Myelosuppression is a dose-limiting complication of systemic chemotherapy that can result in serious and life-threatening infections.1,2 Febrile neutropenia is a medical emergency and can lead to considerable morbidity, mortality, and associated costs if not managed appropriately.1,2 Febrile neutropenia is defined as a single oral temperature of 38.3°C or higher, or 38.0°C or higher sustained for more than 1 hour, and an absolute neutrophil count (ANC) of <500 cells/mm3 or <1000 cells/mm3 with an anticipated decline to ≤500 cells/mm3 during the next 48 hours.3
Febrile neutropenia has been associated with a mortality risk exceeding 50% in adults with cancer who have multiple comorbidities. This supports the clinical importance of proper patient evaluation and management of febrile neutropenia.2 Because of the severity of febrile neutropenia, dose reductions of systemic chemotherapy and delays of treatment are often warranted. However, these approaches can result in suboptimal cancer therapy.4
Myeloid growth factors have been shown to reduce the incidence and severity of chemotherapy-related neutropenia and febrile neutropenia and are recommended in certain patient populations at risk for infectious complications.3,5,6 Based on results from a medication use evaluation at Inova Fairfax Hospital demonstrating poor adherence to myeloid growth factor clinical practice guidelines, we developed institution-specific guidelines in 2013 for hospitalized patients with cancer who are receiving tbo-filgrastim, the current agent for the prophylaxis and treatment of febrile neutropenia on our hospital formulary.
The Inova guidelines (see Appendix) were based on the 2006, and later the 2015, American Society of Clinical Oncology (ASCO) guideline recommendations for the use of white blood cell growth factors in adults with cancer.7 The intent of the Inova guidelines was to promote the cost-effective use of tbo-filgrastim and assist physicians in maintaining prescribing practices consistent with evidence-based guidelines.
Primary granulocyte colony-stimulating factor (G-CSF) prophylaxis has been associated with a reduction in febrile neutropenia incidence, early mortality, and infection-related mortality, as well as in an increase in chemotherapy dose intensity.5,6 A patient’s overall risk for febrile neutropenia is determined by 2 aspects—the incidence of febrile neutropenia that is associated with the chemotherapy regimen, and the presence of patient-specific risk factors for infectious complications. In the Inova guidelines, tbo-filgrastim is recommended for primary prophylaxis with chemotherapy regimens that are associated with a high risk (>20%) for febrile neutropenia,8 as shown in Table 1.
In the presence of at least 2 patient-specific risk factors for febrile neutropenia, tbo-filgrastim may also be considered with intermediate-risk chemotherapy regimens (10%-20%).8 These risk factors include patients aged 65 years or older, preexisting neutropenia from bone marrow involvement, poor performance status, poor nutritional status, extensive previous chemotherapy or previous irradiation to a large volume of bone marrow, open wounds or active infections, recent surgery, poor renal function, liver dysfunction, and HIV infection (Table 2).3,8 According to the Inova hospital guidelines, primary G-CSF prophylaxis is generally not recommended for patients who are receiving low-risk chemotherapy (<10%).3,8
In addition to the benefits of primary prophylactic therapy, current evidence suggests that adjuvant G-CSF with antibiotics for the treatment of febrile neutropenia is associated with a faster recovery of neutrophils and fever, decreased duration of neutropenia, and reduced duration of hospital stay.9 However, G-CSF treatment for febrile neutropenia did not demonstrate any overall survival advantage.9 Inova guidelines currently recommend the use of G-CSF for the treatment of febrile neutropenia exclusively in patients at risk for poor clinical outcomes or for infectious complications,8 as shown in Table 2. These risk factors include neutropenia that is expected to last more than 10 days, profound neutropenia, age 65 years or older, pneumonia, sepsis syndrome, invasive fungal infection, other clinically documented infections, and being hospitalized at the time of fever development.3,8 G-CSF is not recommended in patients with afebrile neutropenia, because of the lack of benefit in this patient population.8
According to the Inova guidelines, tbo-filgrastim dose should be rounded to the nearest vial size based on a weight limit. Patients weighing ≤75 kg receive the 300-mcg dose, and patients weighing >75 kg receive the 480-mcg dose. In addition, tbo-filgrastim is recommended to be initiated 24 to 72 hours after the last dose of chemotherapy, and discontinued when the ANC is more than 1000 cells/mm3 for 3 consecutive days or more than 1500 cells/mm3 for 2 consecutive days.8
Previous studies have revealed significant discrepancies between G-CSF prescribing patterns in clinical practice and guideline recommendations.10,11 In our study, we assessed the current use of tbo-filgrastim in patients with cancer and measured the rate of adherence to Inova guidelines. Assessing adherence to institution-specific recommendations for appropriate G-CSF indications will help identify opportunities and develop avenues for safe, cost-effective use of G-CSF in hospitalized adults with cancer.
Key secondary objectives of this study included evaluation of tbo-filgrastim dose and duration of therapy, ANC level at the time that tbo-filgrastim was initiated (ie, treatment group), and when it was discontinued (ie, prophylaxis and treatment groups), incidence of febrile neutropenia, and timing of tbo-filgrastim administration after completion of chemotherapy. We studied tbo-filgrastim, because this is the only myeloid growth factor listed in our hospital formulary. Pegylated filgrastim is available in the outpatient clinics, but its use was not evaluated in this study.
This single-center, retrospective chart review was conducted from January 1, 2015, to December 31, 2015, in an 833-bed community teaching hospital. The study was approved by the local Institutional Review Board.
Eligible patients were identified by a patient report created in the EPIC systems software. Hospitalized patients with cancer who received at least 1 dose of tbo-filgrastim were included in the analysis. Patients who received tbo-filgrastim for stem-cell mobilization or for nononcologic indications, patients aged <18 years, and those with incomplete medical records were excluded. Medical records were considered incomplete if data points were missing for the final analysis. Descriptive statistics were used to summarize the data.
Data collected included age; sex; weight; type of malignancy; chemotherapy regimen; goal of treatment; tbo-filgrastim indication, dose, and duration of therapy; ANC; and patient-specific factors that increase the risk for neutropenic complications.
Patients were stratified into several groups, including primary prophylaxis, secondary prophylaxis, treatment of febrile neutropenia, or afebrile neutropenia, based on their indication for G-CSF administration. The primary prophylaxis group was further categorized into low-, intermediate-, or high-risk for febrile neutropenia subsets, based on the type of chemotherapy regimens used (Table 3). The risk for febrile neutropenia was determined by reviewing studies on each regimen and using the ASCO guidelines.3,4,6,7
Patients in the intermediate- or low-risk category and those in the treatment group were evaluated for the presence of risk factors to determine if G-CSF use was warranted. Afebrile neutropenia was defined as a temperature of <38.0°C and an ANC <1000 cells/mm3. The severity of neutropenia was grade 1 to 4, in accordance with the Common Terminology Criteria for Adverse Events (Table 4).12 The performance status was based on the Eastern Cooperative Oncology Group grading scale. Poor performance status was defined as a grade 2 or higher. Poor nutritional status was subjectively assessed through progress notes in the patient’s medical record. Significant changes in weight, changes in appetite, and route of nutritional support (eg, use of enteral feeding tube) were considered when assessing nutritional status.
Overall, 121 patients were screened and 100 patients were included in the study. A total of 21 patients were excluded because of incomplete medical records (N = 3), stem-cell mobilization (N = 3), and tbo-filgrastim use for nononcologic indications (N = 15; Figure 1).
Table 5 outlines the baseline characteristics and demographics of the enrolled patients. The most common types of cancer in this patient population were acute leukemias (N = 24) and non-Hodgkin lymphoma (N = 17). Tbo-filgrastim was given as primary prophylaxis for 47 (47%) patients. Of these 47 patients, 22%, 17%, and 8% were classified into high-, intermediate-, and low-risk categories, respectively, for febrile neutropenia, as shown in Figure 2. In addition, 3% of the patients received tbo-filgrastim for secondary prophylaxis. Tbo-filgrastim was administered in combination with antibiotics for the treatment of febrile neutropenia in 34% of patients, and 16% of patients received tbo-filgrastim for afebrile neutropenia.
The most common patient-specific risk factors in the intermediate-risk group were poor nutritional status (N = 11), open wounds or active infections (N = 8), aged ≥65 years (N = 7), and poor performance status (N = 7). The most common risk factors in the febrile neutropenia treatment group were presence of other infections (N = 17), aged >65 years (N = 13), and profound neutropenia (N = 13). The mean number of risk factors per patient in the intermediate-risk and treatment groups was 2.
Overall adherence to the Inova guideline recommendations was followed in 59% of patients and not followed in 41% of patients. According to the Inova guidelines, patients at intermediate-risk who have ≥2 risk factors should receive G-CSF prophylaxis, as shown in Table 2. Of the 47 patients who received primary prophylaxis, 17 patients were classified as intermediate-risk, and 15 patients of the intermediate-risk cohort had ≥2 risk factors warranting G-CSF prophylaxis. However, 16% of the patients were prescribed tbo-filgrastim for afebrile neutropenia and 8% were prescribed it for low-risk prophylaxis; these are 2 situations that do not warrant G-CSF use. Tbo-filgrastim was dosed correctly in 81% of the patients and timed correctly in 94% of the patients. Among the patients who received tbo-filgrastim not according to guideline recommendations, 40 doses of 300 mcg and 100 doses of 480 mcg were administered. The mean ANC at the time of initiation of tbo-filgrastim for treatment of febrile neutropenia was 310 ± 333 cells/mm3 (Table 6).
The mean duration of tbo-filgrastim therapy for prophylaxis, febrile neutropenia treatment, and afebrile neutropenia was 6.4 ± 5.8 days, 5.1 ± 8.9 days, and 2.9 ± 1.7 days, respectively. Of the full patient population, 29% of patients received only 1 day of G-CSF therapy, 19% received 2 days, and 38% received therapy for ≥5 days. In the cohort that received 1 to 2 days of tbo-filgrastim (N = 48), 60% (N = 29) of patients received the drug not according to the Inova guidelines. In the cohort that received ≥5 days of therapy (N = 38), 44% of patients were prescribed prophylactic therapy because of high-risk chemotherapy, and 13 patients (26%) who received growth factor support for prophylaxis had febrile neutropenia.
Bone marrow suppression is a detrimental complication of cytotoxic chemotherapy that can result in potentially fatal complications. G-CSF has been proved to decrease the number of febrile neutropenia events significantly when used prophylactically.5,6 Furthermore, G-CSF has been shown to facilitate faster neutrophil recovery when used to treat febrile neutropenia in high-risk patients. However, the benefits of G-CSF are not consistent for all patients with cancer who are receiving chemotherapy.9 Therefore, it is important to individualize G-CSF prescribing according to the patient’s risk for febrile neutropenia and infectious complications.
Current evidence suggests there is a wide variation between G-CSF guideline recommendations and prescribing patterns among clinicians.1,10,11 This ultimately results in overuse and unnecessary costs to the healthcare system. In a retrospective medical chart review of 88 patients conducted by Waters and colleagues, approximately 46% of pegfilgrastim doses were given to patients at low- or intermediate-risk for febrile neutropenia in the absence of risk factors.10 The 1-year cost of unwarranted pegfilgrastim administration was $712,264.10
In a second retrospective chart review of 256 patients conducted by Butler and colleagues, approximately 33% of patients receiving low-risk chemotherapy regimens were administered G-CSF for primary prophylaxis.11 Conversely, 23% of patients who received high-risk regimens were not given G-CSF prophylaxis. Based on the number of inappropriate G-CSF administrations, that institution concluded that it could have saved more than $600,000 if all G-CSF administrations were in accordance with the ASCO guidelines.7,11
ASCO recognizes the regulation of G-CSF use as a top opportunity to decrease costs without compromising the quality of patient care.7,13 Unwarranted G-CSF administrations not only lead to unnecessary costs but also expose patients to preventable adverse effects of G-CSF, such as medullary bone pain or flulike symptoms.3,14-16 This underscores the importance of proper G-CSF prescribing, which can be achieved through improved adherence to the ASCO guidelines.7
This study was designed to capture tbo-filgrastim prescribing patterns to identify methods to facilitate improved prescriber adherence to published guidelines. By recognizing which patient populations, patient risk factors, and G-CSF indications are prone to inappropriate G-CSF use, clinicians will be better informed when prescribing myeloid growth factors.
Inova Fairfax Hospital developed its tbo-filgrastim prescribing guidelines for patients with cancer as a means to guide G-CSF prescribing. However, even with institution-specific guidelines, our study showed that 41% of patients received tbo-filgrastim not based on the recommendations. In addition, almost 50% of all patients received only 1 or 2 days of tbo-filgrastim therapy, a duration unlikely to produce a significant clinical benefit.16 This high rate of inappropriate use illustrates a need to improve adherence through supplementary strategies, such as optimization of order sets and education. Currently, the Inova tbo-filgrastim guidelines are only accessible through an internal Intranet search.
This study should be interpreted in light of several limitations. First, only patients who received tbo-filgrastim were evaluated. The patient report generated by the pharmacy database was unable to account for patients who did not receive tbo-filgrastim but might have been appropriate candidates to receive this drug. Excluding this population challenges the external validity of this study.
Second, patient-specific risk factors were identified through written documentation, potentially creating room for error when interpreting medical records.
Finally, this study analyzed only inpatient administration of tbo-filgrastim and did not address subsequent outpatient doses. Future studies may address the appropriate use of tbo-filgrastim in the outpatient setting or focus on the administration of the longer acting growth factor, pegfilgrastim.
Based on our research, adherence to Inova guidelines would decrease G-CSF use by approximately 27% and would result in cost-savings of more than $36,000 per 100 patients receiving tbo-filgrastim based on the Centers for Medicare & Medicaid Services’ average sales price. Healthcare systems can utilize several strategies to mitigate inappropriate administration and promote cost-effective myeloid growth factor use. First, healthcare systems can assist providers by developing institution-specific prescribing guidelines. Incorporating parts of our Inova guidelines into order sets will increase its accessibility and assist providers and pharmacists in determining the appropriateness of growth factor therapy.
In addition, pharmacists can help facilitate appropriate G-CSF use through educational feedback to providers during the verification process, when necessary. By implementing interventions, pharmacists can assist in supporting proper prescribing practices of myeloid growth factors. By applying the strategies mentioned, physicians and pharmacists can bridge gaps in quality care and uncover opportunities to ensure safe, cost-effective use of myeloid growth factors in patients with cancer.
Author Disclosure Statement
Dr Dakwala-Sheik, Dr Moore, Dr Mohassel, and Dr Washington have no conflicts of interest to report.
- 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.
- Kuderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106:2258-2266.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Myeloid Growth Factors. Version 2.2013. August 3, 2013. www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf. Accessed February 1, 2016.
- Aapro MS, Bohlius J, Cameron DA, et al; for the European Organisation for Research and Treatment of Cancer. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011;47:8-32.
- Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol. 2007;25:3158-3167.
- Cooper KL, Madan J, Whyte S, et al. Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis. BMC Cancer. 2011;11:404-415.
- Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015;33:3199-3212.
- Inova Fairfax Hospital. Guidelines for the use of tbo-filgrastim (Granix) in adult hematology/oncology patients. (Access limited to those with Inova Internal Intranet.)
- Mhaskar R, Clark OA, Lyman G, et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia (review). Cochrane Database Syst Rev. 2014:CD003039.
- Waters GE, Corrigan P, Gatesman M, Smith TJ. Comparison of pegfilgrastim prescribing practice to national guidelines at a university hospital outpatient oncology clinic. J Oncol Pract. 2013;9:203-206.
- Butler TW, Waddell JA, Crane BJ, Porter AM. Evaluation of G-CSF in a single institution and development of pocket reference for primary prophylaxis of chemotherapy-induced febrile neutropenia. J Hematol Oncol Pharm. 2014;4:9-14.
- US Department of Health & Human Services, National Institutes of Health, National Cancer Institute. Common terminology criteria for adverse events (CTCAE). Version 4.03. www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed September 1, 2017.
- Schnipper LE, Smith TJ, Raghavan D, et al. American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: the top five list for oncology. J Clin Oncol. 2012;30:1715-1724.
- Bennett CL, Djulbegovic B, Norris LB, Armitage JO. Colony-stimulating factors for febrile neutropenia during cancer therapy. N Engl J Med. 2013;368:1131-1139. Erratum in: N Engl J Med. 2013;369:293.
- Freifeld A, Sankaranarayanan J, Ullrich F, Sun J. Clinical practice patterns of managing low-risk adult febrile neutropenia during cancer chemotherapy in the USA. Support Care Cancer. 2008;16:181-191.
- Wright JD, Neugut AI, Ananth CV, et al. Deviations from guideline-based therapy for febrile neutropenia in cancer patients and their effect on outcomes. JAMA Intern Med. 2013;173:559-568.