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Granulocyte Colony-Stimulating Factor Use in Patients With Chemotherapy-Induced Neutropenia:

Granulocyte Colony-Stimulating Factor Use in Patients With Chemotherapy-Induced Neutropenia:

Neutropenia is the primary dose-limiting toxicity in patients treated with myelosuppressive chemotherapy, leading in some cases to substantial morbidity and early mortality, and disrupting treatment with potentially curative regimens. The use of granulocyte colony-stimulating factors (G-CSFs) such as filgrastim (Neupogen) and pegfilgrastim (Neulasta), as primary prophylaxis starting in the first cycle of chemotherapy, has been shown to reduce the rates of febrile neutropenia (FN) and of FN-related hospitalization, as well as the use of intravenous anti-infectives. A recent meta-analysis has shown significantly lower infection-related mortality with the first-cycle use of G-CSFs. Both filgrastim and pegfilgrastim were originally approved on the basis of their effectiveness in patients treated with chemotherapy regimens that are associated with a 40% or greater risk of FN. Pegfilgrastim, which is given once per cycle, has been shown to reduce the risk of FN by 94% in breast cancer patients treated with docetaxel (Taxotere). In addition, a recent cost-minimization analysis has shown that first-cycle use of pegfilgrastim may be cost-neutral in patients in whom the predicted risk of FN is less than 20%. These findings have important implications for clinical guidelines for preventing chemotherapy-induced neutropenia and FN.

Chemotherapy-induced neutropenia (CIN) is the primary dose-limiting toxicity in patients with cancer treated with systemic myelosuppressive agents. The most serious manifestation of neutropenia, febrile neutropenia (FN), which may be a sign of life-threatening infection, particularly in patients who are frail or elderly and in those with comorbidities.[1] It frequently necessitates chemotherapy dose reductions and delays, which have been shown to compromise the efficacy of some chemotherapy regimens.[2-4] In addition, CIN and FN have negative effects on patients’ quality of life (QOL), an outcome that is getting more attention in the treatment of cancer.[5,6] Because the risk of CIN and FN is greatest in the first cycle of chemotherapy,[7] appropriate supportive care should be initiated in the first cycle in patients who are at increased risk to minimize the effects of neutropenia and its complications.

The proactive use of the granulocyte colony-stimulating factors (G-CSFs) filgrastim (Neupogen) and pegfilgrastim (Neulasta) can reduce the incidence, severity, and duration of neutropenia and its complications. Filgrastim, which was approved by the US Food and Drug Administration (FDA) in 1991, is given daily in weight-based doses.[8] Pegfilgrastim, a G-CSF that was bioengineered to have a sustained duration of action and was approved in 2002, is given once per cycle in a fixed dose.[9]

Both filgrastim and pegfilgrastim were FDA approved on the basis of their efficacy in decreasing the risk of FN in patients with cancer who were treated with highly myelosuppressive chemotherapy regimens (rates of FN of ≥ 40%).[10-13] The results of more recent studies support the efficacy[14] and cost-effectiveness[15] of pegfilgrastim given in the first cycle with chemotherapy regimens with which the risk of FN is less than 20%. In this article, I review the clinical and economic benefits of initiating filgrastim and pegfilgrastim in the first cycle of chemotherapy.

Pivotal Trials of Filgrastim

Filgrastim was approved for managing CIN on the basis of the results in two multicenter trials in patients with small-cell lung cancer who were treated with cyclophosphamide (Cytoxan, Neosar), doxorubicin, and etoposide, a regimen associated with a risk of FN of about 60%.[10,11] Patients in both studies were randomized to filgrastim 4 to 8 µg/kg or to placebo on days 4 through 17 after the chemotherapy (the filgrastim could be discontinued if the postnadir absolute neutrophil count [ANC] exceeded 10 × 109/L after day 12). The primary end point was the incidence of FN, defined as a temperature ≥ 38.2°C and ANC < 1.0 × 109/L.

In both studies, the incidence of FN was lower by about 50% with filgrastim.[10,11] In one of them, the incidence was 77% in the placebo group and 40% in the filgrastim group (P < .001)[10]; in the other, it was 53% and 26% (P < .002), respectively.[11] Furthermore, filgrastim also significantly reduced the incidence of culture-confirmed infections; the incidence and duration of grade 4 neutropenia (ANC < 0.5 × 109/L); the number of days of intravenous (IV) antibiotic use or the proportion of patients treated with IV antibiotics; and the number of days of hospitalization or the proportion of patients hospitalized. The only adverse event that was attributed to filgrastim was mild-to-moderate musculoskeletal pain, which was not dose-limiting.

Pivotal Trials of Pegfilgrastim

The approval by the FDA of pegfilgrastim for prevention of CIN was based on the results of two large randomized controlled trials in patients with breast cancer who were treated with doxorubicin and docetaxel (Taxotere),[12,13] a regimen that is associated with an FN rate of 38% in patients with breast cancer when it is used without growth factors.[14]

The trials were similar in design and investigated whether pegfilgrastim was as effective as filgrastim in managing CIN. Patients were randomized to a single injection of pegfilgrastim per chemotherapy cycle followed by daily injections of placebo, or to daily injections of filgrastim 5 µg/kg. The pegfilgrastim was given as a weight-based dose (100 µg/kg) in one of the studies[12] and as a fixed dose (6 mg) in the other.[13] Treatment began on day 2 of each cycle, about 24 hours after the chemotherapy. The filgrastim or placebo injections were continued for 14 days or until the ANCwas at least 10 × 109/L after the nadir.

A single dose of pegfilgrastim was at least as effective as daily filgrastim in both trials. The incidence and duration of grade 4 neutropenia were similar with both agents in all cycles, and the agents were comparable in terms of the depth of the ANC nadir and the time to neutrophil recovery. There were no differences in safety. The trials were not designed to detect this effect, but in both, the incidence of FN (temperature ≥ 38.2°C and ANC < 0.5 × 109/L) was lower with pegfilgrastim (Figure 1), and in one of them, the difference was significant (P = .029).[12] Retrospective analysis of pooled data from these studies showed that treatment with both filgrastim and pegfilgrastim helped make it possible to give the planned doses of chemotherapy on time.[15] At least 90% of the patients in both groups were treated with an average relative dose intensity (RDI) of 85% or higher. Both studies also showed that the efficacy of the G-CSFs was greater in the later cycles, with the incidence of grade 4 neutropenia being lower in cycles 2 through 4 than in cycle 1 (Figure 2a).[12,13] One of the studies also reported that the duration of grade 4 neutropenia in cycles 2 through 4 was significantly shorter with pegfilgrastim than with filgrastim (Figure 2b).[12]

A more recent pivotal trial has shown that pegfilgrastim as primary prophylaxis also has clinical benefits when it is given with a less toxic moderately myelosuppressive regimen.[16] This randomized, multicenter, multinational, double-blinded study was conducted in 928 patients with breast cancer treated with single-agent docetaxel, 100 mg/m2 every 3 weeks, a regimen that has been associated with FN rates of 10% to 20% in the absence of CSFs.[17,18] The patients were randomized to pegfilgrastim 6 mg or placebo once per cycle, given approximately 24 hours after the chemotherapy. Patients in whom FN developed were treated with open-label pegfilgrastim in the following cycles. The primary end point was the incidence of FN, defined as in the other pivotal trials of pegfilgrastim.

The overall incidence of FN was 94% lower in patients randomized to pegfilgrastim than in those randomized to placebo, and the rates of FN-related hospitalization and use of IV anti-infectives were also significantly lower with pegfilgrastim (all P < .001) (Figure 3). Full-dose chemotherapy was given on schedule in similar proportions of patients (pegfilgrastim 80% and placebo 78%). This was expected, because the study design specified that patients in either group in whom FN developed be switched to open-label pegfilgrastim. It should also be noted that a greater proportion of patients in the placebo group were switched to open-label pegfilgrastim (19% vs 2%). There were two deaths due to infection-related complications in the placebo group but none in the pegfilgrastim group.

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