What evidence is available comparing pegfilgrastim administration on day of versus day after chemotherapy?
Introduction
Pegfilgrastim is a colony stimulating factor (CSF) indicated for the prevention of infection in patients receiving myelosuppressive chemotherapy with high (>20%) risk of febrile neutropenia.1,2 Pegfilgrastim is the long-acting, pegylated formulation of filgrastim, a once daily CSF. Recommended dosing for pegfilgrastim is 6 mg subcutaneously once per cycle to be administered at least 24 hours after and 14 days prior to chemotherapy administration. The National Comprehensive Cancer Network (NCCN) 2020 guideline for hematopoietic growth factors recommends administration of pegfilgrastim the day after chemotherapy, which is a category 1 recommendation. Administration on the day following chemotherapy was recommended based on the mechanism that administration of pegfilgrastim on the day of chemotherapy could potentially exacerbate neutropenia by stimulating progenitor cells that can then be targeted by the chemotherapy agents.
Neulasta® prefilled syringe was the first formulation of pegfilgrastim approved by the Food and Drug Administration (FDA) in 2002.1-3 Administration of pegfilgrastim prefilled syringe can be performed at home by the patient or caregiver or more commonly by a healthcare provider, which requires an additional clinic visit for the patient. Given logistical reasons such as scheduling, travel, and reimbursement/cost, a survey found that 41.3% of patients administered pegfilgrastim received it on the same day as chemotherapy.4 In 2014, the OnPro® device was approved for administration of pegfilgrastim, which mitigated the need for an additional clinic visit.3 The OnPro® device is an on body autoinjector that is applied to a patient as early as the same day as chemotherapy and delivers the pegfilgrastim dose approximately 27 hours later. The NCCN guideline recognizes that institutions administer pegfilgrastim on the same day as chemotherapy due to travel burden and recommends the use of the on body autoinjector as an alternative to same day administration.2
Over the past several years, the FDA has approved 3 biosimilar pegfilgrastim agents. These approvals include pegfilgrastim-JMDB (FULPHILA®) in June 2018, pegfilgrastim-CBQV (UDENYCA®) in November 2018, and most recently in November 2019, pegfilgrastim-BMEZ (ZIEXTENXO®).3 The NCCN guideline specifies that a biosimilar agent can be substituted for the reference pegfilgrastim product.2 Additionally, the American Society of Clinical Oncology (ASCO) issued a statement on biosimilars in oncology in 2018 highlighting the potential cost savings of biologics.5
These new pegfilgrastim biosimilars currently do not have an on body autoinjector device approved for administration, and their use entails similar logistical concerns that were prominent prior to the approval of the OnPro® device.3 A review of literature can provide insight into efficacy and safety considerations for administering pegfilgrastim on the day of chemotherapy versus days after.
Literature evaluation
Several articles have been published examining pegfilgrastim administration on the day of chemotherapy, which are summarized in table 1. One systematic review containing 4 prospective trials and 7 retrospective studies was identified; however, additional information on this topic is limited to retrospective, single center studies with small sample sizes and retrospective cohort studies based on insurance claim data. Many of these studies are older and were published prior to the approval of the OnPro® device.
| Table 1. Literature evaluating administration of pegfilgrastim on the same day as chemotherapy6-14 | |||
|---|---|---|---|
| Citation/ Design | Population/ chemotherapy regimen | CSF regimen | Outcomes |
| Systematic review | |||
| Lyman et al. 20176 SR 4 prospective studies, 7 retrospective studies | Cancer types: NSCLC, breast cancer, NHL, ovarian cancer, head and neck cancer, urothelial carcinoma, gynecologic malignancies, and other solid tumor types Chemotherapy: not specified | Same day vs. next day pegfilgrastim (9 studies) Same day vs. next day pegfilgrastim or filgrastim (1 study) Day 3 vs. day 7 filgrastim or pegfilgrastim with DCF on days 1 to 5 (1 study) | Same day administration associated with: · Higher rates and longer duration of neutropenia/FN in 6 studies (2 RCT, 4 retrospective) · Lower/comparable rates and duration of neutropenia/FN in 5 studies (2 RCT; 3 retrospective) o 2 retrospective studies showed similar/lower rates of neutropenia with same day administration in gynecologic cancer o Some studies showing lower/comparable rates with same day had limitations (low sample size or evaluating day 3 vs. day 7 administration with DCF) |
| Retrospective, SC studies | |||
| Eckstrom et al. 20197 Retrospective, SC, single-arm | N=109 patients Cancer types: Esophageal, gastric, appendiceal, or colorectal cancer Chemotherapy: FOLFOX or FOLFIRI | Same day pegfilgrastim (administration on day of d/c from 5-FU pump) | Same day administration associated with: · FN incidence: 4 patients (3.7%) · Grade 3 or 4 neutropenia: 13 patients (11.9%) · Dose delay or reduction due to neutropenia: 11 patients (10.1%) · Hospitalization due to FN: 5 patients (4.6%) |
| Bilen et al. 20178 Retrospective, SC September 2010 to September 2014 | N=151 patients in cycle 1; 116, cycle 2; 85, cycle 3; 61, cycle 4 Cancer types: Metastatic castration-resistant prostate cancer Chemotherapy: cabazitaxel with or without carboplatin | Pegfilgrastim within 24 hours or not within 24 hours during first 4 cycles of chemotherapy | Same day administration was associated with: · Lower incidence of infection compared to after 24 hours during cycle 1 (6% vs. 26%; p=0.01) · No statistically significant difference in infection compared with after 24-hour administration during cycle 2 (12% vs. 6%, p=0.69), cycle 3 (9% vs. 7%, p=1), or cycle 4 (12% vs. 0%, p=0.58) |
| Schuman et al. 20099 Retrospective, SC, single-arm | N=46 patients in 269 cycles Cancer types: Ovarian cancer (epithelial, 76%; germ cell, 9%; stromal, 2%), peritoneal cancer (13%) Chemotherapy: docetaxel/ carboplatin (48%), paclitaxel/ carboplatin (26%), or gemcitabine/ cisplatin (15%) | Pegfilgrastim administered 1 hour after chemotherapy administration completion (secondary ppx, 15%, primary ppx, 85%) | Neutropenia incidence: · Grade 1/2: 3.7% (10/269 cycles) · Grade 3/4: no episodes Neutropenic events (FN, hospitalization, antibiotic use): no episodes |
| Lokich 200610 Retrospective, SC | N=10 patients, representing 43 cycles (21 cycles with pegfilgrastim, 22 with no pegfilgrastim) Cancer type: NHL Chemotherapy: CHOP-R (5 patients, and 4 patients receiving liposomal doxorubicin), hyperCVAD (1 patient) | Same day administration or no pegfilgrastim | FN incidence: · Pegfilgrastim: 1 patient · No pegfilgrastim: 0 patients Grade 4 leukopenia: · Occurred in 6 patients · Pegfilgrastim: 4/21 cycles · No pegfilgrastim: 2/22 cycles |
| Lokich 200511 Retrospective, SC, single-arm | N=24 patients Cancer type: NSCLC Chemotherapy: weekly docetaxel and cisplatin alternating with vinorelbine and gemcitabine (n=15); weekly docetaxel, cisplatin, and irinotecan alternating with vinorelbine, cisplatin, and gemcitabine (n=9); weekly paclitaxel and carboplatin (n=4) | Pegfilgrastim every 2 weeks on same day as chemotherapy (secondary ppx) | No patients experienced leukopenia requiring dose interruption No patients experienced FN |
| Retrospective cohort studies | |||
| Weycker et al. 201812 Retrospective cohort evaluation utilizing claims data Data source = Medicare claims from January 2007 to September 2015 | N=65,003 patients (same day pegfilgrastim, 3,340; days 1 to 3, 61,663) in 261,184 cycles Cancer types: Non-metastatic breast cancer, NHL Chemotherapy: intermediate/high risk of FN, common regimens were TC, TCH, TAC, dose dense AC-T/AC, and CHOP-R | Pegfilgrastim administered same day (day 0) vs. days after (day 1 to 3) | Cycle 1 FN incidence: occurred in more patients receiving pegfilgrastim on day 0 compared to day 1 to 3 (11.4% vs. 8.4%; OR, 1.4; 95% CI, 1.3 to 1.6; p<0.001) FN incidence: occurred more in cycles receiving pegfilgrastim on day 0 compared to day 1 to 3 (7.7% vs. 6.0%; OR=1.3; 95% CI, 1.2 to 1.4; p<0.001) |
| Weycker et al. 2017 [a]13 Retrospective cohort evaluation utilizing claims data Data source= 2 claims repositories for private US health plans January 2010 to March 2016 | N=53,814 patients (same day pegfilgrastim, 4726; day 1 to 3, 48740; days 4 to 5, 348) in 217,273 cycles Cancer types: Non-metastatic breast cancer (83%), NHL (12%), non-metastatic lung cancer (2%), non-metastatic ovarian cancer (3%) Chemotherapy: intermediate/high risk FN | Pegfilgrastim administered same day (day 0), days 1 to 3 following chemotherapy, or days 4 to 5 following chemotherapy | Cycle 1 FN incidence: occurred in more patients receiving pegfilgrastim on days 4 to 5, followed by day 0, then day 1 to 3 (6.0%, 3.4%, and 2.5%, respectively; OR, day 0 vs. 1 to 3, 1.4; 95% CI, 1.2 to 1.7; p<0.001) FN incidence: occurred more in cycles receiving pegfilgrastim on day 4 to 5, followed by day 0, then day 1 to 3 (33.4%, 2.2%, and 1.8%, respectively; OR=1.3; 95% CI, 1.2 to 1.4; p<0.001) |
| Weycker et al. 2017 [b]14 Retrospective cohort evaluation Data source= 2 claims repositories for private US health plans January 2006 to December 2012 | N=6,355 FN episodes in 5,379 patients Cancer types: Non-metastatic breast cancer, NHL Chemotherapy: breast=TAC, AC-T, AC, dose dense AC-T/AC; NHL=CHOP/CHOP-R | N/A Study objective: Characterize CSF use (pegfilgrastim, filgrastim, sargramostim) and patterns among FN episodes | Use of CSF during cycle of FN: · 41.3% did not receive CSF Patterns of CSF use during cycle of FN: · 8.6% received same day pegfilgrastim · 49.1% received pegfilgrastim days 2 to 4 |
| Abbreviations: 5-FU=5-fluorouracil; AC=doxorubicin and cyclophosphamide; AC-T=doxorubicin, cyclophosphamide + docetaxel/paclitaxel; CI=confidence interval; CHOP-R=cyclophosphamide, doxorubicin, vincristine, and prednisone; CSF=colony stimulating factor; DCF=docetaxel, cisplatin, and 5-fluorouracil; FN=febrile neutropenia; FOLFIRI=5-fluorouracil, leucovorin, and irinotecan; FOLFOX=5-fluorouracil, leucovorin, and oxaliplatin; hyperCVAD= oral cyclophosphamide, etoposide, doxorubicin, and prednisone; NHL=non-Hodgkin’s lymphoma; NSCLC=non-small cell lung cancer; ppx=prophylaxis; SC=single center; SR=systematic review; TAC=doxorubicin, cyclophosphamide, docetaxel; TC=docetaxel and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab. | |||
Summary of literature
Systematic review
A systematic review was published examining safety and efficacy outcomes for same day versus next day administration of any long-acting granulocyte-CSF, which included pegfilgrastim as well as agents not available commercially in the U.S., such as balugrastim, lipegfilgrastim, and empegfilgrastim.6 Based on the 11 studies included in the systematic review, 6 studies (2 randomized and 4 retrospective) showed increased incidence or longer duration of neutropenia and febrile neutropenia with same day administration. These studies were in patients with breast cancer, non-Hodgkin’s lymphoma (NHL), non-small cell lung cancer (NSCLC), and a variety of solid tumors. Studies showing no difference or improvement with same day administration included patients with head and neck, urothelial, gynecologic, and ovarian cancers. Many of the studies that did not detect any differences with same day administration had small sample sizes and, therefore, may have been underpowered to detect a difference between groups. Of note, the authors of this systematic review all disclosed a relationship with Amgen Inc., the manufacturer of Neulasta® and Neulasta® OnPro®, potentially introducing bias in favor of next day administration.
Retrospective, single center studies
Two retrospective, single center studies were published after the completion of the systematic review, by Eckstrom et al. and Bilen et al.7,8 Eckstrom and colleagues specifically reviewed same day pegfilgrastim for gastrointestinal cancers, administered on the day of 5-FU pump completion.7 This study did not include a comparator arm. Incidence of neutropenia and neutropenic events were compared to rates from a study comparing next day pegfilgrastim administration to placebo by Hecht and colleagues. Eckstrom and colleagues’ findings for same day administration were similar to or better than the rates reported for next day administration published by Hecht and colleagues; however, confounders and differences in study design may limit this comparison.
Bilen and colleagues investigated the incidence of infection in patients with castrate resistant prostate cancer receiving cabazitaxel with or without carboplatin when pegfilgrastim is administered within 24 hours of chemotherapy versus after 24 hours.8 This study found a significant reduction in infection when pegfilgrastim was administered on the same day as chemotherapy during cycle 1 (6% vs. 26%; p=0.01). During cycles 2 through 4, infection rate was numerically higher in patients receiving same day pegfilgrastim, although there was no significant difference. The sample size decreased each cycle, so the study may be underpowered to find a difference in cycles 2 through 4. Additionally, it is unclear whether administration of pegfilgrastim after 24 hours of chemotherapy occurred within the guideline recommended time frame.
Three additional retrospective, single center reviews were published between 2004 and 2009, prior to the approval of the on body autoinjector.9-11 These reviews did not include comparator arms for same day pegfilgrastim administration but characterized the rates of neutropenia and neutropenic events as low (see Table 1). Each of these studies had a small sample size, which limits generalizability of these findings.
Cohort studies
Weycker and colleagues published a series of retrospective cohort studies examining patterns of febrile neutropenia related to CSF administration, all of which were funded by Amgen Inc.12-14 These studies included patients with non-metastatic breast cancer and NHL, as well as non-metastatic ovarian and lung cancer in 1 study. The first study reported that in patients identified with febrile neutropenia, 8.6% received same day pegfilgrastim (day 1) compared to 49.1% on days 2 to 4.14 In the additional 2 studies, Weycker and colleagues found a significantly higher incidence of febrile neutropenia with same day administration (day 0) compared to administration on days 1 to 3 during cycle 1 (based on Medicare claims: 11.4% vs. 8.4%, respectively; OR, 1.4; 95% CI, 1.3 to 1.6; p<0.001; based on private insurance claims: 3.4% vs. 2.5%; OR, 1.4; 95% CI, 1.2 to 1.7; p<0.001).12,13 These studies included a large sample size, and difference in febrile neutropenia rates may not represent clinical significance.
Practice considerations
According to ASCO, biosimilar availability has the potential to decrease medication costs and can affect reimbursement patterns.5 Reimbursement and cost may largely dictate whether the reference product or one of the biosimilar agents is utilized in practice. In the case of pegfilgrastim, this could restrict the use of the on body autoinjector and limit the ability to administer pegfilgrastim on the day after chemotherapy as recommended by NCCN.
In 2018, a cost utility analysis showed that same day administration of pegfilgrastim had lower costs compared to next day administration for ovarian cancer ($17,195 versus $17,681).15 The difference in cost was driven by the facility/administration fee, travel expenses, and wages. This study does not account for the use of the autoinjector or availability of biosimilar agents.
Conclusion
Given the recent approval of several pegfilgrastim biosimilars that do not have an autoinjector device, administration of pegfilgrastim on the same day as chemotherapy offers a logistical advantage to facilitate the use of biosimilar agents. A number of studies have been published examining same day administration of pegfilgrastim, of which only a few include a comparator arm. Numerous small, retrospective, single-center studies suggest similar outcomes with same day pegfilgrastim; however, these studies largely lack comparator arms, are underpowered, and have wide variability in cancer types and chemotherapy regimens, which limits generalizability. A number of cohort studies based on insurance claim data and funded by the manufacturer of the OnPro® device show statistically significant increases in febrile neutropenia with same day administration; however, these findings are due to a large sample size and should be evaluated for clinical significance. Finally, a systematic review of 11 studies found benefit of next day administration in 6 studies compared to 5 studies showing similar or better outcomes with same day administration. The authors of this study concluded that data supports pegfilgrastim administration 1 day after chemotherapy; however, the authors of this review disclosed potential conflicts of interest due to relationships with Neulasta® OnPro®’s manufacturer and may include bias. In summary, available literature shows mixed outcomes with same day pegfilgrastim and have many notable limitations.
References
- Neulasta [package insert]. Thousand Oaks, CA: Amgen, Inc; 2020.
- National Comprehensive Cancer Network. Hematopoietic growth factors (Version 1.2020). https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf. Accessed January 18, 2020.
- Drugs@FDA: FDA-approved drugs [database on the internet]. Silver Spring, MD: Food and Drug Administration (US), Center for Drug Evaluation and Research; 2020. Available at https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed January 18, 2020.
- Marion S, Tzivelekis S, Darden C, et al. “Same-Day” administration of pegfilgrastim following myelosuppressive chemotherapy: clinical practice and provider rationale. Support Care Cancer. 2016;24(9):3889-96.
- Lyman GH, Balaban E, Diaz M, et al. American Society of Clinical Oncology Statement: Biosimilars in Oncology. J Clin Oncol. 2018;36(12):1260-1265.
- Lyman GH, Allcott K, Garcia J, et al. The effectiveness and safety of same-day versus next-day administration of long-acting granulocyte colony-stimulating factors for the prophylaxis of chemotherapy-induced neutropenia: a systematic review. Support Care Cancer. 2017;25(8):2619-2629.
- Eckstrom J, Bartels T, Abraham I, et al. A single-arm, retrospective analysis of the incidence of febrile neutropenia using same-day versus next-day pegfilgrastim in patients with gastrointestinal cancers treated with FOLFOX or FOLFIRI. Support Care Cancer. 2019;27(3):873-878.
- Bilen MA, Cauley DH, Atkinson BJ, et al. Safety of same-day pegfilgrastim administration in metastatic castration-resistant prostate cancer treated with cabazitaxel with or without carboplatin. Clin Genitourin Cancer. 2017;15(3):e429-e435.
- Schuman SI, Lambrou N, Robson K, et al. Pegfilgrastim dosing on same day as myelosuppressive chemotherapy for ovarian or primary peritoneal cancer. J Support Oncol. 2009;7(6):225-8.
- Lokich JJ. Same day Pegfilgrastim and CHOP chemotherapy for non-Hodgkin lymphoma. Am J Clin Oncol. 2006;29(4):361-3.
- Lokich J. Same-day pegfilgrastim and chemotherapy. Cancer Invest. 2005;23(7):573-6.
- Weycker D, Hanau A, Lonshteyn A, et al. Risk of chemotherapy-induced febrile neutropenia with same-day versus next-day pegfilgrastim prophylaxis among patients aged ≥65 years: a retrospective evaluation using Medicare claims. Curr Med Res Opin. 2018;34(9):1705-1711.
- Weycker D, Bensink M, Lonshteyn A, Doroff R, Chandler D. Risk of chemotherapy-induced febrile neutropenia by day of pegfilgrastim prophylaxis in US clinical practice from 2010 to 2015. Curr Med Res Opin. 2017[a];33(12):2107-2113.
- Weycker D, Li X, Tzivelekis S, et al. Burden of chemotherapy-induced febrile neutropenia hospitalizations in US clinical practice, by use and patterns of prophylaxis with colony-stimulating factor. Support Care Cancer. 2017[b];25(2):439-447.
- Billingsley CC, Cohn DE, Crim AK, et al. Is it reasonable to administer pegfilgrastim on day 1 of a myelosuppressive chemotherapy regimen? A cost-utility analysis. Cancer Treat Res Commun. 2018;14:21-25.
Prepared by:
Amanda Gerberich, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
February 2020
The information presented is current as January 18, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.