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
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
Patients with neutropenia resulting from chemotherapy for hematological malignancies are at risk for considerable morbidity and mortality due to invasive fungal infections and should, thus, be treated with antifungal agents. Caspofungin has been one of the most common antifungal agents used for this purpose; its analogue micafungin may also be appropriate, but has not been tested as extensively. Accordingly, the authors of this article conducted a retrospective study to compare these two agents; the results contribute to the literature regarding the use of micafungin for the treatment of invasive fungal infections.
Invasive fungal infections are associated with morbidity and mortality in neutropenia secondary to hematological malignancies. Empirical antifungal agents are used to reduce their consequences. Caspofungin is the only echinocandin approved for this indication. Micafungin was compared with caspofungin for the treatment of patients with hematological malignancies and prolonged neutropenia.
A retrospective cohort study was conducted involving patients who had hematological malignancies with profound neutropenia for a minimum of 10 days, and received empirical micafungin or caspofungin for a minimum of five days, between April 2005 and November 2009. Successful outcome was based on a composite end point: survival for a minimum of seven days following antifungal cessation, successful treatment of baseline fungal infection, absence of adverse events and absence of breakthrough fungal infection. Fungal infections were defined according to revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC-MSG) criteria, with modification of the diagnostic imaging criteria.
Micafungin had similar overall success to caspofungin (60.4% [29 of 48] versus 57.3% [47 of 82], respectively; P=0.729). Survival was higher in the micafungin group compared with the caspofungin group (100% [48 of 48] versus 89% [73 of 82]; P=0.02). No baseline invasive fungal infections were identified in the micafungin group, compared with three proven infections treated successfully with caspofungin (3.7%; P=0.18). Three proven breakthrough infections were observed in the micafungin group (three of 48 [27.3%]) compared with none in the caspofungin group (zero of 82; P=0.02).
Micafungin has similar efficacy to caspofungin as empirical antifungal therapy in febrile neutropenic patients with hematological malignancies. Verification of these results in a prospective trial is warranted.
Echinocandins; Fungal; Infection; Leukemia; Neutropenia
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.
Chemotherapy with platinum agent and etoposide for small-cell lung cancer (SCLC) is supposed to be associated with intermediate risk (10–20%) of febrile neutropenia. Primary prophylaxis with granulocyte colony-stimulating factors (G-CSFs) is not routinely recommended by the treatment guidelines. However, in clinical practice febrile neutropenia is often observed with standard etoposide/platinum regimen. The aim of this analysis was to evaluate the frequency of neutropenia and febrile neutropenia in advanced SCLC patients in the first cycle of standard chemotherapy. Furthermore, we explored the association between severe neutropenia and etoposide peak plasma levels in the same patients.
The case series based analysis of 17 patients with advanced SCLC treated with standard platinum/etoposide chemotherapy, already included in the pharmacokinetics study with etoposide, was performed. Grade 3/4 neutropenia and febrile neutropenia, observed after the first cycle are reported. The neutrophil counts were determined on day one of the second cycle unless symptoms potentially related to neutropenia occurred. Adverse events were classified according to Common Toxicity Criteria 4.0. Additionally, association between severe neutropenia and etoposide peak plasma concentrations, which were measured in the scope of pharmacokinetic study, was explored.
Two out of 17 patients received primary GCS-F prophylaxis. In 15 patient who did not receive primary prophylaxis the rates of both grade 3/4 neutropenia and febrile neutropenia were high (8/15 (53.3%) and 2/15 (13.3%), respectively), already in the first cycle of chemotherapy. One patient died due to febrile neutropenia related pneumonia. Neutropenic events are assumed to be related to increased etoposide plasma concentrations after a standard etoposide and cisplatin dose. While the mean etoposide peak plasma concentration in the first cycle of chemotherapy was 17.6 mg/l, the highest levels of 27.07 and 27.49 mg/l were determined in two patients with febrile neutropenia.
Our study indicates that there is a need to reduce the risk of neutropenic events in chemotherapy treated advanced SCLC, starting in the first cycle. Mandatory use of primary G-CSF prophylaxis might be considered. Alternatively, use of improved risk models for identification of patients with increased risk for neutropenia and individualization of primary prophylaxis based on not only clinical characteristics but also on etoposide plasma concentration measurement, could be a new, promising options that deserves further evaluation.
small cell lung cancer; platinum-etoposide chemotherapy; etoposide; febrile neutropenia; plasma drug concentration
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
This study sought to evaluate factors associated with hospital length of stay in cancer patients with febrile neutropenia.
A prospective cohort study was performed at a single tertiary referral hospital in southern Brazil from October 2009 to August 2011. All adult cancer patients with febrile neutropenia admitted to the hematology ward were evaluated. Stepwise random-effects negative binomial regression was performed to identify risk factors for prolonged length of hospital stay.
In total, 307 cases of febrile neutropenia were evaluated. The overall median length of hospital stay was 16 days (interquartile range 18 days). According to multiple negative binomial regression analysis, hematologic neoplasms (P = 0.003), high-dose chemotherapy regimens (P<0.001), duration of neutropenia (P<0.001), and bloodstream infection involving Gram-negative multi-drug-resistant bacteria (P = 0.003) were positively associated with prolonged hospital length of stay in patients with febrile neutropenia. The condition index showed no evidence of multi-collinearity effect among the independent variables.
Hematologic neoplasms, high-dose chemotherapy regimens, prolonged periods of neutropenia, and bloodstream infection with Gram-negative multi-drug-resistant bacteria are predictors of prolonged length hospital of stay among adult cancer patients with febrile neutropenia.
Prophylaxis with granulocyte colony-stimulating factor (G-CSF) reduces the severity of chemotherapy-induced neutropenia. Biosimilar G-CSF is now approved for use, based on comparable efficacy, safety and quality with the originator product.
We conducted a retrospective review of patients’ charts following the switch from originator G-CSF (Neupogen®) to biosimilar G-CSF (Zarzio®/Filgrastim Hexal®) in a large community oncology practice. A total of 77 consecutive patients with cancer who received biosimilar G-CSF were reviewed, as were 25 patients who received originator G-CSF at the same centre.
The median age of patients in the biosimilar G-CSF cohort was 67 years (range 20−83). In this cohort 48% had chemotherapy with a febrile neutropenia risk of >20%. Biosimilar G-CSF was given as primary prophylaxis in 52% and as secondary prophylaxis in 48% of patients. Age and febrile neutropenia in medical history or in previous chemotherapy were factors that triggered the use of G-CSF in patients with a febrile neutropenia risk of <20%. One patient developed febrile neutropenia. Neutropenia led to chemotherapy dose reductions in five patients (6.5%) and discontinuation in two patients (2.5%). No unexpected safety findings were observed. Patient characteristics were generally similar in the originator G-CSF cohort. Only 24% of patients had a febrile neutropenia risk >20% and 36% received primary prophylactic G-CSF. One patient developed febrile neutropenia. Neutropenia led to chemotherapy dose reductions in two patients (8%) and discontinuation in two patients (8%).
Biosimilar G-CSF was effective and prevented dose reductions/discontinuation in the majority of patients. Biosimilar G-CSF was considered clinically comparable to its reference product.
biosimilars; chemotherapy; granulocyte colony-stimulating factor; 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
Chemotherapy effectiveness in clinical practice may differ from the efficacy demonstrated in clinical trials, particularly among populations underrepresented in clinical trials, such as elderly patients with cancer. This review suggests that without other reasons for withholding treatment, elderly patients with stage III colon cancer should receive chemotherapy as often as nonelderly patients.
CME Learning Objectives
Describe evidence of differential treatment response of chemotherapy in elderly versus nonelderly stage III colon cancer patients.Synthesize differences in evidence of effectiveness and safety of chemotherapy between elderly and nonelderly stage III colon cancer patients to inform patient decision making and physician prescribing practices.
Chemotherapy effectiveness in clinical practice may differ from the efficacy demonstrated in clinical trials, particularly among populations underrepresented in clinical trials, such as elderly patients with cancer. This review aims to examine the relative effectiveness of chemotherapy for stage III colon cancer in elderly versus nonelderly patients.
A systematic literature review was conducted using the Agency for Healthcare Research and Quality approach. Literature searches were performed in Medline and Evidence-Based Medicine Reviews databases. Chemotherapy regimens approved for stage III colon cancer were reviewed. Four effectiveness and 15 safety outcomes were extracted.
From 708 identified articles, 25 articles provided data on the relative effectiveness and safety of chemotherapy among elderly versus nonelderly patients. Four of 14 studies showed lower overall survival treatment effects, whereas one of five and one of four studies indicated more favorable treatment effects for time to progression and overall response rate. Grade 3 or 4 adverse events were higher among elderly patients for cardiac disorder (2/5 studies), leukopenia (1/5), neutropenia (4/16), thrombocytopenia (2/13), febrile neutropenia (1/4), infection (2/10), dehydration (2/6), diarrhea (6/20), and fatigue (6/13). Grade 3 or 4 adverse events were lower for neutropenia (2/16 studies), nausea/vomiting (1/16), and neuropathy (1/9).
The majority of the evidence suggests that chemotherapy has similar relative effectiveness and safety for patients >65 years of age versus younger patients with stage III colon cancer. When differences are reported, treatment effects are more often worse among the elderly. This review suggests that without other reasons for withholding treatment, elderly patients should receive chemotherapy as often as nonelderly patients.
Colorectal neoplasms; Aged; Drug therapy; Comparative effectiveness research; Treatment outcome
LÓPEZ-POUSA A., RIFÀ J., CASAS DE TEJERINA A., GONZÁLEZ-LARRIBA J.L., IGLESIAS C., GASQUET J.A. & CARRATO A. (2010) European Journal of Cancer Care Risk assessment model for first-cycle chemotherapy-induced neutropenia in patients with solid tumours
Chemotherapy-induced neutropenia, the major dose-limiting toxicity of chemotherapy, is directly associated with concomitant morbidity, mortality and health-care costs. The use of prophylactic granulocyte colony-stimulating factors may reduce the incidence and duration of chemotherapy-induced neutropenia, and is recommended in high-risk patients. The objective of this study was to develop a model to predict first-cycle chemotherapy-induced neutropenia (defined as neutropenia grade ≥3, with or without body temperature ≥38°C) in patients with solid tumours. A total of 1194 patients [56% women; mean age 58 ± 12 years; 94% Eastern Cooperative Oncology Group (ECOG) status ≤1] with solid tumours were included in a multi-centre non-interventional prospective cohort study. A predictive logistic regression model was developed. Several factors were found to influence chemotherapy-induced neutropenia. Higher ECOG status values increased toxicity (ECOG 2 vs. 0, P= 0.003; odds ratio 3.12), whereas baseline lymphocyte (P= 0.011; odds ratio 0.67) and neutrophil counts (P= 0.026; odds ratio 0.90) were inversely related to neutropenia occurrence. Sex and treatment intention also significantly influenced chemotherapy-induced neutropenia (P= 0.012). The sensitivity and specificity of the model were 63% and 67% respectively, and the positive and negative predictive values were 17% and 94% respectively. Once validated, this model should be a useful tool for clinical decision making.
solid tumours; neutropenia; predictive model
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.
Use of granulocyte colony-stimulating factor (g-csf) as primary prophylaxis against chemotherapy-induced neutropenia has significant cost implications. We examined use of g-csf for early-stage breast cancer patients at our centre. The study also examined the pattern of nurse-led patient teaching with respect to drug self-administration.
Patients who received g-csf between November 2009 and October 2010 were identified from pharmacy records. After consent had been obtained, electronic charts were examined to extract data on chemotherapy and use of g-csf. Patients were contacted by telephone to obtain information on the utilization of home-care nursing visits for g-csf administration.
The study analyzed 36 patients. Median age was 58 years (range: 31–78 years). Of the 36 patients, 30 (83%) had received adjuvant treatment, and 6 (17%), neoadjuvant treatment. Most patients (71%) received 10 days (range: 7–10 days) of filgrastim. Of the 36 patients, 29 (81%) received g-csf as primary prophylaxis. In 90% of those patients, primary prophylaxis commenced with the taxane component of treatment. Of the 36 patients, 7 (19%) received g-csf after neutropenia, including 2 who had febrile neutropenia. In 96% of the patients, injections were received at home with the help of a nurse; those patients were subsequently taught self-injection techniques. The median number of nursing visits was 2 (range: 1–3 visits). Most patients were satisfied with the home care and g-csf teaching they received.
Most of the g-csf used in breast cancer treatment during the study period was given for primary prophylaxis. A major reason for the decision to use g-csf appears to have been physician-perceived risk of febrile neutropenia. Delivery of g-csf by home-care nurses was well received by patients.
Growth factor; breast cancer; chemotherapy; neutropenia; febrile neutropenia; prophylaxis; drug administration
Anthracyclines and taxanes have historically constituted the backbone of chemotherapy regimens for patients with breast cancer positive for the human epidermal growth factor receptor 2 (her2). For a subset of patients who categorically refuse alopecia, or for those with a contraindication to those drugs, there is an urgent need to define alternative regimens. Here, we report our institutional experience with trastuzumab and vinorelbine (tv), a combination with good clinical activity and a good side effect profile for patients with her2-positive breast cancer.
In a retrospective analysis, outcomes data were extracted for patients receiving tv as their only chemotherapy in the non-metastatic setting at the Jewish General Hospital. For the most part, tv was administered weekly for 6 months, followed by trastuzumab for 6 months.
The analysis identified 46 patients (mean age: 64 years) who received tv between 2003 and 2012 (n = 36 adjuvant, n = 10 neoadjuvant). Of the patients in the adjuvant group, 81% had stage i disease. In the neoadjuvant group, 3 patients experienced a complete pathologic response. Only 1 patient experienced local recurrence after a short course (3 months) of adjuvant tv. Overall survival and breast cancer–specific survival were 94% and 98% respectively at a median 5 years of follow-up. Febrile neutropenia–induced sepsis resulted in the death of 1 patient with significant medical comorbidities; 2 other patients died of comorbidities unrelated to their cancer or treatment. Grades 3 or 4 adverse events included neutropenia (23%), febrile neutropenia (10%), fatigue (2%), and anemia (2%).
For patients with non-metastatic breast cancer refusing alopecia, or for patients who are not candidates for standard chemotherapy, tv is a reasonable alternative to standard adjuvant chemotherapy.
Breast cancer; small tumours; early breast cancer; her2-positivity; trastuzumab; Herceptin; vinorelbine; Navelbine
Febrile neutropenia is an important cause of mortality and morbidity in hematology–oncology patients undergoing chemotherapy. The management of febrile neutropenia is typically algorithm-driven. The aim of this study was to assess the results of a standardized protocol for the treatment of febrile neutropenia.
A retrospective cohort study (2011–2012) was conducted of patients with high-risk neutropenia in a hematology–oncology service.
Forty-four episodes of 17 patients with a median age of 48 years (range: 18–78 years) were included. The incidence of febrile neutropenia was 61.4%. The presence of febrile neutropenia was associated with both the duration and severity of neutropenia. Microbiological agents were isolated from different sources in 59.3% of the episodes with bacteremia isolated from blood being the most prevalent (81.3%). Multiple drug-resistant gram-negative bacilli were isolated in 62.5% of all microbiologically documented infections. Treatment of 63% of the episodes in which the initial treatment was piperacillin/tazobactam needed to be escalated to meropenem. The mortality rate due to febrile neutropenia episodes was 18.5%.
The high rate of gram-negative bacilli resistant to piperacillin/tazobactam (front-line antibiotics in our protocol) and the early need to escalate to carbapenems raises the question as to whether it is necessary to change the current protocol.
Neutropenia; Clinical protocols; Hematologic diseases; Gram-negative bacterial infections; Drug resistance, bacterial
Introduction: Bacteremia remains a major cause of life-threatening complications in patients receiving anticancer chemotherapy. The spectrum and susceptibility profiles of causative microorganisms differ with time and place. Data from Lebanon are scarce. We aim at evaluating the epidemiology of bacteremia in cancer patients in a university hospital in Lebanon, emphasizing antibiotic resistance and risk factors of multi-drug resistant organism (MDRO)-associated bacteremia.
Materials and Methods: This is a retrospective study of 75 episodes of bacteremia occurring in febrile neutropenic patients admitted to the hematology-oncology unit at Makassed General Hospital, Lebanon, from October 2009-January 2012. It corresponds to epidemiological data on bacteremia episodes in febrile neutropenic cancer patients including antimicrobial resistance and identification of risk factors associated with third generation cephalosporin resistance (3GCR) and MDRO-associated bacteremia.
Results: Out of 75 bacteremias, 42.7% were gram-positive (GP), and 57.3% were gram-negative (GN). GP bacteremias were mostly due to methicillin-resistant coagulase negative staphylococci (28% of total bacteremias and 66% of GP bacteremias). Among the GN bacteremias, Escherichia coli (22.7% of total, 39.5% of GN organisms) and Klebsiella pneumoniae(13.3% of total, 23.3% of GN organisms) were the most important causative agents. GN bacteremia due to 3GC sensitive (3GCS) bacteria represented 28% of total bacteremias, while 29% were due to 3GCR bacteria and 9% were due to carbapenem-resistant organisms. There was a significant correlation between bacteremia with MDRO and subsequent intubation, sepsis and mortality. Among potential risk factors, only broad spectrum antibiotic intake >4 days before bacteremia was found to be statistically significant for acquisition of 3GCR bacteria. Using carbapenems or piperacillin/tazobactam>4 days before bacteremia was significantly associated with the emergence of MDRO (p < 0.05).
Conclusion: Our findings have major implications for the management of febrile neutropenia, especially in breakthrough bacteremia and fever when patients are already on broadspectrum antibiotics. Emergence of resistance to 3GCs and, to a lesser extent, to carbapenems in GN isolates has to be considered seriously in our local guidelines for empiric treatment of febrile neutropenia, especially given that their occurrence was proven to be associated with poorer outcomes.
febrile neutropenia; bacteremia; 3GCR gram-negative bacteria; MDR gram-negative bacteria; Lebanon
Biosimilars are similar, but non-identical, versions of existing biological drugs for which patents have expired. Despite the rigorous approval process for biosimilars, concerns have been expressed about the efficacy and safety of these products in clinical practice. Biosimilars of filgrastim, based on the originator product Neupogen®, have been available since 2008 and are now in widespread clinical use in Europe and elsewhere. Three biosimilar G-CSFs have been approved based on a combination of physicochemical and biological protein characterisation, pharmacokinetic and pharmacodynamic assessment in healthy volunteers and efficacy and safety data in patients with cancer. To assess whether biosimilars are effective in the real-world clinical practice setting, a pooled analysis of five post-approval studies of biosimilar G-CSF (Zarzio®) that included 1,302 adult patients who received at least one cycle of chemotherapy with G-CSF support for the prevention of neutropenia was conducted. A total of 36 % of patients had a febrile neutropenia risk of >20 %, while 39.6 % had a risk of 10–20 % based on chemotherapy regimen. The occurrence of severe or febrile neutropenia was within the range of that observed in previous studies of originator G-CSF. In addition, the safety profile of Zarzio® was consistent with that reported for originator G-CSF and the known safety profile of G-CSF. Initial concerns about the use of biosimilars, at least with regard to biosimilar G-CSFs, appear to be unfounded. Adoption of cost-effective biosimilars should help reduce healthcare costs and improve patient access to biological treatments.
Biosimilar; Chemotherapy-induced neutropenia; Cost-effectiveness; Filgrastim; G-CSF
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
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 objective of this study was to establish the efficacy and safety of a new treatment regimen consisting of dose-dense cisplatin-based chemotherapy and radical surgery in children with high-risk hepatoblastoma.
SIOPEL-4 was a prospective single-arm feasibility study. Patients aged 18 years or younger with newly diagnosed hepatoblastoma with either metastatic disease, tumour in all liver segments, abdominal extrahepatic disease, major vascular invasion, low α fetoprotein, or tumour rupture were eligible. Treatment consisted of preoperative chemotherapy (cycles A1–A3: cisplatin 80 mg/m2 per day intravenous in 24 h on day 1; cisplatin 70 mg/m2 per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m2 per day intravenous in 24 h on days 8, 9, 36, 37, 57, and 58) followed by surgical removal of all remaining tumour lesions if feasible (including liver transplantation and metastasectomy, if needed). Patients whose tumour remained unresectable received additional preoperative chemotherapy (cycle B: doxorubicin 25 mg/m2 per day in 24 h on days 1–3 and 22–24, and carboplatin area under the curve [AUC] 10·6 mg/mL per min per day intravenous in 1 h on days 1 and 22) before surgery was attempted. After surgery, postoperative chemotherapy was given (cycle C: doxorubicin 20 mg/m2 per day in 24 h on days 1, 2, 22, 23, 43, and 44, and carboplatin AUC 6·6 mg/mL per min per day in 1 h on days 1, 22, and 43) to patients who did not receive cycle B. The primary endpoint was the proportion of patients with complete remission at the end of treatment. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00077389.
We report the final analysis of the trial. 62 eligible patients (39 with lung metastases) were included and analysed. 60 (98%, 95% CI 91–100) of 61 evaluable patients (one child underwent primary hepatectomy) had a partial response to preoperative chemotherapy. Complete resection of all tumour lesions was achieved in 46 patients (74%). At the end of therapy, 49 (79%, 95% CI 67–88) of 62 patients were in complete remission. With a median follow-up of 52 months, 3-year event-free survival was 76% (95% CI 65–87) and 3-year overall survival was 83% (73–93). 60 (97%) patients had grade 3–4 haematological toxicity (anaemia, neutropenia, or thrombocytopenia) and 44 (71%) had at least one episode of febrile neutropenia. Other main grade 3 or 4 toxicities were documented infections (17 patients, 27%), anorexia (22, 35%), and mucositis (seven, 11%). One child died of fungal infection in neutropenia. Moderate-to-severe ototoxicity was documented in 31 (50%) patients. 18 serious adverse events (including two deaths) reflecting the observed side-effects were reported in the trial (the most common was ototoxicity in five patients).
The SIOPEL-4 treatment regimen is feasible and efficacious for complete remission at the end of treatment for patients with high-risk hepatoblastoma.
Cancer Research UK and Cancer Research Switzerland/Oncosuisse.
Advanced pancreatic cancer confers poor prognosis and treatment advancement has been slow. Recent randomized clinical trials (RCTs) have demonstrated survival benefits for combination therapy compared to gemcitabine alone. However, the comparative benefits and harms of available combination chemotherapy treatments are not clear. We therefore conducted a systematic review and Bayesian network meta-analysis to assess the comparative safety and efficacy of chemotherapy regimens for the treatment of advanced pancreatic cancer.
MEDLINE, PubMed, EMBASE, Cochrane Central Registry of Clinical trials and abstracts from major scientific meetings were searched for RCTs published from 2002 to 2013. Key outcomes were overall survival (OS), progression free survival (PFS), and safety including grade 3–4 febrile neutropenia, neutropenia, vomiting, diarrhea, fatigue and sensory neuropathy. Bayesian network meta-analyses were conducted to calculate survival and safety outcomes using gemcitabine (GEM) as the reference comparator. Effect estimates and 95% credible intervals were calculated for each comparison. Mean ranks and the probability of being best were obtained for each treatment analyzed in the network meta-analysis.
The search identified 23 studies involving 19 different treatment regimens and 9,989 patients. FOLFIRINOX, GEM/cisplatin/epirubicin/5FU (PEFG), GEM/NAB-paclitaxel (NAB-P), GEM/erlotinib+/-bevacizumab, GEM/capecitabine, and GEM/oxaliplatin were associated with statistically significant improvements in OS and PFS relative to gemcitabine alone and several other treatments. They were amongst the top ranked for survival outcomes amongst other treatments included. No significant differences were found for other combination chemotherapy treatments. Effect estimates from indirect comparisons matched closely to estimates derived from pairwise comparisons. Overall, combination therapies had greater risk for evaluated grade 3–4 toxicities over gemcitabine alone.
In the absence of head-to-head comparisons, we performed a mixed-treatment analysis to achieve high-quality information on the effectiveness and safety of each treatment. This study suggests that some combination therapies may offer greater benefits in the treatment of advanced pancreatic cancer than others. To more fully elucidate the comparative benefits and harms of different combination chemotherapy regimens, rigorously conducted comparative studies, or network meta-analysis of patient-level data are required.
Advanced pancreatic cancer; Chemotherapy; Gemcitabine; Combination therapy; Randomized clinical trials; Systematic review; Network meta-analysis
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.
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
Integrated cancer systems have the potential to transform the current model of cancer care to one which is designed around the needs of the patient
Evidence suggests that better integrated delivery can improve quality and reduce the cost of healthcare, and ultimately improve health outcomes
Involvement of all the organisations involved in the cancer care pathway is essential for true integration to enhance quality
Commissioners and providers will be required to work more closely together to achieve effective integration of services and improved patient outcomes
This article explores the potential for integrated cancer systems to improve the quality of care and deliver cost efficiencies and improve outcomes for cancer patients. Currently, patients in the UK still have poorer survival rates than comparable countries such as Canada, Sweden, Norway and Australia. Improving the quality of cancer services is a key policy objective and cancer is a priority outcome measure in both the NHS and Public Health Outcomes Framework.
Evidence suggests that better integrated delivery has the potential to improve the quality and reduce the cost of healthcare, and ultimately improve health outcomes. One of the key themes from the Model of Care for Cancer Services1 was that cancer services should be commissioned along pathways and that provider networks should be established to deliver care. London has two integrated cancer systems; one covering north central and east London (London Cancer) and the other covering west and south London (London Cancer Alliance).
There a number of areas in cancer care that the current model of service provision has failed to adequately address and which have the potential to improve significantly though implementation of integrated services. These include improving early diagnosis, reducing inequalities in access to treatment and outcomes and maximising research and training across the system.
Important drivers for the integration of cancer services are strong clinical leadership, shared informatics systems, focusing on quality of services and improving patient experience. Emerging needs of integrated cancer in London are around strengthening the involvement of primary care, public health and the third sector; working to develop sufficient capacity and expertise in primary care and collaborating more closely with commissioners to develop integrated systems.
integrated health care systems; cancer; patient-centred care; health care costs; primary health care
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