SAN FRANCISCOAdministering a single dose of pegylated
filgrastim (pegfilgrastim) each chemotherapy cycle is as effective as daily
doses of filgrastim (Neupogen) in reducing neutropenia among breast cancer
patients receiving myelosuppressive chemotherapy, according to two studies
presented at the 37th Annual Meeting of the American Society of Clinical
Both trialsone with pegfilgrastim doses calculated by
weight, the other with fixed doses of pegfilgrastimproduced comparable
outcomes in patients given the new longer-acting medication and in a control
group treated with filgrastim (G-CSF), which is given daily for up to 2 weeks
after each chemotherapy cycle.
Although febrile neutropenia occurred in about one in five
patients treated with filgrastim in both studies, investigators Frankie Ann
Holmes, MD, of US Oncology, Houston, and Michael Green, MD, of Royal Melbourne
Hospital, Australia, each reported that it appeared to be somewhat less of a
problem in patients who received pegfilgrastim.
"It’s like the new improved Tidea better version of
G-CSF," Dr. Holmes told ONI. She predicted that the new drug would be much
easier on patients and physicians. "Patients will need only one shot to
prevent neutropenia," she said. "In this study, we gave an average of
11 shots to patients on the filgrastim arm."
Amgen, Inc., of Thousand Oaks, California, has submitted a
biologics license application for pegfilgrastim to the US Food and Drug
Administration (FDA), according to William R.L. Parker, director of product
development. "Our intention is to recommend the fixed dose, but obviously
that’s up to the FDA," he said.
Dr. Holmes reported that 62 centers enrolled 310 patients for
the calculated-dose trial: 156 randomized to filgrastim and 154 to
pegfilgrastim. Most were below Medicare age and had not received prior
chemotherapy or radiation. All had high-risk stage II/III breast cancer or
stage IV breast cancer. They were scheduled to receive four cycles of
doxorubicin (60 mg/m2) and docetaxel (Taxotere) (75 mg/m2). The regimen produces a response in 90% of patients, Dr. Holmes noted,
but has approximately a 40% incidence of febrile neutropenia.
Patients in the pegfilgrastim arm received 100 µg/kg per
21-day chemotherapy cycle and a daily placebo to maintain the blind in the
trial. The control group was given 5 µg/kg of filgrastim daily for up to 14
days. Cytokine therapy was started 24 hours after chemotherapy. In both groups,
92% of patients completed four cycles of treatment, with more than 90% of
patients receiving their planned dose on time, Dr. Holmes said.
Average duration of severe neutropeniadefined as absolute
neutrophil count (ANC) less than 0.5 × 109/Lduring the first cycle of
chemotherapy was virtually identical for pegfilgrastim and filgrastim: 1.7 days
and 1.6 days, respectively. The incidence of severe neutropenia during cycle 1
was 76% for both groups, but the overall incidence of febrile neutropenia for
the pegfilgrastim group was half that of the filgrastim arm: 9% vs 18%,
Dr. Holmes speculated that the long action of pegfilgrastim
provided constant stimulation that made neutropenia less likely and less severe
in later cycles. "This chemotherapy regimen produces early and deep
neutropenia, but once patients recover, they do not have a second nadir,"
Both agents were well tolerated. About one third of patients in
both groups had bone pain, which Dr. Holmes categorized as mild.
‘You Can’t Overdose a Patient’
Overshooting with too big a dose is unlikely with the new
medication, Dr. Holmes said, because pegfilgrastim is self-regulating. The
kidneys wash out filgrastim. In pegfilgrastim, however, a polyethylene glycol
(PEG) unit has been bound to filgrastim, creating a larger molecule that is too
big for the kidneys to handle.
Instead, the newly formed white blood cells consume the
pegfilgrastim, "somewhat like Pac Man," Dr. Holmes quipped, so that
by the time the normal white blood cell count has been reached, all of the
pegfilgrastim has been consumed. "So you can’t overdose the patient. It’s
almost like a thermostat," she said.
Dr. Green used the same protocol, except for delivering a fixed
6-mg dose of pegfilgrastim per 21-day chemotherapy cycle. Conducted in Europe,
Australia, and the United States, this trial enrolled 157 patients with stage
II-IV breast cancer receiving up to four cycles of the same chemotherapy
regimen as in Dr. Holmes’ study.
In cycle 1, the mean duration of grade 4 neutropenia was 1.6
days in the filgrastim group vs 1.8 days in the pegfilgrastim groupa
difference of about 4 hours. About 20% of patients in the filgrastim group and
13% in the pegfilgrastim group experienced febrile neutropenia in the study,
Dr. Green said.
The median time to absolute neutrophil recovery was 8 days for
both groups, he said, and the incidence of severe neutropenia was lower in
later cycles. Bone pain was the most frequent cytokine-related toxicity with no
difference between the two groups.
Pegfilgrastim, Dr. Green concluded, "has the potential to
simplify the management of chemotherapy-induced neutropenia for patients and
health care providers."