Effects of a Reduced Dose of Pegfilgrastim on the Incidence of Febrile Neutropenia and Bone Pain: A Retrospective Analysis

JHOP - September 2012 VOL 2, NO 3
Lew Iacovelli, BS, PharmD, BCOP, CPP
Pharmacy Manager, Clinical Oncology Specialist and PGY2 Oncology Residency Program Director, Conehealth Cancer Center,
Greensboro, NC
Richard Harms, PharmD, RPh
Director of Medical Communications, Oncology Intl TA Head,
Thousand Oaks, CA
May Mo, MS
Biostatistics Senior Manager, Amgen, Inc,
Thousand Oaks, CA
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Background: Pegfilgrastim 6 mg given 24 hours after chemotherapy reduces the incidence of febrile neutropenia (FN) in patients with nonmyeloid malignancies. Some clinicians have advocated reduced doses of pegfilgrastim to decrease the risk of pegfilgrastim-associated bone pain.
Objective: To investigate the effects of pegfilgrastim doses equivalent to 3 mg or 6 mg on the incidence of FN and bone pain.

Methods: This retrospective analysis included first-cycle data from 5 published clinical studies of pegfilgrastim administered at various weight-based doses. A total of 557 patients were evaluated, 22 of whom received a dose equivalent to a fixed dose of approximately 3 mg (“half dose”) and 66 of whom received a dose equivalent to a fixed dose of approximately 6 mg (“full dose”). The primary end point was the incidence of FN; the secondary end point was the incidence of bone pain adverse events (any grade and grade 3/4).

Results: In this retrospective analysis of data from 5 clinical trials, the incidence of cycle 1 FN was 18.2% (95% confidence interval [CI], 5.2%-40.3%) in the half-dose group (N = 22) and 10.6% (95% CI, 4.4%-20.6%) in the full-dose group (N = 66). The incidence of bone pain of any grade was 45.5% (95% CI, 24.4%-67.8%) in the half-dose group versus 37.9% (95% CI, 26.2%-50.7%) in the full-dose group. The incidence of grade 3/4 bone pain was 7.6% (95% CI, 2.5%-16.8%) in the full-dose group; no patients in the half-dose group had grade 3/4 bone pain (95% CI, 0.0%-15.4%).

Conclusion: In this retrospective study, patients who received the approximately half dose (3 mg) of pegfilgrastim had higher rates of FN and overall bone pain than patients who received the full dose (6 mg) of pegfilgrastim. Although these results have limitations, including a small sample size, further research is warranted.

Pegfilgrastim is a granulocyte colony-stimulating factor (G-CSF) that is indicated to reduce the incidence of febrile neutropenia (FN) in patients with nonmyeloid malignancies who are receiving myelosuppressive chemotherapy that is associated with a clinically significant incidence of FN.1 In addition to reducing the incidence of FN, prophylactic pegfilgrastim has been shown to decrease FN-related hospitalizations and the use of anti-infectives and to facilitate administration of full-dose chemotherapy regimens2; pegfilgrastim is among the most frequently prescribed myeloid growth factors.3 Peg­filgrastim at a single fixed dose of 6 mg given 24 hours after chemotherapy is associated with predictable and consistent recovery of absolute neutrophil count (ANC), and its safety and efficacy are comparable with filgrastim 5 µg/kg administered daily until recovery of ANC.4,5

Bone pain is the most often reported adverse event (AE) associated with G-CSF therapy, and it is generally mild to moderate in severity. In a retrospective analysis of 23 pegfilgrastim clinical trials, bone pain was most often reported in the first cycle of chemotherapy.6 In cycle 1, the incidence of bone pain of any grade was 35.1%, and the incidence of grade 3/4 bone pain was 3.3%. In addition, the incidence and severity of bone pain were similar between patients treated with pegfilgrastim and those treated with filgrastim.6

In an attempt to reduce the severity of bone pain, some clinicians have suggested reducing the recommended 6-mg dose of pegfilgrastim.7 Two small retrospective studies reported reductions in bone pain after empiric dose reduction of pegfilgrastim from 6 mg to 3 mg or 4 mg.7,8 The first study, a retrospective chart review reported in 2007, evaluated 34 patients with breast cancer who were treated with doxorubicin-cyclophosphamide-taxane (n = 12), with a dose-dense doxorubicin-cyclophosphamide-taxane (n = 13), or with other unspecified regimens (n = 9).8 Among the 32 of 34 patients who had dose reductions of pegfilgrastim (from 6 mg to 3 mg), there was a significant reduction in patient-reported bone pain severity.8 Although postchemotherapy white blood cell (WBC) counts were significantly lower with 3-mg pegfilgrastim, grade 3/4 neutropenia was not reported with either dose. However, the criteria (eg, severity of bone AEs) on which the decision to reduce the dose of pegfilgrastim was based were not described8; consequently, it is unclear whether the results were confounded.

The second study, reported in 2008, evaluated 25 patients with breast cancer who experienced bone pain associated with normal or high leukocyte counts during recovery and subsequently had dose reductions to 4-mg pegfilgrastim.7 Patients were treated with adjuvant or with neoadjuvant chemotherapy (14 patients received doxorubicin/cyclophosphamide, followed by docetaxel) plus 6-mg pegfilgrastim. After the dose of pegfilgrastim was reduced, no bone pain was reported; however, the ANC data were insufficient to draw a conclusion regarding efficacy.7

The objective of this present retrospective analysis is to provide additional information regarding the effects of a reduced dose of pegfilgrastim on the incidence of FN (ie, efficacy) and bone pain (ie, safety). The analysis includes pooled clinical study data from patients with cancer who received chemotherapy and weight-based pegfilgrastim at doses equivalent to fixed doses of approximately 3 mg or 6 mg.

Method
Studies and Patients
A review of the protocols and clinical study reports of 34 Amgen-sponsored pegfilgrastim interventional studies identified 5 clinical trials (3 of which were dose-finding studies) that randomly assigned patients to receive pegfilgrastim or filgrastim.4,9-12 Once-daily subcutaneous injections of filgrastim 5 µg/kg were given beginning 24 hours after chemotherapy administration and continued for up to 14 days or until ANC ≥10 × 109/L after the expected nadir, whichever occurred first.4,9-12 A single subcutaneous injection of pegfilgrastim per cycle was given 24 hours after chemotherapy administration at doses of 30, 100, or 300 µg/kg10; 30, 60, or 100 µg/kg9; 60 or 100 µg/kg11; and 100 µg/kg.4,12 For this present analysis, weight-based doses of pegfilgrastim were converted to equivalent “fixed” doses for the categorization of patients into approximate half-dose (~3 mg) and full-dose (~6 mg) groups (Figure 1). Patients from the 5 clinical trials were included in this analysis only if they fell into either of these 2 groups.4,9-12

The 557 patients enrolled in the 5 clinical trials were chemotherapy-naive, received previous adjuvant therapy, and/or received chemotherapy for their disease (Table 1).4,9-12 These studies included patients with stage II, III, or IV breast cancer who received doxorubicin/ docetaxel (AT),4,9 patients with non–small-cell lung cancer (NSCLC) who received carboplatin/paclitaxel (CP),10 and patients with lymphoma who received either cyclophosphamide/doxorubicin/vincristine/ prednisone (CHOP) or etoposide/methylprednisolone/ cisplatin/cytarabine (ESHAP).11,12 Patients were eligible for inclusion if they had adequate ANC or WBC counts (ANC ≥1.5 × 109 cells/L,4,10,12 ANC ≥2 × 109 cells/L,11 or WBC count ≥4 × 109 cells/L9); an adequate platelet count (either ≥100 × 109/L4,10-12 or ≥150 × 109/L9); and adequate renal, hepatic, and cardiac function. In addition, patients were required to be capable of self-care (Karnofsky performance status ≥70%10 or Eastern Cooperative Oncology Group performance status ≤24,9,11,12).

Patients were excluded if they had received recent (within 2-4 weeks of randomization4,9,12) or extensive (>25% of red bone marrow11) radiotherapy. In each study, informed consent was obtained from patients before enrollment, and an institutional review board at each participating center approved all study procedures.

End Points
The primary end point for the present analysis was the incidence of FN, which was defined as a temperature of ≥38.2°C, with an ANC of <0.5 × 109/L. The secondary end point was the incidence of bone pain AEs (any grade and grade 3/4). AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA; version 11). AE preferred terms that were considered bone pain were predetermined and were used to identify bone pain–related AEs, such as “bone pain,” “back pain,” “neck pain,” “pain in hip,” “pain in shoulder,” “aching in limb,” and “pain in extremity” that occurred in the “musculoskeletal and connective tissue disorders” system organ class. Pain-related preferred terms in other system organ classes (eg, “rib pain” in “repiratory, thoracic, and mediastinal disorders” and “toothache” in “gastrointestinal disorders”) were also identified as bone pain.

Bone pain severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE; version 3.0)13 as in the original studies. If a patient had multiple bone pain AEs in cycle 1, the severity of the AE with the highest CTCAE grade was considered as the bone pain severity for the cycle. Because of differences in the number of treatment cycles across the 5 studies, and because bone pain incidence is highest in the first cycle, only events occurring during the first chemotherapy cycle were evaluated. Homogeneity of studies was evaluated by examining the end point definitions of the individual studies.

Statistical Analyses
Weight-based doses were converted to equivalent “fixed” doses using the following formula: dose (mg) = dose per kg (µg/kg) × baseline weight in kg per 1000.

A total of 557 patients were categorized into dose groups according to the pegfilgrastim dose they received. Patients were then further categorized into the approximate half- or full-dose groups as follows: half-dose patients (N = 22) received doses between 2.5 mg and <3.5 mg (~3-mg dose), and full-dose patients (N = 66) received doses between 5.5 mg and <6.5 mg (~6-mg dose).

Data analysis was performed using SAS Version 9.1 (SAS Institute; Cary, NC). Summaries of demographic data and baseline characteristics were generated by pegfilgrastim dose level (3 mg or 6 mg). Because of the limited sample size and low event rate, exact binomial confidence intervals (CIs) were calculated for the incidences of FN and bone pain in cycle 1 of chemotherapy.

Results and Discussion
A non–evidence-based practice has emerged in which there have been attempts by physicians to mitigate pegfilgrastim-associated bone pain in patients with cancer by administering a dose of pegfilgrastim lower than the recommended 6-mg dose. In this study we analyzed pooled patient-level data from 5 clinical trials to investigate whether reduced pegfilgrastim dosing affects the incidence of FN and bone pain. Of the 557 patients with cancer enrolled in the 5 clinical trials and included in the present analysis (Table 1), 22 received the approximate 3-mg dose (“half dose”) of pegfilgrastim, and 66 received the approximate 6-mg dose (“full dose”) of pegfilgrastim. Patient demographics and baseline characteristics are shown in Table 2.4,9-12

Most patients had either NSCLC or breast cancer (a smaller proportion had non-Hodgkin lymphoma), and the majority received either CP or AT regimens. The half-dose group included a greater proportion of male patients, a higher mean body weight, and a greater proportion of patients with NSCLC who received CP.4,9-12 In contrast, the full-dose group included all 9 of the patients with lymphoma and a greater proportion of female patients with breast cancer who received AT.

The incidence of FN, bone pain of any grade, and grade 3/4 bone pain for both dose groups during cycle 1 are shown in Figure 2. The 22 patients receiving the half dose of pegfilgrastim tended to have a higher incidence of FN during the first chemotherapy cycle (18.2%; 95% CI, 5.2%-40.3%) than the 66 patients receiving the recommended full dose of pegfilgrastim (10.6%; 95% CI, 4.4%-20.6%).4,9-12

The bone pain AEs (by MedDRA preferred term) were bone pain, arthralgia, pain in extremity, pain, back pain, noncardiac chest pain, and musculoskeletal pain. The incidence of bone pain of any grade during the first cycle of chemotherapy was 45.5% (95% CI, 24.4%-67.8%) among patients who received the half dose of pegfilgrastim and 37.9% (95% CI, 26.2%-50.7%) among patients who received the recommended full dose. No patients in the half-dose group (95% CI, 0%-15.4%) and 7.6% (95% CI, 2.5%-16.8%) of patients in the full-dose group had grade 3/4 bone pain.4,9-12

The higher incidence of grade 3/4 bone pain could be attributed to the greater exposure to pegfilgrastim in the full-dose group. However, imbalances between the full-dose and the half-dose groups in the administration of chemotherapy regimens with potential to cause bone pain, such as doxorubicin, paclitaxel, and carboplatin,14-17 may also have been a contributing factor. A higher proportion of patients in the full-dose group than in the half-dose group received AT, whereas a higher proportion of patients in the half-dose group received CP.

Considering that the response to chemotherapy and pegfilgrastim may differ between patients with solid tumors versus hematologic malignancies, we performed an ad hoc analysis, which showed that excluding the 9 patients with lymphoma had a negligible effect on the observed differences in the incidence of grade 3/4 bone pain between the full-dose and half-dose groups (data not shown).

Previous studies have shown that the incidence of bone pain associated with pegfilgrastim is highest during the first chemotherapy cycle, then it generally decreases or resolves in subsequent cycles.6,18 Because of this decrease in the incidence of bone pain after cycle 1, ascribing the reduction of bone pain to a reduction in the dose of pegfilgrastim may be a confounded conclusion.

The findings of the 2007 and the 2008 retrospective studies among patients with breast cancer who had empiric reductions of the pegfilgrastim dose in subsequent cycles as a result of bone pain7,8 should also be considered in light of this limitation: a decreased incidence of bone pain in later cycles would be expected even if the pegfilgrastim dose had remained at 6 mg.

In a recent retrospective analysis that included 23 pegfilgrastim studies (1862 patients who received pegfilgrastim 100 µg or 6 mg once per chemotherapy cycle), the incidence of bone pain of any grade during the first cycle was 35.1% and the incidence of grade 3/4 bone pain was 3.3%.6

Of note, there is some overlap between the patient populations analyzed in the present analysis and those in the retrospective study by Gregory and colleagues,6 and all 5 studies included in the present analysis (Table 1) were included in the study by Gregory and colleagues.6

Limitations
The current study had several limitations. First, the study was not large enough to detect statistically significant differences between the pegfilgrastim dose groups.

Second, because this analysis included only trials with available patient-level data, the generalizability of the findings may be limited.
Third, by pooling data from different existing trial data sets, the current analysis may not be well controlled for potential confounding factors such as tumor type and chemotherapy regimen.

Fourth, because patients were categorized into the approximate fixed-dose treatment groups retrospectively based on the narrow ranges of weight-based pegfilgrastim doses administered, it was not possible to ensure balance in distribution of patients between the half-dose and full-dose groups.

Finally, because bone pain was not a prespecified end point in the included trials, data regarding some important covariates related to bone pain, such as bone metastases and bone pain before entry into the trial, were not collected.

Conclusions
In this retrospective study, patients who received the approximate half dose (3 mg) of pegfilgrastim had higher rates of FN and overall bone pain than patients who received the full dose (6 mg) of pegfilgrastim. Although these results have limitations, including a small sample size, further research is warranted.

Acknowledgments
The authors would like to thank Margit Rezabek, DVM, PhD, and Benjamin Scott, PhD, whose work was funded by Amgen, Inc, for assistance in the preparation of this manuscript.

Author Disclosure Statement
Dr Iacovelli is a consultant to and has received honoraria from Amgen Inc. Dr Harms and Ms Mo are employees of and have stock in Amgen Inc.

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