Purpose of review
This review updates treatment of neutropenia from articles published from January 2008 through April 2009.
Chemotherapy-induced neutropenia occurs most commonly in the first cycle of treatment. Older patients, patients with multiple co-morbidities, and those receiving more myelotoxic drugs are prone to develop neutropenia and its complications. Current guidelines recommend use of the myeloid growth factors for the first cycle of chemotherapy for patients with more that a 20 % risk of febrile neutropenia. Meta-analysis from randomized trials shows that granulocyte colony-stimulating factor (G-CSF) prophylaxis is associated with patients receiving more intensive chemotherapy, having better survival, but also having a higher risk of secondary AML. Antibiotic remain the mainstay of treatment of febrile neutropenia and are increasingly used for prophylaxis in “low risk” patients. Diagnosis and treatment of other type of neutropenia is also steadily improving.
The myeloid growth factor G-CSF has radically changed our approach to the management of neutropenia. Antibiotics remain the mainstay of treatment of febrile neutropenia.
neutrophil; neutropenia; granulocyte colony-stimulating factor (G-CSF); chemotherapy-induced neutropenia
During the period of neutropenia induced by chemotherapy, patients have a high risk of infection. The use of antibiotic prophylaxis to reduce neutropenia-related complications in patients with cancer is still disputed. Recent meta-analysis and clinical trials demonstrated that antibiotic prophylaxis with quinolones reduces febrile episodes, bacterial infections and mortality in adult oncological patients with neutropenia induced by chemotherapy in acute leukaemia. In paediatric patients, the only randomized, double-blind, prospective study until now suggests that amoxicillin/clavulanate may represent an effective prophylactic treatment in reducing fever and infections in oncological children with neutropenia, with an efficacy that is statistically demonstrated only in patients with acute leukaemia. Considering the risk of resistances, antibiotic-prophylaxis should be used only in selected patients.
neutropenia; antibiotic; prophylaxis; cancer; fever.
Myelosuppressive chemotherapy can lead to dose-limiting febrile neutropenia. Prophylactic use of recombinant human G-CSF such as daily filgrastim and once-per-cycle pegfilgrastim may reduce the incidence of febrile neutropenia. This comparative study examined the effect of pegfilgrastim versus daily filgrastim on the risk of hospitalization.
This retrospective United States claims analysis utilized 2004–2009 data for filgrastim- and pegfilgrastim-treated patients receiving chemotherapy for non-Hodgkin’s lymphoma (NHL) or breast, lung, ovarian, or colorectal cancers. Cycles in which pegfilgrastim or filgrastim was administered within 5 days from initiation of chemotherapy (considered to represent prophylaxis) were pooled for analysis. Neutropenia-related hospitalization and other healthcare encounters were defined with a “narrow” criterion for claims with an ICD-9 code for neutropenia and with a “broad” criterion for claims with an ICD-9 code for neutropenia, fever, or infection. Odds ratios (OR) for hospitalization and 95% confidence intervals (CI) were estimated by generalized estimating equation (GEE) models and adjusted for patient, tumor, and treatment characteristics. Per-cycle healthcare utilization and costs were examined for cycles with pegfilgrastim or filgrastim prophylaxis.
We identified 3,535 patients receiving G-CSF prophylaxis, representing 12,056 chemotherapy cycles (11,683 pegfilgrastim, 373 filgrastim). The mean duration of filgrastim prophylaxis in the sample was 4.8 days. The mean duration of pegfilgrastim prophylaxis in the sample was 1.0 day, consistent with the recommended dosage of pegfilgrastim - a single injection once per chemotherapy cycle. Cycles with prophylactic pegfilgrastim were associated with a decreased risk of neutropenia-related hospitalization (narrow definition: OR = 0.43, 95% CI: 0.16–1.13; broad definition: OR = 0.38, 95% CI: 0.24–0.59) and all-cause hospitalization (OR = 0.50, 95% CI: 0.35–0.72) versus cycles with prophylactic filgrastim. For neutropenia-related utilization by setting of care, there were more ambulatory visits and hospitalizations per cycle associated with filgrastim prophylaxis than with pegfilgrastim prophylaxis. Mean per-cycle neutropenia-related costs were also higher with prophylactic filgrastim than with prophylactic pegfilgrastim.
In this comparative effectiveness study, pegfilgrastim prophylaxis was associated with a reduced risk of neutropenia-related or all-cause hospitalization relative to filgrastim prophylaxis.
Febrile neutropenia commonly complicates cancer chemotherapy. Outpatient treatment may reduce costs and improve patient comfort but risk progression of undetected medical problems.
Patients and Methods
By using our validated algorithm, we identified medically stable inpatients admitted for febrile neutropenia (neutrophils < 500/μL) after chemotherapy and randomly assigned them to continued inpatient antibiotic therapy or early discharge to receive identical antibiotic treatment at home. Our primary outcome was the occurrence of any serious medical complication, defined as evidence of medical instability requiring urgent medical attention.
We enrolled 117 patients with 121 febrile neutropenia episodes before study termination for poor accrual. We excluded five episodes as ineligible and three because of inadequate documentation of the study outcome. Treatment groups were clinically similar, but sociodemographic imbalances occurred because of block randomization. The median presenting absolute neutrophil count was 100/μL. Hematopoietic growth factors were used in 38% of episodes. The median neutropenia duration was 4 days (range, 1 to 15 days). Five outpatients were readmitted to the hospital. Major medical complications occurred in five episodes (8%) in the hospital arm and four (9%) in the home arm (95% CI for the difference, −10% to 13%; P = .56). No study patient died. Patient-reported quality of life was similar on both arms.
We found no evidence of adverse medical consequences from home care, despite a protocol designed to detect evidence of clinical deterioration. These results should reassure clinicians who elect to treat rigorously characterized low-risk patients with febrile neutropenia in suitable outpatient settings with appropriate surveillance for unexpected clinical deterioration.
Daily granulocyte colony-stimulating factors [(G-CSFs); e.g. filgrastim, lenograstim] are frequently used to reduce the duration of chemotherapy-induced neutropenia (CIN) and the incidence of febrile neutropenia (FN) in cancer patients. A pegylated formulation of filgrastim, pegfilgrastim, which is administered once per cycle, was introduced in Spain in 2003. LEARN was a multi-centre, retrospective, observational study in Spain comparing patterns of use of daily G-CSF and pegfilgrastim, and CIN-related outcomes in adults with non-myeloid malignancies receiving myelosuppressive chemotherapy. Outcome measures were the percentage of patients receiving G-CSF for primary prophylaxis versus secondary prophylaxis/treatment, duration of treatment with G-CSF and incidence of CIN-related complications. Medical records from consecutive patients with documented pegfilgrastim (n = 75) or daily G-CSF (n = 111) use during 2003 were included. The proportion of patients receiving primary or secondary prophylaxis was comparable between the pegfilgrastim (39 and 48% respectively) and daily G-CSF (40 and 48% respectively) groups. However, there was a trend towards less frequent use to treat a neutropenic event such as FN or neutropenia in the pegfilgrastim group (17 versus 30% with daily G-CSF). Chemotherapy-induced neutropenia-related complications were less frequent in patients receiving pegfilgrastim (e.g. FN 11 versus 24% with daily G-CSF). This is the first study to show the potential benefits of pegfilgrastim over daily G-CSF in Spanish clinical practice.
pegfilgrastim; G-CSF; pattern of use; neutropenia; febrile neutropenia
The use of granulocyte colony-stimulating factors to treat patients with chemotherapy-induced neutropenia is well accepted. To assess whether administration of filgrastim along with standard empiric antibiotic therapy is beneficial for patients with chemotherapy-induced febrile neutropenia (FN), we conducted an open, non-randomized clinical trial.
Materials and Methods:
This was a prospective, open, Phase IV clinical trial in patients receiving chemotherapy for histologically confirmed cancer, with an oral temperature of >38.2°C and absolute neutrophil count (ANC) of <500/mm 3. Filgrastim was administered subcutaneously in a dose of 5 mcg/kg/day, 24 hours after administration of cytotoxic therapy, for up to two weeks or until the ANC reached 10,000 cells/mm 3. The parameters of assessment included duration of neutropenia, fever, hospitalization and antibiotic usage.
All 24 evaluable patients recovered from neutropenia, fever and FN in a median duration of two days. This result is similar to that reported in earlier studies with filgrastim. Despite the acceleration in recovery from neutropenia and fever, it also reduced the duration of hospital stay and usage of intravenous (IV) antibiotic. Only two adverse events were reported, which were of mild nature.
Filgrastim, when used in patients with chemotherapy-induced neutropenia, exhibited efficacy in accelerating the recovery from neutropenia and fever comparable to that reported with filgrastim in literature. The data from this study suggest that filgrastim is effective in the treatment of chemotherapy-induced neutropenia and is well tolerated by Indian patients.
Febrile neutropenia; filgrastim; granulocyte colony-stimulating factor
To study the antimicrobial management of cancer patients with chemotherapy-induced neutropenia by Canadian physicians.
A cohort of 274 cancer patients with severe neutropenia (ie, less than 0.5×109 neutrophils/L) who participated in a prospective double-blind, placebo controlled study on antifungal prophylaxis conducted in 14 Canadian university-affiliated centres. Antifungal prophylaxis (oral fluconazole 400 mg daily) was administered to 153 of 274 (56%) patients.
Antibacterial prophylaxis with a quinolone was given to 87 patients (32%) at the onset of chemotherapy whereas trimethoprim/sulphamethoxazole was given to 56 (20%) patients. Fever (ie, 38°C or over) occurred in 216 (79%) patients after a median duration of neutropenia of four days (range one to 31 days). Empirical antibacterial antibiotics were administered in 214 febrile patients. In 164 (77%) patients antibiotics were started during the first 24 h of fever. Monotherapy with a third generation cephalosporin and duotherapy with a antipseudomonal beta-lactam and an aminoglycoside were prescribed in 69 (32%) and 61 (28%) of the febrile patients, respectively. Inclusion of vancomycin in the initial empirical regimen was noted in 32 (15%) patients. Modifications of the initial regimen occurred in 187 (87%) patients after a median of five days (range one to 28 days). Empirical systemic amphotericin B was added after a median duration of nine days (range one to 34 days) of the empirical antibacterial regimen.
Overall, the antimicrobial management of cancer patients with chemotherapy-induced neutropenia by Canadian physicians follows the current guidelines promulgated by the Infectious Diseases Society of America.
Antimicrobial management; Cancer patients; Febrile neutropenia
Cancer, chemotherapy, and infections all together make changes in blood rheology and may affect the defense mechanisms by changing the thrombocyte function and endothelial cell. We have examined changes of blood rheology on plasma viscosity to put on probable following criteria for starting the treatment of febrile neutropenia immediately. A total of 27 postchemotherapy patients (16 males and 11 females) with febrile neutropenia diagnosed according to international guidelines have been included into the study. The plasma viscosity of the patients whose febrile neutropenia has been successfully treated was also measured to assess the impact of the duration of neutropenia on viscosity. The plasma viscosities of the patients were significantly higher during neutropenic episode than in nonneutropenic state (P = 0.006) except for alkaline phosphatase. All study parameters, particularly acute phase reactants, were statistically similar during both states. In the correlation of analysis with study parameters and stages, significant correlation was not observed between plasma viscosity alteration and leukocyte-neutrophil alteration, also other study parameters. We have demonstrated significantly elevated plasma viscosity in our patients during febrile neutropenic episode. Despite normal values of various parameters known to trigger plasma viscosity, particularly fibrinogen, it can be easily argued that the main mechanism may be the endothelial injury during infectious process and immune response mediated microcirculatory blood flow alterations.
Primary prophylaxis with granulocyte colony–stimulating factors (pp-g-csf) is recommended in patients undergoing chemotherapy carrying a febrile neutropenia (fn) risk of 20% or more. In the present study, we examined clinical practice patterns and the impact of pp-g-csf on fn incidence in women with early-stage breast cancer (ebc) treated with modern adjuvant chemotherapy (act).
This single-centre retrospective cohort study of women with ebc, who were identified from the pharmacy database and who received at least 1 cycle of modern act from January 2009 to December 2011, was conducted at the Cancer Centre of Southeastern Ontario. Data on patient demographics, pathology, stage distribution, chemotherapy, pp-g-csf use, dose reductions, chemotherapy delays, treatment discontinuation, relative dose intensity, and fn events were collected. Chi-square tests, t-tests, univariate and multivariate logistic regression analyses, and nonparametric Mann–Whitney U-tests were used for data analysis.
Of the 239 women eligible for analysis, 145 (61%) received pp-g-csf, and 50 (21%) developed at least 1 episode of fn. Use of pp-g-csf was associated with a significantly lower rate of fn (14% vs. 31%, p = 0.002) and trends to fewer dose delays (17% vs. 27%, p = 0.060) and dose reductions (19% vs. 25%, p = 0.28). Among women receiving pp-g-csf, higher fn rates were associated with an age of 65 years or older, taxane-based chemotherapy, and prophylaxis with filgrastim
Clinical practice patterns at our institution showed that more than 50% of ebc patients treated with modern act received pp-g-csf, which led to fewer fn episodes and increased delivery of planned act. The observed high fn risk despite pp-g-csf was linked to older age, taxane-based chemotherapy, and filgrastim.
Adjuvant chemotherapy; early-stage breast cancer; febrile neutropenia; filgrastim; pegfilgrastim; practice patterns; primary prophylaxis with granulocyte colony-stimulating factors
Neutropenia is a common adverse reaction of chemotherapy. We assessed whether chemotherapy-induced neutropenia could be a predictor of survival for patients with non-small-cell lung cancer (NSCLC).
A total of 387 chemotherapy-naïve patients who received chemotherapy (vinorelbine and gemcitabine followed by docetaxel, or paclitaxel and carboplatin) in a randomised controlled trial were evaluated. The proportional-hazards regression model was used to examine the effects of chemotherapy-induced neutropenia and tumour response on overall survival. Landmark analysis was used to lessen the bias of more severe neutropenia resulting from more treatment cycles allowed by longer survival, whereby patients who died within 126 days of starting chemotherapy were excluded.
The adjusted hazard ratios for patients with grade-1 to 2 neutropenia or grade-3 to 4 neutropenia compared with no neutropenia were 0.59 (95% confidence interval (CI), 0.36–0.97) and 0.71 (95% CI, 0.49–1.03), respectively. The hazard ratios did not differ significantly between the patients who developed neutropenia with stable disease (SD), and those who lacked neutropenia with partial response (PR).
Chemotherapy-induced neutropenia is a predictor of better survival for patients with advanced NSCLC. Prospective randomised trials of early-dose increases guided by chemotherapy-induced toxicities are warranted.
non-small-cell lung cancer; chemotherapy-induced neutropenia; overall survival; tumour response; landmark analysis
The article investigates the effects of MBL2 genotypes on irinotecan-induced febrile neutropenia in patients with solid tumors. Patients with high MBL2 promoter genotypes and haplotypes seemed more at risk for developing febrile neutropenia.
Mannose-binding lectin (MBL) is important in the innate immune response. MBL2 gene polymorphisms affect MBL expression, and genotypes yielding low MBL levels have been associated with an elevated risk for infections in hematological cancer patients undergoing chemotherapy. However, these reported associations are inconsistent, and data on patients with solid tumors are lacking. Here, we investigated the effects of MBL2 genotypes on irinotecan-induced febrile neutropenia in patients with solid tumors.
Patients and Methods.
Irinotecan-treated patients were genotyped for the MBL2 gene. Two promoter (−550 H/L and −221 X/Y) and three exon polymorphisms (52 A/D, 54 A/B, and 57 A/C) were determined, together with known risk factors for irinotecan-induced toxicity. Neutropenia and febrile neutropenia were recorded during the first course.
Of the 133 patients, 28% experienced severe neutropenia and 10% experienced febrile neutropenia. No associations were found between exon polymorphisms and febrile neutropenia. However, patients with the H/H promoter genotype, associated with high MBL levels, experienced significantly more febrile neutropenia than patients with the H/L and L/L genotypes (20% versus 13% versus 5%). Moreover, patients with the HYA haplotype encountered significantly more febrile neutropenia than patients without this high MBL-producing haplotype (16% versus 4%). In the subgroup with wild-type exon polymorphisms (A/A), patients with the high MBL promoter phenotype had the highest incidence of febrile neutropenia, regardless of known risk factors.
Patients with high MBL2 promoter genotypes and haplotypes seem more at risk for developing febrile neutropenia. If confirmed, these preliminary findings may contribute to more individualized approaches of irinotecan treatment.
Irinotecan; MBL; Polymorphisms; Genotypes; Toxicity; Febrile neutropenia
Chemotherapy-induced neutropenia is a major cause of morbidity and mortality. It frequently causes dose reductions or treatment delay, which can be prevented or treated by the administration of granulocyte-colony-stimulating factor (G-CSF). However, a better knowledge of the incidence, day of onset after therapy, and duration of neutropenia is essential to optimize the use of G-CSF.
Design and methods
Six hundred and ninety-four patients from a single institution, affected by lympho-proliferative diseases, were retrospectively reviewed for the occurrence of grade 4 neutropenia and febrile neutropenia (FN). Duration of neutropenia and time of neutrophil nadir were also retrieved. The diagnoses included non-Hodgkin's lymphoma, Hodgkin's lymphoma, and multiple myeloma. Chemotherapy regimens were obviously different according to the diagnosis, disease stage, and first or subsequent lines of therapy.
No patient received G-CSF as primary prophylaxis. Median nadir did not significantly differ among patients treated with first or successive lines of therapy. The incidence of grade 4 neutropenia and FN ranged from 0 to 94%, depending on the chemotherapy regimen. Patients receiving a first-line chemotherapy regimen had a significantly lower incidence of febrile grade 4 neutropenia compared to patients treated with a second or subsequent line of therapy. The duration of grade 4 neutropenia was significantly longer in patients given second or subsequent lines.
The results of this study could be useful to define the nadir onset in the hematologic setting in order to correctly tailor timing and duration of G-CSF prophylaxis and to assess the lowest fully effective dose.
Chemotherapy; G-CSF; Neutropenia; Non-Hodgkin's lymphoma; Hodgkin's lymphoma; Multiple myeloma
Hematologic toxicities of cancer chemotherapy are common and often limit the ability to provide treatment in a timely and dose-intensive manner. These limitations may be of utmost importance in the adjuvant and curative intent settings. Hematologic toxicities may result in febrile neutropenia, infections, fatigue, and bleeding, all of which may lead to additional complications and prolonged hospitalization. The older cancer patient and patients with significant comorbidities may be at highest risk of neutropenic complications. Colony-stimulating factors (csfs) such as filgrastim and pegfilgrastim can effectively attenuate most of the neutropenic consequences of chemotherapy, improve the ability to continue chemotherapy on the planned schedule, and minimize the risk of febrile neutropenia and infectious morbidity and mortality. The present consensus statement reviews the use of csfs in the management of neutropenia in patients with cancer and sets out specific recommendations based on published international guidelines tailored to the specifics of the Canadian practice landscape. We review existing international guidelines, the indications for primary and secondary prophylaxis, the importance of maintaining dose intensity, and the use of csfs in leukemia, stem-cell transplantation, and radiotherapy. Specific disease-related recommendations are provided related to breast cancer, non-Hodgkin lymphoma, lung cancer, and gastrointestinal cancer. Finally, csf dosing and schedules, duration of therapy, and associated acute and potential chronic toxicities are examined.
Canadian recommendations; neutropenia; febrile neutropenia; supportive care; colony-stimulating factors; chemotherapy-induced neutropenia; safety
At Sunnybrook Health Sciences Centre in Toronto, Ontario, the recommended empiric regimen for febrile neutropenia has been cefazolin and tobramycin for at least 25 years. However, we had no objective data to reassure us that patient mortality had not increased over the past five years.
A retrospective chart review of 48 episodes occurring in 44 patients admitted for the treatment of febrile neutropenia secondary to chemotherapy in 2002, and initially managed with cefazolin and tobramycin was conducted. Prospective data from 48 episodes in 2007 had previously been collected. Patients who developed febrile neutropenia while in hospital were excluded. The primary objective of the present study was to compare the all-cause mortality in 2007 with that from 2002.
There were no statistically significant differences between the groups (P>0.05). All-cause mortality in 2007 was 8.3% (four of 48) compared with 10.4% (five of 48) in 2002 (P=1). All deaths occurred in patients considered to be at high risk according to the Talcott score.
Mortality has not increased in the past five years with the use of empiric cefazolin and tobramycin for the treatment of patients admitted with febrile neutropenia at Sunnybrook Health Sciences Centre. Rates are comparable with those reported in the literature for similar patients. The results of the present study provide reassurance that the regimen continues to be effective for lower-risk febrile neutropenic patients.
Cefazolin; Fever; Mortality; Neutropenia; Tobramycin
Nivestim™ (filgrastim) is a follow-on biologic agent licensed in the EU for the treatment of neutropenia and febrile neutropenia induced by myelosuppressive chemotherapy. Nivestim™ has been studied in phase 2 and 3 clinical trials where its efficacy and safety was found to be similar to its reference product, Neupogen®. Follow-on biologics continue to be scrutinised for safety. We present a design for two observational phase IV studies that are evaluating the safety profile of Nivestim™ for the prevention and treatment of febrile neutropenia (FN) in patients treated with cytotoxic chemotherapy in general clinical practice.
The NEXT (Tolérance de Nivestim chez les patiEnts traités par une chimiothérapie anticancéreuse cytotoXique en praTique courante) and VENICE (VErträglichkeit von NIvestim unter zytotoxischer Chemotherapie in der Behandlung malinger Erkrankungen) trials are multicentre, prospective, longitudinal, observational studies evaluating the safety profile of Nivestim™ in 'real-world’ clinical practice. Inclusion criteria include patients undergoing cytotoxic chemotherapy for malignancy and receiving Nivestim as primary or secondary prophylaxis (NEXT and VENICE), or as treatment for ongoing FN (NEXT only). In accordance with European Union pharmacovigilance guidelines, the primary objective is to evaluate the safety of Nivestim™ by gathering data on adverse events in all system organ classes. Secondary objectives include obtaining information on patient characteristics, efficacy of Nivestim™ therapy (including chemotherapy dose intensity), patterns of use of Nivestim™, and physician knowledge regarding filgrastim prescription and the reasons for choosing Nivestim™. Data will be gathered at three visits: 1. At the initial inclusion visit, 2. At a 1-month follow-up visit, and 3. At the end of chemotherapy.
Recruitment for VENICE commenced in July 2011 and in November 2011 for NEXT. VENICE completed recruitment in July 2013 with 407 patients, and NEXT in September 2013 with 2123 patients. Last patient, last visit for each study will be December 2013 and March 2014 respectively.
The NEXT and VENICE studies will provide long-term safety, efficacy and practice pattern data in patients receiving Nivestim™ to support myelosuppressive chemotherapy in real world clinical practice. These data will improve our understanding of the performance of Nivestim™ in patients encountered in the general patient population.
NEXT NCT01574235, VENICE NCT01627990
Granulocyte colony-stimulating factor; G-CSF; Filgrastim; Safety; Efficacy; Hospitalisation; Practice patterns; CD34; Chemotherapy; Neutropenia
BACKGROUND: Febrile neutropenia (FN) and myelosupression remain a challenging oncologic medical emergency and dose limiting toxicity associated with chemotherapy for cancers. Various factors are known to affect the outcomes for patients diagnosed with FN. Electrolyte abnormalities have commonly been observed, but the real incidence and their impact has been only scarcely studied in literature.
METHODS: This was a prospective, observational study. A total of two hundred and fifteen (215) patients admitted between January 2007 and August 2008 were included. Analysis of data was made using SPSS version16.0.Toxicity profile was graded according to CTC version 3.0.
RESULTS: Almost equal number of FN was observed in both solid tumors and hematological cancers with almost equal gender distribution. Of all 83.5% patients demonstrated some electrolyte abnormalities. All grades combined, hypokalemia was seen in 48% of patients, with 51.4% having grade I, 33.3% grade III and 15.2% G IV (life threatening) hypokalemia. Hyponatremia of all grades was seen in 67.9% patients, of them 60.3% had Grade I, 33.3% grade III and 0.7% patients had grade IV hyponatremia. Hypomagnesaemia (70 patients assessed) was seen in 54.3% patient, 94.7% having grade I decline. Average length of stay for patients who received IV electrolyte replacement was 6.3 days compared to 4.9 days in those who did not. Out of 90 patients who required special care unit 75 had electrolyte abnormalities, of 15 patients who expired 13 had electrolyte abnormalities
CONCLUSION: This analysis, which is first of its kind, suggests that decline in electrolyte levels is frequently observed in patients presenting with FN. These abnormalities can have independent negative impact on the outcome for such patients. Special attention should be paid to electrolyte imbalance right from the outset.
Febrile Neutropenia; Myelosupression; Baseline Electrolyte Abnormalities
Fever during neutropenia may be a symptom of severe life threatening infection, which must be treated immediately with antibiotics. If signs of infection persist, therapy must be modified. Diagnostic measures should not delay treatment. If the risk of febrile neutropenia after chemotherapy is ≥20%, then prophylactic therapy with G-CSF is standard of care. After protocols with a risk of febrile neutropenia of 10–20%, G-CSF is necessary, in patients older than 65 years or with severe comorbidity, open wounds, reduced general condition. Anemia in cancer patients must be diagnosed carefully, even preoperatively. Transfusions of red blood cells are indicated in Hb levels below 7–8 g/dl. Erythropoiesis stimulating agents (ESA) are recommended after chemotherapy only when hemoglobin levels are below 11 g/dl. The Hb-level must not be increased above 12 g/dl. Anemia with functional iron deficiency (transferrin saturation <20%) should be treated with intravenous iron, as oral iron is ineffective being not absorbed. Nausea or emesis following chemotherapy can be classified as minimal, low, moderate and high. The antiemetic prophylaxis should be escalated accordingly. In chemotherapy with low emetogenic potential steroids are sufficient, in the moderate level 5-HT3 receptor antagonists (setrons) are added, and in the highest level Aprepitant as third drug.
neutropenia; febrile neutropenia; documented infection; antibiotic therapy; G-CSF; anemia; erythropoiesis stimulating agents; nausea and emesis after chemotherapy; diarrhea
Febrile neutropenia is common in children with cancer and can also occur outside of the oncology setting. The present article provides an overview of febrile neutropenia from the general paediatric perspective.
In cancer patients, the principles of febrile neutropenia management have remained relatively constant. For neutropenic children with cancer, empirical antibiotics should be initiated at the onset of fever. There is insufficient evidence at this point to recommend exclusively outpatient management of the child with cancer-related febrile neutropenia.
Far less is known about febrile neutropenia in the noncancer setting. The approach to this condition should be influenced by the underlying condition and its associated risk of invasive infection and serious outcome in the absence of hospitalization and empirical antibiotic therapy.
Cancer; Children; Empirical antibiotics; Febrile neutropenia
In newly diagnosed patients with Hodgkin lymphoma (HL) the effect of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD)-related neutropenia on chemotherapy delivery is poorly documented. The aim of this analysis was to assess the impact of chemotherapy-induced neutropenia (CIN) on ABVD chemotherapy delivery in HL patients.
Data from two similarly designed, prospective, observational studies conducted in the US and the EU were analysed. One hundred and fifteen HL patients who started a new course of ABVD during 2002-2005 were included. The primary objective was to document the effect of neutropenic complications on delivery of ABVD chemotherapy in HL patients. Secondary objectives were to investigate the incidence of CIN and febrile neutropenia (FN) and to compare US and EU practice with ABVD therapy in HL. Pooled data were analysed to explore univariate associations with neutropenic events.
Chemotherapy delivery was suboptimal (with a relative dose intensity ≤ 85%) in 18-22% of patients. The incidence of grade 4 CIN in cycles 1-4 was lower in US patients (US 24% vs. EU 32%). Patients in both the US and the EU experienced similar rates of FN across cycles 1-4 (US 12% vs. EU 11%). Use of primary colony-stimulating factor (CSF) prophylaxis and of any CSF was more common in the US than the EU (37% vs. 4% and 78% vs. 38%, respectively). The relative risk (RR) of dose delays was 1.54 (95% confidence interval [CI] 1.08-2.23, p = 0.036) for patients with vs. without grade 4 CIN and the RR of grade 4 CIN was 0.35 (95% CI 0.12-1.06, p = 0.046) for patients with vs. without primary CSF prophylaxis.
In this population of HL patients, CIN was frequent and FN occurrence clinically relevant. Chemotherapy delivery was suboptimal. CSF prophylaxis appeared to reduce CIN rates.
The use of quinolone prophylaxis in high-risk neutropenic patients is considered standard of care but the development of resistance is a concern. Previous studies have focused mainly on quinolone resistance among patients receiving prophylaxis, with very few data reporting its impact on the hospital microbial epidemiology.
We analyzed a cohort of 329 episodes of chemotherapy-induced neutropenia in adults, and compared two periods: 2005 (period 1, no prophylaxis, n=110) and 2006-2008 (period 2, ciprofloxacin prophylaxis, n=219). Outcomes analyzed were the frequency of febrile neutropenia, bacteremia, duration of antibiotic therapy and hospitalization, and antimicrobial resistance to ciprofloxacin and extended-spectrum beta-lactamase [ESBL] production. We analyzed resistance rates (by patients-day) in the cohort, as well as in other patients (neutropenic and non-neutropenic, 11,975 patients-day) admitted to the hematology unit in the same period, taking into consideration the general resistance patterns in the hospital.
Quinolone prophylaxis (period 2) resulted in fewer episodes of febrile neutropenia (159/219 [73%] vs. 102/110 [93%], Chi-square 18.09, p = 0.00002), and bacteremia (49/219  vs. 36/110 [33%], Chi-square 4.10, p = 0.04), shorter duration of antibiotic therapy (p = 0.0002) and hospitalization (p = 0.002), but more frequent use of carbapenems (79/219 [36%] vs. 15/110 [14%], Chi-square 18.06, p = 0.0002). In addition, period 2 was associated with higher rates of quinolone resistance (6.77 vs. 3.02 per 1,000 patients-day, p = 0.03). The rate of ESBL-producing enterobacteria in the two periods was slightly higher in patients receiving quinolone prophylaxis (1.27 vs. 0.38 per 1,000 patients-day, p = 0.26) as well as in the hematology unit overall (1.59 vs. 0.53 per 1,000 patients-day, p = 0.08), but remained stable in the whole hospital (0.53 vs. 0.56 per 1,000 patients-day, p = 0.74).
Ciprofloxacin prophylaxis was beneficial in high risk neutropenic patients, but important modifications in the prescription of carbapenems and on antimicrobial resistance patterns of isolates were observed. The importance of hospital or ward ecology must be taken into account when deciding for quinolone prophylaxis in high-risk neutropenic patients.
Neutropenia; Prophylaxis; Quinolone; Febrile neutropenia; Resistance
Myelosuppression that occurs during chemotherapy has been reported to be a predictor of better survival in patients with breast or lung carcinomas. We evaluated the prognostic implications of chemotherapy-induced neutropenia in advanced gastric carcinoma. Data from a prospective survey of oral fluoropyrimidine S-1 for advanced gastric cancer patients in Japan were reviewed. We identified 1055 untreated patients with adequate baseline bone marrow function. During treatment with S-1, a total of 293 (28%) patients experienced grade 1 or higher neutropenia. The adjusted hazard ratio of death for the presence of neutropenia, as compared with the absence of such toxicity, from a multivariate Cox model was 0.72 (95% confidence interval, 0.54–0.95; P=0.0189) for grade 1 neutropenia, 0.63 (0.50–0.78; P<0.0001) for grade 2 neutropenia and 0.71 (0.51–0.98; P=0.0388) for grade 3–4 neutropenia. These findings suggest that the occurrence of neutropenia during chemotherapy is an independent predictor of increased survival in patients with advanced gastric cancer, whereas the absence of such toxicity indicates that the dosages of drugs are not pharmacologically adequate. Monitoring of neutropenia in patients who receive chemotherapy may contribute to improved drug efficacy and favourable survival.
gastric cancer; S-1; neutropenia; prognosis; time-dependent variable
Infection is the main treatment-related cause of mortality in cancer patients. Rapid and accurate diagnosis to facilitate specific therapy of febrile neutropenia is therefore urgently warranted. Here, we evaluated a commercial PCR-based kit to detect the DNA of 20 different pathogens (SeptiFast) in the setting of febrile neutropenia after chemotherapy. Seven hundred eighty-four serum samples of 119 febrile neutropenic episodes (FNEs) in 70 patients with hematological malignancies were analyzed and compared with clinical, microbiological, and biochemical findings. In the antibiotic-naïve setting, bacteremia was diagnosed in 34 FNEs and 11 of them yielded the same result in the PCR. Seventy-three FNEs were negative in both systems, leading to an overall agreement in 84 of 119 FNEs (71%). During antibiotic therapy, positivity in blood culture occurred only in 3% of cases, but the PCR yielded a positive result in 15% of cases. In six cases the PCR during antibiotic treatment detected a new pathogen repetitively; this was accompanied by a significant rise in procalcitonin levels, suggestive of a true detection of infection. All patients with probable invasive fungal infection (IFI; n = 3) according to the standards of the European Organization for Research and Treatment of Cancer had a positive PCR result for Aspergillus fumigatus; in contrast there was only one positive result for Aspergillus fumigatus in an episode without signs and symptoms of IFI. Our results demonstrate that the SeptiFast kit cannot replace blood cultures in the diagnostic workup of FNEs. However, it might be helpful in situations where blood cultures remain negative (e.g., during antimicrobial therapy or in IFI).
AIMS—To evaluate the
pharmacokinetics of once daily (OD) gentamicin and its effectiveness as
part of an OD regimen for the empirical treatment of febrile
neutropenia in children with cancer.
aged 6 months to 16 years (mean (SD) 5.7 (4) years) with febrile
neutropenia (neutrophil count < 0.5 × 109/l) after chemotherapy.
METHODS—Over one year,
113 febrile neutropenic episodes were treated empirically with an OD
antibiotic regimen of ceftriaxone (80 mg/kg; maximum 4 g) and
gentamicin (7 mg/kg; infused over 60 minutes, no maximum). The
patients were assessed after 48hours.
RESULTS—86 of the 113 episodes settled with the first line antibiotic regimen. In 29 episodes, blood cultures identified a causative bacterial pathogen; for
17 of these, the first line antibiotic regimen was adequate; in four
episodes, although the episode settled, ceftriaxone was replaced by a
more appropriate antibiotic and OD gentamicin was continued; in the
remaining eight episodes, a glycopeptide antibiotic was deemed
necessary. There was no failure of treatment in organisms sensitive to
gentamicin, including Pseudomonas aeruginosa. In 27 episodes (24%),
resolution was obtained by the empirical introduction of a second line
regimen of ceftazidime and a glycopeptide antibiotic, and/or
amphotericin. Gentamicin concentrations were measured in 110 episodes
and they were all below the 24 hour line indicating that there was no
need to change the dosing interval. In two episodes
(2%), serum creatinine rose transiently by more
than 50% of the baseline concentration. Although there was no
vestibular toxicity, three of 30 children who underwent pure tone
audiometry reported high frequency hearing loss in one ear.
gentamicin can be used safely and effectively to treat febrile
neutropenia in children with cancer. When used for a short period
(< 5 days), in children not receiving other nephrotoxic drugs and who
have normal serum creatinine, serum gentamicin estimations are unnecessary.
The efficacy and toxicity of teicoplanin and vancomycin in the initial empirical antibiotic regimen in febrile, neutropenic patients with hematologic malignancies were compared in a prospective, randomized, unblinded, multicenter trial in the setting of 29 hematologic units in tertiary-care or university hospitals. A total of 635 consecutive febrile patients with hematologic malignancies and chemotherapy-induced neutropenia were randomly assigned to receive intravenously amikacin plus ceftazidime plus either teicoplanin at 6 mg/kg of body weight once daily or vancomycin at 1 g twice daily. An efficacy analysis was done for 527 evaluable patients: 275 treated with teicoplanin and 252 treated with vancomycin. Overall, successful outcomes were recorded for 78% of patients who received teicoplanin and 75% of those who were randomized to vancomycin (difference, 3%; 95% confidence interval [CI], -10 to 4%; P = 0.33). A total of 102 patients presented with primary, single-agent, gram-positive bacteremia. Coagulase-negative staphylococci accounted for 42%, Staphylococcus aureus accounted for 27%, and streptococci accounted for 21% of all gram-positive blood isolates. The overall responses to therapy of gram-positive bacteremias were 92 and 87% for teicoplanin and vancomycin, respectively (difference, 5%; CI, -17 to 6%; P = 0.22). Side effects, mainly represented by skin rash, occurred in 3.2 and 8% of teicoplanin- and vancomycin-treated patients, respectively (difference, -4.8%; CI, 0.7 to 8%; P = 0.03); the rate of nephrotoxicity was 1.4 and 0.8% for the teicoplanin and vancomycin groups, respectively (difference, 0.6%; CI, -2 to 1%; P = 0.68). Further infections were caused by gram-positive organisms in two patients (0.7%) treated with teicoplanin and one patient (0.4%) who received vancomycin (difference, 0.3%; CI, -0.9 to 1.0%; P = 0.53). Overall mortalities were 8.5 and 11% for teicoplanin- and vancomycin-treated patients, respectively (difference, -2.5%; CI, - 2 to 7%; P = 0.43); death was caused by primary gram-positive infections in three patients (1%) in each treatment group. When used for initial empirical antibiotic therapy in febrile, neutropenic patients, teicoplanin was at least as efficacious as vancomycin, but it was associated with fewer side effects.
The aim of this study was to study clinical profile with bacterial spectrum and susceptibility patterns of pathogens in culture positive febrile neutropenic (FN) patients of hematological malignancies.
Materials and Methods:
We retrospectively reviewed the medical records of 23 hematological malignancy patients admitted with chemotherapy induced febrile neutropenia with culture positive results, at our institute between June 2011 and December 2011.
A total of 23 patients were studied 12 males and 11 females, with a median age of 35 years. Most common diagnosis was acute leukemia (78%) with the majority of patients developing febrile neutropenia during the induction phase of treatment. Most common presenting symptoms were fever, cough, dyspnea, and diarrhea. Primary site of infection was not found in 47% of patients while the rest had lung, gastro-intestinal and skin/soft-tissue infection. Overall 23 organisms were isolated during the study period, from blood (56%), sputum (46%), stool (23%), and nasal swab from one patient. Gram negative bacteria accounted for 78% of organisms while gram positive organisms accounted for 22% of the total isolates. The most common organisms were: Escherichia coli (43%), Staphylococcus aureus (22%), Pseudomonas aeruginosa (17.4%) and Klebsiella pneumonia (17.4%). Antibiotic sensitivity patterns of these bacteria were studied. Gram negative bacterial infections were associated with higher mortality (89%).
Induction phase of treatment in acute leukemia is the major cause of FN in hematological malignancies at our institute and gram negative organisms are the predominant organisms with E. coli as major isolate while S. aureus represents the most common gram positive organism. Amikacin and cefoperazone/sulbactum appears to be initial antibiotic appropriate to cover most gram negative pathogens while vancomycin to be added for suspected gram positive infections. FN represents a major cause of morbidity and mortality in hematological malignancy patients, high index of suspicion and early empirical antibiotics with supportive care are main interventions to reduce high mortality for these patients. Antibiotics should be modified according to culture sensitive report as soon as possible.
Antibiotics; febrile neutropenia; hematological malignancies