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Med Oncol (2014) 31:797

DOI 10.1007/s12032-013-0797-z

ORIGINAL PAPER

A prospective observational study to evaluate G-CSF usage


in patients with solid tumors receiving myelosuppressive
chemotherapy in Italian clinical oncology practice
S. Barni • V. Lorusso • M. Giordano • G. Sogno • T. Gamucci • A. Santoro •

R. Passalacqua • V. Iaffaioli • N. Zilembo • M. Mencoboni • M. Roselli •


G. Pappagallo • P. Pronzato

Received: 29 May 2013 / Accepted: 27 November 2013 / Published online: 5 December 2013
Ó Springer Science+Business Media New York 2013

Abstract Febrile neutropenia (FN) is a severe dose-lim- Primary objective was to explore G-CSF use in Italian
iting side effect of myelosuppressive chemotherapy in clinical practice; therefore, data were collected on the
patients with solid tumors. Clinical practice guidelines G-CSF type, timing of administration, and number of
recommend primary prophylaxis with G-CSF in patients doses. 512 eligible patients were enrolled (median age, 62).
with an overall C20 % risk of FN. AIOM Italian guidelines The most common tumor types were breast (36 %), lung
recommend starting G-CSF within 24–72 h after chemo- (18 %), and colorectal (13 %). A total of 1,164 G-CSF
therapy; for daily G-CSF, administration should continue cycles (daily G-CSF, 718; pegfilgrastim, 446) were
until the absolute neutrophil count (ANC) is 1 9 109/L observed. Daily G-CSF was administered later than 72 h
post-nadir and should not be terminated after ANC increase after chemotherapy in 42 % of cycles, and the median
in the early days of administration. The aim of this study [range] number of doses was four [1, 10]. Pegfilgrastim
was to assess guideline adherence in oncology practice in was administered later than 72 h in 8 % of cycles. G-CSF
Italy. In this multicenter, prospective, observational study, prophylaxis in Italy is frequently administered in a manner
patients were enrolled at the first G-CSF use in any cycle which is not supported by evidence-based guidelines. As
and were followed for two subsequent cycles (or until the this practice may lead to poor outcomes, educational ini-
end of chemotherapy if less than two additional cycles). tiatives are recommended.

This study was carried out on behalf of OBSERVE investigators.

S. Barni A. Santoro
Oncology Department, Azienda Ospedaliera Treviglio, Humanitas Cancer Center, Rozzano, Milan, Italy
Treviglio, BG, Italy
R. Passalacqua
S. Barni (&) Oncology Department, Istituti Ospitalieri, Cremona, Italy
Ospedale di Treviglio, Treviglio, BG, Italy
e-mail: sandro.barni@ospedale.treviglio.bg.it V. Iaffaioli
Oncology Department, I.N.T. Fondazione G Pascale, Naples,
V. Lorusso Italy
National Cancer Research Centre Istituto Tumori Giovanni
Paolo II, Bari, Italy N. Zilembo
Oncology Department ‘‘Oncologia Medica 1’’, Fondazione
M. Giordano IRCCS ‘‘Istituto Nazionale dei Tumori’’, Milan, Italy
Oncology Department, Azienda Ospedaliera Sant’Anna, Como,
Italy M. Mencoboni
Oncology Department, Ospedale Villa Scassi, Genoa, Italy
G. Sogno
Oncology Department, Ospedale San Paolo, Savona, Italy M. Roselli
Oncology Department, Tor Vergata Clinical Center, University
T. Gamucci of Rome Tor Vergata, Rome, Italy
Oncology Department, Osp SS Trinità, Sora, Italy

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Keywords G-CSF  Solid tumors  Observational frame for initiation of daily G-CSF dosing is within
study  Oncology practice  Italy  Guidelines 24–72 h after the end of chemotherapy according to the
AIOM guidelines (not less than 24 h following cytotoxic
chemotherapy in the Neupogen/GranulokineÒ1 SPC (Sup-
Introduction plementary Protection Certificate); the lenograstim SPC
states only that dosing should not commence before 24 h
Patients with solid tumors receiving myelosuppressive after chemotherapy end) [17, 18].
chemotherapy are at risk of developing severe neutropenia With respect to the length of dosing, the AIOM guide-
or FN, a major dose-limiting side effect of cancer treat- lines recommend dosing with daily G-CSF until the ANC
ment. FN is a serious complication that can lead to life- is 1,000/mm3 (1 9 109/L) after nadir and dosing should not
threatening infections, hospitalization, and antibiotic be discontinued following ANC increase in the early days
treatment; thus, it is both a major cause of mortality and a of administration [15]. In contrast, ASCO guidelines rec-
source of significant health care resource utilization [1]. ommend dosing until the absolute neutrophil count (ANC)
Furthermore, patients who develop FN are often unable to is 2–3 9 109 after nadir [13], while the EORTC [12],
receive their subsequent dose of chemotherapy on time or NCCN [14], and ESMO [16] guidelines do not specify a
in full, which can have a negative impact on the success of stopping ANC. Manufacturers’ recommendations do not
the cancer treatment [2, 3]. Delivery of the planned dose of specify a stopping ANC: the Neupogen/GranulokineÒ2
chemotherapy is particularly important where the treatment SPC states that dosing should continue until the neutrophil
goal is cure or extension of life. count returns to normal after the nadir, which may be up to
Prophylactic granulocyte colony-stimulating factors (G- 14 days based on clinical trials in which the ANC goal was
CSF; filgrastim, lenograstim, or pegfilgrastim) have been C10 9 109/L [4, 17, 19]; the lenograstim SPC states that
shown to reduce the incidence of FN and to enhance the dosing should continue until the expected nadir has passed
likelihood of delivering the full dose intensity of chemo- and the neutrophil count returns to a stable level compat-
therapy [4–7]. Patients hospitalized with FN have an ible with treatment discontinuation, with, if necessary, a
overall mortality risk of 10 % [1], and systematic reviews maximum of 28 consecutive days of treatment [18]. Thus,
have shown that prophylactic G-CSF also reduces the risk recommendations on the length of dosing for daily G-CSF
of both infection-related [6] and all-cause mortality [8]. are diverse, also because specific factors may be consid-
Prophylactic G-CSF has rendered the use of highly myel- ered, e.g., impact of different chemotherapy type. Obser-
osuppressive dose-dense regimens feasible [3, 9–11]. vational studies have shown that physicians in clinical
International oncology guidelines, as well as the Italian practice often use a short course of daily G-CSF (5–6 doses
Association of Oncology Medicine (AIOM) guidelines, or fewer) [20–23] which has been associated with higher
recommend prophylactic G-CSF, when using a chemo- FN rates [20–22, 24].
therapy regimen associated with FN in [20 % patients; Pegfilgrastim is a long-acting G-CSF created by cova-
besides, guidelines recommend to give particular attention lently attaching a polyethylene glycol molecule to filgra-
to patient-related risk factors that may increase the overall stim, hence altering the mode of clearance from renal
risk of FN, when using a chemotherapy regimen associated clearance to a self-regulating, neutrophil-mediated mech-
with FN in 10–20 % patients [12–16]. For regimens with a anism [25, 26]. Due to this neutrophil-regulated clearance,
risk between 10 and 20 %, physicians are advised to con- pegfilgrastim is active throughout the period of neutropenia
sider the presence of other risk factors, such as age and requires only a single dose [26, 27]. In registration
[65 years, performance status, comorbidities, reduced trials, a single dose of pegfilgrastim was equivalent to daily
bone marrow reserve, and immunosuppression in the G-CSF dosed to ANC C10 9 109/L (10–11 doses) [27–
decision to use G-CSF. 29]. AIOM guidelines recommend that pegfilgrastim
Filgrastim and lenograstim must be administered daily should be given as a single dose within 24–72 h after the
due to the shorter half-life of these agents, which are end of chemotherapy, while the manufacturer recommends
eliminated predominantly by renal clearance. The time one 6 mg dose of pegfilgrastim for each chemotherapy
cycle, administered as a subcutaneous injection approxi-
mately 24 h following cytotoxic chemotherapy (NeulastaÒ
G. Pappagallo
Office of Clinical Epidemiology, Department of Medical SPC [30]).
Sciences, Azienda ULSS 13, Mirano, VE, Italy During a series of expert panels conducted in Italy in
2007, a survey of G-CSF administration practice suggested
P. Pronzato
Oncology Department A, IST, Istituto Nazionale per la Ricerca
sul Cancro, IRCCS Azienda Ospedaliera Universitaria San
1
GranulokineÒ is the Italian brand name for NeupogenÒ.
Martino, Genoa, Italy 2
GranulokineÒ is the Italian brand name for NeupogenÒ.

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Med Oncol (2014) 31:797 Page 3 of 7 797

that G-CSFs were frequently not administered as recom- Table 1 Baseline demographics and disease characteristics
mended by guidelines as well as stated by SPCs. To Characteristic All patients (n = 512)
evaluate this practice and its potential implications, we
designed a prospective study to record G-CSF usage pat- Median (range) age (years) 62 (21–88)
terns in patients with solid tumors receiving myelosup- Female, n (%) 325 (64 %)
pressive chemotherapy in clinical practices throughout Tumor type, n (%)a
Italy. Breast 184 (36 %)
Lung 93 (18 %)
Colorectal 64 (13 %)
Methods Ovarian 29 (6 %)
Sarcoma 24 (5 %)
This was a multicenter prospective observational study Stomach 23 (5 %)
conducted in Italy. The primary objective of the study was Head and neck 15 (3 %)
to examine the usage patterns of G-CSF in clinical practice, Endometrial 13 (3 %)
while secondary objectives were to record the incidence of Skin 13 (3 %)
FN, Grade 3/4 neutropenia, hospitalization, and antibiotic Other 54 (11 %)
use. The target sample size was 500 patients with a mini- Disease stage
mum of 16 patients per center. A sample of 500 patients Early, n (%) 150 (30 %)
was considered adequate, because analyses were descrip- Locally advanced, n (%) 82 (16 %)
tive and no formal hypothesis was tested. Participating Metastatic, n (%) 280 (55 %)
centers included those who had participated in the expert a
Total percentage greater than 100 % due to rounding
panels (both academic and community practices were
included).
Patients included in the study were C18 years old and chemotherapy administration including dose delays and
had a diagnosis of a non-hematologic malignancy. Eligible reductions, the type of G-CSF (filgrastim [Neupogen/
patients were receiving chemotherapy (initial or sub- GranulokineÒ3 was the only available filgrastim in Italy at
sequent course) and receiving the first administration of the time of this study], lenograstim, or pegfilgrastim), the
G-CSF, not limited to primary prophylaxis within the timing of initiation of G-CSF dosing, the number of G-CSF
current course (in any cycle; not restricted to the first cycle doses administered, and the occurrence of adverse events
of chemotherapy). Informed consent was obtained prior to including FN, grade 3/4 neutropenia, hospitalizations, and
the collection of data. Patients who had received prior antibiotic use.
G-CSF for the current course of chemotherapy, had The primary outcomes included the initial type of
received G-CSF for pre-transplant stem cell mobilization, G-CSF (filgrastim, lenograstim, or pegfilgrastim), the tim-
were HIV positive, or were participating in a concurrent ing of G-CSF administration relative to the end of che-
clinical trial evaluating a treatment or experimental scheme motherapy administration, and the number of doses of
were excluded from the study. G-CSF administered. Secondary outcomes included anti-
Data were to be collected from each patient starting with biotic use, hospitalization for neutropenia, febrile neutro-
the first cycle of chemotherapy in which G-CSF was used penia, and chemotherapy delivery.
(in any cycle; not restricted to the first cycle of chemo- Only patients who met the eligibility requirements were
therapy) and continuing for 2 subsequent cycles (or to the included in the analyses. Descriptive summary statistics
end of chemotherapy if less than 2 additional cycles). Since were generated for continuous variables and an estimated
the study was prospective and since the aim of the study frequency, and 95 % confidence interval was calculated for
was to collect real-life data on GCSF use avoiding bias categorical variables.
whenever possible, a direct question was not made whether
G-CSF was used for primary or secondary prophylaxis or
reactive treatment, and the reason for using G-CSF. At Results
each center, consecutive patients were to be enrolled in the
study at the time of receiving their first dose of G-CSF for Patients
the course of chemotherapy. At the time of enrollment, age,
tumor type, and disease stage were recorded. During the A total of 518 patients were enrolled between 10/2007 and
first G-CSF exposure and all successive chemotherapy 10/2008 of whom 512 met the eligibility criteria and were
cycles in which data were collected, the following were
recorded on the case report form: the details of 3
GranulokineÒ is the Italian brand name for NeupogenÒ.

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Table 2 Chemotherapy regimens by G-CSF type


Chemotherapy regimen Daily Pegfilgrastim All G-CSF
G-CSF cycles cycles
cycles (n = 446) (n = 1,164)
(n = 718) n (%) n (%)
n (%)

CT given on day 1 and 362 (50 %) 284 (64 %) 646 (56 %)


recycling every 14, 21,
or 28 days
CT given over multiple 185 (26 %) 110 (25 %) 295 (25 %)
days with at least
2 weeks between
cycles
CT given once weekly 32 (5 %) 1 (\1 %) 33 (3 %)
CT given over 1 week 129 (18 %) 39 (9 %) 168 (14 %)
with at least 2 weeks
between cycles
Other 10 (1 %) 12 (3 %) 22 (2 %)

Fig. 2 Number of doses delivered per cycle for daily G-CSF cycles
(n = 718)

and lenograstim usage, these two types of G-CSF were


pooled for the analyses as ‘‘daily G-CSF’’. No patient
received more than one type of G-CSF throughout their
treatment period. G-CSF was administered in a total of
1,164 cycles (pegfilgrastim, 446 cycles [38 %]; daily
G-CSF, 718 cycles [62 %]).
Chemotherapy regimens by G-CSF type are shown in
Table 2. These data show that usage of daily G-CSF and
pegfilgrastim was influenced by the type of chemotherapy
regimen. Usage of pegfilgrastim was higher than daily
G-CSF in regimens in which chemotherapy was delivered
in 1 day cycling every 14, 21, and 28 days (64 % of peg-
filgrastim cycles and 50 % of daily G-CSF cycles). Daily
Fig. 1 Timing of initiation of G-CSF dosing relative to the end of G-CSF was more likely to be used than pegfilgrastim in
chemotherapy for daily G-CSF cycles (n = 718; light blue) and weekly regimens (5 % of daily G-CSF cycles vs. \1 % of
pegfilgrastim cycles (n = 446; dark blue) pegfilgrastim cycles) and in regimens where chemotherapy
was delivered over 1 week with at least 2 weeks between
cycles (18 % of daily G-CSF cycles vs. 9 % of pegfilgra-
included in the analysis; 5 patients did not meet the eligi- stim cycles).
bility criteria (administration of G-CSF in the prior che- Figure 1 shows the timing of initiation of G-CSF dosing
motherapy cycle) and 1 received only radiotherapy. Age, relative to the end of chemotherapy. While most pegfil-
tumor type, and disease stage are shown in Table 1. The grastim injections (92 % of cycles) occurred within the
majority of patients (64 %) were female, and the most AIOM-recommended time frame (within 72 h after che-
common tumor type was breast, representing 36 % of all motherapy end), daily G-CSF was frequently initiated later
tumors. Over half of the patients (55 %) had metastatic (42 % of cycles). Furthermore, in 19 % of daily G-CSF
disease. cycles, dosing was initiated later than 7 days after com-
pletion of chemotherapy. Pegfilgrastim was administered
G-CSF usage after a median of 1 day (range 1–2 days) following che-
motherapy administration.
One-third of patients (34 %) received pegfilgrastim, while Most courses of daily G-CSF were very short in dura-
two-thirds (66 %) received daily G-CSF (40 % lenogra- tion, with fewer than six doses administered in 86 % of
stim; 26 % filgrastim). Due to the similarity of filgrastim cycles and fewer than four doses in nearly half of the cycles

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(Fig. 2). The median number of daily G-CSF doses was 4 observed, which has previously been associated with
(range 1–10). In 13 % of cycles, daily G-CSF doses were delayed neutrophil recovery and a greater number of febrile
administered in a non-consecutive manner. Pegfilgrastim days [31, 32]. In almost one-fifth of cycles observed in the
requires only one dose and was administered correctly present study, daily G-CSF was initiated more than 7 days
except for two cycles (one each in two different patients) in after the end of chemotherapy. Furthermore, G-CSF was
which more than one dose was administered. not administered in number of subsequent cycles (932
cycles). The reasons for this are not known, but these
Chemotherapy delivery instances may represent reactive attempts to treat neutro-
penia; however, this is not recommended by AIOM or
Chemotherapy delivery was determined for G-CSF cycles international guidelines and has no biological rationale [33]
for which data from at least one subsequent chemotherapy or demonstrated clinical benefit.
cycle were available (726 cycles). Delays of chemotherapy We observed that less than six doses of G-CSF were
delivery of C7 days occurred in 12 % of cycles (89/726 administered in the majority of daily G-CSF cycles. The
cycles). In patients receiving daily G-CSF, delays of median number of days of G-CSF required to bring the ANC
C7 days occurred in 6 % of cycles (9/143) when G-CSF to 1 9 109/L as recommended by the AIOM guidelines is not
was given within 72 h of chemotherapy administration and known, as this has not been previously reported in the litera-
at least 6 vials were administered in a given cycle, and ture, and we did not record ANC at the time of G-CSF ces-
delays occurred in 20 % of cycles (55/225) when G-CSF sation in this study. We note that ANC of 1 9 109/L is
was not given within 72 h of chemotherapy or less than 6 considered to be Grade 3 neutropenia, whereas ASCO
vials were administered in a given cycle. Reductions to the guidelines recommend treatment until ANC = 2–3 9 109/L
planned dose of chemotherapy of [10 % occurred in 14 % [13], and the registrative filgrastim and pegfilgrastim studies
of cycles (102/726). In patients receiving daily G-CSF, continued administration until ANC was 10 9 109/L [4, 19].
dose reductions of [10 % occurred in 5 % of cycles (7/ However, the AIOM guidelines do state that daily G-CSF
143) when G-CSF was given within 72 h of chemotherapy dosing should not be withdrawn in the early days of admin-
administration and at least 6 vials were administered in a istration, which clearly occurred frequently in this study.
given cycle, and in 23 % of cycles (64/280) when G-CSF Evidence has been mounting to suggest that delivery of
was not given within 72 h of chemotherapy or less than 6 5–6 doses of daily G-CSF leads to increased risk of FN rel-
vials were administered in a given cycle. ative to one dose of pegfilgrastim [2, 3, 9, 20–22, 24]. In the
GEPARTRIO trial of TAC as neo-adjuvant therapy in 1,256
Neutropenic events and management patients with breast cancer, pegfilgrastim was superior to six
doses of G-CSF delivered on days 5–10 in reducing FN (7 vs
A total of 36 patients (7 %) had Grade 3/4 neutropenia; in 18 %) [9]. In a retrospective observational study of G-CSF
29/36 (80 %) of these patients, neutropenia was the pre- usage in 186 patients with solid tumors in Spain, Almenar
cipitating factor for reactive G-CSF administration. Of the et al. [20] showed that patients received a median 5–6 doses
7/512 patients (1 %) who experienced neutropenia fol- of G-CSF for primary and secondary prophylaxis with an FN
lowing administration of G-CSF, 5 of the 7 (3, daily rate of 24 % in patients given G-CSF and 11 % in patients
G-CSF; 2, pegfilgrastim) had Grade 3/4 neutropenia and 2 given pegfilgrastim. Similarly, in a large observational study
of the 7 (both daily G-CSF) had FN. One of the patients in the United States, Morrison et al. [22] reported that
with FN died. Three patients (1 %) were hospitalized (2 patients received an average of 5 doses of G-CSF in clinical
patients with FN who were given daily G-CSF and 1 practice, and the rate of FN in these patients was 7 versus 5 %
patient given pegfilgrastim), and two patients (\1 %) were (OR: 1.41, p = 0.04) for patients treated with pegfilgrastim.
treated with antibiotics (1, daily G-CSF; 1, pegfilgrastim). In a retrospective study of a claims database which evaluated
length of G-CSF dosing and outcomes, Weycker et al. [21]
showed that the risk of hospitalization for neutropenia or
Discussion infection decreased with each additional day of daily G-CSF
prophylaxis in patients with a variety of solid tumors treated
The results of this prospective, multicenter, observational in routine clinical practice in the USA. The negative impact
study in 512 patients with solid tumors receiving myelo- of short courses of daily G-CSF is not confined to increased
suppressive chemotherapy indicate that administration of rates of FN and hospitalization; some analyses have also
daily G-CSF in routine oncological practice in Italy is shown negative effects on the achievement of the full rela-
frequently not in accordance with AIOM guidelines. tive dose intensity of chemotherapy [2, 3].
Administration of the first dose of daily G-CSF later In the current study, we evaluated the chemotherapy
than 72 h after the end of chemotherapy was frequently delivered in two different groups of daily G-CSF cycles:

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those in which daily G-CSF was initiated according to Similar to the findings of similar studies conducted in
AIOM guidelines (within 72 h of chemotherapy adminis- other countries [20, 22], the results of this prospective
tration and not discontinued early) or those in which it was observational study suggest a strong need for educational
not. Both chemotherapy dose delays and dose reductions programs in Italy to raise awareness of the importance of
occurred more frequently in patients who initiated G-CSF adherence to G-CSF guidelines to obtain the best outcomes
later than guideline recommendations. Reduced chemo- and avoid waste of resources.
therapy dose intensity is associated with lack of G-CSF
primary prophylaxis (starting within the first 3 days che- Acknowledgments This study was supported by Amgen-Dompé,
Milan, Italy. Wanda J. Krall, PhD, a medical writer funded by Amgen
motherapy) [23], and our results further suggest that late (Europe) GmbH, assisted with the drafting of this manuscript. Thanks
initiation of G-CSF may affect chemotherapy delivery. to Valter Torri for providing some additional statistical analysis.
Despite the evidence for poorer outcomes, many phy-
sicians continue to use a shortened course of daily G-CSFs Conflict of interest The authors declare no conflict of interest.
as a cost-saving measure. The results of this study suggest
that the use of only a few G-CSF doses is widespread in
Italy; this practice, in which it appears that physicians are
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