Use and effectiveness of pegfilgrastim prophylaxis in US clinical practice:a retrospective observational study

Low neutrophil count (“neutropenia”) is a frequent side effect of myelotoxic chemotherapy and increases infection risk. Neutropenia in the presence of fever (“febrile neutropenia” [FN]) typically necessitates inpatient care and may result in delays, reductions, and/or discontinuation of chemotherapy that can—in turn—lead to adverse outcomes [1‐11]. For patients whose projected FN risk is high (> 20%) based on the planned chemotherapy regimen and individual risk factors (e.g., age > 65 years, comorbidity profile), prophylaxis with granulocyte colony-stimulating factor (G-CSF) is recommended [1, 9, 12‐14]. However, published evidence indicates that many patients who are candidates for G-CSF are not administered it, or are not administered it per recommendations, and thus may be at elevated risk of FN and hospitalization [12‐27].

Pegfilgrastim, which requires only a single dose per cycle of chemotherapy, is the most commonly used CSF agent in the US, with previous evaluations reporting that it accounted for > 90% of all CSF prophylaxis use in their study populations [12, 15, 20, 24, 28, 29]. Moreover, pegfilgrastim has been reported—in post-hoc analyses of clinical trials, meta-analyses of clinical trials, and real-world evaluations—to be more efficacious and effective than other CSFs in preventing FN [12, 15, 20, 28‐33]. Notwithstanding the availability of pegfilgrastim since 2002 and clinical practice guidelines supporting its use, relatively little is known about patterns of pegfilgrastim use across multiple cycles of chemotherapy during the course, the influence of FN on subsequent pegfilgrastim use, and the impact of pegfilgrastim on the incidence of FN [34]. We therefore undertook two retrospective observational cohort studies, the first using data from two large healthcare claims repositories and the second using data from Medicare Claims Research Identifiable Files (RIFs), to examine these issues among patients with non-metastatic breast cancer or non-Hodgkin’s lymphoma (NHL) receiving chemotherapy regimens with an intermediate to high risk for FN in US clinical practice.

The methods of this study—including the design, identification of source/study populations, and variable definitions—are largely the same as those employed in prior evaluations conducted by some of the investigators involved in the present research [16, 17, 23, 35]. An additional file provides a detailed description of study methods and source databases (Additional file 1); a brief description follows.

In this retrospective observational cohort study of patients with non-metastatic breast cancer or NHL who received chemotherapy with an intermediate to high risk for FN, we examined patterns of pegfilgrastim prophylaxis across cycles of chemotherapy, the influence of FN in one chemotherapy cycle on prophylaxis in subsequent cycles, and the incidence of FN among patients who did and did not receive prophylaxis. The findings from this examination—which were based on data from 50,778 commercial patients who received 190,622 cycles of chemotherapy and 71,037 Medicare patients who received 271,944 cycles— suggest that not only does a large minority of patients for whom prophylaxis is recommended fail to receive it (beginning in the first cycle), but that those patients have significantly higher odds of FN than patients who receive pegfilgrastim prophylaxis.

We found that approximately one in every three patients in this study did not receive pegfilgrastim prophylaxis in cycle 1—when FN risk is highest—and comparable proportions did not receive prophylaxis in subsequent cycles, thus exposing patients to a potentially fatal yet preventable complication of myelosuppressive chemotherapy [38]. We also found that while a history of FN does appear to increase the odds of receiving prophylactic coverage, more than one in seven commercial patients and one in four Medicare patients did not receive prophylaxis in a given cycle despite having FN in a prior cycle. Finally, we found that the adjusted incidence of FN in a given cycle was significantly higher among patients in our study population who did not receive prophylaxis in that cycle, highlighting the effectiveness of pegfilgrastim. We note that our findings are based on two large samples of patients with non-metastatic breast cancer and NHL who received chemotherapy regimens that are among the most commonly used in current clinical practice, and are largely consistent with the limited evidence that is currently available [39‐47].

Two systematic reviews of randomized, controlled clinical trials comparing G-CSF prophylaxis with no prophylaxis showed significantly reduced risk of FN with pegfilgrastim [39, 43]. Similar results have been observed in real-world data. In Hershman et al., which included 3123 randomly selected patients with solid tumors and lymphomas treated at 99 community practices in 2003, FN risk during the chemotherapy course was reported to be two-times higher among patients who did not receive primary prophylaxis (i.e., in cycle 1) versus those who did (adjusted OR = 2.0 [95% CI 1.4–2.9]) [46]. In a study of 239 women receiving adjuvant chemotherapy for early-stage breast cancer at a single clinic from 2009 to 2011, the FN odds ratio for patients not receiving G-CSF primary prophylaxis (versus those receiving prophylaxis) was 2.6 (p = 0.002) [44]. The results of two other smaller studies were similar [41, 45]. Accordingly, the results of these studies provide robust clinical and real-world evidence regarding the effectiveness of pegfilgrastim prophylaxis in the prevention of chemotherapy-induced FN among cancer patients of all ages.

Our results also are noteworthy given that clinical practice guidelines recommend administration of G-CSF in the first cycle when the risk of FN is > 20%, and in subsequent cycles after FN or a dose-limiting neutropenic event where no prior G-CSF has been used. Unfortunately, the reasons why prophylaxis was not administered to so many patients in this study are unknown. While it is possible that other steps were taken to reduce the risk of FN, such as chemotherapy dose reductions (which are unobservable in the study database), it is also possible that patients were reluctant to return to the clinic to receive a pegfilgrastim injection on the day after chemotherapy [48, 49]. Regardless of the reasons or the steps other than prophylaxis that were taken to prevent FN, our results demonstrate that patients with a history of FN were substantially more likely to experience a subsequent FN episode during their chemotherapy course, consistent with previous studies [38, 50].

There are several notable limitations to our study. A diagnosis code for FN does not exist, and thus FN was ascertained using operational algorithms and codes for neutropenia, fever, and infection that appeared during the pre-defined exposure period. We note that the recording of these diagnosis codes—especially those appearing earlier in the cycle (e.g., day 14 or earlier)—during the chemotherapy course increases the probability that the condition (i.e., neutropenia, infection, and/or fever) is associated with chemotherapy. In addition, ascertainment of FN in hospital was based on diagnosis codes alone as data on inpatient drug utilization are not available in the study databases. Because results from lab and other tests are unavailable in the study databases, and because other information (e.g., chemotherapy dose) is unavailable, not all FN risk factors were considered in analyses described herein. Because the validity of algorithms for identifying primary tumor type, metastatic disease, and comorbidity profiles has not been formally evaluated, their accuracy is unknown. Thus, to the extent that there may be unobserved systematic differences between patients who did (vs. did not) receive pegfilgrastim prophylaxis, study results may be confounded.

While approximately 20% of the commercial population and 40% of the Medicare population received an intermediate-risk chemotherapy regimen, it is likely that most of those patients would be classified as high-risk when considering patient risk factors (e.g., age > 65 years, comorbidities) and thus recommended to receive G-CSF prophylaxis [51]. It is possible, however, that a small percentage of patients in the study population may have had a projected risk of FN < 20%. While over 95% of CSF prophylaxis patients received pegfilgrastim, a small percentage received one of the daily agents (principally filgrastim) and thus overall CSF use is somewhat higher than reported estimates. While the study period overlapped for a few months with the availability of the Neulasta® Onpro® kit—an on-body injector that is applied 1 day and delivers pegfilgrastim approximately 27 h later—these patients were excluded from analyses if their pegfilgrastim administration was identified as having occurred on the same day as chemotherapy. Based on the timing of the data relative to Onpro® availability, the net impact of such exclusions was likely small. Because our study population was limited to patients with non-metastatic breast cancer or NHL who received selected intermediate/high-risk chemotherapy regimens, study results may not be generalizable to other cancers or other regimens.

In this retrospective evaluation of non-metastatic breast cancer and NHL patients receiving select chemotherapy regimens with an intermediate/high-risk for FN, a sizeable portion of patients did not receive G-CSF prophylaxis, and an important minority did not receive G-CSF prophylaxis in cycles following FN. Patients not receiving G-CSF prophylaxis had a markedly higher incidence of FN versus those who received G-CSF prophylaxis. Accordingly, appropriate use of G-CSF prophylaxis may reduce exposure to a potentially fatal but largely preventable complication of myelosuppressive chemotherapy.