Colony-Stimulating Factors Including Biosimilars for At-Risk Patients

The purpose of this study was to review the best current evidence for the efficacy of G-CSFs (filgrastim, pegfilgrastim, and lenograstim) for the primary and secondary prophylaxis of chemotherapy-induced neutropenia, specifically for the primary outcomes of incidence and risk of neutropenia, infections, and infection-induced mortality. Secondary aims include review of the best and current evidence for the efficacy of G-CSFs for the outcomes of duration of neutropenia, hospitalizations, and antibiotic therapy.

MEDLINE (1966 to date), EMBASE (1980 to date), the Cochrane Library, and the Odyssey databases were searched.
Key words included colony-stimulating factors, filgrastim, nuepogen, pegfilrastim, neulasta, lenograstim, granocyte, neutropenia, fever

Inclusion criteria:

• Randomized, controlled trials (RCTs) from the year 2000 and newer with more than 80 participants that investigated the named G-CSFs in comparison to placebo, other G-CSFs or no treatment, or in combination with antibiotics versus antibiotics alone for initiation of treatment (prior to neutropenia onset) or secondary prophylaxis during chemotherapy (minimum three-week follow-up (initiated during chemotherapy cycles following neutropenia of febrile neutropenia onset in a previous cyle).
• Data from meta-analyses, overviews of more than two studies, and systematic reviews of trial involving the named G-CSFs and where available, cost-effectiveness analyses of any of the studies meeting the inclusion criteria also were included.

Exclusion criteria:

• Non-English publications and studies published in abstract form only

Initially, 11 RCTs, two study overviews, four meta-analyses, and three economic analyses were reviewed. One RCT was excluded to bring the total to 10.

The inclusion criteria state that RCTs included in this review needed to have more than 80 participants, yet one study included had 49. In addition, the inclusion of three economic studies did not match the study aim of efficacy of use of G-CSFs for reduction of neutropenia and related complications. Two of these economic studies were analyses of two of the RCTs being evaluated for efficacy in neutropenia prevention/reduction. The third economic study did not have details about the trial disclosed.

• 20 studies were included in the total sample
• 7,409 subjects in total
• The sample range across studies was 49–1,823 subjects

The use of G-CSF is overall effective for the reduction of neutropenia, febrile neutropenia, associated infections, antibiotic use, and hospitalizations in various populations of adult patients with cancer. The use of pegfilgrastin is more effective than filgrastin in reducing the risk of febrile neutropenia and pegfilgrastin is as effective as filgrastin in reducing the duration of severe neutropenia.

In the pediatric population with cancer, use of G-CSFs is effective in reducing the risk of febrile neutropenia and associated hospitalizations, but is not effective in reducing infections.In older adult populations, G-CSFs were effective for reduced use of antibiotics but not for risk of febrile neutropenia.

Current trials show that G-CSFs are overall effective in reducing the risk of neutropenia, febrile neutropenia, and associated infections, hospitalizations, and antibiotic use for various populations of patients with cancer undergoing chemotherapeutic treatments.

Current American Society of Clinical Oncology recommendations promote the use of G-CSFs for patients receiving chemotherapeutic treatments that have a greater than 20% risk of inducing febrile neutropenia. Although this review found mixed results within the studies evaluated and the criteria for this review stated was not completely followed; overall findings do indicate that G-CSF continues to be an effective therapy in the reduction of neutropenic events and related sequelae.

Implications for nursing practice include understanding the use and effectiveness of administration of G-CSF, promoting its use, and continued monitoring for neutropenia, febrile neutropenia, and infections.

The purpose of this study was to determine the effectiveness of G-CSF and GM-CSF in patients with malignant lymphomas for improving overall survival (OS) and freedom from treatment failure (FFTF). Secondary goals were to to decrease the risk and duration of neutropenia and febrile neutropenia, infection and mortality during chemotherapy; improve received dose intensity, tumor response, and quality of life; and examine adverse effects.

Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CancerLit, Medikat, Russmed Articles, SOMED, Toxline, BIOSIS Previews, and LILACS databases were used.

In addition, Internet databases of grey literature (SIGLE) and ongoing trials were reviewed, as were conference proceedings. Experts and pharmaceutical companies also were contacted for unpublished or ongoing trials. Citations of identified trials also were searched.

Key words included granulocyte–colony-stimulate factor (G-CSF), granulocyte-macrophage–colony-stimulating factor (GM-CSF), malignant lymphoma
 
Studies were included if they were randomized, controlled trials (RTCs) conducted from January 1980 to April, 2008 comparing G-CSF or GM-CSF prophylaxis with placebo or no prophylaxis; studies on long-lasting G-CSFs (e.g., filgrastim) also were included. Abstracts and unpublished data were included if enough data were available on study design, patient characteristics, interventions, and outcomes.
 

Studies were excluded if they were crossover studies, quasi-randomisedand, or nonrandomised comparative studies.

306 total abstracts were reviewed. Of these, 90 studies were evaluated and 74 excluded for not meeting inclusion criteria. The remaining 16 RTCs met inclusion criteria, but three of these were later excluded due to not fulfilling all criteria.

Subgroup analysis and investigation of heterogeneity (drug type: G-CSF versus GM-CSF; Hodgkin disease versus non-Hodgkin lymphoma; age [trials that included all ages 16 and older versus those restricted to older than age 60 years]; administration of prophylactic antibiotics during chemotherapy; different toxicity of chemotherapies); sensitivity analysis (placebo-controlled versus open label; concealment of allocation; size of studies [less than 100 versus 100 or greater]; published versus unpublished, unreported, or abstract based; and duration of follow-up). Statistical analyses included hazard ratios (OS and FFTF) (missing patient data analyzed using published survival curve methods); relative risk and 95% confidence interval (CI) (binary data) using the Mantel-Haenszel method for pooling (pooled using a fixed effect model); continuous data calculated as weighted mean differences with 95% CI; heterogeneity of treatment effect via chi-squared (p < 0.05); robustness of overall results and causes of heterogeneity assessed by sensitivity and subgroup analyses; funnel plots and linear regression (for bias; 0.1 = significant) used for meta-analyses of four or more trials; all data based on intention-to-treat or full set analysis.

• The final sample size included 13 RTCs.
• Total subjects across reviewed studies ranged from 25–784.
• 2,607 randomized patients were included in the review.
• Patients were aged 16 years and older with malignant lymphomas (Hodgkin disease or non-Hodgkin lymphoma) with the histological classifications of Working Formulation, Kiel, REAL, and WHO.
• All participants received standard nonmyeloablative chemotherapeutic agents and either G-CSF or GM-CSF within 72 hours of receiving the chemotherapy and prior to onset of neutropenia in the first or second line treatment of their malignant lymphoma.
• The control groups had to receive the same chemotherapies and same supportive care.

• The phase of care was active treatment
• Application was for elderly care

The prophylactic use of G-CSF or GM-CSF in patients aged 16 years and older with malignant lymphomas who underwent standard chemotherapy treatment had a reduced risk of neutropenia, febrile neutropenia, and infections. The prophylactic use of G-CSF or GM-CSF in this patient population does not increase overall survival or freedom from treatment failure.

Since neutropenia, febrile neutropenia, and infections are prevalent among patients with malignant lymphomas being treated with chemotherapeutic agents, the prophylactic use of G-CSF and GM-CSF is warranted to decrease the risk of these deleterious treatment effects.

Implications for nursing practice include knowledge about the efficacy of using these growth factors, advocating for their use, and close patient monitoring.

PHASE OF CARE: Active antitumor treatment

883 patients across studies did not receive G-CSFs, of which 21.97% developed FN (adjusted rate 23.2%). Compared to patients who did not receive G-CSFs, patients who received G-CSFs had an OR of 0.077 (95% CI [0.013, 0.460]), a 92.3% lower incidence rate. Patients younger than age 65 also had a lower rate of FN (4.2%–66.7%) compared to patients 65 and older (7.7%–88.2%).

Use of G-CSFpp significantly reduces the risk of FN in patients with early-stage breast cancer receiving TC therapy. Patients younger than age 65 also have a reduced risk of FN compared to patients 65 years and older.

The reporting of findings differed between use of G-CSF (OR) and no use (%). They did report a 93% lower risk with use of G-CSF. The reporting of age differences did not differentiate between use or no use of G-CSF.

Aside from the limitations noted above, use of G-CSF as primary prophylaxis reduces the risk of FN in this patient population. Oncology nurses should be aware of the risks of FN in patients being treated with TC for early-stage breast cancer and promote use of G-CSFpp.

STUDY PURPOSE: Analyzing interventions for management of chemotherapy-induced febrile neutropenia in adult patients with cancer.

TYPE OF STUDY: Systematic review

DATABASES USED: LILACS (Latin American and Caribbean Literature in Health Sciences), SciELO (Scientific Electronic Library Online), BVS (Virtual Library of Health), PubMed, CINAHL (The Cumulative Index to Nursing and Allied Health Literature), and Web of Science

YEARS INCLUDED: 2010-2015

INCLUSION CRITERIA: Primary articles published in English, Portugese, or Spanish, articles with methodology demonstrating interventions related to the management of chemotherapy-induced febrile neutropenia in adult patients, published between 2010-2015, full-text article availability in the selected databases

TOTAL REFERENCES RETRIEVED: 2,892 articles

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Duplicate articles were first removed from the original 2,892 articles retrieved, followed by elimination of articles that did not cover the research topic, and then finally articles that did not meet the inclusion criteria were removed from the original sample.

• FINAL NUMBER STUDIES INCLUDED: 12 
• TOTAL PATIENTS INCLUDED IN REVIEW: Information not included in the article
• SAMPLE RANGE ACROSS STUDIES: Adult patients treated for both hematologic and oncologic malignancies with chemotherapy who developed febrile neutropenia during some course of treatment, use of growth factors in this population in some studies as well 
• KEY SAMPLE CHARACTERISTICS: Adult patients with cancer being treated with chemotherapy, development of febrile neutropenia, treatment with various pharmacologic treatment

PHASE OF CARE: Active anti-tumor treatment

Prophylactic use of colony stimulating factors in patients was effective in avoiding reduction of chemotherapy doses and cycle delays. One of the studies cited use of piperacillin/tazobactam as effective treatment for febrile neutropenia while another one compared ciprofloxacin and cefepime, noting cefepime to be more effective. Neither study reviewed by authors presented a strong case for one antibiotic treatment over another. There were some studies included citing use of biomarkers to classify febrile neutropenia risk in patients and treat prophylactically for those at high risk in the outpatient setting.

Based on the review of these 12 studies, it is evident that the prophylactic use of growth stimulating factors in patients with cancer limits episodes of febrile neutropenia, particularly in diseases such as breast cancer and lymphoma where febrile neutropenia is well documented. There was not a general consensus that could be made for a specific antimicrobial treatment for these patients as many studies cited different medications that deemed effective for patients. Authors note lack of interdisciplinary literature regarding febrile neutropenia guidelines.

• Limited search
• Limited number of studies included

Authors cite the need to have nurses, as well as pharmacists and other members of the interdisciplinary team, involved in development of guidelines and protocols as all members of the team treat these patients and need to be knowledgeable about febrile neutropenia.

The purpose of the article is to assess the influence of colony-stimulating factors (CSFs) on the prevention and treatment of infectious complications in patients with acute myelogenous leukemia (AML).

The Cochrane Central Register of Controlled Trials, MEDLINE (January 1966 to July 2010), and LILACS (through December 2009) databases were searched, as were ongoing trials and conference proceedings from January 2002 to June 2010 from the European Group for Bone and Marrow Transplantation, the Annual Meeting of the European Hematology Association, the Annual Meeting of the Society for Hematology and Stem Cells, and the Center for International Blood and Marrow Transplant Research (CIBMTR).

Articles included in this review were randomized, controlled trials that compared the addition of CSFs during and following chemotherapy to chemotherapy alone in patients with AML and included age, type of AML (morphology criteria according to the FAB classification), leukemia type (de novo AML, secondary AML, refractory AML, relapsed AML), white blood cell count, platelet count, and treatment stage (induction, consolidation, relapse).

Articles were excluded if they were reporting on trials evaluating the role of CSFs administered for the purpose of stem cell collection and/or priming (e.g., before and/or only for the duration of chemotherapy).

1,421 total references were retrieved.

Following a review of each study by two reviewers, statistical analyses were conducted including relative risk with a 95% confidence interval (CI) for dichotomous data and hazard ratios for time-to-event outcome. Cochrane handbook criteria were used to assess study quality.

• 19 studies were included in the final review.
• The total sample size of the combined studies was 5,256.
• The sample size across studies ranged from 53–803.
• The patient population was diagnosed with AML (per World Health Organization 2008 classification), were at any stage of treatment following chemotherapy, and were of all ages.
• The ages varied per study with one pediatric study including patients younger than 16 years old (Nakajima) and another (Lehrnbecher) aged 0–18. Four studies contained patients aged 15–60, six contained patients older than age 55, and eight had patients older than age 15.
• Chemotherapy regimens also varied and included numerous agents used as induction, consolidation, or salvage therapy, or conditioning regimens for HCT.
• All patients in the intervention arms of the studies evaluated received CSF (G-CSF or GM-CSF), IV or subcutaneous, started with or following chemotherapy.
• Those receiving CSF as part of the HCT cell collection or conditioning were excluded.
   

Active treatment

No statistically significant differences were found between patients who received CSF with chemotherapy compared to those who did not. This included no differences in 30 day all-cause mortality (RR = 0.97; 95% CI [0.8, 1.18]) and end of follow-up (RR = 1.01; 95% CI [0.98, 1.05]), overall survival (HR = 1.00; 95% CI [0.93, 1.08]), complete remission (RR = 1.03; 95% CI [0.99, 1.07]), relapse (RR = 0.97; 95% CI [0.89, 1.05]), disease-free survival (HR = 1.00; 95% CI [0.9, 1.13]), decrease in bacteremias (RR = 0.96; 95% CI [0.82, 1.12]) or invasive fungal infections (RR = 1.4; 95% CI [0.9, 2.19]). There was a slight increase in adverse events requiring discontinuation of CSFs in intervention groups compared to controls (RR = 1.33; 95% CI [1.00, 1.56]). Among 17 studies in which duration of neutropenia was reported, in all but one study the duration of neutropenia was significantly shortened with CSFs. Several studies reported a significant shortening of duration of hospital stay with CSFs, while others showed no difference.

Administration of CSFs is associated with decreased episodes of febrile neutropenia and febrile days; however, it shows no statistically significant benefit of being administered with chemotherapy for improved survival and decreased infection rates. Since hematopoiesis is different in pediatric patients compared to adults (occurring in the bone marrow of long bones and at higher rates in pediatric populations, and in flat bones at slower rates in adults and older adults), benefits may be found in older age groups when using CSF with chemotherapy. Among the studies that had a mean age of patients at 58 years and older (n = 7), six of them showed more favorable outcomes in patients who received CSF.

The composite evaluation of all age groups together.

Implications for practice based on this study are unfavorable to use CSF for decreased infection rates among all age groups. Further evaluation in older age groups may be warranted.

The purpose of the study was to compare the effectiveness of prophylactic G-CSF or GM-CSF with prophylactic antibiotics for the prevention of febrile neutropenia, severe infection, infection-related mortality, and overall mortality in patients of all ages with any type of malignancy receiving myeloablative chemotherapy.

The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE databases were searched from January 1985 to January 2008, as were proceedings from the American Society of Clinical Oncology and the American Society of Hematology (2000–2007). In addition, references from identified trials, relevant reviews, guidelines, and ongoing clinical trials were searched.

Key words included  granulocyte–colony-stimulate factors (G-CSF), granulocyte macrophage–colony-stimulating factors(GM-CSF), antibiotics, cancer

Studies were included if they were randomized, controlled trials conducted from January 1980 to January 2008 comparing G-CSF or GM-CSF prophylaxis with antibiotic prophylaxis in patients with cancer receiving myeloablative chemotherapy.

Studies were excluded if they were non-randomixed and were quasi-randomized with information on perioperative infection prophylaxis, stem cell mobilization, and priming of malignant cells with G-CSF or GM-CSF.

10,924 abstracts and 473 full-text articles were reviewed.

Forty-four were considered for the review.

Two articles were included in the final review.

Subgroup analyses conducted for types of underlying malignancies, baseline risk factors for febrile neutropenia for infection, inpatient versus outpatient setting, type of treatment (chemotherapy, hematopoietic stem cell transplantation), types of growth factors administered, age, and antimycotic prophylactic administration.

It was not possible to conduct a meta-analysis as planned due to differences in outcomes among the two studies included in this review.

Studies that were excluded were made up of 36 trials that compared antibiotics and G-CSF prophylaxis to antibiotic prophylaxis alone, four trials that compared prophylactic antibiotics and growth factors to growth factors prophylaxis alone, one due to different chemotherapeutic agents used in each of the study arms, and one non-randomized study comparison. Therefore, only two studies fit the exact inclusion criteria.

• 195 randomized patients were included in this review.
• The sample size across studies ranged from 40–155 participants.
• Participants were adults with solid tumors (small cell lung cancer or breast cancer) who received either oral antibiotics (ciprofloxacin and amphotericin B or cotrimoxazole) or subcutaneous injections of G-CSF or GM-CSF.

In the two trials evaluated, both showed efficacy for use of prophylactic colony-stimulating factors (G-CSF or GM-CSF) or antibiotics for decreased risk of infection; however neither colony-stimulating factors or antibiotics proved better than the other in adults with solid tumors who received myeloablative chemotherapy. No differences were found for infection-related mortality, treatment-related or early mortality, febrile neutropenia, the incidence of severe infections, or infectious episodes.

The use of prophylactic treatment with G-CSF, GM-CSF, or antibiotics for the reduction of risk of infections among adults receiving myeloablative chemotherapy for the treatment of small cell lung cancer or breast cancer is effective; however, use of a colony-stimulating factor versus an antibiotic is inconclusive in terms of better efficacy. More trials are warranted to evaluate prophylactic antibiotic versus colony-stimulating factor use for reduced risk of neutropenia, febrile neutropenia, infections, hospitalizations, and survival.

Implications for nursing practice include knowledge of the known literature and lack of information available. Use of a prophylactic treatment (colony-stimulating factor or antibiotic) for infection prevention is warranted.

The primary purpose of this study was to determine the percentage of patients experiencing febrile neutropenia. A secondary goal was to examine infection-related mortality, all early mortality during chemotherapy, bone pain or musculoskeletal pain, and relative dose intensity.

Medline, EMBASE, Cancerlit, Cochrane, Database of Systematic Reviews,and Cochrane Central Register of Controlled Trials database were reviewed.

Key words include G-CSF, granulocyte–colony-stimulating factor, colony-stimulating factors (CSFs), recombinant G-CSF, lenograstim, filgrastim, pegfilgrastim, and pegylated filgrastim, randomized controlled trials

Inclusion criteria was primary and secondary G-CSF prophylaxis   

Studies were excluded if they encompassed those with granulocyte macrophage–colony-stimulating factor (GM-CSF), RCTs in children, leukemia or multiple myeloma, bone marrow or peripheral blood stem cell transplantation, and studies of established neutropenia or febrile neutropenia.
 

12,128 potentially relevant papers were reviewed.

Cochran’s Q statistic and inconsistency index of Higgins,fixed-effects model, and random effects models.

The Jadad scale was used to evaluate study quality.

17 randomized, controlled trials (RCTs) were included.

The total sample size was 3,493 patients  

The sample across all studies ranged from 31–928

Key characteristics included filgrastim in 10 trials (59%), lenograstim in six trials (35%), and pegfilgrastim in one trial (6%). Eleven trials (65%) involved patients with solid tumors and six (35%) were in patients with lymphoma, including four (24%) limited to older adult patients, eight studies using placebo control, and three that permitted secondary G-CSF in control patients (two prohibited its use and the remaining studies did not specify). Five RCTs prohibited the use of prophylactic antibiotics and three used antibiotic prophylaxis. The remaining did not specify.

Active treatment

Reductions in infection-related and early mortality with G-CSF were seen in patients with solid tumors but not among those with lymphoma.

This analysis and review confirms that primary prophylaxis with G-CSF significantly reduces the risk of febrile neutropenia while sustaining and enhancing chemotherapy dose delivery in patients receiving conventional chemotherapy across a broad range of baseline risk in eligible trials. The most important and previously unreported observation that emerged from this overview is the observed reduction in infection-related (RR = 0.552, p = 0.018) and all-cause (RR = 0.599, p = 0.002) early mortality in patients randomized to receive primary prophylaxis with G-CSF. There were no differences based on whether or not patients also received prophylactic antibiotics or between those receiving G-CSF as primary or secondary prophylaxis. 

• Early mortality was not defined in this analysis.
• Although methods for determination of heterogeneity were discussed, findings regarding heterogeneity were not reported.

To evaluate primary granulocyte colony-stimulating factor (G-CSF) prophylaxis versus a placebo or untreated control group

DATABASES USED: Electronic databases through December 2006: MEDLINE, EMBASE, CANCERLIT, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effect, and Conference Proceedings (American Society of Clinical Oncology and American Society of Hematology). In addition, references from included articles and relevant published reports were hand searched, and references from leaders in the field were solicited. The literature search had no language restrictions.

INCLUSION CRITERIA:

• Eligible studies were those of adult patients with cancer receiving conventional-dose chemotherapy for solid tumors or malignant lymphoma and randomly assigned to primary G-CSF prophylaxis versus a placebo or untreated control group.
• Primary G-CSF prophylaxis refers to G-CSF administration in the first cycle of chemotherapy before the onset of neutropenia, whereas secondary G-CSF prophylaxis is defined as G-CSF prophylaxis started in the chemotherapy cycle after the first episode of febrile neutropenia (FN). Patients may have received prophylactic antibiotics as long as they were permitted equally in both study arms.
• G-CSF must have been administered continuously until neutrophil recovery. Previous studies and guidelines concluded that myeloid growth factors are less effective if administered on the same day as chemotherapy, delayed more than four days following chemotherapy, or delayed until the onset of neutropenia. Therefore, studies were eligible only if the initiation of G-CSF was one to three days after the completion of myelosuppressive chemotherapy in each cycle.
• Studies in which control patients received secondary G-CSF prophylaxis after the first cycle with the same myeloid growth factor were permitted.

EXCLUSION CRITERIA:

• Studies were excluded if they used granulocyte-macrophage colony stimulating factor, were studies of children or patients with leukemia or multiple myeloma, included bone marrow or peripheral blood stem cell transplantation, or represented an economic analysis.
• Studies also were excluded if G-CSF was administered for established neutropenia or FN. Studies of patients receiving dose-dense or dose-escalation chemotherapy were excluded, as were studies that allowed differing drugs, doses, or schedules of chemotherapy or G-CSF in the different study arms.

FINAL NUMBER STUDIES INCLUDED = 17 RCTs of primary prophylactic G-CSF

TOTAL PATIENTS INCLUDED IN REVIEW = 3,493 patients

KEY SAMPLE CHARACTERISTICS:

• Ten studies (59%) used filgrastim, six (35%) used lenograstim, and one (6%) used pegfilgrastim.
• The cancer types consisted of solid tumors in 11 trials (65%) and aggressive non-Hodgkin lymphoma in six RCTs (35%).
• Four RCTs (24%) were limited to elderly patients with lymphoma.
• Eight studies used placebo control.
• At least three trials permitted secondary prophylaxis with G-CSF in control patients, with only two reports explicitly prohibiting this use of G-CSF. Eleven trials failed to specify whether secondary prophylaxis with G-CSF was allowed in controls.
• Prophylactic antibiotics were used in three trials, prohibited in five trials, and not specified in eight trials.

The occurrence of FN was reported as an outcome in 15 trials with 3,182 patients.

• G-CSF reduced the risk of FN by 46%.
• FN occurred one or more times in 39.5% of controls and 22.4% of G-CSF patients, resulting in a weighted summary RR of 0.54 (95% CI, 0.43 to 0.67; P < .0001).
• Filgrastim (RR = 0.61; 95% CI, 0.53 to 0.72) and lenograstim (RR = 0.62; 95% CI, 0.44 to 0.88) had similar efficacy.
• The single pegfilgrastim study demonstrated significantly greater efficacy (RR = 0.08; 95% CI, 0.03 to 0.18) compared with filgrastim and lenograstim (P < .0001).

Infection-related mortality was reported as an outcome in 12 trials including 1,454 control patients and 1,463 patients receiving G-CSF.

• Overall, infection-related mortality was observed in 2.8% of controls and 1.5% of G-CSF patients, for a weighted summary RR of 0.55 (95% CI, 0.34 to 0.90; P = .018).
• Reductions in infection-related mortality with G-CSF were observed among studies of filgrastim (RR = 0.53; 95% CI, 0.30 to 0.92; P = .024). Statistical analysis of the subset of patients who received lenograstim or pegfilgrastim was not possible because the sample size was too low to detect differences.

Early mortality was reported in 13 trials with 3,122 patients.

• Overall, early mortality was observed in 5.7% of control patients and 3.4% of G-CSF patients, resulting in a weighted summary RR of 0.60 (95% CI, 0.43 to 0.83; P = .002).
• Reductions in early mortality with G-CSF were observed among studies of filgrastim (RR = 0.60; 95% CI, 0.41 to 0.89; P = .010) and pegfilgrastim (RR = 0.36; 95% CI, 0.13 to 0.99; P = .047) but not lenograstim (RR = 0.84; 95% CI, 0.38 to 1.83; P = .657).

Relative dose intensity (RDI) was reported as an outcome in 10 trials. The average RDI among control patients in these studies ranged from 71.0%–95.0%, with a mean RDI of 86.7% (median RDI: 88.5%).

• Among G-CSF-treated patients, the average RDI ranged from 91.0%–99.0%, with a mean RDI of 95.1% (median RDI: 95.5%). RDI differences between study arms ranged from 2.8%–20.0%, with average differences of 8.4% (P = .001). None of the 10 G-CSF treatment arms reported an average RDI of less than 90%, whereas 6 of 10 control groups reported a mean RDI of less than 90%, with four control arms averaging an RDI of 85% or less.

Bone or musculoskeletal pain during the course of chemotherapy was reported as an outcome in 14 trials including 3,029 patients.

• Bone pain was reported in 10.4% of controls and 19.6% of G-CSF-treated patients, for a weighted summary RR of 4.023 (95% CI, 2.156 to 7.52; P < .0001).

The purpose of the study was to evaluate colony-stimulating factors (CSFs) administered prophylactically, before the onset of neutropenia or fever, compared with concurrent placebo or untreated controls not allowing any dose escalation.

MEDLINE, EMBASE, and Cochrane Library databases were searched, and hand searches of references from published reports were conducted.

Eight randomized, controlled trials (RCTs), including 1,144 patients receiving chemotherapy for solid tumors (n = 753) or malignant lymphomas (n = 391); studies of patients who were receiving high-dose therapy that required stem cell or bone marrow transplantation (BMT) support or who were being treated for acute or chronic leukemia were excluded.

The overall mean risk of febrile neutropenia was 51% among patients not receiving CSFs, and the overall mean risk of febrile neutropenia was 32% among patients receiving CSFs.

CSFs significantly reduced:

• Febrile neutropenia by 37%
• Documented infections by 6%
• Chemotherapy dose reduction or treatment delay by 20%.

CSFs increased the risk of:

• Bone pain by 15%.

CSFs did not improve infection-related mortality.

The authors concluded that CSFs are effective in reducing the risk of febrile neutropenia, documented infections, and chemotherapy dose reductions or delays, but they increase the risk of bone pain. CSFs had no impact on infection-related mortality.

STUDY PURPOSE: To evaluate the relative merits of same-day versus next-day dosing of long-acting G-CSFs. Study aims are to conduct a broad search of the literature, to examine the volume of data on same day versus next-day long acting G-CSFs, and to explore the relationship between timing of administration and efficacy, effectiveness, and safety

TYPE OF STUDY: Systematic review

DATABASES USED: Ovid MEDLINE^®, Embase^®, Congress abstracts

YEARS INCLUDED: (Overall for all databases) no limit up to May 8, 2016 (Ovid MEDLINE and Embase); January 1, 2011 to April 6, 2016 (Congress abstracts)

INCLUSION CRITERIA: Followed the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Publications reporting results from studies in humans in the English language, intervention included long-acting G-CSFs (pegfilgrastim, balugrastim, lipegfilgrastim, and empegfilgrastim) for the prophylaxis of chemotherapy-induced neutropenia were included. Included comparisons included long-acting G-CSF administration on the same day as chemotherapy and administration of long-acting G-CSF on the next day within the same study. Outcomes included neutropenia, leukopenia, FN, ANC, neutropenia-related infection, hospitalization, anti-infective use, or G-CSF--related safety outcome. Acceptable study designs included RCTs, prospective and retrospective non-randomized trials, longitudinal studies, registry studies, and open-label studies 

EXCLUSION CRITERIA: Studies were excluded if they did not meet inclusion criteria (most notably had no relevant outcomes, no relevant comparison between same-day and next-day long-acting G-CSF administration, wrong indication, or were not in humans), were duplicate studies, or were not deemed to be an acceptable design

TOTAL REFERENCES RETRIEVED: 1,736 publications, of which 11 were found to meet all inclusion criteria and were included in the review 

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Participants, interventions, comparisons, outcomes, and study design (PICOS) criteria were prospectively defined. Identified abstracts through the broad search were analyzed by two reviewers using PICOS criteria to determine eligibility. Full-text publications from the initial eligibility review were examined by two independent reviewers to confirm eligibility. Conflicts were resolved by a third senior reviewer. Data from eligible publications were extracted into a purpose-created data table; however, no formal statistical analysis was planned nor completed.

• FINAL NUMBER STUDIES INCLUDED: 11 studies, including 4 randomized or single-arm prospective studies, 7 retrospective studies
• TOTAL PATIENTS INCLUDED IN REVIEW: 46,979
• SAMPLE RANGE ACROSS STUDIES: Single-arm studies ranged from 19 to 192, retrospective studies ranged from 24 to 45,592
• KEY SAMPLE CHARACTERISTICS: Tumor types included non-small cell lung cancer, breast cancer, head and neck cancer, urothelial carcinoma, gynecologic malignancies, and other solid tumors. Nine of 11 studies evaluated pegfilgrastim on the same day or after chemotherapy. One study evaluated daily filgrastim or a single dose of pegfilgrastim administered on the same day or day 2-plus. One study evaluated filgrastim or pegfilgrastim administered on day 3 versus day 7 during a five-day chemotherapy course.

PHASE OF CARE: Active anti-tumor treatment

Safety: Safety results showed only small differences in the rates of all-grade adverse events and serious adverse events between the same-day and next-day pegfilgrastim groups

Neutropenia: Of the 11 publications included in the review, six reported higher rates and longer duration of neutropenia and/or FN for same-day LA G-CSF administration compared with next day administration (included data from two randomized studies and four retrospective). In these studies, same-day LA G-CSF administration was associated with increased grade 4 neutropenia compared with next-day administration in up to four treatment cycles. Retrospective safety studies and a large cohort study using claims data from more than 45,000 patients support the findings from the randomized trials that demonstrated next-day LA G-CSF administration resulted in lower rates of grade 3/4 neutropenia and/or FN compared with same-day LA G-CSF. Five studies showed lower or comparable rates and duration of neutropenia and/or FN for same-day compared to next-day LA G-CSF administration. These studies generally included small patient populations, retrospective designs, or did not have an adequate control arm to allow for accurate comparison. Nearly all studies reporting safety outcomes showed only small differences in the rates of all-grade adverse events and serious adverse events for same-day LA G-CSF versus next-day LA G-CSF.

Administration of pegfilgrastim at least 24 hours after chemotherapy (next day LA G-CSF) resulted in improved outcomes for patients with various tumor types receiving chemotherapy, including reduced incidence of grade 3/4 neutropenia and/or FN. Additionally, safety results for same-day LA G-CSF versus next-day LA G-CSF showed only small differences in the rates of all-grade adverse events and serious adverse events.

• Limited number of studies included
• Low sample sizes
• Study funded by Amgen Inc., maker of pegfilgrastim; authors are stockholders in Amgen

Findings show that administration of pegfilgrastim 24 to 72 hours after the completion of myelosuppressive chemotherapy (next-day LA G-CSF) is more effective than same-day LA G-CSF in preventing neutropenia and/or febrile neutropenia and is associated with fewer incidences of grade 3/4 neutropenia

• FINAL NUMBER STUDIES INCLUDED = 18; 3 were conference abstracts 
• TOTAL PATIENTS INCLUDED IN REVIEW = 22,882
• SAMPLE RANGE ACROSS STUDIES: 20–32,072
• KEY SAMPLE CHARACTERISTICS: Multiple tumor types

PHASE OF CARE: Active antitumor treatment

Findings suggest that the use of long-acting CSFs was associated with a lower risk of FN, FN hospitalizations, and other related adverse patient outcomes.

• Tumor types varied. Those with hematologic cancers were included, but there was no subgroup analysis to differentiate from those with lower-risk solid tumor types.
• Variability of chemotherapy regimens involved
• Variation in the timing and duration of short-acting CSF interventions and dose differences that were not captured in the data
• Known potential inaccuracies of medical claims data from which most cases were obtained
• There is no single diagnosis code for FN, and the algorithms used to define FN can vary.
• Low GRADES quality rating of studies included.
• Some data was provided per patient, and some was provided per cycle.
• In some studies, patients had received both filgrastim and pegfilgrastim.

Findings suggest that use of long-acting CSF may provide better prophylaxis for FN and FN-related events, but data and limitations of this review were insufficient to draw firm conclusions. Because of the variety of new biosimilar alternatives, additional work to determine comparative effectiveness and cost-benefit analysis of various formulations is increasingly important. This study does raise the question of what denominator is best used in outcomes measurement, whether outcomes should be viewed per patient, per cycle, or per patient-cycle.

TOTAL REFERENCES RETRIEVED: 731 full publications and 108 Congress abstracts; duplicates were removed, leaving 700 items

PHASE OF CARE: Active antitumor treatment

Pegfilgrastim did not consistently show better efficacy or effectiveness in all studies, but the vast majority showed better efficacy and effectiveness compared to daily G-CSF, no upfront pegfilgrastim, no G-CSF or placebo in regards to CIN, febrile neutropenia (FN), chemotherapy dose reductions/delays, antibiotic use, and neutropenia-related hospitalizations. It is suggested that pegfilgrastim has an acceptable safety profile with similar AEs between pegfilgrastim and filgrastim.

Pegfilgrastim is currently being widely used in clinical practice, showing similar efficacy/effectiveness with acceptable safety profiles.

Limitations include the quality of the underlying studies. Some studies did not report number of patients receiving primary prophylaxis versus secondary prophylaxis, which may have led to underestimation of effectiveness. Studies were not consistent in their definitions of FN and CIN. Combined measures of effect are missing in the analysis.

Further studies in broader patient populations are needed to confirm. This review adds to the body of evidence that shows mixed findings regarding the question of whether pegfilgrastim use achieves better patient outcomes than daily filgrastim. It is also unclear if either of these has better results for primary or secondary prophylaxis.

The purpose of this meta-analysis and systematic review was to obtain pooled estimates of comparative efficacy of pegfilgrastim and filgrastim.

The PubMed and EMBASE databases were used.

Key words were neupogen, filgrastim, recombinant methionyl human granulocyte–colony-stimulating factor, G-CSF, CSF, longrastim, polyethylene glycol conjugated filgrastim and related terms

Studies were included if they were randomized, controlled trials (RCTs) if the patients were adults with non-myeoloid cancer, had a test of a single 6 mg dose or 100 mcg/ke of pegfilgrastim after start of chemotherapy, and a daily filgrastim comparator. Endpoints included grade 4 neutropenia, febrile neutropenia, and time to ANC recovery.

94 total references were retrieved.

• Five studies were included in the final analysis.
• The sample consisted of 617 patients, and size range across the five studies was 27–296.
• Key characteristics were breast cancer,  lymphoma, and non-Hodgkin lymphoma.

Active anti-tumor treatment

Standard mean difference (SMD) for time to ANC recovery showed mixed results across studies and pooled SMD to time to recovery was not statistically significant. There was no significant difference between drugs in rates of bone pain. Multiple different grouping and analyses of data were done to try to show differentiation of effect and when meta-analysis was limited to two phase III trials. Relative risk (RR) for febrile neutropenia for pegfilgrastim relative to filgrastim was 0.56 (95% CI [0.35, 0.89], p < 0.016).  Rates for neutropenia were not different.

Results suggest that daily filgrastim and single-dose pegfilgrastim provide essentially the same effect for time to ANC recovery, grade 4 neutropenia rates, and bone pain.

Some studies had very small samples, and heterogeneity with all studies was significant. Studies involved the use of different chemotherapy regimens which could have influenced findings here.

Both pegfilgrastim and filgrastim appear to provide similar clinical effects for prevention of neutropenia and febrile neutropenia. The side effect of bone pain was similar with both treatments. Pegfilgrastim dosing requires fewer subcutaneous injections.

The purpose of this meta-analysis and systematic review was to examine the effects of prophylactic colony-stimulating factors (CSFs) related to reduction in incidence and duration of febrile neutropenia as well as “all-cause” and infection-related mortality in patients with breast cancer undergoing chemotherapy.

Various national and international databases were examined.

Articles were examined if they were randomized, controlled trials (RCTs) comparing CSFs with placebo or no treatment for patients with breast cancer and all stages identified as at-risk for developing febrile neutropenia during chemotherapy

Articles were excluded if they reported on trials for secondary prophylaxis with G-CSF or GM-CSF or primary prophylaxis with G-CSF.

1,023 total references were retrieved

Quality of the evidence was evaluated using the guidelines from the Cochrane Handbook for Systematic Reviews of Interventions for risk of bias. The GRADES levels of evidence were applied to study outcome areas.

• Eight studies were included in the final analysis.
• The sample range across all eight studies was 20–928
• Patients were aged 18-78 years, with a mean age of 50. 
• Patients had a diagnosis of breast cancer and were receiving chemotherapy (any regimen).

• The phase of care was active antitumor treatment  
• Application was for elder care

Effect of primary prophylactic CSF use on rate of febrile neutropenia showed a risk ratio (RR) of 0.27 (95% CI [0.11, 0.7]) in favor of CSF prophylaxis. Evidence in this area was graded as moderate.
Early mortality risk was significantly lower in the intervention group (RR = 0.32; 95% CI [0.13, 0.77].  When one large study was taken out of analysis, accounting for five deaths in the control course and 14 in the control group, the significance was not realized (RR = 0.19; 95% CI [0.03, 1.24]) The grade of evidence in this area was deemed to be low. There was minimal size of effect on the outcome of rate of infection related mortality with (RR = 0.14; 95% CI [0.02, 1.20]). Evidence in this area was graded as low.

Conclusions are difficult to summarize because the studies did not use standard definition of febrile neutropenia, subjects were not homogenous for breast cancer (stage, pathology, treatment, and risk for FN).
No recommendations can be made based on quality and limitations of studies.

Six of the studies identified risk of bias, three of these six had more than one bias risk.  Forty percent of patients included in summary are from one study. Overall, studies were of low to only moderate level of quality. This review includes only studies conducted on patients with breast cancer.

This report does not strengthen evidence already available from guidelines for prophylactic use of CSFs in breast cancer.

To evaluate prophylactic colony-stimulating factors (CSFs) given concurrently with or after initiation of chemotherapy prior to the development of neutropenia compared with placebo or no therapy in patients with cancer undergoing chemotherapy or hematopoietic stem cell transplantation (HSCT)

The standard Quality of Reporting of Meta-Analyses (QUOROM) guidelines were used to guide the search.

DATABASES USED: Electronic searches of Ovid MEDLINE from 1966–April 24, 2007; EMBASE from 1980–April 26, 2007; and  the Cochrane Central Register of Controlled Trials Register (CENTRAL) through the second quarter of 2006 were performed. The pharmaceutical manufacturers of granulocyte CSFs (G-CSFs) and granulocyte macrophage CSFs (GM-CSFs) also were contacted.

INCLUSION CRITERIA: Patients randomly were assigned to CSFs or to placebo or no therapy. CSFs were given concurrently with or after initiation of chemotherapy or conditioning for stem cell transplantation but before neutropenia developed. Chemotherapy or conditioning regimens or other supportive care was not planned to systematically differ between study groups.

FINAL NUMBER STUDIES INCLUDED = 148 RCTs

TOTAL PATIENTS INCLUDED IN THE REVIEW: 16,839 participants or cycles; 8,474 randomly were assigned to CSF and 8,365 to placebo or no treatment.

KEY SAMPLE CHARACTERISTICS: The RCTs included adult or pediatric patients with cancer undergoing chemotherapy or HSCT. The results were analyzed at the study level, not at the patient level.

Compared with the control, prophylactic CSFs did not significantly affect

• Overall all-cause mortality (7.6 % rate in the CSF group and 8.0% in the control group)
• Risk for infection-related mortality (3.1% rate in the CSF group and 3.8% in the control group).

Compared with the control, prophylactic CSFs significantly reduced

• Documented infections by 15%
• Microbiologically documented infections by 14%
• Clinically documented infections by 25%
• Episodes of febrile neutropenia by 29%
• Duration of febrile neutropenia by a mean difference of 1.38 days
• Duration of fever by a mean difference of 0.45 days
• Time to absolute neutrophil count (ANC) of 500 cells/mcL or more by a mean difference of 3.79 days
• Time to ANC of 1,000 cells/mcL or more by a mean difference of 5.03 days
• Duration of parenteral antibiotic therapy by a mean difference of 1.81 days
• Duration of hospitalization by a mean difference of 2.41 days.

The median rate of febrile neutropenia in the placebo groups was 44.2% versus 25.3% in the CSF groups.

The use of G-CSFs had a greater effect than the use of GM-CSFs on reducing documented infections and febrile neutropenia, but all-cause mortality and infection-related mortality did not differ.

The purpose of this study was to examine colony-stimulating factors (CSFs) given to children with cancer prophylactically after initiation of chemotherapy prior to the development of febrile neutropenia.

OVID MEDLINE (January 1966 to July 2003) and EMBASE (January 1980 to July 2003) databases were searched. The search was limited to randomized, controlled trials (RCTs) that included children 18 years and younger. References were hand searched for relevant literature, and conference proceedings from meetings of the American Society of Hematology, American Society of Clinical Oncology, Society Internationale Oncologie Pediatric, and the American Society of Pediatric Hematology/Oncology from January 2001 to January 2003 were reviewed. Manufacturers of G-CSF and GM-CSF were contacted.

16 RCTs. Five studies evaluated GM-CSF, and 11 examined G-CSF.

1,183 children, 592 of whom were randomized to CSF and 591 to the control arm.

In children with cancer:

• CSFs reduced the rate of febrile neutropenia by 20%.
• CSFs reduced hospitalization duration by two days.
• CSFs reduced the documented infection rate by 22%.
• CSFs reduced the duration of neutropenia by four days.
• CSFs reduced the rate of amphotericin use by 50%.
• CSFs were not associated with a reduction in infection-related mortality.
• CSFs were not associated with a difference in duration of parenteral antibiotics.
• CSFs were not associated with a difference in the duration of chemotherapy delay.

The rates of febrile neutropenia in all of the included studies were 39% or higher, so the researchers concluded that prophylactic CSFs should be used in children with cancer who are receiving chemotherapy with an anticipated rate of febrile neutropenia 40% or higher. No explicit measurement of quality of life exists, but researchers hypothesize that decreasing hospitalization and febrile neutropenia would contribute to improved quality of life.

The purpose of this systematic review was to compare the efficacy of pegfilgrastim primary prophylaxis (PPP) with current practice (CP [short course of treatment and not beginning in the first cycle]) neutropenia management in breast cancer.

MEDLINE, a clinical trial database at Amgen, and abstracts from the American Society of Clinical Oncology meetings from 2000–2005 were researched.

Key words were taxoids, (pegylated) doxorubicin, adriamycin, epirubicin, docetaxel, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil combined with febrile neutropenia, neutropenia, leucopenia, and infection
 
Inclusion was based on English-language studies (randomized, controlled trials [RCTs], prospective observational studies, retrospective studies) on human subjects who received common breast cancer chemotherapy regimens associated with a febrile neutropenia risk 15% or greater. 

Studies were excluded if they had patients who received two weekly treatment cycles.

513 total references were retrieved.

The proportion of patients with febrile neutropenia across all cycles and the proportion of patients with febrile neutropenia in cycle 1, febrile neutropenia-related hospitalizations, chemotherapy dose delays of three or more days, dose reductions of 15% or greater, and grades 3 and 4 hematologic toxicities. An integrated analysis was conducted on individual patient data. Descriptive summaries of demographic information and disease characteristics for individual and integrated populations within each group (PPP versus CP). G-CSF was characterized by administration. For the comparative analysis homogeneity of patient populations within each group and then between each group was evaluated. A generalized linear mixed model was fitted for the outcome of febrile neutropenia across all cycles and for cycle 1 per type of prophylactic treatment (PPP or CP). Other variables in the model included age, disease stage, and prior chemotherapy/radiation treatment. Variables were adjusted using the least square means. Sensitivity analyses also were conducted. Studies that included G-CSF given within seven days of the last chemotherapy dose in cycle one were removed for the CP group in the analysis.

• 19 studies were included in the final review.
• The sample range across studies was 7–927 participants
• 2,282 total patients were included in this review (1,303 PPP and 979 CP)
• Female patients with breast cancer who received chemotherapy treatments with an associated 15% or greater risk of febrile neutropenia.
• The majority of patients were older than age 50 years, were Caucasian, and had an ECOG status of 0 or 1.
• The majority of patients also had a stage II, III, or IV diagnosis and most had not had prior therapy.
• 981 patients had an unknown estrogen receptor status, 564 were receptor negative, and 737 were receptor positive.
• 338 patients had adenocarcinomas, and the histology was unknown for the remaining patients.
• Chemotherapy regimens varied and included doxorubicin, cyclophosphamide, carboplatin, doecetaxel, epirubicin, and paclitaxel.

Active treatment

The incidence of febrile neutropenia for all cycles and in cycle one were lower in patients who received PPP compared to those who received CP (p < 0.0001). An increased risk of febrile neutropenia was found for older patients and for those with stage IV disease. Hospitalizations associated with febrile neutropenia also were lower for the PPP group compared to the CP group. Grades 3 and 4 neutropenia were lower in the PPP group (47%, 95% CI [9%, 89%]) compared to the CP group (96%, 95% CI [70%, 99%]) adjusted rates and similarly for leucopenia were also lower in the PPP group (47%, 95% CI [15%, 82%]) compared to the CP group (94%, 95% CI [74%, 99%]).

The use pegfilgrastim primary prophylaxis for the prevention of febrile neutropenia, grades 3 and 4 neutropenia, and neutropenia-related hospitalizations is more effective than current practice use of G-CSF (short course of treatment and not beginning in the first cycle) for patients receiving myelosuppressive chemotherapy for treatment of breast cancer.

Oncology nurses can advocate for the use of PPP for this patient population.

• FINAL NUMBER STUDIES INCLUDED = 27 (evaluated 30 trials in total)
• TOTAL PATIENTS INCLUDED IN REVIEW = 6,037
  • Primary lipegfilgrastim compared to primary pegfilgrastim (two studies n = 306) 
  • Primary lipegfilgrastim compared to no primary G-CSF/placebo (one study n = 375) 
  • Primary lenograstim compared to no primary G-CSF/placebo (five studies n = 467)
  • Primary filgrastim compared to no primary G-CSF/placebo (11 studies n = 2,181) 
  • Primary pegfilgrastim compared to no primary G-CSF/placebo (five studies n = 2,060) 
  • Primary pegfilgrastim compared to primary filgrastim (six studies n = 647)
• KEY SAMPLE CHARACTERISTICS: Adult patients who received myelosuppressive chemotherapy for solid tumors or non-Hodgkin lymphoma

PHASE OF CARE: Active antitumor treatment

• Primary prophylaxis using filgrastim, pegfilgrastim, lenograstim, and lipegfilgrastim were statistically significantly better than not using G-CSF or placebo for the reduction of FN risk. Across all chemotherapy cycles, pegfilgrastim was slightly better than lipegfilgrastim for reducing NF risk, but this finding was not significant.

• Using direct comparison, FN risk was significantly reduced following PP with pegfilgrastim, filgrastim, or lenograstim compared to no G-CSF PP or a placebo. 
• Using indirect comparison, PP with pegfilgrastim or filgrastim significantly reduced FN risk compared to no G-CSF PP or a placebo.  
• Using mixed-treatment comparison, PP with pegfilgrastim, filgrastim or lenograstim, significantly reduced FN risk compared to no G-CSF PP or a placebo. PP with pegfilgrastim significantly reduced FN risk compared to filgrastim PP. PP with lipegfilgrastim significantly reduced FN risk compared to no G-CSF or a placebo.
• Using mixed-treatment comparison, PP with pegfilgrastim, filgrastim, and lipegfilgrastim significantly reduced FN risk in the first cycle and across all cycles of chemotherapy compared to no G-CSF or a placebo. PP with pegfilgrastim significantly reduced FN compared to filgrastim PP. No significant difference was found in FN risk during first cycle of chemotherapy using PP with either pegfilgrastim or lipegfilgrastim.
• A meta-analysis of all cycles with adjustment of RDI could not be evaluated.

Prophylaxis with G-CSF reduces the risk for NF during myelosuppressive chemotherapy.

• More information could be obtained if the RDI adjustment could have been conducted.
• There was some heterogeneity between studies, limiting the ability to evaluate relative dose intensities, number of chemotherapy cycles, and dose delays.
• Detailed study characteristics were lacking.
• The Bayesian method was appropriate to use as a prediction model but may not accurately capture true events.
• Publication bias: No specific data comparing G-CSF effect and type of myelosuppressive regimen

Patients with cancer undergoing myelosuppressive chemotherapy are at risk for FN. Prophylaxis with G-CSF can reduce this risk for improved patient outcomes.

To determine if the granulocyte–colony-stimulating factor (G-CSF) biosimilar filgrastim had similar outcomes for adults and older adult patients actively undergoing treatment for cancer

This was a prospective observational study of patients prescribed biosimilar filgrastim in 140 centers in 12 European countries.

• N = 1,447 patients; 41% were older than age 65 years (cut-off at age 65 years) and put into the older adult category   
• AGE = Adults aged 18 years or older
• MALES: 49.8% older adult, 31% adult
• FEMALES: 50.2% older adult, 69% adult
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Stage III–IV breast, ovarian, bladder, and lung cancer; metastatic prostate cancer as well as stage III–IV large B-cell lymphoma and multiple myeloma

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: 12 European countries

• PHASE OF CARE:  Active antitumor treatment
• APPLICATIONS: Elder care

Prospective observational

Comparative analysis of various components outlined by the authors

No statistically significant differences existed in the rates of chemotherapy-induced neutropenia and febrile neutropenia episodes between either groups. G-CSF support is equally important in both groups. Older adult patients with underlying chronic conditions may be at higher risk for febrile neutropenia; in both groups, it is important to provide timely prophylaxis.

Timely G-CSF support is important in both older adult and adult patients receiving myelotoxic chemotherapy.

Nurses need to be aware of G-CSF administration for patients after chemotherapy. Independent of age group, it is important that patients receiving specific regimens get timely G-CSF treatment to prevent neutropenia duration.

To provide information about patterns of granulocyte colony-stimulating factors (G-CSF) use in Spanish oncology clinical practice and to compare neutropenia-related outcomes in patients treated daily with G-CSF with patients receiving nondaily G-CSF (pegfilgrastim)

Medical records were reviewed for data collection and analysis of outcomes in patients who received pegfilgrastim compared to those who received daily G-CSF.

• N = 391 patients from 34 participating centers 
• AGE: Older than 18 years
• MALES: 46.4% in daily G-CSF group, 31.8% in pegfilgrastim group  
• KEY DISEASE CHARACTERISTICS: Solid tumors excluding breast
• OTHER KEY SAMPLE CHARACTERISTICS: Had chemotherapy with at least one concomitant G-CSF administration more than two months prior; 79.3% had stage 3 or 4 disease

• SITE: Multi-site
• SETTING TYPE: Outpatient
• LOCATION: Spain

• PHASE OF CARE: Active treatment

• Retrospective, multi-center, observational
  • Each investigator reviewed the most recent charts of five patients treated with daily G-CSF and of another five most recently treated with pegfilgrastim.

• Percentage of patients with grade 3 or 4 neutropenia (absolute neutrophil count [ANC], .0 x 10⁹/L) and incidence of febrile neutropenia (FN), defined as ANC 0.5 x 10⁹/L and temperature 38°C or higher during the same day
• Percentage of patients experiencing dose delays (more than three days during any cycle) and dose reductions (less than 84% of planned dose)
• Percentage of patients with dose intensity was 85% or higher (defined as 85% or more of planned dose for all agents in regimen and three days or less of dose delay)
• FN-related hospitalizations and response to chemotherapy—complete, partial, or nonresponse per physician’s criterion

In the multivariate analysis following adjustment for possible confounding factors, a significantly higher risk (OR 1.73, 95% CI 1.004–2.97) of severe neutropenia was associated with daily G-CF versus pegfIlgrastim. The patient group receiving daily G-CSF had a 73% higher probability of grade 3 or 4 neutropenia. Patients receiving daily G-CSF experienced a greater number of dose reductions (38.4% versus 31/6%, p = 0.116) and delays (54.7% versus 41.7%, p = 0.013). Chemotherapy dose intensity of less than 85% also was greater in the daily G-CSF group (39.4% versus 28.9%,p = 0.030). Response rates also were lower in the daily G-CSF group. Complete responses were 17% for daily G-CSF versus 26.4% for the pegfilgrastim group (p = 0.028) and partial response was 41.2% for daily G-CSF versus 52% for the pegfilgrastim group (p = 0.009), again demonstrating better response in the pegfilgrastim group. The two main adverse reactions reported were bone pain and asthenia, with a higher incidence noted in the daily G-CSF group (6.2% versus 1.7%, p = 0.025). Patients receiving at least five days of daily G-CSF, versus those who received fewer than five days, experienced better outcomes.

G-CSF and pegfilgrastim can reduce the incidence and adverse outcomes of treatment-related neutropenia. If G-CSF is stopped prematurely, the efficacy is compromised. This study demonstrates that G-CSF often is initiated later than recommended following chemotherapy, and patients receive fewer days per cycle than required for optimum efficacy.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement validity/reliability questionable

Daily G-CSF and pegfilgrastim are used prophylactically to reduce grade 3 or 4 neutropenia, incidence of FN, dose delays and reductions, and FN-related hospitalizations, and to increase response to chemotherapy, measured as complete, partial, or nonresponse per physician’s criterion. Suboptimal dosing is more prevalent with daily G-CSF because of starting later than recommended following myelosuppressive chemotherapy and stopping too early.

The purpose of the study was to evaluate incidence of febrile neutropenia and grade 4 neutropenia after receiving lenograstim prophylaxis.

All patients received G-CSF prophylaxis with 263 mcg from days 5–9 in patients receiving three cycles of epirubicin and ifosamide for soft tissue sarcoma. Patients were observed for three cycles. Blood counts were done on days 8,15, and 22.

• 36 total participants
• Median age was 53, range was 19–72
• 48% were male, 52% were female
• All had soft tissue sarcoma and were receiving chemotherapy regimens associated with a 50% risk of febrile neutropenia 
• All patients were chemotherapy naive.

• Single site
• Outpatient
• Italy

Active antitumor treatment

Observational

• CTCEA [v.4.03]
• Febrile neutropenia was defined as an absolute neutrophil count of less than 1,000/mm³ and single temperature greater than 38.3ºC.

There were no episodes of febrile neutropenia. Grade 4 neutropenia was seen in 17% of patients—58% on day 8, 29% on day 15, and 13% on day 22.  No treatment delays or dose reductions were required.

G-CSF as given here was effective in preventing the risk of febrile neutropenia and grade 4 neutropenia in patients receiving chemotherapy associated with high risk for these adverse events.

• Small sample (less than100)
• Risk of bias (no control group) 
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias(sample characteristics)
• Findings not generalizable
• Homogenous group of patients receiving the same chemotherapy regimen
• Findings may not be generalizable to other groups

Prophylactic G-CSF reduced risk of febrile neutropenia and grade 4 neutropenia in patients at risk for these problems during chemotherapy for soft tissue sarcoma. The most appropriate timing of prophylactic colony-stimulating factor is not clear. The timing studied here appeared to be effective.

The purpose of the study was to compare the proportion of elderly patients with febrile neutropenia while receiving pegfilgrastim from the first cycle of chemotherapy (proactive) with the proportion with febrile neutropenia using the current practice of receiving pegfilgrastim after observed severe neutropenia or neutropenia-related events.

Patients randomized to either proactive pegfilgrastim (subcutaneous injection 6 mg one time per cycle 24 hours after chemotherapy completion staring with cycle one) or secondary prophylaxis with pegfilgrastim (subcutaneous injection 6 mg one time per cycle 24 hours after chemotherapy completion starting after cycle one) at physician’s discretion.

• 852 total patients
• Patients were age 65 or older
• 64.3% were female, 35.7% were male
• Cancers of the lung, breast, ovary, or non-Hodgkin lymphoma
• Patients with with a life expectancy of three months or longer
• ECOG performance status score of 2 or lower

Multiple outpatient settings in community cancer center across the United States.

• The phase of care was active treatment
• Application was elderly care

Phase IV, open-label, randomized, controlled trial.

• Febrile neutropenia
• Grade 3 or grade 4 neutropenia
• Chemotherapy regimen
• Solid tumor type
• Pegfilgrastim administered
• Dose delay, dose reduction, hospitalization, and antibiotic use
   

For the reduction of febrile neutropenia, pegfilgrastim in all chemotherapy cycles was statistically significantly better than use of pegfilgrastim at the physician’s discretion for both solid tumors (p = 0.001) and non-Hodgkin lymphoma (p = 0.004). Pegfilgrastim throughout cycles showed better results than physician discretion for fewer events of grade 3 or 4 neutropenia, hospitalizations and antibiotic use for both solid tumor and non-Hodgkin groups, and for less dose delay and dose reduction in the solid tumor group.

The most common adverse events related to pegfilgrastim was arthralgia.
 

Pegfilgratim use in older adults undergoing chemotherapy appears safe and effective with use starting in the first cycle for the reduction of neutropenia, febrile neutropenia, grade 3 or 4 neutropenia, hospitalizations, and antibiotic use.

The study was not blinded. Fewer patients with non-Hodgkin lymphoma were able to be randomized to the discretion arm since physicians often wanted pegfilgrastim started early in these patients due to known neutropenic outcomes. It also was unclear as to the amount of pegfilgrastim delivered in the physician discretion arm.

The administration of pegfilgrastim starting with the first cycle of chemotherapy may reduce neutropenic events and related complications in older adults with cancer. Nurses can be at the forefront of advocating for this therapy, administering it, and monitoring patients for effective outcomes and/or adverse events.

To compare the efficacy and safety of a pegfilgrastim biosimilar to reference pegfilgrastim

Patients were randomized to receive 6 mg of either reference pegfilgrastim or a biosimilar. The colony-stimulating factor (CSF) was given on day 2 of each cycle. ANC was measured on day 1 of cycle 1, then daily until recovery after nadir or until day 15. A margin of one day of neutropenia was established as the margin for noninferiority analysis.

• N = 275   
• MEAN AGE = 48.9 years
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Patients with breast cancer receiving docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy 

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: European countries

• PHASE OF CARE: Active antitumor treatment

• Noninferiority, randomized, controlled trial

• Consecutive days of neutropenia 
• Depth of absolute neutrophil count (ANC) nadir
• Days to ANC recovery
• Infections

All study outcomes were similar in both groups. Over 95% of both groups had musculoskeletal adverse events, including bone pain, myalgia, arthralgia, and back pain (13.7%–16.1% of patients).

The CSF biosimilar evaluated here demonstrated similar efficacy and safety to that of the reference pegfilgrastim.

Pegfilgrastim and the CSF biosimilar evaluated were shown to be therapeutically equivalent.

To compare the biosimilar to reference filgrastim

Patients were randomized to receive the biosimilar or filgrastim for the duration of treatment or to alternate at each chemotherapy cycle. Chemotherapy was given every three weeks for six cycles. Patient assessments were done at baseline, on day 1 of each cycle. For cycles 2–6, complete blood counts were assessed on day 7 and daily thereafter.

• N = 218   
• MEDIAN AGE = 50 years
• AGE RANGE = 23–76 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Breast cancer 
• OTHER KEY SAMPLE CHARACTERISTICS: Patients undergoing treatment with docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Eastern European countries

• PHASE OF CARE: Active antitumor treatment

• Noninferiority, double-blind, randomized, controlled trial

• Days of neutropenia—absolute neutrophil count (ANC) < 0.5 x 10⁹ to ≥ 0.5 x 10⁹  number of consecutive days
• Infections 
• Incidence of hospitalization related to febrile neutropenia (FN)

The number of consecutive days of neutropenia was 1.17 in the biosimilar group and 1.2 in the filgrastim group. No significant differences existed in the time to ANC recovery or adverse events. In those receiving the biosimilar, fever episodes were reported in 15% compared to 4.3% of those receiving filgrastim.

This study showed no clinically meaningful differences in neutropenia-related outcomes between patients receiving figrastim and a colony-stimulating factor (CSF) biosimilar.

The findings showed similar clinical results with filgrastim and this CSF biosimilar.

To confirm the safety and efficacy of the cost-effective filgrastim biosimilar EP2006 through a phase III, randomized, double blind study from the original PIONEER study, analyzing alternating treatments of EP2006 and reference filgrastim among patients receiving myelosuppressive chemotherapy. The alternating treatments were used to show there was no difference in efficacy, safety, or immunogenicity compared to patients who received EP2006 or filgrastim only.

Two patient groups from the original PIONEER study in which patients were randomized into one of four arms in a 1:1:1:1 ratio was analyzed in this study. Patients received an initial dose of either EP2006 or filgrastim and then alternated treatments over six cycles of chemotherapy TAC regimen (docetaxel 75 mg/m², doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m²). The filgrastim was administered as 5 µg/kg body weight per day, subcutaneous injection from the second day of chemotherapy until reaching ANC ≥ 10 x 10⁹/l following nadir or for a maximum of 14 days.

• N = 109   
• AGE: Mean age = 48.6 years
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Women with confirmed breast cancer, Eastern Cooperative Oncology Group performance status ≤ 2, and adequate bone marrow function
• OTHER KEY SAMPLE CHARACTERISTICS: Patients were excluded if they had a history of myelogenous leukemia, myelodysplastic syndrome or concomitant sickle cell disease, concurrent or prior radiotherapy within four weeks of randomization, use of prophylactic antibiotics, prior chemotherapy or anticancer treatment of breast cancer or previous G-CSF therapy.

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: 25 European centers

PHASE OF CARE: Active anti-tumor treatment

Randomized, double-blind, parallel-group, multicenter study of women (aged 18 years and older) with breast cancer receiving myelosuppressive chemotherapy

Multiple variables from the original dataset were measured including: FN (oral temperature 38.3 C and ANC < 0.5x10⁹/l on the same day), incidence of infections, incidence of hospitalizations due to FN, time and depth of ANC nadir (the patient’s lowest ANC in the respective chemotherapy cycle), time to ANC recovery, and ANC profile. Adverse events were also evaluated across all cycles of chemotherapy and included patients who received one or more dose of study medication and had one or more post-baseline safety assessment and the switched safety population of all patients who received one or more dose of study medication after cycle 1. Immunogenicity was evaluated.

Comparing the switched groups (n = 109) to the filgrastim reference group (n = 52), there were three patients (3.4%) in the switched group who had febrile neutropenia across cycles 2-6 compared to no patients with FN in the reference group. Infections occurred in 9.3% of patients in the switched group and 9.9% in the reference group. There were no differences between groups for depth of ANC nadir, time of ANC nadir, and time course of ANC recovery. Treatment emergent adverse events were similar between groups with 42.1% in the switched group and 39.2% in the reference group. No neutralizing antibodies against recombinant human G-CSF were detected.

The biosimilar EP2006 is as safe and effective as filgrastim. There was no compromise in immunogenicity in EP2006, and EP2006 was shown to be equally clinically meaningful to filgrastim, but is more cost-effective.

Knowledge regarding risks for infections in women with breast cancer receiving TAC therapy and the utilization of EP2006 as an alternative to filgrastim for cost-effective improved outcomes.

This study used the amended EORTC algorithm (that classified patients based on prophylaxis intensity levels, for myelotoxic chemotherapy regimen and patient risk factors associated with CIN/FN) to explore the impact of prophylaxis intensity using biosimilar filgrastim comparing these outcomes with dosing for under, correctly, or over prophylaxis guideline-recommended levels.

This was a real-world observational study evaluating patients as they received myelosuppressive chemotherapy and CIN/FN prophylaxis with biosimilar filgrastim. The evaluation of data for the study stratified patients into groups with biosimilar GCSF by prophylaxis intensity levels (under, correctly, or over-prophylaxis). Patient outcomes were compared first on demographics and clinical status at the start of chemotherapy to identify prophylaxis patterns, clinical, and safety outcomes. Data for patient-level evaluations were collected as patients progressed through chemotherapy treatments to isolate outcomes experienced at any time during the whole period of chemotherapy. The study collected ongoing data for a cycle-level analyses to evaluate outcomes during a particular cycle and from one cycle to the next, to evaluate outcomes as patients progressed through their cycles of chemotherapy. 

Of note: 

• Sample groups had different types of prophylaxis (primary/secondary) and time to initiation of biosimilar GCSF for prophylaxes 
• 100% under-prophylacted received secondary prophylaxis, 92.4% correctly prophylacted received primary prophylaxis, 76.6% over-prophylacted given primary, and 23.4% secondary prophylaxis 
• Mean day of initiation biosimilar GCSF different for groups: 2.7 over, 2.99 for under, and 3.26 mean days for correctly prophylacted
• 19.5% over-prophylacted initiated on day one after chemotherapy; 12.1% under-prophylacted initiated on day one after chemotherapy; 11.2% initiated on day one after chemotherapy for correctly-prophylacted
• Median prophylaxis duration same for all cohorts; mean duration of prophylaxis shortest for over-prophylacted

• N = 1,444  (251 under-prophylacted; 817 correct prophylacted; 376 over-prophylacted)
• AGE: 61.56  (65.2 under-prophylaxes; 61.8 correct prophylaxes; 57.7 over-prophylaxes averaged)
• MALES: 40% (45.0% under-prophylaxes; 37.2% correct prophylaxes; 37.8% over-prophylaxes averaged)  
• FEMALES: 60% (55% under-prophylaxes; 62.8% correct prophylaxes; 62.2% over-prophylaxes averaged)
• CURRENT TREATMENT: Chemotherapy, combination radiation, and chemotherapy
• KEY DISEASE CHARACTERISTICS: Adults (aged 18 years or older) stages III or IV breast, ovarian, bladder, or lung cancer; metastatic prostate cancer; stage III or IV diffuse large B cell lymphoma or multiple myeloma
• OTHER KEY SAMPLE CHARACTERISTICS: Patients were treated with myelosuppressive chemotherapy for up to six cycles receiving biosimilar filgrastim GCSF prophylaxis; cohort groups had baseline differences for age, FN risk factors; advanced disease, Hx of FN, ECOG performance status, poor nutritional status, HGB less than 12, presence of renal, CV, or liver disease, prior chemotherapy, presence of renal cardiovascular or liver disease, prior treatments, chemotoxicity

• SITE: Multi-site   
• SETTING TYPE: Inpatient    
• LOCATION: 140 cancers centers in 12 European countries

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS: Elder care, palliative care

Non-experimental prospective longitudinal observational cohort study (real-world observational study)

Chemotherapy associated FN risk was established using an author developed tool, Patient Risk Score (PRS), for a weighted sum of eight patient risk factors associated with CIN/FN specified in EORTC guidelines; prophylaxis patterns collected for GCSF decisions for primary or secondary prophylaxis and duration of prophylaxis; CIN/FN prior cycle; ECOG performance status; history of repeated infections; cancer tumor type, prior treatments chemotherapy/radiation therapy; and chemotoxicity. Data was collected (patient and cycle levels) for number  of episodes of CIN and grade (CIN1/4), number of episodes of FN; number of episodes of CIN/FN related to a hospitalization or chemotherapy disturbance (dose reduction, delay in administration of chemotherapy, cancellation of administration of chemotherapy); and a (worst-case) composite index of occurrence for any of the previous outcomes.

Different rates of CIN, grades 1-4, and CIN/FN-related hospitalization (all p ≤ 0.001)

There was no significant difference for proportions of patients with CIN/FN chemotherapy disturbances. 

The proportion of cycles of chemotherapy interruptions due to CIN/FN was significantly higher for under prophylaxes (p = 0.32) 

Patient level pairwise analysis: No difference between groups for the likelihood of CIN/FN. 

• Over-prophylacted less likely for ever experiencing compared to correctly prophylacted during chemotherapy; CIN/FN (all p ≤ 0.001) or in any given cycle (p < 0.001 for CIN, p = 0.004 for FN) 
• Under-prophylacted CIN more likely (p = 0.044) FN (p ≤ 0.001) at any time during chemotherapy 

Cycle-level pairwise analysis: likelihood of CIN/FN in any one cycle between under and correctly prophylacted no significant difference

• Over-prophylacted significantly less likely than correctly prophylacted for CIN/FN in any one cycle (p < 0.001 for all CIN, p = 0.004 for FN)
• Under-prophylacted more likely for CIN/FN in any one cycle compared to over-prophylacted (p = 0.025 to p < 0.001)
• In patients over-prophylacted, rates of chemotherapy-induced neutropenia (CIN) (all grades), FN, and CIN-related hospitalizations were consistently lower compared to under- and correctly prophylacted

Patients CIN/no GCSF safety differences between groups (except for headaches, p = 0.027, correct and over had higher percentage compared to under)

Comparing biosimilar GCSF prophylaxis intensity groups (under, correct, and over-prophylacted), GCSF support at levels above current guideline recommendations may reduce CIN, FN, and CIN/FN-related hospitalization. Patients who are under-prophylacted with biosimilar GCSF are at higher risk for disturbances to their chemotherapy regimens.

• Baseline sample/group differences of import        
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias (no appropriate attentional control condition)
• Risk of bias (sample characteristics)
• Unintended interventions or applicable interventions not described that would influence results
• Key sample group differences that could influence results
• Measurement validity/reliability questionable
• Use on non-validated PRS tool developed by authors
• Findings not generalizable
• Other limitations/explanation: Cycle data were nested under patients and patients under centers, violating the assumption of statistical independence; statistical adjustments were required; there were more under-prophylaxes patients aged 65 and older who also had a history of FN, a Hb less than 12 g/dl, and renal, cardiovascular, or liver disease; the study design was not an experimental/RCT design, limiting its rigor and control for bias; issues concerning reliability and intervention fidelity, reduced rigor for internal and external validity; no effect sizes reported

Oncology nurses must evaluate patients for CIN/FN risk each cycle and adhere to current guideline recommendations for CIN/FN prophylaxis with GCSF to reduce risk of CIN/FN and chemotherapy interruptions. Large RCTs are necessary to evaluate if changing current recommended GCSF dosing schedule improves patient-related outcomes, to evaluate patient risk stratification and potential side effects of a different dosing schedule.

To test the safety and efficacy of biosimilar granulocyte–colony-stimulating factor (G-CSFs) filgrastim as prophylactic treatment for the reduction of severe chemotherapy-induced neutropenia in patients undergoing treatment for early and advanced soft-tissue sarcoma with anthracycline and ifosfamide–based chemotherapy

G-CSFs were administered in one of three forms (biosimilar filgrastim, originator filgrastim, or lenograstim) as primary prophylactic treatment for patients with a 20% or greater risk for febrile neutropenia per the European Organization for Research and Treatment of Cancer's (EORTC's) clinical guidelines based on the administration of epirubicin and ifosfamide (EI) treatment for soft-tissue sarcomas.

• N = 67   
• MEDIAN AGE = 60 years
• AGE RANGE = 28–78 years
• MALES: 41.8%, FEMALES: 58.2%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Soft-tissue sarcoma, primary or metastatic
• OTHER KEY SAMPLE CHARACTERISTICS: Patients treated with EI from 2003–2013 were included in the study.

• SITE: Not stated/unknown   
• SETTING TYPE: Multiple settings    
• LOCATION: Not clearly specified. PI is from a cancer research institute in Italy.

PHASE OF CARE: Active antitumor treatment

Retrospective analyses

Outcome measures included overall survival, neutropenia, and sepsis. A cost analysis was also conducted. Dependent variables included patient demographic information (age, sex, body mass index, and setting) and type of G-CSF administered.

No statistically significant differences were found between the administration of biosimilar filgrastim, originator filgrastim, or lenograstim for the outcome variables. A difference existed in the cost-savings model with the cumulative cost of treatment with biosimilar filgrastim (€35.82 on day 3 to €131.34 on day 11) compared to originator filgrastim (€170.97 on day 3 to €626.89 on day 11) and lenograstim (€193.02 on day 3 to €707.74 on day 11). However, statistically significant differences were not reported.

The use of prophylactic biosimilar filgrastim is equally effective yet less expensive than originator filgrastim or lengrastim for overall survival, neutropenia, and sepsis in patients undergoing treatment for early and advanced soft-tissue sarcoma with anthracycline and ifosfamide–based chemotherapy.

• Small sample (< 100)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Findings not generalizable

Understanding that biosimilar filgrastim is equally effective yet more economical than originator filgrastim or lengrastim can help guide treatment decision making for patients with advanced soft-tissue sarcoma at risk for chemotherapy-induced neutropenia.

To provide information about organizational experience with use of pegfilgrastim following dose intensive chemotherapy for solid tumors in pediatric patients with cancer.

Medical records of patients receiving myelosuppressive therapy supported with pegfilgrastim were reviewed (cases from 2007–2008). By protocol, pegfilgrastim was given in the outpatient clinic by subcutaneous injection at 0.1 mg/kg to a maximum does of 6 mg 24–48 hours after completion of chemotherapy. Complete blood counts (CBCs) were routinely monitored  every 7–10 days during therapy cycles, then every 2–5 days until neutrophil recovery. Analysis was limited to the first four courses of chemotherapy.

• 47 patients completed 176 courses of chemotherapy.
• Median age was 13 years, with a range of 2 months to 23 years.
• Females made up 53% of the sample; males made up 47%
• Key disease characteristics included Hodgkins disease, rhabdo myosarcoma, neuroblastoma, osteosarcoma, and Ewing sarcoma.
   

• Single site
• Outpatient
• Seattle, WA

• The phase of care was active antitumor treatment.
• The application was for pediatrics.

Retrospective descriptive

• Severe neutropenia was classified as an absolute neutrophil count (ANC) of less than 200 mm³
• Neutrophil recovery was an ANC greater than 200 mm³
• Febrile neutropenia was defined as severe neutropenia with temperature of 38.3ºC or higher with hospitalization and parenteral antibiotic therapy.
   

There were no significant adverse effects observed with pegfilgrastim. Leukocytosis was observed in 73% of patients, with no adverse sequelae. Severe neutropenia occurred in 57% of chemotherapy courses, and febrile neutropenia was seen in 28% of courses. Course delay occurred in 9% of courses, with a mean duration of two days of delay.

 This report provides evidence regarding the safety and efficacy of pegfilgrastim among a pediatric cancer population.

• Risk of bias (no control group) 
• Risk of bias (no blinding)  
• Risk of bias (no random assignment)
• Unintended interventions or applicable interventions not described that would influence results
• Key sample group differences that could influence results
• Retrospective study design with associated risk of bias in results. 
• No information is provided regarding any other prophylactic medications for prevention of infection in this population.

Findings suggest that pegfilgrastim is effective and can be safety given to pediatric patients.

To compare the effectiveness of a new biosimilar colony-stimulating factor (CSF) compared to reference CSF medications

Data were obtained from medical records in a tertiary cancer center for women with breast cancer who had received TAC chemotherapy. The febrile neutropenia management protocol was the same in all cohorts. Outcomes were compared across cohorts of patients who had received the biosimilar filgrastim, reference filgrastim, and pegfilgrastim.

• N = 420
• MEDIAN AGE = 50 years 
• AGE RANGE = 25–76 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: All women had breast cancer.

• SITE: Single site  
• SETTING TYPE: Not specified  
• LOCATION: Portugal

• PHASE OF CARE: Active antitumor treatment

• Retrospective cohort comparison

• Febrile neutropenia (FN) defined at body temperature ≥ 38 C and ANC ≤ 500 cell/mcl
• ANC
• FN-related treatment delays, reductions, or terminations

FN episode rates were 16%, 9%, and 16% in the reference filgrastim, pegfilgrastim, and biosimilar groups respectively. ANC at the time of FN diagnosis was lower in the biosimilar group in comparison with reference filgrastim (p = 0.015), and FN episodes were more frequent in the biosimilar group compared to both other groups (p ≤ 0.02). There were more chemotherapy delays in the biosimilar group compared with pegfilgrastim (p = 0.04). There were no other differences between groups.

Findings suggest the need for ongoing studies to determine comparative efficacy of this biosimilar CSF for prevention of febrile neutropenia and related complications in patients receiving cancer treatment.

• Baseline sample/group differences of import
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Key sample group differences that could influence results
• There were differences among cohorts in age, extent of disease, and use of antibiotic prophylaxis, which could have influenced results.

There are a growing number of biosimilar CSF agents being produced, and it is not yet clear if there are important clinical differences in bioavailability and activity in the clinical setting. Nurses should be aware of patients who are receiving biosimilar agents and monitor them for signs of FN or infection. Ongoing research is needed to determine safety and efficacy of these newer CSF agents over time.

The purpose of the study was to compare severe neutropenia duration and incidence of febrile neutropenia in patients getting chemotherapy with pegfilgrastim on the same day or 24 hours later.

Four studies were analyzed separately, and data were not compiled for overall analysis across cancer types. In all settings, patients were randomly assigned to either receive pegfilgrastim 6 mg on the last day of the chemotherapy cycle and placebo injection 24 hours later, or placebo on the last day of the cycle and pegfilgrastim 6 mg 24 hours later. Anti-infective prophylaxis was not allowed. Incidence of grade 4 neutropenia was the primary study endpoint, and patients were included and analyzed for one cycle. Complete blood counts were obtained weekly for each chemotherapy cycle.

• 275 participants were included.
• The mean age was 58.6 years.
• Females made up 67.6% of the sample; males made up 32.4%.
• This report is of four studies with the same design, one in breast cancer cases, one in non-Hodgkin lymphoma, one in non-small cell lung cancer, and one in ovarian cancer.
• Disease stages varied
   

• Multi-site (74 sites in the United States) 
• Setting type was not specified  

Active antitumor treatment

Randomized, double-blind placebo controlled

Not stated

In the breast study, grade 4 neutropenia was reported in 93% of same day patients and 78% of next day patients. Mean duration of severe neutropenia was 1.2 days longer in the same day group. In the lymphoma study, severe neutropenia was reported among 86% of same day pegfilgrastim patients and 64% of next day patients. Mean duration of severe neutropenia was 0.9 days longer in the same day group. Incidence of febrile neutropenia was essentially the same in both groups. In the lung cancer group, only 5% of patients experienced severe neutropenia. Analysis of the ovarian group was not done due to study closure prior to obtaining a sufficient sample. Authors report that noninferiority statistical analysis showed that next day pegfilgrastim was not inferior to same day pegilgrastim.

 Findings suggest that different timing of pegfilgrastim administration  within a two day window may not make a difference in incidence of severe neutropenia in these patient groups.

• Risk of bias(sample characteristics)
• Measurement/methods not described  
• Measurement validity/reliability questionable
• The authors note that some of the studies were underpowered to detect significant differences.
• Various samples were highly variable in terms of disease type and stage, and though data were reported by study, no further subgroup analysis was possible. 
• Method of measurement of grade of neutropenia was not described and timing of this determination not stated. 
• In some cases, it appears that analysis was done only in cycle 1 but, in other sections of the report, this is not clear.
• Chemotherapy agents used were not reported, so it is unclear how myelosuppressive they were and potential differences.

This report provides some information from four studies to examine differences in timing of administration of colony-stimulating factors. The most beneficial and cost-effective formulations, dosages, and timing have not been determined. This report has several limitations in study design and results reported.

The study aim was to compare the effectiveness of primary prophylaxis with filgrastim and pegfilgrastim to prevent the incidence of febrile neutropenia in Asian patients with cancer undergoing chemotherapy.  

Data analyzed on intent-to-treat basis from January 2008 and August 2009 identified from the pharmacy prescription database. The G-CSF must have been administered at least 24 hours after chemotherapy administration for primary prophylaxis against febrile neutropenia. Crossover between the two G-CSFs was allowed and the patient was assigned to the treatment group according to the G-CSF used with the first cycle.

• 204 total patients were examined
• 81 received filgrastim, and 123 received pegfilgrastim
• Mean age was 56.7 years (SD = 13.1)  in the  filgrastim group and 55.3 (SD = 14.8) years in the pegfilgrastim group.
• Males outnumbered females, 54% to 46%, respectively
• Patients with non-Hodgkin lymphoma  who underwent chemotherapy
• Primary prophylaxis with filgrastim and pegfilgrastim
   

• Single site  
• Setting type was not specified 
• Location was Singapore
   

Active treatment

Single-center, retrospective study

• Primary end point: Incidence of febrile neutropenia defined as temperature 38.3°C or greater and absolute neutrophil count (ANC) less than 500 mcl.     
• Secondary endpoints: Dose delay of more than three days days or dose reduction of 15% or greater  in subsequent chemotherapy cycles
   

During the first cycle of chemotherapy, six (7.4%) and 11 (8.9%) patients developed FN in the filgrastim and pegfilgrastim arms, respectively (p = 0.8). Across all cycles of chemotherapy treatments, the overall incidence of FN in both arms was much higher than in the first cycle. However, the incidence of FN between the filgrastim group and the pegfilgrastim group remained similar (13.6% in the filgrastim arm versus 16.3% in the pegfilgrastim arm; p = 0.69) across all cycles. More patients in the filgrastim arm experienced treatment delays (8.6%) and chemotherapy dose reductions (4.9%) compared to those who were administered pegfilgrastim (incidence of dose delay = 5.7%, p = 0.25; incidence of dose reduction = 3.3%, p = 0.45) during the first cycle. However, these differences were not statistically significant. The cumulative occurrences of dose delays or dose reductions in all cycles were higher among patients who received pegfilgrastim (absolute difference of dose delay = 2.7%, p = 0.71; absolute difference of dose reduction = 0.7%, p = 1.00). Across all cycles, for regimens that possess a FN risk below 20%, a lower incidence of FN was observed in patients who received filgrastim than those who received pegfilgrastim (12.2 versus 21.4%, respectively; p = 0.31). Similar trends also were observed with the cumulative incidence of treatment delay and chemotherapy dose reduction: patients receiving pegfilgrastim were more likely to suffer from the complications of FN. With regards to the chemotherapy regimens that possess FN risk of 20% or greater, the incidence of FN, treatment delays, and dose reductions all were  similar in both treatment arms (absolute difference in the incidence of FN = 5.6%, p = 0.52; absolute difference in the incidence of dose delays = 0.5%, p = 1.00; absolute difference in the incidence of dose reductions = 4.3%, p = 0.46).

There was no statistically significant difference between filgrastim and pegfilgrastim for the primary prophylaxis of febrile neutropenia in Asian patients undergoing chemotherapy. There was no statistically significant difference between filgrastim and pegfilgrastim with regard to the incidence of dose delays or dose reductions.

Retrospective study that relied on the accuracy of the medical records reviewed.

Filgrastim and pegfilgrastim are equally effective to prevent chemotherapy-induced febrile neutropenia and to prevent dose delays and dose reductions in subsequent cycles.

To compare the rate of febrile neutropenia and neutropenia grade 4 among patients receiving pegfilgrastim on the same day of chemotherapy and after 24 hours of the chemotherapy administration

A retrospective, single-center, non-randomized, cohort study was conducted that includes the evaluation of the eligible patient’s chart selected via an institutional electronic device. Patients should be 18 years and older. They have conducted this study from May 2007 to January 2013. In this study, researchers reviewed the administration of 6 mg of pegfilgrastim in patients on the same day of chemotherapy (day 1) or on day 2 or beyond (up to day 8) of CHOP chemotherapy with or without rituximab every three weeks for a total of eight cycles. The researchers highlighted the potential risk factors contributing to febrile neutropenia. The febrile neutropenia criteria includes temperature of at least 38 C and ANC < 500cells/mm3. 

• N = 141  
• AGE = 18 years and older
• KEY DISEASE CHARACTERISTICS: Non-Hodgkin lymphoma

• SITE: Single site    
• SETTING TYPE: Outpatient    
• LOCATION: United states of America

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

Retrospective, non-randomized, cohort study was conducted that contains chart review through institution electronic records.

• Fisher exact test
• SPSS software

Patients who received pegfilgrastim on the same day of chemotherapy had the highest incidence of febrile neutropenia (9.4%) compared to those who received the drug on day 1 or beyond (5.1%), showing a significant difference among both groups. In addition, the highest rate of dose reduction scenario was found in the day 1 group as compared to the day 2 and beyond  group (51.7% versus 40%). On the contrary, hospital stay duration and ICU admissions were high in the day 2 or beyond group versus the day 1 group (four admissions versus one admission).

The incidences of febrile neutropenia was less among the day 2 or beyond group of R-CHOP or CHOP.

• Baseline sample/group differences of import
• Key sample group differences that could influence results
• Measurement validity/reliability questionable 
• Findings not generalizable
• Time and duration of grade 4 neutropenia was not cleared, chemotherapy regimens were not standardized, and doses and cycles also differed.
• The type of infection was not clarified.

Additional studies need to be conducted for more accurate and reliable results.

The purpose of the study was to determine the efficacy and safety of administering pegfilgrastim less than 14 days from the next chemotherapy cycle in patients receiving a regimen containing 5-FU that infuses over at least 46 hours or more.

Authors reviewed the electronic health record for criteria of patients who received chemotherapy containing 5-FU over at least 46 hours. In addition to demographic data, each unique chemotherapy cycle was evaluated, and patients were put into 1 of 4 groups: (a) Cycles of chemotherapy where pegfilgrastim was given less than 14 days from the next chemotherapy cycle; (b) cycles where pegfilgrastim was given more than 14 days from the next chemotherapy cycle;(c) cycles where filgrastim was given instead of pegfilgrastim after chemotherapy; (d) cycles where no colony stimulating factors were given.

• N = 51 patients included in study (translates into 536 chemotherapy cycles containing 5-FU)   
• AGE: 18 years and older
• MALES: 59.5%  
• FEMALES: 40.5%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Diagnosed cancer that requires treatment with chemotherapy treatment that includes 5-FUCI as one of the drugs
• OTHER KEY SAMPLE CHARACTERISTICS: On FUCI for 14-day treatment cycle infused over at least 46 hours

• SITE: Single site   
• SETTING TYPE: Outpatient    
• LOCATION: Loma Linda University Medical Center, Loma Linda, CA

PHASE OF CARE: Active anti-tumor treatment

This was a single-institution retrospective cohort study of patients who received chemotherapy treatment from June 2013 to December 2015.

Counts and percentages were used for data analysis of demographic data as well as generalized linear models to compare mean ANC and WBC counts of the four different groups within the analysis.  A generalized linear model with generalized estimating equations was used to compare mean ANC and WBC with 95% CI limits. Poisson regression models were used to estimate relative risk for neutropenia. All analyses were two sided and conducted at a significance level of 0.05.

The primary study outcome was the number of chemotherapy cycles with neutropenia, febrile neutropenia, and/or hospitalization in cycles where pegfilgrastim was given less than 14 days before the next chemotherapy cycle. The secondary outcome was evaluation of the incidences of neutropenia, mean ANC, and mean WBC for each of the four groups that were evaluated as part of this analysis. 536 total chemotherapy cycles were evaluated based on inclusion criteria. The group that received pegfilgrastim less than 14 days from their chemotherapy cycle did not show evidence of neutropenia or hospitalization as a result of febrile neutropenia. This group demonstrated a mean ANC and WBC count that was statistically significantly higher than the other three research groups as noted above.

Based on the data reviewed, it does not appear as though administering pegfilgrastim less than 14 days before the next chemotherapy cycle causes harm to patient nor increased myeloid toxicity. While this study was small and specific to one site, it may be beneficial for continued research with a larger sample.

• Small sample (< 100)
• Risk of bias (no random assignment)
• Risk of bias (sample characteristics)
• Other limitations/explanation: Single study retrospective review, limited to records available within institution that may not have accounted for care patient’s received elsewhere.

As nurses are the ones to administer pegfilgrastim, it is important for nurses to understand the implications of administration of the drug and how it impacts patient outcomes.

The purpose of the study was to demonstrate the activity and safety of XM02 compared to filgrastim for the prevention of chemotherapy-induced neutropenia in patients with non-Hodgkin lymphoma.

Patients randomized in a 2:1 ratio of XM02 to filgrastim for the first cycle of chemotherapy (CHOP or R-CHOP [rituximab added per national guidelines and physician discretion]). All patients received XM02 in subsequent cycles, with a maximum of six cycles; three weeks per cycle. Subcutaneous injections given daily (5 mg/kg per day) for at least five days and a maximum of 14 days. Drug stopped with the absolute neutrophil count (ANC) of  10 x 10⁹/L or greater after nadir was reached (blood samples to evaluate ANC taken within 24 hours prior to start of chemotherapy and then daily from day 2 on in the first cycle and day 5 on in cycles 2–6 until day 15 or until ANC reached greater than 2.0 x10⁹/L). Body temperature measured daily until day 15 or until ANC reached greater than 2.0 x10⁹/L.

• 92 total patients were in the sample.
• Age ranged from 18-83 years.
• For women, were in the XM02 group and 12 were in the filgrastim group.
• For men, 31 were in the XM02 group and 17 were in the filgrastim group.
• Patients had aggressive NHL, defined as diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, follicular lymphoma grade 3, or anaplastic large cell lymphoma.
• Eligible patients had to be chemotherapy-naïve, have a life expectancy of six months or longer, an international prognostic index score of 3 or lower, an ANC greater than 15 x 10⁹/L, a platelet count greater than 100 x 10⁹/L, and adequate hepatic, cardiac, and renal function for the chemotherapy regimen.

Multiple inpatient and outpatient settings

Active treatment

Phase III, randomized, controlled trial

• Duration of severe neutropenia (DSN)    
• Febrile neutropenia    
• ANC
• Adverse events: musculoskeletal and connective tissue disorders (bone pain, arthralgia, back pain, musculoskeletal pain, jaw pain); general disorders and administration site conditions (pyrexia, fatigue, flu like illness); gastrointestinal (diarrhea); nervous system (HA), vascular (hot flush); and blood and lymphatic (anemia)
• Pharmacokinetics
   

XM02 was found to be pharmacokinetically similar to filgrastim and not statistically significantly different from filgrastim for febrile neutropenia (FN) in cycle 1 (11.1% for XM02 and 20.7% for filgrastim). ANC values in both groups reached a maximum at day 4 and decreased to a nadir on day 9 followed by an increase reaching a maximum on day 11, with a return to day 1 mean values reached on day 21 (similar to other filgrastim studies). Drug-related adverse events were not statistically different between XM02 and filgrastim.

The administration of G-CSFs for the prevention of chemotherapy-induced neutropenia and related adverse events has been proven effective in many trials. Use of XM02 has similar pharmacokinetics, safety, and efficacy compared to the established filgrastim. Other studies show greater efficacy with pegylated filgrastim that requires less dosing than the daily doses of filgrastim. The use of XM02 instead of filgrastrim does not seem favorable based on these results.

• Small sample size (less than 100 participants)
• This study was sponsored and funded by BioGeneriX AG, the manufacturer of XM02.
• Filgrastim was only compared to XM02 in the first chemotherapy cycle, then all patients received XM02; yet the results evaluated outcomes throughout the duration of all chemotherapy doses.
   

Based on this study alone, nurses can be aware that XM02 for patients 18 and older with aggressive NHL for the risk reduction of neutropenia and related adverse outcomes will be similarly effective to filgrastrim.

The purpose of the study was to compare the use of pegfilgratim in all chemotherapy cycles with pegfilgrastim use at the clinician’s discretion for the reduction of febrile neutropenia, grade 3 or 4 neutropenia, dose delay, dose reduction, hospitalization, antibiotic use, and infections in older adults with cancer.

Study period was June 2002 to Nov 2004.

Older adults with cancer of the breast, ovary, lung, or aggressive non-Hodgkin lymphoma (NHL) were randomized to pegfilgrastim (subcutaneous injection 6 mg one time per cycle 24 hours after chemotherapy completion staring with cycle one) or secondary prophylaxis with pegfilgrastim (subcutaneous injection 6 mg one time per cycle 24 hours after chemotherapy completion staring after cycle one at physician’s discretion [discretion may be in response to severe neutropenia, netropenia-related events during chemotherapy, dose delays, dose reductions, or no changes in dose or timing]).

• The total sample size was 852.
• All participants were aged 65 years and older.
• The amount of women was 548; the amount of men was 304.
• Key disease characteristics were lung, breast, or ovarian cancer or aggressive NHL.
• In the solid tumor and NHL groups, each of the following age groups were comprised of 33% of the patients: 65–69 years old, 70–74 years old, and 75 years and older.
• 90% were Caucasian and 90% had an ECOG score of 0 or 1.
• The majority of all patients were diagnosed with disease stage III or IV.

• Multi-site  
• Outpatient setting  
• Community cancer centers nationwide

• The phase of care was active treatment
• Application was for elderly care

Phase IV, open-label, randomized, multicenter, community-based trial

• Febrile neutropenia 
• Grade 3 neutropenia
• Chemotherapy regimen
• Solid tumor type
• Pegfilgrastin administered
• Dose delay, dose reduction, hospitalization, and antibiotic use

701 patients with solid tumors. Fifteen were excluded, making the sample size 686 (343 in the pegfilgrastim arm, 343 in the physician discretion arm). Those who completed the study in each arm was 198 in the pegfilgrastim arm  and 175 in the physician discretion arm. Forty-two percent of patients in the discretion arm received pegfilgrastim, most often for grade 3 or 4 neutropenia. There were 151 patients with NHL. Five were excluded, making the sample size 146 (73 in the pegfilgrastim arm, 73 in the physician discretion arm). Thirty-eight patients in each arm completed the study. In the discretion arm, 64% received pegfilgratim.
 

Febrile neutropenia was lower in the all-cycle pegfilgrastim arm compared to the discretion arm, with a 60% reduction in incidence of febrile neutropenia for patients with solid tumors (p = 0.001) and 59% reduction of febrile neutropenia for patients with NHL (p = 0.004). Grade 4 febrile neutropenia was 22% for patients with solid tumors and 75% for patients with NHL in the all-cycle pegfilgrastim arm compared to 58% for patients with solid tumors and 86% for patients with NHL in the discretion arm. Rates of febrile neutropenia in the first cycle for patients with solid tumors were 3%, and 7% for NHL patients in the all-cycle pegfilgrastim arm compared to 7% for solid tumors and 25% for NHL patients in the discretion arm.

Overall, for patients with solid tumors, the all-cycle pegfilgrastim arm had lower rates of grade 3 or 4 neutropenia, dose delays, dose reductions, decreased hospitalizations, and decreased antibiotic use compared to the discretion arm; and similarly for patients with NHL with the exceptions of higher rates of dose delay and dose reductions in the all-cycle pegfilgrastim arm. None of these findings were statistically significant.
 

The most serious adverse event related to pegfilgrastim use was bone pain (12%) in the solid tumor group and in the NHL group (9%) for those receiving all-cycle pegfilgrastim compared to 5% and 4%, respectively, for the discretion arm.

Pegfilgrastin use in older adults undergoing chemotherapy for cancer of the lung, breast, or ovary, or for NHL is safe and effective with use starting in the first cycle for the reduction of febrile neutropenia, grade 3 or 4 neutropenia, febrile neutropenia-related hospitalizations, and antibiotic use. Dose delay and dose reduction were shown to be increased for patients with NHL who received pegfilgrastin at all cycles compared to physician discretion, which may be due to increased use of pegfilgrastin through physician discretion in this population. In addition, due to the use of pegfilgrastin by physician discretion as the comparison group and the unknown information about frequency of dosing in the discretion arm outside of the majority beginning pegfilgrastin treatment following a grade 3 or 4 febrile neutropenic event, coupled with limited statistically significant outcomes, it is difficult to have a definitive conclusion based on these findings. Clinically, however, the outcomes do appear favorable towards use of pegfilgrastin beginning with the first cycle.

• This study was funded by Amgen, the manufacturer of pegfilgrastim, and the study was not blinded. 
• The use of pegfilgrastim for neutropenia and related adverse events in patients with other types of malignancies were not evaluated in this study.
• Fewer patients with NHL were able to be randomized to the discretion arm since physicians often wanted pegfilgrastim started early in these patients due to known neutropenic outcomes.
• In addition, this article was a replication of the article by Balducci et al. (2007), which was the original report of the findings; therefore, this article published two years after the original does not add to the knowledge of efficacy of use of pegfilgrastim.

The administration of pegfilgrastin starting with the first cycle of chemotherapy may reduce neutropenic events and related complications in older adults with cancer. Nurses can be at the forefront of advocating for this therapy, administering it, and monitoring patients for effective outcomes and/or adverse events.

To prevent the recurrence of neutropenic events (NEs) in patients with solid tumors and identify potential predictive factors of recurrence of NEs

The study was a prospective, multi-center, observational study to describe prophylactic strategies, including cycle delay, dose reduction, and granulocyte colony-stimulating factor (G-CSF), that were developed to prevent the recurrence of an NE subsequent to a previous episode in patients with solid tumors, and to evaluate their respective efficacy (primary endpoint). Secondary objectives assessed the recurrence rate of NEs and factors predictive of recurrence.

• N = 548  
• MEDIAN AGE = 63 years (range: 18–92 years)
• MALES: 31%, FEMALES: 69%
• KEY DISEASE CHARACTERISTICS: 40% were patients with breast cancer; no hematologic malignancy
• OTHER KEY SAMPLE CHARACTERISTICS: 43.6% of patients were older than 65 years; 59.9% were treated for metastatic disease

• SITE: Multi-site   
• SETTING TYPE: Outpatient   
• LOCATION: 62 cancer centers in France

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

• Observational

• Incidence of febrile neutropenia, treatment delays, and chemotherapy dose reductions
• Neutropenic events defined as any episode of febrile neutropenia (single temperature elevation over one hour) or any episode of neutropenia with a significant impact in terms of cycle delay or dose reduction

During cycle A, 16.1% experienced febrile neutropenia, 7.7% experienced neutropenic fever, and 76.3% experienced all-grade neutropenia. Cycle B was delayed in 44.5%, dose reductions occurred in 22.3%, and prophylactic G-CSF was given to 85% (59.7% received pegfilgrastim). The incidence of cycle delay and chemotherapy dose reduction decreased with further cycles of chemotherapy. The median number of G-CSF administrations with subsequent cycles, excluding pegfilgrastim, was five. The proportion of patients who experienced an NE was 29% when receiving G-CSF versus 68% for patients who did not. Only use of G-CSF was associated with a lower recurrence rate of febrile episodes (p < .001). In multivariate analysis, factors associated with a greater rate of NE occurrence were prior episode of febrile neutropenia, lung or colorectal cancer, metastatic disease, and prior radiotherapy.

Only the prophylactic administration of G-CSF was found to be an independent predictor of lower recurrence rate of NEs.

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias (no appropriate attentional control condition)

Teaching needs to be done related to G-CSF administration and the necessity of use. Further research is needed in G-CSF prophylaxis and the quality-of-life impact of other methods such as delay/dose reduction.

To evaluate the efficacy and safety of balugrastim compared to pegfilgrastim

Patients were randomized to receive either once per cycle 40–50 mg balugrastim or 6 mg pegfilgrastim by subcutaneous injection 24 hours after administration of chemotherapy. Blood samples were obtained twice weekly after post-nadir absolute neutrophil count (ANC) was greater than two, and temperature was measured twice daily.

• N = 238
• MEAN AGE = 49.9 years
• MALES: 0.04%, FEMALES: 99.6%
• KEY DISEASE CHARACTERISTICS: Patients with breast cancer. Approximately one-third had metastatic disease.
• OTHER KEY SAMPLE CHARACTERISTICS: Patients were excluded if they had received more than one prior chemotherapy cycle.

• SITE: Multi-site  
• SETTING TYPE: Not specified  
• LOCATION: Russia and Ukraine

• PHASE OF CARE: Active antitumor treatment

• Open-label randomized noninferiority trial

• Duration of severe neutropenia defined as ANC < 0.5 x 10⁹/L
• Incidence of febrile neutropenia (oral temp ≥ 38.2 C)
• Time to ANC nadir
• Duration and depth of ANC nadir
• Time to ANC recovery
• National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0

Difference in duration of severe neutropenia was less than one day between balugrastim and pegfilgrastim, and was similar in both dosages of balugrastim. Duration and incidence of severe neutropenia were reduced in subsequent cycles in all groups. There were no significant differences in incidence of febrile neutropenia. In cycle one, time to ANC recovery was shorted in the balugrastim group (2.0–2.1 days versus 2.6 days, p = 0.005). Adverse effects were similar in both groups. Presence of antibodies to the medication was similar in both groups.

A single fixed dose of balugrastim was not inferior to pegfilgrastim for management of neutropenia.

• Risk of bias (no blinding)

Balugrastim is an effective alternative to pegfilgrastim in patients with breast cancer receiving myelosuppressive chemotherapy. A single fixed dose per cycle was as effective as pegfilgrastim. Further research comparing various colony-stimulating factors (CSFs) and biosimilar agents are needed to continue to identify the most acceptable and cost-effective methods for hematopoetic support in patients receiving myelosuppressive chemotherapy with a high risk of febrile neutropenia.

To evaluate the efficacy of primary prophylactic pegfilgrastim compared to on-demand daily G-CSF after treatment with cladribine in patients with hairy-cell leukemia (HCL)

This was a retrospective chart review of 40 patients with HCL (1991–2012) treated with cladribine (0.1 mg/kg per day) for five to seven days either subcutaneously (SC) or IV, receiving a total of 40 courses of therapy treated with filgrastim (300 mcg per day) on demand until the patients' absolute neutrophil counts (ANCs) were > 2.0 x 10⁹ compared to nine courses of therapy with primary pegfilgrastim prophylaxis (6 mg SC for 24 hours after the completion of chemotherapy).

• N = 40 (on-demand filgrastim arm had 31 patients; primary pegfilgrastim prophylaxis arm had nine patients)   
• RANGE AGE = 23–76 years  
• MALES: 80%, FEMALES: 20%
• KEY DISEASE CHARACTERISTICS: HCL diagnosis confirmed by bone marrow biopsy and additional flow cytometry confirmation (after 2004); no significant difference in clinical and laboratory parameters between study populations before therapy including cytopenias, spleen size, ANC, platelet count, hemoglobin count, nadir duration, infections requiring hospitalization, and duration of hospitalization
• OTHER KEY SAMPLE CHARACTERISTICS: The on-demand filgrastim arm included two patients who received three cycles because of relapsed disease, seven patients who were treated with two cycles, and 31 patients who received only one course of therapy. In the primary prophylaxis pegfilgrastim arm, nine consecutive courses were given to nine patients 24 hours after the completion of chemotherapy.

• SITE: Medical centers
• SETTING TYPE: Inpatient  
• LOCATION: Haifa, Israel

• PHASE OF CARE: Active treatment

Retrospective, historical control study of patients with HCL prescribed cladribine determining the effect of IV pegfilgrastim versus filgrastim on neutropenia, hospitalization, 2⁰ FN, severity of infection, and ANC nadir

• The incidence of neutropenia (defined as an ANC < 1.0 x 10⁹ /L)
• Fever (defined as a temperature > 38.2 ^oC)
• Number of days of hospitalization because of FN
• Details of severity of infection
• Number days from the last day of therapy until ANC recovery (defined as an ANC > 1.0 x 10⁹ /L)

The median follow-up was 94 months (range = 12–312 months). No significant difference was found between primary prophylaxis with pegfilgrastim versus on-demand filgrastim for patients with HCL treated with cladribine for the variables of incidence of neutropenia, number days of hospitalization because of FN, severity of infection, or the number of days from the last day therapy till ANC recovery.

This retrospective study demonstrated no difference in the clinical effectiveness of primary pegfilgrastim versus on-demand filgrastim after cladribine therapy for patients with HCL.

• Small sample (< 100)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Key sample group differences that could influence results
• Measurement/methods not well described
• Measurement validity/reliability questionable
• Findings not generalizable
• Questionable protocol fidelity
• Other limitations/explanation: The majority of patients were in the filgrastim group (n = 31) compared to the pegfilgrastim group (n = 9). There may have been differences between the sites that were not disclosed. The grade of neutropenia not described. There were differences between the study groups (relapsed patients in the filgrastim on-demand arm). There were unknown comorbities in study population. Previous patient chemotherapy exposure was unknown. The details of the types and severity of infections post-treatment were not well-reported or described.

This study demonstrated no difference in the incidence of neutropenia, FN, or infections requiring hospitalization between the use of pegfilgrastim versus filgrastim after treatment with cladribine. Large, prospective, randomized trials need to be conducted to validate this study's results. Nurse-sensitive interventions remain critical in the prevention of infection for patients with HCL and prolonged neutropenia caused by disease and treatment.

The purpose of the study was to evaluate the efficacy of a single fixed 6 mg dose of pegfilgrastim compared with daily filgrastim.

Patients were randomly assigned to receive either a single fixed dose injection of 6 mg pegfilgrastim on day 2 of their treatment cycle or daily injections of filgrastim 5 mcg/kg per day, begun about 24 hours after chemotherapy until documented absolute neutrophil count (ANC) of 10 x 10⁹/L or greater. Chemotherapy dose reductions were permitted if patients had grade 3-4 non-hemopoetic toxicities.

• 152 total participants were evaluated.
• Mean age of the participants was 52.4 years, with a range of 30–75 years.
• All of the participants were women.
• The disease type was not stated. All were receiving doxorubicin and docetaxel chemotherapy every three weeks.
• Patients were excluded if they received systemic anti-infective treatment within 72 hours of chemotherapy.

• Multi-site
• Outpatient 
• 37 centers in Europe, Australia, and the United States

Active antitumor treatment

Double-blind randomized phase III

• Weekly blood samples for ANC determination
• Grade 4 neutropenia defined as ANC less than 0.5 x 10⁹/L
• Neutrophil recovery defined as ANC of 2.0 x 10⁹/L or greater

In cycle 1, mean duration of neutropenia was 1.8 days with pegfilgrastim and 1.6 days in the filgrastim group—no significant difference.  There were no differences between groups for duration of grade 4 neutropenia during other treatment cycles. The safety profile of pegfilgrastim was similar to that for filgrastim.

A single fixed dose of pegfilgrastim per chemotherapy cycle is as safe and effective as daily filgrastim injections.

No significant study limitations were identified.

This study demonstrated that a single fixed dose of pegfilgrastim was as safe and effective as daily filgrastim in these patients. The ability to provide the same effectiveness with fewer injections can be beneficial to patients.

To examine the effect of colony-stimulating factors (CSFs) used as primary and secondary prophylaxis on incidence of febrile neutropenia, infection, and survival in older adults.

The study used data from the Surveillance, Epidemiology, and End Results (SEER) Medicare database. ICD-9 codes were used to define inclusion diagnoses and definition of febrile neutropenia. 

Use of CSF, the type of chemotherapy administered, and the use of antibiotics were defined in terms of CPT codes. Regression analysis was used to analyze effects of primary and secondary CSF prophylaxis on outcomes of interest. Primary prophylaxis was defined as CSF during chemotherapy before occurrence of fever, infection, or neutropenia. Secondary prophylaxis was CSF administration that occurred after these events. Study used data from 1992–2002.

• Total cases numbered 13,203, with 5,266 receiving any CSF.
• Mean age was 74.9 years, with a range of 65–102.
• Women made up 53% of the sample; men made up 47%.
• All patients had non-Hodgkin lymphoma (NHL). 
• 62% had low comorbidity burden, as defined by ICD-9 coding.
• 44% had large B-cell lymphoma.
• 18% had follicular lymphoma. 
• 89.2% were Caucasian. 
• All socioeconomic groups were essentially equally represented.
   

Multi-site (SEER data)

There were mutliple phases of care

Application is for elder care

Retrospective cohort study

• Chemotherapy administration defined as ICD-9 code 9925; CPT codes 96400-96549, J9000-9999, and Q0083-0085; revenue codes 0331, 0332, and 0335; and ICD-9 V codes, k V58.1, V66.2, and V67.2.
• Use of CSF was identified by CPT codes J1440, J1441, and J2820.
• Febrile neutropenia was defined as the combination of neutropenia (ICD-9 288.0) and fever present (780.6).

Sixty percent of cases did not receive any CSF. Those who had 5–9 CSF administrations for primary prophylaxis has a 42% lower risk of febrile neutropenia (OR = 0.58, 95% confidence interval [CI] [0.41, 0.83]) and those with 10 or more administrations had a 48% lower risk after data were adjusted for age, marital status, stage, and other characteristics. Those with 5–9 administrations had a 27% lower incidence of infection, and those with 10 or more administrations had a 52% lower risk (OR = 0.48, 95% CI [0.35, 0.66]). Primary prophylactic CSF was not associated with longer overall survival. Secondary prophylaxis was associated with improved overall survival, with a strong dose-response effect. A range of 11–23 administrations was associated with a 23% lower risk of mortality (HR = 0.77, 95% CI [0.71, 0.84]), and those with more than 23 administrations had a 13% lower risk of mortality than others. Protective effects of primary prophylaxis was highest in those receiving the largest number of chemotherapy administrations and in those with large B-cell lymphoma.

Primary prophylaxis with CSF in older adults is effective in preventing febrile neutropenia and infection, but was not associated with improved survival. Secondary prophylaxis was associated with longer overall survival.

• Risk of bias (sample characteristics)
• Measurement validity/reliability questionable
• Findings not generalizable
• Measurement validity/reliability questionable
• The sample was limited to patients with NHL from 1992–2002, and findings would not necessarily be applicable to patients with other types of disease and those receiving newer and other treatment regimens. 
• Although data were stratified for classes of chemotherapeutic drugs there was no specific subgroup analysis based on different types of chemotherapy or other treatments.
• Reliability of medical records coding is across organizations is known to be questionable, so findings should be considered with this in mind.
• Definition of neutropenia by code, which depends upon physician documentation and does not specify actual lab results as criteria can be questionable.
• A higher proportion of patients who got primary prophylaxis had higher stage disease—it is not stated as to whether there were statistically significant differences in this factor or not and those who received CSF were more likely to have received radiation therapy as well.   
• Although data were said to be stratified for age, it is not clear if the factor of combined therapy was considered in analysis.

Findings support the use of primary prophylactic CSF for prevention of infection and febrile neutropenia, and secondary prophylaxis in improving survival in this group of patients. Limitation of retrospective statistical analysis using medical records code data only need to be considered in interpretation and application of these results.

The purpose of the study was to evaluate the feasibility and efficacy of G-CSF secondary prophylaxis in patients with solid tumors undergoing chemotherapy.

Patients in the study required IV antibiotics filgrastim 300 mg per day subcutaneously starting 24–30 hours after the last chemotherapy dose in a subsequent cycle. A total of 8–9 alternate day doses were given. If no other dose limiting toxicity was seen, patients received full chemotherapy dosing with filgrastim support for following treatment cycles. Duration of hospital stay, days on antibiotic therapy, incidence of fever, time to resolve fever, dose reductions or delays, neutrophil recovery time, and incidence of adverse events were recorded. Results compared to findings in the same patients during the previous chemotherapy cycle.

• The total sample size was 50.
• Participants had a median age of 47, with a range of 22–75.
• The most common cancer types were lymphoma and breast cancer.
• Fifty-eight percent were receiving adriamycin-containing regimens.
   

Single-site location in India

Active antitumor treatment

Prospective, single group, observational study

No specific measure definitions were provided.

Neutrophil recovery time, duration of fever, duration of antibiotics and duration of hospitalization, cycle delays, and chemotherapy dose reductions declined with each course of chemotherapy. The decrease in all measures was significant across four treatment cycles (p < 0.01).

Study findings provide some support the use of colony-stimulating factor as secondary prophylaxis in patients receiving myelosuppressive chemotherapy. A number of study limitations limit the strength of these findings.

• Small sample (less than 100 participants)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement/methods not described  
• Measurement validity/reliability questionable
• The stated sample size varies in the report from 54 to 50, and authors stated that two patients who developed overwhelming febrile neutropenia during the study were eliminated from analysis, demonstrating no intent to treat analysis.
• No definition of neutropenia for determination of recovery time is provided.

This study provides limited evidence supporting the use of colony-stimulating factors as secondary prophylaxis in patients receiving chemotherapy. CSF was given every other day in this trial, adding to the body of evidence in which the frequency of administration varies. Secondary prophylaxis can play an important role in sustaining the treatment dosages of chemotherapy cycles.

The purpose of the PROTECT-1 study was to confirm efficacy and safety of the biosimilar pegfilgrastim (LA-EP2006) with reference pegfilgrastim (Neulasta^®) in the reduction of duration of severe neutropenia (DSN) in patients with breast cancer receiving myelosuppressive chemotherapy.

1:1 stratified randomization of adult (aged 18 years or older) women with breast cancer (stratified by Europe, Asia, or European region and receipt of adjuvant or neoadjuvant myelosuppressive TAC regimen chemotherapy [docetaxel 75 mg/m², doxorubicin 50 mg/m², and cyclosphosphamide 500 mg/m²]) into a one of two groups to receive either LA-EP2006 or Neulasta. TAC was administered on day 1 of each cycle and then every 3 weeks up to 6 cycles. Patients could remain in the study if they had a 25% reduction in chemotherapy due to a grade 3-4 nonhematologic toxicity, grade 4 thrombocytopenia, or febrile neutropenia. A 6 mg subcutaneous injection of LA-EP2006 or Neulasta was administered on day 2 of each cycle (24 hours or longer following the end of chemotherapy). Patients were followed for 6 months following the last dose of LA-EP2006 or Neulasta.

• N = 316   
• AGE: Mean = 50.2 years (range = 40.4-61.4)
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Stage I-IV breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: ECOG performance status of 2 or lower; ANC of 1.5 x10⁹/L or greater; platelet count 100 x 10⁹/L or greater; hemoglobin 10 g/dl or greater; normal total bilirubin; AST and ALT 2 x upper limit of normal (ULN) or less; liver-derived alkaline phosphatase 3x ULN or less; creatinine 1.5 x ULN or less; and a negative pregnancy test within seven days of randomization and use of effective birth control for women of childbearing potential. Women were excluded if they had a history of previous or current malignancies and/or hematologic disorders (myelodysplastic syndrome, sickle cell disease, CML) and any current medical condition and concurrent or prior treatment for breast cancer.

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: 42 sites across cancer centers in Europe, Asia, and America

PHASE OF CARE: Active anti-tumor treatment

Randomized, double-blind study

Outcomes of mean duration of severe neutropenia–number of consecutive days of grade IV neutropenia: ANC 0.5x10⁹/L or less during cycle 1, depth of ANC nadir, time to ANC recover (nadir to ANC 2 x 10⁹/L or greater in cycle 1; incidence of febrile neutropenia (PO temp 38.3^oC or greater with ANC 0.5 x 10⁹ or less) or neutropenic sepsis (FN/NS) by cycle and across cycles; number of patients with fever(PO temp 38.3^oC or greater) per cycle; number of patients with infections per cycle and across cycles; and infection-related mortality. Safety was also measured through the incidence, occurrence, and severity of treatment-emergent adverse events (TEAEs) using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. FNs were reported as AEs. ELISA testing was used to validate immunogenicity of LA-EP2006 or Neulasta.

RESULTS: There were no demographic differences between groups. 159 patients were in the LA-EP2006 group and 157 were in the neulasta group. 19 and 7 discontinued treatment in the LA-EP2006 and neulasta groups, respectively. 2 patients in the neulasta group died from infections; 4 patients in the LA-EP2006 group died (cause of death not disclosed). In cycle 1, the DSN was 0.75 (SD = 0.88) days with LA-EP2006 and 0.83 (SD = 0.9) days with Neulasta. The difference between the groups was 0.07 days (90% CI [-0.09, 0.23]; 95% CI [-0.12, 0.26]).Similar findings in the per protocol analysis No clinically meaningful differences were found between groups for depth of ANC nadir, mean days to ANC recovery,  and time course of mean ANC. Frequency of infections (cycle 1: 4.4%, n = 7 versus 2.5%, n = 4; across cycles: 13.8%, n = 22 versus 15.3%, n = 24). No differences between groups were found for safety (TEAE 1 or greater 88.1% LA-EP2006 and 82.8% neulasta) or neutralizing antibodies.

LA-EP2006 was found to be as effective and safe as neulasta. Use of biosimilar pegfilgrastim can potentially increase the availability of patients receiving prophylactic pegfrilgrastim for improved outcomes while undergoing chemotherapy treatment for cancer.

Infections were not defined and the causes of death of the four patients in the LA-EP2006 arm were not disclosed.

Nurses being aware of biosimilars for pegfilgratim can help guide practice for use of prophylactic pegfilgrastim when standard pegfilgrastim (neulasta) is not available. In addition, nurses can assess patients for risks of adverse events related to chemotherapy treatments.

The purpose of this study is to evaluate whether prophylactic pegfilgrastim administered with first- or second-line chemotherapy was feasible and reduced the incidence of grade 3/4 neutropenia and neutropenia-related complications in patients receiving 14-day oxaliplatin- or irinotecan-containing 5-FU–based chemotherapy regimens for advanced or metastatic colorectal cancer (CRC). 

One of three chemotherapy regimens (FOLFOX 4, FOLFIRI, or FOIL) was selected by physician discretion. Patients were randomized to receive either pegfilgrastim 6 mg or placebo on day 4 of each 14-day regimen. During the study period (the first four cycles of chemotherapy), the incidence of grade 3/4 neutropenia and febrile neutropenia were compared between the pegfilgrastim and placebo groups.

• The sample size was 241 at baseline; 135 completed the study.  
• All were adults aged 18 years or older.
• Men made up 67% of the sample; women made up 33%.
• A key disease characteristic was locally advanced or metastatic CRC not curable by surgery and not amenable to curative radiation therapy

• Multi-site (54 sites) 
• Outpatient settings  
• United States
   

Active treatment

Randomized, controlled trial, double-blinded. The control group received placebo.

• Laboratory results (complete blood count with five-part differential)    
• Patient temperatures, either reported or taken by healthcare provider
• Adverse events (nausea, diarrhea, fatigue, anemia, vomiting, anorexia, dehydration, abdominal pain, asthenia, pyrexia, decreased weight, hypokalemia, insomnia, neutropenia, constipation, alopecia, bone pain, dyspnea, pain, and febrile neutropenia)
   

Patients treated with pegfilgrastim were significantly less likely (13%) to develop grade 3/4 neutropenia than those who received a placebo (43%) (p < 0.05). The pegfilgrastim group also experienced significantly fewer dose delays or dose reductions (33.4% versus 45%) (p < 0.05).

The study compares pegfilgrastim versus placebo, but does not consider pegfilgrastim versus filgrastim, which may have similar efficacy at reduced expense. Additional study is warranted, including a cost-benefit analysis.

•  The study authors disclosed potential conflicts of interest, including owning stock in Amgen, the company that produces pegfilgrastim.
•  Amgen also provided writing assistance for this article, which raises questions of bias.

Patients with CRC receiving every-two-week chemotherapy regimens may benefit from supportive medications to stimulate neutrophil production.

To compare the efficacy and safety of two filgrastim formulations for controlling chemotherapy-induced neutropenia and to evaluate the noninferiority of the test drug against the original

Patients with grade 4 neutropenia were randomized 1:1 to Eurofarma filgrastim or Roche filgrastim. Doses were administered subcutaneously daily 5 mg/kg until absolute neutrophil count was 10,000/mm³ or greater or until the 15th day of the chemotherapy cycle (V14). Only a single event of febrile neutropenia was considered during the study period per patient. Neutrophil counts were drawn every two days.

• N = 219   
• AGE = 49–51 years
• MALES: Not specified
• FEMALES: Not specified
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Breast cancer stages II–IV
• OTHER KEY SAMPLE CHARACTERISTICS: Full dose of TAC or AT chemotherapy

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Brazil

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care, palliative care

Phase III, open-label, noninferiority, randomized, two-group trial

• Kolmogorov-Smirnov test with Lilliefors correction used to evaluate standard distribution of the outcome variables
• Lillifors correction also used to adjust the estimated population parameters (mean and variance, standard deviation)

To assess the noninferiority of the test drug to the original the 90% confidence interval for the difference in the rates of grade 4 neutropenia between the two groups were initially calculated.

No significant difference (p = 0.9971) in the rate of grade 4 neutropenia existed in the total number of patients in each group during the first chemotherapy cycle.

Risk of bias (no blinding)

The increased surveillance of patients’ neutrophils may have produced better outcomes. The difference between the two drugs was negligible. Strong patient teaching is warranted, regardless of the process of events during the chemotherapy cycle.

The purpose of the study was to investigate the efficacy, safety, and pharmacokinetics of various single doses of pegfilgrastim per chemotherapy cycle in women receiving chemotherapy with doxorubicin and docetaxel.

On day 2 of each chemotherapy cycle, 24 hours after chemotherapy completion, patients either received a single subcutaneous injection of pegfilgrastim or began daily injections of filgrastim for 14 days or until absolute neutrophil count (ANC) recovery to 10 x 10⁹/L after nadir. Within the pegfilgrastim group, patients received 30, 60 or 100 mcg/kg. Filgastrim was given at 5 mcg/kg per day. Patients were randomly assigned to treatment group. Treatment was repeated for each cycle, up to four cycles. Blood samples were collected at screening, before each chemotherapy cycle, and once weekly during cycle 1. Findings were evaluated regarding duration of grade 4 neutropenia and rates of febrile neutropenia.

• 137 participants
• The mean age was 50 years (SD = 9)
• Women made up 100% of the sample.
• All had breast cancer and were receiving the same type of chemotherapy regimen.  
• About 33% had stage II disease, 33%had stage III, and about 33% had stage IV disease.

Multiple sites in the United States

Active antitumor treatment

Randomized dose finding phase II. Analysis also included open-label phase data.

• Grade 4 neutropenia defined as ANC less than 0.5 x 10⁹/L
• Febrile neutropenia was defined as grade 4 neutropenia plus an oral temperature of 38.2ºC or higher.

Mean duration of grade 4 neutropenia in patients on filgastrim during cycle 1 was 2.5, and was 2.0 in patients receiving 30 mcg/kg pegfilgastrim (95% CI [0.35,1.93]). There was not a statistically significant difference in cycle 1 with the other pegfilgastrim dosage groups. Mean time to ANC recovery for cycle 1 was 9.4 days with filgastrim, 9.5 with 100 mcg pegfilgastrim (p = 0.05), 10.3 with 60 mcg (p = 0.05) pegfilgastrim,  and 11 with 30 mcg doses (not significant). There were no significant differences across groups in any other outcome measure. There were no significant differences in adverse events. A single dose of pegilfrastim produced a sustained serum concentration, with maximum concentration at about 24 hours, and was sustained until ANC nadir.

Pegfilgastrim at a single dose per chemotherapy cycle was similar to daily filgastrim in efficacy and adverse effects.

• Risk of bias (no blinding)
• Selective outcomes reporting
• Measurement/methods not well described
• Results reporting is somewhat confusing, as the sample sizes per measure vary throughout.  
• Only data from cycle 1 was fully analyzed.  
• Authors state that they pooled results from the open-label phase and randomized study phase, but it is not clear which data are which.

Findings suggest that single dose of pegfilgastrim per chemotherapy cycle is similar to daily filgastrim dosing in terms of safety and efficacy. The need for fewer subcutaneous injections with single dosing may be beneficial to patients.

The purpose of the study was to compare effects of two different doses of G-CSF in pediatric patients receiving high-dose chemotherapy.

Patients receiving induction chemotherapy were randomly assigned to receive either 5 mcg/kg or 10 mc/kg G-CSF daily after the first and second chemotherapy induction courses. Differences in number of neutropenic days, hospital days, number of febrile neutropenic episodes, episodes of infection, use of IV antibiotics, antifungal therapy courses, number of transfusions, cost of supportive care, and estimates of event-free survival.

• 46 total participants
• Median age was 9.03 years, with a range of 0.05–21 years.
• Females made up 53% of the sample; males made up 47% of the sample
• All participants had previously untreated AML or myelodyplastic syndrome and were receiving induction chemotherapy.
• Specific chemotherapy protocol used is described.
   

Single-site inpatient location

The phase of care was active antitumor treatment.

The application was for pediatrics.

Double-blind, randomized, controlled trial

• NCI Common Toxicity Criteria [v.2.0]
• Neutropenia was defined as a neutrophil count of less than 0.5 x 10⁹/L
• Event-free survival was defined as time between randomization and disease recurrence, death, secondary malignancy, or last follow-up.
   

No significant differences were noted between study groups in number of neutropenic days, episodes of febrile neutropenia, days of hospitalization, episode of antibiotic and antifungal therapy, transfusions, or cost of supportive care. There was no difference between groups in proportion of complete responses, or estimates of event-free and overall survival.

No difference was noted in measured outcomes between groups of patients treated with two different doses of G-CSF.

• Small sample (less than 100 participants)
• It is unclear if patients were given prophylactic antibiotics or antifungal therapy, which would have affected related outcomes. Sample included both patients who did and did not receive allogeneic stem cell transplantation.

Findings suggest that lower daily doses of prophylactic G-CSF can be as effective as higher doses in pediatric patients during induction chemotherapy. Dosage and timing of prophylactic G-CSF is not fully clear.

To determine the extent to which pegfilgrastim reduces the risk of febrile neutropenia (FN) in Japanese women with early-stage breast cancer receiving docetaxel and cyclophosphamide (DC) chemotherapy

Pegfilgrastim at 3.6 mg or a placebo was administered subcutaneously on day 2 (at least 24 hours after DC chemotherapy) of a 21-day cycle. The study compared the incidence of FN between the pegfilgrastim and placebo cohorts. The incidence of FN during the first cycle of chemotherapy, incidence of hospitalization related to FN, incidence of grade 4 neutropenia, and percentage of patients who received antibiotics as a result of FN also were tracked.

• N = 346
• MEDIAN AGE = 50–51 years (range = 26–69 years)
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Stages I–III primary invasive breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Not applicable

• SITE: Multi-site  
• SETTING TYPE: Not specified  
• LOCATION: Japan

• PHASE OF CARE: Active antitumor treatment

Randomized, double-blinded, controlled trial using pegfilgrastim versus a placebo

FN was defined as an absolute neutrophil count < 500 and an axillary temperature at or above 37.5°C on the same day or the following day. Complete blood counts were checked on days 1, 2, 8, 11, and 15 during cycle 1 and on days 1, 2, 8, and 11 of subsequent cycles. Axillary body temperature was measured daily.

Patients treated with pegfilgrastim experienced a significantly lower incidence of FN (1.2%) compared to those who received a placebo (68.8%; p < 0.001). The measurement of secondary endpoints also revealed significant differences between the two groups. None of the patients in the pegfilgrastim group required hospitalization for FN whereas 6.9% of the placebo group did (p < 0.001). Patients who received pegfilgrastim were significantly less likely to require antibiotics to treat FN (0.6%) than those in the control group (56.6%; p < 0.001). During the first chemotherapy cycle, only one patient (0.6%) in the pegfilgrastim cohort developed FN compared to greater than half (57.8%) of the placebo group (p < 0.001). Only 4% of the pegfilgrastim group developed grade 4 neutropenia during chemotherapy whereas all of the placebo group developed this grade (p < 0.001).

Previous studies demonstrated the value of pegfilgrastim in significantly reducing FN in European and North American patients with breast cancer receiving chemotherapy with docetaxel. This study confirmed the efficacy of pegfilgrastim (using a dose of 3.6 mg) for use in Japanese female patients with breast cancer receiving DC chemotherapy. These results suggest that additional studies should be designed to determine if the lower pegfilgrastim dose of 3.6 mg is not inferior to the standard 6 mg dose.

• Findings not generalizable
• Other limitations/explanation: This study used pegfilgrastim at 3.6 mg, not the 6 mg that is the standard dose in the United States and Europe. The authors chose 3.6 mg for their study population because this dose has been demonstrated to be effective in reducing the incidence of FN following docetaxel, doxorubicin, and cyclophosphamide chemotherapy in Japanese patients.

The focus of this study was to demonstrate pegfilgrastim's efficacy in female Japanese patients with breast cancer, and it used a smaller pegfilgrastim dose than is commonly prescribed in the United States or Europe. Additional study is warranted to determine the appropriate dosage of pegfilgrastim for this particular population.

To compare effectiveness of pegfilgrastim given as a prophylactic single-fixed dose versus daily filgrastim for incidence of febrile neutropenia (FN), severe neutropenia, treatment delays, and dose reductions in high-risk breast cancer patients receiving adjuvant dose dense chemotherapy. The secondary aim was to evaluate the impact of both granulocyte–colony-stimulating factors (G-CSFs) on patients’ overall survival (OS).

All patients treated with E-T-CMF received G-CSF in each cycle of chemotherapy. Patients randomized to receive ET-CMF received G-CSF only during intensified phase of CMF treatment; patients randomized to receive E-CMF-DOC or E-CMF-PAC received G-CSF during the intensified phase of epirubicin and CMF treatment. G-CSF was arbitrarily chosen by physicians. Patients received either single fixed dose of pegfilgrastim 6 mg on the next day after chemotherapy completion or daily administration of filgrastim 5 mcg/kg per day on days 2-7 of each cycle (compliance for filgrastim was more than 90% of cycles).

• N = 1,058 (529 filgrastim; 529 pegfilgrastim)  
• MEAN AGE = 52.3 years
• AGE RANGE = 22–79 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Postoperative high-risk patients with breast cancer receiving sequential chemotherapy with epirubicin, pacitaxel, or docetaxel, and CMF supported by G-CSF.
• OTHER KEY SAMPLE CHARACTERISTICS: No difference in menopausal status, higher % of patients had positive estrogen/progesterone status, no difference in tumor size, number of positive nodes, 92% completed treatment in filgrastim arm/95.3% in pegfilgrastim arm. Eligible patients came from sample of 2,123 participants in randomized trials: ACTR N12609001036202 (HE10/00) (reported in: Fountizilas, G et al. [2008]. Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: Safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00. Annals of Oncology, 19(5):853–860). ACTRN12610000151033 (HE 10/05) and 989 participants in an observational study (protocol HE 10/08).
• INCLUSION CRITERIA: Exposure to pegfilgrastim or nonexposure (i.e., filgrastim) during treatment with dose-dense sequential chemotherapy E-T-CMF and E-CMF-DOC or E-CMF-PAC
• EXCLUSION CRITERIA: Patients treated with ET-CMF; patients whose supportive care switched from pegfilgrastim to filgrastim and vice versa throughout the period they received chemotherapy, as well as those who received pegfilgrastim on the same day as chemotherapy

• SITE: Multisite
• SETTING TYPE: Unknown
• LOCATION: Greece

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

• Retrospective cohort study with matched sampling using data from prior prospective randomized phase III trials and an observational study

Data endpoints were rates of FN, severe (grade 3 or 4) neutropenia, dose reduction, and treatment delay. FN was defined as body temperature > 38.2 °C and neutrophil count < 0.5 × 10⁹/L. Severe (grade 3 or 4) neutropenia was assessed according to standard NCI criteria. Dose reduction was defined as any reduction greater than 10% of the dose planned based on the protocol assigned, and treatment delay was defined as chemotherapy administration with more than a two-day delay from the planned date.

No difference in rates of febrile neutropenia comparing filgrastim and pegfilgrastim arms existed. A significant increase in rates of severe neutropenia, treatment delays, and dose reduction in patients receiving prophylaxis with filgrastim was reported. More than half of the total episodes of febrile neutropenia occurred during the first four cycles of chemotherapy. No difference in overall survival between the two groups existed.

This retrospective study with matched sampling using data taken from a former prospective study of high-risk patients with breast cancer receiving postoperative dose dense sequential epirubicin, paclitaxel, and CMF matched samples found that those patients receiving pegfilgrastim had reduced incidence and risk for FN, dose delay, and dose reduction compared to filgrastim. No difference was found in reducing rates of neutropenia.

• Risk of bias (no random assignment)
• Unintended interventions or applicable interventions not described that would influence results
• Measurement/methods not well described
• Questionable protocol fidelity
• This study was not designed for the purpose of evaluating neutropenia as a secondary analysis with post hoc matching. 
• Unknown sampling technique and methods for patient selection were poorly described. 
• Retrospective data were from two randomized trials evaluating breast cancer treatment regimens ACTR N12609001036202 (HE 10/00) - ACTRN12610000151033 (HE 10/05) and one observational study (protocol HE 10/08). 
• Treatment dose of filgrastim two to seven days compared to pegfilgrastim could be considered unequal dosing/timing support for neutropenia prophylaxis. 
• Selection bias with G-CSF chosen arbitrarily by physician
• Several different chemotherapy regimens had no data for incidence of grades of neutropenia or FN specific to the type of regimen comparing filgrastim versus pegfilgrastim.
• No data existed for sequelae of FN events or infectious events.

Pegfilgrastim 6 mg 24 hours after chemotherapy is more effective in reducing incidence/risk of FN, dose delay, and dose reduction compared to filgrastim 5 mcg/kg/d on days two through seven in high-risk patients with breast cancer receiving postoperative adjuvant sequential chemotherapy regimens with epirubicin, paclitaxel, or docetaxel and CMF. Prospective randomized, controlled trials are needed to validate these results and to determine specific treatment regimens/population where pegfilgrastim or filgrastim dose/timing may be more effective in preventing FN.

To compare the safety and efficacy of pegfilgrastim and filgrastim in patients being treated with intensive chemotherapy for malignant lymphoma

Patient receiving CHASE(R) chemotherapy were randomized to receive either a single dose of pegfilgrastim or daily doses of filgrastim starting on day 4 after the completion of therapy. The primary endpoint was the duration of severe neutropenia.

• N = 111 randomized, 109 treated, 107 evaluable   
• MEDIAN AGE = 61 years (pegfilgrastim group), 60.5 years (filgrastim group)
• MALES: 66% (pegfilgrastim), 57.4% (filgrastim); FEMALES: 34% (pegfilgrastim), 42.6% (filgrastim)
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Pegfilgrastim: 94.3% (non-Hodgkin lymphoma [NHL]), 5.7% (Hodgkin lymphoma [HL]); filgrastim: 92.6% NHL, 7.4% HL
• OTHER KEY SAMPLE CHARACTERISTICS: Bone marrow involvement in 11.3% of the pegfilgrastim group and 9.3% of the filgrastim group; radiotherapy prior to current regimen in 13.2% of the pegfilgrastim group and 11.1% of the filgrastim group

• SITE: Multi-site   
• SETTING TYPE: Outpatient    
• LOCATION: Japanese Cancer Centers

• PHASE OF CARE: Active antitumor treatment

• Multicenter, randomized, double-blind, phase-III trial

The primary endpoint was the duration of severe neutropenia. Secondary endpoints were the duration of neutropenia and the incidence of febrile neutropenia.

The mean duration of severe neutropenia in patients receiving pegfilgrastim was 4.5 days (SD = 1.2) and 4.7 days (SD = 1.3) in the filgrastim group (p < 0.001). This demonstrated that noninferiority of pegfilgrastim compared to filgrastim. The neutrophil count peaked on the day after the start of the study drug administration for pegfilgrastim and on day 5 for filgrastim. The peak of the nadir was between days 8 and 10 for both groups and then returned to ≥ 1.0 x 10^9/L by day 16 in all patients. The mean duration of neutropenia was 5.2 (SD = 1.3) days for pegfilgrastim and 5.1 (SD = 1.3) days for filgrastim. The mean neutrophil count at nadir was 0.013 (SD = 0.026) x 10^9/L in the pegfilgrastim group and 0.017 (SD = 0.055) x 10^9/L in the filgrastim group. The incidence of febrile neutropenia was 56.6% in the pegfilgrastim group and 55.6% in the filgrastim group.

In respect to both primary and secondary endpoints, noninferiority was proven. While not an endpoint of the study, the adverse effects were very similar as well.

• Risk of bias (no control group)

Education about neutropenia, the duration of neutropenia, and the risk of febrile neutropenia as well as the importance of a granulocyte–colony-stimulating factor (G-CSF), whether filgrastim or pegfilgrastim, is important. In addition, nurses should provide education on the side effects of both medications.

The study focused on the secondary prevention of febrile neutropenia with G-CSF and antibiotics.

G-CSF (5 mcg/kg subcutaneous) or G-CSF with antibiotics (ciprofloxacin 500 mg by mouth every eight hours and amoxicillin 500 mg by mouth or clavulanate 125 mg by mouth every eight hours) daily starting 48 hours after chemotherapy and continuing until the absolute neutrophil count is greater than 2,000 cells/mm³. Patients were included in the study for one treatment cycle.
 

• The 48 eligible patients were adults who received chemotherapy for solid tumors and had experienced a prior episode of febrile neutropenia.
• Patients were scheduled to continue on the same regimen without dose reduction.
• Most patients were receiving treatment for breast, ovarian, or lung cancer.

Two sites in Europe.

Prospective, randomized pilot trial.

Patients were evaluated with:

• Regular complete blood counts
• Temperature monitoring once daily
• Observation for adverse effects of the prophylactic antibiotics.

In the event of a fever, the antibiotic prophylaxis was discontinued and a complete clinical evaluation for infection was completed.

No episodes of febrile neutropenia occurred in the G-CSF group, and only one incident of febrile neutropenia was reported in the combined group (p = 1). Reported side effects were similar and mild.

G-CSF reduced the risk of febrile neutropenia recurrence. Antibiotics did not provide any additional benefit in terms of prophylaxis.

• Not placebo controlled, not blinded.
• Patients were not stratified, and the groups were not balanced, particularly by disease and the number of prior chemotherapy cycles.
• The study was inadequately powered, since the frequency of the outcome measure was close to none (febrile neutropenia episodes).
• Cost implications were discussed but not in detail.

To identify an optimal dose of GCPGC and compare its safety and efficacy to that of pegfilgrastim

This study involved two phases—a phase II trial to identify optimal dosage followed by a phase III study to determine efficacy and safety of GCPGC in comparison to standard pegfilgrastim. In phase II, patients were randomized to receive either 3.6 mg  or 6 mg of GCPGC on day 2 of a cycle. There were no differences in neutropenic outcomes between groups, and researchers decided to use 6 mg for phase III. In phase III, patients were randomized to receive either 6 mg pegfilgrastim or 6 mg GCPGC on day 2 of their treatment cycle. Outcomes per treatment cycle were evaluated. During phase III, prophylactic antibiotics were not permitted in the first cycle but could be used in subsequent cycles according to physician discretion.

• N = 59 phase II, 117 phase III  
• MEDIAN AGE = 49 years phase II
• AGE RANGE = 28–74 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: All had breast cancer and were scheduled to receive 4–6 cycles of docetaxel anddoxorubicin (DA) or docetaxel, doxorubicin, and cyclophosphamide (TAC) regimens

• SITE: Multi-site    
• SETTING TYPE: Not specified  
• LOCATION: South Korea

• PHASE OF CARE: Active antitumor treatment

• Noninferiority phase III, double-blind, multi-site randomized, controlled trial with active control

• Duration of grade 4 neutropenia during the first cycle (ANC < 500/mcl)
• Time to ANC recovery
• Incidence of febrile neutropenia (FN) defined as ANC < 500/mcl and with single oral temperature ≥ 38.3 C or two or more instances of temperature ≥ 38 C
• Hospital days
• IV antimicrobial usage

There were no significant differences in outcomes between groups other than time to ANC recovery. ANC recovery time after cycle 1 was a mean of 8.85 in the GCPGC group compared to 9.83 in the pegfilgrastim group (p < 0.0001). Incidence of treatment delay or dose reduction was higher in the pegfilgrastim group (p < 0.09). Adverse drug reactions that may have been associated with the study drug were 5.3% in the GCPGC group and 3.4% in the pegfilgrastim group, and included dizziness, eukocytosis, blurred vision, injection-site pain, pyrexia, headache, and peripheral sensory neuropathy.

GCPGC was not inferior to pegfilgrastim for prevention of febrile neutropenic complications in women receiving myelosuppressive chemotherapy. Additional research is needed to confirm its efficacy and safety.

• Risk of bias (sample characteristics)

GCPGC provided similar results as pegfilgrastim in terms of neutropeni- related complications with this type of myelosuppressive chemotherapy. However, adverse events appeared to be somewhat higher in the GCPGC group. Additional research is needed to confirm the safety profile of this new CSF.

To examine the cost-benefit of primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) in patients with non-Hodgkin lymphoma (NHL) receiving cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) chemotherapy

In 2007, the study site implemented standard primary prophylaxis with G-CSF in this group of patients. Outcomes were compared to a historical control group that had not received primary prophylaxis. Analysis of cost was based on institutional direct costs for treatment of febrile neutropenia (FN).

• N = 65
• MEDIAN AGE = 61 years
• AGE RANGE = 20–85 years
• MALES: 51%, FEMALES: 49%
• KEY DISEASE CHARACTERISTICS: All had NHL and were receiving R-CHOP chemotherapy
• OTHER KEY SAMPLE CHARACTERISTICS: Patients receiving hematopoietic stem cell transplantation were excluded.

• SITE: Single site
• SETTING TYPE: Inpatient 
• LOCATION: New Zealand

• PHASE OF CARE: Active antitumor treatment

• Retrospective, descriptive, two-group comparison

• Incidence of FN

Patients who received primary G-CSF prophylaxis were compared to a group of patients who did not receive primary prophylaxis prior to 2007, when primary prophylaxis was instituted as the standard of care for these patients. Among those who received prophylaxis, the incidence of FN was 5%, compared to 60% of those who had not received prophylaxis (p < .0001). Cost-benefit analysis using the number needed to treat and the average cost of an FN episode showed that prophylaxis increased the cost by $238 (New Zealand dollars), including only direct costs.

Primary G-CSF prophylaxis was associated with a significant reduction in the incidence of FN for a small additional cost of overall care throughout CHOP chemotherapy.

• Small sample (less than 100)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Measurement/methods not well described
• Findings not generalizable
• Other limitations/explanation: The definition of FN used in the study is not provided. Costs may not be applicable to those in other countries.

Primary G-CSF prophylaxis was associated with significantly lower prevalence of FN. Based only on direct healthcare costs, this study showed that primary prophylaxis was associated with a small, incremental increased cost, but these data do not account for other indirect costs and the full range of healthcare utilization that may be associated with treatment of FN. The authors concluded that primary prophylaxis in this group of patients was cost-effective. The cost-benefit of primary G-CSF prophylaxis has been a recent area of interest in oncology care. Further, well-designed economic analyses would be useful in exploring these questions among varied groups of patients.

To compare the efficacy and safety of PEG-rhG-CSF (prevention cohort) and rhG-CSF (delayed therapy cohort) for febrile neutropenia and, therefore, hospitalization of concurrent chemoradiation treatment of esophageal carcinoma and patients with lung cancer

Prophylactic application: G-CSF administered 24 hours after chemotherapy completion, 100 μg/mg PEG-rhG-CSF subcutaneously injected, whereas 150 μg of rhG-CSF was subcutaneously injected; the injection was performed once daily until leukocytes >10×10⁹. Delayed application: G-CSF administered 5 days after the completion of chemotherapy.

• N = 163   
• AGE: 18-65 years
• MALES (%): not stated  
• FEMALES (%): not stated
• CURRENT TREATMENT: Combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Locally advanced esophageal carcinoma, non-surgical candidates, and patients with lung cancer endured induction plus concurrent chemoradiotherapy
• OTHER KEY SAMPLE CHARACTERISTICS: KPS score of 90 points or greater; patients without serious complications; ANC ≥ 1.5; plt ct ≥ 100; Exclusions were patients with bone metastasis or bone marrow metastasis; ALT/AST ≥ 1.5 (ULN) and combined with ALK PO4 ≥ 2.5 (ULN) or bili > 2 (ULN) or creatinine > 1.5 (ULN); or patients with histories of chemoradiotherapy or radiotherapy systemically; unmanageable infection

• SITE: Multi-site   
• SETTING TYPE: Multiple settings    
• LOCATION: China

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS: Adult care

Active treatment study for neutropenia-related hospitalizations for patients receiving concurrent chemoradiotherapy

SPSS, version 22.0, software (α = 0.05)

Comparison between the prevention group and the delayed group showed that the incidence of neutropenia-related hospitalizations were 4.44% and 14.62%, respectively (OR = 0.272, 95% CI [0.115, 0.642], p = 0.002). Comparison between the prevention group and the delayed group showed that the incidence of febrile neutropenia was 5.56% and 18.46%, respectively (OR = 0.26, 95% CI [0.12, 0.565], p = 0.001).

Prophylactic use of GCF decreased hospitalization rates and the use of IV antibiotics.

• Small sample (< 30)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)

Nursing would teach effects of chemotherapy and depletion of white cells which could lead to hospitalizations and neutropenic fever. Administering this medication prophylactically would ensure less hospitalizations and less severe fevers as well as decrease use of antibiotics.

The purpose of the study was to examine the superiority in reducing grade 4 leucopenia of pegfilgrastim given on day 4 over giving pegfilgrastim on day 2.

Patients were randomized to receive pegfilgrastim subcutaneously (6 mg) on day 2 or on day 4 in a 1:1 ratio. All sub study patients received intense dose-dense (IDD) chemotherapy consisting of epirubicin 150 mg/m² every two weeks for three cycles, paclitaxel 225 mg/m² every two weeks for three cycles, and cyclophosphomide 2,000 mg/m² every two weeks for three cycles. All received prophylactic oral quinolone antibiotics.

• 355 patients were randomized to receive pegfilgrastim on day 2 (n = 177) or day 4 (n = 178).  
• The median age was 45 years with a range of 24–69 years.
• 100% of the participants were female.
• Female patients biologically younger than 65 years with histologic confirmed, unilateral, or bilateral node-positive breast carcinoma.   
• Patients were required to have adequate surgical treatment with histologic complete resection (R0) of the tumor and greater or equal 10 axillary nodes with primary wound healing and no signs of infection.
   

A single-site setting in Germany

• The phase of care was active treatment.
• The application was for late effects and survivorship.
   

Randomized two-group trial

GAIN (German Adjuvant Intergroup Node Positive) study toxicity grading

The study failed to demonstrate that pegfilgrastim on day 4 was more efficacious than on day 2 with respect to grade 4 leucopenia. For patients receiving epirubicin overall, 11% of patients receiving day 2 dosing had an episode of grade 4 leucopenia during the first three cycles of chemotherapy, compared to 4% of those receiving CSF on day 4 (p = 0.015). There were no significant differences between groups in chemotherapy dose reductions or delays. During cyclophosphamide, significantly more infections occurred in the day 2 administration group (p = 0.035). Across the entire treatment, there were no differences between groups in febrile neutropenia, infections, and treatment alterations.

This study failed to demonstrate that administering pegfilgrastim on day 4 was more efficacious than on day 2 with respect to grade 4 leucopenia (the primary endpoint), febrile neutropenia, or infections.

No blinding
 

The data does not support a change in the current standard dosing schedule; however, it does suggest that administration of colony-stimulating factor on day 4 might be an appropriate alternative to day 2 dosing.

The purpose of the study was to compare efficacy of pegfilgrastim and filgrastim administered after chemotherapy in children with Ewing sarcoma. 

All patients received both types of G-CSF in different treatment courses of chemotherapy, which consisted of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE); vincristine, atinomycin D, and ifosfamide (VAI); or vincristine, atcinomycin D, and cyclophosphade (VAC). A single injection of pegfilgrastim 100 mcg/kg subcutaneously or a daily injection of filgrastim 5–10 mcg/kg subcutaneously was administered 48–72 hours after the completion of chemotherapy. Twenty children were included. A total of 178 chemotherapy courses were administered and evaluated, including 134 courses with pegfilgrastim and 44 courses with filgrastim.

• 20 participants
• Median age was 12.8 years, with a range of 9–17 years.
• Females made up 65% of the sample; males made up 35%.
• Participants had  Ewings sarcoma
• Participants' weight range was 28–90 kg  with median weight of 45.2 kg.
   

Single-site location in Marseille, France
 

• The phase of care was active treatment
• Application was for pediatrics

Retrospective chart review

• Proportion of chemotherapy courses with grade 4 neutropenia    
• Duration of grade 4 neutropenia
• Proportion with severe neutropenia
• Proportion with febrile neutropenia
• Duration of antibiotic treatment
• Duration of hospitalization
• Percentage of patients receiving transfusion
   

Considering all types of chemotherapy combined, those courses in which pegfilgrastim was used were associated with a significantly lower incidence versus severe neutropenia (0.21 versus 0.85; p = 0.034), a shorter duration of severe neutropenia (0.49 versus 2.36 days; p = 0.01), and a shorter duration of antibiotic treatment (1.07 versus 4.22 days; p = 0.03) compared with courses with filgrastim. No statistically significant differences were observed for the proportion of febrile neutropenia, duration of hospitalization, or transfusions.

Using pegfilgrastim after chemotherapy courses was associated with significantly reduced frequency and shorter duration of severe neutropenia compared with those courses followed by filgrastim.

•  Small sample (less than 30 participants)
•  Administration of G-CSF was not randomized.

Randomized, controlled trials are needed to confirm the results.

The purpose of the study was to evaluate a protocol change of not routinely prescribing G-CSF to manage uncomplicated neutropenia in patients with Hodgkin lymphoma on adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) therapy.

Eligible patients who consented to participate had baseline data collected (demographics, comorbidities, standard blood tests, routing staging via computed tomography scan, and bone marrow biopsies when indicated, and prognostic factors). Response rates were evaluated via repeat computed tomography scans following completion of ABVD therapy. Patients with limited stage disease received 2–4 cycles of ABVD with involved field radiation and those with advanced stage disease received 6–8 cycles of ABVD. Blood tests were taken every two weeks. No primary prophylactic G-CSF was administered; but was given as secondary prophylactic for febrile neutropenia. Adjustments were made to the chemotherapy regimen for nonhematologic toxicities (peripheral neuropathy or lung toxicity). Comparisons were made to a retrospective chart review in which C-GSF was administered as primary prophylaxis.

• 33 in the prospective group, 89 in the retrospective study group
• Mean age was 38 years in the prospective group and 42 years in the retrospective group.
• 18 males (55%) were in the prospective group and 50 (56%) were in the retrospective group. 15 females (45%) were in the prospective group and 39 (46%) were in the retrospective group
• Key disease characteristics include biopsy-proven Hodgkin lymphoma
• Participants were excluded if neutropenic or if they had significant cytopenias prior to starting chemotherapy, Hodgkin lymphoma-related bone marrow involvement, initiating chemotherapy as an inpatient, and/or comorbidities of HIV, active infection, or severe cardiac or pulmonary disease

A single-site outpatient location (the London Regional Cancer Program)

Active antitumor treatment

Prospective cohort with comparison to historical cohort

• Statistical analyses included using two-tailed Mann-Whitney U test for continuous variable comparisons with chi-square or Fisher’s exact test for proportional comparisons.
• Taylor series approximation was used to calculate the absolute difference in risk of developing febrile neutropenia.
• Cost analysis was also conducted.

Six percent of patients in the prospective group (did not receive primary prophylactic G-CSF) acquired febrile neutropenia, interfering with 0.6% of chemotherapy treatments. There was no significant difference from the retrospective comparison group in rate of febrile neutropenia, although the prospective group had a significantly higher rate of neutropenia (p < 0.001). The cost savings to the institution of not using primary prophylactic G-CSF was $10,241.

Not using G-CSF as a primary prophylactic treatment for patients with uncomplicated neutropenia who are being treated with ABVD for Hodgkin lymphoma is safe and cost saving.

• Small sample (less than 100 participants)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)

Closely monitoring patients for febrile neutropenia would be highly important in patients not receiving G-CSF as primary prophylaxis. Educating patients and healthcare providers about the safety of not using G-CSF as a primary prophylactic treatment is important. While this study provides some evidence that primary prophylaxis may not be of benefit related to development of febrile neutropenia, the ability to draw firm conclusions is limited by study design and other limitations. Ongoing research in the most cost effective way to prevent infection is needed.

To describe GCSF use and incidence of febrile neutropenia in patients aged 60 years or older with diffuse large B-cell lymphoma receiving initial CHOP or R-CHOP therapy.

Patients enrolled on the United States Intergroup Trial (CALGB 9793/ECOGSWOG 4494) were randomized to CHOP or RCHOP chemotherapy for the initial treatment of diffuse large B-cell lymphoma. The protocol did not allow CSF use for the first cycle.  

If day 1 ANC was less than 1,500 cells/mm³, treatment was delayed a week. If FN occurred in the prior treatment cycle, cyclophosphamide and doxorubicin doses were reduced by 50% in the next cycle. These doses could be increased by 25% if the subsequent cycle was well tolerated, with no grade 3/4 hematologic toxicities.
Colony stimulating factor (CSF) could be used starting with second cycle to maintain dose intensity in event of neutropenic fever or dose reduction/delay.

• N = 520   
• AGE: 60 years or older
• MALES: 50%  
• FEMALES: 50%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Previously untreated diffuse large B-cell lymphoma
• OTHER KEY SAMPLE CHARACTERISTICS: Age greater than 60 years and receiving initial therapy with RCHOP or CHOP on the United States Intergroup Trial (CALGB 9793/ECOGSWOG 4494)

• SITE: Multi-site   
• SETTING TYPE: Outpatient    
• LOCATION: United States

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS: Elder care

Observational study

Data measured included the timeliness of chemotherapy administration (treatment delay), CSF use, reason for CSF use, febrile neutropenia, neutropenia, and chemotherapy dose reduction.

49% of patients received CSF during therapy. The median number of cycles for which CSF was used was three (range = 1-7) and the median duration of CSDF use was nine days. CSF was used to prevent chemotherapy dose reduction/dose delay in approximately 60% of patients, and for secondary prophylaxis in cycle(s) following FN hospitalization in one third of patients. Overall CSF was used during 16% of administered chemotherapy cycles. Significantly more patients were treated with CSF in later cycles of therapy. FN occurred in 41% of patients, and 38% of the episodes occurred in cycle 1.

For patients with diffuse large B-cell lymphoma who are 60 years of age and older who are receiving initial therapy with CHOP or RCHOP, CSFs helped maintain dose intensity and to prevent febrile neutropenia.

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)

CSF is recommended for patients with diffuse large B-cell lymphoma who are 60 years of age and older who are receiving initial therapy with CHOP or RCHOP to prevent febrile neutropenia and maintain dose intensity. This is consistent with current standard practice.

The purpose of this study was to investigate of the influences of high-dose (20 mg/kg per day) methyl prednisolone (HDMP) and granulocyte–colony-stimulating factor (G-CSF) in shortening the duration of chemotherapy-induced neutropenia encountered in children with ALL receiving maintenance therapy.

Comparison of HDMP (oral), G-CSF (subcutaneous), or no treatment following neutropenic events in children with acute lymphoblastic leukemia (ALL) receiving St Jude XIII maintenance protocol (details of the protocol not provided with the exception of vepeside-cyclosphosphamide noted as part of the protocol). The protocol for administration of HDMP or G-CSF included an absolute neutrophil count (ANC) below the required level to administer chemotherapy (more than 1,500/mm³ for patients receiving high-dose methotrexate and more than 1,000/mm³ for patients receiving drugs other than methotrexate). The goal was to increase neutrophil count by day 2 or day 4 so that the chemotherapy could continue to be administered. Non-febrile neutropenia was defined as having an ANC below the accepted level for chemotherapy administration with the absence of a fever or laboratory signs of infection.

• 29 participants took part
• The mean age of participants was 7.9 years, with a range of 2.8–17.6.
• Males outnumbered females 52% to 48%, respectively.
• ALL was the key diagnosis characteristic

A single-site outpatient location (Ondokuz Mayis University, Samsun, Turkey)

• The phase of care was active antitumor treatment
• Application was for pediatrics

Retrospective

Statistical analyses included comparisons between no treatment, G-CSF, and HDMP with number of neutropenic events. Chi-square or Fisher’s exact chi-square tests were used for frequency differences, normally distributed variables were evaluated with analysis of variance (ANOVA) and non-normally distributed variables were evaluated with the Kruskal-Wallis test. The Mann-Whitney U test with Bonferroni correction was used for group differences.

There were 64 non-febrile neutropenic events among 29 patients. Second day and overall success rates (not defined) were higher for G-CSF and HDMP groups compared to no treatment for a neutropenic event. No differences were found between G-CSF and HDMP. Second day and overall neutrophil counts were higher in the G-CSF group.

HDMP was equal to G-CSF for successful outcome of shortening the course of delayed treatment due to neutropenia. The researchers noted HDMP is less expensive than G-CSF and may be a good option for the treatment of neutropenia in children with ALL.

• Small sample (less than 30 participants)
• Risk of bias (no control group)
• Risk of bias (no blinding)
• Both HDMP and G-CSF were noted as tolerable, but side effects were not discussed.

Use of HDMP or G-CSF can limit treatment delays due to neutropenia. Understanding the differences between HDMP and G-CSF (higher neutrophil count return with G-CSF) and similarities (same outcome goal reached of shortening treatment delay) is important to discuss regarding treatment decision-making. HDMP may be more cost-effective.

To demonstrate that DA-3031 is not inferior to daily filgrastim to manage neutropenia

Patients were randomly assigned to receive daily filgrastim or DA-3031. Daily filgrastim at 100mcg/m² began 24 hours after chemotherapy was started and continued until absolute neutrophil count was at least 5 x 10⁹, or for 10 days. Those in the experimental group received 6 mg DA-3031 by subcutaneous injection on day 2 of each chemotherapy cycle. Patients received TAC chemotherapy every three weeks up to six cycles. The noninferiority margin set was two days for the duration of grade 4 neutropenia.

• N = 74 for ITT analysis, 63 completed the protocol
• MEAN AGE = 6.44
• AGE RANGE = 30–67 years
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: All had breast cancer and were receiving TAC chemotherapy.
• OTHER KEY SAMPLE CHARACTERISTICS: Previous colony-stimulating factor exposure, prior hematopoietic cell transplantation, and prior treatment with antibiotics within 72 hours of starting chemotherapy were exclusions.

• SITE: Multi-site   
• SETTING TYPE: Outpatient    
• LOCATION: Korea

PHASE OF CARE: Active antitumor treatment

Open-label, noninferiority, randomized, controlled trial

• Common Terminology Criteria for Adverse Events, version 4
• Time to absolute neutrophil count recovery to at least 2 x 10⁹/L

Mean duration of grade 4 neutropenia was 2.08 (SD = 0.85) days for the filgrastim group and 2.28 (SD = 1.14) days for the DA-3031 group. The difference between groups was 0.2 (SD = 1) days, supporting noninferiority of DA-3031. There were no significant differences between groups in absolute neutrophil coutn recovery time, incidence of febrile neutropenia, hospitalization, or requirement for intravenous antibiotics. There was no significant difference between groups in musculoskeletal symptoms associated with colony-stimulating factor administration. The findings were similar across all chemotherapy cycles. ITT and per protocol analysis were similar.

DA-3031, a once-per-cycle colony-stimulating factor, was not inferior to daily filgrastim.

• Small sample (< 100)
• Risk of bias (no blinding)
• ITT analysis had a 90% power.

DA-3031, a pegylated colony-stimulating factor was comparable to daily pegfilgrastim for neutropenia-related outcomes among women receiving TAC therapy. A once-per-cycle colony-stimulating factor can be more practical for patients because it does not require daily injections. Comparative costs of these two approaches was not discussed and may need to be considered in the selection of an approach.

To evaluate the safety and efficacy of once-per-cycle DA-3031 in patients receiving chemotherapy for breast cancer

Patients were randomized to daily injections of filgrastim 100 mcg/m²beginning 24 hours after chemotherapy until absolute neutrophil count (ANC) was 5x10⁹ after nadir or up to 10 days, or to one of two doses of pegfilgrastim (3.6 mg or 6 mg). The primary endpoint was duration of grade 4 neutropenia.

• N = 61
• MEAN AGE = 44.9 years
• AGE RANGE = 29–67 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: All had breast cancer and were receiving chemotherapy consisting of doxorubicin, cyclophosphamide, and docetaxel. Chemotherapy was given every three weeks for up to six cycles.

• SITE: Multi-site 
• SETTING TYPE: Outpatient 
• LOCATION: South Korea

• PHASE OF CARE: Active antitumor treatment

• Randomized, open-label, phase II

• National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.01)

No significant differences were seen among groups in ANC nadirs or time to recovery. Overall incidence of febrile neutropenia was 9.8%, with no significant differences between groups. The most common adverse event was musculoskeletal pain, with no significant differences between groups, although pain was slightly higher in the 6 mg pegfilgrastim group.

Single-dose pegfilgrastim had similar efficacy and side effects to daily filgrastim.

• Small sample (less than 100)
• Risk of bias (no blinding)

Daily dosing of filgrastim had essentially the same efficacy and side effects as once-per-cycle pegfilgrastim. Severity of musculoskeletal pain appeared to be slightly higher with the higher dose of pegfilgrastim. Reducing the need for daily injections may be an important consideration for some patients and has been shown to have essentially the same effects. Higher doses may be associated with increased musculoskeletal pain. Although not statistically significant, this can be an important consideration to promote patient quality of care.

To determine the effectives of an erythropoietin-stimulating agent (ESA) and granulocyte–colony-stimulating factor (G-CSF) in reducing blood transfusion needs and neutropenia incidence in community-dwelling older adults with ovarian cancer

Woman aged older than 65 years diagnosed with stage III–IV epithelial ovarian cancer (from January 2000–December 2009) were identified as having received chemotherapy by procedure codes in Medicare within nine months of diagnosis. Cox models were used for analysis and included time-dependent covariates. ESAs and G-CSFs were identified by Healthcare Common Procedure Coding System codes for epoetin-alfa/darbepoetin-alfa and filgrastim/pegfilgrastim. Blood transfusion need was measured from the time of diagnosis to first Medicare claim indicating the receipt of blood transfusion. Neutropenia incidence was measured from the time of the first chemotherapy administration to the first claim of neutropenia. Patients who did not receive a blood transfusion or did not develop neutropenia were censored at the date of death or last date in Medicare claims (i.e., December 31, 2010), whichever occurred first. Overall survival was measured from the time of first chemotherapy administration until death or the end of the follow-up period (December 31, 2011). Patients not experiencing the event (death) by this date were censored.

• N = 5,572   
• AGE = Older than 65 years
• FEMALES: 100%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Stage III–IV epithelial ovarian cancer 
• OTHER KEY SAMPLE CHARACTERISTICS: Sociodemographics

• SITE: Multi-site   
• SETTING TYPE: Not specified

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

Retrospective cohort study using SEER Medicare linked database

• Cox Model
• Kaplan-Meier curves
• Propensity scores
• Logistic regression model
• Propensity score distribution plots

ESAa were effective in reducing blood transfusion need. G-CSFs were effective in lowering neutropenia incidence and were associated with improved survival in older adults with ovarian cancer. The interaction between ESA time and CSF time was significant (p = 0.0001).

The findings demonstrated that using epoetin-alfa or darbepoetin-alfa effectively lowers the blood transfusion needs by 48%–78% in patients receiving chemotherapy, which is comparable to prior randomized trials of patients with gynecologic and ovarian cancer. The use of a G-CSF was associated with a longer survival compared to those who received at least three doses of a G-CSF. The findings showed that patients who received fewer than three prophylactic G-CSF administrations did not experience better outcomes.

• Risk of bias (no random assignment)
• Findings not generalizable
• No ability to look at laboratory data that triggered the use of ESAs and G-CSFs
• No ability to look at intensity of chemotherapy
• Potential risk of ESAs or G-CSFs in relation to thrombocytopenia and bleeding events

This was a good study; however, it had a very focused patient population and may not be reproducible in the younger population. In addition, no information was provided regarding adverse events related to the use of ESAs or G-CSFs. Prior studies have shown a possible higher risk for mortality with the use of ESAs and G-CSFs. It is important to continue to look at established guidelines (Oncology Nursing Society, American Society for Clinical Oncology, National Comprehensive Cancer Network, Food and Drug Administration) for the use of ESAs and G-CSFs in the cancer population.

The purpose of the study was to study the effect of administration of primary prophylactic (PPG) colony-stimulating factory and duration of administration on the occurrence of chemotherapy-induced neutropenia hospitalization in older adult patients with breast cancer.

The study sample included women older than age 66 years. Women with stage 0 were excluded because stage 0 does not require chemotherapy, and women with stage 4 were excluded because stage 4 palliative therapy is very different from standard first-course administration.

The SEER data from 16 registries (1994–2002) was used. The outcome of interest was neutropenia hospitalizations defined as ICD9 code 288.0X in the first, third or sixth months after the first course of chemotherapy.  Administration of G-CSF had to be initiated within five days after the first course of chemotherapy as primary prophylaxis. G-CSF was defined according to procedures codes.

• The total sample was 10,441 patients aged 66 years and older.
• All participants were female
• All had stage l, ll, or lll breast cancer
• Patients had to be receiving chemotherapy with in six months of diagnosis.
• Neutropenia hospitalization had to occur within the first three or six months.
• Exclusion criteria: Chemotherapy initiation after six months.
   

Inpatient

Observational study

• End result Medicare data from 1994–2003
• Outcomes and treatment defined by ICD9 diagnosis and procedure codes
   

Administration of PPG-CSF during the first course of chemotherapy reduced neutropenia hospitalizations by 16% with in first three months and 17% within the first six months of chemotherapy. Hospitalization rates within the first three months of chemotherapy initiation were three times higher in women receiving less than five days of PPG-CSF compared to women receiving PPG-CSF for five or more days. Hospitalization rates within the first one and six months were also lower with longer PPG-CSF.

PPG-CSF use is associated with reductions in patient healthcare utilization.

• No controls.
• The study does not focus on incidence of neutropenia and, rather, worked on severity
• Many mild cases of neutropenia go unreported as ANC less than 2,000.
• Neutropenia hospitalization was taken as a dependant variable for the study and patients with mild neutropenia would not be taken as a part of the study,
• Retrospective data analysis only
   

PPG-CSF received during the first three months, particularly after five days of initiation of the therapy, and to be taken for at least five days, would reduce the risk of neutropenia hospitalization among older adult patients with breast cancer.

To assess the efficacy and safety of daily FSK0808 injections to treat neutropenia in patients with breast cancer

Daily injections of FSK0808 were used to treat neutropenia experienced by patients in the course of chemotherapy treatment.

• N = 104  
• AGE RANGE = 20–70 years
• AVERAGE AGE = 51.1 years
• FEMALES: 100%
• KEY DISEASE CHARACTERISTICS: Pre- and post-menopausal patients with breast cancer receiving fluorouracil, epirubicin, and cyclophosphamide (FEC100) before and after surgical intervention.

• SITE: Multi-site 
• SETTING TYPE: Outpatient 
• LOCATION: Japan

• PHASE OF CARE: Active treatment

• Multi-center, non-randomized study

Efficacy was measured by drawing blood to calculate the patients’ absolute neutrophil count. Vital signs also were performed to assess patients for fever.

The study showed that FSK0808 reduced the recovery time from neutropenia caused by the treatment of breast cancer with FEC100. The average of 2.2 days of neutropenia was comparable to the 2.1 days reported in a comparative study that used filgrastim. Adverse drug reactions were similar to those experienced with filgrastim, and most events were mild.

FSK080 is safe and well tolerated in patients with breast cancer going through chemotherapy and successfully stimulated neutrophil recovery.

• Risk of bias (no control group)
• Risk of bias (no blinding) 
• Risk of bias (no random assignment)

This study shows that FSK0808 is a safe and viable alternative to filgrastim, meaning that nurses will have to familiarize themselves with the use and side effects of this new medication.

To compare the effectiveness, toxicities, and cost of two granulocyte colony-stimulating factor (G-CSF) preparations

Patients were randomized to two group—one receiving filgrastim and one receiving lenograstim  after one chemotherapy treatment cycle. Patients then crossed over to the opposite preparation for the next chemotherapy cycle.

• N = 29
• AGE RANGE = 2–16 years
• MALES: 62%, FEMALES: 38%
• KEY DISEASE CHARACTERISTICS: Multiple tumor types; most frequent were Ewing sarcoma, osteosarcoma, and neuroblastoma

• SITE: Single site 
• SETTING TYPE: Multiple settings 
• LOCATION: Turkey

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Palliative care

• Crossover, randomized, two-group trial

Febrile neutropenia was defined as absolute neutrophil count less than .05x10³ cells per µL and oral or axillary temperature above 38.3 degrees centigrade or 38.0 for more than one hour.

No differences were seen in treatments in febrile neutropenia, antibiotic use, rate of infection, use of platelet transfusions, or hospitalization. Cost was significantly lower with filgrastim (p = .002). No differences were seen between treatments in adverse effects. Bone pain was the most frequent side effect, with no significant differences between treatments

Findings suggest that efficacy and side effects of filgrastim and lenograstim are equivalent. Filgrastim use was less costly.

• Small sample (less than 100)
• Risk of bias (no blinding)
• Other limitations/explanation: Patients had a variety of diseases and were getting a wide variety of chemotherapy treatments given the small sample size, which potentially would impact the risk of febrile neutropenia.

Findings show that both of these G-CSF formulations provide similar results but differ substantially in cost. Nurses can advocate for less costly alternatives for care according to patients’ financial situations. The main side effect for patients is bone pain, which needs to be addressed effectively.

To compare the efficacy and safety of a single subcutaneous injection of pegylated filgrastim with daily filgrastim as a prophylaxis for neutropenia induced by commonly used chemotherapy regimens

Fifteen centers enrolled 337 chemotherapy-naïve patients with cancer with normal bone marrow function. All patients were randomized into AOB and BOA arms and received two cycles of chemotherapy. Patients received a single dose of pegylated filgrastim 100 mg/kg in cycle 1 (AOB) or cycle 2 (BOA) and daily doses of filgrastim 5 lg/kg/day in cycle 1 (BOA) or cycle 2 (AOB). In the AOB arm, 173 patients were enrolled and 155 completed the two cycles. In the BOA arm, 164 patients were enrolled and 142 completed the two cycles. Efficacy and safety parameters were recorded. The primary endpoint was the rate of protection against grade 4 neutropenia after chemotherapy (defined as the rate at which the absolute neutrophil count [ANC] remained greater than 0.5 x 10⁹/L throughout the entire cycle).

• N = 337  
• AGE = 18–70 years
• MALES: 68 (AOB), 60 (BOA); FEMALES: 101 (AOB), 97(BOA)
• KEY DISEASE CHARACTERISTICS: Primarily breast, non-small cell lung cancer, and non-Hodgkin lymphoma; study arms essentially equal, except the BOA arm did enroll two patients with head and neck cancer; stage of disease was split equally throughout both arms
• OTHER KEY SAMPLE CHARACTERISTICS: The groups were well matched with respect to demographics, history of disease, disease severity, and ANC at baseline. The median age of patients in the study was 50 years, and almost 40% of the patients were men. Breast cancer was the most common histology. About 50% of the enrolled patients previously had undergone surgery.

• SITE: Multi-site   
• SETTING TYPE: Outpatient   
• LOCATION: Republic of China

• SITE: Multi-site   
• SETTING TYPE: Outpatient   
• LOCATION: Republic of China

• Multi-center, randomized, open-label, crossover, noninferiority study

Blood samples were collected for complete blood counts with differential on days 0, 3, 5, 7, 9, 11, 13, 17, and 21 of each cycle. The primary efficacy endpoint was the rate of protection from grade 4 neutropenia (ANC remains greater than 0.5 through the entire cycle) after chemotherapy. The secondary efficacy endpoints included the rate of grade 3/4 neutropenia, time to neutrophil recovery (defined as the time from chemotherapy administration until the ANC increased to 2.0 [after the expected nadir]), incidence of febrile neutropenia (ANC less than 0.5 and axillary temperature higher than 38.1°C), incidence of antibiotic administration, and ANC profile.

Ninety-four percent of patients receiving pegylated filgrastim or filgrastim did not develop grade 4 neutropenia. In cycle 1, the rates of protection were 89.7% (pegylated filgrastim) and 89.5% (filgrastim). In cycle 2, no episodes of grade 4 neutropenia occurred. In subgroup analysis according to chemotherapy regimens, the protective rates of pegylated filgrastim did not differ significantly from the protective rates of filgrastim.

This trial provides direct evidence that pegylated filgrastim is comparable to filgrastim in efficacy and safety when administered in support for commonly used, standard-dose, mild-to-moderate myelosuppressive chemotherapy regimens. In addition, the single injection per cycle may lead to increased patient satisfaction and compliance.

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Other limitations/explanation: Not clear that the sample was at risk for neutropenia

Increased use of pegylated filgrastim across solid tumor types with mild-to-moderate myelosuppressive chemotherapy regimens. The lower frequency of visits may lead to increased emergency department visits for toxicities that normally would be caught at the daily injection visits. Education will be key in this patient population. For some patients, avoidance of daily injections may be important.

The purpose of this article is to evaluate the safety, clinical response, and pharmacokinetics of pegfilgrastim compared to filgrastim in pediatric patients with sarcoma receiving dose-intensive vincristine-doxorubicin-cyclophosphamide/ifosfamide-etoposide (VDC/IE) chemotherapy.

Pediatric patients with biopsy-proven sarcomas scheduled to receive four cycles of VDC (cycles 1 and 3) / IE (cycles 2 and 4) chemotherapy in three-week intervals were randomized in a 6:1 ratio (pegfilgrastim to filgrastim). Pegfilgrastim group received one subcutaneous injection of 100 mcg/kg and filgrastim group received daily subcutaneous injections 5 mg/kg daily. Both groups received injections starting about 24 hours after completion of week 1 chemotherapy with continuation until a post-nadir absolute neutrophil count (ANC) greater than 10 x 10⁹/L achieved or until 24 hours prior to the next chemotherapy cycle. ANC greater than 1 x 10⁹/L and platelets greater than 100 x 10⁹/L were the minimum acceptable levels for chemotherapy. Chemotherapy modifications were made for infections requiring intensive care or for typhlitis, meningitis, or O₂-dependent pneumonia.

• 35 patients were in the sample.
• The age range was 0–21 years.
• 36.4% of the sample were female, 63.6% were male
• Diagnoses were ewing sarcoma family, rhabdomyosarcoma, and other soft-tissue sarcoma.
• 35 patients were White; 3 were Black, 5 were Hispanic, and  one was classified as Other.

10 outpatient settings in the United States and Australia

• The phase of care was active treatment
• Applications was for pediatrics

Phase II randomized, controlled trial (RCT), open-label.

• Duration of grade 4 neutropenia (ANC of 0.5 x 10⁹/L or lower) during cycles 1 and 3.
• Time to ANC recovery to 0.5 x 10⁹/L or greater in cycles 1 and 3
• Rate of febrile neutropenia (defined as ANC less than 0.5 x 10⁹/L) and an oral or oral-equivalent temperature of 38.2°C or greater on the same day.
   

85% of patients in the filgrastim group had febrile neutropenia compared to 68% in the pegfilgrastim group. The duration of grade 4 neutropenia was about equal in both groups with a median duration of 1 day less in the pegfilgrastim group during cycle 1. The median recovery to ANC time was also the same in both groups. One patient in the pegfilgrastim group in cycle 1 and three in cycle 3 failed to have neutrophil recovery. All patients in the filgrastim group had neutrophil recovery. The pharmacokinetics were similar for pegfilgrastim and filgrastim. In the pegfilgrastim group, duration of grade 4 neutropenia was inversely related to age (i.e., the younger the patient, the longer the duration). Adverse events were statistically equivalent between the groups; however, more types of events occurred in the pegfilgrastim group.

The use of pegfilgrastim is as safe and effective to use as filgrastim in pediatric patients with sarcomas and requires just one dose compared to daily doses of filgrastim.

• Small sample (less than 100)
• No blinding with risk of bias
• The 6:1 ratio of patients receiving pegfilgrastim versus filgrastim makes the comparisons between groups more challenging in determining the efficacy of outcomes.
   

The administration of pegfilgratim as a one-time dose can be as effective as daily doses of filgrastim against neutropenia in pediatric patients being treated with myelosuppressive chemotherapy for sarcomas. Nurses can advocate for the use of pefgilgrastim to decrease the burden of number of injections in pediatric patients with sarcomas.

The purpose of the study was to evaluate the safety and efficacy of a new rG-CSF in patients receiving chemotherapy for breast cancer.
 

Patients receiving either doxorubicin and docetaxel or docetaxel alone were entered into the study.  Patients were given rG-CSF  5 mcg/kg per day by subcutaneous injection starting on day 2 of each chemotherapy cycle, 24 hours after chemotherapy completion, that continued for either five days or until absolute neutrophil count (ANC) was greater than 1.5 x 10⁹/L. The study duration was 13 months. Severity and incidence of adverse events and antibody formation to the study drug were done. Study endpoints were incidence and duration of febrile neutropenia, duration of fever, chemotherapy cycle delays or dosage reductions, and incidence of antibiotic therapy.

• 50 patients were studied.
• Mean age of the participants was 53.54 years (SD = 10.47).
• All participants were female.
• All had breast cancer; 44% were chemotherapy naïve.

Multiple site in Lithuania.

Active antitumor treatment

Open label phase IV

• Febrile neutropenia defined as axillary temperature greater than 38.5ºC and ANC less than 0.5 x 10⁹/L.
• Common Toxicity Criteria
   

273 cycles of chemotherapy were examined. Mean duration of rG-CSF administration per cycle was 6.3 days. Eight patients withdrew from the study for various reasons. Most adverse events were associated with the chemotherapy. The most frequent grade 3–4 toxicity was neutropenia. Incidence of  grade 4 neutropenia was 47% in cycle 1 and 42% overall in patients receiving docetaxel/doxorubicin and 29% in cycle 1 and 21% overall in patients receiving docetaxel only. Most frequent study drug-related adverse events were bone pain and leukocytosis (21%), headache and musculoskeletal pain (14%), and back pain (7%).  Only bone pain was seen to be of more than mild-to-moderate severity. No neutralizing antibodies were found. Total incidence of febrile neutropenia (FN) was 14%. Mean duration of FN was 2–2.3 days. Mean duration of fever was 2.1–3.6 days depending on chemotherapy group. There was an overall incidence of chemotherapy delays or dosage changes of 1%. Overall, 20% of patients received IV antibiotics.

Overall, the study drug showed similar efficacy to other colony-stimulating factors and appeared to be well tolerated.

• Small sample (less than 100 participants)
• Risk of bias (no control group) 
• Risk of bias (no blinding)  
• Risk of bias (no random assignment)
• Findings were not generalizable
• It is not clear if analysis accounted for study withdrawals as percentages shown assume initial study sample size. Intent to treat analysis is not clearly stated. Open label design and no direct comparison with other formulations. These findings may not be generalizable to patients receiving other chemotherapeutic agents.

 Findings demonstrate effects of another G-CSF formulation.

To determine whether pegfilgrastim reduces leukopenia and infectious complications in patients with recurrent glioma treated with teniposide and a nitrosourea

Patients received nitrosourea 90 mg/m² on day 1 and teniposide 60 mg/m² on days 1–3 of every cycle. Cycles were given every six weeks until progression. The control group did not receive prophylactic pegfilgrastim, and the intervention group received pegfilgrastim 6 mg subcutaneously 8–24 hours after the third teniposide infusion.

• N = 60
• MEDIAN AGE = 56 years (range = 27–72 years)
• MALES: 55%, FEMALES: 45%
• KEY DISEASE CHARACTERISTICS: Patients with recurrent glioma treated with teniposide and a nitrosourea

• SITE: Single site    
• SETTING TYPE: Multiple settings  
• LOCATION: Germany

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care 

Retrospective review of medical records of patients treated at a neuro-oncology hospital

• Absolute neutrophil count

The expected nadir of teniposide is between days 8–17, and the nadir caused by the nitrosourea is expected after day 35. Therefore, patients may have an early nadir (defined as the period before day 30) and a late nadir (defined as the period from day 30 and beyond). Pegfilgrastim is expected to be active between days 3–11. Pegfilgrastim decreased the number of patients who had grade 3 neutropenia during the early nadir (9% with pegfilgrastim and 31% in the control group, p = 0.04). However, there was no difference in the rate of grade 4 neutropenia during the early nadir. Pegfilgrastim did not prevent any grade of neutropenia in the late nadir. Seven patients (27%) in the control group and six patients (17%) in the pegfilgrastim group were hospitalized because of myelosuppression or infections. There was no difference in the number of days these patients had to be hospitalized or needed intravenous antibiotics during the first two cycles of chemotherapy (p = 0.27 and p = 0.3, respectively).

The prophylactic administration of pegfilgrastim in patients treated with teniposide and nitrosourea for recurrent glioma did not reduce the frequency of grade 4 leukopenia, the need for antibiotics, or the number of days of hospitalization. It did reduce the incidence of grade 3 neutropenia in the nadir that occurred in the first 30 days.

• Small sample (< 100)
• Baseline sample/group differences of import
• Risk of bias (no random assignment)
• Risk of bias (sample characteristics)
• Key sample group differences that could influence results

The routine prophylactic administration of pegfilgrastim does not seem to provide a relevant benefit for nitrosourea and teniposide chemotherapy in patients with recurrent glioma other than reduction in the incidence of grade 3 neutropenia during the first 30 days.

The purpose of the study was to establish the maximum-tolerated dose of paclitaxel and investigate whether prophylactic G-CSF and antibiotics would allow further dose escalation of paclitaxel in treatment-naïve patients.

Doses were given in increasing increments to groups of three patients to determine dose-limiting toxicity (DLT). Part A: Paclitaxel escalation without prophylactic G-CSF (unless DLT from neuropathy). Part B: Level 7 etoposide administered with G-CSF. Part C: Same as part B plus prophylactic antibiotics (ciprofloxacin and roxithromycin). With a hematologic toxicity recovery to CTC less than 3, a subsequent cycle was allowable with a max delay of two weeks. Dose reduction was given if grade 2 CTC hematologic toxicity persisted after a two-week delay and/or there was a greater than grade 2 nephro- or neurotoxicity.

• 47 participants were included in the study.
• Age range was 32–74 years.
• 31.9% were women; 68.1% were men
• Non-small cell lung cancer: squamous cell carcinoma (n = 20), adenocarcinoma (n = 18), other (n = 9)
• World Health Organization performance status 0 (n = 13), 1 (n = 29), 2 (n = 3), unknown (n = 2)
• Stage IIIA (n = 13), IIIB (n = 9), and IV (n = 25).

Single-site outpatient setting in the Netherlands.

Active treatment

Prospective dose-finding study.

• Dose-limiting toxicity: defined as granulocytes less than 0.5×10⁹/L lasting for seven days or more, granulocytes less than 0.5×10⁹/L, fever of 38.5ºC or higher, platelet count less than 25×10⁹/L, and any toxicity higher than grade 2 (with the exception of nausea/vomiting responsive to treatment) occurring during the first cycle
• Blood cell counts: WBC, ANC, platelets, hemoglobin
• Adverse events: fever, polyneuropathy, anorexia, nausea, vomiting, diarrhea, cardiac, asthenia, hemorrhage, electrolyte disorder, hematologic toxicity
• Infections
   

In total, 189 cycles of chemotherapy were administered. Forty-three of the 47 patients enrolled survived treatments. Thirty-four completed the full protocol (febrile neutropenia or dose delays from toxicity were the main reasons for incomplete cycles).

The use of G-CSF and antibiotics allows for higher chemotherapy doses in patients with stage IIIA, IIIB, and IV non-small cell lung cancer, which could increases survival.

• Small sample (less than 100 participants)
• The findings circumvent details about survival time in the patients who received G-CSF and prophylactic antibiotics allowing for higher chemotherapy doses; therefore, it is unknown if the patients who survived the longest were the recipients of the higher chemotherapy doses with G-CSF and antibiotics, which was the goal of the study.
   

The administration of G-CSF and prophylactic antibiotics may reduce neutropenia and infections increasing the DLT, allowing for higher doses of chemotherapy for better chance of prolonged survival. However, research in this area needs further exploration.

To study the potential benefits and risks of using lipegfilgrastim to reduce neutropenia in patients receiving myelosuppressive chemotherapy for advanced non-small cell lung cancer, and to compare the outcomes of older adults (defined as patients aged older than 65 years) and adults

After receiving first-line chemotherapy (cisplatin 80 mg/m² IV on day 1 and etoposide 120 mg/m² IV on days 1–3 every three weeks) for non-small cell lung cancer, participants were randomized 2:1 to receive a single subcutaneous injection of lipegfilgrastim 6 mg or placebo, administered approximately 24 hours after the last etoposide infusion. Patients received up to four cycles of cisplatin/etoposide, with the study medication given after each cycle. Monitoring for adverse events continued until three weeks after the last intervention. Blood was drawn (for complete blood count and chemistry testing) before each cycle and on day 15 of each cycle.

• N = 375 (intention to treat [ITT] analysis), with 250 completing the study
• MEAN AGE = 62.3 years
• MALES: 87%, FEMALES: 13%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Stage IIIb–IV non-small cell lung cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Individuals with high risk for febrile neutropenia (FN) were excluded because of ethical concerns

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Study participants came from 72 chemotherapy centers in eight European countries (Belarus, Bosnia-Herzegovina, Bulgaria, Poland, Romania, Russia, Serbia, and Ukraine).

PHASE OF CARE: Active antitumor treatment

This study was a post hoc analysis of subgroups of patients who had enrolled in a double-blinded, randomized, controlled trial.

To determine efficacy, the authors studied the incidence of FN following the first cycle of cisplatin/etoposide chemotherapy. FN was defined as an oral temperature greater than 38.5 degrees C on two or more consecutive measurements at least 60 minutes apart, with a concurrent absolute neutrophil count (ANC) less than 0.5 x 10⁹/L, or neutropenic sepsis or potentially life-threatening neutropenic infection. The authors also compared the incidence and duration of severe neutropenia (DSN), defined as grade 4 neutropenia with an ANC less than 0.5 x 10⁹/L; the time to ANC recovery, defined as the time from any post-chemotherapy day with an ANC less than  2 x 10⁹/L to the first day with an ANC of 2 x 10⁹/L or less; and the depth of ANC nadir. For study safety, patients were not assessed for adverse events (AEs) until three weeks after the last dose of study medication.

There was no significant difference in the incidence of FN following the first chemotherapy cycle between the lipegfilgrastim and placebo groups for patients aged 65 years or younger. None of the older patients who received lipegfilgrastim developed FN during the first chemotherapy cycle, compared to 13.3% in the placebo group. The difference in incidence of severe neutropenia between the placebo and lipegfilgrastim groups was more pronounced in younger patients (56.8% versus 27.6%) than in those older than 65 years (66.7% versus 49.1%). In both age groups, the mean DSN during cycle 1 was shorter (0.6 days versus 2.1 days for patients aged 65 years or younger; 1 day versus 3 days in patients aged older than 65 years) for patients who received lipegfilgrastim compared to those who received placebo. Mean time to ANC recovery during cycle 1 was less with lipegfilgrastim than with placebo and was comparable in both age groups (6.8 days versus 13.3 days for patients aged 65 years or younger; 6.5 days versus 12.2 days in patient aged older than 65 years). Similarly, mean depth of ANC nadir during cycle 1 was also higher with lipegfilgrastim than with placebo and was comparable in both age groups (1.6 x 10⁹/L versus 0.7 x 10⁹/L for patients aged 65 years or younger; 1.5 x 10⁹/L versus 0.5 x 10⁹/L for patients aged older than 65 years). Most AEs were likely attributable to the chemotherapy, and the incidence was similar between treatment groups. The exception was the incidence of hypokalemia (6.2% versus 2.1% in patients aged 65 years or younger; 15.1% versus 3.3% in patients aged older than 65 years) and hypophosphatemia (3.6% versus 1.1% in patients aged 65 years or younger; 9.4% versus 3.3% in patients aged older than 65 years), which were higher in the lipegfilgrastim group versus the placebo group. The older adults who received lipegfilgrastim also had a higher incidence of decreased appetite (17%) than the placebo group (6.7%).

In patients aged 65 years and younger, lipegfilgrastim did not decrease the incidence of FN but limited the severity, duration, and time to recovery of neutropenia. In older adults, who have a greater risk for myelosuppression, lipegfilgrastim significantly reduced the incidence of FN in addition to the benefits realized by younger patients.

• Risk of bias (no appropriate attentional control condition)
• Risk of bias (sample characteristics)
• Findings not generalizable
• Although the overall sample size is acceptable (n = 375), only 13% were female. It has been established that growth factors generally do not benefit patients aged younger than 65 years treated with cisplatin/etoposide; therefore, the National Comprhensive Cancer Network guidelines recommend the use of growth factors only for patients aged older than 65 years for this chemotherapy regimen. The appropriate study population is the group of patients aged older than 65 years and the sample sizes in the older adult subgroups were small (n = 25 in the placebo group and n = 46 in the intervention group). In addition, those at high risk for FN were excluded from the study, leading to an artificially low incidence of FN among the study population. Last, in patients aged older than 65 years, lipegfilgrastim should have been compared to the standard of care (pegfilgrastim/filgrastim) rather than placebo to demonstrate noninferiority.

The addition of lipegfilgrastim to a cisplatin/etoposide chemotherapy regimen for non-small cell lung cancer is beneficial in reducing the incidence, severity, and duration of FN in patients aged older than 65 years. Lipegfilgrastim was generally well tolerated in both the older adult and adult populations, but those aged older than 65 years may be at risk for hypokalemia, hypophosphatemia, and decreased appetite. The sample sizes in this study were too small to be of value.

The purpose of the study was to compare rates of febrile neutropenia between four treatments: (a) ciprofloxacin 500 mg PO BID on days 5–14, (b) G-CSF (filgrastim 5 mg/kg per day or lenograstim 150 mg/m² per day) on days 5–10, (c) pegfilgratim 6 mg on day 2, and (d) pegfilgrastim plus ciprofloxacin.

A secondary aim was to compare the incidence of neutropenia and other hematologic toxic effects, infection, nonhematologic toxic effects, and hospitalization.

Patients enrolled in the German GeparTrio study from April 2001 and June 2005 who received one of the four neutropenia prophylactic regimens were analyzed. Patients analyzed had completed at least one cycle of TAC and were not randomized to no treatment.

• 1,256 participants were enrolled.
• All were aged 18 years or older
• All were female
• All were diagnosed with breast cancer

89 outpatient sites in Germany

Active treatment

Retrospective cohort study of women with breast cancer enrolled in the Germany GeparTrio study.

• Febrile neutropenia
• Grade 4 neutropenia
• Hematologic toxicities (leukopenia, anemia [hemoglobin lower than 10 g/dl], thrombocytopenia)
• Hospitalizations
• Non-hematologic toxicities (infection without neutropenia, stomatitis, dysphagia/esophagitis, diarrhea)
   

Among the 1,256 patients in the analyses, 1,057 completed all planned cycles of treatment (six cycles, n = 793; eight cycles, n = 264). The combination of pegfilgrastim and ciprofloxacin was statistically significantly better than other regimens for the prevention of overall febrile neutropenia (p < 0.001), febrile neutropenia during the first chemotherapy cycle (p < 0.001), lower incidences of grade 4 neutropenia, prevention of leukopenia and anemia (p < 0.001), fewer hospitalizations (p < 0.001), and for the reduction of stomatitis/mucositis, dysphagia/esophagitis, and diarrhea. Pegfilgrastim alone was as effective as pegfilgrastim and cipro for overall febrile neutropenia (p < 0.001) and for the reduction of grade 4 neutropenia, leukopenia, and anemia (p < 0.01). Daily G-CSF was better than cipro alone for the reduction of grade 4 neutropenia. Thrombocytopenia was lowest for cipro alone (p < 0.001). Infection with neutropenia was not statistically different between groups.

The use of pegfilgratim, especially in combination with ciprofloxacin, is superior to ciprofloxacin alone or daily G-CSF for the reduction of febrile neutropenia, grade 4 neutropenia, and related hospitalizations. No regimen proved superior over others for the prevention of infection with neutropenia.

The administration of daily G-CSF was not given according to protocol of beginning 24 hours after the last dose of chemotherapy with continuation until absolute neutrophil count (ANC) has returned to normal range or for a maximum of 14 days. G-CSF was started at a later time in the cohorts who received G-CSF which could have skewed the results in favor of pegfilgrastim, which was given according to protocol.

The use of pegfilgratim, especially with ciprofloxacin, for the prevention of febrile neutropenia, grade 4 neutropenia, and neutropenic-related hospitalizations appears beneficial for women with stage T2–T4 primary breast cancer. Oncology nurses can advocate for use of this regimen for their patients.

The purpose of the study was to demonstrate bioequivalence of two different filgrastim products.

Patients were randomized to receive one of the two types of filgrastim at the same dose and schedule. Treatment was 5 mcg subcutaneously daily on day 2 of chemotherapy in each cycle, and continued until absolute neutrophil count (ANC) was greater than 3 x 10⁹/L or treatment had been given for 14 days.

• 276 participants were studied.
• Mean age was 49.8 years (SD = 8.88)
• All were female
• All had breast cancer at various stages and were receiving chemotherapy with doxorubicin and docetaxel.
• Patients did not have any radiotherapy within six weeks of study entry, or prior chemotherapy within four weeks.
   

37 European outpatient centers in various countries

Mutliple phases of care

Randomized, double-blind phase III

• Duration of severe neutropenia for each chemotherapy cycle defined as ANC less than 0.5 x 10⁹/L
• Time to ANC recovery (greater than 3 x 10⁹/L)
• Incidence of febrile neutropenia (ANC less than 0.5 x 10⁹/L and temp 38.5ºC or higher)
• Incidence of documented infection
• NCI CTCAE [v.3.0]
   

Incidence of severe neutropenia was 77.6% in one group and 68.2% in the other, with no statistically significant difference. Duration of severe neutropenia across groups in cycle 1 ranged from 1.3 –1.6 days on average, and was lower in both groups in subsequent cycles. There were no differences in outcomes between the two. Those receiving Hospira filgrastim had a slightly higher incidence of  bone pain than Amgen filgrastim; however, overall prevalence of skeletal pain was similar in both groups.

 The results of this study showed that these two different preparations of filgrastim are bioevquivalent.

• Risk of bias (sample characteristics)
• The sample was almost 98% Caucasians. 
• Those receiving Hospira filgrastim who had more bone pain, also had a higher prevalence of bone metastases at baseline. It is not clear if these may have been related.

 This study was designed purely to demonstrate bioequivalence of these two filgrastim products.

To compare the cost-effectiveness of various strategies of myeloid growth factor prophylaxis for reducing the risk of febrile neutropenia (FN) in patients with non-Hodgkin lymphoma in Singapore who are undergoing R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy with curative intent

Seven prophylaxis strategies were evaluated: (a) primary prophylaxis (PP) with biosimilar filgrastim throughout all cycles of chemotherapy, (b) PP with biosimilar filgrastim during the first two cycles of chemotherapy, (c) secondary prophylaxis (SP) with biosimilar filgrastim, (d) PP with pegfilgrastim throughout all cycles of chemotherapy, (e) PP with pegfilgrastim during the first two cycles of chemotherapy, (f) SP with pegfilgrastim, and (g) no prophylaxis (NP). Cost-effectiveness was expressed as the cost per episode of FN avoided over six cycles of chemotherapy.

• N = N/A   
• AGE = N/A
• MALES: N/A, FEMALES: N/A
• CURRENT TREATMENT: Chemotherapy, immunotherapy
• KEY DISEASE CHARACTERISTICS: Patients with non-Hodgkin lymphoma (NHL) treated with R-CHOP

• SITE: Single site   
• SETTING TYPE: Not specified    
• LOCATION: Singapore

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care

• Case-controlled study using published data set to estimate the rate of FN
• A mathematical model was used to compare anticipated costs.

A Markov model was constructed with TreeAge Pro 2013 to compare seven prophylaxis strategies for FN. Primary prophylaxis was defined as the routine administration of a granulocyte–colony-stimulating factor (G-CSF) with each cycle of chemotherapy, regardless of whether the patient had previously experienced an episode of FN. Secondary prophylaxis was defined as the initiation of a G-CSF in subsequent cycles of chemotherapy after the patient experienced a FN episode. The model target population was a hypothetical cohort of patients with NHL (mean age = 55 years) undergoing R-CHOP as a curative treatment. The time horizon of this model was 18 weeks, which was the period of six chemotherapy cycles. The Markov model was used with a cycle length of one week (seven days). Data from observational studies were used to determine the anticipated rate of FN.

The costs associated with the strategies were $3,813 (strategy 2), $4,056 (strategy 5), $4,545 (strategy 1), and $5,331 (strategy 4), respectively. The incremental cost-effectiveness ratios were $13,532 for strategy 5 versus strategy 2, $22,565 for strategy 1 versus strategy 5, and $30,452 for strategy 4 versus strategy 1, respectively, per episode of FN avoided. Strategy 2 was the most cost-effective.

The routine use of prophylactic G-CSF in the first two cycles of R-CHOP for NHL was more cost-effective than the routine use of G-CSF for all cycles of chemotherapy, with minimal clinical significance on efficacy. Routine use of prophylactic G-CSF during the first two cycles of R-CHOP for NHL or during all cycles of R-CHOP was more cost-effective than no prophylaxis.

• Risk of bias (no random assignment)
• This study used a mathematical model with data sets to predict the costs associated with G-SCF use.
• The study did not enroll patients to evaluate outcomes.
• The authors assumed that using a biosimilar filgrastim for seven days would have the same outcomes as pegfilgrastim.

Using G-CSF is a cost-effective way to prevent FN in patients undergoing R-CHOP chemotherapy. Cost-effectiveness is further improved when a G-CSF is used during the first two cycles, but this may produce different clinical benefits, requiring further study.

To determine if the duration of filgrastim prophylaxis affects the risk of chemotherapy-induced neutropenic complications (CINC), healthcare costs, and mortality

This is a retrospective study of medicals claims from two large healthcare claims databases, the Thomson Reuters MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Database (MarketScan Database, 2001–2010) and the Intercontinental Marketing Services LifeLink Database (LifeLink Database, 2001–2008). Claims for chemotherapy, filgrastim, and hospital admissions were analyzed to determine the number of daily filgrastim doses following a chemotherapy cycle and neutropenic complications.

• N = 14,288 daily filgrastim prophylaxis patient cycles  
• AGE = 18 years and older
• MALES: About 20%, FEMALES: About 80%
• KEY DISEASE CHARACTERISTICS: Patients who initiated one or more courses of myelosuppressive chemotherapy for a solid tumor or non-Hodgkin lymphoma and who received daily filgrastim prophylaxis during one or more cycle

• SITE: Multi-site    
• SETTING TYPE: Multiple settings    
• LOCATION: United States

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care  

Retrospective study of medical claims

• Data collection from databases using HCPCS, ICD-9-CM, or UB-92 codes and analyzed with statistical analysis software

If patients were treated with one to three days of filgrastim prophylaxis, the risk of CINC during a cycle of chemotherapy was 2.9%. If they were treated with four to six days of filgrastim prophylaxis, the risk of CINC was 2.7%. If the patient was treated with seven or more days, the risk of CINC was 1.8%. In adjusted analyses, the odds of CINC were 2.4 (95% = CI, 1.6–3.4) higher with one to three days of filgrastim prophylaxis versus seven or more days and 1.9 (1.3–2.8) times higher with four to six days of filgrastim prophylaxis versus seven or more days. In the pivotal trials of filgrastim prophylaxis, 10–11 days of filgrastim prophylaxis were needed for adequate neutrophil recovery, yet this study demonstrated that in actual practice, 95% of patients received fewer than 10 days of filgrastim prophylaxis and 58% received only one to three days. In a subgroup of 358 patients who developed CINC and the healthcare expenditures were available, CINC-related healthcare expenditures were $18,912 (14,570– 23,581) with one to three days of prophylaxis (n = 225), $14,907 (11,155–19,728) with four to six days (n = 94), and $13,165 (9,595–17,144) with seven or more days (n = 39). In a subgroup of 228 patients for whom discharge status was available, in-hospital mortality was 8.4% (4.6–14.8) with one to three days of prophylaxis (n = 119), 4% (1.4–11.1) with four to six days (n = 75), and 0% (0–10.2) with seven or more days (n = 34).

Administration of less than seven days of daily filgrastim was not as effective as seven or more days of daily filgrastim to prevent chemotherapy-induced neutropenic complications. The use of seven or more days of filgrastim as primary prophylaxis to prevent chemotherapy-induced neutropenic complications also decreased healthcare costs and mortality.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Unintended interventions or applicable interventions not described that would influence results
• Key sample group differences that could influence results

In clinical trials evaluating the efficacy of CSF prophylaxis, patients were treated with 10 or more daily doses of filgrastim. However, in actual practice, the majority of patients receive prophylaxis with fewer than 10 doses of daily filgrastim, which increases the risk of chemotherapy-induced neutropenic complications, mortality, and healthcare costs. Clinicians need to be aware of most effective CSF dosing requirements.

To investigate the receipt of colony-stimulating factor (CSF) prophylaxis and associated risks of febrile neutropenia (FN)

Data from two large U.S. claims repositories from 2006–2014 were obtained for analysis. Data included patients aged older than 18 years who received at least two cycles of myelosuppressive chemotherapy. The analysis was focused on the use of pegfilgrastim; patients who received other CSFs were excluded from the analysis. Patients who received and did not receive pegfilgrastim prophylaxis were matched according to variables in multivariate regression, including the being at intermediate/high risk for neutropenia and cancer type.

• N = 42,314   
• MEAN AGE = 54.6 years (SD = 10.7)
• MALES: 10.4%, FEMALES: 89.6%
• CURRENT TREATMENT: Combination radiation and chemotherapy
• KEY DISEASE CHARACTERISTICS: Patients with breast, colorectal, lymphoma, and lung cancer
• OTHER KEY SAMPLE CHARACTERISTICS: The majority were chemotherapy naive.

• SITE: Multi-site   
• SETTING TYPE: Multiple settings    
• LOCATION: United States

• PHASE OF CARE: Active antitumor treatment

• Retrospective cohort comparison

FN episodes were identified based on hospital admission with a diagnosis of neutropenia, fever, or infection. FN episodes requiring outpatient care, including emergency department visits, were defined as Healthcare Common Procedure Coding System (HCPCS) code for IV antimicrobial therapy on the same date as a diagnosis of neutropenia, fever, or infection.

Of the patients, 5.3% were not given second-cycle pegfilgrastim prophylaxis. Second-cycle FN among comparison patients was 3.8% versus 2.2% among those who received propylaxis (95% confidence interval [CI] [1.2, 2.5], p = 0.002). With a narrower definition of FN, 3.5% without prophylaxis had FN compared to 0.8% in the group that received second-cycle pegfilgrastim (odds ratio [OR] = 3.5, p < 0.001).

The findings suggest that the odds of developing FN in the second cycle of chemotherapy are higher among patients who discontinue CSF prophylaxis compared to those who continue prophylaxis.

• Findings not generalizable
• Does not account for potential differences in absolute neutrophil count (ANC) between groups, which would account for different use of CSF prophylaxis
• No single diagnosis code exists for FN, so the definition is somewhat questionable, which could result in an under or overestimation of incidence.
• Included only patients younger than 65 years with private insurance, so it may not reflect other populations
• The study was funded by Amgen, Inc., which makes pegfilgrastim.

Some evidence suggest that ongoing CSF prophylaxis is not consistently provided in at-risk patients. This study, although it had some limitations, suggests that the discontinuation of prophylaxis along the course of treatment with myelosuppressive chemotherapy for patients at an intermediate or high risk for FN is associated with an increased incidence of FN.

The purpose of this study was to assess differences in risk of hospitalization for neutropenic complications among patients with solid tumors who received prophylactic filgrastim, pegfilgrastim, or sargramostim during their first observed course of chemotherapy from July 2001 to June 2007.

Prophylactic administration of filgrastim, pegfiltrastim, or sargramostim

• 208,401 participants
• Participants were 18–98 years old, with a mean age of 60 (filgrastim), 58 (pegfilgrastim), 61 (sargramostim), respectively.
• Males made up 53.6% of the participants; females made up 46.4%
• Cancers of the breast (female only), non-Hodgkin lymphoma, trachea, bronchus, lung, prostate, colon/rectum, Hodgkin disease, genitourinary, bone, connective tissue, and skin, with or without metastasis to bone or other sites who received filgrastim, pegfilgrastim, or sargramostim prophylaxis and/or chemotherapy cycles in which these colony-stimulating factors (CSFs) were administered as prophylaxis.
• Mean comobidity index 3.8 (pegfilgrastim), 3.7 (filgrastim), 3.6 (sargramostim)

• Multiple settings 
• Data obtained from two healthcare claims databases
• Includes patients treated nationwide in inpatient and outpatient settings

• The phase of care was active anti-tumor treatment
• Application was for elder care

Retrospective cohort study

Statistical analyses included using medical claims information from two large databases (Thomson Reuters MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Database), calculation of duration in days of use of each CSF, independent samples t test for continuous factors and chi-square for multilevel categorical factors. Generalized estimating equations were used to assess risk of hospitalizations.

Risk of hospitalization for neutropenia was 2.1% (filgrastim prophylaxis, n = 8,286), 1.1% (pegfilgrastim prophylaxis, n = 67,247), and 2.5% (sargramostim prophylaxis, n = 1,736) and, for nuetropenia, fever, or infection for prophylactic use of filgratim, pegfilgratim, and sargramostim was 4%, 2.6%, and 2.5%, respectively. Risk of hospitalizations for all causes was 7.9%, 5.3%, and 9.6%, respectively. Adjustments were made in the statistical analysis for patient characteristics, type of cancer, and chemotherapy regimen.

Prophylactic pegfilgrastim administration is associated with less risk of hospitalizations for neutropenia/neutropenic-related complications than either prophylactic filgrastim or sargramostim in patients undergoing chemotherapy treatments for a variety of cancers.

• Retrospective study using two  healthcare claims databases.
• Data were based on insurance claims, which may not be completely accurate.
• This also does not capture individuals on insurance plans not part of these databases or the non- or underinsured (however, it likely captures a large percent of the population treated for cancer in the United States).

Recommendation of the use of prophylactic pegfilgratim may be warranted. Patient education regarding neutropenia, neutropenic-related complications, and side effects of pegfilgratim is essential. Nurse-led discussions of using pegfilgratim instead of filgratim or sargramostim with the oncology healthcare team could ensue.

To estimate the odds of FN, beginning with second chemotherapy cycle, among patients who received prophylactic pegfilgrastim in that cycle and all previous cycles versus those who received prophylactic pegfilgrastim in all previous cycles only.

This is a descriptive study using a retrospective matched-cohort design utilizing pooled data from two healthcare claims repositories, the MarketScan Database and LifeLink Database, spanning the period from January 1, 2010 through September 30, 2015. The study is not prospective, but rather completes a secondary analysis of existing data.

• N: 8,450 matched pairs of patients undergoing chemotherapy: comparison group received pegfilgrastim following first cycle only, source group received pegfilgrastim following each cycle
• AGE: Mean in comparison = 53.6 years, in pegfilgrastim = 53.9 years 
• MALES: Not identified, missing data 
• FEMALES: Not identified; study reports 89% of matched patients had breast cancer and 2% ovarian 
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: 89% of matched had breast cancer, 7% had NHL, 2% lung, 2% ovarian, less than 1% colorectal
• OTHER KEY SAMPLE CHARACTERISTICS: 52% of the 89% of those with breast cancer received doxyrubicin and cyclophosphamide. The majority  of participants had surgery within the preceding 90 days

• SITE: Multi-site
• SETTING TYPE: Not specified; data obtained from larger number of participating private U.S. health plans. Appears to be primarily outpatients receiving chemotherapy with some hospital admissions    
• LOCATION: Varied throughout the United States

PHASE OF CARE: Active anti-tumor treatment

Retrospective matched-cohort design

Comparison of the incidence and odds ratios of FN were determined between comparison and pegfilgrastim patients. Data was evaluated using generalized estimating equation regression models. No standardized measurement or instrument used; data obtained from charts.

Second-cycle incidence of FN was greater is the comparison patients with an odds ratio of 1.7 and p < 0.001 (broad definition). Second-cycle incidence proportions for FN was greater in the comparison group (narrow definition), with an odds ratio of 4.3 and p < 0.001. All cycles from the third through course completions, the odds ratio for FN was 1.6 with p < 0.001 (broad definition).

In this retrospective, matched-cohort study, those who did not continue pegfilgrastim prophylaxis subsequent to the first cycle of chemotherapy had a higher risk for FN compared to those who continue pegfilgrastim prophylaxis after each cycle of chemotherapy. Therefore, the administration of pegfilgrastim following each chemotherapy cycle (as opposed to abbreviated use) appears to have a protective effective in reducing the incidence of FN.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Risk of bias (no appropriate attentional control condition)
• Unintended interventions or applicable interventions not described that would influence results
• Selective outcomes reporting
• Key sample group differences that could influence results
• Measurement/methods not well described
• Measurement validity/reliability questionable 
• Findings not generalizable
• Other limitations/explanation: Cannot be generalized to the larger population due to the lack of rigor in the design. The non-experimental retrospective design cannot establish causal relationships, only show correlations. In addition, those whose who are publicly insured and older adults were poorly represented. Lastly, the study was funded by maker of pegfilgrastim and the authors are stockholders in Amgen.

This retrospective, matched-cohort study indicates that premature discontinuation of pegfilgrastim prophylaxis following chemotherapy is commonplace in U.S. practice and is associated with additional febrile neutropenia events. The decision to prematurely discontinue pegfilgrastim prophylaxis following chemotherapy should be carefully weighed against the associated risk of FN. Although this study was a retrospective design, the findings continue to support the importance of adhering to current standards of nursing care practice with pegfilgrastim prophylaxis for the prevention of FN. Additional independent research is necessary, particularly evaluating the risk of FN in the older adult and publicly insured populations, which are under-represented in this study.

The purpose of the study was to evaluate the clinical efficacy of G-CSF and cost of daily versus every other day G-CSF for preventing and reducing duration of febrile neutropenia.

After treatment with the first course of R-CHOP, 100 mcg per person, G-CSF subcutaneously was begun when the white blood cell counts (WBC) were less than 1.5x10⁹/L and/or neutrophil counts were less than 0.5 x 10⁹/L. Patients were randomly assigned to receive G-CSF daily or every other day. Treatment was stopped when WBC recovered to greater than 5 x 10⁹/L. Total dosages and duration of G-CSF and any subsequent antibiotics were used for cost calculations

• 30 participants
• Mean age was 66 years, with a range = 24–80
• 53.3% were male; 46.7% were female
• All had diffuse large B-cell non-Hodgkin lymphoma and were receiving R-CHOP chemotherapy.  There was no bone marrow involvement
• All had ECOG performance status of 0–3.  Baseline WBC counts were similar in both groups
   

Single site

Active antitumor treatment

 Randomized, controlled trial

Recovery of WBC as defined required 4.0 ±1.4 days and 4.0±1.3 days in those receiving daily and every other day G-CSF respectively. Neutrophil count recovered in 3.4±1.1 days for those receiving daily treatment and in 3.6±1.4 days in those given G-CSF every other day. In the daily use group, three patients developed febrile neutropenia, and two patients in the every other day group developed febrile neutropenia. The same number of patients in each group who were given prophylactic antibiotics developed febrile neutropenia. Cost of treatment in those receiving daily G-CSF was significantly higher than cost in the every other day group (p < 0.0001).

There was no clinical difference in WBC and neutrophil recovery time between patients who were given daily or every other day G-CSF during a course of R-CHOP chemotherapy

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Limited study duration and duration of follow-up

Findings suggest that less frequent G-CSF administration may be as effective as daily administration to facilitate WBC and neutrophil recovery. Further larger scale research in this area is warranted.  If this approach is further supported, it can provide less costly care to achieve desired results.
 

To determine if mecapegfilgrastim, a biosimilar, is as effective as pegfilgrastim in preventing febrile neutropenia (FN) in patients with advanced non-small cell lung cancer

One hundred fifty-one patients were split into three groups—two with two different doses of mecapegfilgrastim and one with normal saline (control). After the initial cycle, the control group received recombinant human granulocyte–colony-stimulating factor (rhG-CSF), while the other two groups continued their doses of mecapegfilgrastim.

• N = 146 
• MEAN AGE = 55.89 years 
• MALES: 69.2%, FEMALES: 30.8% 
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Non-small cell lung cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Patients receiving platinum-based chemotherapy

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: China

• PHASE OF CARE: Active antitumor treatment

• Double-blind, three-group, randomized trial followed by an open-label

• Neutropenia grade 3 or 4 (absolute neutrophil count [ANC] 1–0.5 x 10⁹/l)
• FN temperature of 38.5 degrees with neutropenia as above
• Duration of neutropenia from nadir to ANC 2 x10⁹/L
• Depth of ANC nadir

For the first phase of the study, both mecapegfilgrastim arms showed a lower incidence of grade 3 or greater neutropenia (p < 0.0001 and p = 0.0001). For the second phase, which was unblinded, the incidence of FN was lower across all cycles with both doses of the biosimilar (p < 0.023 and p < 0.0001) compared to placebo. No significant differences existed in FN incidence in those cycles when compared to G-CSF. Time to ANC recovery was significantly lower with the biosimilar compared to placebo and no different from the time to recovery with G-CSF.

Both doses of mecapegfilgrastim were effective in reducing neutropenia within each cycle of chemotherapy compared to rhG-CSF.

• Risk of bias (no blinding)
• Risk of bias (sample characteristics)
• Findings not generalizable

As more biosimilars make their way to the market, studies such as this will be important in determining the care nurses provide to their patients. Nurses need to be aware of current literature and the implications for their patients. This study showed that the biosimilar CSF was more effective than placebo and as effective as G-CSF.

The purpose of this article was to update existing guidelines for prophylactic granulocytye–colony-stimulating factor (G-CSF). The article focuses on patients receiving chemotherapy, not limited to one definition of febrile neutropenia (FN). No studies with pediatric patients or patients with leukemia were included.

This guideline resource used a process where articles were rated using the table listing below.

Level                Type of Evidence
A                        Evidence of type I or consistent findings from multiple studies of types II, III, or IV
B                       Evidence of types Ii, II, or IV and findings are generally consistent
C                       Evidence of types Ii, II, or IV, but findings are inconsistent
D                       Little or no systematic empirical evidence 

Information from papers included in meta-analyses were only used to answer questions not included in the meta-analyses. Publications available from Congress presentations previously included as abstracts were only used is they provided answers not yet presented. Authors were contacted if their abstracts were relevant and publications noted as missing or “in press” were included.

Regarding a search strategy, the MEDLINE, PreMEDLINE, EMBASE, and Cochrane Library databases were used.

Key words included antineoplastic agents, filgrastim, granulocyte–colony-stimulating factor, lenograstim, neoplasms, neutropenia, pegfilgrastim, and guideline

Articles were included if they were recent reviews, any primary papers deemed relevant, and meta-analyses subject to manual review. In addition to filgrastim and pegfilgrastim, two filgrastim biosimilar molicules, XMO2 and EP2006, daily G-CSFs have been approved in Europe. 

Articles were excluded if their studies included patients younger than age 18 years or patients with a diagnosis of leukemia.
 

• The phase of care is active chemotherapy treatment
• Applications is adult patients receiving chemotherapy.
   

Recommendations  Primary prophylactic G-CSF is recommended for patients at risk and should be started 24–72 hours following completion of the first cycle.

Step I:

• Assess frequency of FN associated with planned chemotherapy regimen, and reassess with each cycle.
• If FN risk is less than10%, G-CSF prophylaxis is not recommended. If FN risk is greater than 20%, prophylactic G-CSF is recommended.
• If FN risk 10%–20%,  proceed to step 2.

Step 2: 

• Assess for high risk: age older than 65 years.  
• Increased risk (level I, II evidence): Advanced disease, history of prior FN, no antibiotic prophylaxis, no G-CSF use
• Other factors (level III, IV evidence): Poor performance/nutritional status, female, Hgb < 12 g/dl, liver, renal, cardiovascular disease
• and then proceed to step 3

Step 3: 

• Define the patient’s overall FN risk for planned chemotherapy regimen.
• If overall FN risk is greater than 20%
• Secondary prophylaxis: Start G-CSF if neutropenic event occurred in previous cycle.

Provides percent risk for development of FN for some tumor types based on chemotherapy regimen. Identifies additional risk factors, but provides little guidance on how to use these to calculate an increase in risk that would warrant prophylactic G-CSF.
 

The article included results from an updated literature search to identify patient and chemotherapy regimen risk factors for developing FN, use of prophylactic G-CSF, G-CSF with existing FN, impact of overall FN risk on G-CSF use, and choice of G-CSF formulation. It was difficult to identify new information as recommendations were combined with existing recommendations.

PURPOSE: To evaluate the use of granulocyte-colony stimulating factor (G-CSF) in adult patients receiving chemotherapy for cancer

TYPES OF PATIENTS ADDRESSED: Adult patients receiving chemotherapy for cancer

PROCESS OF DEVELOPMENT:

The following questions were applied by the European Organisation for Research and Treatment of Cancer (EORTC) G-CSF Guidelines Working Party.

In adult patients with cancer receiving chemotherapy:

1. Is there evidence that patient-related factors increase the risk of febrile neutropenia (FN)?
2. Is there evidence that certain chemotherapy regimens increase the risk of FN?
3. Is there evidence that some patients are more at risk for severe morbidity as a result of an FN episode?
4. Is there evidence to support the use of G-CSF when there is a 20% risk level for FN?
5. Is there evidence to support the use of G-CSF to
   1. Maintain the correct dose of chemotherapy and relative dose intensity and density?
   2. Improve overall and progression-free survival?
6. Is there evidence to support the use of G-CSF to enable the delivery of dose-dense and -intense chemotherapy
   1. By increasing the dose?
   2. By withdrawing one drug and increasing the dose of the remaining drugs?
   3. By increasing the dose frequency?
7. Is there evidence to support the use of G-CSF to reduce the risk of infection-related mortality?
8. Is there evidence to support the use of G-CSF to reduce the incidence of FN?
9. Is there evidence to support the use of G-CSF for the treatment of ongoing FN?
10. Is there evidence to support the use of different G-CSFs?

The article describes guidelines prepared by the G-CSF Guidelines Working Party of the EORTC to systematically review available published data and derive evidence-based recommendations on the appropriate use of G-CSF in adult patients receiving chemotherapy for cancer.

The following are levels of evidence applied by the EORTC G-CSF Guidelines Working Party.

• Level I: Evidence obtained from meta-analysis of multiple, well-designed, controlled studies or from high-power randomized, controlled clinical trial
• Level II: Evidence obtained from at least one well-designed experimental study or low-power randomized, controlled clinical trial
• Level III: Evidence obtained from well-designed, quasi-experimental studies such as nonrandomized, controlled single-group, pre-post, cohort, time, or matched case-control series
• Level IV: Evidence obtained from well-designed, non-experimental studies such as comparative and correlational descriptive and case studies
• Level V: Evidence obtained from case reports and clinical examples

The following grades of recommendations were applied by the EORTC G-CSF Guidelines Working Party.

• Grade A: There is evidence of type I or consistent findings from multiple studies of types II, III, or IV.
• Grade B: There is evidence of types II, III, or IV, and findings are generally consistent.
• Grade C: There is evidence of types II, III, or IV, but findings are inconsistent.
• Grade D: There is little or no systematic empirical evidence.

DATABASES USED: MEDLINE, PreMEDLINE, EMBASE, and the Cochrane Library.

INCLUSION CRITERIA: Articles selected were published in English from December 31, 1994–September 16, 2005. Reference lists of the identified meta-analyses were interrogated manually, and any primary papers considered relevant were included. Abstract books from key international congresses were searched manually to identify relevant evidence presented at meetings from 2003–2005.

EXCLUSION CRITERIA: Studies involving children younger than 18 years of age or patients with leukemia were excluded, as were cost analyses, as these lack international applicability. Relevant articles “in press” and additional papers identified by members of the working party were included in limited instances.

Recommendation 1: Patient-related risk factors for increased incidence of FN

• Patient-related risk factors should be evaluated in the overall assessment of FN risk prior to each cycle of chemotherapy. Particular consideration should be given to the elevated risk of FN for patients aged 65 years or older. Other adverse risk factors that may influence FN risk based on level I and II evidence included advanced stage of disease, experience of previous episode(s) of FN, and lack of G-CSF use and antibiotic prophylaxis. However, please note that the indiscriminate use of antibiotic prophylaxis is not recommended by either the Working Party or the EORTC Infectious Disease Group. Risk factors that may influence FN risk based on level III and IV evidence included poor performance and/or nutritional status, female gender, hemoglobin less than 12 g/dl, and liver, renal, or cardiovascular disease.
• Recommendation grade B

Recommendation 2: Chemotherapy regimens associated with increased risk of FN

• Consideration should be given to the elevated risk of FN with certain chemotherapy regimens. The risk of FN for certain chemotherapy regimens is summarized in Table 4 of the original paper.
• Recommendation grade A/B (depending on the evidence for each chemotherapy regimen)

Recommendation 3: G-CSF to support chemotherapy

• In situations in which dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF should be used as a supportive treatment. If reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis should be used to maintain chemotherapy. Examples of this could be when the patient is receiving adjuvant or potentially curative treatment, or when the treatment intent is to prolong survival. When this is not crucial, use of less myelosuppressive chemotherapy or dose and schedule modifications should be considered.
• Recommendation grade A

Recommendation 4: Impact of the overall FN risk on G-CSF use

• The risk of complications related to FN should be assessed individually for each patient. When assessing FN risk, the clinician should take into account patient-related risk factors, the chemotherapy regimen and associated complications, and treatment intent. If the patient is at more than 20% overall risk of FN, prophylactic G-CSF is recommended. With chemotherapy regimens associated with an FN risk of 10%–20%, particular attention should be given to the assessment of patient characteristics that may increase the overall risk of FN.
• Recommendation grade A

Recommendation 5: G-CSF in patients with existing FN

• Treatment with G-CSF for patients with solid tumors and ongoing FN is indicated only in special situations. These are limited to those patients who are not responding to appropriate antibiotic management and who are developing life-threatening infections (e.g., severe sepsis, septic shock).
• Recommendation grade B

Recommendation 6: Choice of formulation

• Filgrastim, lenograstim, and pegfilgrastim have clinical efficacy, and the authors recommend the use of any of these agents to prevent FN and FN-related complications, where indicated.
• Recommendation grade A

• Eighteen citations listed: No evaluative summary of sources or levels of evidence 
• Note provided by authors on levels of evidence (I-V) and grades of recommendation (A-D) as used by the American Society of Clinical Oncology provided in the tables of recommendations
• Statements within the guidelines without grading were considered standard clinical practice as recommended by the expert authors and the ESMO faculty

• Definition: Incidence of FN, complications, and mortality rates
• Regimens: Risk of FN > 20%
• Indication: FN primary prophylaxis with ​hematopoietic growth factors (hGFs)
• Special situations: hGFs and standard therapy
• Dose schedule: Administration of granulocyte-colony stimulating factor (G-CSF) and pegfilgrastim
• Indications: Use G-CSF and pegfilgrastim; high-risk situations
• G-CSF after autologous stem-cell transplant or allogeneic transplant
• Mobilization of peripheral blood stem cell autologous or allogeneic settings
• G-CSF treatment for radiation injury

• Data sources before 2010 may be outdated.
• Not all tumor types and treatments were represented.
• No process was provided for how these guidelines were developed.
• The inclusive resources cited were not evaluated separately with a table of evidence.
• These guidelines were established on expert opinion, consensus of ESMO faculty, and the adoption of ASCO levels of evidence and grades of recommendations.

Identifying patients at-risk for FN and the appropriate use of hGFs is critical to improve patient outcomes. Nurses must consider the strength of evidence for and the process of guideline development of treatments before using clinical practice guidelines in patient care.

To provide a guide for the use of antimicrobial agents for chemotherapy-induced fever and neutropenia in patients with cancer. The patient population targeted included adult and pediatric patients with neutropenia.

For this guideline document, the IDSA Standards and Practice Guidelines Committee reconvened many members of their original guideline panel, together with additional experts, in the management of patients with fever and neutropenia. The committee included experts in infectious diseases, oncology, and hematopoietic stem cell transplantation (HSCT) in both adult and pediatric patients. The literature was reviewed and graded according to a systematic weighting of the level and grade of the evidence for making a recommendation.

Patients were undergoing the active treatment phase of care.

Antibiotic Prophylaxis 

Fluoroquinolone prophylaxis should be considered for high-risk neutropenic patients (patients expected to have absolute neutrophil counts (ANCs) of 100 cells/mm³ or lower for more than seven days. Levofloxacin and ciprofloxacin are the agents that have been evaluated the most and are generally equivalent, although levofloxacin is preferred for patients at risk for oral mucositis-related invasive viridans group streptococcal infection (B-1). The addition of a gram-positive active agent to fluoroquinolone prophylaxis is not recommended (A-1). Antibacterial prophylaxis is not indicated for low-risk patients anticipated to be neutropenic for less than seven days (A-III). 

Antifungal Prophylaxis

Patients at high risk for candida infection, such as recipients of allogeneic HSCT and patients with acute leukemia undergoing intensive chemotherapy, should be treated with antifungal prophylaxis with fluconazole, itraconazole, voriconazole, posaconazole, micafungin, or caspofungin (A-I). Patients aged 13 years or older who are undergoing intensive chemotherapy for acute leukemia or myelodysplastic syndrome who are at high risk for aspergillus infection may be treated with posaconazole for antifungal prophylaxis (B-I). Prophylaxis against aspergillus infection is not effective in recipients of pre-engraftment HSCTs, but it is recommended for patients with a prior history of invasive aspergillosis (A-III), anticipated neutropenia of at least two weeks (C-III), or a prolonged period of neutropenia prior to transplantation (C-III). Antifungal prophylaxis is not recommended for patients with an anticipated duration of neutropenia of less than seven days (A-III). 

Antiviral Prophylaxis

Herpes simplex virus–positive patients undergoing allogeneic HSCT or leukemia induction therapy should receive acyclovir antiviral prophylaxis (A-I). Annual influenza vaccination is recommended for all patients being treated for cancer (A-II). The optimal timing has not been established, but serologic responses may be best between chemotherapy cycles (more than seven days after the last treatment) or more than two weeks prior to the start of therapy (B-III). 

Colony-Stimulating Factors

Colony-stimulating factors are recommended for prophylaxis against neutropenia when the anticipated risk of fever and neutropenia is 20% or greater.

Prevention of Catheter-Related Bloodstream Infections

Hand hygiene, maximal sterile barrier precautions, and cutaneous antisepsis with chlorhexidine are recommended for all central venous catheter insertions (A-I). 

Hand Hygiene

Hand hygiene is the most effective means of preventing infection in the hospital (A-II).

Environment

HSCT recipients should be in private rooms (B-III). Patients with neutropenia do not need to be placed in single-patient rooms. Allogeneic HSCT recipients should be in rooms with more than 12 air exchanges, high-efficiency particulate absorption filtration, and positive pressure (A-III). Plants and dried or fresh flowers should not be allowed in the rooms of hospitalized neutropenic patients (B-III). 

Isolation and Barrier Precautions

No specific protective gear (gowns, gloves, or masks) are necessary during the routine care of neutropenic patients. Standard barrier precautions should be used for all patients when contact with body fluids is anticipated.

Food

In general, food should be well cooked. Well-cleaned uncooked fruits and vegetables are acceptable.

Skin and Oral Care

Daily showers are recommended to maintain skin integrity (expert opinion). Patients should brush their teeth two times per day or more with a regular toothbrush, and flossing can be performed if it can be performed without trauma (expert opinion). Patients with mucositis should rinse their mouths with sterile water, saline, or sodium bicarbonate rinses four to six times per day (expert opinion). Menstruating immunocompromised women should avoid tampons (expert opinion). Rectal thermometers, enemas, suppositories, and rectal examinations are contraindicated for patients with neutropenia (expert opinion).

This was a comprehensive guideline developed by the Infectious Diseases Society of America (IDSA) to guide clinicians in the care of patients with chemotherapy-induced neutropenia and in the management of febrile neutropenia. The full guide can be located at http://cid.oxfordjournals.org/content/52/4/e56.full.

The purpose of the study was to facilitate practice based on clinical evidence by establishing practice guidelines on the use of myeloid growth factors. Adults in hematology and oncology were studied.
 

The resource type was evidence-based guideline. The process of development included a review of the meta-analysis, systematic Cochrane review, and a review of several randomized clinical trials.

The Cochrane database was reviewed. Keywords included  neutropenia, febrile neutropenia, myeloid growth factors, G-CSF, clinical practice guidelines, filgrastim, and pegfilgrastim
 

Active antitumor treatment

This article did not discuss the specific evidence, but outlined benefits of treatment with colony-stimulating factor (CSF) and its use in chemotherapy regimens. Distinguished use as secondary or therapeutic and reviewed the different types of CSFs to be used with which tumor types. The volume of citations was 35.

The use of CSF for primary prophylaxis should be based on the risk of an episode of febrile neutropenia based on disease and chemotherapy regimen. Chemotherapy regimens with risk of febrile neutropenia greater than 20% of primary prophylaxis with CSF is recommended; 10%–20% febrile neutropenia CSF should be considered and less than 10% risk CSF is not recommended. Secondary prophylaxis following an episode of febrile neutropenia or dose-limiting neutropenia, CSF should be considered if not given previously or in cases in which a reduction or delay of the dose is associated with poor prognosis.  Therapeutic use when patients present with febrile neutropenia is recommended based on the existing risk factors for poor clinical outcomes or for developing infection-associated complications.

Risk factors are older than age 65 years, sepsis syndrome, severe neutropenia, absolute neutrophil count (ANC) less than 100 mcl or prolonged duration of more than 10 days, pneumonia, invasive fungal infection or other clinically documented infections, hospitalization at time of fever, and prior episode of febrile neutropenia.

Provides professional evidence-based guidelines for use of CSFs for prophylaxis and treatment of febrile neutropenia. Recommendations here are consistent with those of past versions, and are consistent with those of the National Comprehensive Cancer Network and other relevant professional groups.

RESOURCE TYPE: Consensus-based guideline

PHASE OF CARE: Active antitumor treatment

• Prophylactic use of colony-stimulating factors (CSFs) for individuals at greater than 20% risk for febrile neutropenia (FN) based on chemotherapy regimen, patient risk factors, and treatment intent. For high risk patients (greater than 20%), all treatment intents are considered for CSF recommendation.
• Prophylactic use should be considered for all treatment intents in those at 10%–20% risk for FN.
• Recommends no CSFs for those with less than a 10% risk for FN
• Secondary prophylaxis with CSFs is recommended for consideration among those with FN or a dose-limiting neutropenic event in a prior cycle who had no prior use of CSFs.
• Suggests that prophylactic use of biosimilars in the general oncology population at high risk, but inclusion for stem-cell mobilization or use in those with chronic neutropenia has not been fully accepted.

Limited database to PubMed, no full evidence evaluation provided. Although they suggest prophylaxis based on a percentage risk and suggest chemotherapy dosages accordingly, it does not match current practice in which dosages and regimens may not always be standard, causing a lack of clarity for clinical implementation of these standards.

Both chemotherapy regimens as well as patient-specific risk factors need to be considered to determine patients’ level of risk for developing FN. CSFs have been shown to reduce the incidence of FN and some infection events; however, evidence suggests that relevant guidelines and recommendations regarding the use of CSFs are not routinely followed in clinical practice. Nurses can advocate for adherence to CSF prophylaxis in at-risk patients.

The purpose of this review was to review guidelines for the supportive treatment of patients undergoing adjuvant breast cancer, and to evaluate strategies that can be used to improve the safety of these regimens.  All of the studies included were with patients receiving chemotherapy for breast cancer.

Databases used were not stated.

Key words used include anthracyclines, filgrastim, hematopoietic growth factors, myelosuppression, pegfilgrastim, cost/benefit analysis

The number of studies included in the report was 29.

Sample sizes were not reported.

One meta-analysis showed that adding G-CSF prophylactically during the first cycle of chemotherapy in patients being treated for various cancer types helped to decrease the rate of febrile neutropenia from 39% in the control group versus 22.4% in the G-CSF group and made chemotherapy more tolerable, allowing patients to get the appropriate dosages. Another trial compared patients receiving TAC versus FAC initially without G-CSF for either group; researchers did give G-CSF to patients in the TAC group after febrile neutropenia rates soared and rates of febrile neutropenia in the TAC group declined and the rate of trial completion of chemotherapy increased. CALGB9741 also was analyzed and it was discovered that patients receiving the two-week cycle with G-CSF, as compared to the three-week cycle, did remarkably better in declining rates of febrile neutropenia. Another phase III trial showed that patients receiving pegfilgrastim versus placebo had significantly lower rates of febrile neutropenia.

Many of the studies mentioned by the author contributed to the determination that G-CSF should only be given on day 2 due to the elimination period of the drug and that giving it earlier than day 2 may actually increase the risk of febrile neutropenia. The other studies cited in the article were different studies that all showed improvement of febrile neutropenia rates and increase compliance with therapy due to G-CSF.

G-CSF decreases the risk of febrile neutropenia in patients with cancer undergoing chemotherapy treatment. Chemotherapeutic regimens that are dose dense also benefits from G-CSF to decrease the risk of febrile neutropenia. These studies also determined that day 2 is the appropriate day to administer G-CSF, as giving it earlier may actually increase the risk of febrile neutropenia.

The purpose of the article was to assess systemic reviews of best available evidence, including consideration of cost, management of neutropenic sepsis leading to avoidable deaths, and the lack of systems for urgent assessment and lack of institutional policies for managing neutropenic sepsis. Adults (aged 18 or older) with acute leukaemias, stem cell transplantations or solid tumors with expected neutropenia of 0.5 x 10⁹/L or less post-chemotherapy were assessed.

This was an evidence-based guideline with a guideline summary process of development.

Inclusion criteria included adult patients receiving chemotherapy. Exclusion criteria included being younger than age 18 and a diagnosis of lymphoma.

The phase of care was active anti-tumor treatment

High-quality evidence based on systematic reviews/meta-analyses of randomized, controlled trials (RCTs), moderate quality evidence based on systematic reviews, experienced opinion of Guideline Development Group (GDG), and National Cancer Action Team referenced as experience and opinion sources. Low-level evidence includes observational studies.

High-quality evidence (systematic reviews/meta-analysies of RCTs):

• Initiate monotherapy antibiotics when neutropenic sepsis suspected as acute emergency
• No routine prophylaxis with G-CSFs
• Monotherapy for first-line empirical antibiotic

Moderate quality evidence (systematic reviews):

• Outpatient antibiotics considered for low-risk patients after screening
• Oncology-trained professional assessment of septic risk complications during first 24 hours using tool validated for risk score

Experienced opinion of Guideline Development Group (GDG):

• Inform caregiver/ patients before chemotherapy about neutropenia risk and management.  Provide verbal and written information before and throughout treatment.
• Train healthcare professionals to identify and manage potential or actual neutropenic sepsis.
• Monitor antibiotic resistance for flouroquinolones used prophylactically for neutropenic sepsis.
• Assess when to begin or continue empirical antibiotic therapy.

Low level evidence (observational studies):

• Chest x-ray, removal of vascular access device (plus GDG guideline) only when clinically indicated
• Temperature greater than 38⁰C and neutrophil count of 0.5 x 10⁹/L as a neutropenic sepsis diagnosis

• Cannot be applied to children, patients younger than 18 years, or anyone with lymphoma. 
• No external peer review.

High-quality evidence exists for practice recommendations:  

• Initiate monotherapy antibiotics when neutropenic sepsis is suspected as acute emergency
• No routine prophylaxis with granulocyte colony stimulating factors differs from other professional guideline recommendations regarding primary and secondary prophylaxis for at-risk patients.
• Monotherapy for first-line empirical antibiotic

RESOURCE TYPE: Evidence-based guideline

PHASE OF CARE: Active antitumor treatment

Sixty-six publications formed the evidence base for the recommendations. Forty-one were randomized, controlled trials.

• Secondary CSF prophylaxis is recommended for patients who have a neutropenic complication from a prior cycle of chemotherapy.
• CSFs should be administered after an autologous HCT (strong recommendation) and may be administered after allogeneic hematopoietic cell transplantation (HCT) (weak recommendation).
• The use of CSFs as primary prophylaxis in children is reasonable.
• Prophylactic CSF for patients with aggressive lymphoma aged 65 and older undergoing curative treatment should be provided (moderate strength recommendation).

The guidelines provide general recommendations for the primary and secondary prophylactic use of CSFs in patients being treated for cancer, and also outlines concerns regarding cost and the potential overuse of CSFs. The determination of a 20% risk for febrile neutropenia was not straightforward given patient variation and regimen alterations according to individual patient responses. Further work is needed to develop and evaluate clear individualized risk-based models for CSF use in a variety of patients with cancer.