Lyman, G.H., Allcott, K., Garcia, J., Stryker, S., Li, Y., Reiner, M.T., & Weycker, D. (2017). The effectiveness and safety of same-day versus next-day administration of long-acting granulocyte colony-stimulating factors for the prophylaxis of chemotherapy-induced neutropenia: A systematic review. Supportive Care in Cancer, 25, 2619–2629.
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.
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.
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
Harbeck, N., Lipatov, O., Frolova, M., Udovitsa, D., Topuzov, E., Ganea-Motan, D.E., . . . Blackwell, K. (2016). Randomized, double-blind study comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. Future Oncology, 12, 1359–1367.
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.
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 38.3oC 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 38.3oC 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.
Donkor, K.N., Selim, J.H., Waworuntu, A., & Lewis, K. (2017). Safety and efficacy of pegfilgrastim when given less than 14 days before the next chemotherapy cycle: Review of every 14-day chemotherapy regimen containing 5-FU continuous infusion. Annals of Pharmacotherapy, 51, 840–847.
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.
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.
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.
Bokemeyer, C., Gascon, P., Aapro, M., Ludwig, H., Boccadoro, M., Denhaerynck, K., . . . MacDonald, K. (2017). Over- and under-prophylaxis for chemotherapy-induced (febrile) neutropenia relative to evidence-based guidelines is associated with differences in outcomes: Findings from the MONITOR-GCSF study. Supportive Care in Cancer, 25, 1819–1828.
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:
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.
Cycle-level pairwise analysis: likelihood of CIN/FN in any one cycle between under and correctly prophylacted no significant difference
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.
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.
Hockings, J.K., Owolabi, D.K., Broyles, J.E., & Wheelis, S.C. (2017). Impact of recommended weight-based dosing of granulocyte-colony stimulating factors in acute leukemia and stem cell transplant patients. Supportive Care in Cancer, 25, 1853-1858.
To evaluate the effect of recommended weight-based GCSF dosing (under, recommended and over) on duration of neutropenia, compared to under and overweight-based dosing; secondary endpoints were LOS, FN incidence, and mortality between all three dosing groups
Retrospective chart review of 75 patients during 94 admissions for treatment of AML/ALL with induction/consolidation chemotherapy or admitted for a HSCT, admissions divided into weight-based dosing groups of GCSF under 5 mcg/kg; recommended 5 mcg/kg (plus or minus 10%); or over 5 mcg/kg; data collected from initiation of G-CSF to three weeks post: for number of documented doses, ANC nadir, neutropenia duration, time to first fever, and patient disposition at end of study period
Retrospective chart review: sample collected from database ICD-9-CM codes for acute leukemia or stem cell transplantation for patients admitted from May 2009 through September 2015
Actual body weight, temperature, neutropenia ANC < 500, nadir ANC; length of neutropenia in number of days; length of stay in number of days; FN incidence (%); mortality incidence (%)
Comparing weight-based dosing of GCSF administered (under 5 mcg/kg; recommended 5 mcg/kg (plus or minus 10%); or more than 5 mcg/kg) during patient admissions for chemotherapy induction/consolidation or HSCT, the study found that recommended dosing for at least three doses leads to lower incidence of febrile neutropenia (p = 0.003); there was no significant differences between the groups for duration of neutropenia, LOS, or mortality rate.
Recommended weight-based dosing of GCSF at 5 mcg/kg of at least three doses showed a reduction in FN incidence for this population of patients
This retrospective chart review indicates that recommended GCSF weight-based dosing of at least three doses reduces risk of FN. Larger multi-site randomized controlled trials need to be conducted that will effectively evaluate differences of weight-based dosing on clinical outcomes to determine best practice. Nurses need to remain vigilant and adhere to current recommended GCSF weight-based dosing to reduce incidence of FN and potential infectious risks.
Liu, J.Y., Sheng, Y.J., Ding, X.C., Tang, H., Tong, S.W., Zhang, D.Z., . . . Hu, H.D. (2015). The efficacy of lamivudine prophylaxis against hepatitis B reactivation in breast cancer patients undergoing chemotherapy: A meta-analysis. Journal of the Formosan Medical Association, 114, 164-173.
STUDY PURPOSE: Evaluate the efficacy of lamivudine prophylaxis (100 mg daily) on HBsAg seropositive patients with breast cancer undergoing chemotherapy.
TYPE OF STUDY: Meta analysis and systematic review
DATABASES USED: Medline, Embase, and the Cochrane databases
INCLUSION CRITERIA: (a) Types of studies: randomized controlled cohort, retrospective comparative case series, and prospective, controlled, non-randomized studies; (b) studies that included a lamivudine prophylaxis group and a group that did not receive lamivudine prophylaxis; and (c) all patients received chemotherapy and were HBsAg sero-positive.
EXCLUSION CRITERIA: Patient populations were excluded if: (a) the study did not measure HBV reactivation/flare as a specific outcome; (b) the patients did not receive chemotherapy; (c) patients had HIV co-infection; (d) patients had hepatitis D virus, hepatitis C virus, or other liver diseases; (e) there was no lamivudine prophylaxis and non-prophylaxis group; and (f) there was insufficient analytic information available.
TOTAL REFERENCES RETRIEVED: 16
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Two independent reviewers retrieved and evaluated studies using a validated tool for scoring the quality of the study. Meta-analysis was performed using Review Manager Software 5.0.
PHASE OF CARE: Active anti-tumor treatment
Lamivudine prophylaxis significantly reduced the risk of HBV reactivation in HBsAg seropositive patients (RR = 0.23, 95% CI [0.13, 0.39], p < 0.00001); the risk of hepatitis (RR = 0.2, 95% CI [0.08, 0.47], p =0.002); the rate of overall chemotherapy disruptions (RR = 0.36, 95% CI [0.21, 0.64], p = 0.0004); and the rate of delay of eight days or greater between cycles in those patients who completed chemotherapy (RR = 0.42, 95% CI [0.21, 0.82], p = 0.01).
Lamivudine 100 mg daily used as prophylaxis for HBsAg-seropositive patients undergoing chemotherapy significantly reduces the risk of hepatitis B reactivation and prevents chemotherapy delays.
Lamivudine 100 mg daily is recommend to prevent hepatitis B reactivation in patients who are HbsAg seropositive. There is no consensus on timing and duration of lamivudine prophylaxis. Some experts recommend lamivudine should be started at least one week before initiation and be continued until at least six weeks after the chemotherapy.
Wang, C.H., Kan, L.P., Lin, H.A., Chang, F.Y., Wang, N.C., Lin, T.Y., . . . Lin, J.C. (2016). Clinical efficacy and safety of primary antifungal prophylaxis with posaconazole versus fluconazole in allogeneic blood hematopoietic stem cell transplantation recipients: A retrospective analysis of a single medical center in Taiwan. Journal of Microbiology, Immunology, and Infection, 49, 531–538.
To determine the safety and efficacy of posaconazole versus fluconazole as antifungal prophylaxis in patients receiving allo-HSCT during early neutropenic phase without GVHD
Medical records were retrospectively reviewed for allo-HSCT recipients from a single institution, who received oral fluconazole (January 2005 to June 2011) or oral posaconazole (June 2011 to December 2013) during the early neutropenic stage.
PHASE OF CARE: Transition phase after active treatment
All patients who received allo-HSCT in the HSCT-dedicated room and were given prophylactic oral posaconazole (June 2011 to December 2013) or fluconazole (January 2005 to June 2011) were included. Exclusions were active infections, secondary fungal infections, or given an agent other than the two stated. Observation began seven days prior to transplantation and continued 90 days after transplantation.
Suspected invasive fungal infection was characterized as unexplained persistent fever that lasted 72-96 hours despite empiric broad spectrum antibiotics. Clinical and laboratory values were collected at baseline and throughout the study. ALT, AST, and total bilirubin were collected for hepatic toxicity. Incidence of neutropenic fever and overall mortality at 90 days post-transplantation was assessed.
Fluconazole had a greater risk for development of invasive fungal infections during the 90 days (42.5% versus 8.3%, p = 0.039) even at higher doses of fluconazole. Both groups had similar rates of neutropenic fevers (83.3% versus 87.5%, p = 0.656) and mortality (8.3% versus 22.5%, p = 0.04). Early discontinuation due to intolerance was lower in posaconazole than fluconazole (8.3% versus 50.0%, p = 0.017). Both had similar rates of GI upset, but fluconazole patients were more likely to have diarrhea. No patient discontinued either drug due to liver impairment, although both groups saw equally elevated laboratory values that normalized after discontinuation except for four patients (n = 1 posaconazole and n = 3 fluconazole).
Results concluded that implementing a prophylaxis regimen with posaconazole for preventing invasive fungal infections in allo-HSCT patients during the early neutropenic phase through 90 days post-transplantation was better tolerated with better efficacy and similar safety concerns when compared to fluconazole.
Small sample (< 100)
Nurses could incorporate evidence-based practices of hand hygiene, isolation, low microbial diets, teaching, and reinforcement plans for these fragile patients to work synonymously with the prophylaxis antifungal.
Mellinghoff, S.C., Panse, J., Alakel, N., Behre, G., Buchheidt, D., Christopeit, M., . . . Cornely, O.A. (2018). Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). Annals of Hematology, 97, 197–207.
PURPOSE: To provide evidence-based guidelines for the prevention of fungal infections
TYPES OF PATIENTS ADDRESSED: Adults with hematologic malignancies, particularly acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) receiving chemotherapy
RESOURCE TYPE: Evidence-based guideline
PROCESS OF DEVELOPMENT: Guideline was prepared by German clinical experts in hematology, oncology, stem cell transplantation, and infectious diseases. This was done by a stepwise consensus process. Data was extracted and tabulated; the preliminary recommendations were discussed and sent to a committee of authors. Once revised by the authors, there was a discussion by email and telephone conference. If the vote was not unanimous, the majority vote was adopted. The final version was approved by the AGIHO plenary session.
DATABASES USED: Not specifically described
INCLUSION CRITERIA: Clinical trials regarding antifungal prophylaxis in patients with hematologic malignancies
PHASE OF CARE: Active anti-tumor treatment
There were seven clinical trials since the 2014 edition of the recommendations that were included in the 2017 update. These trials included a total of 1,227 patients.
Allogeneic stem cell transplantation recommendations were removed from this guideline and placed in a separate guideline.
Recommended antifungal prophylaxis in patients with neutropenia (neutrophils less than 500 cells/mcl for more than seven days (summary of table 2):
Recommendations for dosages (from table 3):
Recommendation for therapeutic drug monitoring (table 4):
The guidelines are limited to a very specific group of patients–those with hematologic malignancies that will have a low neutrophil count (less than 500 cells/mcl for more than 7 days)
There is strong support for the use of antifungal prophylaxis, but the cost and effectiveness of the antifungal agent must be taken into account. Know the common fungal infectious causes in the geographical area and choose the right drug according to the specific fungus that is thought to be most prominent. Education about fungal infections as well as prevalence in this population is critical.