S1415CD, Trial Assessing CSF Prescribing Effectiveness and Risk (TrACER)

PRIMARY OBJECTIVES:

I. To compare the use of primary prophylactic colony stimulating factor (PP-CSF) according to recommended clinical practice guidelines among patients registered at intervention components versus usual care components.

II. To compare the rate of febrile neutropenia (FN) among patients registered at intervention components versus usual care components.

III. To compare the rate of FN among intermediate risk patients registered at intervention components by component treatment assignment (administer PP-CSF to intermediate risk patients versus not).

SECONDARY OBJECTIVES:

I. To compare the rate of FN among low-risk patients registered at intervention components versus usual care components.

II. To compare the FN-related health-related quality of life (HRQOL) among low-risk patients registered at intervention components versus usual care components.

III. To compare patient adherence to PP-CSF prescribing among patients registered at intervention components versus usual care components.

IV. To compare patient knowledge of the indications for, efficacy of, and side effects associated with PP-CSF between the initiation and conclusion of the first cycle of myelosuppressive systemic therapy among patients registered at intervention components versus usual care components.

V. To compare the proportion of patients completing the initial systemic therapy regimen at planned duration and at planned dose intensity among patients registered at intervention components versus usual care components.

VI. To compare antibiotic use both as prophylaxis and as treatment for FN among patients registered at intervention components versus usual care components.

VII. To compare the rate of FN-related emergency department visits and hospitalizations among intermediate risk patients registered to Intervention components by component treatment assignment (administer PP-CSF to intermediate risk patients versus not).

VIII. To compare the FN-related health-related quality of life (HRQOL) among intermediate risk patients registered to intervention components by component treatment assignment (administer PP-CSF to intermediate risk patients versus not).

IX. To compare overall survival among intermediate risk patients registered to intervention components by component treatment assignment (administer PP-CSF to intermediate risk patients versus not).

TERTIARY OBJECTIVES:

I. To characterize and descriptively report the differences among cohort components and the intervention and usual care components.

II. To evaluate the time to invasive recurrence in non-metastatic patients by component treatment assignment

OUTLINE: Patients are randomized to 1 of 4 clinic groups.

CLINIC GROUP 1 (CLINIC WITH AUTOMATED SYSTEM): Patients with a high risk of developing FN receive CSF based on the automated system recommendations. The automated system suggests that CSFs not be used for drugs that have a low risk of FN.

CLINIC GROUP 2 (CLINIC WITH NO AUTOMATED SYSTEM): Patients receive CSF based on clinical practice guidelines.

CLINIC GROUP 3 (CLINIC WITH AUTOMATED SYSTEM): Patients with a high or moderate risk of developing FN receive CSF based on the automated system recommendations. The automated system suggests that CSFs not be used for drugs that have a low risk of FN.

CLINIC GROUP 4 (CLINIC WITH AUTOMATED SYSTEM): Patients with a high risk of developing FN receive CSF based on the automated system recommendations. The automated system suggests that CSF not be used for drugs that have a moderate risk of FN.

After completion of study treatment, patients are followed up for 12 months.

• Preventive Intervention (Other), also known as PREVENTATIVE, Prevention, Prevention Measures, Prophylaxis, PRYLX: Automated ordering system recommends prescribing or not prescribing CSF based on drug's risk level for FN
• Quality-of-Life Assessment (Other), also known as Quality of Life Assessment: Ancillary studies
• Questionnaire Administration (Other): Ancillary studies

Primary outcomes

• Percentage of Participants With CSF Prescribed as Primary Prophylaxis [Baseline to up to 14 days]: To compare the use of primary prophylactic colony stimulating factor (PP-CSF) according to recommended clinical practice guidelines among participants registered at intervention components versus usual care components. Primary prophylaxis of CSF (PP-CSF) is defined as the initiation of granulocyte CSFs during the first cycle of myelosuppressive systemic therapy, given 24 to 72 hours after cessation of systemic therapy. Separate mixed effects logistic models will be fit to assess the effect of the intervention on PP-CSF use. The rate of CSF prescribing is defined as the percent of participants prescribed CSF as primary prophylaxis out of the total number of participants within each arm.
• Incidence of Febrile Neutropenia [Within 6 months post registration]: To compare the rate of febrile neutropenia (FN) among participants, at any risk level, registered at intervention components versus usual care components. Febrile neutropenia is defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) as an absolute neutrophil count (ANC) < 1000/µL and a single temperature of > 38.3°C (101°F) or a sustained temperature of ≥ 38°C (101°F) for more than one hour.
• Incidence of Febrile Neutropenia Among Intermediate Risk Participants [Within 6 months post registration]: To compare the rate of FN among intermediate risk participants registered at intervention components by component treatment assignment (administer PP-CSF to intermediate risk participants versus not). Febrile neutropenia is defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) as an absolute neutrophil count (ANC) < 1000/µL and a single temperature of > 38.3°C (101°F) or a sustained temperature of ≥ 38°C (101°F) for more than one hour.

Secondary outcomes

• Incidence of Febrile Neutropenia Among Low Risk Participants [Within 6 months of registration]: To compare the rate of FN among low-risk participants registered at intervention components versus usual care components. Febrile neutropenia is defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) as an absolute neutrophil count (ANC) < 1000/µL and a single temperature of > 38.3°C (101°F) or a sustained temperature of ≥ 38°C (101°F) for more than one hour.
• FN-related Health-Related Quality of Life (HRQOL) Among Low Risk Participants [Baseline to up to 14 days]: To compare the FN-related health-related quality of life (HRQOL) among low-risk participants registered at intervention components versus usual care components. Assessed using the Functional Assessment of Cancer Therapy - Febrile Neutropenia (Version 4) (FACT-N). Includes FACT general cancer score and FN-related score. A linear mixed effects model will be fit to assess the effect of the intervention on HRQOL. Component-level characteristics, patient-level clinical and demographic variables will be adjusted.
• Participant Adherence Rates to PP-CSF Prescription [Within 14 days after the completion of first course of therapy]: To compare adherence to PP-CSF prescribing among participants registered at intervention components versus usual care components. Participant adherence rates are obtained from the proportion receiving PP-CSF among those for whom PP-CSF was ordered by the physician. The primary adherence measure will be obtained from the participant's chart; secondary adherence will be measured via self-report on the Follow-Up Participant Survey. For the home and clinic settings, separate mixed effects logistic models will be used to assess the effect of the intervention on adherence to PP-CSF orders, treating adherence after the start of the study. Component-level characteristics, participant-level clinical and demographic variables will be adjusted.
• Change in Participant Knowledge of PP-CSF Indications [Baseline to up to 14 days]: To compare participant knowledge of the indications for, efficacy of, and side effects associated with PP-CSF between the initiation and conclusion of the first cycle of myelosuppressive systemic therapy among participants registered at intervention components versus usual care components. Linear mixed effects model with a time variable and an interaction between randomized group and time will be used to analyze change in the patient knowledge score. Random effects will be used to accommodate both the correlation among measures from the same patient as well as the correlation among patients from the same component. Component-level characteristics, participant-level clinical and demographic variables will be adjusted.
• Proportion Completing Initial Systemic Therapy Regimen: a) at Planned Duration and b) at Planned Dose Intensity (Clinical) [Up to 12 months]: To compare the proportion of participants completing the initial systemic therapy regimen at planned duration and at planned dose intensity among participants registered at intervention components versus usual care components.Two separate mixed effects logistic models will be used to assess the effect of the intervention on completion of the initial systemic therapy regimen (i) at planned duration and (ii) at planned dose intensity. Component-level characteristics, patient-level clinical and demographic variables will be adjusted.
• Prophylactic and FN-Related Antibiotic Use [Within 30 days of therapy]: To compare antibiotic use both as prophylaxis and as treatment for FN among participants registered at intervention components versus usual care components. Prophylactic and FN-related antibiotic use will be measured as total number of antibiotic agents used and duration of antibiotic use. A linear mixed effects model will be fit to assess the effect of the intervention on duration of antibiotics use with number of days. Mixed effects Poisson models will be used to assess the effect of the intervention on total number of antibiotics agents used. Three separate models will be fit, with the following outcomes: (i) the number of times antibiotics were used as prophylaxis, (ii) the number of times antibiotics were used as treatment for FN, and (iii) t
• Rate of FN-Related Emergency Department Visits and Hospitalizations [At 6 months]: To compare the rate of FN-related emergency department (ED) visits and hospitalizations among intermediate risk participants registered to intervention components by component treatment assignment (administer PP-CSF to intermediate risk participants versus not). FN-related ED visits and hospitalizations are defined as admission to ED or hospital with documentation of fever and decreased ANC. A mixed effects Poisson model will be used to assess the effect of the intervention on FN-related ED visits and hospitalizations. Robust variance estimation will be used to relax the strong assumptions about the variance made by Poisson regression. If a large number of zero counts is observed, then zero-inflated Poisson regression will be used.
• FN-related Health-Related Quality of Life (HRQOL) Among Intermediate Risk Participants [Baseline to up to 14 days]: To compare the FN-related health-related quality of life (HRQOL) among intermediate risk participants registered to intervention components by component treatment assignment (administer PP-CSF to intermediate risk participants versus not). Assessed using the Functional Assessment of Cancer Therapy - Febrile Neutropenia (Version 4) (FACT-N). Includes FACT general cancer score and FN-related score. A linear mixed effects model will be fit to assess the effect of the intervention on HRQOL. Component-level characteristics, participant-level clinical and demographic variables will be adjusted.
• Overall Survival (OS) [Time from date of registration to date of death due to any cause, assessed up to 12 months]: To compare overall survival among intermediate risk participants registered to intervention components by component treatment assignment (administer PP-CSF to intermediate risk participants versus not). A Cox proportional hazards model will be used to model survival. Component-level characteristics, participant-level clinical and demographic variables will be adjusted. A separate analysis of cause-specific survival to address FN-related deaths will also be conducted.

Other outcomes

• Time to Invasive Recurrence in Non-Metastatic Participants [Time from registration to documented invasive local or regional recurrence, assessed up to 12 months]: To evaluate the time to invasive recurrence in non-metastatic participants by component treatment assignment. Analysis will be exploratory and comparative.
• Differences Among Cohort Components and Intervention and Usual Care Components [Up to 12 months post registration]: To characterize and descriptively report the differences among cohort components and the intervention and usual care components.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients must have a current diagnosis of breast cancer, non-small cell lung cancer, or colorectal cancer; the current diagnosis may be an initial diagnosis or recurrence and/or progression of previously diagnosed disease; cancer may be metastatic or non-metastatic
* Patients must be registered prior to or on the same day as their first cycle of chemotherapy for their current disease and stage 9or disease setting).
* Patients must not have had any systemic therapy (chemotherapy or combination regimens) in the 180 days just prior to registration. Prior biologic therapy, immunotherapy, tyrosine kinase inhibitors, and hormonal therapy are allowed.
* Patients must be planning to receive one of the study-allowed regimens as their initial treatment for their current disease; myelosuppressive therapy must follow the standard regimen, although a dose reduction of up to 10% is permitted. This treatment may be neoadjuvant or adjuvant chemotherapy.
* Patients must not be receiving or planning to receive concurrent radiation during systemic treatment.
* Patients must not have any known contraindication to CSFs prior to registration, including prior hypersensitivity to Escherichia coli-derived proteins, filgrastim, pegfilgrastim, or tbo-filgrastim
* Patients must be able to understand and provide information for the patient-completed study forms in either English or Spanish
* Patients may have had a prior malignancy
* Patients must not be participating or plan to participate in other clinical trials that involve investigational systemic cancer treatments or investigational uses of CSF during their first 6 months after registration
* Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
* As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

Participant flow

Outcome results

• Percentage of Participants With CSF Prescribed as Primary Prophylaxis (Primary), Number, percentage of participants: Active Comparator: Clinic Group 1 (Clinics With Existing Automated System for CSF Prescribing) 8.3; Active Comparator: Clinic Group 2 (Clinics With no Automated System for CSF Prescribing) 5.5; Experimental: Clinic Group 3 (Clinics With Automated System for CSF Prescribing) 7.2; Experimental: Clinic Group 4 (Clinics With Automated System for CSF Prescribing) 5.3 (p 0.21)
• Incidence of Febrile Neutropenia (Primary), Number, percentage of participants: Active Comparator: Clinic Group 1 (Clinics With Existing Automated System for CSF Prescribing) 1.7; Active Comparator: Clinic Group 2 (Clinics With no Automated System for CSF Prescribing) 0.8; Experimental: Clinic Group 3 (Clinics With Automated System for CSF Prescribing) 1.6; Experimental: Clinic Group 4 (Clinics With Automated System for CSF Prescribing) 1.5 (p 0.26)
• Incidence of Febrile Neutropenia Among Intermediate Risk Participants (Primary), Number, percentage of participants: Active Comparator: Clinic Group 1 (Clinics With Existing Automated System for CSF Prescribing) 5.9; Active Comparator: Clinic Group 2 (Clinics With no Automated System for CSF Prescribing) 2.9; Experimental: Clinic Group 3 (Clinics With Automated System for CSF Prescribing) 3.7; Experimental: Clinic Group 4 (Clinics With Automated System for CSF Prescribing) 3.7 (p 0.74)
• Incidence of Febrile Neutropenia Among Low Risk Participants (Secondary), Number, percentage of participants: Active Comparator: Clinic Group 1 (Clinics With Existing Automated System for CSF Prescribing) 1.8; Active Comparator: Clinic Group 2 (Clinics With no Automated System for CSF Prescribing) 0.8; Experimental: Clinic Group 3 (Clinics With Automated System for CSF Prescribing) 1.8; Experimental: Clinic Group 4 (Clinics With Automated System for CSF Prescribing) 1.5
• FN-related Health-Related Quality of Life (HRQOL) Among Low Risk Participants (Secondary)
• Participant Adherence Rates to PP-CSF Prescription (Secondary)
• Change in Participant Knowledge of PP-CSF Indications (Secondary)
• Proportion Completing Initial Systemic Therapy Regimen: a) at Planned Duration and b) at Planned Dose Intensity (Clinical) (Secondary)
• Prophylactic and FN-Related Antibiotic Use (Secondary)
• Rate of FN-Related Emergency Department Visits and Hospitalizations (Secondary)
• FN-related Health-Related Quality of Life (HRQOL) Among Intermediate Risk Participants (Secondary)
• Overall Survival (OS) (Secondary)
• Time to Invasive Recurrence in Non-Metastatic Participants (Other pre specified)
• Differences Among Cohort Components and Intervention and Usual Care Components (Other pre specified)

Adverse events

Time frame: Adverse events were monitored/assessed through the end of first anti-cancer treatment cycle, an average of 21 days. While All-Cause Mortality was monitored/assessed for the entire duration participants are followed for the study, an average of 12 months.

Serious adverse events by term

Other adverse events by term

60 more sites not listed.

• Results publication: Hershman DL, Bansal A, Barlow WE, Arnold KB, Watabayashi K, Bell-Brown A, Sullivan SD, Lyman GH, Ramsey SD. Intervention Nonadherence in the TrACER (S1415CD) Study: A Pragmatic Randomized Trial of a Standardized Order Entry for CSF Prescribing. JCO Oncol Pract. 2023 Dec;19(12):1160-1167. doi: 10.1200/OP.23.00219. Epub 2023 Oct 3. PMID 37788414
• Results publication: Lyman GH, Bansal A, Sullivan SD, Arnold KB, Barlow WE, Hershman DL, Lad TE, Ramsey SD. Impact of treatment experience on patient knowledge of colony-stimulating factors among patients receiving cancer chemotherapy: evidence from S1415CD-a large pragmatic trial. Support Care Cancer. 2023 Sep 28;31(10):598. doi: 10.1007/s00520-023-08056-z. PMID 37770704
• Results publication: Ramsey SD, Bansal A, Sullivan SD, Lyman GH, Barlow WE, Arnold KB, Watabayashi K, Bell-Brown A, Kreizenbeck K, Le-Lindqwister NA, Dul CL, Brown-Glaberman UA, Behrens RJ, Vogel V, Alluri N, Hershman DL. Effects of a Guideline-Informed Clinical Decision Support System Intervention to Improve Colony-Stimulating Factor Prescribing: A Cluster Randomized Clinical Trial. JAMA Netw Open. 2022 Oct 3;5(10):e2238191. doi: 10.1001/jamanetworkopen.2022.38191. PMID 36279134
• Results publication: Hershman DL, Bansal A, Sullivan SD, Barlow WE, Arnold KB, Watabayashi K, Bell-Brown A, Le-Lindqwister NA, Dul CL, Brown-Glaberman UA, Behrens RJ, Vogel V, Alluri N, Ramsey SD. A Pragmatic Cluster-Randomized Trial of a Standing Order Entry Intervention for Colony-Stimulating Factor Use Among Patients at Intermediate Risk for Febrile Neutropenia. J Clin Oncol. 2023 Jan 20;41(3):590-598. doi: 10.1200/JCO.22.01258. Epub 2022 Oct 13. PMID 36228177
• Results publication: Watabayashi KK, Bell-Brown A, Kreizenbeck K, Egan K, Lyman GH, Hershman DL, Arnold KB, Bansal A, Barlow WE, Sullivan SD, Ramsey SD. Successes and challenges of implementing a cancer care delivery intervention in community oncology practices: lessons learned from SWOG S1415CD. BMC Health Serv Res. 2022 Apr 1;22(1):432. doi: 10.1186/s12913-022-07835-4. PMID 35365139

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form (PDF, 2019-11-13)

• Scott Ramsey, Principal investigator, SWOG Cancer Research Network

NIH grants: UG1CA189974