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Supportive Oncology
However, this study has several serious design issues including being a in sequential cohorts of patients receiving neoadjuvant TAC chemotherapy
retrospective review, underpowered due to small sample groups and using during a large clinical trial.
42
Cohorts included ciprofloxacin alone, daily G-
only a moderately myelosuppressive regimen with a baseline FN risk of 7%. CSF from days five to 10 of each cycle, pegfilgrastim once per cycle or the
A retrospective claims database consisting of patients with NHL, breast combination of pegfilgrastim and ciprofloxacin. The pegfilgrastim arms
cancer or lung cancer was analysed by days of prophylactic G-CSF were superior to the antibiotic or abbreviated G-CSF arms, with 22%
administration. The risk of hospitalisation for neutropoenia or infection experiencing FN with ciprofloxacin, 18% with daily G-CSF for six days, 7%
declined with each additional day of filgrastim prophylaxis.
35
Thus, with pegfilgrastim once per cycle and 5% with pegfilgrastim +
discontinuation of growth factor before neutrophil recovery appears to be ciprofloxacin (p<0.01). Hospitalisation was significantly lower in the growth
less effective under conditions of more myelosuppressive regimens and is factor groups and pegfilgrastim lowered hospitalisation rates compared
not recommended. with filgrastim. These results highlight the importance of growth factor
support as the primary prophylactic strategy against FN when
Clearance of filgrastim occurs mainly through renal mechanisms while myelosuppressive chemotherapy is given.
pegfilgrastim appears to be metabolised by cellular endocytosis after
binding of G-CSF to its receptor on newly formed myeloid progenitors. This Current Guidelines
self-regulating mechanism explains the long action of the drug pegfilgrastim Several organisations have periodically released guidelines regarding the use
is generally not administered less than 13 days before the next cycle of of G-CSF to reduce complications of CIN based on updated reviews of the
chemotherapy. A study in Hodgkin’s disease patients tested pegfilgrastim literature. In general, the American Society of Clinical Oncology (ASCO),
43
after each cycle of bi-weekly adriamycin (doxorubicin), bleomycin, National Comprehensive Cancer Network (NCCN)
44
and the European
vinblastine and dacarbazine (ABVD) and demonstrated efficacy and safety of Organisation for Research and Treatment of Cancer (EORTC)
45
guidelines
once per cycle dosing.
36
are very similar in their recommendations. All recommend primary
prophylaxis with G-CSF when the risk of FN is approximately 20% or greater
The toxicities of G-CSF are generally mild and self limited. Neutrophilia is based on a careful consideration of both patient risk factors and
occasionally seen on day 1 of subsequent cycles of chemotherapy after chemotherapy regimens. All three groups recommend considerations of
administration of G-CSF. This finding is typically of no clinical significance. growth factor prophylaxis when the risk of FN falls in the 10–20% range,
Splenic enlargement and splenic rupture occur rarely. The most commonly depending upon the intent of treatment – curative or life-prolonging versus
reported toxicity of filgrastim, lenograstim and pegfilgrastim is bone pain.
23
palliative – desire to maintain dose intensity, and patient risk factors. The
This occurred at any severity in 25–50% of patients in clinical trials, while EORTC and ASCO guidelines emphasise the importance of age >65 as a
severe bone pain occurred in fewer than 10% of patients. Pain typically critical consideration for use of growth factor support. A prospective trial of
starts one to three days after initiation of G-CSF and appears to be worse in G-CSF prophylaxis in elderly patients supports this concept.
46
the first cycle of therapy.
37
Bone pain may be exacerbated by certain
chemotherapeutics such as taxanes. Most patients require acetaminophen The use of pegfilgrastim once per cycle given 24 hours after
or other non-narcotic analgesics to control the pain. Reports of chemotherapy simplifies treatment. Many clinicians would like to provide
discontinuation of G-CSF for toxicity are rare. Pre-treatment education of chemotherapy and supportive care on the same day, particularly in the
patients about this potential side effect in the author’s experience reduces US where self-injectables are often not reimbursed. There are potential
the intensity and impact of bone pain on activities of daily living. safety issues arising from earlier administration of G-CSF; these include
efficacy concerns as well as the theoretical risk of exposing mitotically
Antiobiotic Usage in Chemotherapy-induced Neutropoenia stimulated myeloid precursors to genotoxic chemotherapy. A study in
Primary antibiotic prophylaxis with or without growth factors has been breast cancer patients receiving TAC demonstrated a three-fold increase
evaluated in a variety of oncologic settings. A randomised trial of 760 in FN from 7% to 22% in patients receiving pegfilgrastim the same day
patients receiving high-dose chemotherapy for solid tumours or treatment as chemotherapy compared with the next day.
47
Trials in other tumour
for leukaemia or lymphoma showed a significant reduction in FN with daily types are awaiting publication, but at this time patients receiving
oral levofloxacin compared with placebo.
38
However, the rates of fever were myelosuppressive chemotherapy and prophylactic growth factors should
high in both groups: 65% for the antibiotic group versus 85% in the continue to initiate G-CSF 24 hours after chemotherapy, as indicated in
placebo group. current guidelines.
A meta-analysis published in 2005 reviewed prophylactic antibiotic use in Cost-effectiveness of Prophylaxis with Growth Factors
95 studies involving 9,283 patients with neutropoenia.
39
Most studies were Growth factor support adds to the overall cost of treatment, but the cost
conducted with in-patients with haematological cancers. Antibiotics, of FN, direct hospital costs, out-patient costs and indirect costs to patients
particularly quinolones, showed efficacy with an RR of 0.67 (95% CI, and care-givers can be enormous. Cost and cost utility analyses have
0.55–0.81) for all-cause mortality and RR of 0.38 (95% CI, 0.21–0.69) for demonstrated that utilising G-CSF in the appropriate primary prophylactic
fluoroquinolones versus no antibiotics in infection-related mortality. setting is cost-effective compared with US and European costs for inpatient
Nonetheless, in more myelosuppressive regimens antibiotic prophylaxis care,
48,49
and could be cost saving when indirect costs and out-of-pocket
alone is not sufficient to prevent FN, as seen in two trials comparing costs are included.
50,51
When a more effective, but more myelosuppressive,
taxotere, adriamycin (doxorubicin) and cyclophosphamide (TAC) with regimen is appropriate the use of this regimen with growth factor support
fluorouracil, adriamycin (doxorubicin) and cyclophosphamide (FAC) in appears cost effective as well.
52
Another recent analysis of cost-
breast cancer patients.
40,41
In this setting, the addition of prophylactic G- effectiveness utilising the payer’s perspective in Europe has concluded that
CSF to antibiotic therapy markedly reduced the FN rate. Recently, a study secondary prophylaxis with antibiotics is more cost-effective than a
evaluating a variety of approaches to the prevention of FN was evaluated combined strategy of antibiotics and G-CSF.
53
28 EUROPEAN ONCOLOGY
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