Are We Ready for Same-Day Pegfilgrastim and Chemotherapy?

In this issue of the Journal of Hematology Oncology Pharmacy, Weise and colleagues (can be accessed here) at the University of Kansas Cancer Center conducted a retrospective study of 87 patients with breast cancer who received chemotherapy and same-day or next-day pegfilgrastim to lessen the risk for neutropenia-related events (NREs).¹ The composite outcomes were 20.7% for the same-day administration of pegfilgrastim and 10.3% for the next-day administration of pegfilgrastim. The use of same-day pegfilgrastim did not significantly increase the risk for NREs. The investigators concluded that same-day treatment with pegfilgrastim is safe and effective in patients with breast cancer who are receiving chemotherapy that has a high risk for myelotoxicity.

The convenience of receiving pegfilgrastim on the same day as chemotherapy is a major benefit for patients, especially for those who travel far distances for treatment or who have extenuating circumstances. Because the same-day administration of pegfilgrastim and chemotherapy was not proved to be detrimental in patients with breast cancer at the University of Kansas Cancer Center, the researchers have continued collecting data to evaluate this strategy for other malignancies.

To date, only 2 studies have evaluated same-day pegfilgrastim in patients with breast cancer.^2,3 In 2010, Burris and colleagues conducted a prospective study of pegfilgrastim received on the same day as chemotherapy versus on the day after receiving chemotherapy in patients with non-Hodgkin lymphoma, breast cancer, non–small cell lung cancer, or ovarian cancer.²

In the breast cancer study, 93 patients received paclitaxel, doxorubicin, and cyclophosphamide (TAC) every 3 weeks, including 47 patients in the same-day pegfilgrastim arm and 46 in the next-day pegfilgrastim arm.² In treatment cycle 1, 93% of the patients who received same-day pegfilgrastim versus 78% of those who received next-day pegfilgrastim had grade 4 neutropenia. The duration of severe neutropenia of ≥3 days occurred in 50% of the patients who received same-day pegfilgrastim versus in only 18% of those who received next-day pegfilgrastim. The mean duration of severe neutropenia was 1.2 days longer in the same-day pegfilgrastim group than in the next-day pegfilgrastim group (mean, 2.6 days vs 1.4 days, respectively; 95% confidence interval, 0.7-1.6). However, these results show that the same-day pegfilgrastim group was statistically noninferior to the next-day pegfilgrastim group by less than a 2-day margin.²

The incidence of febrile neutropenia was 22% for the patients who received same-day pegfilgrastim and 7% for the patients who received next-day pegfilgrastim, with most patients having febrile neutropenia in cycle 1.2 Across all cycles of chemotherapy, the incidence of febrile neutropenia was 33% for the patients who received same-day pegfilgrastim and 11% for those who received next-day pegfilgrastim. The higher rate of febrile neutropenia with same-day versus next-day pegfilgrastim could be a result of the sensitizing effect of pegfilgrastim on neutrophils when receiving the drug the same day as cytotoxic chemotherapy. Thus, the investigators recommend that patients receive pegfilgrastim the next day after chemotherapy.²

In 2022, Hobbs and colleagues published the results of a multi-site, retrospective review of 360 patients with breast cancer who received dose-dense doxorubicin and cyclophosphamide.³ A total of 146 patients received pegfilgrastim on the same day as chemotherapy at one treatment site whereas 214 additional patients received pegfilgrastim the day after receiving chemotherapy at 2 other treatment sites. The study results favored next-day pegfilgrastim over the use of same-day pegfilgrastim. Of the 146 patients who received same-day pegfilgrastim, 36 (24.6%) had febrile neutropenia compared with 25 (11.7%) of the 214 patients who received next-day pegfilgrastim (P=.002). In addition, compared with next-day pegfilgrastim, the use of same-day pegfilgrastim increased the incidence of acute care visits (2.8% vs 11.6%, respectively; P=.0016), increased the incidence of chemotherapy dose reductions (6.1% vs 21.2%, respectively; P<.0001), increased the use of antibiotics (12.6% vs 26.7%, respectively; P=.0001), and increased the incidence of grade ≥3 neutropenia (13.6% vs 38.4%, respectively; P<.0001). However, the rates of hospitalization (11.2% vs 15%, respectively; P=.36) and delay of the next cycle of chemotherapy by ≥1 day (6.1% vs 8.2%, respectively; P=.57) as a result of neutropenia did not significantly increase between the next-day pegfilgrastim and same-day pegfilgrastim groups.³

Alrawashdh and colleagues conducted a recent meta-analysis of the administration of same-day versus next-day pegfilgrastim stratified by the risk for myelotoxic febrile neutropenia and tumor type.⁴ They noted that the risk for febrile neutropenia depends on the myelotoxicity of the treatment regimens received (elevated in high-risk regimens, but not in intermediate-risk regimens) and the tumor type. In patients with breast cancer, the use of dose-dense doxorubicin plus cyclophosphamide is considered a high-risk regimen, whereas cyclophosphamide, doxorubicin, vincristine, and prednisone without or (more frequently) with rituximab in patients with lymphoma is considered an intermediate-risk regimen. Their analyses showed that same-day pegfilgrastim may decrease the risks for febrile neutropenia, grade 3 or 4 chemotherapy-induced neutropenia, and chemotherapy dose reductions or delays. The investigators suggest that further research that depends on the disease state and myelotoxicity of the chemotherapy regimen is necessary to determine if the same-day administration of pegfilgrastim is safe and effective.⁴

How does one resolve this situation? The studies by Burris and colleagues and Hobbs and colleagues^2,3 differ from the Weise study in efficacy and adverse events. In the review by Alrawashdh and colleagues, they contend that the myelotoxicity of the regimen plays a role.⁴ It is well known that risk factors, such as age, sex, general health, performance status, nutritional status, and comorbidities are often considered in drug selection, because these factors could affect a patient’s response to chemotherapy and adverse events. A patient with breast cancer and no major comorbidities is more likely to tolerate a high-risk chemotherapy regimen than a patient with multiple risk factors. Similarly, a patient with no comorbidities who receives a moderate-risk chemotherapy regimen, such as doxorubicin plus cyclophosphamide every 3 weeks or docetaxel plus cyclophosphamide every 3 weeks, should be able to receive same-day pegfilgrastim and chemotherapy safely.

Because of the risk for febrile neutropenia after receiving same-day pegfilgrastim that could result in neutrophil sensitization, an on-body injector device was developed and approved to deliver pegfilgrastim 27 hours after the administration of chemotherapy. Although the accuracy of the device has been confirmed, to date there are no clinical trial results on the efficacy and adverse events of the device in patients with cancer. However, device failure rates between 1.7% and 6.9% have been reported for the on-body injector, which can increase the patients’ risk for febrile neutropenia and the cost of treatment.^5-8 A cost-benefit analysis of the injector system is warranted.

In conclusion, receiving pegfilgrastim on the same day as chemotherapy is safe for use in select patients, such as those receiving moderately cytotoxic chemotherapy regimens. However, patients receiving dose-dense chemotherapy with doxorubicin and cyclophosphamide have a higher risk for adverse events, and only patients with few risk factors should be considered for treatment with same-day pegfilgrastim. Other considerations for same-day pegfilgrastim include patient-related challenges (eg, having to travel far distances or stay overnight, those with additional direct and indirect costs, those with a physical or psychological burden) and clinic-related factors (ie, staffing and other resourcing) associated with an additional office visit. If febrile neutropenia occurs after the administration of same-day pegfilgrastim, pegfilgrastim should be given as the standard next-day regimen for future treatments.

References

1. Weise MP, Cascone V, Tran H, et al. Evaluation of same-day versus next-day administration of pegfilgrastim in patients with breast cancer. J Hematol Oncol Pharm. 2023;13(5):241-245.
2. Burris HA, Belani CP, Kaufman PA, et al. Pegfilgrastim on the same day versus next day of chemotherapy in patients with breast cancer, non–small-cell lung cancer, ovarian cancer, and non-Hodgkin’s lymphoma: results of four multicenter, double-blind, randomized phase II studies. J Oncol Pract. 2010;6:133-140.
3. Hobbs J, Lowe J, Ferdinand A, et al. Efficacy of same-day versus next-day administration of pegfilgrastim for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients receiving dose-dense doxorubicin and cyclophosphamide: a retrospective multi-site analysis. J Oncol Pharm Pract. 2022 Dec 29;10781552221148116. Online ahead of print.
4. Alrawashdh N, McBride A, Oh M, et al. Meta-analysis of same-day pegfilgrastim administration stratified by myelotoxic febrile neutropenia risk and tumor type. J Adv Pract Oncol. 2022;13:796-811.
5. Joshi RS, Egbuna OI, Cairns AS, et al. Performance of the pegfilgrastim on-body injector as studied with placebo buffer in healthy volunteers. Curr Med Res Opin. 2017;33:379-384.
6. Stuessy P, Sanchez FA, Schober M. Retrospective review of pegfilgrastim on-body injector delivery rates in a large health system. J Clin Oncol. 2017;35(15 suppl):e18273.
7. Mahler LJ, DiBlasi R, Perez A, et al. On-body injector: an administration device for pegfilgrastim. Clin J Oncol Nurs. 2017;21:121-122.
8. Townley C, Porter C, McMullen N. Comparing grade 4 neutropenia associated with pegfilgrastim administered via the Onpro device versus manual injection with a prefilled syringe. J Hematol Oncol Pharm. 2018;18(3):119-125.