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Management of Chemotherapy-induced Neutropoenia
A long-acting form of filgrastim was developed by adding a polyethylene findings were observed across a broad array of tumour types, regimens and
glycol molecule to the N-terminus of the G-CSF protein, which greatly baseline risk of FN.
increases the hydrodynamic size of the molecule, preventing renal clearance
while preserving activity. Pegfilgrastim (Neulasta) given once per cycle was A meta-analysis of 12 randomised clinical trials in 1,823 patients with NHL
compared with daily filgrastim in two randomised double-blind placebo- and Hodgkin’s disease determined that prophylactic CSF significantly
controlled studies in breast cancer patients receiving doxorubicin and reduced FN (RR=0.74; 95% CI, 0.62–0.89), severe neutropoenia (RR=0.67;
docetaxel.
19,20
The control arm consisted of daily injections of filgrastim 95% CI, 0.60–0.73) and infection (RR=0.74; 95% CI, 0.64–0.85).
29
Based
continued until an ANC recovery of >10x10
9
/l. Both trials demonstrated on these analyses, it is clear that when the a priori risk of FN is approximately
non-inferiority of a single dose of pegfilgrastim given the day after 20% or greater, the use of prophylactic G-CSF improves outcome.
chemotherapy compared with an average of 11 doses of daily filgrastim. A
combined analysis of the two studies suggested clinical superiority for Secondary Prophylaxis Against Chemotherapy-induced
pegfilgrastim based on a reduction in FN to 11% versus 19% for filgrastim Neutropoenia with Growth Factors
with a risk ratio (RR) of 0.56.
21
Pegfilgrastim was further studied against The use of CSF is recommended after a patient experiences CIN and
placebo in a multicentre randomised trial of patients receiving a less complications arise during a previous cycle of chemotherapy, assuming that
myelosuppressive regimen consisting of single-agent docetaxel 100mg/m
2
.
22
maintenance of dose intensity is important. A randomised trial utilising a
The incidence of FN was markedly reduced from 17% in the control group conditional model based on first-cycle ANC <0.5x10
9
/l demonstrated a
to 1% (p<0.001) and the incidence of hospitalisation was likewise markedly lower risk of FN and FN-related complications and greater preservation of
reduced from 14 to 1% (p<0.001). No differences in toxicity between dose intensity when G-CSF was used in subsequent cycles.
30
Once a patient
filgrastim and pegfilgrastim have been observed. A meta-analysis comparing experiences FN, the risk of recurrent FN remains substantial in subsequent
the efficacy of pegfilgrastim with filgrastim in five randomised clinical trials cycles and measures to reduce this risk, including growth factor support,
showed a significant difference in FN favouring pegfilgrastim, with an RR of are indicated.
0.64 (95% confidence interval (CI), 0.43–0.97).
23
Treatment of Chemotherapy-induced Neutropoenia with
Primary Prophylaxis Against Chemotherapy-induced Growth Factors
Neutropoenia with Growth Factors There is no evidence that patients who develop SN and no associated
The use of G-CSF support after the first and subsequent cycles of co-morbidity benefited from the addition of CSF. Whether or not planned
myelosuppressive chemotherapy to prevent FN is recommended by various dose on schedule could be maintained with this approach has not been
organisational guidelines. Clinical trial data supports the use of primary tested. Studies have been conducted evaluating the worth of G-CSF begun
prophylaxis when the risk of FN is in the range of 20% or greater. when patients experience FN. One prospective trial from Spain randomising
Myelosuppression and FN risk are dependent upon many factors including FN patients receiving intravenous antibiotics to G-CSF or not showed a
the chemotherapy regimen, patient age, prior chemotherapy or reduction in the duration of FN, length of hospitalisation, and duration of
radiotherapy, bone marrow involvement by tumour, and other co- antibiotic therapy in the G-CSF arm.
31
A Cochrane meta-analysis including
morbidities. Risk models that can be used to define the probability of FN 1,518 patients from 13 trials evaluated the use of CSF in the treatment of
have been developed and are clinically useful.
24
In addition, many of the FN.
32
This systematic review showed less prolonged neutropoenia, less
same co-morbidities and risk factors also predict for prolonged hospitalisation, less infection-related mortality but no significant difference
hospitalisation and risk of mortality following the development of FN.
25
in overall mortality. Based on these findings, prophylaxis against the
These factors should all be taken into account when making a decision development of FN is much preferred to growth factor treatment started at
about utilisation of G-CSF for primary prophylaxis after chemotherapy. the time of FN.
The risk of FN from any given regimen appears to be highest after the first Dosing of Granulocyte Colony-stimulating Factor for
cycle of chemotherapy. Prospective studies in breast cancer and Prophylaxis of Chemotherapy-induced Neutropoenia
retrospective analyses of non-Hodgkin’s lymphoma (NHL indicate that The recommended schedule and dose of G-CSF is to begin administration
50–65% of FN events occur in the first cycle.
22,26
Recently, a prospective of the agent 24–72 hours after myelosuppressive therapy and to continue
nationwide study of community practices in the US examining a large until count recovery after nadir, typically for 10–12 days. The G-CSF label
number of patients and tumour types demonstrated 58.9% of FN events calls for dosing at 5µg/kg/day given subcutaneously. Pegfilgrastim is given
occurred in cycle 1.
27
Including SN, the incidence in cycle 1 was 68.8%. subcutaneously 24 hours after myelosuppressive chemotherapy at a fixed
Patients who had first-cycle FN were twice as likely to undergo planned dose dose of 6mg. Previous studies demonstrated no difference in outcome
reductions in cycle 2 (11.1% versus 5.9%, p=0.0033) and also exhibited between weight-based and fixed dosage of pegfilgrastim, resulting in the
significantly increased dose delays (22.2% versus 13.0%). This resulted in an single fixed dosage being commercially available for adults.
19
Evaluation of
unplanned relative dose intensity of <85% in over one-third of patients. pegfilgrastim in the paediatric population has been limited, and
pegfilgrastim is not currently indicated for paediatric use. One small study
The impact of primary prophylaxis on patient outcome was subject to a showed safety and efficacy of pegfilgrastim at 100µg/kg in repetitive cycles
recently reported systemic review of 17 randomised controlled studies of of myelosuppressive chemotherapy in 28 children.
33
growth factors in 3,491 patients receiving conventional chemotherapy.
28
Infection-related mortality had an RR of 0.552 (95% CI, 0.338–0.902; Less frequent dosing of daily G-CSF through a cycle has been studied in the
p=0.018) with G-CSF and early mortality was significantly reduced as well; setting of patients receiving relatively lower myelosuppressive
RR=0.599 (95% CI, 0.433–0.833; p=0.002). The risk of FN with G-CSF was chemotherapy, consisting of an anthracycline and cytoxan for breast
reduced with a summary RR of 0.54 (95% CI, 0.43–0.67; p<0.0001). These cancer.
34
Intermittent schedules were not significantly worse in daily dosing.
EUROPEAN ONCOLOGY 27
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