Attitudes of physicians towards assessing risk and using granulocyte-colony stimulating factor as primary prophylaxis in patients receiving chemotherapy associated with an intermediate risk of febrile neutropenia
Gilles Freyer • Ewa Kalinka-Warzocha • Konstantinos Syrigos • Mihai Marinca •
Giuseppe Tonini • Say Liang Ng • Zee Wan Wong • Antonio Salar • Guenther
Steger • Mahmoud Abdelsalam • Lucy DeCosta • Zsolt Szabo
G. Freyer ([email protected])
Department of Medical Oncology, Hospices Civils de Lyon Cancer Institute and Lyon
University, Lyon, France
E. Kalinka-Warzocha
Chemotherapy Department, Provincial Specialist Hospital, M Kopernika, Lodz, Poland
K. Syrigos
Sotiria General Hospital, University of Athens Medical School, Athens, Greece
M. Marinca
Department of Oncology, Faculty of Medicine, University of Medicine and Pharmacy ‘Grigore
T Popa’, Iasi, Romania
G. Tonini
Department of Oncology, Campus Bio-Medico University of Rome, Rome, Italy
S. L. Ng
Oncology Unit, Bendigo Health Care Group, Bendigo, Victoria, Australia
Z. W. Wong
Oncology Unit, Goulburn Valley Health, Shepparton, and University of Melbourne,
Melbourne, Victoria, Australia
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A. Salar
Department of Clinical Haematology, Hospital del Mar, Barcelona, Spain
G. Steger
Department of Internal Medicine I/Oncology, Medical University of Vienna, Vienna, Austria
M. Abdelsalam
Medical Oncology, The Moncton Hospital, Moncton, New Brunswick, Canada
L. DeCosta
Amgen Ltd, Uxbridge, UK
Z. Szabo
Amgen (Europe) GmbH, Zug, Switzerland
* Corresponding author at: Department of Medical Oncology, Hospices Civils de Lyon
Cancer Institute and Lyon University, Lyon, France
Tel.: 00 33 478 864 318; fax: 00 33 478 864 319
E-mail address: [email protected]
Funding support: This study was funded by Amgen.
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Abstract
Background: Febrile neutropenia (FN) is a potentially fatal complication of chemotherapy.
This prospective, observational study describes physicians’ approaches towards assessing
FN risk in patients receiving chemotherapy regimens with an intermediate (10-20 %) FN risk.
Methods: In the baseline investigator assessment, physicians selected factors considered important when assessing overall FN risk and deciding on granulocyte-colony stimulating factor (G-CSF) primary prophylaxis (PP).Physicians then completed patient assessments using the same lists of factors. The final FN risk scores and whether G-CSF PP was planned were reported.
Results: The final analysis included 165 physicians and 944 patients. The most frequently considered factor in both assessments was chemotherapy agents in the backbone (88 % of investigator and 93 % of patient assessments). History of FN (83 %), baseline laboratory values (76 %) and age (73 %) were commonly selected at baseline, whereas tumor type
(72 %), guidelines (62 %) and tumor stage (43 %) were selected most during patient assessments. Median investigator-reported FN risk threshold for G-CSF PP was 20 %
(range, 10–85 %). G-CSF PP was planned in 82 % of patients with an FN risk at or above this threshold; therefore, almost one-fifth of qualifying patients would not receive G-CSF PP.
Conclusions: Physicians generally follow guidelines, but also consider individual patient characteristics when assessing FN risk and deciding on G-CSF PP. A standardized FN risk assessment may optimize the use of G-CSF PP, which may minimize the incidence of FN in patients undergoing chemotherapy with an intermediate FN risk.
ClinicalTrials.gov Identifier: NCT01813721.
Keywords Febrile neutropenia • Chemotherapy • Granulocyte-colony stimulating factor •
G-CSF • Prophylaxis • Risk factors
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Introduction
Febrile neutropenia (FN) is a potentially life-threatening complication of chemotherapy [1]: mortality attributable to FN in patients with cancer is between 4 % and 12.5 % [2-4], and the presence of comorbidities greatly increases the risk of death [5]. Prolonged neutropenia can also lead to chemotherapy dose reductions or interruptions [3, 6-8], potentially compromising tumor control [9–11].
Granulocyte-colony stimulating factor (G-CSF) primary prophylaxis (PP) significantly reduces the incidence of FN [12–16]. Consequently, the risks of infection-related and all-cause mortality [17], as well healthcare resource utilization and hospitalizations [16, 18], are significantly reduced, and chemotherapy can be maintained at a higher relative dose intensity (RDI) than in patients receiving no such support [7, 17, 19].
The European Organisation for Research and Treatment of Cancer (EORTC) guidelines recommend that physicians evaluate the FN risk associated with any planned chemotherapy regimen [20]. G-CSF PP is recommended for regimens with high (≥20 %) FN risk; however, the decision to initiate G-CSF PP is less clear for regimens with intermediate
(10–20 %) risk. Thus, individual patient risk factors must also be considered [20]. Other guidelines provide similar recommendations [2, 21–23].
Several FN risk factors have been identified by the EORTC, including age
(≥65 years), advanced disease stage, poor performance status, previous FN, lack of G-CSF use, comorbidities and planned high chemotherapy RDI [20]. Similar risk factors have also been identified in various studies using multivariate FN risk models [24]. There is a lack of data on which factors are considered important by physicians in clinical practice when assessing FN risks and when deciding whether to prescribe G-CSF PP. This international study aimed to investigate how physicians assess the risk of FN in patients who are scheduled to receive chemotherapy with intermediate FN risk, and how the subsequent decision to administer G-CSF PP is made.
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Methods
Objectives
The primary objective was to describe physicians’ approaches to assessing FN risk in patients scheduled to receive chemotherapy with intermediate risk of FN. Key secondary objectives were to describe physicians’ assessments of risk factors when deciding whether to prescribe G-CSF PP. Additional exploratory objectives were to report the number of risk factors considered when evaluating FN risk, physicians’ self-reported FN-risk intervention thresholds, FN risk determined for each patient and subsequent decisions on G-CSF prescription.
Populations enrolled
Physicians with a range of experience in clinical practice (≤10 years or >10 years) were enrolled to represent typical treatment settings for each country. Physicians prospectively identified 5–10 sequential patients who met the following eligibility criteria: aged 18 years or older; diagnosed with non-Hodgkin lymphoma, small-cell lung cancer, non-small-cell lung cancer or breast cancer; scheduled to initiate a pre-specified, standard-dose chemotherapy regimen classified as having intermediate (10–20 %) FN risk according to published data or guidelines (supplementary Table 1). Planned dose modifications within 10 % were permitted.
The appropriate written informed consent was obtained if required by local regulations.
Study design
This multicenter, prospective, observational study (ClinicalTrials.gov Identifier:
NCT01813721) was conducted in Europe, Australia and Canada, and was divided into two parts (Figure 1): baseline investigator assessment, which was completed before patient identification, and patient assessment, which was completed before initiating chemotherapy.
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Baseline investigator and patient assessments
For both assessments, physicians were given the same lists of risk factors from which to select important factors according to their usual clinical practice when (1) assessing overall
FN risk and (2) deciding whether to prescribe G-CSF PP (supplementary Tables 2 and 3).
Information from the baseline investigator assessment was documented by the physicians using an interactive web response system (IWRS) before enrolling any patients and could not be subsequently changed. Data entered into the IWRS were mapped to electronic case report forms. The study also recorded physicians’ self-reported FN-risk intervention thresholds for the use of G-CSF PP, physician demographics and center characteristics.
Physicians could only begin to enroll patients once they had completed the baseline investigator assessment. In the patient assessment, physicians estimated each patient’s final FN risk score and reported whether they planned to initiate G-CSF PP. Additional patient baseline data, such as demographics, planned chemotherapy regimen and laboratory values, were recorded. Patients were not followed-up during chemotherapy and no further data (e.g. outcomes such as FN) were collected.
Statistical analysis
The planned sample sizes were 150–200 physicians and 800–1000 patients from approximately 100 centers. These ranges of sample sizes were expected to produce an acceptable degree of precision for estimates of incidence of age and chemotherapy regimen selected as FN risk factors (half-width of the 95 % confidence interval <10 %). All physicians who enrolled at least one eligible patient were included in the investigator-level analysis.
Eligible patients who had at least one FN risk factor selected by the physician were included in the patient-level analysis.
A two-level multilevel modeling approach was used to account for the expected correlation in results obtained from the same centers (intra-center correlation at the investigator level) and a three-level multilevel modeling method was used to account for
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intra-investigator correlation at the patient level. To minimize any potential bias due to a small number of centers in the investigator-level analysis or a small number of investigators in the patient-level analysis, subgroups were analyzed only if they included a minimum of
40 physicians (for investigator-level analyses) or at least 100 patients (for patient-level analyses).
Results
Baseline physician characteristics
Between December 2012 and November 2013, 205 physicians were registered from
81 centers. Overall, 165 physicians enrolled eligible patients into the study. Most (67 %) physicians were medical oncologists, and 71 % had more than 10 years’ clinical experience
(Table 1). University hospitals were the most common type of center (n = 29; 36 %), followed by general hospitals (n = 23; 28 %), private centers (n = 21; 26 %) and comprehensive cancer centers (n = 8; 10 %).
Baseline patient characteristics
Of 1007 patients enrolled, 944 met the eligibility criteria. Median age was 61 years and most
(62 %) patients were younger than 65 years (Table 1). More than half (59 %) of patients were female, and breast cancer was the most common malignancy (42 % of all patients).
The chemotherapeutics that physicians most frequently planned to use were alkylating agents (n = 471; 50 %), anthracyclines (n = 402; 43 %), platinums (n = 356; 38 %) and taxanes (n = 323; 34 %). The planned chemotherapy was first-line in most (83 %) patients.
Factors considered important in overall FN risk assessment
Baseline investigator assessment
”Chemotherapy agents in the backbone” was the most frequently selected FN risk factor in the baseline investigator assessment (88 % of physicians; Table 2). Anthracyclines (41 %) were the most frequently selected chemotherapy agent, followed by taxanes (25 %),
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platinum-based agents and alkylating agents (22 % each). History of FN (83 %) and baseline laboratory values (76 %) were more commonly chosen than age (73 %) (Table 2). The median number of FN risk factors selected by physicians in this assessment was 12 (range,
1–22).
The results observed differed depending on the length of physicians’ clinical experience. Physicians with greater than 10 years’ experience were more likely than those with less experience to select performance status and comorbidities, but less likely to select guidelines and history of FN (Figure 2A).
Patient assessment
“Chemotherapy agents in the backbone” was the most frequently selected FN risk factor in the patient assessment (93 % of patients; Table 2), and the same chemotherapy agents were selected as for the baseline investigator assessment (anthracyclines, 36 %; taxanes,
17 %; platinum-based agents, 10 %; and alkylating agents, 7 %). Tumor type (72 %), guidelines (62 %) and tumor stage (43 %) were also commonly selected, but history of FN was rarely selected (4 %; Table 2). The median number of FN risk factors selected in this assessment was 5 (range, 0–20).
The FN risk assessment at the patient level differed according to physicians’ clinical specialties and length of clinical experience. Medical oncologists selected guidelines for a larger proportion of patients than hematologists (72 % versus 28 %; Figure 2B), whereas hematologists were more likely than medical oncologists to consider tumor type (81 % versus 73 %), age (55 % versus 41 %) and comorbidities (27 % versus 14 %). Physicians with more than 10 years’ clinical experience were more likely than those with less experience to select guidelines and individual risk factors, including tumor type, age, tumor stage, treatment intent and performance status (Figure 2C).
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Factors considered important when deciding whether to prescribe G-CSF PP
Baseline investigator assessment
When deciding whether to prescribe G-CSF PP, the outcome of the overall FN risk assessment was the most frequently selected factor (89 %), followed by age (80 %;
Table 3). The most frequently selected non-clinical factor was the patient living far from the clinic (34 %), followed by estimated compliance (24 %) and local access to reimbursed
G-CSF PP (23 %; Table 3). The median number of factors considered by physicians in
G-CSF PP decision making during this assessment was 7 (range, 1–20).
Patient assessment
The outcome of the overall FN risk assessment was also the most frequently selected factor when deciding whether to initiate G-CSF PP in the patient assessment (79 %; Table 3).
Guidelines and treatment intent were the next most frequently considered factors (67 % each), followed by age (51 %). A lower number of risk factors were chosen in this assessment (median, 4 [range, 1–19]) compared with the baseline investigator assessment.
When deciding whether to initiate G-CSF PP, medical oncologists were more likely than hematologists to consider guidelines (73 % versus 33 %), but less likely to consider age
(50 % versus 74 %), planned RDI (10 % versus 19 %) and length of chemotherapy cycle
(10 % versus 24 %).
Overlap between the baseline investigator and patient assessments
Chemotherapy agents in the backbone was selected most often by physicians in both assessments (77 % overlap), followed by guidelines and tumor type (48 % overlap each; supplementary Table 4). When deciding whether to initiate G-CSF PP, the outcome of the overall FN risk assessment (62 %) had the greatest overlap, followed by guidelines (51 %) and treatment intent (50 %; supplementary Table 5).
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Physicians’ FN-risk intervention thresholds for G-CSF PP
The median FN-risk intervention threshold at which physicians would typically prescribe
G-CSF was 20 % (range, 10–85 %; Figure 3a). G-CSF PP was more likely to be planned when physicians scored the overall FN risk at 20 % or more than when the risk was scored below 20 % (Figure 3b). G-CSF PP was planned in 82 % of patients with an overall FN risk score at or above the physician’s G-CSF PP intervention threshold, and in 19 % of patients with an overall FN risk score below their threshold.
Discussion
This large, international study found that physicians’ assessments of FN risk closely matched recommendations from the EORTC guidelines for use of G-CSF to reduce the incidence of chemotherapy-induced FN [20]. Most risk factors stipulated by the guidelines were among the most commonly selected factors in this study, namely chemotherapy agents in the backbone, age, baseline laboratory values, comorbidities and disease stage. Female sex was the only risk factor specified in the EORTC guidelines that was not selected by a high proportion of physicians in this study.
There was little overlap between the FN risk factors selected in the two assessments, with chemotherapy agents in the backbone the only factor selected in both assessments for more than 50 % of patients. Furthermore, fewer factors were considered in the patient assessment than in the baseline investigator assessment (medians, 5 versus 12), suggesting that while physicians are aware of a broad range of potential FN risk factors only a small number are considered on an individual patient basis. Nonetheless, the overlapping factors may reflect those considered to be the most important factors in routine practice.
Clinical factors were selected more often than non-clinical factors; however, the importance of some factors, such as the patient living far from the clinic and estimated compliance, was evident. Other factors that may have influenced FN risk assessment and
G-CSF PP decisions were not assessed in this study, such as variations in reimbursement among countries or patient education.
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Incorporation of risk factors into routine decision making appears to increase with clinical experience: physicians were more likely to consider risk factors at the patient level if they had been practicing for over 10 years. There were also variations in decision making according to physicians’ specialties: hematologists considered guidelines less frequently than medical oncologists and more frequently selected patient-related factors when evaluating FN risk and G-CSF PP prescription. This may be due to the general characteristics of patients with hematological malignancies, such as existing cytopenias and prior episodes of FN [25–27]. In clinical practice, G-CSF is prescribed more frequently to those with hematological malignancies than to patients with other cancer types [28], perhaps due to the high dose intensity of chemotherapy regimens used in hematology.
The median FN risk threshold for G-CSF PP in our study was 20 %, consistent with the level advocated by guidelines [20]; however, there was a large range of reported thresholds (10–85 %). Furthermore, G-CSF PP was not planned in almost one fifth of patients when the estimate of FN risk was at or above the physician’s FN risk threshold.
Assessing the FN risk associated with chemotherapy regimens can be challenging owing to inconsistent and perhaps inadequate reporting in the literature [29–31]. For example, while guidelines report the FN risk of the FEC-D regimen (5-fluorouracil-epirubicin- cyclophosphamide-docetaxel) as intermediate, in clinical practice the FN risk is twice that reported in clinical trials [32], and a systematic review found it to exceed the 20 % G-CSF PP threshold [33]. Additionally, patient characteristics may vary from those in published studies, and physicians may prescribe chemotherapy doses that deviate from standard regimens in certain clinical situations.
Introduction of FN risk assessment tools at individual centers has been shown to reduce the incidence of FN and increase chemotherapy delivery [34, 35]. Moreover, studies suggest that standardized risk assessment and use of G-CSF PP are feasible in routine practice and can greatly improve FN outcomes in patients undergoing chemotherapy.
Despite the enrolment of a large cohort of physicians and patients across multiple centers, this study has some limitations. Bias could be introduced owing to non-random
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selection of centers and physicians, and probable inclusion of physicians with a greater than average interest in FN risk assessment or G-CSF PP use. Indeed, we found that G-CSF PP was planned in most eligible patients. Additionally, more than half of physicians in this study worked at university hospitals or comprehensive cancer centers, which may not wholly reflect real-world practice. Furthermore, the behavior of physicians may have been altered by inclusion in this study. Nonetheless, this study provides valuable information on physicians’ decision-making process during risk assessment in patients receiving chemotherapy associated with intermediate FN risk.
Physicians use guideline recommendations and a patient-centered approach when assessing FN risk and defining G-CSF intervention thresholds. In almost 20 % of patients who were considered to be at or above the risk threshold for G-CSF PP, treatment was not planned, suggesting a gap in patient care. A standardized approach to risk factor assessment may aid G-CSF PP use and effective delivery of cancer treatment in patients receiving chemotherapy regimens associated with intermediate FN risk.
Conflicts of interest
Gilles Freyer, Giuseppe Tonini, Konstantinos Syrigos, Zee Wan Wong, Say Liang Ng and
Antonio Salar have declared no conflicts of interest.
Ewa Kalinka-Warzocha has received honoraria from Amgen and Teva.
Mihai Marinca has received honoraria from Amgen and Sandoz.
Guenther Steger has received honoraria from and has participated in advisory board meetings for Amgen and Teva.
Mahmood Abdelsalam has received consultancy fees from Sanofi and honoraria from Eli
Lilly and Johnson & Johnson. He has also received travel grants from Amgen, Roche and
Astellas, and has participated in advisory board meetings for Amgen, Janssen and Innomar
Strategies.
Lucy DeCosta and Zsolt Szabo are employees and shareholders of Amgen.
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Acknowledgements
This study was sponsored by Amgen. We thank all patients, physicians, coordinators and other staff who participated in the study. Medical writing support was provided by Elizabeth
Hartfield (PhD) from Oxford PharmaGenesis, Oxford, UK. Funding for this support was provided by Amgen (Europe) GmbH.
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Table 1 Physician and patient characteristics at baseline
Physicians
(N = 165)
Specialty
Medical oncology 110 (66.7)
Hematology 31 (18.8)
Respiratory medicine 10 (6.1)
Radiation oncology 8 (4.8)
Medical gynecology 4 (2.4)
Gynecological surgery 2 (1.2)
Time in oncology/hematology clinical practice
>10 years 117 (70.9)
10 years 48 (29.1)
Patients
(N = 944)
Sex
Male 390 (41.3)
Female 554 (58.7)
Age (years)
Mean 59.8
SD 11.4
Median 61.0
Q1, Q3 53.0, 68.0
Min., max. 20, 94
Age group
<65 years 587 (62.2)
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65 years 357 (37.8)
Tumor type
Breast cancer 395 (41.8)
NSCLC 248 (26.3)
NHL 182 (19.3)
SCLC 119 (12.6)
Disease stage
I 107 (11.3)
II 203 (21.5)
III 252 (26.7)
IV 323 (34.2)
Not available 59 (6.3)
Secondary malignancy
Yes 5 (0.5)
No 939 (99.5)
History of FN 14 (1.5)
Patients reporting at least one comorbidity 423 (44.8)
Cardiovascular disease 288 (30.5)
COPD/pulmonary disease 125 (13.2)
Diabetes mellitus 87 (9.2)
Liver disease 35 (3.7)
Current infection 29 (3.1)
Renal disease/impaired renal clearance 25 (2.6)
Open wound 19 (2.0)
Data shown are patient number (%), unless otherwise stated
COPD, chronic obstructive pulmonary disease; FN, febrile neutropenia; NHL, non-Hodgkin lymphoma; NSCLC, non-small-cell lung cancer; Q, quartile; SCLC, small-cell lung cancer;
SD, standard deviation
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Table 2 Factors considered important by physicians in the overall FN risk assessment
Baseline investigator assessment Patient assessment
(N = 165) (N = 944)
Factor % (95 % CI) Factor % (95 % CI)
Chemotherapy agents in the backbone 88 (82–93) Chemotherapy agents in the backbone 93 (88–96)
History of FN 83 (76–89) Tumor type 72 (61–82)
Baseline laboratory values 76 (68–83) Guidelines 62 (48–74)
Age 73 (64–81) Tumor stage 43 (34–53)
Previous chemotherapy 71 (62–78) Age 39 (32–48)
Guidelines 70 (60–78) Treatment intent 31 (24–39)
Previous radiotherapy involving bone marrow 65 (56–73) ECOG/Karnofsky performance status 28 (21–36)
ECOG/Karnofsky performance status 64 (55–72) Female sex 18 (13–26)
Tumor type 63 (53–72) Comorbidities 16 (12–20)
Comorbidities 63 (54–71) Baseline laboratory values 15 (11–21)
Documented bone marrow involvement 62 (52–72) Personal experience of FN risk of the 15 (10–22)
chemotherapy regimen
Tumor stage 62 (53–70) Previous chemotherapy 15 (12–19)
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Treatment intent 50 (41–59) Nutritional status 8 (6–12)
Nutritional status 49 (40–58) Planned RDI 7 (4–12)
Medications taken 48 (38–58) Medications taken 5 (4–8)
Current infection 45 (37–55) History of FN 4 (3–7)
Concurrent radiotherapy 42 (32–53) Documented bone marrow involvement 4 (3–7)
Personal experience of FN risk of the 40 (33–49) Previous radiotherapy involving bone marrow 4 (3–6) chemotherapy regimen
Open wounds 37 (28–47) Current infection 4 (2–6)
Planned RDI 26 (18–35) Concurrent radiotherapy 2 (1–4)
Female sex 23 (16–33) Open wounds 2 (1–4)
Other disease-/treatment-related 4 (2–9) Other patient-related 2 (1–4)
Other patient-related 2 (0.9–6) Other disease-/treatment-related 0.8 (0.4–2)
CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; FN, febrile neutropenia; RDI, relative dose intensity
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Table 3 Factors considered important by physicians when deciding whether to prescribe G-CSF PP
Baseline investigator assessment Patient assessment
(N = 165) (N = 944)
Factor % (95 % CI) Factor % (95 % CI)
Outcome of the overall FN risk assessment 89 (83–93) Outcome of the overall FN risk assessment 79 (71–84)
Age 80 (71–87) Guidelines 67 (53–79)
Baseline laboratory values 74 (64–82) Treatment intent 67 (59–74)
Guidelines 71 (61–78) Age 51 (43–60)
Treatment intent 69 (61–77) ECOG/Karnofsky performance status 36 (28–45)
ECOG/Karnofsky performance status 66 (56–75) Baseline laboratory values 18 (13–25)
Medications taken 51 (41–61) Length of chemotherapy cycle 13 (9–20)
Length of chemotherapy cycle 50 (39–60) Planned RDI 10 (6–16)
Planned RDI 34 (26–44) Outpatient care of the patient 8 (5–13)
Patient lives far from the clinic 34 (25–43) Patient lives far from the clinic 7 (5–11)
Safety risk of intensive chemotherapy 31 (23–40) Medications taken 7 (4–11)
Estimated compliance of the patient or caregiver 24 (17–32) Estimated compliance of the patient or caregiver 5 (3–8) with the treatment plan with the treatment plan
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Local access to reimbursed G-CSF PP 23 (15–32) Safety risk of G-CSFs in general 4 (3–6)
Outpatient care of the patient 21 (15–28) Local access to reimbursed G-CSF PP 3 (2–7)
Safety risk of G-CSFs in general 20 (13–28) Family/caregiver/nurse support to the patient 3 (2–5)
Hospitalized patient 16 (11–24) Retired versus employed/active status of the 3 (2–5)
patient
Family/caregiver/nurse support to the patient 14 (8–21) Hospitalized patient 2 (1–4)
Wait-and-see approach 10 (6–16) Safety risk of intensive chemotherapy 2 (1–4)
Retired versus employed/active status of the 9 (5–14) Wait-and-see approach 2 (1–3) patient
Private health insurance of the patient 6 (3–12) Private health insurance of the patient 1 (0.5–2)
Other 0.6 (0.1–4) Other 0.4 (0.1–1)
CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; FN, febrile neutropenia; G-CSF, granulocyte-colony stimulating factor;
PP, primary prophylaxis; RDI, relative dose intensity
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