Improving the Management of Chemotherapy-Induced Neutropenia: Progress in Developing Once-per-Cycle Cytokine Support
Presenter: Jeffrey Crawford, MD
Chemotherapy induced neutropenia is one of the primary dose limiting toxicities of cancer treatment, putting patients at risk of infection and frequently leading to treatment interruptions and sub-optimal chemotherapy or radiotherapy dosing. Daily filgrastim is a widely used agent to reduce the clinical impact of neutropenia during myelosupressive chemotherapy. Pegfilgrastim is an investigational agent made by covalently bonding a polyethylene glycol moiety to the N-terminus of filgrastim. This gives it a much longer serum half-life due to greatly reduced renal clearance, making once per cycle administration a possibility. The median half-life of pegfilgrastim is 46-62 hours compared to 3-4 hours for filgrastim. The primary mode of clearance is granulocyte mediated.
A single subcutaneous dose of pegfilgrastim provides a dose dependent increase in the absolute neutrophil count (ANC). The duration of the response is dose dependent. This neutrophil response is also seen in patients with lung cancer undergoing carboplatin and paclitaxel chemotherapy. Following carboplatin/paclitaxel chemotherapy, a single dose of pegfilgrastim provided similar effects on ANC as daily filgrastim 5 ug/kg/day. A prolonged plateau in serum pegfilgrastim level was seen in patients after chemotherapy and during neutropenia. Once neutrophil levels recovered, pegfilgrastim levels decreased, consistent with its neutrophil dependent clearance. This "self-regulating" property of pegfilgrastim allows it to maintain ANC levels for extended periods of time relative to conventional filgrastim. A phase 2 study of breast cancer patients undergoing doxorubicin and docetaxel chemotherapy showed that pegfilgrastim 100 ug/kg/cycle was equivalent to filgrastim 5 ug/day in minimizing longer durations (3-5 days) of severe neutropenia.
A phase 3 study of pegfilgrastim (100ug/kg) versus filgrastim 5 ug/kg/day in breast cancer patients treated with doxorubicin and docetaxel showed similar duration of severe neutropenia. The overall incidence of febrile neutropenia was significantly less in the pegfilgrastim arm (9% vs 18%). In a similar trial with the same chemotherapy regimen, fixed dose pegfilgrastim 6mg/cycle was compared with daily filgrastim 5ug/kg. Results again showed similar duration of severe neutropenia and a decrease in febrile neutropenia with pegfilgrastim. Pegfilgrastim has also been evaluated in Hodgkin's and non-Hodgkin's lymphomas treated with various chemotherapy regimens. Again, pegfilgrastim has a similar effect as filgrastim on avoidance of severe neutropenia.
In summary, once-per-cylce pegfilgrastim is a well-tolerated agent for avoiding severe neutropenia during cancer chemotherapy. Its efficacy is similar to that of daily filgrastim and avoids the necessity of daily injections, promising fewer problems with patient compliance. Some preliminary data suggest that pegfilgrastim may actually be superior in reducing the incidence of febrile neutropnenia. It may have the potential to both improve patient outcomes and simplify treatment for patients and providers.