Pegfilgrastim prophylaxis is associated with a lower risk of hospitalization of cancer patients than filgrastim prophylaxis: a retrospective United States claims analysis of granulocyte colony-stimulating factors (G-CSF)

Patients receiving myelosuppressive chemotherapy are at risk of developing febrile neutropenia, a major dose-limiting toxicity of systemic chemotherapy associated with hospitalization, use of intravenous antibiotics, and significant morbidity, mortality, and costs [1‐10]. Recombinant human granulocyte colony-stimulating factor (G-CSF; filgrastim and pegfilgrastim) is indicated to reduce the incidence of infection in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy [2, 4, 5]. Guidelines recommend the prophylactic use of G-CSF in patients receiving chemotherapy regimens that have a 20% or greater risk of febrile neutropenia [11, 12]. In addition, patients receiving chemotherapy regimens associated with a febrile neutropenia risk below 20% may have a total combined risk above 20% if they have additional risk factors, such as comorbid conditions or advanced age. Thus, these patients may benefit from prophylactic G-CSF use as well [11‐13].

Filgrastim is recommended to be administered at a recommended starting dose of 5 mcg/kg per day until neutrophil recovery occurs after the expected chemotherapy-induced nadir. Its short circulating half-life (~3.5 hours) necessitates that it be given daily. The efficacy of filgrastim depends on the number of days it is administered. Randomized comparative clinical trials have shown that patients treated with a mean of 10–11 filgrastim doses per chemotherapy cycle reported a similar decrease in the duration of severe neutropenia as patients treated with pegfilgrastim once per chemotherapy cycle [14‐18]. In clinical practice, filgrastim is often administered for fewer than 10–11 days and may be associated with reduced efficacy [19]. A chart review study found that the risk of hospitalization was approximately one-third higher with filgrastim use compared to pegfilgrastim use [20]. An additional retrospective observational study of United States claims databases showed that prophylactic use of pegfilgrastim was associated with a one-third to two-thirds reduction in the risk of hospitalization for febrile neutropenia relative to the risk in patients who received filgrastim prophylaxis [21]. Two more recent studies on comparative effectiveness of G-CSF prophylaxis reported similar findings based on United States claims data [22, 23].

Neutropenic complications following chemotherapy contribute significantly to the costs of cancer care. During 1989–2007, the number of neutropenia-related hospitalizations among cancer patients in the United States was estimated to be approximately 57,000–103,000 per year [10]. In a study using 1995–2000 data, the average cost per hospitalization due to febrile neutropenia was reported to be $12,372 for breast cancer patients, $18,437 for lymphoma patients, and $38,583 for leukemia patients [3]. Another study using 2005–2008 data found that mean hospitalization costs were $18,042 for cancer patients with neutropenia, $22,839 for those with neutropenia plus infection or fever, and $27,587 for those with neutropenia plus infection [9]. Clearly, neutropenic complications in patients receiving chemotherapy pose a significant medical and financial burden.

The primary objective of the current study was to determine whether a difference in the risk of neutropenia-related and all-cause hospitalization between chemotherapy cycles associated with filgrastim prophylaxis and cycles with pegfilgrastim prophylaxis. This study from a United States claims database included data from January 2004 through February 2009 regarding filgrastim and pegfilgrastim administration patterns and related clinical outcomes. Additionally, economic data in the form of comparative healthcare utilization and costs results are described.

In this retrospective United States claims analysis, use of prophylactic pegfilgrastim was associated with a decreased risk of neutropenia-related hospitalization (narrow definition: OR = 0.43, 95% CI: 0.16–1.13; broad definition: OR = 0.38, 95% CI: 0.24–0.59) and all-cause hospitalization (OR = 0.50, 95% CI: 0.35–0.72) when compared to that seen with the use of prophylactic filgrastim. Patients who received filgrastim prophylaxis in this study had a mean 4.8 days of prophylaxis, which is much shorter than the duration which has been demonstrated to be non-inferior to pegfilgrastim prophylaxis in clinical trials [14‐18]. These results are consistent with previous findings that hospitalization risk was more significantly reduced by pegfilgrastim prophylaxis than by filgrastim prophylaxis in clinical practice [20‐23]. Key findings regarding utilization included an increase in neutropenia-related ambulatory visits and hospitalizations with filgrastim prophylaxis compared to pegfilgrastim prophylaxis. In addition, mean per-cycle neutropenia-related costs were greater with filgrastim prophylaxis than with pegfilgrastim prophylaxis.

In a previous study that used a large managed care claims database in the United States, Weycker et al. performed a retrospective cohort analysis of cancer patients who received filgrastim or pegfilgrastim during their first course of chemotherapy (2003–2005) [21]. Both all-cause (OR = 0.73, 95% CI: 0.59–0.91) and neutropenia-related (narrow definition: OR = 0.64, 95% CI: 0.41–0.99; broad definition: OR = 0.69, 95% CI: 0.52–0.92) hospitalization risk was lower with pegfilgrastim prophylaxis compared to filgrastim prophylaxis. Two subsequent claims studies reported similar results [22, 23]. The consistent finding that filgrastim prophylaxis is associated with higher hospital risks than pegfilgrastim prophylaxis may be related to the less than optimal use of filgrastim in clinical practice. Specifically, while in the comparative clinical trials, filgrastim was given for an average of 10–11 days [14‐18]; in the clinic, filgrastim is often given for far fewer days, resulting in suboptimal prevention of neutropenia and thus greater rates of hospitalization for neutropenic complications [19‐23].

One distinct aspect of this study is that comparative filgrastim and pegfilgrastim costs and resource utilization data were reported, including details such as the number of hospitalizations, ambulatory and ER visits, and per-cycle costs. Comparative studies assessing cost and resource utilization of filgrastim and pegfilgrastim in the United States are limited. A retrospective single-time-point survey conducted by Fortner et al. assessed the human resource costs required for administering filgrastim or pegfilgrastim [28]. They concluded that a single administration with filgrastim or pegfilgrastim had equivalent human resource costs, but because of the greater number of visits required with filgrastim, the total time and human resource cost with filgrastim (14.8 hours and $364.66) in a 21-day chemotherapy cycle were more than those with pegfilgrastim (2.4 hours and $57.30).

In this study utilizing a large claims database, all-cause costs were roughly equivalent for filgrastim and pegfilgrastim on a per-cycle basis, with more spent on hospitalizations with filgrastim and more spent on ambulatory care with pegfilgrastim. It is interesting to note that although pegfilgrastim cycles had greater costs for ambulatory care, there were proportionally more ambulatory visits for filgrastim cycles. The increased all-cause per-cycle cost of pegfilgrastim ambulatory care may reflect the greater drug costs of pegfilgrastim compared to filgrastim, especially when fewer than the recommended number of filgrastim doses were administered. Neutropenia-related costs were greater for filgrastim than pegfilgrastim because of the greater costs of both inpatient and ambulatory care during filgrastim cycles. Overall, these data suggest that the greater drug costs with pegfilgrastim are offset by decreased hospitalization costs.

There are several sources of bias and limitations inherent in the study design that could influence interpretation of these results. As this was a database of a large employment-sponsored managed care population, patients would most likely be in the 18–64 year age range. Thus, the effects of G-CSF on outcomes in the population of patients aged 65 years or above were not fully captured. Additionally, the data are dependent on the accuracy of claims coding and hence contain any errors or omissions that occurred during that coding. By using the broad criteria for neutropenia, as well as all-cause utilization, we were able to more accurately provide upper limits for our estimates. It should be noted that this study compared risk between treatment cohorts. The potential under-coding and mistakes in coding of febrile neutropenia are unlikely to be associated with G-CSF selection and thus do not affect the estimates of interest (ie, ORs). Sample size is another issue that affects the statistical power of our estimates, as there were fewer than 400 cycles with prophylactic filgrastim use. Another source of bias is the assumption that G-CSF administration by day 5 of a cycle represents prophylaxis rather than treatment. Although this definition has been used in other studies [19, 21], its validity has not yet been confirmed in the literature. Thus, it is uncertain whether earlier or later onset of administration may represent prophylaxis or treatment in a clinical setting. Likewise, our categorization of certain cycles as containing highly myelosuppressive chemotherapy based on the presence of individual agents used in that cycle may not adequately capture the various factors that affect the myelosuppressive effects of a chemotherapy regimen, such as combination chemotherapy and doses of specific agents. Furthermore, potential differences across health plans covered in the study sample were not adjusted for comparison of costs between filgrastim and pegfilgrastim cycles.

It is unclear whether this study adequately captured the various known patient, disease, and treatment characteristics that are risk factors for developing febrile neutropenia [6, 12]. The claims database contained several of these, such as age, sex, comorbidities, recent history of anemia, history of radiation, tumor type, and number of myelosuppressive agents. To reduce the effect of possible selection bias, data were adjusted for those covariates in the GEE model. However, the claims database did not include other potential predictors of febrile neutropenia, such as treatment intent, disease stage, chemotherapy dose, previous febrile neutropenia events, laboratory values, and concomitant medications. Some of these factors could influence selection of G-CSF as either filgrastim or pegfilgrastim. Thus the study results may still be confounded by possible differences in those unobserved characteristics between filgrastim and pegfilgrastim groups.

The use of per-cycle analyses for utilization and costs has the disadvantage of not capturing costs associated with cycles in which G-CSF was not administered. However, per-patient analyses would not allow us to temporally associate use of either G-CSF with utilization. For instance, in a per-patient analysis, a patient hospitalized in cycle 1 who subsequently received G-CSF in cycle 2 would have those two events associated, when clearly the hospitalization was independent of any effects from G-CSF. Another disadvantage of per-patient analyses is that while on average, each patient who received filgrastim received it for a mean of 2.3 cycles, while each patient who received pegfilgrastim received it for a mean of 3.5 cycles. The accompanying drug costs would make it difficult to discern any possible effect of either medication on all-cause medical costs.

In conclusion, the results of this claims analysis indicate that prophylactic use of filgrastim as compared with pegfilgrastim is associated with an increased risk of hospitalization from all causes as well as neutropenia-related causes. Results from this analysis and others indicate that other factors influence the risk of hospitalization, including comorbidities, history of anemia, age, and presence of metastatic disease [2, 6, 11, 12, 29]. Future studies that explore the role of these characteristics will help further clarify the various factors that lead to febrile neutropenia and associated complications.

This retrospective comparative effectiveness study used claims data to examine prophylactic use of filgrastim and pegfilgrastim in cancer patients receiving chemotherapy. The key finding of the study is that pegfilgrastim prophylaxis was associated with a reduced risk of hospitalization due to neutropenia or all-cause.