INTRODUCTION — Cytotoxic chemotherapy can cause profound and sometimes prolonged neutropenia, which may result in hospitalization for treatment of fever or cause a potentially fatal infection [1,2]. Although profound prolonged neutropenia is most likely in the pre-engraftment phase of hematopoietic cell transplantation (HCT; particularly allogeneic) and in patients undergoing induction therapy for acute leukemia, chemotherapy-related neutropenia can also occur in patients receiving standard-dose chemotherapy for other neoplasms. In an attempt to decrease infectious complications, recombinant human granulocyte colony stimulating factor (G-CSF; filgrastim and pegylated filgrastim) and granulocyte-macrophage colony stimulating factor (GM-CSF; sargramostim) have been used to reduce the duration and degree of neutropenia.
The role of the G-CSFs in patients receiving standard-dose myelosuppressive chemotherapy for conditions other than acute leukemia or myelodysplastic syndrome (MDS) or in patients undergoing HCT will be reviewed here. The role of G-CSFs in patients with myelodysplastic syndrome, in those undergoing induction chemotherapy for acute leukemia, and in the setting of HCT is addressed elsewhere, as are the potential side effects of CSFs (eg, bone pain, risk of therapy-related myeloid neoplasms). (See "Prevention of infections in hematopoietic cell transplant recipients", section on 'Immunomodulation' and "Introduction to recombinant hematopoietic growth factors", section on 'Toxicity of colony-stimulating factors' and "Hematopoietic support after hematopoietic cell transplantation", section on 'Growth factor support' and "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Adjunctive care' and "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Neutropenia'.)
An overview of neutropenic fever syndromes; antibacterial, antifungal, and antiviral prophylaxis for patients undergoing myelosuppressive chemotherapy or induction therapy for acute leukemia or HCT; and the management of patients with neutropenic fever are discussed elsewhere. (See "Overview of neutropenic fever syndromes" and "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults" and "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients" and "Prevention of infections in hematopoietic cell transplant recipients" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Adjunctive care'.)
Neutropenia — Although definitions are variable from institution to institution, severe neutropenia is defined as an absolute neutrophil count (ANC) of <500/microL or an ANC that is expected to decrease to <500/microL within the next 48 hours . Profound neutropenia is defined as an ANC <100/microL. The ANC is equal to the product of the white blood cell count (WBC) and the fraction of polymorphonuclear cells (PMNs) and band forms:
ANC = WBC (cells/microL) x percent (PMNs + bands) ÷ 100
Neutrophilic metamyelocytes and younger forms are usually not included in this calculation (calculator 1). The risk of a clinically important infection rises as the neutrophil count falls below 500/microL (table 1). (See "Overview of neutropenic fever syndromes".)
The terms leukopenia and granulocytopenia are sometimes used interchangeably with neutropenia, although they are somewhat different. Leukopenia refers to a low total WBC, while granulocytopenia refers to a reduced number of all granulocytes (neutrophils, eosinophils, and basophils). Agranulocytosis literally means the absence of granulocytes, but the term is variably used in the literature to indicate very severe or profound neutropenia (ie, ANC <100/microL, or sometimes a value that is <500/microL). Clinicians focus primarily on the number of neutrophils (predominantly bands and segmented forms) since the risk of infection is most strongly related to the number of circulating neutrophils. Other granulocytes play a minimal role in the defense against bacterial and fungal infections. Thus, neutropenia is the preferred term. (See "Overview of neutropenia in children and adolescents", section on 'Introduction' and "Approach to the adult with unexplained neutropenia", section on 'Introduction'.)
Fever — Fever in a neutropenic patient is usually defined as a single temperature ≥38.3°C (101°F) or a temperature ≥38°C (100.4°F) sustained over a one-hour period . However, infection can occur in neutropenic patients and other immunocompromised patients in the absence of fever. This occurs more often in older adult patients and those receiving corticosteroids. Presenting signs of infection in such patients may include hypothermia, hypotension, confusion, or clinical deterioration. (See "Overview of neutropenic fever syndromes".)
GRANULOCYTE COLONY STIMULATING FACTORS — G-CSFs, which are also known as myeloid growth factors, have been evaluated for prophylactic use following the administration of chemotherapy when neutropenia is anticipated ("primary prophylaxis"), during retreatment after a previous cycle of chemotherapy that caused neutropenic fever ("secondary prophylaxis"), and to shorten the duration of severe chemotherapy-induced neutropenia in patients who have neutropenia without fever ("afebrile neutropenia"). They are generally not recommended for routine use in patients with established fever and neutropenia . (See 'Therapeutic use in patients with neutropenia' below.)
The likelihood of developing neutropenic fever in patients treated with a given chemotherapy regimen is the primary factor that determines whether or not prophylactic CSFs are indicated. The incidence of neutropenic fever following treatment is influenced by the intensity of chemotherapy, the presence and degree of injury to the gastrointestinal mucosa, the presence of underlying damage to the patient's hematopoietic stem cells, the concurrent use of radiation, and the overall clinical status of the patient (ie, age and comorbid conditions).
Primary prophylaxis — Primary prophylaxis refers to the initiation of G-CSFs during the first cycle of myelosuppressive chemotherapy, with the goal of preventing neutropenic complications throughout all of the chemotherapy cycles. Primary prophylaxis may be used to decrease the incidence of neutropenic fever and the need for hospitalization. Primary prophylaxis may also be used to maintain dose-dense or dose-intense chemotherapy strategies that have survival benefits, or if reductions in chemotherapy dose-intensity or dose-density are known to be associated with a poorer prognosis.
Indications, benefits, and guidelines — The updated 2015 guidelines from the American Society of Clinical Oncology (ASCO), updated 2016 guidelines from the European Society for Medical Oncology (ESMO), 2010 guidelines from the Infectious Diseases Society of America (IDSA), and consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) all recommend primary prophylaxis when the anticipated incidence of neutropenic fever is approximately 20 percent or higher with a given regimen [3-7]. Previous guidelines had recommended a cut-off of 40 percent . The change in recommendation was driven by randomized trials showing that primary prophylaxis was cost effective when the risk of neutropenic fever with a specific regimen exceeded 20 percent [9,10].
This benchmark may change, given the high cost of treatment for neutropenic fever, which typically involves hospitalization . Furthermore, at least some data suggest that rates of febrile neutropenia are much higher in observational cohorts than they are in randomized trials. In one systematic review, after adjusting for age, chemotherapy intent, and regimen, a 13 percent rate of febrile neutropenia in randomized trial populations translated into a 20 percent rate in observational studies . Large population-based studies are needed to confirm febrile neutropenia rates in the real world. Until then, it is reasonable to maintain the 20 percent benchmark for use of primary prophylaxis and to individualize the use of primary prophylaxis in patients receiving regimens that have a risk between 10 and 20 percent based on other risk factors for increased complications from prolonged neutropenia.
Evidence from multiple randomized trials and meta-analyses supports the benefit of primary prophylaxis in reducing the frequency of hospitalization for antibiotic therapy, documented infection, and rates of neutropenic fever in adults [13-17]. The impact on survival (both short-term and long-term) is less clear :
●In a meta-analysis that included 3493 patients treated in 17 randomized controlled trials , primary prophylaxis was associated with a 46 percent decrease in the risk of neutropenic fever (relative risk 0.54, 95% CI 0.43-0.67), a 45 percent decrease in infection-related mortality (relative risk 0.55, 95% CI 0.33-0.90), and a 40 percent decrease in all-cause mortality during the chemotherapy period (relative risk 0.60, 95% CI 0.43-0.87). This meta-analysis was not able to address the impact of primary prophylaxis on disease-free or cancer-specific survival.
●Another meta-analysis of 148 trials of primary CSF prophylaxis in patients with cancer or undergoing hematopoietic cell transplant (HCT) also found a significant decrease in the rates of documented infections and neutropenic fever but could not confirm a reduction in short-term all-cause mortality or infection-related death .
●Yet another meta-analysis focusing on 61 randomized controlled trials comparing chemotherapy with or without CSF support and reporting all-cause mortality with at least two years of follow-up concluded that primary prophylaxis modestly but significantly reduced all-cause mortality (relative risk 0.93, 95% CI 0.90-0.96) . The impact was most pronounced (but still modest) in randomized controlled trials of dose-dense therapy (relative risk 0.89, 95% CI 0.85-0.94).
The potential benefit of primary prophylaxis in children is less clear .
The risk of febrile neutropenia appears to be highest during the first two cycles of chemotherapy, regardless of tumor type or chemotherapy regimen [10,21-23], leading some to question the effectiveness of G-CSF use throughout later cycles. This issue was directly addressed in a randomized trial in which 167 women receiving chemotherapy for breast cancer with an estimated >20 percent risk for febrile neutropenia were randomly assigned to G-CSF during the first two cycles only, or throughout all cycles . The trial was closed prematurely when an interim analysis disclosed a significantly higher rate of febrile neutropenia in the group receiving G-CSF during the first two cycles only (36 versus 10 percent). Thus, the continued use of primary G-CSF prophylaxis during all chemotherapy cycles is indicated.
Estimated risk of febrile neutropenia <20 percent — Guidelines, including those from the NCCN , specifically recommend against the routine administration of G-CSFs for primary prophylaxis in previously untreated adult patients receiving chemotherapy regimens with a low probability (<10 percent) of causing fever during anticipated periods of neutropenia [3-6]. However, primary prophylaxis may be appropriate in a number of clinical settings in which the estimated risk of neutropenic fever is between 10 and 20 percent [4,6,25]. Factors to consider when assessing the risk of a febrile neutropenic episode in patients undergoing cytotoxic chemotherapy for malignancy are summarized in the table (table 2):
●Primary prophylaxis may be indicated in patients who are being treated with curative intent (eg, lymphoma, adjuvant treatment for breast cancer, testicular cancer) to reduce the likelihood of dose-limiting neutropenia [18,26-28]. The benefit of CSFs in this setting was illustrated in a controlled trial in which 80 patients with high-grade non-Hodgkin lymphoma were randomly assigned to receive VAPEC-B chemotherapy alone or with daily G-CSF . The use of G-CSF was associated with less grade 4 neutropenia (37 versus 85 percent), less neutropenic fever (22 versus 44 percent), and a lesser likelihood of chemotherapy dose reduction (10 versus 33 percent).
Updated 2015 guidelines from ASCO specifically recommend primary prophylaxis with CSFs for selected situations :
•Patients 65 and older with diffuse aggressive lymphoma who are being treated with curative chemotherapy, particularly in the presence of comorbidities .
•Patients receiving dose-dense chemotherapy regimens that are supported by convincing efficacy data (eg, adjuvant treatment of high-risk breast cancer; high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin for urothelial cancer) . (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Importance of chemotherapy schedule' and "Neoadjuvant treatment options for muscle-invasive urothelial bladder cancer".)
•In other situations, they recommend secondary rather than primary prophylaxis following a neutropenic complication from a prior cycle of chemotherapy.
An important point is that controversy has surrounded the use of G-CSFs for patients with Hodgkin lymphoma undergoing chemotherapy with bleomycin-containing regimens, especially ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), given a possible increase in pulmonary toxicity. However, this toxicity potential is unclear for regimens such as BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) or VEPEMB (vinblastine, cyclophosphamide, procarbazine, prednisolone, etoposide, mitoxantrone, bleomycin) for non-Hodgkin lymphoma. Clinicians should be alert to the signs and symptoms of this complication in such patients. An increase in bleomycin pulmonary toxicity has not been reported with G-CSF use in bleomycin-containing testicular cancer chemotherapy regimens . (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'BEACOPP chemotherapy' and "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma", section on 'Older adults' and "Bleomycin-induced lung injury", section on 'Colony stimulating factors' and "Bleomycin-induced lung injury", section on 'Risk factors'.)
●High-risk patients who are treated with less myelosuppressive regimens may also benefit from prophylactic CSFs if they have one or more risk factors for febrile neutropenia . The key factors associated with an increased risk of neutropenic events include age >65 years [29-31], preexisting neutropenia or extensive bone marrow involvement by tumor [31,32], more advanced cancer , poor performance and/or nutritional status , renal or hepatic dysfunction , or in the case of epithelial ovarian cancer, extensive prechemotherapy surgery, particularly if it included a bowel resection .
In addition, NCCN guidelines include previous chemotherapy or radiation therapy (RT), and recent surgery and/or open wounds as potential risk factors that should be considered when evaluating a patient's overall risk for febrile neutropenia . ESMO guidelines also suggest that primary prophylaxis be considered in patients with reduced bone marrow reserve due to extensive RT or in patients who are neutropenic in the context of HIV infection . Formal clinical risk prediction models have been validated to assist in clinical decision making .
Use with concomitant chemoradiotherapy — For treatment of some solid tumors, chemotherapy is given concurrently with RT in an effort to increase local control and survival [35,36]. Combined modality treatment also increases the incidence of neutropenic fever compared with RT alone [35,36].
However, caution must be used in this setting as the use of G-CSFs has been associated with adverse outcomes, as illustrated by the following:
●Use of granulocyte-macrophage colony stimulating factor (GM-CSF) has been associated with a higher incidence of thrombocytopenia and other complications when given with concurrent chemoradiotherapy. This was illustrated in a Southwest Oncology Group (SWOG) trial in which 215 patients with small cell lung cancer were randomly assigned to receive concurrent chemotherapy and thoracic RT with or without GM-CSF . The incidence of grade 3 and 4 thrombocytopenia was significantly higher in the GM-CSF arm (91 versus 18 percent), and there were more treatment-related deaths among those receiving GM-CSF (9 versus 1, respectively). This increase in toxicity may be specific to thoracic chemoradiotherapy and/or GM-CSF. However, because of these data, many clinicians avoid CSFs in patients receiving concurrent chemoradiotherapy for lung cancer outside of a clinical trial setting. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Investigational approaches'.)
●In a trial of concurrent chemoradiotherapy with hyperfractionated accelerated RT for locally advanced oropharyngeal and hypopharyngeal cancer, patients randomized to prophylactic G-CSF experienced significantly reduced locoregional tumor control . Although it is unclear if this conclusion is applicable to all squamous cancers of the head and neck, these findings suggest that G-CSF should be used cautiously, if at all, during concomitant chemoradiotherapy for head and neck cancer. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Granulocyte colony-stimulating factor'.)
Secondary prophylaxis — Secondary prophylaxis refers to the administration of a G-CSF in subsequent chemotherapy cycles after neutropenic fever has occurred in a prior cycle. A prior episode of fever during neutropenia is a risk factor for developing fever during neutropenia in later cycles, with recurrences noted in 50 to 60 percent of patients [21,39,40]. Secondary prophylaxis with CSFs reduces this risk by approximately one-half .
The concept of secondary prophylaxis also includes the use of a G-CSF to speed recovery from neutropenia due to a previous cycle of chemotherapy, thus preventing delay in the administration of a subsequent chemotherapy cycle. There are no data proving the benefit of CSFs in this setting, and it is not clear that they are needed. At least some data support the safety of administering adjuvant anthracycline-containing chemotherapy without CSF support and without the need for dose reduction in women with uncomplicated neutropenia whose neutrophil count on the day of planned treatment is ≤1500 per microL .
In both of these settings, the goal of secondary prophylaxis is to maintain chemotherapy dose intensity while avoiding dose reduction. However, dose reduction after an episode of severe neutropenia should be considered the primary therapeutic option, unless chemotherapy is being administered for the treatment of curable tumors (eg, lymphoma, germ cell cancer, early stage breast cancer) . In theory, the survival benefit associated with potentially curative chemotherapy is preserved as long as doses are not reduced below a critical level. However, no published regimen has ever shown improved disease-free or overall survival when secondary prophylaxis was instituted and the dose of chemotherapy maintained in any setting, including these potentially curable tumors.
ASCO and ESMO guidelines suggest that secondary prophylaxis with granulocyte CSFs be limited to patients who experience a neutropenic complication (ie, fever, treatment delay) from a prior cycle of chemotherapy (for which primary prophylaxis was not received) if reduced dose intensity might compromise treatment outcome [4,6]. We agree with these recommendations.
Therapeutic use in patients with neutropenia
Neutropenia without fever — There is no established role for the use of CSFs in afebrile patients who have already developed severe neutropenia after chemotherapy, and we recommend against their use. The lack of benefit from CSFs in this setting was illustrated in a controlled trial in which 138 afebrile outpatients with severe chemotherapy-induced neutropenia (absolute neutrophil count [ANC] ≤500/microL) were randomly assigned to G-CSF or placebo until the ANC recovered to at least 500/microL . The duration of severe neutropenia was modestly shorter with G-CSF (two versus four days), but there was no effect on the rate of hospitalization or number of culture-positive infections.
Neutropenic fever — The use of therapeutic granulocyte CSFs in patients with established fever and neutropenia is controversial; the results of randomized trials have been mixed. A 2014 meta-analysis of 14 randomized trials (a total of 1553 participants) addressing the role of CSFs plus antibiotics in febrile neutropenia came to the following conclusions :
●The methodologic quality was low to moderate across different outcomes.
●Use of CSFs did not significantly improve overall mortality (hazard ratio [HR] 0.74, 95% CI 0.47-1.16) or infection-related mortality (HR 0.75, 95% CI 0.47-1.20) as compared with antibiotics alone.
●Individuals who received CSFs were significantly less likely to be hospitalized for longer than 10 days (risk ratio 0.65, 95% CI 0.44-0.95), and they had significantly shorter duration of neutropenia (standardized mean difference [SMD] -1.7 days, 95% CI -2.65 to -0.76), shorter duration of antibiotic use (SMD -1.50 days, 95% CI -2.83 to -0.18), and faster recovery from fever (SMD -0.49 days, 95% CI -0.90 to -0.09).
●Use of CSFs was associated with a significantly higher incidence of bone or joint pain or flu-like symptoms (risk ratio 1.59, 95% CI 1.04-2.42).
Clinical prediction models have been developed to help prospectively identify patients with cancer who are at high risk of complications as a result of neutropenic fever (see "Risk assessment of adults with chemotherapy-induced neutropenia"). However, while a number of clinical characteristics may provide prognostic information regarding the outcomes of patients with neutropenic fever, predictive models are needed to better identify high-risk patients who may benefit from the addition of granulocyte CSFs to antibiotics. A risk model for mortality in hospitalized cancer patients with neutropenic fever has been reported in which several independent risk factors were identified, including age ≥65, cancer type (leukemia, lung cancer), comorbidities (heart failure, pulmonary embolus, lung, renal, liver, cerebrovascular disease), and infectious complications (hypotension, pneumonia, bacteremia, fungal infection) .
Recommendations from expert groups for use of therapeutic CSFs in established fever and neutropenia differ:
●Given their cost and potential adverse effects, as well as the lack of consistent clinical data demonstrating benefit, guidelines from the IDSA recommend against the use of G-CSFs for patients with established fever and neutropenia .
●Guidelines from ASCO also recommend against routine use of CSFs in this setting, but they suggest that CSFs be "considered" for patients at high risk for infection-associated complications or who have prognostic factors that are predictive of a poor clinical outcome . These features include expected prolonged (>10 days) or profound (<100 cells/microL) neutropenia, age >65, pneumonia or other clinically documented infections, sepsis syndrome, invasive fungal infection, prior episode of febrile neutropenia, or being hospitalized at the time of the development of fever.
●ESMO guidelines do not address this issue specifically .
●The NCCN recommends that granulocyte CSF be continued in patients who are receiving prophylactic CSFs at the time of the presentation with neutropenic fever . They also suggest "consideration" of CSFs in patients who did not receive prophylactic CSFs and in whom there are risk factors for an infection-related complication, similar to those outlined in the ASCO guideline.
We follow the guidelines from ASCO. Given that it takes several days for CSF to produce a response with increased circulating neutrophils, antibiotics will always work faster. CSFs can also be a useful adjunct for patients who remain neutropenic and febrile and are not rapidly responding to antibiotics.
GM-CSF versus G-CSF and biosimilars — Many placebo-controlled trials have shown that both G-CSF and GM-CSF (sargramostim) are effective at reducing the incidence of neutropenic fever and infectious complications in cancer patients receiving chemotherapy. In different markets, G-CSF is commercially available as filgrastim (Neupogen) and lenograstim (Granocyte, Neutrogin, Myelostim). Several biosimilar forms of filgrastim are available worldwide. Updated guidelines from ASCO suggest that all of these preparations of G-CSF, including biosimilars, can be used for the prevention of treatment-related febrile neutropenia and that the choice of agent should be based on convenience, cost, and clinical situation .
There are only limited comparative data of G-CSF versus GM-CSF, which are conflicting about both safety and efficacy [46-51]:
●Only one randomized trial directly compared G-CSF with GM-CSF in 181 afebrile cancer patients undergoing myelosuppressive chemotherapy . Patients receiving G-CSF had a one-day shorter time to recovery from neutropenia, but the difference was neither clinically meaningful nor statistically significant.
●A prospective medication use evaluation study found similar efficacy, safety, and tolerability with G-CSF and GM-CSF .
●Two retrospective studies reported more adverse events and/or neutropenic fever with GM-CSF than with G-CSF [48,49]. By contrast, a retrospective matched pair cohort analysis derived from a health insurance claims database (and partially funded by the manufacturer of GM-CSF) concluded that patients receiving GM-CSF after outpatient chemotherapy had a lower risk of infection-related hospitalization compared with those receiving G-CSF or pegfilgrastim, a pegylated formulation of G-CSF that has a prolonged half-life .
In the absence of additional comparative data from randomized controlled trials, there is no basis for recommending one CSF over the other for prophylaxis of infection during chemotherapy-induced neutropenia. However, in practice, most institutions use G-CSF.
Dose and timing of G-CSF and GM-CSF — When used for primary and secondary prophylaxis, the recommended dose of G-CSF (filgrastim, filgrastim-sndz, tbo-filgrastim) is 5 mcg/kg per day and for GM-CSF (sargramostim), 250 mcg/m2 per day. To reduce cost, the dose is usually rounded off to the nearest vial size. Therapy is usually begun 24 to 72 hours after cessation of chemotherapy.
There is no consensus as to the optimal duration for either primary or secondary prophylaxis, and several strategies have been suggested:
●Year 2000 guidelines from ASCO suggest daily growth factor administration with twice weekly monitoring of blood counts until the ANC reaches 5000 to 10,000/microL; continuation until clinically adequate neutrophil recovery is achieved is a reasonable alternative .
●NCCN guidelines suggest daily administration until the post-nadir ANC recovers to normal or near-normal levels by laboratory standards .
●Several dose-dense chemotherapy regimens utilize a fixed schedule of G-CSF administration (eg, dose-dense AC plus T chemotherapy for adjuvant therapy of breast cancer suggests seven consecutive days of G-CSF (table 3)). However, at least one randomized trial suggests that daily administration of G-CSF for 5 days in the setting of primary prophylaxis is at least as effective as 7 or 10 days of daily administration, less costly, and associated with fewer adverse events driving G-CSF schedule changes .
In our view, either approach is reasonable. However, in either case, premature discontinuation of G-CSF or GM-CSF, before the nadir of the white blood cell count has been reached, should be avoided. These data may not apply much to women receiving breast cancer treatment in the United States where use of pegfilgrastim is more prominent. Furthermore, factoring in the cost of weekly complete blood count to monitor the neutrophil count and having the patient return to clinic daily for an injection, there might be minimal cost savings with either strategy.
Shorter administration schedules may have similar efficacy with lower cost and increased convenience for the patient . However, these approaches have not been compared with standard regimens in randomized trials.
Because of the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, growth factors should be discontinued several days before the next chemotherapy treatment and they should not be given on the same day as chemotherapy . Experience from clinical trials indicates that myelosuppression is more profound if the myeloid growth factors were given immediately prior to or on the same day as the chemotherapy. For the same reason, growth factors should not be given concurrently with RT directed at portals containing active marrow.
Long-acting agents — Pegfilgrastim, a pegylated formulation of G-CSF, was the first long-acting formulation of G-CSF. Since then, several other similar agents have shown efficacy. Choice between them is based on availability and cost, given comparable efficacy and side effects.
●Pegfilgrastim – Pegfilgrastim has a prolonged half-life, permitting the administration of a single dose rather than daily administration. The recommended dose (6 mg in adults, 100 mcg/kg [maximum 6 mg] in children ) is given 24 hours after chemotherapy , with at least 14 days elapsing until the next planned chemotherapy dose. Blood counts are typically not routinely monitored in patients receiving pegfilgrastim.
Multiple randomized trials and a meta-analysis have shown that pegfilgrastim is at least as effective as and more convenient to administer than G-CSF for primary prophylaxis in patients requiring CSF treatment during myelosuppressive chemotherapy [58-63]. Many trials in fact suggest better efficacy for pegfilgrastim over G-CSF .
•Related agents – Lipegfilgrastim, a glycoPEGylated, long-acting form of recombinant human filgrastim, which is marketed as Lonquex, is approved in the United Kingdom and by the European Medicines Agency (EMA), but it is not approved in the United States or Canada. Pegteograstim, marketed as Neurapeg, is another formulation of pegylated G-CSF that is approved in South Korea. Efficacy and safety of both agents appear similar to pegfilgrastim [63-66].
Four biosimilar forms of pegfilgrastim (pegfilgrastim-jmdb [Fulphila], pegfilgrastim-cbqv [Udenyca], pegfilgrastim-bmez [Ziextenzo], and pegfilgrastim-apgf [Nyvepria]) were approved in the United States between 2018 and 2020.
●Efbemalenograstim alfa – Efbemalenograstim alfa, a leukocyte growth factor, is a recombinant fusion protein consisting of human G-CSF, a 16 amino-acid linker, and the Fc portion of human IgG2 . It binds to specific cell surface receptors to stimulate proliferation and activation of leukocytes.
In a randomized trial (GC-627-04 [NCT02872103]) in 122 patients with breast cancer receiving doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 every 21 days for up to four cycles, those randomly assigned to efbemalenograstim alfa on cycle 1, day 2 of chemotherapy experienced a shorter duration of severe (grade 4) neutropenia during this cycle than those assigned to placebo (1.4 versus 4.3 days) . Febrile neutropenia was also lower (4.8 versus 26 percent).
In a separate randomized trial (GC-627-05 [NCT03252431]) in 393 patients with breast cancer receiving docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days for up to four cycles, efbemalenograstim alfa and pegfilgrastim resulted in the same mean number of days of severe neutropenia in cycle 1 (0.2 days with either agent) .
●Eflapegrastim – Eflapegrastim is a long-acting form of G-CSF, which consists of a recombinant human G-CSF analog conjugated to a human aglycosylated IgG4 Fc fragment with a short polyethylene glycol linker. The addition of an Fc fragment and the large size of the molecule extends drug half-life by decreasing clearance, and there is increased uptake in the bone marrow, presumably due to the interaction of the Fc fragment with receptors on surface of endothelial cells [68,69]. The end result is a shortened duration of chemotherapy-associated neutropenia.
In two separate randomized phase III trials, patients with early stage breast cancer treated with four cycles of standard dose docetaxel plus cyclophosphamide were randomly assigned to fixed-dose eflapegrastim (13.2 mg containing 3.6 mg G-CSF) or pegfilgrastim (containing 6 mg G-CSF), both administered on day 2, 24 hours after the end of chemotherapy [70,71]. Efficacy and safety were comparable, and despite the lower G-CSF dose, the incidence of adverse events (ie, musculoskeletal pain, injection site reactions) was not lower with eflapegrastim in either trial. In a preliminary report of a pooled analysis of both studies (totaling 643 patients), eflapegrastim modestly but significantly reduced the mean duration of severe neutropenia, which was defined as ANC <500/microL (0.24 versus 0.36 days, p = 0.029) and the overall risk of severe neutropenia during cycle 1 (17.5 versus 24 percent, relative risk reduction 27 percent, p = 0.043) compared with pegfilgrastim . Benefits were more pronounced in those with weight >75 kg (54 percent of the study population).
Largely based on these results, in September 2022, the US Food and Drug Administration approved eflapegrastim injection to decrease the incidence of infection in adult patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia .
Given the available data, the medications above appear clinically similar when used as supportive care for patients receiving docetaxel and cyclophosphamide. Their use will be determined largely by their relative acquisition costs.
Possible stimulation of malignancy — Because myeloid growth factor receptors are expressed by several hematopoietic and nonhematopoietic cell types, there has been a concern that certain malignant cell lineages might respond to therapy with a granulocyte CSF, potentially worsening the underlying condition or triggering the development of malignancy in a susceptible individual. As an example of such a concern, the use of G-CSFs in patients undergoing induction therapy for acute myeloid leukemia (AML) has been limited by evidence that malignant myeloblasts express receptors for such growth factors. Prophylactic antibacterial and antifungal agents are more commonly used during chemotherapy for AML rather than CSFs. The potential role of CSFs during induction therapy for AML is discussed in greater detail elsewhere. (See "Acute myeloid leukemia: Management of medically unfit adults" and "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Adjunctive care'.)
Several observational studies report that the use of CSFs during chemotherapy for other malignancies such as breast and lung cancer is associated with a small but likely real increased risk of therapy-related hematologic neoplasms, including AML, myelodysplastic syndrome (MDS), and possibly acute lymphoblastic leukemia/lymphocytic lymphoma (ALL/LL) [74-77]:
●This issue was addressed in a systematic review of 64 randomized trials of chemotherapy with or without G-CSF for a variety of neoplasms . Although a secondary malignancy (AML/MDS) was reported in significantly more patients treated with G-CSF (relative risk 1.85, 95% CI 1.19-2.88), all-cause mortality was significantly lower in patients receiving chemotherapy with G-CSF (relative risk for death 0.92, 95% CI 0.90-0.95), and greater reductions in mortality were observed in patients who received dose-dense chemotherapy regimens with G-CSF support compared with controls receiving no G-CSF support (relative risk for death 0.86, 95% CI 0.80-0.92).
●Additional data are available from a French population-based analysis of women who had been diagnosed with an incident breast cancer between 2007 and 2015, and received chemotherapy within six months following primary surgery; among the total 122,373 breast cancer survivors, 39 percent received chemotherapy alone and 61 percent chemotherapy plus G-CSF . The specific chemotherapy regimens were not described. At a median follow-up of 4.9 years (range 2.8-7.2), use of G-CSF was associated with a nonsignificant increase in the risk of AML (adjusted hazard ratio [aHR] 1.3, 95% CI 1.0-1.7), MDS (aHR 1.3, 95% CI 0.9-1.8), and of ALL/LL (aHR 2.0, 95% CI 1.0-4.4). A dose-effect relationship was evident for ALL/LL (1 to 3 cycles, aHR 1.5, 95% CI 0.5-3.9; for 4+ cycles, aHR 2.3, 95% CI 1.0-5.1) analysis, although there was a trend for an increasing hazard rate for both AML and MDS with increased cycles of G-CSF.
Thus, while the use of myeloid growth factors during chemotherapy increases the risk of a therapy-related hematologic neoplasm, the absolute magnitude of the risk is small, and the risk is probably outweighed by the benefits of using CSFs in this setting. Nevertheless, in January 2021, the United States Prescribing Information for both filgrastim and pegfilgrastim was modified to indicate a risk of both MDS and AML with both agents after chemotherapy and/or radiotherapy for lung cancer, and that patients should be monitored for signs and symptoms of AML/MDS in these settings [78,79].
The addition of G-CSF to high intensity, rapidly repeating courses of chemotherapy containing both alkylating agents and topoisomerase II inhibitors, such as doxorubicin plus cyclophosphamide followed by paclitaxel for the adjuvant treatment of breast cancer, has been associated with therapy-related myeloid leukemia with a particularly short latency period of two to three years. These data and this subject are addressed in more detail elsewhere. (See "Introduction to recombinant hematopoietic growth factors", section on 'Possible stimulation of malignancy' and "Overview of side effects of chemotherapy for early-stage breast cancer".)
SUMMARY AND RECOMMENDATIONS
•Patients receiving chemotherapy
-Consistent with guidelines from the American Society of Clinical Oncology (ASCO), the Infectious Diseases Society of America, and the European Society for Medical Oncology when the expected incidence of neutropenic fever with a specific antineoplastic regimen is over 20 percent, we suggest prophylactic colony stimulating factors (CSFs) during all cycles of chemotherapy to reduce the need for hospitalization for antibiotic therapy (Grade 2B). (See 'Indications, benefits, and guidelines' above.)
-When the estimated risk of neutropenic fever is between 10 and 20 percent, the decision to use prophylactic hematopoietic growth factor support should be individualized. Factors to consider when assessing the risk of a febrile neutropenic episode in patients undergoing cytotoxic chemotherapy for malignancy are summarized in the table (table 2).
Examples of specific patients who may be at risk for increased complications from prolonged neutropenia and for whom primary prophylaxis might be justified include individuals over age 65 and older who are receiving potentially curative therapy for diffuse aggressive lymphoma, and individuals undergoing curative-intent dose-dense chemotherapy regimens that are supported by convincing efficacy data (eg, adjuvant treatment of high-risk breast cancer; high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin for urothelial cancer).
In other situations where patients are being treated with curative-intent therapy, secondary prophylaxis is preferred for those who develop a neutropenic complication during a prior cycle of chemotherapy. (See 'Indications, benefits, and guidelines' above.)
However, during the COVID-19 pandemic, updated guidelines from the National Comprehensive Cancer Network (NCCN) and ASCO have lowered the threshold for the use of myeloid growth factors from those chemotherapy regimens which have a 20 percent or higher risk of febrile neutropenia to now include those regimens with a risk of 10 to 20 percent, which includes all of the intermediate-risk chemotherapy regimens.
•Chemoradiotherapy – Given the concerns for adverse events, avoid G-CSFs in patients receiving concomitant chemoradiotherapy for either head and neck or lung cancer. (See 'Use with concomitant chemoradiotherapy' above.)
•Choice of agent – In the absence of additional comparative data from randomized controlled trials, there is no basis for recommending one hematopoietic growth factor (G-CSF, granulocyte-macrophage [GM]-CSF, pegfilgrastim, or a biosimilar product) over the other for prophylaxis of infection during chemotherapy-induced neutropenia. (See 'GM-CSF versus G-CSF and biosimilars' above and 'Long-acting agents' above.)
•For patients who had an episode of neutropenic fever after an earlier cycle of palliative chemotherapy, we suggest dose reduction or delay as the primary therapeutic option rather than routine administration of CSFs (Grade 2C).
•However, consistent with ASCO guidelines, in circumstances in which a reduced dose or treatment delay may compromise disease-free survival, overall survival, or treatment outcomes, we suggest the use of G-CSFs for secondary prophylaxis rather than dose reduction (Grade 2C). (See 'Secondary prophylaxis' above.)
●Therapeutic use in patients with neutropenia
•There is no established role for G-CSFs in afebrile patients who have already developed severe neutropenia after chemotherapy, and we recommend against their use in this setting (Grade 1B). (See 'Neutropenia without fever' above.)
•We also suggest not using G-CSFs routinely as an adjunct to antibiotics for most patients with established fever and neutropenia (Grade 2C). However, CSFs can be a useful adjunct for patients who remain neutropenic and febrile after the initiation of antibiotics.
Consistent with guidelines from ASCO, we restrict use of CSFs to patients at high risk for infection-associated complications or who have prognostic factors that are predictive of a poor clinical outcome. These include expected prolonged (>10 days) or profound (<100 cells/microL) neutropenia, age >65, pneumonia or other clinically documented infection, sepsis syndrome, invasive fungal infection, prior episode of febrile neutropenia, or being hospitalized at the time of the development of fever. (See 'Neutropenic fever' above.)
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