Abstract & commentary
Synopsis: A single fixed dose of pegfilgrastim administered once per cycle of chemotherapy was comparable to multiple daily injections of filgrastim in safely providing neutrophil support during myelosuppressive chemotherapy. Pegfilgrastim may have use in other clinical settings of neutropenia.
Source: Green MD, et al. Ann Oncol. 2003;14:29-35.
The prevention of neutropenia and its infectious sequelae is a clinically important goal in the supportive care of patients receiving chemotherapy. The duration of grade 4 neutropenia and the depth of the nadir correlate with the development of infectious complications.1,2 Filgrastrim (r-metHuG-CSF) stimulates the production of neutrophil precursors, enhances mature neutrophil function, and decreases neutropenia and its complications. It has become a mainstay of current practice. The filgrastim molecule is cleared by renal and neutrophil-mediated mechanisms with a plasma half-life of 3-4 hours. This necessitates daily administration that often requires patients to travel daily to their physicians. There has been a hardship for some patients, particularly the elderly. Proteins can be modified to significantly increase their half-life by the chemical addition of polyethylene glycol (PEG). This PEG-modification of filgrastim results in a new molecule called pegfilgrastim, which in both experimental animals and healthy human volunteers has decreased renal clearance and increased plasma half-life compared with filgrastim, thus sustaining the duration of the pharmacological effect.3 Median plasma half-life values of pegfilgrastim are independent of dose, and range from 46 to 62 h. This has potential therapeutic benefit in eliminating the need for daily injections. The present study evaluates a single fixed dose of pegfilgrastim vs the standard daily filgrastim.4
Comment by Stuart M. Lichtman, MD, FACP
Pegfilgrastim has been previously evaluated in a number of clinical trials.5,6 The trials demonstrated that pegfilgrastim is equivalent to filgrastrim in both efficacy and toxicity. In this study, women with breast cancer receiving doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 every 3 weeks for 4 cycles were evaluated.5 This regimen is associated with an average duration of grade IV neutropenia of 4 days, in the absence of growth factors. Patients were randomized to receive a single subcutaneous dose of pegfilgrastim 6 mg 24 h after chemotherapy administration and repeated with each cycle vs daily filgrastim injections at 5 mg/kg per day. This same design was also used in another phase III trial published by Holmes and colleagues.6 The major difference in the design of the 2 trials was that the Holmes study used a per weight dosing of pegfilgrastim at 100 mg/kg, while the current trial used the fixed dose of 6 mg. This dose was computed from the phase II data in which comparisons with filgrastim showed similar rates of neutrophil recovery. The primary end point of the current trial, the mean duration of grade IV neutropenia, was 1.8 days for the pegfilgrastim group, and 1.6 days for the filgrastim group in the first cycle.7 These differences were not significant by the criteria of the trial. The duration of grade IV neutropenia in later cycles of treatment was again comparable between the pegfilgrastim group and filgrastim group. Importantly, no difference was seen in the duration of grade IV neutropenia across the weight quartiles comparing the fixed dose of pegfilgrastim to the per weight dosed filgrastim patients. In addition, adverse events between the 2 groups were similar with bone pain as the predominant adverse event. Examination by weight quartile showed no variation by weight in the reporting of bone pain. There was a decrease in febrile neutropenia in the pegfilgrastim group but this did not reach statistical significance.
The current study confirms the findings of the Holmes trial and extends the equivalence of pegfilgrastim from a per weight dosing to a fixed-dose schedule.6 In the United States, the indication for pegfilgrastim is "to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia."
Clinical trials are needed to further define the role of pegfilgrastim.7 This can be with other chemotherapy regimens and in other settings, such as dose-dense regimens of every 2 weeks or even weekly chemotherapy particularly in breast cancer and lymphoma. Other areas of potential study are the alteration in schedule (ie, administering pegfilgrastim on the day of chemotherapy, post-transplant, acute leukemia, and neutropenia not associated with malignancy).
The conclusions were that a single fixed-dose of pegfilgrastim administered once per cycle of chemotherapy was comparable to multiple daily injections of filgrastim in safely providing neutrophil support during myelosuppressive chemotherapy. Pegfilgrastim may have use in other clinical settings of neutropenia.
Dr. Lichtman is Associate Professor of Medicine at NYU School of Medicine, Division of Oncology; Don Monti Division of Medical Oncology, North Shore University Hospital, Manhasset, NY.
References
1. Crawford J, et al. N Engl J Med. 1991;325:164-170.
2. Bodey GP, et al. Ann Intern Med. 1966;64:328-340.
3. Delgado C, et al. Crit Rev Ther Drug Carrier Syst. 1992;9:249-304.
4. Green MD, et al. Ann Oncol. 2003;14:29-35.
5. Johnston E, et al. J Clin Oncol. 2000;18:2522-2528.
6. Holmes FA, et al. J Clin Oncol. 2002;20:727-731.
7. Crawford J. Ann Oncol. 2003;14:6-7.
A single fixed dose of pegfilgrastim administered once per cycle of chemotherapy was comparable to multiple daily injections of filgrastim in safely providing neutrophil support during myelosuppressive chemotherapy. Pegfilgrastim may have use in other clinical settings of neutropenia.
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