Primary Prophylactic Colony-stimulating Factor Research Articles

Effects of a Guideline-Informed Clinical Decision Support System Intervention to Improve Colony-Stimulating Factor Prescribing

Colony-stimulating factors are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia. Research suggests that 55% to 95% of colony-stimulating factor prescribing is inconsistent with national guidelines. To examine whether a guideline-based standing order for primary prophylactic colony-stimulating factors improves use and reduces the incidence of febrile neutropenia. This cluster randomized clinical trial, the Trial Assessing CSF Prescribing Effectiveness and Risk (TrACER), involved 32 community oncology clinics in the US. Participants were adult patients with breast, colorectal, or non-small cell lung cancer initiating cancer therapy and enrolled between January 2016 and April 2020. Data analysis was performed from July to October 2021. Sites were randomized 3:1 to implementation of a guideline-based primary prophylactic colony-stimulating factor standing order system or usual care. Automated orders were added for high-risk regimens, and an alert not to prescribe was included for low-risk regimens. Risk was based on National Comprehensive Cancer Network guidelines. The primary outcome was to find an increase in colony-stimulating factor use among high-risk patients from 40% to 75%, a reduction in use among low-risk patients from 17% to 7%, and a 50% reduction in febrile neutropenia rates in the intervention group. Mixed model logistic regression adjusted for correlation of outcomes within a clinic. A total of 2946 patients (median [IQR] age, 59.0 [50.0-67.0] years; 2233 women [77.0%]; 2292 White [79.1%]) were enrolled; 2287 were randomized to the intervention, and 659 were randomized to usual care. Colony-stimulating factor use for patients receiving high-risk regimens was high and not significantly different between groups (847 of 950 patients [89.2%] in the intervention group vs 296 of 309 patients [95.8%] in the usual care group). Among high-risk patients, febrile neutropenia rates for the intervention (58 of 947 patients [6.1%]) and usual care (13 of 308 patients [4.2%]) groups were not significantly different. The febrile neutropenia rate for patients receiving high-risk regimens not receiving colony-stimulating factors was 14.9% (17 of 114 patients). Among the 585 patients receiving low-risk regimens, colony-stimulating factor use was low and did not differ between groups (29 of 457 patients [6.3%] in the intervention group vs 7 of 128 patients [5.5%] in the usual care group). Febrile neutropenia rates did not differ between usual care (1 of 127 patients [0.8%]) and the intervention (7 of 452 patients [1.5%]) groups. In this cluster randomized clinical trial, implementation of a guideline-informed standing order did not affect colony-stimulating factor use or febrile neutropenia rates in high-risk and low-risk patients. Overall, use was generally appropriate for the level of risk. Standing order interventions do not appear to be necessary or effective in the setting of prophylactic colony-stimulating factor prescribing. ClinicalTrials.gov Identifier: NCT02728596.

Can order entry systems improve oncology practice? The TrACER Experience.

339 Background: Primary prophylactic colony stimulating factors (PP-CSF) are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia (FN). Prior research suggested poor adherence to PP-CSF prescribing relative to national guidelines. Accordingly, the objective of the TrACER study was to examine whether a guideline-based standing order entry (SOE) system for PP-CSF improves use and reduces FN. TrACER also included a substudy to evaluate the effectiveness of PP-CSF for patients receiving intermediate risk chemotherapy, where evidence of benefit is weaker. Methods: We conducted a patient-informed, cluster randomized trial among 32 oncology clinics from the NCI Community Oncology Research Program. Patients age ≥18 with breast, colorectal or non-small cell lung cancer initiating cancer therapy were enrolled. Clinics were randomized 3:1 to the implementation of a guideline-based PP-CSF SOE or usual care. Automated orders for PP-CSF were added for high-risk regimens and an alert not to use PP-CSF was included for low-risk regimens. Risk was based on National Comprehensive Cancer Network guidelines. A secondary 1:1 randomization for intermediate risk-regimens assigned 16 intervention sites to either SOE to prescribe or an alert to not prescribe PP-CSF. Results: 2,946 patients were enrolled (2287 intervention, 659 usual care). PP-CSF use among high-risk patients was high and not significantly different between arms (89.2% SOE; 95.8% usual care). FN rates for the SOE and usual care arms were 6.1% and 4.2% and not significantly different. The FN rate among high-risk patients not receiving PP-CSF was 14.9%. Among the 585 patients receiving low-risk regimens, PP-CSF use was low and not different between arms (6.3% SOE, 5.5% usual care). FN rates did not differ between the SOE system (1.5%) and usual care (0.8%). In contrast, for the intermediate risk substudy, rates of PP-CSF use were substantially higher among sites randomized to SOE (37.1% vs 9.9%, OR = 5.91(95% CI 1.77-19.70; p = 0.0038), and rates of FN were low and identical between arms (3.7% vs 3.7%). Similarly, FN rates did not differ between intermediate-risk patients that did or did not receive PP-CSF, irrespective of assignment. Conclusions: Implementation of a guideline-informed SOE system did not impact PP-CSF use or FN rates in high- and low-risk patients, where evidence supporting PP-CSF is stronger, and had a significant impact on PP-CSF use but not FN rates among intermediate risk patients, where evidence of benefit is weak. Overall, adherence to PP-CSF for low- and high-risk chemotherapy was much better than predicted based on evidence available at trial design. SOE interventions may be more useful in situations where more uncertainty of benefit exists. The pragmatic trial design provides high-quality evidence that had previously been lacking on the use and performance of PP-CSF in real world settings across the spectrum of FN risk. Clinical trial information: NCT02728596.

Intervention non-adherence in a pragmatic randomized trial of a standardized order entry for colony stimulating factor prescribing.

374 Background: Pragmatic trials evaluate the effectiveness of interventions in routine practice conditions. Pragmatic trials have high generalizability, but the treatment effect can be influenced by nonadherence to the intervention of interest. We conducted a pragmatic, cluster-randomized trial to test whether a guideline-based standing order entry (SOE) system improves use of primary prophylactic colony stimulating factor (PP-CSF) prescribing for patients receiving myelosuppressive chemotherapy. Clinics were assigned to the SOE or usual care. We investigated variability in adherence to the intervention. Methods: TrACER was a patient-informed, cluster randomized trial among 32 oncology clinics from the NCI Community Oncology Research Program. Clinics were randomized 3:1 to a guideline-based PP-CSF SOE or usual care (primary study). Among SOE intervention sites, automated orders for PP-CSF were included for regimens at high risk for febrile neutropenia (FN) and an alert not to use PP-CSF for low FN risk. A secondary 1:1 randomization assigned the 24 intervention sites to either SOE to prescribe or an alert to not prescribe PP-CSF for patients receiving intermediate FN risk-regimens. Providers were allowed to override the standing orders for individual patients. Results: Overall, 8 sites (659 patients) were randomized to usual care and 24 sites (2287 patients) to the intervention; 12 (1296 patients) were randomized to the intermediated risk SOE intervention and 12 (991 patients) to the alert not to prescribe PP-CSF. PP-CSF use among patients receiving high FN risk treatment was high and not different between arms (89.2% SOE; 95.8% usual care), however rates of PP-CSF use by site ranged from 48.6% to 100%. Among those receiving low FN risk regimens, PP-CSF use was low and not different between arms (6.3% SOE, 5.5% usual care), however PP-CSF use ranged from 0% to 19.4% across sites randomized to the alert to not prescribe. In the intermediate risk sub-study, PP-CSF was higher among sites randomized to SOE vs. the alert not to prescribe PP-CSF (37.1% vs 9.9%, OR = 5.91, 95% CI 1.77-19.70; p = 0.0038). However, there was considerable variability in adherence to intervention assignment: PP-CSF use ranged from 0% to 75% among sites randomized to SOE, and despite an alert to not prescribe, PP-CSF rates ranged among sites from 0% to 33%. FN rates were low and similar in both arms. Conclusions: In this randomized pragmatic trial aimed at improving PP-CSF prescribing, there was substantial variability in site adherence to the intervention assignment. While the ability to opt-out of the intervention is a feature of pragmatic trials, careful pre-study planning to estimate nonadherence is critical to ensure adequate power to detect an effect. Understanding reasons for intervention opt-outs will is also inform future pragmatic studies aimed at improving adherence to practice guidelines. Clinical trial information: NCT02728596.

A pragmatic cluster-randomized trial of a standing physician order entry intervention for colony stimulating factor use among patients at intermediate risk for febrile neutropenia (SWOG S1415CD).

1518 Background: Primary prophylactic colony stimulating factors (PP-CSF) are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia (FN) but their benefit for regimens with intermediate FN risk is uncertain. Within a pragmatic, randomized trial of a standing order entry (SOE) intervention for prescribing PP-CSF, we designed a substudy to evaluate the effectiveness of PP-CSF for patients receiving therapy with intermediate FN risk. Methods: TrACER was a cluster randomized trial where NCI community Oncology Research Program practices were randomized to usual care (UC) or a guideline-based SOE intervention. In the primary study, sites were randomized 3:1 to a SOE of automated PP-CSF orders for NCCN-designated high FN risk chemotherapy regimens and alerts against PP-CSF orders for low FN risk regimens (intervention) versus usual care. A secondary randomization assigned intervention sites to a SOE intervention either to prescribe or not prescribe PP-CSF for patients receiving intermediate FN risk regimens. Clinicians were allowed to override the SOE. Patients age ≥18 with either breast, colorectal or non-small cell lung cancer were enrolled and followed for 12 mo. PP-CSF was defined as initiation within 24-72 hours after systemic chemotherapy. Sample size calculations were based on an FN risk reduction from 15% to 7.5%, and provided 80% power at a planned enrollment of 90 patients per site. Mixed effect logistic regression models were used to test differences between sites randomized to prescribe or not prescribe PP-CSF. Results: Between January 2016 and April 2020, 24 sites (2,287 patients) were randomized to the intervention. Among intervention sites, 12 were randomized to either SOE to prescribe or an alert to not prescribe PP-CSF for the 542 patients receiving intermediate FN risk regimens. Rates of PP-CSF use were higher among sites randomized to prescribe PP-CSF (37.1% vs 9.9%, OR = 5.90 (95% CI 1.72-20.20; p = 0.0048)). Overall, the rates of FN were low and identical between PP-CSF and no PP-CSF arms (3.7% vs 3.7%). Among patients who did not receive PP-CSF, rates of FN were also low and similar between arms (3.8% vs 4.1%). Conclusions: While implementation of a SOE intervention for PP-CSF significantly increased PP-CSF use among patients receiving intermediate risk regimens, FN rates did not differ between arms. Despite SOE, 63% of patients assigned to receive PP-CSF did not receive it. FN rates overall were lower than expected and did not differ between patients that did or did not receive PP-CSF. Although this guideline-informed SOE influenced prescribing, the results suggest that neither the SOE nor PP-CSF itself provide sufficient benefit to justify their use for persons receiving intermediate FN risk regimens. Clinical trial information: NCT02728596.

A pragmatic cluster-randomized trial of a computerized clinical decision support system to improve colony stimulating factor prescribing for patients with cancer receiving myelosuppressive chemotherapy (SWOG S1415CD).

1525 Background: Primary prophylactic colony stimulating factors (PP-CSF) are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia (FN). Prior studies have shown that 55-95% of CSF prescribing is inconsistent with practice guidelines. We conducted a cluster randomized trial to determine if guideline-informed standing orders for PP-CSF improved prescribing and reduced the incidence of FN. Methods: Patients age ≥18 with breast, colorectal or non-small cell lung cancer initiating first cancer-directed therapy with NCCN-recommended regimens were eligible. The intervention consisted of automated PP-CSF orders for high FN risk chemotherapy regimens and an alert not to use PP-CSF for low FN risk regimens. Regimen FN risk was based on NCCN guidelines. Clinicians could override the orders. Primary and secondary outcomes were PP-CSF use among patients receiving high and low risk regimens FN incidence within 6 months of initial therapy. Sample size estimates assumed an FN risk of 25% for high-risk chemotherapy. 32 NCI Community Oncology Research Program (NCORP) practices randomized 3:1 to the order entry system (intervention) versus usual care (UC) provided 90% power to detect a 50% reduction in FN at a planned enrollment of 90 patients per site. Mixed effect logistic regression models were used to test differences among randomized sites. 13 practices with pre-existing PP-CSF order sets enrolled in a parallel cohort study. Patients and other stakeholder groups informed study design, conduct and reporting. Results: Between January 2016 and April 2020, 2,946 patients were randomized (2287 intervention, 659 UC); 718 were enrolled in the cohort. Mean age across arms was 58.1. 77% of patients were female; 61% diagnosed with breast cancer. Among patients receiving high-risk regimens, PP-CSF use did not differ between arms (89.2% intervention; 95.8% UC, adjusted p = 0.21) and was similar to the cohort patients (93.0%). The FN rate for high-risk patients was 5.7% in intervention clinics and 4.2% in UC clinics (adjusted p = 0.26); FN was 14.9% among high-risk patients who did not receive PP-CSF. Among patients receiving low-risk regimens, PP-CSF use did not differ between arms (intervention 6.3%, UC 5.5%, adjusted p = 0.74) and was slightly lower than the cohort (8.3%). FN rates did not differ between low risk groups (intervention 1.5%, UC 0.8%, adjusted p = 0.51). Conclusions: Guideline-informed standing orders did not increase PP-CSF use in high-risk patients, nor did it decrease use in low-risk patients. Adherence to guidelines in both risk groups exceeded historical reports. FN rates among patients not receiving PP-CSF were substantially below those reported in CSF guidelines. Automated standing orders for PP-CSF do not appear to be helpful or necessary. Clinical trial information: NCT02728596.

Successes and challenges of implementing a cancer care delivery intervention in community oncology practices: lessons learned from SWOG S1415CD

BackgroundCancer Care Delivery (CCD) research studies often require practice-level interventions that pose challenges in the clinical trial setting. The SWOG Cancer Research Network (SWOG) conducted S1415CD, one of the first pragmatic cluster-randomized CCD trials to be implemented through the National Cancer Institute (NCI) Community Oncology Program (NCORP), to compare outcomes of primary prophylactic colony stimulating factor (PP-CSF) use for an intervention of automated PP-CSF standing orders to usual care. The introduction of new methods for study implementation created challenges and opportunities for learning that can inform the design and approach of future CCD interventions.MethodsThe order entry system intervention was administered at the site level; sites were affiliated NCORP practices that shared the same chemotherapy order system. 32 sites without existing guideline-based PP-CSF standing orders were randomized to the intervention (n = 24) or to usual care (n = 8). Sites assigned to the intervention participated in tailored training, phone calls and onboarding activities administered by research team staff and were provided with additional funding and external IT support to help them make protocol required changes to their order entry systems.ResultsThe average length of time for intervention sites to complete reconfiguration of their order sets following randomization was 7.2 months. 14 of 24 of intervention sites met their individual patient recruitment target of 99 patients enrolled per site.ConclusionsIn this paper we share seven recommendations based on lessons learned from implementation of the S1415CD intervention at NCORP community oncology practices representing diverse geographies and patient populations across the U. S. It is our hope these recommendations can be used to guide future implementation of CCD interventions in both research and community settings.Trial RegistrationNCT02728596, registered April 5, 2016.

Results of a pilot study to increase adherence to ASCO G-CSF recommendations at community clinics.

19 Background: An ASCO 2012 Choosing Wisely recommendation cautions against the use of primary prophylactic colony stimulating factors (PP-CSF) for chemotherapy regimens with <20% risk of febrile neutropenia (FN). Our pilot aimed to test the feasibility and impact of using academic detailing and an automated CSF ordering system on CSF prescribing at 6 regional community oncology clinics in Washington State. Methods: The intervention was 1) academic detailing for oncologists during a regular staff meeting and 2) reconfiguring ordering systems to show FN risk and PP-CSF recommendation in a passive alert and include or exclude PP-CSF standing orders with >20% or ≤20% FN risk regimens, respectively. Clinic tumor registries were queried for patients with stage II-IV breast, non-small cell lung, or colorectal cancer starting first-line chemotherapy pre- or post-intervention. PP-CSF use, FN risk factors, and chemotherapy regimens matching the study protocol were manually abstracted. A regimen order was coded as adherent if it is low (<10%) FN risk without PP-CSF use; intermediate (10-20%) FN risk without PP-CSF use or FN risk factors are present; or high (>20%) FN risk with PP-CSF use. Results: The intervention was successfully implemented at 4 out of 6 participating clinics. The remaining 2 clinics were transitioning from paper to electronic orders in 1-2 years or using a system managed by a non-participating hospital. Adherence across the four implementing clinics increased after the intervention. *=p<0.05 Implementation of the CSF order-entry intervention was successful across a variety of ordering systems, including paper-based systems. Overall, while adherence prior to the intervention was high for these clinics, the order entry systems significantly improved adherence. Population characteristics and data availability may account for variation in adherence. Conclusions: An intervention with both academic detailing and ordering system presets may help increase adherence to Choosing Wisely recommendations. [Table: see text]

Trends in use of primary prophylactic colony stimulating factors and neutropenia-related hospitalization in commercially insured patients receiving myelosuppressive chemotherapy in the United States: 2005-2017.

Describe temporal changes in use of myelosuppressive chemotherapy, primary prophylactic colony-stimulating factor, and neutropenia-related hospitalization, in commercially insured patients. Using a large commercial administrative database, we identified annual cohorts of adult patients diagnosed with breast or lung cancer, or non-Hodgkin lymphoma and initiating myelosuppressive chemotherapy during 2005-2017. We described yearly changes in proportions of myelosuppressive chemotherapy by febrile neutropenia risk category (high, intermediate, unclassified) and proportion of prophylactic colony-stimulating factor use and unadjusted incidence of neutropenia-related hospitalization in the first cycle of myelosuppressive chemotherapy. Annual cohorts included 4383-5888 eligible patients during 2005-2017. The proportion of eligible patients aged ≥ 65 years increased from 26.0% in 2005 to 58.2% in 2017. Myelosuppressive chemotherapy use with regimens with high risk for febrile neutropenia increased from 15.1% in 2005 to 31.0% in 2017; and regimens with intermediate risk for febrile neutropenia decreased from 63.7% to 48.1% in 2017. Prophylactic colony-stimulating factor use increased from 41.6% in 2005 to 54.3% in 2017. Crude incidence of neutropenia-related hospitalization for all cancers increased from 2.0% to 3.1%, with a substantial increase in neutropenia-related hospitalization observed among non-Hodgkin lymphoma patients (2.8% to 8.5%) during 2005-2017. Among adult patients with breast and lung cancer, and non-Hodgkin lymphoma receiving myelosuppressive chemotherapy, use of regimens with high risk for febrile neutropenia increased, as did the use of prophylactic colony-stimulating factors after 2005. Incidence of neutropenia-related hospitalization increased slightly, particularly among non-Hodgkin lymphoma patients. Further studies are required to understand this increasing trend of neutropenia-related hospitalization, changing patient-level risk factors, and febrile neutropenia management.

Trends in the use of primary prophylactic colony-stimulating factors and neutropenia-related hospitalization in elderly cancer patients receiving myelosuppressive chemotherapy in the USA: 1995-2015.

To assess changes in neutropenia-related hospitalization, myelosuppressive chemotherapy, and primary prophylactic colony-stimulating factor (PP-CSF) use in elderly cancer patients receiving myelosuppressive chemotherapy. We identified annual cohorts of patients aged ≥ 66years with breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL) initiating myelosuppressive chemotherapy during 1995-2015 using Medicare 5% (1994-2008) and 20% (2007-2015) data. We described myelosuppressive chemotherapy changes by febrile neutropenia (FN) risk category (high, intermediate, unclassified), PP-CSF use, and, in the first cycle of myelosuppressive chemotherapy, neutropenia-related hospitalization (ICD-9-CM: 288.0X, first 5 positions). We evaluated hospitalization trends using a logistic regression model with spline curve of calendar year adjusting for baseline characteristics. Annual cohorts included 1451-2114 eligible patients for 1995-2007 and 5272-7603 for 2008-2015. Myelosuppressive chemotherapy use with high/intermediate FN risk increased from 31% in 1995 to 56% in 1999, stabilized through 2008 (range 56-61%), then decreased to 52% in 2015. PP-CSF use increased from 5.5% in 1995 to 52.7% in 2015, mainly due to pegfilgrastim introduction in 2002. Crude neutropenia-related hospitalization incidence decreased from 5.2% in 1995 to 2.7% in 2015; adjusted incidence decreased, on average, by 4.7% yearly before 2010 (p < 0.0001) and was flat from 2010 onward (p = 0.53). Among elderly patients with breast cancer, lung cancer, or NHL receiving myelosuppressive chemotherapy, PP-CSF use increased substantially after 2002. Neutropenia-related hospitalization incidence in the first cycle decreased yearly before 2010 and was flat afterward. Further studies are needed to understand overall decreasing neutropenia-related hospitalization trends and effects of changes in myelosuppressive chemotherapy and FN management.

Impact of clinic characteristics on the adoption of a guideline-based standing order algorithm and patient accrual in the pragmatic cluster-randomized trial SWOG S1415CD (NCT02728596).

60 Background: The S1415CD intervention requires the integration of guideline-based prescribing recommendations and standing orders for primary prophylactic colony stimulating factors into existing chemotherapy order systems at community practices within the National Cancer Institute’s Community Oncology Research Program. We looked at the impact of clinic level characteristics on the length of time needed to successfully adopt the intervention and subsequent patient accrual. Methods: We calculated the length of time between randomization and intervention completion for each intervention arm clinic and classified them as short onset (2-5 months, N = 5), medium onset (6-8 months, N = 12) or long onset (10-12 months, N = 7). We compared baseline survey responses about clinic characteristics to onset times. Results: Type of EMR software and the number of chemotherapy regimens reconfigured for the trial had no effect on onset time. All short and medium onset clinics placed orders through an EMR, while 5 of 7 long onset clinics used paper orders. Long onset clinics had less reported nurse involvement in the reconfiguration workflow (change initiation, approval, fulfillment and dissemination) at 14% of clinics vs. 25% of medium onset and 75% of short onset clinics. The average weekly patient accrual rates observed after intervention completion were 1.0 in the short onset (range 0.6-1.5), 0.8 in the medium onset (0.2-1.3) and 0.6 in the long onset (0.1-2.0). Conclusions: When recruiting clinics for trials that require health record system changes, it may be helpful to consider aspects of the system modification workflow such as type of hospital departments involved, as clinics with less nursing involvement may take longer to complete the changes. The inclusion of clinics using different EMR software did not impede onset, but clinics using paper may require more time. Length of onset had no meaningful impact on weekly accrual rates; however, it did determine when clinics could start recruitment, affecting the total number of months clinics could recruit during the study accrual period. Clinical trial information: NCT02728596.

Abstract 2767: Consistency of standing orders for primary prophylactic CSF within a national network of community oncology practices: SWOG intergroup trial S1415CD

Abstract BACKGROUND Among the 400,000 individuals undergoing chemotherapy for breast, colorectal and lung cancer in the US, many are at risk of febrile neutropenia (FN). Prophylactic colony stimulating factor (CSF) use reduces the risk of FN, yet studies show that 55%-95% of CSF prescribing is inconsistent with clinical practice guidelines. There is lack of evidence and ambiguous guidelines for CSF use in regimens with an intermediate risk of FN. To address these issues, we are conducting a pragmatic trial to assess CSF prescribing and to generate evidence about CSF efficacy with intermediate risk regimens. To inform the design and sample size needs, we conducted a survey of current CSF order system use within a large network of community oncology practices. METHODS The study setting are sites within the NCI Community Oncology Research Program (NCORP), a national network across the U.S. and Puerto Rico that conducts multi-site cancer clinical trials. Between January-September 2016, 58 NCORP practices were surveyed on their existing systems for prescribing CSF prophylaxis. RESULTS 8 clinics (14%) reported that their sites do not use any standing orders for CSF prophylaxis prescribing. Standing order set characteristics for the remaining 50 practices are shown in Table 1. Table 1Summary of CSF standing order implementation in 50 surveyed NCORP clinicsBreast Cancer RegimensNon-Small Cell Lung Cancer RegimensColorectal Cancer RegimensOrder Set CharacteristicDose DenseHigh RiskIntermediate RiskLow RiskIntermediate RiskLow RiskIntermediate RiskLow RiskN (%)N (%)N (%)N (%)N (%)N (%)N (%)N (%)Automatically Included in Order Set (Standing Orders)46 (82%)31 (62%)7 (14%)08 (16%)07 (14%)0Automatically Excluded in Order Set 006 (12%)19 (38%)5 (10%)19 (38%)8 (16%)19 (38%)No automatic ordering- up to physician discretion to add or exclude orders4 (8%)19 (38%)37 (74%)31 (62%)37 (74%)31 (62%)35 (670%)31 (62%) CONCLUSIONS We observed wide variation in the current application of standing orders. Intermediate risk regimens had the most inconsistent practices, with a near equal number of clinics choosing either actively including or excluding CSF order sets. The majority of clinics using standing orders included CSF for dose dense and high risk regimens but only 19 (38%) actively excluded CSF for low risk regimens. These results support the need for more evidence to inform clearer guidelines on CSF use in intermediate risk regimens and studies that evaluate the effects of existing CSF standing orders on guideline adherence and patient outcomes. Funding:PCORI (PCS-1402-09988) and NCORP grant (5UG1CA189974) Citation Format: Scott Ramsey, Dawn Hershman, Ari Bell-Brown, Kate Watabayashi, Karma Kreizenbeck, Sean Sullivan, Aasthaa Bansal, William Barlow, Kathryn Arnold, Gary Lyman. Consistency of standing orders for primary prophylactic CSF within a national network of community oncology practices: SWOG intergroup trial S1415CD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2767. doi:10.1158/1538-7445.AM2017-2767

In women with breast cancer, can primary prophylactic colony-stimulating factors help prevent chemotherapy-induced febrile neutropenia?

In women with breast cancer, can primary prophylactic colony-stimulating factors help prevent chemotherapy-induced febrile neutropenia?

Abstract P6-10-01: Risk of chemotherapy-induced febrile neutropenia (FN) in patients (pts) with non-metastatic breast cancer (BC) and documented risk factors for FN

Abstract Background: Clinical practice guidelines recommend primary prophylactic colony-stimulating factor (CSF) for pts with cancer receiving myelosuppressive chemotherapy when their risk of FN is high (≥20%). Evaluating FN risk in pts who receive regimens that are not documented as high risk in guidelines can be challenging; these pts may be at a high risk of developing FN based on a combination of regimen and pt risk factors. This retrospective study estimated FN risk among subgroups of pts with non-metastatic BC receiving 1 of 3 commonly used, non-high risk chemotherapy regimens. Methods: Pt-level data from 2 US healthcare claims databases comprising medical and outpatient pharmacy claims from commercial and Medicare supplemental plans were pooled. Eligible pts were ≥18 years old and had initiated a course of TC, TCH, or non-dose-dense AC/AC-T for non-metastatic BC between July 1, 2003 and June 30, 2012. Occurrence of FN during any cycle of the first chemotherapy course was identified using diagnosis codes for neutropenia, fever, or infection. Risk factors, documented in guidelines and the published literature, were evaluated during the 12 months before chemotherapy initiation. The percentage of pts, FN risk, and relative risk (RR, compared to pts with no risk factors) for subgroups of pts with specific risk factors are presented. Results: 50,893 pts were included in the analysis. FN risks by chemotherapy regimen and subgroup are shown in the table. TC N=26,266TCH N=9,105AC/AC-T N=15,522 % PtsFN Risk (RR, 95% CI)% PtsFN Risk (RR, 95% CI)% PtsFN Risk (RR, 95% CI)Any risk factor78.114.2 (1.4, 1.3-1.5)74.516.9 (1.3, 1.2-1.5)73.616.6 (1.6, 1.4-1.7)Age ≥6515.116.3 (1.6, 1.4-1.7)11.516.3 (1.3, 1.1-1.5)11.417.9 (1.7, 1.5-1.9)Chronic comorbidities Cardiovascular disease16.816.9 (1.6, 1.5-1.8)14.620.2 (1.6, 1.4-1.8)16.619.5 (1.8, 1.6-2.1)Diabetes11.817.4 (1.7, 1.5-1.9)10.221.3 (1.7, 1.4-2.0)11.120.4 (1.9, 1.7-2.2)Liver disease1.918.7 (1.8, 1.5-2.2)2.220.8 (1.6, 1.2-2.2)2.017.8 (1.7, 1.3-2.2)Lung disease2.023.4 (2.3, 1.9-2.7)1.530.7 (2.4, 1.8-3.2)1.927.1 (2.6, 2.1-3.2)Renal disease1.322.7 (2.2, 1.8-2.7)0.925.0 (2.0, 1.3-2.9)1.026.8 (2.5, 1.9-3.3)Osteoarthritis7.019.6 (1.9, 1.7-2.1)6.121.1 (1.7, 1.4-2.0)6.020.8 (2.0, 1.7-2.3)Thyroid disorder13.015.4 (1.5, 1.3-1.7)11.917.4 (1.4, 1.2-1.6)10.617.2 (1.6, 1.4-1.9)Number of risk factors 133.211.7 (1.1, 1.0-1.2)33.914.1 (1.1, 1.0-1.3)33.714.2 (1.3, 1.2-1.5)224.613.8 (1.3, 1.2-1.5)23.217.4 (1.4, 1.2-1.6)22.916.0 (1.5, 1.3-1.7)312.516.3 (1.6, 1.4-1.8)11.219.8 (1.6, 1.3-1.8)11.121.3 (2.0, 1.8-2.3)4+7.822.8 (2.2, 2.0-2.5)6.125.0 (2.0, 1.6-2.3)5.924.8 (2.3, 2.0-2.7)Reference group (0 risk factor)21.910.4 (NA)25.512.7 (NA)26.411.6 (NA)Selected risk factors are presented. A high proportion of pts (74%-78%) had ≥1 risk factor for FN, and these pts had a higher FN risk than pts with no risk factors. 55.4%, 56.7%, and 42.2% of all pts who received TC, TCH, or AC/AC-T, respectively, received CSF prophylaxis in cycle 1. Conclusions: FN risk assessments are needed for pts who are receiving non-high risk regimens. Citation Format: Derek Weycker, Xiaoyan Li, Richard Barron, Hongsheng Wu, Phuong Khanh Morrow, Hairong Xu, Maureen Reiner, Jacob Garcia, Shivani Mhatre, Gary Lyman. Risk of chemotherapy-induced febrile neutropenia (FN) in patients (pts) with non-metastatic breast cancer (BC) and documented risk factors for FN [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-01.

Incidence of Febrile Neutropenia Among Patients Receiving Chemotherapy Regimens Not Classified As High-Risk in Guidelines for Myeloid Growth Factor Use: Importance of “Risk Factor Stacking”

Background: Clinical practice guidelines recommend primary prophylactic colony-stimulating factor (CSF) when risk of febrile neutropenia (FN) is ≥20%. Evaluating FN risk among patients who receive regimens that are not documented as high risk in guidelines can be challenging, as some patients may be at a high risk based on a combination of the regimen and their risk factors.Methods: A retrospective cohort design and data from two US private healthcare claims repositories (2003-2012) were employed. The study population comprised cancer patients aged ≥18 years who initiated a course of chemotherapy with a regimen classified as “low” or “intermediate”, or that was unclassified, in terms of FN risk based on guidelines for CSF use. For each subject, the first qualifying chemotherapy course, and each cycle and FN episode within the course, was identified; use of CSF prophylaxis also was identified. FN was ascertained using diagnosis codes for neutropenia, fever, and/or infection; for FN requiring outpatient care only, receipt of intravenous antimicrobials also was required. FN incidence proportion was evaluated during the course within cohorts stratified by tumor type and regimen, for all patients in each cohort and by FN risk factor. Risk factors documented in guidelines and the published literature, and listed in the Table herein were evaluated during the 12-month pre-chemotherapy period. Unadjusted relative risks of FN for patients with versus without risk factors, and by the number of risk factors (i.e., “risk factor stacking”), were estimated. Only results for the five most frequently observed tumor/regimen combinations are reported herein.Results: Among patients with one of the five most frequently observed tumor/regimen combinations (n=84,252), 74-97% had ≥1 risk factor for FN and 42-88% had ≥2 (Table). Among patients with ≥1 risk factor, FN incidence ranged from 11-25% (relative risk vs. those without risk factors, 1.4-2.1), and increased in a graded and monotonic fashion with the number of risk factors present (Figure).Conclusion: In this retrospective evaluation of nearly 85,000 cancer patients receiving chemotherapy regimens not classified as high-risk for FN in US clinical practice, the large majority had at least one risk factor for FN and many had two or more. FN incidence was found to be markedly elevated in these patients, especially those with multiple risk factors (i.e., “risk factor stacking”). [Display omitted] [Display omitted] DisclosuresWeycker:Amgen: Research Funding. Li:Amgen: Employment, Equity Ownership. Barron:Amgen: Employment, Equity Ownership. Wu:Amgen: Research Funding. Morrow:Amgen: Employment, Equity Ownership. Xu:Amgen: Employment, Equity Ownership. Reiner:Amgen: Employment, Equity Ownership. Garcia:Amgen: Employment, Equity Ownership. Mhatre:Amgen: Employment. Lyman:Amgen: Research Funding.

Primary prophylactic colony-stimulating factors for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients

High-dose or dose-intensive cytotoxic chemotherapy often causes myelosuppression and severe neutropenia among cancer patients. Severe neutropenia accompanied by fever, named febrile neutropenia (FN), is the most serious manifestation of neutropenia usually requiring hospitalization and intravenous antibiotics. FN and neutropenia can lead to chemotherapy treatment delays or dose reductions, which potentially compromises the effectiveness of cancer treatment and prospects for a cure. Granulocyte-macrophage (GM) and granulocyte colony-stimulating factors (G-CSFs) are administered during chemotherapy in order to prevent or reduce the incidence or the duration of FN and neutropenia. To assess the effect of prophylactic colony-stimulating factors (CSFs) in reducing the incidence and duration of FN, and all-cause and infection-related mortality during chemotherapy in patients with breast cancer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, HEALTHSTAR, International Health Technology Assessment, SOMED, AMED and BIOSIS up to 8 August 2011. We also searched three Chinese databases (VIP, CNKI, CBM), the metaRegister of Controlled Trials, ClinicalTrials.gov, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and OpenGrey.eu up to August 2011. Randomized controlled trials (RCTs) comparing CSFs (any dose) with placebo or no treatment in patients with breast cancer at any stage, at risk of developing FN while undergoing any type of chemotherapy. We used pooled risk ratios (RR) with 95% confidence intervals (CIs) for binary outcomes. At least two review authors independently extracted data and assessed the risk of bias of the included studies. Trial authors were contacted for further details when information was unclear. We included eight RCTs involving 2156 participants with different stages of breast cancer and chemotherapy regimens. The trials were carried out between 1995 and 2008 and judged as being at least at moderate risk of bias. The strength of the evidence was weak for the majority of outcomes, which was mostly because of the small numbers of evaluable patients, varying definitions, as well as unclear measurements of the trials' outcomes and uncertain influences of supportive treatments on them. In most trials, the chemotherapy regimens had a risk of FN that was below the threshold at which current guidelines recommend routine primary prophylaxis with CSFs. Using CSFs significantly reduced the proportion of patients with FN (RR 0.27; 95% CI 0.11 to 0.70; number needed to treat for an additional beneficial outcome (NNTB) 12) but there was substantial heterogeneity which can be explained by possible differential effects of G-CSFs and GM-CSFs and different definitions of FN. A significant reduction in early mortality was observed in CSF-treated patients compared to placebo or no treatment (RR 0.32; 95% CI 0.13 to 0.77; NNTB 79). This finding was based on 23 fatal events in 2143 patients; wherein 19 of these 23 events occurred in one study and 17 events were attributed to progression of the disease by the study authors. For infection-related mortality, there were no significant differences between CSF and control groups (RR 0.14; 95% CI 0.02 to 1.29). In CSF-treated patients, the risk for hospitalization was significantly reduced (RR 0.14; 95% CI 0.06 to 0.30; NNTB 13), as well as the use of intravenous antibiotics (RR 0.35; 95% CI 0.22 to 0.55; NNTB 18). The risks of severe neutropenia, infection or not maintaining the scheduled dose of chemotherapy did not differ between CSF-treated and control groups. CSFs frequently led to bone pain (RR 5.88; 95% CI 2.54 to 13.60; number needed to treat for an additional harmful outcome (NNTH) 3) and injection-site reactions (RR 3.59; 95% CI 2.33 to 5.53; NNTH 3). In patients with breast cancer receiving chemotherapy, CSFs have shown evidence of benefit in the prevention of FN. There is evidence, though less reliable, of a decrease of all-cause mortality during chemotherapy and a reduced need for hospital care. No reliable evidence was found for a reduction of infection-related mortality, a higher dose intensity of chemotherapy with CSFs or diminished rates of severe neutropenia and infections. The majority of adverse events reported from CSF use were bone pain and injection-site reactions but no conclusions could be drawn regarding late-term side effects.

Colony‐Stimulating Factor Use and Impact on Febrile Neutropenia Among Patients with Newly Diagnosed Breast, Colorectal, or Non–Small Cell Lung Cancer Who Were Receiving Chemotherapy

To determine the impact of primary prophylactic colony-stimulating factor (CSF) use on febrile neutropenia in a large patient population receiving contemporary chemotherapy regimens to treat breast cancer, colorectal cancer, or non-small cell lung cancer (NSCLC). Retrospective claims analysis. The Surveillance, Epidemiology, and End Results (SEER)-Puget Sound cancer registry and insurance claims records. A total of 2728 patients aged 25years or older who received a diagnosis of breast cancer (998 patients), colorectal cancer (688 patients), or NSCLC (1042 patients) between January 1, 2002, and December 31, 2005, and received chemotherapy. Initial chemotherapy regimen, CSF use (filgrastim or pegfilgrastim), and febrile neutropenia events were evaluated after the first chemotherapy administration. Subsequently, febrile neutropenia rates in patients receiving primary prophylactic CSF were compared with febrile neutropenia rates in patients receiving CSF in settings other than primary prophylaxis or not at all. The impact of primary prophylactic CSF could not be assessed for patients with colorectal cancer or NSCLC because only 1 and 18 febrile neutropenia events, respectively, occurred in those receiving primary prophylactic CSF. Of the 998 patients with breast cancer, 72 (7.2%) experienced febrile neutropenia, 28 of whom received primary prophylactic CSF. In the patients with breast cancer, we observed that primary prophylactic CSF use was associated with reduced febrile neutropenia rates; however, the analysis may have been confounded by unmeasured factors associated with febrile neutropenia. The impact of primary prophylactic CSFs on febrile neutropenia rates could not be demonstrated. Given the substantive cost of CSFs to pharmacy budgets, there are numerous opportunities for pharmacists to optimize CSF use. Research studies are needed to evaluate if guideline-directed prescribing of primary prophylactic CSFs can improve clinical outcomes.

Changing Patterns of Chemotherapy Delivery and Supportive Care for Aggressive B-Cell Non-Hodgkin's Lymphoma

Abstract▪2670▪This icon denotes a clinically relevant abstract Background:For several decades, non-Hodgkin’s Lymphoma (NHL) has been treated with a CHOP-based chemotherapy regimen with curative intent. In 2004, a large retrospective analysis of patients with aggressive NHL treated at 567 community practices from 1999 to 2001 indicated that only 52% of patients received chemotherapy at a relative dose intensity (RDI) ≥ 85% (Lyman GH, et al. JCO. 2004;22:4302–11). This study showed that primary prophylactic use of colony-stimulating factors (CSF) starting with the first cycle of chemotherapy was associated with a reduced incidence of febrile neutropenia (FN) and was an independent predictor of RDI ≥ 85%. At that time, only about 12% of patients received CSF in the first cycle. To evaluate changes in oncology practice, we reviewed recent treatment patterns, including RDI for delivered chemotherapy and CSF support, for patients with aggressive B-cell NHL at 36 community-based oncology practices and hospitals, the majority of which participated in the previous study. Methods:Patient charts and electronic medical records from January 2006 to December 2009 were reviewed. Patients were included if they had aggressive B-cell NHL, were ≥ 18 years old, and completed ≥ 1 cycle of chemotherapy with the following standard cytotoxic regimens during the chart abstraction period: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); CHOP-rituximab (CHOP-R); or cyclophosphamide, mitoxantrone, vincristine, and prednisone (CNOP). Exclusion criteria included prior stem-cell transplantation, prior/concurrent radiotherapy, and chemotherapy started outside of the chart abstraction period. The primary endpoint was delivered RDI, based on the proportion of chemotherapy actually delivered compared to published standards, as in the previous study. Other endpoints included chemotherapy dose delays and reductions, grade 3/4 neutropenia, grade 3/4 FN, FN-related hospitalization, CSF use, and antimicrobial use. Results:Records of 500 patients were reviewed. Mean patient age was 63.7 years (range: 18–90), and 55% of patients were male. The majority (90.8%) received CHOP-R chemotherapy on a 21-day schedule (CHOP-R 21) for a mean of 5.5 cycles (range: 1–8). The mean RDI delivered for CHOP-21 ± R was 87.6%. Delivered chemotherapy intensity in the current study was considerably greater than that observed in the previous study with an increase in delivered RDI ≥ 85% (current vs previously published: 71% vs 52%) and a decrease in dose reductions (20.6% vs 35%). Dose delays appear similar between the studies (26.4% vs 23%). In the current study, 67% of patients had grade 3/4 neutropenia, compared to 62% of patients in the previous study. In addition, the incidence of clinical FN (12% vs 20.9%) and the number of patients hospitalized for FN (9.6% vs 15.9%) has decreased. Use of primary prophylactic CSF has increased (75% vs 12%) with a shift from support with filgrastim to pegfilgrastim. Filgrastim was the predominant CSF in the previous study while, in the current study, 78.6% of patients received pegfilgrastim only, and 9.2% of patients received pegfilgrastim and filgrastim. While antimicrobial use was not reported in the previous study, in the current study, 51% of patients received at least one antimicrobial; 13% received prophylactic antimicrobials, and 45.8% received therapeutic antimicrobials. Conclusions:Patterns of chemotherapy delivery and supportive care have changed markedly for the management of patients with aggressive B-cell NHL. In the United States, CHOP-R 21 is now the most commonly used regimen, as compared to CHOP-21 in the previous study. Average RDI delivered and prophylactic use of CSF, predominantly pegfilgrastim, have increased, while dose reductions, FN, and FN-related hospitalizations have decreased. However, dose delays and reductions are still relatively common, suggesting opportunities for further improvements in the treatment of patients with aggressive B-cell NHL. Disclosures:Lyman:Amgen: Research Funding. Crawford:Amgen: Consultancy, Honoraria, Research Funding. Dale:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Whittaker:Amgen: Employment. Tomita:Amgen: Employment, Equity Ownership.

Health Care Use and Primary Prophylaxis with Colony-Stimulating Factors

Objectives We examined health care use in conjunction with primary prophylaxis use of colony stimulating factors (CSF) during patients' initial course of chemotherapy. Methods This retrospective cohort study identified adults aged 25 years and older with a diagnosis of breast, colorectal, or nonsmall cell lung cancer between 2002 and 2005 from the Western Washington Surveillance Epidemiology and End Results Puget Sound registry. We linked these records to health insurance claims from four payers representing 75% of those insured in the state. Claims records were used to determine chemotherapy regimen type, CSF use, febrile neutropenia occurrences, and supportive care. Chemotherapy regimens were categorized as conferring high, intermediate, or low risk of myelosuppression according to the National Comprehensive Cancer Network guidelines. CSF use was described as primary prophylaxis, other, or none. Antibiotics and antifungal and antiviral agents per National Comprehensive Cancer Network guidelines for supportive care for cancer infection were categorized using Healthcare Common Procedure Coding System and National Drug Code assignments. Results Use of CSF as primary prophylaxis is not significantly associated with a reduction in antibiotic use or inpatient or outpatient visits. Primary prophylactic CSF use was associated with less use of antiviral drugs. Conclusions CSF use is not associated with a reduction in health care use, with the exception of antiviral drug use. Given the expense associated with CSF use, pragmatic trials and additional research are needed to further assess the affects of CSF on health care use.

Cost-Effectiveness of White Blood Cell Growth Factor Use among a Large Nationwide Cohort of Elderly Non-Hodgkin's Lymphoma Patients Treated with Chemotherapy

Objective To determine the cost-effectiveness (as measured as cost per life-year saved) of white blood cell growth factor or colony-stimulating factor (CSF) use among a large cohort of elderly non-Hodgkin's lymphoma (NHL) patients in a real-world setting. Methods We identified 13,203 NHL patients from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database who received the diagnosis from 1992 to 2002 and who received chemotherapy within 12 months of diagnosis. Benefit (effectiveness) of CSF use (primary and secondary prophylaxis) was measured as observed improvement in overall survival. Costs for each patient were calculated by adding the cumulative reimbursement amounts from Medicare claims. Cost-effectiveness was estimated by modeling the joint influence of CSF use on both costs and effectiveness using a propensity-score net monetary benefit approach. Results Primary prophylactic CSF use was cost-effective at lower willingness-to-pay thresholds, whereas at higher thresholds, not providing prophylactic CSF became the cost-effective strategy. For secondary prophylactic CSF use among patients experiencing neutropenia, fever, and/or infection, the opposite trend was observed. For low willingness-to-pay thresholds (<$20,000 per life-year gained), not administering CSF was the cost-effective strategy, whereas CSF use became cost-effective as willingness to pay increased (from $100,000+ per life-year gained). Conclusion To our knowledge, this is the first large population-based study to empirically measure the cost-effectiveness of CSF among NHL patients treated with chemotherapy. CSF use as primary or secondary prophylaxis may be a cost-effective strategy depending on society's (or payers') willingness to pay for improvements in outcomes.

Chemotherapy characteristics are important predictors of primary prophylactic CSF administration in older patients with breast cancer

Chemotherapy is vital for breast cancer management, but early onset toxicities like neutropenia hinder its administration. Primary prophylactic (PP) use of colony- stimulating factors (CSF) helps prevent neutropenia and ensures successful chemotherapy completion. Nevertheless, lack of specific guidelines for CSF administration in older patients has lead to unexplained geographic and racial, and counter-intuitive clinical variations in CSF administration. This study examined the reasons for these variations and for the first time looked at variations in PP-CSF administration and duration of administration in breast cancer patients receiving chemotherapy. This retrospective observational study of newly diagnosed breast cancer patients receiving chemotherapy used SEER-Medicare data from 1994-2003. Regression analyses were used to explore the factors associated with PP-CSF administration and duration of administration. Clinical and therapeutic characteristics previously unexplored by other studies were included. Univariate analyses demonstrated geographic, racial and clinical disparities similar to previous studies. However, clinical correlations resolved to statistical insignificance after inclusion of chemotherapy characteristics. The analysis showed that significant geographic and racial disparities existed. History of recent antibiotic use was associated with shorter PP-CSF administration. Physicians' decision to administer PP-CSF is predominantly driven by neutropenia risk associated with pre-planned chemotherapy regimen. Older, sicker women at a higher risk of neutropenia receive less intense/toxic chemotherapy and thus do not require PP-CSF. Geographic variations are driven by proportion of physicians administering PP-CSF with no evidence for overuse among specific physicians. Association of recent antibiotic use with shorter PP-CSF administration suggests intended substitution of the expensive PP-CSF with prophylactic antibiotics.