Prophylactic granulocyte colony-stimulating factor in patients receiving dose-intensive cancer chemotherapy: a meta-analysis

PURPOSE: Several studies have evaluated the efficacy of the recombinant colony-stimulating factors in reducing the severity and duration of neutropenia and the risk of infection associated with dose-intensive cancer chemotherapy. We performed a meta-analysis to define better the magnitude of this effect and to assess the generalizability of the results among different diseases and types of treatment. MATERIALS AND METHODS: We used electronic databases and citation lists to identify controlled clinical trials of the prophylactic efficacy of the colony-stimulating factors on neutropenic complications. We selected randomized trials of the use of recombinant colony-stimulating factors before the onset of fever or neutropenia following systemic chemotherapy for solid tumors or malignant lymphomas. RESULTS: We identified eight controlled trials (n = 1144 patients) of prophylactic colony-stimulating factors, including five trials of filgrastim (recombinant granulocyte colony-stimulating factors) and three studies of lenograstim (glycosylated granulocyte recombinant colony-stimulating factors). Five trials were double-blind and placebo-controlled; three included untreated controls. Use of recombinant colony-stimulating factors was associated with a reduced risk of febrile neutropenia (odds ratio [OR] = 0.38; 95% confidence interval [CI]: 0.29 to 0.49), documented infection (OR = 0.51; 95% CI: 0.36 to 0.73), and infection-related mortality (OR = 0.60; 95% CI: 0.30 to 1.22), but a greater risk of bone pain (OR = 2.9; 95% CI: 1.6 to 4.8). CONCLUSION: In this meta-analysis, recombinant colony-stimulating factors were effective in reducing the risk of febrile neutropenia and documented infection associated with several malignancies and dose-intensive treatment regimens.     

Neutrophil recovery in elderly breast cancer patients receiving adjuvant anthracycline-containing chemotherapy with pegfilgrastim support

Shortening duration of chemotherapy-induced neutropenia may reduce risk of infection and aid subsequent chemotherapy delivery. Cycle 1 neutrophil recovery was evaluated in 59 elderly women with breast cancer receiving adjuvant FEC100 (5-fluorouracil 500 mg/m², epirubicin 100 mg/m² and cyclophosphamide 500 mg/m²) and randomized to pegfilgrastim primary prophylaxis (PP) from cycle 1, or secondary prophylaxis (SP, i.e., subsequent to a neutropenic event [no G-CSF in cycle 1]). In cycle 1, grade 4 neutropenia occurred in 77% (PP; N = 30) and 72% (SP; N = 29). Duration of grade 3-4 neutropenia was shorter with pegfilgrastim than without. Mean absolute neutrophil count (ANC) recovered above 1.0 × 10⁹/L by day 9 (pegfilgrastim) versus days 16-18 (without). At last observation (≥day 14 ± 2), no PP patient had ANC <1.0 × 10⁹/L versus approximately 25% of those receiving no pegfilgrastim. In conclusion, cycle 1 pegfilgrastim improved recovery from severe neutropenia in elderly breast cancer patients receiving adjuvant FEC100.     

Early hospital discharge with oral antimicrobial therapy in patients with hematologic malignancies and low-risk febrile neutropenia

Although consensus exists relating criteria for the identification of low-risk patients with febrile neutropenia, no clear indication on how to manage these patients has been so far provided particularly in outpatients affected by hematologic malignancies. The feasibility and safety of early discharge was prospectively evaluated in 100 outpatients with hematologic malignancies and febrile neutropenia. A strategy considering the risk-index of the Multinational Association of Supportive Care in Cancer (MASCC) was applied. High-risk patients were entirely managed at hospital. Low-risk patients were early discharged if they were afebrile since 48 h and not on supportive therapy requiring hospitalization. Out of 90 low-risk episodes, in 69 instances (76.7%), patients were discharged after a median of 4 days and continued home therapy with oral cefixime (78%) or other antibiotics. Only five outpatients (7.2%) had fever recurrence. Twenty-one low-risk patients were not early discharged due to worsening conditions (three deaths), need of multiple daily dose therapy, or discharge refuse. No clinical characteristic was able to predict the eligibility for early discharge. The MASCC risk-index is a useful aid in the identification of high-risk febrile neutropenia needing whole in-hospital treatment. As for low-risk patients, hospitalization at least in the first days of fever is required. Cefixime could be included among the oral antibacterial drugs to be used in the outpatient treatment of adult patients with febrile neutropenia.     

Applying the Multinational Association for Supportive Care in Cancer risk scoring in predicting outcome of febrile neutropenia patients in a cohort of patients

The purpose of this study was to determine if the Multinational Association for Supportive Care in Cancer (MASCC) risk-index score is able to predict the outcome of febrile neutropenia in patients with underlying hematological malignancy and to look at the other possible predictors of outcome. A retrospective study of 116 episodes of febrile neutropenia in patients who were admitted to the hematology ward of a local medical center in Malaysia between January 1st 2004 and January 31st 2005. Patient characteristics and the MASCC score were compared with outcome. The MASCC score predicted the outcome of febrile neutropenic episodes with a positive predictive value of 82.9%, a sensitivity of 93%, and specificity of 67%. Other predictors of a favorable outcome were those patients who had lymphomas versus leukemias, duration of neutropenia of less than 7 days, low burden of illness characterized by the absence of an infective focus and absence of lower respiratory tract infection, a serum albumin of >25 g/l, and the absence of gram-negative bacteremia on univariate analysis but only serum albumin level, low burden of illness, and presence of respiratory infection were significantly associated with unfavorable outcome after multivariate analysis. The MASCC score is a useful predictor of outcome in patients with febrile neutropenia with underlying hematological malignancies. This scoring system may be adapted for use in local settings to guide the clinical management of patients with this condition.     

Compliance with a critical pathway for the management of febrile neutropenia and impact on clinical outcomes

Febrile neutropenia is associated with significant morbidity and mortality. Managing infectious in neutropenic patients remains a dynamic process, making necessary timely and efficient empirical antibiotic therapy. The implementation of critical pathways has been suggested as a strategy to improve clinical effectiveness. This study evaluated the compliance with an institutional critical pathway for the management of febrile neutropenia and the impact on clinical outcomes at Hospital de Clínicas de Porto Alegre, Brazil (HCPA). We performed a cohort study that prospectively included patients hospitalized from January 2004 to December 2005 and presented febrile neutropenia (190 episodes). Historical controls were selected from March 2001 to April 2003 (193 episodes) before the critical pathway was introduced. This study showed a low rate of full compliance (21.6%; 95% CI 15.7–27.5) with the critical pathway. In most cases, there was partial compliance (67.9%; 95% CI 61.3–74.5). Despite the moderate adherence observed, we recorded a decrease in in-hospital all-cause mortality in the sample studied after protocol implementation (from 24.4 to 14.4%; P = 0.017) and reduction in the length of use of cephalosporin and quinolones. In conclusion, implementation of a critical pathway seems to be an effective strategy to improve clinical outcomes in patients hospitalized with febrile neutropenia. Financial support: FIPE/HCPA (Fundo de Incentivo à Pesquisa).     

Analysis of risk factors for central venous port failure in cancer patients

AIM： To analyze the risk factors for central port failure in cancer patients administered chemotherapy, using univariate and multivariate analyses. METHODS： A total of 1348 totally implantable venous access devices （TIVADs） were implanted into 1280 cancer patients in this cohort study. A Cox proportional hazard model was applied to analyze risk factors for failure of TIVADs. Log-rank test was used to compare actuarial survival rates. Infection, thrombosis, and surgical complication rates （Χ^2 test or Fisher＇s exact test） were compared in relation to the risk factors. RESULTS： Increasing age, male gender and open- ended catheter use were significant risk factors reducing survival of TIVADs as determined by univariate and multivariate analyses. Hematogenous malignancy decreased the survival time of TIVADs; this reduction was not statistically significant by univariate analysis [hazard ratio （HR） = 1.336, 95% CI： 0.966-1.849, P = 0.080）]. However, it became a significant risk factor by multivariate analysis （HR = 1.499, 95% CI： 1.079-2.083, P = 0.016） when correlated with variables of age, sex and catheter type. Close-ended （Groshong） catheters had a lower thrombosis rate than open-ended catheters （2.5% vs 5%, P = 0.015）. Hematogenous malignancy had higher infection rates than solid malignancy （10.5% vs 2.5%, P 〈 0.001）.CONCLUSION： Increasing age, male gender, open- ended catheters and hematogenous malignancy were risk factors for TIVAD failure. Close-ended catheters had lower thrombosis rates and hematogenous malig- nancy had higher infection rates.     

Early detection of chronic disseminated Candida infection in leukemia patients with febrile neutropenia: value of computer-assisted serial ultrasound documentation

 Computer tomography (CT) is known to be as sensitive as magnetic resonance imaging (MRI) in detecting fungal microabscesses in chronic disseminated candidiasis. However, all imaging techniques have to be repeated in cases of suspected fungal infection. Therefore, use of the CT or MRI scan is limited. Only ultrasound (US) examinations can be repeated as often as needed. The disadvantage of US is a lack of sufficient documentation. We analyzed the value of computer-assisted documentation in serial ultrasonography of leukemia patients with suspected chronic disseminated candidiasis. From November 1996 until October 1997, a total of 220 ultrasound examinations (Kranzbühler Logiq 500, 3.5 MHz convex array) were performed in 58 patients undergoing intensive chemotherapy. Initial US pictures were stored on a personal computer and compared with the live US at the time of reevaluation in cases of persistent fever. Ultrasound detected microabscesses in liver and/or spleen in eight of the 58 patients. Diagnosis was confirmed by autopsy/biopsy (n=6), blood culture (n=1), and a significant Candida antibody titer (n=1). Focal lesions occurred only after neutrophil recovery. However, a newly evolving nonhomogeneous, micronodular pattern of liver and spleen occurred during febrile neutropenia in three patients, and two of these developed focal lesions subsequently. Follow-up was easy, since US pictures could be compared directly with stored examinations on screen. We conclude that serial US is sensitive in detecting microabscesses in the liver or the spleen. Computer-assisted US documentation proved to be a helpful tool for detection as well as in the follow-up of patients with chronic disseminated candidiasis. Received: January 6, 1998 / Accepted: May 6, 1998     

Meta-analysis: combination of meropenem vs ceftazidime and amikacin for empirical treatment of cancer patients with febrile neutropenia

Background:Meropenem monotherapy vs ceftazidime plus amikacin have been approved for use against febrile neutropenia. To assess the effectiveness and safety of them for empirical treatment of cancer patients with febrile neutropenia, we conducted a meta-analysis of randomized controlled trial.Methods:Randomized controlled trials on ceftazidime plus amikacin, or/and monotherapy with meropenem for the treatment of cancer patients with febrile neutropenia were identified by searching Cochrane Library, PubMed, Science Direct, Wiley Online, Science Citation Index, Google (scholar), National Center for Biotechnology Information, and China National Knowledge Infrastructure. Data on interventions, participants’ characteristics and the outcomes of therapy, were extracted for statistical analysis. Seven trials fulfilled the inclusion criteria.Result:The treatment with ceftazidime plus amikacin was more effective than meropenem (OR = 1.17; 95% CI 0.93–1.46; 1270 participants). However, the treatment effects of the 2 therapy methods were almost parallel in adults (OR = 1.15; 95% CI 0.91–1.46; 1130 participants older than 16). Drug-related adverse effects afflicted more patients treated with ceftazidime plus amikacin (OR = 0.78; 95% CI 0.52–1.15; 1445 participants). The common responses were nausea, diarrhea, rash, and increased in serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase and bilirubin.Conclusion:Ceftazidime plus amikacin should be the first choice for empirical treatment of cancer patients with febrile neutropenia, and meropenem may be chosen as a last defense against pathogenic bacteria.     

Incidence of febrile neutropenia and neutropenic infections in elderly patients receiving anthracycline-based chemotherapy for breast cancer without primary prophylaxis with colony-stimulating factors

There is concern about the potential increase of hematological toxicity in elderly patients treated with chemotherapy. Recently, primary prophylaxis with colony-stimulating factors (CSFs) was proposed for elderly patients receiving moderately toxic chemotherapy. However, evidence for the benefits of this primary prophylaxis for elderly breast cancer patients is currently lacking. We retrospectively analyzed the incidence of febrile neutropenia (FN) and neutropenic infections in elderly breast cancer patients receiving anthracycline-based chemotherapy without primary prophylaxis with colony-stimulating factors. In addition, we assessed the direct costs of hospitalization for these complications. Febrile neutropenia or neutropenic infection occurred in 13% of the 46 patients. Further studies are needed to adequately evaluate the risk of neutropenic complications (NC) in elderly patients receiving standard-dose chemotherapy for breast cancer and the potential benefits of primary prophylaxis with colony-stimulating factors.     

Granulopoiesis in patients with congenital neutropenia

Granulopoiesis was investigated in five patients with congenital neutropenia (CN) (one Kostmann type, four benign forms). In semisolid agar culture, the marrow cells of all five patients produced normal numbers of CFU-c (colony-forming unit-culture). The size and classification of colonies were normal. In suspension culture in vitro with exogenous colony-stimulating factor (CSF) generated from omental-conditioned medium (OMCM), the myeloid precursors of all patients could proliferate and differentiate into normal polymorphonuclear neutrophils (PMNs). But in the absence of exogenous CSF, myeloid precursors of the patient with Kostmann-type CN did not proliferate or differentiate into PMNs at all. In the four patients with benign neutropenia, however, PMNs were found even without exogenous CSF similar to normal individuals. These results suggest that patients with CN may have normal granulopoietic stem cells with normal proliferative and differentiating capacity in response to exogenous CSF. When a small amount of normal human serum was added to normal marrow cultures stimulated by exogenous CSF, the colony growth increased in a superadditive manner. The enhancing activity of serum from neutropenic patients differed from that of normal serum. Especially, the addition of serum from the patient with Kostmann type CN to normal marrow cultures did not show this enhancement effect. The sera of patients with benign neutropenia had less enhancement effect than did normal control serum. These findings might be interpreted as showing an imbalance between CSF enhancer and inhibitors in the patients' serum.     

Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: A systematic review and meta-analysis

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Trends in bacterial infections in febrile neutropenic patients: 1986–1992

Abstract Background: Bacterial infection is a major cause of morbidity and mortality in neutropenic patients. Aims: (1) To review patterns and trends in bacterial infections in three cohorts of febrile neutropenic patients managed by a single unit over a seven year period. (2) To relate any changes to the use of central venous (Hickman's) catheters and high-dose cytosine arabinoside chemotherapy. Methods: Retrospective review of the results of initial bacteriological work-up performed on 344 episodes of febrile neutropenia. The three cohorts were 1986–87 (n= 102), 1989–90 (n= 92) and 1991–92 (n= 150). Results: (1) The ratio of gram-negative to gram-positive bacteraemias fell from 1.36 in the first cohort to 1.05 in the second and 0.40 in the third (p= 0.03). There was a fall in both percentage and number of gram-negative isolates coupled with a rise in the frequency of gram-positive isolates. (2) Coincidentally there was a rise in the frequency of positive cultures from Hickman catheter entry wounds and an increasing frequency of simultaneous isolation of the same organism from the catheter entry site and the blood. The types of organisms isolated from catheter entry wounds showed a trend towards fewer gram-negative and more gram-positive. (3) A relationship was observed between the use of high-dose cytosine arabinoside chemotherapy and the incidence of bacteraemia (p= 0.025) but not with the change in types of organisms. Conclusions: Over seven years we have documented a major change in the types of infections, particularly bacteraemias, seen in febrile neutropenic patients. In our institution the more widespread use of intravenous catheters and high-dose cytosine arabinoside chemotherapy have been identified as two possible contributing factors. (Aust NZ J Med 1994; 24: 374–377.)     

Clinical research in febrile neutropenia in cancer patients: Past achievements and perspectives for the future

Febrile neutropenia (FN) is responsible for significant morbidity and mortality. It can also be the reason for delaying or changing potentially effective treatments and generates substantial costs. It has been recognized for more than 50 years that empirical administration of broad spectrum antibiotics to patients with FN was associated with much improved outcomes; that has become a paradigm of management. Increase in the incidence of microorganisms resistant to many antibiotics represents a challenge for the empirical antimicrobial treatment and is a reason why antibiotics should not be used for the prevention of neutropenia. Prevention of neutropenia is best performed with the use of granulocyte colony-stimulating factors (G-CSFs). Prophylactic administration of G-CSFs significantly reduces the risk of developing FN and consequently the complications linked to that condition; moreover, the administration of G-CSF is associated with few complications, most of which are not severe. The most common reason for not using G-CSF as a prophylaxis of FN is the relatively high cost. If FN occurs, in spite of prophylaxis, empirical therapy with broad spectrum antibiotics is mandatory. However it should be adjusted to the risk of complications as established by reliable predictive instruments such as the Multinational Association for Supportive Care in Cancer. Patients predicted at a low level of risk of serious complications, can generally be treated with orally administered antibiotics and as out-patients. Patients with a high risk of complications should be hospitalized and treated intravenously. A short period of time between the onset of FN and beginning of empirical therapy is crucial in those patients. Persisting fever in spite of antimicrobial therapy in neutropenic patients requires a special diagnostic attention, since invasive fungal infection is a possible cause for it and might require the use of empirical antifungal therapy.     

Comparative efficacy and safety of antipseudomonal β-lactams for pediatric febrile neutropenia: A systematic review and Bayesian network meta-analysis

Background:Antipseudomonal β-lactams have been used for the treatment of febrile neutropenia (FN); however, the efficacy and safety of antipseudomonal β-lactams in pediatric patients remain unclear. The aim of this study was to comprehensively compare the efficacy and side effects of optional antipseudomonal β-lactams for pediatric FN.Methods:PubMed, Embase, Medline, and Cochrane Library were systematically searched from their inception to December 18, 2020. Eligible randomized controlled trials in which pediatric FN patients were treated with an empiric monotherapy of antipseudomonal β-lactams were selected. Data synthesis was performed using WinBUGS 14.0 software and meta packages implemented in R 3.6.2. Random-effects network meta-analysis was performed, and dichotomous data were pooled as odds ratios with 95% confidence intervals. The primary outcome was treatment success without modification; the secondary outcomes were adverse events (AEs), all-cause mortality, and new infections. The GRADE tool was used to assess the quality of the evidence. The protocol was registered with PROSPERO ID CRD42021226763.Results:Eighteen studies with 2517 patients were included. The results showed no statistically significant difference between the optional antipseudomonal β-lactams in the outcomes of treatment success without modification, all AEs, all-cause mortality, and new infections for pediatric FN. Based on the results of Bayesian rank probability, meropenem was ranked highest among all the treatment options with regard to treatment success without modification benefit; ceftazidime and meropenem were associated with a lower risk of AEs; cefoperazone/sulbactam and piperacillin/tazobactam were associated with a lower risk of mortality, and piperacillin/tazobactam and meropenem were associated with a lower risk of new infections. The quality of evidence was moderate.Conclusions:Meropenem and piperacillin/tazobactam were found to be better with regard to treatment success without modification, with a comparable safety profile. Therefore, our findings support the use of meropenem and piperacillin/tazobactam as a treatment option for pediatric FN patients.