Hematopoietic cells — the cells involved in the production and development of blood cells —typically sustain damage during chemotherapy, both immediately, at the time of the first cycle of chemotherapy, as well as cumulatively, over the course of subsequent chemotherapeutic cycles. This damage affects not only mature cells but also the immature hematopoietic progenitor cells, those cells whose job it is to give rise to and replace the blood cells that die off naturally.
The most serious and immediate hematologic consequence of chemotherapy— febrile neutropenia (FN) — occurs in approximately 25% to 40% of treatment-naïve patients who receive common chemotherapy regimens (eg, CHOP). Neutropenia refers to a deficiency of neutrophils, characterized by neutrophil counts of fewer than 500 neutrophils per microliter or, in severe cases, by an absence of neutrophils. Febrile neutropenia is defined as neutropenia accompanied by an oral temperature of ≥38.3○C (101○F) (ie, at a single reading) or of ≥38.0○C (100.4○F) persisting over 1 hour (ie, at more than one temperature reading over the course of an hour). FN is also potentially life-threatening. According to a recent analysis of patients with FN secondary to chemotherapy (n = 5990) and matched controls (n = 5990) followed for an average of 17.6 months, the adjusted risk of mortality was at least 15% greater in the patients with FN compared with controls.
Chemotherapy patients are not only battling their cancer, but their vulnerability to infection is also highly increased due to their chemotherapy-induced neutropenia. So, when you consider not only the high incidence of FN but also its serious risks, a preventive approach toward this potentially deadly complication of chemotherapy clearly makes sense.
According to the National Comprehensive Cancer Network (NCCN) 2014 guidelines for myeloid growth factors, colony-stimulating factors (CSFs), such as tbo-filgrastim, filgrastim, and pegfilgrastim, may be used in the prophylactic treatment of FN. Importantly, the stimulatory effects of CSFs are greatest on immature progenitor cells. The NCCN guidelines state that CSF prophylaxis reduces the incidence, duration, and severity of chemotherapy-related neutropenia in patients with small cell lung cancer, breast cancer, sarcoma, solid tumors, non-small cell lung cancer, and non-Hodgkin’s lymphoma. Meta-analyses have confirmed this. A meta-analysis by Clark et al demonstrated that the use of CSFs resulted in statistically significant reductions in infection-related mortality, in length of hospital stay, and in time to neutrophil recovery. In 2007 Kuderer et al wrote a systematic review of randomized clinical trials on the use of CSFs as primary prophylaxis in 3493 adult patients, reporting a statistically significant reduction in the risk of infection-related mortality and early death in patients receiving chemotherapy. A subsequent systematic review confirmed this survival advantage.
As with any drug, the use of CSFs carries some risk. The most consistently observed toxicity to date is mild to moderate bone pain, which occurs in 10% to 20% of patients who are treated with these agents. While the NCCN guidelines emphasize that ultimately all prescribing decisions should be individualized, they propose a risk stratification system to discriminate between patients who are at greater risk for FN and those at lesser risk— or, in other words, to determine which patients are the best candidates for the drug. This process considers the intensity of the chemotherapy regimen as well as patient factors such as age, previous chemotherapy, performance status, and comorbidities. The NCCN guidelines consider those with a >20% risk of FN to be at high risk, requiring prophylactic CSF therapy. Those with a 10% to 20% probability of developing FN or another neutropenic event are considered to be at intermediate risk, while in those with <10% risk, routine prophylaxis with CSFs is not recommended because other therapies are sufficient and more cost effective.
Inevitably, the use of CSFs for the prevention of FN in chemotherapy patients does add to the overall cost of cancer treatment, but when compared with the costs of additional hospitalization and the subsequent treatment for neutropenia that would otherwise occur, prophylaxis with CSFs may actually equate to cost savings. In fact, during the period from 1993 to 2004 alone, the costs of inpatient hospitalization escalated to such an extent that the average risk threshold estimates for cost savings seen with the use of prophylactic CSFs dropped from 40% to approximately 20%.1
Figure 1. For varying levels of risk with and without CSF prophylaxis, expected total cost associated with either strategy escalates as the risk of FN increases. The threshold is the level of risk (percentage of risk of suffering FN) at which point the costs associated with either strategy intersect (ie, have the same cost). Above this risk level, FN prophylaxis with CSFs represents overall treatment cost savings.1
The NCCN guidelines consider tbo-filgrastim, filgrastim, and pegfilgrastim as category 1 recommendations for prophylaxis of FN. Pegfilgrastim was FDA approved as Neulasta® in 2002, and filgrastim first received FDA approval in 1991 under the brand name Neupogen®.
Tbo-filgrastim (GRANIX®) was FDA approved in 2012 via an original biologic license application (BLA) and is available in the European Union as a filgrastim biosimilar (the biosimilar approval process had not yet been finalized in the United States at the time of the GRANIX approval). Very recently, Zarxio®, a filgrastim biosimilar from Sandoz, a Novartis company, received FDA approval as the first biosimilar in the United States.
- Lyman GH, Kuderer NM. The economics of the colony-stimulating factors in the prevention and treatment of febrile neutropenia. Crit Rev Oncol Hematol. 2004;50:129-146.
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