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.

To compare the efficacy (measured via incidence of febrile neutropenia [FN]) of levofloxacin versus oral third-generation cephalosporins (OTGCs) given as antibacterial prophylaxis during chemotherapy-induced neutropenia in high-risk patients with hematological malignancies. The goal was to demonstrate non-inferiority of OTGCs as an alternate therapy if fluoroquinolones were contraindicated. Secondary outcomes measured the incidence of bacterial infection between prophylactic drugs and compared the specific microorganisms identified in positive cultures.

Following induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), high-risk patients were prescribed levofloxacin 500 mg daily as antibiotic prophylaxis if appropriate. Similar patients who could not take levofloxacin because of intolerance, allergy, drug interaction, or previous adverse drug reactions were prescribed OTGCs (either cefdinir 300 mg twice daily or cefpodoxime 200 mg twice daily). The duration of antibiotic therapy was not specified. Chart reviews began with the start of antibiotic prophylaxis and continued until the earliest of 30 days following the last dose of antibiotic prophylaxis, the beginning of consolidation chemotherapy administration, or death. The two groups were compared for incidence of FN and for the secondary outcomes.

• N: 120   
• AGE: Median = 58.6 years (range = 19-80)
• MALES: 65%  
• FEMALES: 35%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: AML and MDS
• OTHER KEY SAMPLE CHARACTERISTICS: N/A

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: Mayo Clinic, Rochester, MN

PHASE OF CARE: Active anti-tumor treatment

Retrospective chart review, matching patients by OTGCs versus levofloxacin in a 1:2 ratio. Matching factors were age (plus or minus 5 years) and the Charlson comorbidity index (plus or minus 3).

Using retrospective chart review, researchers compared the incidence of FN, time to onset of FN, duration of neutropenia, site of infection, morphology of recovered organisms, and resistance to prophylactic agent.

The incidence of FN within 30 days of initiation of antibiotic prophylaxis was 83.4% (95% CI [65.8, 91.9]) in the OTGC group and 92.5% (95% CI [83.8, 96.5]) in the levofloxacin group, and was similar between the two groups (HR = 0.9, 95% CI [0.54, 1.52], p = 0.7). The median duration of neutropenia was also similar between the two groups, with 46 days (IQR = 26-67 days) for OTGCs and 39 days (IQR = 27-49 days) for levofloxacin. Similarly, the duration of prophylaxis prior to the onset of FN was comparable between the two groups (8 days for OTGCs, IQR = 6-12 days; and 8.5 days for levofloxacin, IQR = 5-13.5 days). Patients receiving OTGCs were significantly more likely to require ICU admission than those receiving levofloxacin (p = 0.04). The two groups had no significant differences in site of infection (p = 0.91) and morphology of recovered microorganism (p = 0.74). The OTGC group experienced significantly more cultures positive for Enterobacter (p = 0.043) than the levofloxacin group.

Although antibiotic prophylaxis with levofloxacin demonstrated advantages over OTGCs in the areas of avoidance of ICU admission and avoidance of cultures positive for the Enterobacter microorganism, OTGCs offer an acceptable alternative for those patients in whom fluoroquinolones are contraindicated.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Other limitations/explanation: Data collected were from only the first episode of FN following antibiotic prophylaxis.

The positive culture site was an implanted central venous catheter in the majority of patients (61.5%). This reinforces the need for nurses to maintain meticulous hand hygiene and infection control practices when working with central venous catheters.

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.

To describe how safe and effective fluoroquinolone prophylaxis is for patients with a deficiency of enzyme G6PD who are undergoing treatment for hematologic malignancies

Study participants received prophylaxis with either levofloxacin (500 mg/qd) or ciprofloxacin (500 mg/bid) beginning with initial chemotherapy administration until absolute neutrophil count recovers to greater than 1,000. Participants also received prophylactic antifungal therapy (fluconazole, posaconazole, or voriconazole).

• N = 242   
• AGE: 18-75
• MALES: 57%  
• FEMALES: 43%
• CURRENT TREATMENT: Chemotherapy, other (HSCT conditioning regimens)
• KEY DISEASE CHARACTERISTICS: Acute leukemia, Hodgkin and non-Hodgkin lymphoma, multiple myeloma
• OTHER KEY SAMPLE CHARACTERISTICS: Hematopoietic stem cell transplantation: autologous (n = 106, 44%); allogeneic (n = 49, 20%)

• SITE: Not stated/unknown   
• SETTING TYPE: Not specified    
• LOCATION: Italy

PHASE OF CARE: Active anti-tumor treatment

Retrospective cohort study

Patients were identified as having G6PD deficiency based on enzyme activity testing using the G6PD/6PGD Automatic Analyzer (KUADRO), Nurex SRL. Study definitions of “infection” included:

• “Microbiological documented infection” – When infectious agent was identified by culture or biopsy
• “Clinical documented infection” – When infection was identified, but infectious agent was not identified. 

Febrile neutropenia was assigned only when it occurred during the patient’s first episode of neutropenia (absolute neutrophil count of 1,000 mm³ or less). However, authors did not include a definition of acute hemolytic anemia.

Overall, patients with G6PD deficiency had fewer cases of febrile neutropenia (p = 0.01; hazard ratio 0.46; 95% confidence interval [0.25, 0.8]). The subset of patients treated for AML with G6PD deficiency had a higher risk of invasive fungal diseases (p < 0.0001; HR 11.4; 95% CI [3.5, 37.05]) and sepsis due to Candida (p = 0.008; HR 37; 95% CI [2.01, 680.9]). However, incidence of bacterial infection between groups was not statistically significant. Incidence of febrile neutropenia was slightly less (p = 0.01) among study participants with G6PD deficiency. Evaluation of 3,904 red blood cell units administered to study participants identified zero cases of acute hemolytic anemia for all patients regardless of G6PD status.

Fluoroquinolone prophylaxis did not appear to increase risk of acute hemolytic anemia-based on G6PD enzyme status. Patients with G6PD deficiency may be at higher risk of fungal infection, but lower risk of febrile neutropenia during intensive chemotherapy to treat hematologic malignancies.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Selective outcomes reporting
• Other limitations/explanation: Molecular testing results for G6PD were not available. In addition, unclear that analysis of a single potential complication (incidence of acute hemolytic anemia) is sufficient to assess safety. Unclear that single institution, retrospective study is sufficient to assess efficacy.

There is no indication that fluoroquinolone prophylaxis is unsafe or ineffective at reducing the risk of febrile neutropenia, regardless of G6PD enzyme status. If G6PD testing results are available, nurses may need to consider their patients with G6PD deficiency at higher risk for invasive fungal infections while on fluoroquinolone prophylaxis.

STUDY PURPOSE: To assess whether the recommendation by the European Conference on Infections in Leukemia to use fluoroquinolone prophylaxis for patients with high-risk neutropenia has resulted in a reduction in infection and mortality. A secondary objective was to assess the effect of fluoroquinolone prophylaxis on antibiotic resistance.

TYPE OF STUDY: Meta analysis and systematic review

DATABASES USED: PubMed

YEARS INCLUDED: 2006-2014

INCLUSION CRITERIA: Article assessed fluoroquinolone prophylaxis among patients with high-risk neutropenia undergoing treatment for blood cancer or patients post-hematopoietic cell transplantation (HCT)

EXCLUSION CRITERIA: (a) No assessment of antibiotic prophylaxis; (b) unable to discern whether the research question was relevant; (c) antibiotic prophylaxis included a non-fluoroquinolone

TOTAL REFERENCES RETRIEVED: N = 68

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Multiple statistical methods were applied to evaluate the studies included in the review. In addition, community prevalence of fluoroquinolone resistance was evaluated based on study data included in the review and previous studies.

FINAL NUMBER STUDIES INCLUDED: 14 

TOTAL PATIENTS INCLUDED IN REVIEW: 5,930

SAMPLE RANGE ACROSS STUDIES: 45–1,981

KEY SAMPLE CHARACTERISTICS: Study populations included patients with acute leukemias, hematologic malignancies, or post-autologous or allogeneic HCT. Studies included years of observation from 1998–2012.

PHASE OF CARE: Active anti-tumor treatment

Of the 14 studies analyzed, 12 were observational and two were randomized controlled trials. Overall, the odds ratio with fluoroquinolone prophylaxis were:

• Overall mortality = 1.01; 95% confidence interval [0.73, 1.41]
• Bloodstream infections = 0.57; 95% CI [0.43, 0.74]
• Febrile neutropenia = 0.32; 95% CI [0.2, 0.5]

However, in the analysis of three meta-analyses, published since 2006, Gafter-Gvili et al. (2012) found a statistically significant decrease in overall mortality (2.8% versus 5.3%, p = 0.00012). The rate of infection caused by fluoroquinolone resistant bacteria was 4% for patients who received prophylaxis and for patients who did not receive prophylaxis. There is insufficient data to determine the role of fluoroquinolone prophylaxis on the appearance of new, resistant bacteria.

Fluoroquinolone prophylaxis did not reduce overall mortality for patients with high risk neutropenia. However, there is some evidence that it may reduce the rate of bloodstream infections and febrile neutropenia. Clinically, the impact of prophylaxis may be low since many patients still develop febrile neutropenia and other risks, including Clostridium difficile infection and fluoroquinolone toxicity, were not analyzed. However, since most international guidelines with the exception of Australia, recommend fluoroquinolone prophylaxis, and there is insufficient conclusive evidence to recommend otherwise, the overall recommendation is to follow institutional policies but seriously consider the risks and benefits of prophylaxis for each patient.

Most of the 14 studies included in the analysis (12) were observational.

In the absence of contraindication or risk of complication with prophylaxis, there is insufficient evidence to routinely omit fluoroquinolone prophylaxis. Consider the risks and benefits of fluoroquinolone prophylaxis for each patient individually. Recognize the clinical benefit for an individual may be minimal. Consider review and update to institutional policies accordingly.

To evaluate the safety and efficacy of oral levofloxacin in preventing febrile neutropenia (FN) in patients who have received consolidation chemotherapy for acute myeloid leukemia (AML)

Following consolidation chemotherapy with: (1) cytarabine 3 g/m² IV q 12 hours on days 1, 3, and 5; (2) fludarabine 30 mg/m² IV on days 1-5, and cytarabine 2 g/m² IV on days 1-5, with or without filgrastim 300-480 mcg SQ daily beginning on day 6 until neutrophil recovery; or (3) mitoxantrone 6 mg/m² IV on days 1-3 and cytarabine 2 g/m² IV q 12 hours on days 1-3 for cycle 1 and 1 g/m² for cycle 2; hematologists chose whether to prescribe levofloxacin or not. This retrospective chart review compared the levofloxacin group to the no levofloxacin group. The primary efficacy outcome compared rehospitalization rates between those who received levofloxacin and those who did not. Secondary outcomes assessed duration of antibiotic treatment needed for FN and compared rates of Clostridium difficile-associated diarrhea (CDAD) between the two groups.

• N = 100   
• AGE: 18 years or older, 31% were aged 60 years or older; mean = 51.2 years
• MALES: 50%  
• FEMALES: 50%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: AML

• SITE: Single site   
• SETTING TYPE: Not specified    
• LOCATION: London, Ontario, Canada

PHASE OF CARE: Transition phase after active treatment

Retrospective chart review of AML patients, 50 of whom had received levofloxacin following consolidation chemotherapy and 50 of whom had not.

To evaluate the primary outcome, researchers tracked the rate of hospital readmission because of FN. Secondary outcomes considered the total number of days of antibiotic therapy required to recover from FN and counted the number of days between hospital discharge after consolidation chemotherapy and readmission for FN. Safety outcomes compared the rate of CDAD between the levofloxacin and no levofloxacin groups within 30 days following hospital discharge following consolidation chemotherapy, the relative rates of positive blood cultures in FN patients, the relative rates of resistance to levofloxacin from positive bacterial cultures, and the impact of levofloxacin on the spectrum of bacteria identified from positive cultures.

Following the first cycle of consolidation chemotherapy, 42% of patients who received levofloxacin were readmitted for FN. The no levofloxacin group had a readmission rate of 72% (p = 0.002). Results following all cycles of consolidation chemotherapy were less dramatic but still demonstrated the benefit of levofloxacin therapy (51.4% readmission for FN in the levofloxacin group, compared to 67% in the no levofloxacin” group (p = 0.023). There were no significant differences between the two groups in terms of total number of antibiotic treatment days (median 11 versus 10, p = 0.639), mean day of readmission after discharge from receiving consolidation chemotherapy (11.58 versus 10.37, p = 0.205), and rate of positive bacterial culture in readmitted FN patients (28.9 versus 42.9, p = 0.148).

This study supports the previously-established Infectious Diseases Society of America and National Comprehensive Cancer Network guidelines for antibiotic prophylaxis for cancer patients at high risk of developing FN. Levofloxacin use had no significant impact on any of the secondary outcome measures.

• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Key sample group differences that could influence results
• Other limitations/explanation: The patients in this study received one of three different regimens of consolidation chemotherapy, but the study did not divide these patients into different arms. Furthermore, the dose and duration of levofloxacin therapy were not standardized.

This retrospective chart review did not separate the various consolidation chemotherapy regimens into separate arms. The authors searched until they found the intended sample size of patients who had received levofloxacin and those who had not. Of note, the levofloxacin dose and duration of fluoroquinolone therapy was not standardized.

STUDY PURPOSE: To compare the effectiveness and safety of antipseudomonal b-lactam empiric monotherapy for febrile neutropenia by network meta-analysis

TYPE OF STUDY: Meta analysis and systematic review

DATABASES USED: PubMed, Cochrane CENTRAL, EMBASE, and Web of Science Core Collection

YEARS INCLUDED: No year limitation

INCLUSION CRITERIA: Definition of febrile neutropenia was ANC less 500 mcl or less than 1,000 mcl and temperature greater than 38 C for more than one hour or temperature greater than 38.3 C. Patients in both arms had to be treated with IV antipseudomonal beta-lactam antibiotic for initial empiric therapy of febrile neutropenia. GCSF use was allowed.

EXCLUSION CRITERIA: Granulocyte transfusion was excluded. Antibiotics not evaluated in a RCT in the past 10 years (since 2006) were excluded.

TOTAL REFERENCES RETRIEVED: 1,275

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Evaluated quality of each study using 6 domains of the Cochrane risk of bias tool

FINAL NUMBER STUDIES INCLUDED: 50 studies

TOTAL PATIENTS INCLUDED IN REVIEW: 10,872 patients

KEY SAMPLE CHARACTERISTICS: Adult and pediatric febrile neutropenia patients undergoing chemotherapy for either solid tumors or hematologic malignancies.

PHASE OF CARE: Active anti-tumor treatment     

APPLICATIONS: Elder care

Treatment success without antibiotic modification was most likely with Cefoperazone/sulbactam followed by imipenem/cilastatin, piperacillin/tazobactam, meropenem, cefepime, cefozopran, ceftazidime and panipenem/betamipron. The risk for all-cause death was lowest in all-cause death were lowest in the imipenem/cilastatin arm and highest in the cefepime arm.

Imipenem/cilastatin followed by piperacillin/tazobactam and meropenem had the best performance in the treatment success without modification and all-cause death.

• Low sample sizes
• Inconsistent definitions of neutropenic fever and treatment success; only included studies of adult patients

Antipseudomonal antibiotics are effective for empiric treatment of febrile neutropenia and imipenem/cilastatin, piperacillin/tazobactam, and meropenem had the best performance in the treatment success without modification and all-cause death. This may be due to increasing incidence of extended spectrum beta lactamase-producing bacteria that are resistant to cefepime. However, cefepime is still recommended by major guidelines for initial use and remains a reasonable choice, particularly given the concern of antibiotic resistance using carbapenems as initial empiric therapy for febrile neutropenia.

The purpose of this study was to evaluate the effect of recombinant factor VIIa (rFVIIa) upon severe bleeding in patients with platelet transfusion refractoriness.

Patients in the intervention group received 60 ug/kg of recombinant factor VIIa intravenously, with or without conventional treatment. Those in the control group received only conventional treatment. Dosing of rFVIIa was dependent on clinical characteristics and response to treatment. Conventional treatments included transfusion of platelets, plasma, or cryoprecipitate, or medications such as hemocoagulase atrox or carbazochrome sodium sulfonate.

• N = 64   
• AGE: Mean age was 35 years.
• MALES: Not available  
• FEMALES: Not available 
• CURRENT TREATMENT: Other
• KEY DISEASE CHARACTERISTICS: Hematologic malignancies

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: University Hospital in Soochow, China

PHASE OF CARE: Active antitumor treatment

This was a controlled prospective study. Randomization was not stated.

Bleeding severity was graded according to criteria established by Nevo et al. (1999): 0 (no bleeding) to 4 (massive bleeding leading to hemodynamic compromise or bleeding into a vital organ). Major bleeding was graded according to criteria from the International Society on Thrombosis and Hemostasis.

Response rates to hemostatic treatment were significantly higher in the intervention group receiving rFVIIa at 24 hours (p = 0.014) and 48 hours (p = 0.020) when compared to the control group. Patients achieving a complete remission were also significantly higher in the intervention group at 24 hours (p = 0.031), 48 hours (p = 0.039), and 72 hours (p = 0.021). Bleeding score and time to control bleeding were significantly reduced in the intervention group (p = 0.029 and p = 0.034).

Administration of rfVIIa was significantly more likely to lead to control of bleeding and decreased time to control bleeding in patients with hematologic malignancies with severe thrombocytopenia, who were refractory to platelet transfusions. In addition, patients receiving rFVIIa were significantly more likely to have a complete remission than those who did not receive rFVIIa.

• Small sample (< 100)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Other limitations/explanation: There were no standard number of doses received or threshold when given, except for clinical assessment (median number was 3, range was 1-15).

The administration of rFVIIa may be considered an effective adjunct to conventional therapy to reduce bleeding in patients with hematologic malignancies who are refractory to platelet transfusions, along with use of HLA-matched or cross-matched platelets, to improve outcomes.

The purpose of this study was to evaluate the effect of a protein pump inhibitor on tumor bleeding prevention in patients with advanced gastric cancer. The primary endpoint was tumor bleeding; secondary endpoints were the number of transfusions received and overall survival.

Patients with inoperable gastric cancer were randomized into one of two groups, with stratification based on hemoglobin level. The study group received lansoprazole 30 mg PO every day. The control group received placebo. Bleeding rates were assessed at 4 months and at a median follow up of 6.4 months. Bleeding was assessed by blood counts every three weeks.

• N = 127   
• AGE: Median is 56 years.
• MALES: 78.7%  
• FEMALES: 21.3%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Unresectable gastric cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Age ≥ 18 years, ECOG 0-2

• SITE: Multisite   
• SETTING TYPE: Outpatient    
• LOCATION: Korea

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

Prospective, randomized, double-blind, placebo controlled trial

Bleeding events were defined as the presence of witnessed melena or hematemesis, decrease in hemoglobin by greater than 2 g/dL in one week, or > 3 g/dL in three weeks, with endoscopic evidence of bleeding. Endoscopic bleeds were graded per Forrest classification. Gray’s test and the Fine-Gray regression model were used to evaluate time to tumor bleeding events and the effect of lansoprazole upon bleeding.

There was no significant difference in tumor bleeding between the two groups.

Lansoprazole did not have a preventive effect on tumor bleeding in patients with inoperable gastric cancer, nor was there a difference in the number of transfusions required. The lansoprazole group did have a significantly reduced number of tumor bleeding events compared with placebo, until the four-month mark. At that point forward, the difference became statistically insignificant. This may be related to disease progression and increased tumor burden during palliative chemotherapy treatment.

• Unintended interventions or applicable interventions not described that would influence results
• Other limitations or explanation: The study was underpowered for the primary outcome. Patients were receiving first- or second-line chemotherapy during the study. The study planned to enroll 394 patients but ended because of a low recruitment rate. The study did not look at various dosing options of lansoprazole. Many patients were lost to follow up. Median follow-up duration was brief. The placebo group included more patients who received second-line chemotherapy.

The risk of tumor bleeding in patients with inoperable gastric cancer is not decreased with 30 mg of lansoprazole daily, nor did it decrease the requirement for transfusions.