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

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 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.

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 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

• N = 75 
• AGE: Mean = 58 years
• MALES: 40%  
• FEMALES: 60%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: AML, n = 68 patients; ALL, n = 2 patients; other, n = 5 patients (non-leukemic admitted for HSCT)
• OTHER KEY SAMPLE CHARACTERISTICS: 68% of patients with overweight BMI, 29% normal BMI, and 3% underweight BMI; reason for admission: 36 patients for induction; 15 for consolidation; 23 for neutropenia; 13 for HSCT; 11 patients had two admissions, 1 patient had three admissions, and 2 patients had four admissions

• SITE: Multi-site   
• SETTING TYPE: Inpatient    
• LOCATION: Tennessee

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

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

• Small sample (< 100)
• 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
• Selective outcomes reporting
• Key sample group differences that could influence results
• Findings not generalizable
• Questionable protocol fidelity
• Other limitations/explanation: Statistical data selectively reported, Fisher exact test indicates limited data set, number of doses not shown in comparison to the reported outcomes, no data shown on neutropenic nadir; GCSF dosing/outcome data was reported on the same patients with multiple admissions, but treated as separate admission data; no power analysis, no effect size reported, HSCT type not distinguished (allo or auto)

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.

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.

• FINAL NUMBER STUDIES INCLUDED: 6 
• TOTAL PATIENTS INCLUDED IN REVIEW: 499
• SAMPLE RANGE ACROSS STUDIES: 20-169
• KEY SAMPLE CHARACTERISTICS: Sample consisted of  Asian female patients with breast cancer who were hepatitis HBsAg seropositive and treated with 4-6 cycles of chemotherapy (AC, AC + T, or CAF).

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.

• Limited number of studies included
• Exclusively Asian population, which is a population that has a high prevalence of hepatitis B carriers
• Only 1 of the 6 studies was a RCT.

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.

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.

• N = 52   
• AGE: 2 younger than age 18 years; all others varied
• MALES: Not diversified  
• FEMALES: Not diversified
• CURRENT TREATMENT: Other
• KEY DISEASE CHARACTERISTICS: Allo-HSCT
• OTHER KEY SAMPLE CHARACTERISTICS: Fluconazole, posaconazole, prophylaxis, transplantation, GVHD

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

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.

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):

• Posaconazole is the level A recommendation (strongest level recommendation)
• Amphotericin B, liposomal, inhalation is a level B recommendations (moderate evidence to support a recommendation for use)
• IV amphotericin B and IV liposomal; caspofungin, fluconazole, itraconazole, intraconazole (IV), voriconazole, micafungin, and isavuconazole are all level C recommendations (poor evidence to support routine use)
• Amphotericin B deoxycholate is level D recommendation (supports a recommendation against use)

Recommendations for dosages (from table 3):

• Posaconazole, oral suspension – 200 mg three times per day
• Posaconazole, tablets – 300 mg daily (twice daily on day 1 only)
• Posaconazole, IV – 300 mg twice daily on day 1 only, then daily.
• Amphotericin B, liposomal, inhalation – 12.5 mg twice weekly
• Amphotericin B, liposomal, IV – 50 mg every 48 hours or 5 mg/kg twice weekly or 15 mg/kg single infusion (less supported)
• Caspofungin 50 mg daily (IV)
• Fluconazole – 400 mg daily
• Itraconazole, capsules – any dose
• Itraconazole, oral solution – 2.5–7.5 mg/kg per day or 200 mg
• Itraconazole, IV – 200 mg daily
• Voriconazole – 200 mg twice daily
• Amphotericin B deoxycholate – any dose
• Micafungin – 50 mg daily
• Isavuconazole – 200 mg daily (three times per day on days 1 and 2 only)

Recommendation for therapeutic drug monitoring (table 4):

• Voriconaozle – target level is 1-2 mg/L (level B)
• Posaconazole – target level is greater than 500 ng/mL (level C)

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.

STUDY PURPOSE: To compare the efficacy and safety of micafungin (MCFG) with triazoles for the prophylaxis and treatment of invasive fungal infections (IFIs) among patients with hematologic malignancies with neutropenia

TYPE OF STUDY: Meta analysis and systematic review

DATABASES USED: PubMed, Embase, Cochrane Central Register of Controlled Trials, and relevant database articles for RCTs

YEARS INCLUDED: (Overall for all databases) through November 2016

INCLUSION CRITERIA: Randomized controlled studies comparing MCFG to the use of triazoles in neutropenic fever. Inclusion criteria consisted of studies that compared efficacy or incidence of AEs in two comparable populations: received IV MCFG for antifungal prevention or treatment and FN defined as absolute neutrophil count less than 1,500/mcl. Search terms included micafungin, micafungin sodium, micamine, FK 463, Echinocandin, Lipopep- tides, antifungal agents, FN, and neutropenic fever

EXCLUSION CRITERIA: Studies that had incomplete data, included duplicate data, did not contain any predetermined clinical outcomes, or could not be pooled with other included studies

TOTAL REFERENCES RETRIEVED: 181

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: PRISMA checklist and a quality assessment of two reviewers following the Cochrane Collaboration Reviewers’ Handbook for Systematic Reviews of Interventions. Articles were scored form 0 (lowest quality level) to 7 (highest quality level) with 1 point given to each area addressed for randomization, concealment of allocation, blinding, reporting of withdrawals, selective reporting, and other bias. Disagreements of assessments were resolved through reviewer discussions.

• FINAL NUMBER STUDIES INCLUDED: 9
• TOTAL PATIENTS INCLUDED IN REVIEW: 2,008 (1,049 cases and 959 controls)
• SAMPLE RANGE ACROSS STUDIES: 70-882
• KEY SAMPLE CHARACTERISTICS: Patients with hematologic malignancies undergoing treatment with intensive chemotherapy or hematopoietic cell transplantation. Mean age ranged from 6.01 to 53 years old. Studies were conducted in China, Korea, Japan, Egypt, and the United States. MCFG dosage ranged from 1 mg/kg per day to 150 mg/day and FLCZ ranged from 8 mg/kg per day to 400 mg/day. Two studies compared MCFG and azoles for empiric treatment and seven for prophylaxis. Patients were followed from 28 days to 6 months.

PHASE OF CARE: Active anti-tumor treatment     

APPLICATIONS: Pediatrics

MCFG was found to have a better treatment success rate compared to triazoles (RR = 1.13; 95% CI [1.02, 1.25]; I² = 87%) in the pooled data for the absence of IFIs during and following treatment. The prophylactic model studies showed better success rates compared to triazoles (RR = 1.15; 95% CI [1.05, 1.25], I² = 69.1%), but no differences were found with the empiric model studies (RR = 1.04; 95% CI [0.67, 21.61], I² = 91%). A 20% RR was found for use of MCFG. MCFG also showed a lower incidence of infections compared to triazoles for rotation of anti-fungal agents in eight pooled trials (n = 1,901; RR = 0.66; 95% CI [0.47, 0.94]; I² = 71.5%). No difference was found between agents for overall mortality. MCFG had a significantly lower rate of premature discontinuation (p < 0.05) and a lower incidence of AEs for hepatic impairment (RR = 0.67; 95% CI [0.22–2.09]; I² = 67%), neurological complications (RR = 0.7; 95% CI [0.5–0.98]; I ² = 3.3%), and GI upset (RR = 0.62; 95% CI [20.42, 0.92]; I² = 0%). There was no publication bias. Heterogeneity was found with age group differences with analyses showing a stronger effect from MCFG in patients younger than age 45 years. Stratified analyses also showed better outcomes with MCFG.

MCFG was better than triazoles for efficacy and fewer AEs when used prophylactically and as effective as triazoles for the treatment of IFIs. MCFGs were also found to be more effective among patients younger than age 45 years. However, mortality was not lower in one group compared to the other.

High heterogeneity

Recommending the use of MCFG prophylactically can decrease the risk of IFIs and related adverse events among patients undergoing treatment for hematologic malignancies.

To examine the rate of probable and proven breakthrough invasive fungal infections (bIFI) with the use of itraconazole prophylaxis as well as the effectiveness and tolerability of itraconazole in patients with acute myeloid leukemia (AML)

All patients admitted to the Royal Prince Albert Hospital who had AML and were undergoing chemotherapy and who were receiving itraconazole for antifungal prophylaxis were given itraconazole 200 mg oral solution twice daily starting 1-2 days prior to the chemotherapy and continuing until the neutrophil count was greater than 500.

• N = 175 episodes total; 148 episodes of febrile neutropenia   
• AGE: Median age was 59 years (range = 44-65)
• MALES: 67.4%  
• FEMALES: 32.6%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: All have AML (primary 62.3%; secondary 9.7%; relapsed 17.1%; refractory 10.9%)
• OTHER KEY SAMPLE CHARACTERISTICS: Neutropenia for more than 7 days in 80.6%; for more than 14 days in 54.3%; median duration of neutropenia was 15 days; mucositis was present in 53.1%; total parenteral nutrition required in 7.4%; febrile neutropenia was present in 84.6%; bacterial infections were present in 60%; mycobacterial infections were present in 0.6%; viral infections were present in 4%; median length of stay was 27 days (range = 22-34).

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: Royal Prince Albert Hospital; Sydney Australia

PHASE OF CARE: Active anti-tumor treatment

Retrospective study

Onset of invasive fungal infection; this was determined three different ways:

1. Starting empiric antifungal therapy
2. High resolution CT that was thought to show invasive fungal infection (IFI)
3. Positive microbiology on biopsy by bronchoalveolar lavage.

bIFI were classified as possible, probable, or proven; a bIFI was one that was diagnosed at least five days after starting antifungal prophylaxis.

Itraconazole was shown to be tolerable with few side effects. CT scans were performed in 55 patients and a bronchoalveolar lavage (BAL) was performed in 20 episodes that were shown to be abnormal on CT scan. Four of those undergoing BAL had positive results constituting probable bIFI. Empiric antifungal therapy was started in 33 patients; there was no evidence of bIFI in 16 of those patients. These possible IFI infections were treated for a median of 19 days with no progression to definitive IFI. Overall bIFI rate was 3.4%. Patients with bIFI have significantly longer length of stays and higher 30-day mortality (11%).

The use of itraconazole is reasonable with low side effects and low rates of bIFI noted in this group. Account of local epidemiology must be considered when choosing an antifungal agent overall.

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Findings not generalizable
• Other limitations/explanation: Only patients with AML receiving chemotherapy

Cost of the intervention in some areas may be problematic. Nurses should work with their pharmacy colleagues to identify the most common fungal epidemiology before the choice of antifungal therapy is chosen. Education with patients is needed about the importance of taking the medications for prophylaxis to prevent bIFI.