JGO-00982; No.

of pages: 7; 4C:
Journal of Geriatric Oncology xxx (2020) xxx

Contents lists available at ScienceDirect

Journal of Geriatric Oncology

Duration of short-acting granulocyte colony-stimulating factor

for primary prophylaxis and risk of neutropenia-related
hospitalization in older patients with cancer
Shuling Li a,⁎, Jiannong Liu a, Tingting Gong a, Haifeng Guo a, Prasad L. Gawade b, Michael A. Kelsh b,
Brian D. Bradbury b, Rajesh Belani c, Gary H. Lyman d
a
Chronic Diseases Research Group, Hennepin Healthcare Research Institute, 701 Park Ave, Suite S2.100, Minneapolis, MN 55415, USA
b
Center for Observational Research, Amgen Inc, 1 Amgen Center Dr, Thousand Oaks, CA 91320, USA
c
US Medical, Amgen Inc, 1 Amgen Center Dr, Thousand Oaks, CA 91320, USA
d
Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, M3-B232, Seattle, WA 98109, USA

a r t i c l e i n f o a b s t r a c t

Article history: Purpose: Evaluate the relationship between duration of primary prophylactic short-acting granulocyte colony-
Received 25 February 2020 stimulating factor (PP-sG-CSF) and risk of neutropenia-related hospitalization (NRH) in older patients receiving
Received in revised form 12 May 2020 myelosuppressive chemotherapy.
Accepted 15 June 2020 Methods: Using the Medicare claims database, we conducted a nested case-control study in a cohort of patients
Available online xxxx
aged ≥66 years with breast, colorectal, lung, ovarian, or prostate cancer, or non-Hodgkin lymphoma who initiated
a first cycle of any myelosuppressive chemotherapy January 1, 2008–September 30, 2016, and received PP-sG-
Keywords:
Febrile neutropenia
CSF. We matched up to four controls to each NRH case by age, cancer type, regimen febrile neutropenia (FN)
Medicare risk category, and year using incidence density sampling. We used conditional logistic regression adjusted for
Myelosuppressive chemotherapy race, sex, and modified Charlson comorbidity index (CCI) to estimate relative risk of NRH related to duration of
Neutropenia-related hospitalization PP-sG-CSF categorized as <5 and ≥ 5 days.
Nested case-control study Results: Of 2148 patients receiving PP-sG-CSF, 108 (5%) experienced NRH in the first cycle. We matched 333 con-
Short-acting granulocyte colony-stimulating trols to 96 cases. Cases were similar to controls in mean age, tumor type, and intermediate/high-risk regimen, but
factors were more likely to have CCI ≥5 and less likely to use PP-sG-CSF ≥5 days (31% vs. 39%). Adjusted ORs (95% CI) for
NRH were 0.69 (0.40–1.19) for ≥5 vs. <5 days of PP-sG-CSF among patients receiving any myelosuppressive che-
motherapy, 0.43 (0.21–0.89) for intermediate/high-risk regimen, and 0.42 (0.19–0.89) for any myelosuppressive
chemotherapy with all agents given on cycle day one only.
Conclusions: Among older patients with cancer who are receiving PP-sG-CSF, ≥5 days of use was associated with
substantial reduction in NRH risk.
© 2020 Elsevier Ltd. All rights reserved.

1. Introduction duration and severity of neutropenia and decrease FN incidence

Chemotherapy-induced febrile neutropenia (FN) is a serious compli-
cation associated with significant morbidity, mortality, and compro-
mised therapeutic benefit due to chemotherapy dose reductions,
delays, or discontinuation [1]. FN occurs more commonly in the first
cycle [2,3] and is considered a medical emergency generally requiring
hospitalization, which on average lasts for a week or more and leads
to increased healthcare costs [4–6] and decreased qualify of life [7].
Primary prophylaxis with granulocyte colony-stimulating factors
(G-CSFs) that stimulate proliferation and survival of neutrophil precur-
sors and mature neutrophils has been shown to successfully reduce the
[8–10]. The National Comprehensive Care Network (NCCN®) clinical
practice guidelines recommend primary prophylaxis G-CSFs for patients
receiving chemotherapy regimens associated with high FN risk (≥20%),
or considering them for patients receiving chemotherapy regimens as-
sociated with intermediate FN risk (10%–20%) if at least one patient-
level risk factor is present [11]. One FN risk factor is age older than
65 years [11,12].
Despite the availability of single-administration, long-acting G-CSF
[13], a substantial proportion of patients continue to receive daily
short-acting G-CSF (sG-CSF) as a primary prophylactic measure against
FN [14]. As per the label, sG-CSF requires daily administration from 24 h

⁎ Corresponding author.
E-mail address: slli@cdrg.org (S. Li).

https://doi.org/10.1016/j.jgo.2020.06.018
1879-4068/© 2020 Elsevier Ltd. All rights reserved.

Please cite this article as: S. Li, J. Liu, T. Gong, et al., Duration of short-acting granulocyte colony-stimulating factor for primary prophylaxis and risk
of n..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.06.018
2 S. Li et al. / Journal of Geriatric Oncology xxx (2020) xxx
after chemotherapy administration for a maximum of two weeks or
until an absolute neutrophil count (ANC) of 10 × 109 L−1 is reached
[15]. Clinical trials have reported that efficacy of 10–11 days of sG-CSF
is equivalent to a single administration of pegfilgrastim, a long-acting
G-CSF [16–18]; however, in routine practice, primary prophylaxis sG-
CSF (PP-sG-CSF) is administered on average for 4 to 7 days [19]. Previ-
ous studies have shown that shorter duration of PP-sG-CSF is associated
with higher risk of neutropenia-related outcomes [20–23], but all were
based on older data, and some were limited to specific cancer types
[20,23] or included patients covered by commercial insurance [21–23].
None of the studies examined patients receiving chemotherapy with in-
termediate or high risk for FN for whom, per clinical practice guidelines
[11], PP-G-CSF is recommended or should be considered.
We used the latest Medicare claims database to evaluate the associ-
ation between number of days of PP-sG-CSF administration and risk of
neutropenia-related hospitalization (NRH) during first cycle of myelo-
suppressive chemotherapy.
2. Materials and Methods
2.1. Study Design and Data Source
We conducted a case-control study nested within a cohort of older
patients diagnosed with breast, colorectal, lung, ovarian, or prostate
cancer, or non-Hodgkin lymphoma (NHL), who received any myelosup-
pressive chemotherapy and PP-sG-CSF (Fig. 1). We used the 2007–2015
Medicare 20% sample data and the 2014–2016 Medicare 100% cancer
patient file from the Centers for Medicare & Medicaid Services (CMS).
Data included the annual denominator file, including demographic
information and Medicare enrollment status, and the annual claims-
based standard analytic files, including Part A institutional and Part B
carrier files [24]. Appendix A details the data source. This study was ap-
proved by the Office for Human Subjects Research of Hennepin
Healthcare System.
2.2. Study Cohort
The cohort entry date was the date of initiation of the first chemo-
therapy cycle when the cohort of patients eligible for the study was as-
sembled (Fig. 1a). We created cohorts of patients initiating parenteral
administration of any myelosuppressive chemotherapy for breast, colo-
rectal, lung, ovarian, or prostate cancer, or NHL, from January 1, 2008, to
December 31, 2014, using the Medicare 20% sample data, and from Jan-
uary 1, 2015, to September 30, 2016, using the Medicare 100% cancer
patient file.
We included patients aged ≥66 years at chemotherapy initiation
who survived the subsequent six days (to ensure the time period
needed to identify regimen and day of chemotherapy completion in
the first cycle), received PP-sG-CSF, and were continuously enrolled in
Medicare Part A and Part B for at least 365 days before and six days
after chemotherapy initiation without enrollment in a health mainte-
nance organization. Initiation of the first observed cycle of chemother-
apy was identified by requiring at least 365 days with no prior
myelosuppressive chemotherapy (Appendix B). We excluded patients
who underwent radiotherapy or stem cell transplant (Appendices C1-
C2) in the 365 days before or six days after chemotherapy initiation,
experienced an FN-related hospitalization in the first four days after
chemotherapy initiation (the case assessment period started on day
5), or received pegfilgrastim or sargramostim before the first dose of
PP-sG-CSF (Appendix C3).
We identified chemotherapy cycles and regimens in Medicare Part A
outpatient and Part B carrier claims using the algorithm described by
Weycker et al. [25]. Briefly, the first myelosuppressive chemotherapy
cycle started on the initiation date (day 1) and ended at the next admin-
istration, at least six days but no more than 35 days, after initiation. If no
second myelosuppressive chemotherapy cycle started before day 35,
Please cite this article as: S. Li, J. Liu, T. Gong, et al., Duration of short-acting granulocyte colony-stimulating factor for primary prophylaxis and risk
of n..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.06.018
the first cycle ended at the earliest of day 35 after initiation, the day
before regimen change, death, stem cell transplant, radiation, or
disenrollment from Part A or B.
We defined chemotherapy regimen based on the Healthcare
Common Procedure Coding System (HCPCS) Level II codes for paren-
terally administered antineoplastic agents (myelosuppressive and
non-myelosuppressive; Appendix B) on claims with service dates
from day one to day six of the first cycle and, on the same claims,
an International Classification of Diseases, Ninth/Tenth Revision,
Clinical Modification (ICD-9-CM/ICD-10-CM) diagnosis code for
breast, colorectal, lung, ovarian, or prostate cancer, or NHL (Appen-
dix C4). Regimens were classified as “intermediate” or “high” with
regard to FN risk based on the NCCN® clinical guideline for use of
myeloid growth factors for 2005 (the earliest year of NCCN guide-
lines available) to 2018 [11] (Appendix D). For regimens listed mul-
tiple times with different risk categories, the latest risk category was
used. Regimens not classified as intermediate or high FN risk at any
time during the study period and with cycle length of ≥11 days
(i.e., biweekly or longer regimens) were grouped into an “Unclassi-
fied” FN risk category. The date of the last administration of myelo-
suppressive chemotherapy agents in the first six days of the cycle
was defined as the date of cycle completion.
The six cancers were defined based on ICD-9-CM/ICD-10-CM diag-
nosis codes reported on the same claims for chemotherapy agents
used to define the regimens. To ensure that the identified regimen
was used to treat the cancer of interest, patients with evidence of
more than one cancer reported on chemotherapy claims in the first
six days of the cycle were excluded.
2.3. Study Period
The baseline period was the twelve months before chemother-
apy initiation (Fig. 1a). Patient-level covariates, including modified
Charlson comorbidity index (CCI) score [26–28], were defined dur-
ing the baseline period and age was defined on the chemotherapy
initiation date (Appendix A, “Covariate Definitions”). Primary can-
cer was included in the calculation of CCI score. The case assessment
period started on day five of the first chemotherapy cycle and ended
on the last day of the first chemotherapy cycle or the date of
switching to pegfilgrastim or sargramostim, whichever occurred
earliest.
2.4. Case Definition
The case, or NRH, was defined as a hospital admission with a princi-
pal or secondary diagnosis of neutropenia in any position (ICD-9-CM di-
agnosis code 288.0; ICD-10-CM diagnosis code D70) in the case
assessment period (based on the admission date; Fig. 1a) [29]. A
broad definition of NRH with a principal or secondary diagnosis code
in any position for neutropenia, fever, or infection (Appendix C5) was
considered in sensitivity analyses [25]. The date of the first NRH event
for the case was defined as the index date.
2.5. Control Selection
All patients who were alive and at risk for an NRH event at the
time of a case event were eligible to be selected as controls
(Fig. 11b). We matched up to four controls to one case by age (+/
− 1 year), tumor type, regimen by FN risk category (intermediate
and high combined, other), and calendar year of cohort entry date
(2008–2010, 2011, 2012–2014, 2015–2016) using incidence den-
sity sampling [30,31]. The index date of a matched control was de-
fined as the matched control's cohort entry date plus the number
of days from the cohort entry date to the index date of the corre-
sponding case.
 S. Li et al. / Journal of Geriatric Oncology xxx (2020) xxx 3

Fig. 1. Study design schema. a) assembling cohort and identifying cases; b) defining exposure for case and the matched controls. Definitions: case, neutropenia event occurring in an
inpatient setting; control, alive and at risk of an NRH event at the case index date, matched on age, tumor type, regimen by febrile neutropenia risk category, and calendar year of
cohort entry date; cycle 1, beginning on the date of chemotherapy initiation (day 1) and ending on the first service date for the next chemotherapy administration occurring at least
six days, but no more than 35 days, after the date of chemotherapy initiation; censoring event, death, stem cell transplant, radiation therapy, disenrollment from Medicare Part A/B, or
first use of pegfilgrastim or sargramostim. NRH, neutropenia-related hospitalization; PP-sG-CSF, short-acting granulocyte colony-stimulating factor for primary prophylaxis.

2.6. Exposure Definition
The primary exposure was duration of PP-sG-CSF. The exposure
assessment period started on the day of chemotherapy initiation
and extended to the day before the index date (Fig. 1b). SG-CSFs in-
clude filgrastim [32], tbo-filgrastim [33], and filgrastim-sndz [34],
and were identified in Medicare Part A outpatient claims or Part B
carrier claims via corresponding HCPCS Level II codes (Appendix
C3). PP-sG-CSF initiation was defined as first administration of
sG-CSF from cycle begin date to five days after chemotherapy com-
pletion in the first cycle, since neutropenic symptoms typically
begin after seven days and resolve fourteen days after chemotherapy
initiation [2,35]. PP-sG-CSF duration was defined as the number of
days that patients received PP-sG-CSF during the exposure
assessment period. Duration of PP-sG-CSF was categorized as <5
and ≥ 5 days based on previous literature [20,21].
2.7. Analysis
Descriptive statistics were used to report patient characteristics for
the overall study cohort and for matched cases and controls. Continuous
variables were expressed as mean and standard deviation (SD) or me-
dian and interquartile range. Conditional logistic regression was used
to estimate the odds ratio (OR) and associated 95% confidence interval
(CI) for the association between PP-sG-CSF duration and NRH risk
with adjusting for race, sex, and CCI. Two subgroup analyses were con-
ducted. The first included patients who received myelosuppressive che-
motherapy regimens with intermediate or high FN risk, restricting the

Please cite this article as: S. Li, J. Liu, T. Gong, et al., Duration of short-acting granulocyte colony-stimulating factor for primary prophylaxis and risk
of n..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.06.018
4 S. Li et al. / Journal of Geriatric Oncology xxx (2020) xxx

study population to patients recommended to receive PP-sG-CSF sup- who received chemotherapy associated with intermediate or high FN
port as per national guidelines [11]. The second subgroup analysis in- risk accounted for 58% of all patients.
cluded patients who received any parenteral administration of We identified 108 (5%) patients with an NRH in the first chemother-
myelosuppressive chemotherapy regimens with all agents adminis- apy cycle. In total, we matched 333 controls to 96 cases; of these, 68
tered on cycle day one to avoid possible bias introduced by the period cases (71%) were matched with exactly four controls. Matched cases
from chemotherapy initiation to completion in the cycle because usu- and controls had similar mean age and distribution of race, sex, cancer
ally no PP-sG-CSF is administrated in this period. A sensitivity analysis type, and chemotherapy regimens associated with intermediate or
was performed using the broad definition of NRH. high FN risk. Cases were more likely than controls to have CCI of ≥5
CCI (31% vs. 23%) (Table 2). Comorbid conditions, specifically congestive
heart failure, cerebrovascular disease, diabetes, and metastatic solid tu-
3. Results
mors, were more prevalent in cases than in controls (Appendix F).
Before matching, ≥5 days of PP-sG-CSF use was 53% in the overall
In total, 2148 patients initiated myelosuppressive chemotherapy for
study cohort and 32% in those who developed NRH. Among matched
breast, colorectal, lung, prostate, or ovarian cancers, or NHL, from 2008
cases and controls receiving any myelosuppressive chemotherapy regi-
to 2016, and received primary prophylaxis with short-acting G-CSF (Ap-
men, cases were less likely than controls to receive ≥5 days of PP-sG-CSF
pendix E). Table 1 presents the characteristics of the study cohort. At co-
(31% vs. 39%). Patterns were the same among matched cases and con-
hort entry, mean (SD) patient age was 75 (6) years; 59% were women
trols receiving myelosuppressive chemotherapy regimens associated
and 88% white. More than half of patients (54%) had CCI of 2–4, and
with intermediate or high FN risk (23%, cases vs. 40%, controls) and
about one-third (32%) had CCI of ≥5. NHL was the most common cancer
any myelosuppressive chemotherapy with all chemotherapy agents
type (36%), followed by lung cancer (27%), breast cancer (21%), colorec-
given on cycle day one (31% vs. 48%). Univariate distribution of days
tal cancer (7%), ovarian cancer (5%), and prostate cancer (3%). Patients
of PP-sG-CSF for the overall study cohort and the matched cases and
controls overall and in the two subgroups are presented in Appendix G.
Fig. 2 shows the adjusted OR for NRH associated with ≥5 days com-
Table 1
pared with <5 days of PP-sG-CSF use. Among matched cases and con-
Baseline characteristics for full cohort of patients receiving primary prophylaxis with
short-acting G-CSF. trols receiving any myelosuppressive chemotherapy regimen, ≥5 days
of PP-sG-CSF use was associated with a 31% decreased rate of NRH com-
Characteristics n %
pared with <5 days (adjusted OR [aOR]: 0.69; 95% CI, 0.40–1.19). When
Total 2148 100.00 we examined this association among matched cases and controls re-
Age (mean years, SD) 74.85 (5.98) ceiving myelosuppressive chemotherapy regimens with intermediate
Age category
66–69 years 557 25.93
or high FN risk, ≥5 days of PP-sG-CSF use was associated with a 57% de-
70–74 years 627 29.19 creased rate of NRH compared with <5 days (aOR: 0.43; 95% CI,
75–79 years 537 25.00 0.21–0.89). Protective results of ≥5 (vs. <5) days of PP-sG-CSF for re-
≥ 80 years 427 19.88 duced risk of NRH were similar for patients who received any myelo-
Female
suppressive chemotherapy regimens that included all chemotherapy
Male 883 41.11
Female 1265 58.89 agents given on cycle day one. In the sensitivity analysis among
Race matched cases and controls receiving any myelosuppressive chemo-
White 1884 87.71 therapy regimen using the broad definition of NRH (neutropenia or
Black 139 6.47 fever or infection-related hospitalization) for cases, ≥5 days of PP-sG-
Other race 125 5.82
Cancer type
CSF was associated with a 26% decreased rate of NRH compared with
NHL 770 35.85 <5 days (aOR: 0.74; 95% CI, 0.51–1.08).
Lung 575 26.77
Breast 460 21.42 4. Discussion
Colorectal 155 7.22
Prostate 75 3.49
Ovarian 113 5.26 Using nationally representative Medicare administrative databases,
FN risk this study showed that longer duration of PP-sG-CSF use (≥5 days) re-
High 402 18.72 duced the rate of NRH (aOR: 0.69) during the first cycle of chemotherapy
Intermediate 849 39.53 among older patients with breast, colorectal, lung, ovarian, or prostate
Others 897 41.76
Modified CCI⁎ (mean, SD) 4.08 (3.24)
cancer, or NHL, receiving any myelosuppressive regimens. The protective
Modified CCI⁎ group effect of ≥5 days of PP-sG-CSF use on NRH risk (aOR: 0.43) was higher for
0–1 297 13.83 patients recommended to receive sG-CSF as per NCCN guidelines,
2–4 1170 54.47 i.e., those receiving regimens with intermediate or high FN risk. The pro-
≥5 681 31.70
tective effect of ≥5 days of PP-sG-CSF use remained for patients receiving
Year of cohort entry
2008 278 12.94 any myelosuppressive chemotherapy that included all chemotherapy
2009 249 11.59 agents given on cycle day one (aOR: 0.42), suggesting consistency of
2010 225 10.47 the effect in a subgroup with similar exposure assessment window.
2011 191 8.89 Our findings are consistent with prior retrospective cohort studies
2012 124 5.77
that reported reduced FN risk with increased PP-sG-CSF duration
2013 105 4.89
2014 95 4.42 [20–23]. Using the Surveillance, Epidemiology, and End Results-
2015 532 24.77 Medicare linked data from 1994 to 2003, Rajan and colleagues [20] ob-
2016 349 16.25 served that ≥5 days of primary prophylaxis with filgrastim reduced NRH
Days of chemotherapy administration
within the first month of chemotherapy initiation by 63% (P ≤ .10)
1 1593 74.16
≥2 555 25.84 among older women with newly diagnosed breast cancer receiving che-
motherapy. Weycker et al. [21] analyzed commercially insured patients
CCI, Charlson comorbidity index; FN, febrile neutropenia; G-CSF, granulocyte colony-stim-
ulating factor; NHL, non-Hodgkin lymphoma; SD, standardized deviation.
diagnosed with breast cancer, lung cancer, or NHL who received myelo-
⁎ References for the coding algorithm and weight assigned for each condition: Table 1 in suppressive regimens and prophylactic filgrastim in ≥1 cycle between
Quan et al. [27] and Table 2 in Quan et al. [28], respectively. 1998 and 2002. FN risk reduction with each additional day of filgrastim

Please cite this article as: S. Li, J. Liu, T. Gong, et al., Duration of short-acting granulocyte colony-stimulating factor for primary prophylaxis and risk
of n..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.06.018
 S. Li et al. / Journal of Geriatric Oncology xxx (2020) xxx 5

Table 2 among all patient-cycles ranged from 9% for lung cancer to 23% for
Baseline characteristics for matched cases and controls. breast cancer. In their 2014 study of patients diagnosed with a solid
Characteristics Cases Controls Standardized tumor or NHL, Weycker et al. [22] reported that shorter duration of
Difference treatment with filgrastim prophylaxis was associated with an increased
n % n % risk of NRH in the first chemotherapy cycle (1–3 days versus ≥7 days, OR
1.60; 4–6 days versus ≥7 days, OR 1.74). The beneficial effect of longer
Total 96 100.0 333 100
Age (mean years, SD) 74.59 5.52 73.98 5.32 0.113 duration of prophylactic filgrastim use on NRH risk was also demon-
Age category, years strated in an earlier study of NHL patients [23].
66–69 23 23.96 96 28.83 0.111 The biological rationale for reduced FN risk with longer sG-CSF dura-
70–74 27 28.13 98 29.43 0.029 tion is based on the maturation time for neutrophils, the duration of neu-
75–79 29 30.21 99 29.73 0.010
≥ 80 17 17.71 40 12.01 0.161
tropenia, and the half-life of sG-CSF [15]. Neutrophils mature from stem
Sex cells, go through mitotic and post-mitotic phases in 10–14 days, and
Male 51 53.13 163 48.95 0.084 spend 6–8 h as peripheral neutrophils in blood [36,37]. Myelosuppres-
Female 45 46.88 170 51.05 0.084 sive chemotherapy reduces the number of these mitotic, post-mitotic,
Race
and peripheral neutrophils and is characterized by a period of neutrope-
White 86 89.58 303 90.99 0.048
Black ⁎ ⁎ ⁎ ⁎ nia (i.e., days with ANC <1 × 109 L−1). The lowest level of ANC, known as
Other race ⁎ ⁎ † † the nadir, is typically reached at least seven days after chemotherapy ini-
Cancer type tiation [10,18,35,38] once the reserve of maturing neutrophils expands,
NHL 58 60.42 203 60.96 0.011 and is characterized by minimal G-CSF efficacy [37]. PP-sG-CSF use re-
Lung 24 25.00 86 25.83 0.019
Breast † † † † duces the time to ANC nadir and the duration of neutropenia [10,38].
Ovarian ⁎ ⁎ ⁎ ⁎ Since the duration of neutropenia is directly associated with increased
FN risk group risk of infection [35], it is important to provide prophylactic G-CSF
High/intermediate 60 62.50 210 63.06 0.012 through the at-risk post-nadir phase (typically 2–3 days) when G-CSF re-
Others 36 37.50 123 36.94 0.012
sponsive cells are proliferating. Given the short half-life of sG-CSF (3.5 h)
Time period of cohort
entry and the rapid metabolism via renal- and neutrophil-mediated mecha-
2008–2010 30 31.25 115 34.53 0.070 nisms, sG-CSF use is recommended for at least two weeks or until ANC
2011 13 13.54 33 9.91 0.113 reaches 10 × 109 L−1 as per the label [15].
2012–2014 15 15.63 42 12.61 0.087 In the sensitivity analysis using the broad definition of NRH (neutro-
2015–2016 38 39.58 143 42.94 0.068
Modified CCI‡ (mean, 4.10 3.18 3.63 2.97 0.012
penia or fever or infection-related hospitalization), the observed benefit
SD) of receiving PP-sG-CSF for ≥5 days was attenuated modestly. This is
Modified CCI‡ group likely attributable to lower specificity with that case definition [29]
0–1 11 11.46 49 14.71 0.097 and the anticipated bias toward the null that occurs with a higher
2–4 55 57.29 206 61.86 0.093
false-positive rate [39].
≥5 30 31.25 78 23.42 0.176
The reasons for shorter PP-sG-CSF duration observed in routine
Note: A standardized difference of less than 0.1 represents a rule of thumb for an accept- practice could be multifactorial (e.g., patient convenience or cost-
able balance in covariate distribution between matched cases and controls.
CCI, Charlson comorbidity index; FN, febrile neutropenia; NHL, non-Hodgkin lymphoma;
saving), but shorter duration is certainly one reason for lower effective-
SD, standardized deviation. ness of daily sG-CSF. Given ongoing efforts to improve quality of patient
⁎ Values for cells with ten or fewer patients are suppressed. care and reduce healthcare costs with alternate payment models
†
Suppressed to avoid derivation of the number of patients in the cell with n < 11. [40,41], understanding contemporary treatment strategies in clinical
‡
References for the coding algorithm and weight assigned for each condition: Table 1 in
practice that minimize patient risks during cancer care is important. In
Quan et al. [27] and Table 2 in Quan et al. [28], respectively.
performance-based payment models that incentivize practices to
lower the total cost of care, important yet expensive medications such
as G-CSF become likely targets. Potentially, practices may choose the
cheaper and less effective sG-CSF over long-acting G-CSF or may admin-
ister shorter duration of sG-CSF. Our results provide additional
supporting evidence for guideline-recommended care that is designed
to minimize the risks of NRH.
Several study limitations are worth noting. Firstly, there is no ICD-9-
CM or ICD-10-CM diagnosis code for febrile neutropenia. The
claims-based definition used to identify NRH cases in this study (i.e., hos-
pitalization with diagnosis claims for neutropenia in any position) has a
sensitivity of 67% and specificity of 94% [29]. Given the moderate sensi-
tivity, this definition may fail to identify some NRH cases, but in the con-
text of this investigation this has no bearing on the validity of the
findings. Secondly, confounding by indication of intended effect is of
some concern in this study [42]. It is likely that patients perceived by
physicians as being at higher risk of NRH are more likely to receive longer
Fig. 2. Adjusted odds ratio and 95% confidence intervals for risk of neutropenia-related sG-CSF duration for primary prophylaxis. Confounding factors were
hospitalization in the first cycle of myelosuppressive chemotherapy related to longer
identified a priori using existing empirical evidence and clinical knowl-
duration of primary prophylaxis with sG-CSF (≥5 days vs. <5 days): nested case-control
analysis. (Up to four controls were matched to one case for age (+/− 1 year), tumor edge about G-CSF use and FN risk [43]. Although we matched cases
type, regimen by FN risk category [intermediate and high combined, other], and and controls by age, cancer type, chemotherapy regimen FN risk cate-
calendar year of cohort entry date [2008–2010, 2011, 2012–2014, 2015–2016] using gory, and calendar year of chemotherapy initiation, and further adjusted
incidence density sampling; results were adjusted for race, sex, and modified Charlson for race, sex, and CCI accounting for systematic differences between
comorbidity index listed in Table 2.) ⁎Regimens with intermediate or high risk for FN
that according to National Comprehensive Cancer Network guidelines should receive G-
matched cases and controls, study results may be confounded with re-
CSF prophylaxis. NRH, neutropenia-related hospitalization; sG-CSF, short-acting gard to unobserved confounders such as performance status, cancer
granulocyte colony-stimulating factor. stage, or relative dose intensity. Thirdly, our study used the Medicare

Please cite this article as: S. Li, J. Liu, T. Gong, et al., Duration of short-acting granulocyte colony-stimulating factor for primary prophylaxis and risk
of n..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.06.018
6 S. Li et al. / Journal of Geriatric Oncology xxx (2020) xxx
database, which accounts for almost all US citizens aged older than
65 years. Based on the trial results showing consistent efficacy of sG-
CSF in reducing FN incidence in younger and older patients with cancer
[44], we see no reason to believe that findings from this study cannot
be applicable to patients aged younger than 65 years. Lastly, timing of
PP-sG-CSF initiation relative to chemotherapy completion in the cycle
and a short course of PP-sG-CSF may affect the risk of NRH differently.
However, due to the sample size, we could not assess this in this study.
In conclusion, our study provides additional confirmatory evidence
that longer duration of sG-CSF therapy is associated with a meaningful
reduction in the risk of NRH. This finding aligns with the prescription
label, which recommends sG-CSF daily for at least two weeks or until
ANC reaches 10 × 109 L−1 to achieve sustained therapeutic response.
Also, the NRH risk reduction associated with more than five days of
PP-sG-CSF was greater in the subgroup of patients recommended to re-
ceive PP-sG-CSF as per national guidelines. Adherence to the prescrip-
tion label and guideline-recommended treatment strategies can help
achieve the goals of improving quality of life and reducing patient risks.
Funding
This study was supported by Amgen, Inc., Thousand Oaks, California,
USA.
Author Contributions
Substantial contributions to the conception or design of the work: SL, JL,
PG, MK, BB, RB, GL; or the acquisition, analysis, or interpretation of data
for the work: SL, JL, TG, HG, PG, MK. Drafting the work or revising it crit-
ically for important intellectual content: SL, JL, TG, HG, PG, MK, BB, RB,
GL. Final approval of the version to be published: all authors. Agreement
to be accountable for all aspects of the work in ensuring that questions
related to the accuracy or integrity of any part of the work are appropri-
ately investigated and resolved: all authors.
Research Involving Human Participants and/or Animals
This article does not contain any studies with human participants or an-
imals performed by any of the authors.
Informed Consent
Formal consent was not required as the article does not contain any
studies involving human participants performed by any of the authors.
Declaration of Competing Interest
Shuling Li, Jiannong Liu, Tingting Gong, and Haifeng Guo are employees
of Chronic Disease Research Group, Hennepin Healthcare Research In-
stitute, which has received project funding from Amgen, Inc. Prasad L.
Gawade, Michael A. Kelsh, Brian D. Bradbury, and Rajesh Belani are em-
ployees of and own stock in Amgen Inc. Gary Lyman has worked as a
consultant for Amgen, Inc.
Acknowledgements
Medical writing support was provided by Peter Alexander, PhD, of
Amgen, Inc. The authors thank Chronic Disease Research Group col-
league Nan Booth, MSW, MPH, ELS, for manuscript editing.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jgo.2020.06.018.
Please cite this article as: S. Li, J. Liu, T. Gong, et al., Duration of short-acting granulocyte colony-stimulating factor for primary prophylaxis and risk
of n..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.06.018
References
[1] Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, et al. 2010 up-
date of EORTC guidelines for the use of granulocyte-colony stimulating factor to re-
duce the incidence of chemotherapy-induced febrile neutropenia in adult patients
with lymphoproliferative disorders and solid tumours. Eur J Cancer 2011;47(1):
8–32.
[2] Crawford J, Dale DC, Kuderer NM, Culakova E, Poniewierski MS, Wolff D, et al. Risk
and timing of neutropenic events in adult cancer patients receiving chemotherapy:
the results of a prospective nationwide study of oncology practice. J Natl Compr Canc
Netw 2008;6(2):109–18.
[3] Lyman GH, Kuderer NM. Epidemiology of febrile neutropenia. Support Cancer Ther
2003;1(1):23–35.
[4] Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH. Mortality, morbidity, and
cost associated with febrile neutropenia in adult cancer patients. Cancer 2006;106
(10) (2258-66.a).
[5] Dulisse B, Li X, Gayle JA, Barron RL, Ernst FR, Rothman KJ, et al. A retrospective study
of the clinical and economic burden during hospitalizations among cancer patients
with febrile neutropenia. J Med Econ 2013;16(6):720–35.
[6] Li S, Liu J, Bowers C, Garawin T, Kim C, Bensink ME, et al. Febrile neutropenia-related
care and associated costs in elderly patients with breast cancer, lung cancer, or non-
Hodgkin lymphoma. Support Care Cancer 2020;28(1):113–22.
[7] Padilla G, Ropka ME. Quality of life and chemotherapy-induced neutropenia. Cancer
Nurs 2005;28(3):167–71.
[8] Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with
granulocyte colony-stimulating factor on febrile neutropenia and mortality in
adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol
2007;25(21):3158–67.
[9] Vogel CL, Wojtukiewicz MZ, Carroll RR, Tjulandin SA, Barajas-Figueroa LJ, Wiens BL,
et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in
patients with breast cancer: a multicenter, double-blind, placebo-controlled phase
III study. J Clin Oncol 2005;23(6):1178–84.
[10] Crawford J, Ozer H, Stoller R, Johnson D, Lyman G, Tabbara I, et al. Reduction by gran-
ulocyte colony-stimulating factor of fever and neutropenia induced by chemother-
apy in patients with small-cell lung cancer. N Engl J Med 1991;325(3):164–70.
[11] Crawford JBP, Alwan L, et al. NCCN clinical practice guidelines in oncology: myeloid
growth factors. www.nccn.org; 2018.
[12] Lyman GH, Kuderer N, Agboola O, Balducci L. Evidence-based use of colony-
stimulating factors in elderly cancer patients. Cancer Control 2003;10(6):487–99.
[13] Food and Drug Administration. Pegfilgrastim [prescribing information]. https://
www.accessdata.fda.gov/drugsatfda_docs/label/2015/125031s180lbl.pdf;; 2018.
[accessed 03/12/2019].
[14] Kozlowski S, Birger N, Brereton S, McKean SJ, Wernecke M, Christl L, et al. Uptake of
the biologic Filgrastim and its biosimilar product among the medicare population.
JAMA 2018;320(9):929–31.
[15] Administration FaD. Filgrastim [prescribing information]. https://www.accessdata.
fda.gov/drugsatfda_docs/label/2015/103353s5183lbl.pdf; 2018. [accessed 05/20/
2019.2019].
[16] Administration FaD. Pegfilgrastim [prescribing information]. https://www.
accessdata.fda.gov/drugsatfda_docs/label/2015/125031s180lbl.pdf; 2015. [accessed
05/20/2019.2019].
[17] Holmes FA, O’Shaughnessy JA, Vukelja S, Jones SE, Shogan J, Savin M, et al. Blinded,
randomized, multicenter study to evaluate single administration pegfilgrastim once
per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with
high-risk stage II or stage III/IV breast cancer. J Clin Oncol 2002;20(3):727–31.
[18] Green MD, Koelbl H, Baselga J, Galid A, Guillem V, Gascon P, et al. A randomized
double-blind multicenter phase III study of fixed-dose single-administration
pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemo-
therapy. Ann Oncol 2003;14(1):29–35.
[19] Mitchell S, Li X, Woods M, Garcia J, Hebard-Massey K, Barron R, et al. Comparative
effectiveness of granulocyte colony-stimulating factors to prevent febrile neutrope-
nia and related complications in cancer patients in clinical practice: a systematic re-
view. J Oncol Pharm Pract 2016;22(5):702–16.
[20] Rajan SS, Lyman GH, Stearns SC, Carpenter WR. Effect of primary prophylactic
granulocyte-colony stimulating factor use on incidence of neutropenia hospitaliza-
tions for elderly early-stage breast cancer patients receiving chemotherapy. Med
Care 2011;49(7):649–57.
[21] Weycker D, Hackett J, Edelsberg JS, Oster G, Glass AG. Are shorter courses of
filgrastim prophylaxis associated with increased risk of hospitalization? Ann
Pharmacother 2006;40(3):402–7.
[22] Weycker D, Barron R, Edelsberg J, Kartashov A, Legg J, Glass AG. Risk and conse-
quences of chemotherapy-induced neutropenic complications in patients receiving
daily filgrastim: the importance of duration of prophylaxis. BMC Health Serv Res
2014;14:189.
[23] Scott SD, Chrischilles EA, Link BK, Delgado DJ, Fridman M, Stolshek BS. Days of pro-
phylactic filgrastim use to reduce febrile neutropenia in patients with non-
Hodgkin’s lymphoma treated with chemotherapy. J Manag Care Pharm 2003;9(2
Suppl):15–21.
[24] Mues KE, Liede A, Liu J, Wetmore JB, Zaha R, Bradbury BD, et al. Use of the Medicare
database in epidemiologic and health services research: a valuable source of real-
world evidence on the older and disabled populations in the US. Clin Epidemiol
2017;9:267–77.
[25] Weycker D, Li X, Tzivelekis S, Atwood M, Garcia J, Li Y, et al. Burden of
chemotherapy-induced febrile neutropenia hospitalizations in US clinical practice,
by use and patterns of prophylaxis with Colony-stimulating factor. Support Care
Cancer 2017;25(2):439–47.
 S. Li et al. / Journal of Geriatric Oncology xxx (2020) xxx
[26] Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with
ICD-9-CM administrative databases. J Clin Epidemiol 1992;45(6):613–9.
[27] Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, et al. Coding algo-
rithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.
Med Care 2005;43(11):1130–9.
[28] Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating
the Charlson comorbidity index and score for risk adjustment in hospital discharge
abstracts using data from 6 countries. Am J Epidemiol 2011;173(6):676–82.
[29] Weycker D, Sofrygin O, Seefeld K, Deeter RG, Legg J, Edelsberg J. Technical evaluation
of methods for identifying chemotherapy-induced febrile neutropenia in healthcare
claims databases. BMC Health Serv Res 2013;13:60.
[30] Richardson DB. An incidence density sampling program for nested case-control
analyses. Occup Environ Med 2004;61(12):e59.
[31] Robins JM, Gail MH, Lubin JH. More on “biased selection of controls for case-control
analyses of cohort studies”. Biometrics 1986;42(2):293–9.
[32] Food and Drug Administration. Filgrastim [prescribing information]. https://www.
accessdata.fda.gov/drugsatfda_docs/label/2015/103353s5183lbl.pdf; 2015.
[accessed 08/12/2019].
[33] Food and Drug Administration. Tbo-filgrastim [prescribing information]. http://
www.accessdata.fda.gov/drugsatfda_docs/label/2012/125294s0000lbl.pdf; 2012.
[accessed 08/12/2019].
[34] Food and Drug Admnistration. Filgrastim-sndz [prescribing information]. https://
www.accessdata.fda.gov/drugsatfda_docs/label/2015/125553lbl.pdf; 2015.
[accessed 08/12/2019].
[35] Li Y, Klippel Z, Shih X, Reiner M, Wang H, Page JH. Relationship between severity and
duration of chemotherapy-induced neutropenia and risk of infection among pa-
tients with nonmyeloid malignancies. Support Care Cancer 2016;24(10):4377–83.
Please cite this article as: S. Li, J. Liu, T. Gong, et al., Duration of short-acting granulocyte colony-stimulating factor for primary prophylaxis and risk
of n..., J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2020.06.018
7
[36] Kim SK, Demetri GD. Chemotherapy and neutropenia. Hematol Oncol Clin North Am
1996;10(2):377–95.
[37] Crea F, Giovannetti E, Zinzani PL, Danesi R. Pharmacologic rationale for early G-CSF
prophylaxis in cancer patients and role of pharmacogenetics in treatment optimiza-
tion. Crit Rev Oncol Hematol 2009;72(1):21–44.
[38] Blayney DW, McGuire BW, Cruickshank SE, Johnson DH. Increasing chemotherapy
dose density and intensity: phase I trials in non-small cell lung cancer and non-
Hodgkin’s lymphoma. Oncologist 2005;10(2):138–49.
[39] Rothman KJ, Greenland S, Lash TL. Modern epidemiology. . 3rd ed.Philadelphia:
Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008.
[40] Kline RM, Bazell C, Smith E, Schumacher H, Rajkumar R, Conway PH. Centers for
Medicare and Medicaid Services: using an episode-based payment model to im-
prove oncology care. J Oncol Pract 2015;11(2):114–6.
[41] McAneny B, Grubbs SS, Birch W, Sayam Zuckerman D. Making sense of advanced
payment models. Am J Manag Care 2017;23(5) [SP199-SP200].
[42] Bosco JL, Silliman RA, Thwin SS, Geiger AM, Buist DS, Prout MN, et al. A most stub-
born bias: no adjustment method fully resolves confounding by indication in obser-
vational studies. J Clin Epidemiol 2010;63(1):64–74.
[43] Lyman GH, Abella E, Pettengell R. Risk factors for febrile neutropenia among patients
with cancer receiving chemotherapy: a systematic review. Crit Rev Oncol Hematol
2014;90(3):190–9.
[44] Welte K, Gabrilove J, Bronchud MH, Platzer E, Morstyn G. Filgrastim (r-metHuG-
CSF): the first 10 years. Blood 1996;88(6):1907–29.