14,800 per LY saved for stage II breast cancer and €7800 per QALY and €6900 per LY saved for NHL; other comparators were either more expensive and less effective than PP or SP with pegfilgrastim or had lower costs but higher ICERs (relative to SP with pegfilgrastim) than PP with pegfilgrastim. Results of the DSA for breast cancer and NHL comparing PP and SP with pegfilgrastim indicate that the model results were most sensitive to the cycle 1 risk of FN, the proportion of FN events requiring hospitalization, the relative risk of FN in cycles ≥2 versus cycle 1, no history of FN, and the mortality hazard ratio for RDI (<90% vs ≥90% [for NHL]). In the PSAs for stage II breast cancer and NHL, the probabilities that PP with pegfilgrastim was cost effective or dominant versus all other prophylaxis strategies at a €30,000/QALY willingness-to-pay threshold were 52% (other strategies ≤24%) and 58% (other strategies ≤24%), respectively. CONCLUSION: From a Belgian payer perspective, PP with pegfilgrastim appears cost effective compared to other prophylaxis strategies in patients with stage II breast cancer or NHL at a €30,000/QALY threshold.

Utilization of osteoporosis medication after a fragility fracture among elderly Medicare beneficiaries.

Osteoporosis medications are recommended for elderly patients after a fragility fracture. However, we found substantial under-treatment in the post-fracture year, especially among patients who had not previously received such medications. Improved treatment of elderly patients experiencing fragility fractures is needed. INTRODUCTION: Osteoporosis medications are recommended for elderly patients after a fragility fracture, but under-treatment is common. We determined osteoporosis medication use after fragility fractures and examined associated factors. METHODS: Our cohort included elderly (age ≥66 years) Medicare-enrolled patients who sustained fragility fractures January 1, 2008-December 31, 2011. Osteoporosis medication prescriptions were determined in the 12 months after the index fracture. Using multivariate logistic models, we examined the association between post-fracture osteoporosis medication use and predictors. RESULTS: Of 145,185 patients with fragility fractures (mean age 80.9 ± 7.8 years; 91.2 % white; 81.3 % female), 29.9 % sustained hip, 31.8 % vertebral, and 38.4 % non-hip-non-vertebral fractures. Overall, 30.4 % of the cohort received an osteoporosis medication in the 12-month post-fracture period. Of patients not receiving an osteoporosis medication in the pre-index period (n = 108,344), 14.9 % of all patients, 16.3 % of women, and 10.3 % of men received one in the post-fracture period. Corresponding values for patients receiving an osteoporosis medication in the pre-index period (n = 36,841) were 76.2, 76.5, and 72.2 %. Odds of post-fracture osteoporosis medication use were 68 % higher for women than for men. Osteoporosis diagnosis (odds ratio, 1.55; P < 0.0001) and bone-mineral-density tests before an index fracture (odds ratio, 1.24; P < 0.001) were associated with post-fracture osteoporosis medication use. CONCLUSIONS: Less than one third of our cohort received an osteoporosis medication in the post-fracture year, when risk of a second fragility fracture is highest. In those not already previously treated with an osteoporosis medication, only about 1 in 7 patients received treatment.

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.

Dose Delays, Dose Reductions, and Relative Dose Intensity in Patients With Cancer Who Received Adjuvant or Neoadjuvant Chemotherapy in Community Oncology Practices.

BACKGROUND: A wide variety of myelosuppressive chemotherapy regimens are used for the treatment of cancer in clinical practice. Neutropenic complications, such as febrile neutropenia, are among the most common side effects of chemotherapy, and they often necessitate delays or reductions in doses of myelosuppressive agents. Reduced relative dose intensity (RDI) may lead to poorer disease-free and overall survival. METHODS: Using the McKesson Specialty Health/US Oncology iKnowMed electronic health record database, we retrospectively identified the first course of adjuvant or neoadjuvant chemotherapy received by patients without metastases who initiated treatment between January 1, 2007, and March 31, 2011. For each regimen, we estimated the incidences of dose delays (≥7 days in any cycle of the course), dose reductions (≥ 15% in any cycle of the course), and reduced RDI (<85% over the course) relative to the corresponding standard tumor regimens described in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). RESULTS: This study included 16,233 patients with 6 different tumor types who received 1 of 20 chemotherapy regimens. Chemotherapy dose delays, dose reductions, and reduced RDI were common among patients treated in community oncology practices in the United States, but RDI was highly variable across patients, regimens, and tumor types (0.486-0.935 for standard tumor regimen cohorts). Reduced RDI was more common in older patients, obese patients, and patients whose daily activities were restricted. CONCLUSIONS: In this large evaluation of RDI in US clinical practice, physicians frequently administered myelosuppressive agents at dose intensities lower than those of standard regimens.

The impact of primary prophylaxis with granulocyte colony-stimulating factors on febrile neutropenia during chemotherapy: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: The study aims to assess the relative efficacy of granulocyte colony-stimulating factor (G-CSF) products administered as primary prophylaxis (PP) to patients with cancer receiving myelosuppressive chemotherapy. METHODS: A systematic literature review identified publications (January 1990 to September 2013) of randomized controlled trials evaluating PP with filgrastim, pegfilgrastim, lenograstim, or lipegfilgrastim in adults receiving myelosuppressive chemotherapy for solid tumors or non-Hodgkin lymphoma. Direct, indirect, and mixed-treatment comparison (MTC) were used to estimate the odds ratio and 95 % credible interval of febrile neutropenia (FN) during cycle 1 and all cycles of chemotherapy combined without adjusting for differences in relative dose intensity (RDI) between study treatment arms. RESULTS: Twenty-seven publications representing 30 randomized controlled trials were included. Using MTC over all chemotherapy cycles, PP with filgrastim, pegfilgrastim, lenograstim, and lipegfilgrastim versus no G-CSF PP or placebo were associated with statistically significantly reduced FN risk. FN risk was also significantly reduced with pegfilgrastim PP versus filgrastim PP. Over all chemotherapy cycles, there was a numerical but statistically nonsignificant increase in the FN risk for lipegfilgrastim PP versus pegfilgrastim PP. Using MTC in cycle 1, PP with filgrastim, pegfilgrastim, and lipegfilgrastim versus no G-CSF PP or placebo were associated with statistically significantly reduced FN risk. CONCLUSIONS: In this meta-analysis, using MTC without adjustment for RDI, PP with all G-CSFs evaluated reduced the FN risk in patients receiving myelosuppressive chemotherapy. Future studies are needed to assess the influence of RDI on FN outcomes and to eliminate potential bias between G-CSF arms receiving more intensive chemotherapy than control arms.

Comparative effectiveness of colony-stimulating factors in febrile neutropenia prophylaxis: how results are affected by research design.

AIMS: To examine the impact of research design on results in two published comparative effectiveness studies. METHODS: Guidelines for comparative effectiveness research have recommended incorporating disease process in study design. Based on the recommendations, we develop a checklist of considerations and apply the checklist in review of two published studies on comparative effectiveness of colony-stimulating factors. Both studies used similar administrative claims data, but different methods, which resulted in directionally different estimates. RESULTS: Major design differences between the two studies include: whether the timing of intervention in disease process was identified and whether study cohort and outcome assessment period were defined based on this temporal relationship. CONCLUSION: Disease process and timing of intervention should be incorporated into the design of comparative effectiveness studies.

Cancer chemotherapy treatment patterns and febrile neutropenia in the US Veterans Health Administration.

BACKGROUND: The Veterans Health Administration (VHA) is the largest integrated health care system in the United States and a major cancer care provider. OBJECTIVE: To use VHA database to conduct a population-based study of patterns of myelosuppressive chemotherapy use and to assess the incidence and management of febrile neutropenia (FN) among VHA patients with lung, colorectal, or prostate cancer or non-Hodgkin lymphoma (NHL). METHODS: Data were extracted for the initial myelosuppressive chemotherapy course for 27,899 patients who began treatment in the period 2006 to 2011. FN-related costs were defined as claims containing FN diagnosis. RESULTS: Most patients were men (98.0%); most were 65 years or older (55.8%). Patients received a mean 3.4 to 3.9 chemotherapy cycles/course (median cycle duration 34-43 days). The incidence of FN among patients with lung, colorectal, or prostate cancer or NHL was 10.2%, 4.6%, 5.4%, and 17.3%, respectively. Primary or secondary prophylactic antibiotics/colony-stimulating factors were received by 21% and 12% of patients, respectively. Antibiotics were more commonly given as primary or secondary prophylaxis for patients with lung, colorectal, and prostate cancer; colony-stimulating factors were more common for patients with NHL. Among patients with FN, those with lung cancer had the highest inpatient mortality (10%); patients with NHL had the highest costs ($24,571) and the longest hospital length of stay (15.4 days). CONCLUSIONS: VHA cancer care was generally consistent with National Comprehensive Cancer Network recommendations; however, compared with the general population, chemotherapy cycles were longer, combination chemotherapy was used less, and treatment to prevent FN was used less, differences that may be attributed to the unique VHA patient population. The impact of these practices warrants further investigation.

Discrete choice experiment to estimate breast cancer patients' preferences and willingness to pay for prophylactic granulocyte colony-stimulating factors.

OBJECTIVES: Rising out-of-pocket costs for cancer patients have increased shared decision making. Clinical guidelines recommend prophylactic granulocyte colony-stimulating factor (G-CSF) for patients receiving chemotherapy with a 20% or greater risk of febrile neutropenia. A discrete choice experiment was conducted to explore breast cancer patients' preferences and willingness to pay (WTP) for prophylactic G-CSF to decrease the risk of chemotherapy-induced febrile neutropenia. METHODS: An online discrete choice experiment questionnaire survey of a national US convenience sample of self-reported breast cancer patients with prior chemotherapy treatment was conducted. Sixteen paired G-CSF treatment scenarios, each with four attributes (risk of disruption to chemotherapy schedule due to low white blood cell counts, risk of developing an infection requiring hospitalization, frequency of administration, and total out-of-pocket cost) were presented with a follow-up "no treatment" option. Participant preferences and WTP out of pocket were estimated by logistic regression. RESULTS: Participants (n = 296) preferred G-CSF regimens with lower out-of-pocket costs, lower risk of chemotherapy disruption, lower risk of infection, and greater convenience (one G-CSF injection per chemotherapy cycle). Participants' WTP was $1076 out of pocket per cycle to reduce the risk (high to low) of disrupting their chemotherapy schedule, $884 per cycle to reduce the risk (24% [high] to 7% [low]) of infection, and $851 per cycle to decrease the number of G-CSF injections (11 to 1) per cycle. CONCLUSIONS: Participants highly valued specific features of prophylactic G-CSF treatment including maintaining their chemotherapy schedule, lowering their risk of infection, and reducing the number of injections. Physicians should consider patient preferences to inform the best treatment choices for individual patients.

Cost-effectiveness of prophylaxis treatment strategies for febrile neutropenia in patients with recurrent ovarian cancer.

OBJECTIVE: Evaluate the cost-effectiveness of primary prophylaxis (PP) or secondary prophylaxis (SP) with pegfilgrastim, filgrastim (6-day and 11-day), or no prophylaxis to reduce the risk of febrile neutropenia (FN) in patients with recurrent ovarian cancer receiving docetaxel or topotecan. METHODS: A Markov model was used to evaluate the cost-effectiveness of PP vs SP from a US payer perspective. Model inputs, including the efficacy of each strategy (relative risk of FN with prophylaxis compared to no prophylaxis) and mortality, costs, and utility values were estimated from public sources and peer-reviewed publications. Incremental cost-effectiveness was evaluated in terms of net cost per FN event avoided, incremental cost per life-year saved (LYS), and incremental cost per quality-adjusted life-year (QALY) gained over a lifetime horizon. Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted. RESULTS: For patients receiving docetaxel, the incremental cost-effectiveness ratio (ICER) for PP vs SP with pegfilgrastim was $7900 per QALY gained, and PP with pegfilgrastim dominated all other comparators. For patients receiving topotecan, PP with pegfilgrastim dominated all comparators. Model results were most sensitive to baseline FN risk. PP vs SP with pegfilgrastim was cost effective in 68% and 83% of simulations for docetaxel and in >99% of simulations for topotecan at willingness-to-pay thresholds of $50,000 and $100,000 per QALY. CONCLUSIONS: PP with pegfilgrastim should be considered cost effective compared to other prophylaxis strategies in patients with recurrent ovarian cancer receiving docetaxel or topotecan with a high risk of FN.

Granulocyte colony-stimulating factor (G-CSF) patterns of use in cancer patients receiving myelosuppressive chemotherapy.

PURPOSE: Febrile neutropenia (FN) is a common and serious complication of myelosuppressive chemotherapy. Guidelines recommend primary granulocyte colony-stimulating factors (G-CSF) prophylaxis (PPG) in patients with a high risk (HR, >20 %) of developing FN. We performed a retrospective analysis using a subset of the Medicare 5 % database to assess patterns of G-CSF use and FN occurrence among elderly cancer patients receiving myelosuppressive chemotherapy. METHODS: Chemotherapy courses for patients aged 65+ years were identified; only the first course was used for this analysis. Using clinical guidelines, chemotherapy regimens were classified as HR or intermediate risk (IR) for FN. The first administration of G-CSF was classified as either PPG (within the first 5 days of the first cycle), secondary prophylaxis, or reactive. RESULTS: Twelve thousand seven hundred seven courses across five tumor types were classified as having a HR or IR regimen. G-CSF was used in 24.5-73.8 % of patients receiving a HR FN regimen, with the highest use in breast cancer or NHL. Except for breast cancer (where PPG was used in 52.1 %), PPG was given in less than half of patients receiving a HR regimen. Depending on the tumor type, 4.8-22.6 % of patients with a HR regimen had a neutropenia-related hospitalization. CONCLUSIONS: Guidelines recommend PPG with HR FN regimens and older age (>65 years), an important risk factor for developing severe neutropenic complications. However, our results show that in this elderly population, PPG was not routinely used (range 4.8-52.1 %) in patients receiving HR FN regimens. Careful attention to FN risk factors, including chemotherapy regimen and patient age, is needed when planning treatment strategies.