Real-World Use of Granulocyte-Colony Stimulating Factor in Patients with Breast Cancer from Alberta, Canada
1
Oncology Outcomes, Calgary, AB T2N 4Z6, Canada
2
Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R7, Canada
3
Division of Medical Affairs, Apobiologix, Toronto, ON M9L 2Z7, Canada
4
Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N2, Canada
*
Author to whom correspondence should be addressed.
Cancers 2022, 14(24), 6197; https://doi.org/10.3390/cancers14246197
Submission received: 4 November 2022
/
Revised: 9 December 2022
/
Accepted: 9 December 2022
/
Published: 15 December 2022
(This article belongs to the Special Issue Supportive Care for Patients with Cancer)
Abstract
Simple Summary
Most chemotherapy regimens used in the setting of non-metastatic breast cancer are myelosuppressive and are associated with toxicities with significant clinical implications, including febrile neutropenia. The use of granulocyte colony-stimulating factor (G-CSF) reduces the severity and duration of febrile neutropenia, following the initiation of myelosuppressive chemotherapy. The practice of G-CSF prophylaxis is a proven form of supportive care that is shifting with the introduction of biosimilars. As published data are limited, we characterized the patterns and predictors of G-CSF use in a large real-world Canadian cohort over an 11-year period. Our results demonstrate that G-CSF use can be further optimized to align with current guidelines and to improve supportive care for patients with breast cancer.
Abstract
Background: There are limited published data in the Canadian healthcare system on the use of granulocyte colony-stimulating factor (G-CSF) among patients with breast cancer. This study characterized real-world G-CSF use during the period surrounding the introduction of filgrastim biosimilar. Methods: Electronic medical records were reviewed retrospectively for patients with breast cancer who received moderately or highly myelosuppressive (neo)adjuvant chemotherapy from 2008 to 2019 in Alberta, Canada. Trends in G-CSF usage were plotted to elucidate temporal variations and multivariable regression models were constructed to identify clinical factors associated with G-CSF use. Results: We included 6662 patients in our analyses. G-CSF was used in 57.1% of patients during their treatment trajectory. Among the 3801 patients who were treated with G-CSF, the majority received pegfilgrastim only (91.5%; n = 3477) versus filgrastim only (5.7%; n = 217). G-CSF use increased linearly more than two-fold over the 11-year study period. Predictors of G-CSF use included younger age, south zone of residence, higher neighborhood education, inferior disease stage, highly neutropenic risk chemotherapy, and more recent chemotherapy initiation. Conclusions: Despite increasing G-CSF usage over time, an appreciable proportion of patients for whom G-CSF prophylaxis is recommended did not receive it. G-CSF use could be further optimized to align with supportive care clinical guidelines and reduce the impact of neutropenia and its associated complications.
1. Introduction
The primary curative intent treatment modality for non-metastatic breast cancer is surgery, but patients with high-risk clinical or pathological features are commonly also offered neoadjuvant or adjuvant therapy as a standard of care. Most chemotherapy regimens used in this setting are myelosuppressive and are associated with a variety of hematological toxicities, including neutropenia and febrile neutropenia (FN). In particular, FN represents the most important dose-limiting toxicity of myelosuppressive chemotherapy, posing significant issues in the management of patients and contributing to a heightened risk of significant morbidity and mortality, increased healthcare resource use, and potential dose modifications with a subsequent failure to achieve optimal relative dose intensity (RDI) [1,2]. Approximately 20–30% of patients with FN require hospitalization, where the mortality rate can be as high as 10% [2]. Moreover, the impact on RDI is a significant concern in the setting of breast cancer management, since failure to achieve an RDI of over 80% may worsen survival outcomes [3,4].
The use of granulocyte colony-stimulating factor (G-CSF) reduces the severity and duration of neutropenia following myelosuppressive chemotherapy, and prophylaxis has been shown to significantly decrease the risk of FN in patients [2,5]. G-CSF may be administered as primary prophylaxis to help prevent a patient’s first episode of FN or as secondary prophylaxis after an episode of FN, where G-CSF is used in subsequent cycles following a previous neutropenic event [6]. G-CSFs, in the form of daily filgrastim or the once-per-cycle, long-acting pegfilgrastim, may be used inconsistently in practice, despite the considerable evidence that they reduce the incidence of FN and related complications [7]. Based on real-world comparative effectiveness studies, pegfilgrastim has been associated with a lower risk of neutropenia-related and all-cause hospitalizations, compared to filgrastim, which may be a result of the under-dosing of short-acting G-CSFs in general practice [8,9,10]; however, current clinical guidelines on myeloid growth factors assume that filgrastim and pegfilgrastim are clinically equivalent.
International guidelines have a high degree of consensus and uniformly recommend prophylactic use of G-CSF when there is a high risk (>20%) of FN [11,12]. FN risk is determined through consideration of both chemotherapy regimen- and patient-specific risk factors. When the chemotherapy risk alone is >20%, G-CSF prophylaxis is recommended. If the chemotherapy risk is moderate (10% to 20%), the presence of one or more patient risk factors may prompt prophylactic G-CSF use. Numerous patient- and disease-related factors are associated with increased overall FN risk, including age ≥ 65 years, advanced disease, poor performance status, presence and number of comorbidities, female sex, prior FN, and laboratory abnormalities (e.g., albumin < 35 g/L, hemoglobin < 12 g/L) [13].
Since the use of supportive care medications in real-world clinical practice varies from the guideline recommendations, and these medications are not uniformly reimbursed in Canada, there are concerns that G-CSF use may be suboptimal or overall under-utilized [14]. In 2017, the filgrastim biosimilar Grastofil was introduced in Alberta, Canada. The reduced costs of biosimilars may diminish some of the barriers associated with G-CSF access. To date, the published data on the use of G-CSF in Canadian patients with breast cancer are lacking, as comprehensive databases linking drug use to patient data and clinical outcomes are not generally available or different to evaluate in a systematic fashion. Additionally, few studies have evaluated the overall use of biosimilar drugs in the years immediately following initial availability, noting that their adoption at the provincial level has varied widely, from a low of 0.1% to a high of 81.6% [15]. The primary objective of this study was to characterize the patterns and predictors of G-CSF use in the period prior to and the initial 2-year period following the introduction of filgrastim biosimilar in Alberta, Canada.
2. Methods
2.1. Study Design
This was a retrospective, population-based study conducted in Alberta, Canada, which represents the country’s fourth-largest province, with a population of over four million residents. The Alberta Cancer Registry (ACR) was the primary data source for patient demographics, tumor characteristics, and treatment patterns, which were collected prospectively for all patients diagnosed with cancer in the province. Additional data sources included ambulatory care records, physician billing claims, and hospital discharge abstracts, based on previously validated coding algorithms of the International Classification of Diseases and Related Health Problems (ICD). The study protocol was reviewed and approved by the research ethics committee prior to data collection and analysis. This study’s design, analysis, and reporting all adhere to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines [16].
2.2. Patient Population
Included patients were those aged 18 years or older, newly diagnosed with stage I to III breast cancer in Alberta, from January 2008 to December 2017, who received at least one cycle of moderately or highly myelosuppressive chemotherapy in the neoadjuvant or adjuvant setting. Patients who were diagnosed with multiple cancers were excluded. Patients were also excluded if they had received G-CSF as part of a clinical study protocol or if they were treated with myelosuppressive.
2.3. Study Data
The main outcome of interest was the receipt of either filgrastim or pegfilgrastim during the study period, January 2008 to November 2019. The date of initiation of the first cycle of chemotherapy was considered the study index date. Primary prophylaxis was defined as G-CSF administration within seven days of the start of a chemotherapy cycle. Chemotherapy regimens with high neutropenic risk included AC-T (doxorubicin hydrochloride and cyclophosphamide followed by paclitaxel), DC (docetaxel and cyclophosphamide), ddAC (dose-dense doxorubicin and cyclophosphamide), FEC-D (5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel), and TCH (docetaxel, carboplatin, and trastuzumab), whereas those with moderate neutropenic risk were CMF (cyclophosphamide, methotrexate, and 5-fluorouracil), 3-weekly docetaxel, and FEC (5-fluorouracil, epirubicin, and cyclophosphamide) [9].
Demographic information retrieved from the ACR comprised age at treatment initiation and residential postal code. Postal codes were used to derive information on neighborhood-level socioeconomic status, including educational attainment and annual household income, based on 2011 census data, which represented the most recent year of available data.
2.4. Statistical Analysis
Descriptive statistics were used to analyse the baseline demographic- and treatment-related characteristics. To elucidate differences in baseline characteristics between groups, the Wilcoxon rank-sum test was used for continuous variables, whereas Pearson’s Chi-squared test or Fisher’s exact test were used for categorical variables. Additionally, standardized mean difference (SMD) was computed to reinforce comparisons of baseline characteristics, with SMD > 0.1 considered indicative of imbalance. Multivariable logistic regression analyses were performed to assess the likelihood of receiving G-CSF as a binary variable (yes/no) and that of receiving filgrastim over pegfilgrastim. All statistical tests were two-sided, and the significance level was defined a priori as <0.05. All analyses were performed using R.
3. Results
3.1. Cohort Characteristics
In total, we identified 6662 patients diagnosed with early-stage breast cancer from 2008 to 2017 who received either moderately or highly myelosuppressive (neo)adjuvant chemotherapy (Table 1). Among them, 1492 (22.4%), 3602 (54.1%), and 1568 (23.5%) were, respectively, diagnosed with stage I, II, and III disease. The median age at treatment initiation was 54 (interquartile range (IQR) 46–61) years. The majority (97.7%) of patients received (neo)adjuvant chemotherapy regimens with high neutropenic risk.
3.2. G-CSF Use
Of the entire study cohort, 3801 (57.1%) patients received G-CSF at some point during the chemotherapy treatment trajectory (Table 1). Patients who received G-CSF were more likely to have a younger age, south or Calgary zone of residence, higher neighborhood education, higher neighborhood income, advanced disease stage, chemotherapy with high neutropenic risk, or more recent year of chemotherapy initiation (p < 0.001, SMD > 0.1 for each). Among the 3801 patients who received G-CSF, the vast majority received pegfilgrastim only (91.5%; n = 3477), whereas the others received either filgrastim only (5.7%; n = 217) or both pegfilgrastim and filgrastim (2.8%; n = 107). Patients who received filgrastim only were more likely to have a younger age, Calgary zone of residence, higher neighborhood education, advanced disease stage, or more recent year of chemotherapy initiation (p ≤ 0.02, SMD > 0.1 for each) (Table 2). Among the patients treated with G-CSF, most did not receive the drug as primary prophylaxis in the first chemotherapy cycle (87.5%; n = 3323), but those who did were more likely to receive filgrastim versus pegfilgrastim (p < 0.001, SMD = 0.251).
3.3. Temporal Trends in G-CSF Use
Examining treatment patterns by calendar year, G-CSF use over the 11-year study period appeared to increase linearly from 34.2% in 2008 to 78.0% in 2018 (Figure 1). Among patients who received G-CSF, trends in usage by G-CSF type were more consistent (Figure 2). Even so, there was a marked increase in filgrastim use, accompanied by a proportional decrease in pegfilgrastim use from 2015 to 2018.
3.4. Factors Associated with G-CSF Use
In the first multivariable logistic regression model where the outcome was the use of any G-CSF, younger age, south zone of residence, higher neighborhood education, advanced disease stage, receipt of chemotherapy regimens with high neutropenic risk, and more recent chemotherapy initiation were factors that significantly correlated with greater odds of G-CSF use (p < 0.01 for all) (Table 3). In the second model where the outcome was the use of filgrastim only versus pegfilgrastim only, younger age, Calgary zone of residence, receipt of chemotherapy regimens with moderate neutropenic risk, more recent chemotherapy initiation, and G-CSF use as primary prophylaxis for the first chemotherapy cycle emerged as statistically significant factors associated with greater odds of filgrastim use (p ≤ 0.02 for all) (Table 4).
4. Discussion
This was a large retrospective study of a population-based cohort of patients with early-stage breast cancer to describe the use of G-CSF over an 11-year period in Alberta, Canada. Overall, we observed that G-CSF was not used consistently in the setting of myelosuppressive chemotherapy with a high or moderate risk of FN, where only approximately half of the study cohort had a record of at least one G-CSF prescription. In most of these cases, G-CSF was not used as primary prophylaxis for the first chemotherapy cycle. Despite guidelines that recommend primary G-CSF prophylaxis for chemotherapy regimens with an FN risk of >20%, other longitudinal real-world evidence studies have also reported an underutilization of G-CSF in patients with cancer, including patients with non-metastatic breast cancer at high risk of FN based on chemotherapy and patient-related factors [17].
A retrospective study by Fine et al. included 395 patients who initiated G-CSF in the oncology outpatient setting between January 2008 and January 2009 in the Canadian provinces of Ontario and Quebec [14]. Overall, 42% of patients received G-CSF as primary prophylaxis. Of the patients who initiated G-CSF, 44% were treated with pegfilgrastim in Ontario compared to only 2% in Quebec, where pegfilgrastim was not covered by provincial health insurance. The reported differences in the rates of G-CSF use as primary prophylaxis between our study (12.5%) and that of Fine et al. (42%) might be attributable to methodological reasons, such as the sample size and observational period, in addition to the provincial coverage of these medications and other factors that would influence the rates of overall use. As demonstrated in the Fine et al. study, the systemic barriers to G-CSF access and delivery may contribute to lower-than-expected usage rates. As funding for supportive care medications in Alberta, including G-CSF, is not currently covered by the cancer care budget, access to these medications is reliant upon self-pay or private insurance. According to a pan-Canadian analysis of prescription drug coverage by the Canadian Alliance for Sustainable Health Care, 30% of Alberta residents below 65 years of age were not enrolled in public or private coverage in 2017 [18]. Furthermore, physicians may have varying levels of knowledge regarding G-CSF guidelines and understanding of the FN risks associated with common chemotherapy regimens [19]. Improved physician awareness about G-CSF use may also lead to higher quality of care.
Even though G-CSF use was suboptimal overall, we observed sizeable and consistent growth in G-CSF use from 2008 to 2018, both graphically and through regression analysis. These temporal trends were concordant with the analysis of a US Medicare population of older women receiving adjuvant chemotherapy for early-stage breast cancer between 2002 and 2012 [20]. Such positive progress on the use of G-CSF prophylaxis for at risk groups could be due to the improved education of patients and providers, regarding the utility of G-CSF in improving treatment outcomes and its positive impact on health-related quality of life, given the high burden of FN and its associated complications. Prior to the availability of biosimilar G-CSF agents, primary prophylaxis with G-CSF may be less cost-effective for FN prevention in breast cancer, when compared to secondary prophylaxis [21]. However, a recent cost-effectiveness analysis of biosimilar filgrastim found primary prophylaxis to be cost-effective and supported expanding the use of G-CSF as an effective method of reducing unnecessary healthcare facility visits, especially in the context of the COVID-19 pandemic [22].
The introduction of biosimilars, such as Grastofil, may further improve G-CSF use. This biosimilar of filgrastim was introduced in Alberta in 2017, toward the end of our study period. While the change in overall G-CSF use was linear throughout our study period, we observed an increase in the proportion of patients receiving filgrastim, compared to pegfilgrastim around 2017. This may indicate a shifting treatment paradigm, attributed to the introduction of Grastofil and to the fact that some private insurance plans implemented a preferential listing of Grastofil over pegfilgrastim in fall 2016. The role of biosimilars in improving access by reducing cost-associated barriers is well-supported. The launch of biosimilar filgrastim in Europe was associated with initial cost savings of 14–27%, increased access, and decreased rates of FN-related hospitalization [23,24,25]. Moreover, numerous studies have suggested that the most cost-efficient approach to reducing the incidence of FN in chemotherapy-treated patients is through use of biosimilars and that savings could be used to expand access or reallocated to other anti-neoplastic therapy options on a budget-neutral basis [26,27]. Significant cost savings and increased access could potentially be realized for health systems that prioritize the use of biosimilars [22]. Nevertheless, the association between biosimilars and trends in G-CSF use in the Canadian context remains unclear and can be a compelling issue for additional investigation, including the extent to which FN-related hospitalizations have been impacted due to increased utilization of G-CSF prophylaxis.
We found certain patient factors to be associated with the increased use of G-CSF and the preference of one G-CSF type over another. Of the demographic characteristics analysed, zone of residence, neighborhood education, and age were significant predictors of G-CSF use. Since southern-most zones of residence are also those with relatively higher population density, we hypothesize that geographic barriers to care may have contributed to the variations in the rates of G-CSF use across the province. Neighborhood education may serve as a surrogate measure of health literacy, which has well-established links with access to care and health outcomes [28,29]. Low health literacy is also a recognized barrier to effective patient care that is especially prevalent in older adults [30]. Some factors associated with G-CSF receipt, namely having advanced disease and receiving chemotherapy regimens with higher FN risk, were concordant with the findings from previous studies [19,31]. Our findings may inform the development of educational tools that promote the appropriate use of G-CSF and policies that enhance access to important supportive therapies in cancer.
Our study design has inherent limitations. We focused on patients with breast cancer due to the high incidence of FN in this population, but we inevitably excluded other patients treated with myelosuppressive chemotherapy, who may benefit from G-CSF. We extracted data for G-CSF and chemotherapy administration from pharmacy dispensing records, rather than usage records; thus, we could not assess G-CSF use after the first cycle of chemotherapy. Lastly, our retrospective approach to data collection may have introduced unknown variables with the potential to confound the relationship between patient factors and G-CSF use.
5. Conclusions
There was a consistent rise in G-CSF use in the Alberta healthcare system from 2008 to 2018, yet an appreciable proportion of patients with breast cancer for whom G-CSF prophylaxis is recommended did not receive it. Opportunities exist to further optimize G-CSF use to align with current supportive care clinical guidelines and to reduce the impact of neutropenia and its associated complications. Characteristics of the patient and their cancer treatment should be carefully taken into consideration when planning strategies for supportive care. Potential directions for future research include expanding the evaluation of G-CSF use into other cancer sites and unpacking the impact of biosimilars on improving G-CSF access at a pan-Canadian level.
Author Contributions
Conceptualization, P.Q.D., B.J.N. and W.Y.C.; methodology, P.Q.D., B.J.N. and W.Y.C.; software, P.Q.D.; validation, P.Q.D., B.J.N. and W.Y.C.; formal analysis, P.Q.D.; investigation, P.Q.D., B.J.N. and W.Y.C.; resources, P.Q.D. and W.Y.C.; data curation, P.Q.D. and W.Y.C.; writing—original draft preparation, P.Q.D. and W.Y.C.; writing—review and editing, P.Q.D., B.J.N. and W.Y.C.; visualization, P.Q.D., B.J.N. and W.Y.C.; supervision, B.J.N. and W.Y.C.; project administration, B.J.N. and W.Y.C. All authors have read and agreed to the published version of the manuscript.
Funding
Funding was provided by Apobiologix as an unrestricted research grant under project ID 18-0547.
Institutional Review Board Statement
Approval for the study was obtained through the Health Research Ethics Board of Alberta—Cancer Committee (protocol code HREBA.CC-18-0547, approved on 15 February 2018).
Informed Consent Statement
Patient consent was waived, due to the retrospective nature of this study.
Data Availability Statement
Data will not be shared, due to patient confidentiality, according to the ethics approval for this study.
Acknowledgments
We thank Pascal Bergeron and Shay Yamini of Apobiologix for their assistance with reviewing the manuscript.
Conflicts of Interest
P.Q.D. and W.Y.C. have no relevant financial or non-financial interests to disclose. B.J.N. is employed by Apobiologix, which markets G-CSF biosimilar products.
References
- Kuderer, N.M.; Dale, D.C.; Crawford, J.; Cosler, L.E.; Lyman, G.H. Mortality, Morbidity, and Cost Associated with Febrile Neutropenia in Adult Cancer Patients. Cancer 2006, 106, 2258–2266. [Google Scholar] [CrossRef] [PubMed]
- Klastersky, J.; de Naurois, J.; Rolston, K.; Rapoport, B.; Maschmeyer, G.; Aapro, M.; Herrstedt, J. Management of Febrile Neutropaenia: ESMO Clinical Practice Guidelines. Ann. Oncol. 2016, 27, v111–v118. [Google Scholar] [CrossRef] [PubMed]
- Qi, W.; Wang, X.; Gan, L.; Li, Y.; Li, H.; Cheng, Q. The Effect of Reduced RDI of Chemotherapy on the Outcome of Breast Cancer Patients. Sci. Rep. 2020, 10, 13241. [Google Scholar] [CrossRef] [PubMed]
- Nielson, C.M.; Bylsma, L.C.; Fryzek, J.P.; Saad, H.A.; Crawford, J. Relative Dose Intensity of Chemotherapy and Survival in Patients with Advanced Stage Solid Tumor Cancer: A Systematic Review and Meta-Analysis. Oncologist 2021, 26, e1609–e1618. [Google Scholar] [CrossRef] [PubMed]
- Crawford, J.; Dale, D.C.; Lyman, G.H. Chemotherapy-Induced Neutropenia. Cancer 2004, 100, 228–237. [Google Scholar] [CrossRef]
- Crespo, A.; Forbes, L.; Vu, K.; Gallo-Hershberg, D.; Enright, K.; Abdallah, M.; Febbraro, M.; Gowanlock, T.; Kennedy, K.; Lim, C.; et al. Prevention and Outpatient Management of Febrile Neutropenia in Adult Cancer Patients; Cancer Care Ontario: Toronto, ON, Canada, 2021. [Google Scholar]
- Cooper, K.L.; Madan, J.; Whyte, S.; Stevenson, M.D.; Akehurst, R.L. Granulocyte Colony-Stimulating Factors for Febrile Neutropenia Prophylaxis Following Chemotherapy: Systematic Review and Meta-Analysis. BMC Cancer 2011, 11, 404. [Google Scholar] [CrossRef]
- Henk, H.J.; Becker, L.; Tan, H.; Yu, J.; Kavati, A.; Naeim, A.; Deeter, R.; Barron, R. Comparative Effectiveness of Pegfilgrastim, Filgrastim, and Sargramostim Prophylaxis for Neutropenia-Related Hospitalization: Two US Retrospective Claims Analyses. J. Med. Econ. 2013, 16, 160–168. [Google Scholar] [CrossRef]
- Mitchell, S.; Li, X.; Woods, M.; Garcia, J.; Hebard-Massey, K.; Barron, R.; Samuel, M. Comparative Effectiveness of Granulocyte Colony-Stimulating Factors to Prevent Febrile Neutropenia and Related Complications in Cancer Patients in Clinical Practice: A Systematic Review. J. Oncol. Pharm. Pract. 2016, 22, 702–716. [Google Scholar] [CrossRef]
- Weycker, D.; Malin, J.; Barron, R.; Edelsberg, J.; Kartashov, A.; Oster, G. Comparative Effectiveness of Filgrastim, Pegfilgrastim, and Sargramostim as Prophylaxis Against Hospitalization for Neutropenic Complications in Patients with Cancer Receiving Chemotherapy. Am. J. Clin. Oncol. 2012, 35, 267–274. [Google Scholar] [CrossRef]
- Aapro, M.S.; Cameron, D.A.; Pettengell, R.; Bohlius, J.; Crawford, J.; Ellis, M.; Kearney, N.; Lyman, G.H.; Tjan-Heijnen, V.C.; Walewski, J.; et al. EORTC Guidelines for the Use of Granulocyte-Colony Stimulating Factor to Reduce the Incidence of Chemotherapy-Induced Febrile Neutropenia in Adult Patients with Lymphomas and Solid Tumours. Eur. J. Cancer 2006, 42, 2433–2453. [Google Scholar] [CrossRef]
- Crawford, J.; Becker, P.S.; Armitage, J.O.; Blayney, D.W.; Chavez, J.; Curtin, P.; Dinner, S.; Fynan, T.; Gojo, I.; Griffiths, E.A.; et al. Myeloid Growth Factors, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 2017, 15, 1520–1541. [Google Scholar] [CrossRef] [PubMed]
- Lyman, G.H.; Abella, E.; Pettengell, R. Risk Factors for Febrile Neutropenia among Patients with Cancer Receiving Chemotherapy: A Systematic Review. Crit. Rev. Oncol. Hematol. 2014, 90, 190–199. [Google Scholar] [CrossRef] [PubMed]
- Fine, S.; Koo, M.; Gill, T.; Marin, M.; Poulin–Costello, M.; Barron, R.; Mittmann, N. The Use of Granulocyte Colony–Stimulating Factors in a Canadian Outpatient Setting. Curr. Oncol. 2014, 21, 229–240. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Mansell, K.; Bhimji, H.; Eurich, D.; Mansell, H. Potential Cost-Savings from the Use of the Biosimilars Filgrastim, Infliximab and Insulin Glargine in Canada: A Retrospective Analysis. BMC Health Serv. Res. 2019, 19, 827. [Google Scholar] [CrossRef]
- von Elm, E.; Altman, D.G.; Egger, M.; Pocock, S.J.; Gøtzsche, P.C.; Vandenbroucke, J.P. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies. J. Clin. Epidemiol. 2008, 61, 344–349. [Google Scholar] [CrossRef] [PubMed]
- Weycker, D.; Bensink, M.; Lonshteyn, A.; Doroff, R.; Chandler, D. Use of Colony-Stimulating Factor Primary Prophylaxis and Incidence of Febrile Neutropenia from 2010 to 2016: A Longitudinal Assessment. Curr. Med. Res. Opin. 2019, 35, 1073–1080. [Google Scholar] [CrossRef] [PubMed]
- Sutherland, G.; Dinh, T. Understanding the Gap: A Pan-Canadian Analysis of Prescription Drug Insurance Coverage; The Conference Board of Canada: Ottawa, ON, Canada, 2017. [Google Scholar]
- Barnes, G.; Pathak, A.; Schwartzberg, L. G-CSF Utilization Rate and Prescribing Patterns in United States: Associations between Physician and Patient Factors and GCSF Use. Cancer Med. 2014, 3, 1477–1484. [Google Scholar] [CrossRef]
- Goyal, R.K.; Tzivelekis, S.; Rothman, K.J.; Candrilli, S.D.; Kaye, J.A. Time Trends in Utilization of G-CSF Prophylaxis and Risk of Febrile Neutropenia in a Medicare Population Receiving Adjuvant Chemotherapy for Early-Stage Breast Cancer. Supportive Care Cancer 2018, 26, 539–548. [Google Scholar] [CrossRef]
- Younis, T.; Rayson, D.; Jovanovic, S.; Skedgel, C. Cost-Effectiveness of Febrile Neutropenia Prevention with Primary versus Secondary G-CSF Prophylaxis for Adjuvant Chemotherapy in Breast Cancer: A Systematic Review. Breast. Cancer Res. Treat. 2016, 159, 425–432. [Google Scholar] [CrossRef]
- Li, E.; Mezzio, D.J.; Campbell, D.; Campbell, K.; Lyman, G.H. Primary Prophylaxis with Biosimilar Filgrastim for Patients at Intermediate Risk for Febrile Neutropenia: A Cost-Effectiveness Analysis. JCO Oncol. Pr. 2021, 17, e1235–e1245. [Google Scholar] [CrossRef]
- IMS Institute for Healthcare Informatics. Delivering on the Potential of Biosimilar Medicines; IMS Institute for Healthcare Informatics: Parsippany, NJ, USA, 2016. [Google Scholar]
- Schwartzberg, L.S.; Lal, L.S.; Balu, S.; Campbell, K.; Brekke, L.; DeLeon, A.; Elliott, C.; Korrer, S. Clinical Outcomes of Treatment with Filgrastim Versus a Filgrastim Biosimilar and Febrile Neutropenia-Associated Costs Among Patients with Nonmyeloid Cancer Undergoing Chemotherapy. J. Manag. Care Spec. Pharm. 2018, 24, 976–984. [Google Scholar] [CrossRef] [PubMed]
- IQVIA. The Impact of Biosimilar Competition in Europe; IQVIA: London, UK, 2018. [Google Scholar]
- Aapro, M.; Cornes, P.; Abraham, I. Comparative Cost-Efficiency across the European G5 Countries of Various Regimens of Filgrastim, Biosimilar Filgrastim, and Pegfilgrastim to Reduce the Incidence of Chemotherapy-Induced Febrile Neutropenia. J. Oncol. Pharm. Pract. 2012, 18, 171–179. [Google Scholar] [CrossRef]
- McBride, A.; Wang, W.; Campbell, K.; Balu, S.; MacDonald, K.; Abraham, I. Economic Modeling for the US of the Cost-Efficiency and Associated Expanded Treatment Access of Conversion to Biosimilar Pegfilgrastim-Bmez from Reference Pegfilgrastim. J. Med. Econ. 2020, 23, 856–863. [Google Scholar] [CrossRef] [PubMed]
- Levy, H.; Janke, A. Health Literacy and Access to Care. J. Health Commun. 2016, 21 (Suppl. 1), 43–50. [Google Scholar] [CrossRef] [PubMed]
- Berkman, N.D.; Sheridan, S.L.; Donahue, K.E.; Halpern, D.J.; Crotty, K. Low Health Literacy and Health Outcomes: An Updated Systematic Review. Ann. Intern. Med. 2011, 155, 97–107. [Google Scholar] [CrossRef] [PubMed]
- Chesser, A.K.; Keene Woods, N.; Smothers, K.; Rogers, N. Health Literacy and Older Adults: A Systematic Review. Gerontol. Geriatr. Med. 2016, 2, 2333721416630492. [Google Scholar] [CrossRef] [PubMed]
- Mäenpää, J.; Varthalitis, I.; Erdkamp, F.; Trojan, A.; Krzemieniecki, K.; Lindman, H.; Bendall, K.; Vogl, F.D.; Verma, S. The Use of Granulocyte Colony Stimulating Factor (G-CSF) and Management of Chemotherapy Delivery during Adjuvant Treatment for Early-Stage Breast Cancer—Further Observations from the IMPACT Solid Study. Breast 2016, 25, 27–33. [Google Scholar] [CrossRef]
Figure 1.
Trends in G-CSF usage by calendar year.
Figure 2.
Trends in G-CSF usage by calendar year among patients who received G-CSF, stratified by G-CSF type.
Figure 2.
Trends in G-CSF usage by calendar year among patients who received G-CSF, stratified by G-CSF type.
Table 1.
Baseline characteristics of the study population, stratified by G-CSF receipt.
| Characteristic | Overall (n = 6662) | G-CSF Receipt | p Value | SMD | |
|---|---|---|---|---|---|
| No (n = 2861) | Yes (n = 3801) | ||||
| Age at chemotherapy initiation, y (n = 6662) | 54 (46, 61) | 54 (47, 62) | 53 (45, 61) | <0.001 ** | 0.144 † |
| <45 | 1394 (20.9%) | 518 (37.2%) | 876 (62.8%) | <0.001 ** | 0.137 † |
| 45–54 | 2139 (32.1%) | 921 (43.1%) | 1218 (56.9%) | ||
| 55–64 | 2089 (31.4%) | 926 (44.3%) | 1163 (55.7%) | ||
| ≥65 | 1040 (15.6%) | 496 (47.7%) | 544 (52.3%) | ||
| Rurality of residence (n = 6662) | 0.21 | 0.031 | |||
| Rural | 1327 (19.9%) | 590 (44.5%) | 737 (55.5%) | ||
| Urban | 5335 (80.1%) | 2271 (42.6%) | 3064 (57.4%) | ||
| Zone of residence (n = 6662) | <0.001 ** | 0.277 † | |||
| Calgary | 2717 (40.8%) | 1015 (37.4%) | 1702 (62.6%) | ||
| Central | 722 (10.8%) | 290 (40.2%) | 432 (59.8%) | ||
| Edmonton | 2283 (34.3%) | 1156 (50.6%) | 1127 (49.4%) | ||
| North | 566 (8.5%) | 282 (49.8%) | 284 (50.2%) | ||
| South | 374 (5.6%) | 118 (31.6%) | 256 (68.4%) | ||
| Neighborhood education quartile (n = 6613) | <0.001 ** | 0.114 † | |||
| Lowest | 1654 (25.0%) | 760 (45.9%) | 894 (54.1%) | ||
| Second | 1653 (25.0%) | 751 (45.4%) | 902 (54.6%) | ||
| Third | 1652 (25.0%) | 660 (40.0%) | 992 (60.0%) | ||
| Highest | 1654 (25.0%) | 666 (40.3%) | 988 (59.7%) | ||
| Neighborhood income quartile (n = 6617) | <0.001 ** | 0.109 † | |||
| Lowest | 1653 (25.0%) | 736 (44.5%) | 917 (55.5%) | ||
| Second | 1654 (25.0%) | 766 (46.3%) | 888 (53.7%) | ||
| Third | 1655 (25.0%) | 682 (41.2%) | 973 (58.8%) | ||
| Highest | 1655 (25.0%) | 655 (39.6%) | 1000 (60.4%) | ||
| Cancer stage (n = 6662) | <0.001 ** | 0.276 † | |||
| I | 1492 (22.4%) | 823 (55.2%) | 669 (44.8%) | ||
| II | 3602 (54.1%) | 1464 (40.6%) | 2138 (59.4%) | ||
| III | 1568 (23.5%) | 574 (36.6%) | 994 (63.4%) | ||
| Neutropenic risk of chemotherapy regimen (n = 6662) | <0.001 ** | 0.138 † | |||
| High | 6510 (97.7%) | 2761 (42.4%) | 3749 (57.6%) | ||
| Moderate | 152 (2.3%) | 100 (65.8%) | 52 (34.2%) | ||
| Year of chemotherapy initiation (n = 6662) | <0.001 ** | 0.689 † | |||
| 2008 | 342 (5.1%) | 225 (65.8%) | 117 (34.2%) | ||
| 2009 | 483 (7.3%) | 325 (67.3%) | 158 (32.7%) | ||
| 2010 | 535 (8.0%) | 342 (63.9%) | 193 (36.1%) | ||
| 2011 | 652 (9.8%) | 375 (57.5%) | 277 (42.5%) | ||
| 2012 | 705 (10.6%) | 385 (54.6%) | 320 (45.4%) | ||
| 2013 | 470 (7.1%) | 177 (37.7%) | 293 (62.3%) | ||
| 2014 | 684 (10.3%) | 261 (38.2%) | 423 (61.8%) | ||
| 2015 | 843 (12.7%) | 303 (35.9%) | 540 (64.1%) | ||
| 2016 | 882 (13.2%) | 227 (25.7%) | 655 (74.3%) | ||
| 2017 | 861 (12.9%) | 196 (22.8%) | 665 (77.2%) | ||
| 2018 | 205 (3.1%) | 45 (22.0%) | 160 (78.0%) | ||
SMD standardized mean difference. Values presented as median (interquartile range) or count (column percentage). ** p < 0.01. † SMD > 0.1.
Table 2.
Baseline characteristics among patients who received either filgrastim or pegfilgrastim, stratified by G-CSF type.
Table 2.
Baseline characteristics among patients who received either filgrastim or pegfilgrastim, stratified by G-CSF type.
| Characteristic | Overall (n = 3694) | G-CSF Type | p Value | SMD | |
|---|---|---|---|---|---|
| Pegfilgrastim Only (n = 3477) | Filgrastim Only (n = 217) | ||||
| Age at chemotherapy initiation, y (n = 3694) | 53 (45, 61) | 53 (45, 61) | 51 (43, 58) | 0.003 ** | 0.216 † |
| <45 | 851 (23.0%) | 786 (22.6%) | 65 (30.0%) | <0.001 ** | 0.451 † |
| 45–54 | 1173 (31.8%) | 1110 (31.9%) | 63 (29.0%) | ||
| 55–64 | 1138 (30.8%) | 1056 (30.4%) | 82 (37.8%) | ||
| ≥65 | 532 (14.4%) | 525 (15.1%) | 7 (3.2%) | ||
| Rurality of residence (n = 3694) | 0.16 | 0.103 † | |||
| Rural | 715 (19.4%) | 681 (19.6%) | 34 (15.7%) | ||
| Urban | 2979 (80.6%) | 2796 (80.4%) | 183 (84.3%) | ||
| Zone of residence (n = 3694) | <0.001 ** | 0.410 † | |||
| Calgary | 1668 (45.2%) | 1533 (44.1%) | 135 (62.2%) | ||
| Central | 416 (11.3%) | 404 (11.6%) | 12 (5.5%) | ||
| Edmonton | 1084 (29.3%) | 1041 (29.9%) | 43 (19.8%) | ||
| North | 275 (7.4%) | 257 (7.4%) | 18 (8.3%) | ||
| South | 251 (6.8%) | 242 (7.0%) | 9 (4.1%) | ||
| Neighborhood education quartile (n = 3670) | 0.02 * | 0.223 † | |||
| Lowest | 869 (23.7%) | 830 (24.0%) | 39 (18.0%) | ||
| Second | 884 (24.1%) | 840 (24.3%) | 44 (20.3%) | ||
| Third | 964 (26.3%) | 890 (25.8%) | 74 (34.1%) | ||
| Highest | 953 (26.0%) | 893 (25.9%) | 60 (27.6%) | ||
| Neighborhood income quartile (n = 3672) | 0.16 | 0.159 † | |||
| Lowest | 894 (24.3%) | 841 (24.3%) | 53 (24.4%) | ||
| Second | 868 (23.6%) | 819 (23.7%) | 49 (22.6%) | ||
| Third | 940 (25.6%) | 895 (25.9%) | 45 (20.7%) | ||
| Highest | 970 (26.4%) | 900 (26.0%) | 70 (32.3%) | ||
| Cancer stage (n = 3694) | 0.28 | 0.108 † | |||
| I | 653 (17.7%) | 606 (17.4%) | 47 (21.7%) | ||
| II | 2084 (56.4%) | 1966 (56.5%) | 118 (54.4%) | ||
| III | 957 (25.9%) | 905 (26.0%) | 52 (24.0%) | ||
| Neutropenic risk of chemotherapy regimen (n = 3694) | 0.12 | 0.104 † | |||
| High | 3643 (98.6%) | 3432 (98.7%) | 211 (97.2%) | ||
| Moderate | 51 (1.4%) | 45 (1.3%) | 6 (2.8%) | ||
| Year of chemotherapy initiation (n = 3694) | <0.001 ** | 0.947 † | |||
| 2008 | 113 (3.1%) | 100 (2.9%) | 13 (6.0%) | ||
| 2009 | 153 (4.1%) | 143 (4.1%) | 10 (4.6%) | ||
| 2010 | 189 (5.1%) | 184 (5.3%) | 5 (2.3%) | ||
| 2011 | 268 (7.3%) | 263 (7.6%) | 5 (2.3%) | ||
| 2012 | 311 (8.4%) | 308 (8.9%) | 3 (1.4%) | ||
| 2013 | 282 (7.6%) | 280 (8.1%) | 2 (0.9%) | ||
| 2014 | 408 (11.0%) | 400 (11.5%) | 8 (3.7%) | ||
| 2015 | 533 (14.4%) | 513 (14.8%) | 20 (9.2%) | ||
| 2016 | 641 (17.4%) | 604 (17.4%) | 37 (17.1%) | ||
| 2017 | 643 (17.4%) | 554 (15.9%) | 89 (41.0%) | ||
| 2018 | 153 (4.1%) | 128 (3.7%) | 25 (11.5%) | ||
| G-CSF as primary prophylaxis for first chemotherapy cycle (n = 3694) | <0.001 ** | 0.251 † | |||
| No | 3233 (87.5%) | 3062 (88.1%) | 171 (78.8%) | ||
| Yes | 461 (12.5%) | 415 (11.9%) | 46 (21.2%) | ||
SMD standardized mean difference. Values presented as median (interquartile range) or count (column percentage). * p < 0.05. ** p < 0.01. † SMD > 0.1.
Table 3.
Multivariable logistic regression analysis of predictors of G-CSF use.
| Variable | OR for Receiving G-CSF (95% CI) | p Value |
|---|---|---|
| Age at chemotherapy initiation, y | <0.001 a** | |
| <45 | Reference | |
| 45–54 | 0.84 (0.72–0.98) | |
| 55–64 | 0.76 (0.65–0.89) | |
| ≥65 | 0.57 (0.48–0.68) | |
| Rurality of residence | 0.84 | |
| Rural | Reference | |
| Urban | 1.01 (0.83–1.23) | |
| Zone of residence | <0.001 ** | |
| Calgary | Reference | |
| Central | 0.97 (0.78–1.22) | |
| Edmonton | 0.59 (0.52–0.67) | |
| North | 0.59 (0.46–0.75) | |
| South | 1.12 (0.87–1.46) | |
| Neighborhood education quartile | 0.004 a** | |
| Lowest | Reference | |
| Second | 1.07 (0.91–1.26) | |
| Third | 1.28 (1.07–1.53) | |
| Highest | 1.29 (1.06–1.57) | |
| Neighborhood income quartile | 0.12 a | |
| Lowest | Reference | |
| Second | 0.88 (0.75–1.03) | |
| Third | 1.06 (0.90–1.26) | |
| Highest | 1.09 (0.91–1.31) | |
| Cancer stage | <0.001 a** | |
| I | Reference | |
| II | 1.93 (1.69–2.21) | |
| III | 2.60 (2.22–3.05) | |
| Neutropenic risk of chemotherapy regimen | 0.009 ** | |
| High | Reference | |
| Moderate | 0.57 (0.39–0.82) | |
| Year of chemotherapy initiation | <0.001 a** | |
| 2008 | Reference | |
| 2009 | 0.90 (0.67–1.22) | |
| 2010 | 1.15 (0.85–1.55) | |
| 2011 | 1.48 (1.11–1.97) | |
| 2012 | 1.68 (1.27–2.22) | |
| 2013 | 3.01 (2.23–4.09) | |
| 2014 | 3.24 (2.44–4.32) | |
| 2015 | 3.71 (2.82–4.91) | |
| 2016 | 6.37 (4.80–8.49) | |
| 2017 | 7.61 (5.71–10.19) | |
| 2018 | 8.55 (5.67–13.10) |
OR odds ratio, CI confidence interval. a p for trend. ** p < 0.01.
Table 4.
Multivariable logistic regression analysis of predictors of filgrastim use among patients who received either filgrastim or pegfilgrastim.
Table 4.
Multivariable logistic regression analysis of predictors of filgrastim use among patients who received either filgrastim or pegfilgrastim.
| Variable | OR for Receiving Filgrastim Only vs. Pegfilgrastim Only (95% CI) | p Value |
|---|---|---|
| Age at treatment initiation, y | 0.001 a** | |
| <45 | Reference | |
| 45–54 | 0.75 (0.52–1.09) | |
| 55–64 | 0.98 (0.69–1.40) | |
| ≥65 | 0.15 (0.06–0.32) | |
| Rurality of residence | 0.77 | |
| Rural | Reference | |
| Urban | 0.93 (0.57–1.56) | |
| Zone of residence | <0.001 ** | |
| Calgary | Reference | |
| Central | 0.40 (0.19–0.78) | |
| Edmonton | 0.42 (0.28–0.61) | |
| North | 0.75 (0.40–1.35) | |
| South | 0.46 (0.21–0.91) | |
| Neighborhood education quartile | 0.33 a | |
| Lowest | Reference | |
| Second | 1.30 (0.79–2.14) | |
| Third | 1.82 (1.09–3.08) | |
| Highest | 1.33 (0.75–2.35) | |
| Neighborhood income quartile | 0.67 a | |
| Lowest | Reference | |
| Second | 0.78 (0.50–1.22) | |
| Third | 0.59 (0.36–0.95) | |
| Highest | 0.91 (0.56–1.47) | |
| Cancer stage | 0.73 a | |
| I | Reference | |
| II | 0.85 (0.59–1.23) | |
| III | 0.95 (0.62–1.48) | |
| Neutropenic risk of chemotherapy regimen | <0.001 ** | |
| High | Reference | |
| Moderate | 2.75 (0.95–6.90) | |
| Year of chemotherapy initiation | <0.001 a** | |
| 2008 | Reference | |
| 2009 | 0.53 (0.21–1.29) | |
| 2010 | 0.21 (0.06–0.59) | |
| 2011 | 0.14 (0.04–0.40) | |
| 2012 | 0.08 (0.02–0.28) | |
| 2013 | 0.06 (0.01–0.24) | |
| 2014 | 0.17 (0.06–0.44) | |
| 2015 | 0.36 (0.17–0.81) | |
| 2016 | 0.58 (0.29–1.25) | |
| 2017 | 1.54 (0.80–3.18) | |
| 2018 | 1.81 (0.84–4.09) | |
| G-CSF as primary prophylaxis for first chemotherapy cycle | 0.02 * | |
| No | Reference | |
| Yes | 1.44 (0.98–2.07) |
OR odds ratio, CI confidence interval. a p for trend. * p < 0.05. ** p < 0.01.
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Ding, P.Q.; Newcomer, B.J.; Cheung, W.Y. Real-World Use of Granulocyte-Colony Stimulating Factor in Patients with Breast Cancer from Alberta, Canada. Cancers 2022, 14, 6197. https://doi.org/10.3390/cancers14246197
AMA Style
Ding PQ, Newcomer BJ, Cheung WY. Real-World Use of Granulocyte-Colony Stimulating Factor in Patients with Breast Cancer from Alberta, Canada. Cancers. 2022; 14(24):6197. https://doi.org/10.3390/cancers14246197
Chicago/Turabian StyleDing, Philip Q., Brandt J. Newcomer, and Winson Y. Cheung. 2022. "Real-World Use of Granulocyte-Colony Stimulating Factor in Patients with Breast Cancer from Alberta, Canada" Cancers 14, no. 24: 6197. https://doi.org/10.3390/cancers14246197
APA StyleDing, P. Q., Newcomer, B. J., & Cheung, W. Y. (2022). Real-World Use of Granulocyte-Colony Stimulating Factor in Patients with Breast Cancer from Alberta, Canada. Cancers, 14(24), 6197. https://doi.org/10.3390/cancers14246197
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