Neutropenia Control: Optimising Therapeutic Gains
Neutropenia is often the dose limiting toxicity in chemotherapy treatment. A great advance came with filgrastin, decreasing the incidence of febrile neutropenia and hospitalizations in patients given the injections following chemotherapy. The use of filgrastin, however, requires daily injections which can be inconvenient or even impossible for many patients. Therefore, there was great interest in the development of a longer lasting G-CSF that was at least equally efficacious. Pegfilgrastin is a larger molecule that has less renal clearance with a subsequent longer half life and more stable serum concentrations.
Early studies were performed comparing filgrastin to pegfilgrastin in both lung cancer and breast cancer. The conclusion of both studies were that one dose of pegfilgrastin 100 mcg/kg was equally efficacious to daily doses of filgrastin 5 mcg/kg (up to 14 doses). The incidence of neutropenia and length of neutropenia were very similar in both groups in both studies. In addition, serum analyses revealed that pegfilgrastin had more stable serum levels and that filgrastin had much more variation, even within a single day. Both had the expected clearance of the drug with the increase of the white blood cell count.
This led to the initiation of two phase III studies comparing pegfilgrastin to filgrastin. Both studies were done in patients with stage II to IV breast cancer who were receiving doxorubicin 60 mg/m2 and docetaxel 75 mg/m2. The two studies were virtually identical in design with the exception of how the once per cycle dose of pegfilgrastin was dosed. In the study run in the United States (Holmes, JCO, 2002), pegfilgrastin was dosed individually, according to the weight of the patient, giving 100 mcg/kg. In the Australian study (Green, Ann Oncol , 2003), the dose of pegfilgrastin was 6 mg as a fixed dose. The pegfilgrastin arm was compared to an arm dosed with filgrastin 5 mcg/kg/day for 14 doses. In the pegfilgrastin arm, placebo injections were given in order to keep the study blinded. The primary endpoint was the duration of severe neutropenia, defined of the absolute neutrophil count (ANC) of less than 500/liter. In the Holmes study (n=260 patients), the mean duration of severe neutropenia was 1.8 days in the filgrastin arm compared to 1.7 days in the pegfilgrastin arm. In the Green study (n=157 patients), the mean duration of severe neutropenia was 1.6 days in the filgrastin arm vs. 1.8 days in the pegfilgrastin arm. Perhaps more clinically significant, the incidence of febrile neutropenia was lower in the pegfilgrastin arms in both studies (9% vs. 18% in the Holmes study and 13% vs 20% in the Green study). There were also trends toward decreased hospitalization time and decreased use of anti-infection agents in the pegfilgrastin groups. Although no numerical toxicity data was given during the presentation, the side effect profiles were similar between the two groups with the expected mild to moderate bone pain predominating.
This study reports on at least equal efficacy of pegfilgrastin when compared to filgrastin in patients receiving neutropenia-causing chemotherapy, as the incidence of severe neutropenia is equal in patients receiving filgrastin or pegfilgrastin. What is not mentioned is cost of the therapy, which is likely to be more expensive with pegfilgrastin. Whether this is outweighed by the clinical parameters of pegfilgrastin should be decided individually by the clinician. What is more clinically significant, however, is the amount of febrile neutropenia observed in the two studies. Pegfilgrastin reduced the incidence of febrile neutropenia in both studies. The qualities attributable to pegfilgrastin that cause this are unknown, though it was hypothesized that perhaps the more stable serum concentrations of pegfilgrastin may play a role. Regardless, if less febrile neutropenia is noted with pegfilgrastin, this may balance the increased cost. What cannot be measured is the convenience of pegfilgrastin to the patients being treated. More convenient dosing with pegfilgrastin may supercede anything else in these patients undergoing aggressive therapy.