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1.  Pegfilgrastim prophylaxis is associated with a lower risk of hospitalization of cancer patients than filgrastim prophylaxis: a retrospective United States claims analysis of granulocyte colony-stimulating factors (G-CSF) 
BMC Cancer  2013;13:11.
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.
PMCID: PMC3559272  PMID: 23298389
2.  Effects of Mannose-Binding Lectin Polymorphisms on Irinotecan-Induced Febrile Neutropenia 
The Oncologist  2010;15(10):1063-1072.
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.
PMCID: PMC3227891  PMID: 20930093
Irinotecan; MBL; Polymorphisms; Genotypes; Toxicity; Febrile neutropenia
3.  Factors Associated with Hospital Length of Stay among Cancer Patients with Febrile Neutropenia 
PLoS ONE  2014;9(10):e108969.
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.
PMCID: PMC4186788  PMID: 25285790
4.  Granulocyte colony-stimulating factor (filgrastim) in chemotherapy-induced 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.
PMCID: PMC3009438  PMID: 21206712
Febrile neutropenia; filgrastim; granulocyte colony-stimulating factor
5.  Micafungin compared with caspofungin for the treatment of febrile episodes in neutropenic patients with hematological malignancies: A retrospective study 
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.
PMCID: PMC4277157  PMID: 25587291
Echinocandins; Fungal; Infection; Leukemia; Neutropenia
6.  Relative Effectiveness and Safety of Chemotherapy in Elderly and Nonelderly Patients With Stage III Colon Cancer: A Systematic Review 
The Oncologist  2013;18(1):54-63.
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.
PMCID: PMC3556257  PMID: 23299774
Colorectal neoplasms; Aged; Drug therapy; Comparative effectiveness research; Treatment outcome
7.  Safety of Early Discharge for Low-Risk Patients With Febrile Neutropenia: A Multicenter Randomized Controlled Trial 
Journal of Clinical Oncology  2011;29(30):3977-3983.
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.
PMCID: PMC3675706  PMID: 21931024
8.  Use and delivery of granulocyte colony–stimulating factor in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy—single-centre experience 
Current Oncology  2012;19(4):e239-e243.
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.
PMCID: PMC3410835  PMID: 22876152
Growth factor; breast cancer; chemotherapy; neutropenia; febrile neutropenia; prophylaxis; drug administration
9.  Advances in the Treatment of Neutropenia 
Purpose of review
This review updates treatment of neutropenia from articles published from January 2008 through April 2009.
Recent findings
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.
PMCID: PMC3390973  PMID: 19550332
neutrophil; neutropenia; granulocyte colony-stimulating factor (G-CSF); chemotherapy-induced neutropenia
10.  A non-interventional study of biosimilar granulocyte colony-stimulating factor as prophylaxis for chemotherapy-induced neutropenia in a community oncology centre 
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.
PMCID: PMC3481562  PMID: 23118804
biosimilars; chemotherapy; granulocyte colony-stimulating factor; neutropenia
11.  Neutropenia and G-CSF in lymphoproliferative diseases 
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.
PMCID: PMC3648783  PMID: 23321273
Chemotherapy; G-CSF; Neutropenia; Non-Hodgkin's lymphoma; Hodgkin's lymphoma; Multiple myeloma
12.  Chemotherapy regimens for advanced pancreatic cancer: a systematic review and network meta-analysis 
BMC Cancer  2014;14:471.
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.
PMCID: PMC4097092  PMID: 24972449
Advanced pancreatic cancer; Chemotherapy; Gemcitabine; Combination therapy; Randomized clinical trials; Systematic review; Network meta-analysis
13.  Antimicrobial regimens prescribed by Canadian physicians for chemotherapy-induced febrile neutropenic episodes 
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.
PMCID: PMC3250710  PMID: 22346394
Antimicrobial management; Cancer patients; Febrile neutropenia
14.  The trastuzumab and vinorelbine combination: an alternative to taxane-based chemotherapy for early-stage and locally advanced her2-positive breast cancer 
Current Oncology  2014;21(5):e723-e727.
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.
PMCID: PMC4189578  PMID: 25301539
Breast cancer; small tumours; early breast cancer; her2-positivity; trastuzumab; Herceptin; vinorelbine; Navelbine
15.  Results of high-risk neutropenia therapy of hematology–oncology patients in a university hospital in Uruguay 
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.
PMCID: PMC4318844  PMID: 25638764
Neutropenia; Clinical protocols; Hematologic diseases; Gram-negative bacterial infections; Drug resistance, bacterial
16.  Bacterial infection profiles in lung cancer patients with febrile neutropenia 
BMC Infectious Diseases  2011;11:183.
The chemotherapy used to treat lung cancer causes febrile neutropenia in 10 to 40% of patients. Although most episodes are of undetermined origin, an infectious etiology can be suspected in 30% of cases. In view of the scarcity of data on lung cancer patients with febrile neutropenia, we performed a retrospective study of the microbiological characteristics of cases recorded in three medical centers in the Picardy region of northern France.
We analyzed the medical records of lung cancer patients with neutropenia (neutrophil count < 500/mm3) and fever (temperature > 38.3°C).
The study included 87 lung cancer patients with febrile neutropenia (mean age: 64.2). Two thirds of the patients had metastases and half had poor performance status. Thirty-three of the 87 cases were microbiologically documented. Gram-negative bacteria (mainly enterobacteriaceae from the urinary and digestive tracts) were identified in 59% of these cases. Staphylococcus species (mainly S. aureus) accounted for a high proportion of the identified Gram-positive bacteria. Bacteremia accounted for 60% of the microbiologically documented cases of fever. 23% of the blood cultures were positive. 14% of the infections were probably hospital-acquired and 14% were caused by multidrug-resistant strains. The overall mortality rate at day 30 was 33% and the infection-related mortality rate was 16.1%. Treatment with antibiotics was successful in 82.8% of cases. In a multivariate analysis, predictive factors for treatment failure were age >60 and thrombocytopenia < 20000/mm3.
Gram-negative species were the most frequently identified bacteria in lung cancer patients with febrile neutropenia. Despite the success of antibiotic treatment and a low-risk neutropenic patient group, mortality is high in this particular population.
PMCID: PMC3147018  PMID: 21707992
17.  18F-FDG PET/CT for diagnosing infectious complications in patients with severe neutropenia after intensive chemotherapy for haematological malignancy or stem cell transplantation 
Between 30 and 50% of febrile neutropenic episodes are accounted for by infection. C-reactive protein (CRP) is a nonspecific parameter for infection and inflammation but might be employed as a trigger for diagnosis. The aim of the study was to evaluate whether 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT can be used to detect inflammatory foci in neutropenic patients with elevated CRP and whether it helps to direct treatment.
Twenty-eight consecutive patients with neutropenia as a result of intensive chemotherapy for haematological malignancies or myeloablative therapy for haematopoietic stem cell transplantation were prospectively included. 18F-FDG PET/CT was added to the regular diagnostic workup once the CRP level rose above 50 mg/l.
Pathological FDG uptake was found in 26 of 28 cases despite peripheral neutrophil counts less than 0.1 × 10−9/l in 26 patients: in the digestive tract in 18 cases, around the tract of the central venous catheter (CVC) in 9 and in the lungs in 7 cases. FDG uptake in the CVC tract was associated with coagulase-negative staphylococcal bacteraemia (p < 0.001) and deep venous thrombosis (p = 0.002). The number of patients having Streptococcus mitis bacteraemia appeared to be higher in patients with grade 3 oesophageal FDG uptake (p = 0.08). Pulmonary FDG uptake was associated with the presence of invasive fungal disease (p = 0.04).
18F-FDG PET/CT scanning during chemotherapy-induced febrile neutropenia and increased CRP is able to detect localized foci of infection and inflammation despite the absence of circulating neutrophils. Besides its potential role in detecting CVC-related infection during febrile neutropenia, the high negative predictive value of 18F-FDG PET/CT is important for avoiding unnecessary diagnostic tests and therapy.
PMCID: PMC3227801  PMID: 21947022
Febrile neutropenia; Neutropenia; 18F-FDG PET/CT; Invasive fungal disease; Mucosal barrier injury; Septic thrombophlebitis
18.  Mortality in a heterogeneous population of low-risk febrile neutropenic patients treated initially with cefazolin and tobramycin 
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.
PMCID: PMC2807246  PMID: 21119792
Cefazolin; Fever; Mortality; Neutropenia; Tobramycin
19.  Chemotherapy-induced neutropenia as a prognostic factor in advanced non-small-cell lung cancer: results from Japan Multinational Trial Organization LC00-03 
British Journal of Cancer  2009;101(9):1537-1542.
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.
PMCID: PMC2778518  PMID: 19862000
non-small-cell lung cancer; chemotherapy-induced neutropenia; overall survival; tumour response; landmark analysis
20.  Intercalated Erlotinib-Docetaxel Dosing Schedules Designed to Achieve Pharmacodynamic Separation: Results of a Phase I/II Trial 
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). Based on preclinical models, we hypothesized pharmacodynamic separation, achieved by intermittent delivery of EGFR TKIs intercalated with chemotherapy, as a reasonable strategy to deliver combination therapy.
A Phase I dose-escalating trial employing two scheduling strategies (arm A and arm B) was conducted in advanced solid tumor patients to determine the feasibility of intermittent erlotinib and docetaxel. Phase II efficacy evaluation was conducted in an expanded cohort of previously treated advanced NSCLC patients using arm B scheduling. Docetaxel was given every 21 days (70–75 mg/m2 intravenously) in both arms. In arm A, erlotinib was administered on Days 2, 9, and 16 (600–1000 mg); in arm B, erlotinib was delivered on Days 2 through 16 (150 – 300 mg). Patients without progression or unacceptable toxicity after 6 cycles continued erlotinib alone.
Eighty-one patients were enrolled in this study (17 arm A; 25 arm B; 39 at phase II dose). Phase I patients had advanced solid tumors and 22 with NSCLC (10 and 12 patients for arms A and B, respectively). Treatment was well-tolerated for both arms, with dose-limiting toxicities including: grade 3 infection and febrile neutropenia in arm A (maximum tolerated dose [MTD] of erlotinib 600 mg/docetaxel 70 mg/m2); grade 4 rash, febrile neutropenia, grade 3 mucositis, and grade 3 diarrhea in arm B (MTD of erlotinib 200 mg/docetaxel 70 mg/m2). The MTD for arm B was chosen for phase II evaluation given the feasibility of administration, number of responses (1 complete response, 3 partial responses), and achievement of pharmacodynamic separation. The response rate for patients treated at the phase II dose was 28.2% and disease control rate was 64.1%. Median progression-free and overall survival was 4.1 and 18.2 months, respectively. Common grade ≥ 3 toxicities were neutropenia (36%) and diarrhea (18%).
Pharmacodynamic separation utilizing intercalated schedules of erlotinib delivered on an intermittent basis together with docetaxel chemotherapy is feasible and tolerable. Further studies employing this approach together with interrogation of relevant molecular pathways are ongoing.
PMCID: PMC3219834  PMID: 21892109
erlotinib; docetaxel; pharmacodynamic separation; non-small cell lung cancer; phase II
21.  Pegfilgrastim and daily granulocyte colony-stimulating factor: patterns of use and neutropenia-related outcomes in cancer patients in Spain – results of the LEARN Study 
European Journal of Cancer Care  2009;18(3):280-286.
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.
PMCID: PMC2702003  PMID: 19076208
pegfilgrastim; G-CSF; pattern of use; neutropenia; febrile neutropenia
22.  Comparing the Efficacy of Ceftazidime and Meropenem in Treatment of Febrile Neutropenia in Pediatric Patients with Cancer  
In cancer patients, various infections were developed due to severe neutropenia resulted from chemotherapy. Ceftazidime is commonly used as monotherapy of cancer patients with fever and neutropenia. Meropenem is a new carbapenem with more extended antibacterial spectrum including anaerobes. It provides better coverage against gram positives. This trial compared the efficacy and safety of meropenem with ceftazidime as empirical monotherapy for febrile neutropenia in pediatric patients with cancer.
Materials and Methods
A prospective, double-blind, randomized clinical trial was conducted at Departments of Pediatric Haematology/Oncology, University Hospitals, Yazd, Iran, during the years 2012 to 2013. A total of 48 cancer patients participated in the trial.
In this study, 26 patients (54.16%) were treated by ceftazidime and 22 patients (45.84%) by meropenem. Mean duration of fever in those who responded to treatment in ceftazidime group was 19.43+/-31.04 hours, and in meropenem group was 16.53+/-28.77 hours (P-value = 0.965).
Finding of this study indicate that ceftazidime and meropenem have similar efficacy in treatment of fever and sever neutropenia. Due to more availability and lower cost of ceftazidime than meropenem, ceftazidime is suggested as a first line treatment in fever and neutropenia.
PMCID: PMC3921881  PMID: 24575280
Ceftazidime; Meropenem; Pediatrics
23.  Clinical experience with Zarzio® in Europe: what have we learned? 
Supportive Care in Cancer  2013;21(10):2925-2932.
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.
PMCID: PMC3765845  PMID: 23903799
Biosimilar; Chemotherapy-induced neutropenia; Cost-effectiveness; Filgrastim; G-CSF
24.  Efficacy and safety analysis of once per cycle pegfilgrastim and daily lenograstim in patients with breast cancer receiving adjuvant myelosuppressive chemotherapy FEC 100: a pilot study 
Neutropenia is a common toxicity in patients receiving myelosuppressive chemotherapy. In this prospective pilot study, we compared the efficacy and safety profiles of pegfilgrastim administered subcutaneously once per cycle and lenograstim administered subcutaneously daily six times per cycle, for primary neutropenia prophylaxis in women with breast cancer receiving adjuvant anthracycline-based chemotherapy.
Materials and methods
Twenty women were enrolled. All patients received epirubicin 100 mg/m2 with 5-fluorouracil 500 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 and every 21 days thereafter, according to the FEC 100 chemotherapy regimen. Eight patients received a single dose of pegfilgrastim on day 2, while 12 patients were treated with daily administration of lenograstim from days five to ten. Absolute neutrophil count and duration of grade 3–4 neutropenia were monitored using seriated blood samples. The incidence of bone pain was evaluated using the visual analog scale (VAS).
The incidence of grade 3–4 neutropenia was 75% in patients who received pegfilgrastim, and 25% in patients who received lenograstim. One case of febrile neutropenia was shown in pegfilgrastim patients. The mean duration of grade 3–4 neutropenia was 2 days in pegfilgrastim group versus 1.4 days in the lenograstim group. Bone pain was present in 37.5% of pegfilgrastim patients versus 58.3% of lenograstim patients. The mean duration of bone pain in the pegfilgrastim group was 4 days versus 6 days in the lenograstim group.
In our experience, a single injection of pegfilgrastim was less effective for controlling neutropenia than six daily injections of lenograstim. The safety profiles of pegfilgrastim and lenograstim were similar with a lower incidence of bone pain in patients treated with pegfilgrastim.
PMCID: PMC3832460  PMID: 24255599
lenograstim; pegfilgrastim; neutropenia; bone pain; breast cancer; adjuvant anthracycline-based chemotherapy
25.  Technical evaluation of methods for identifying chemotherapy-induced febrile neutropenia in healthcare claims databases 
Healthcare claims databases have been used in several studies to characterize the risk and burden of chemotherapy-induced febrile neutropenia (FN) and effectiveness of colony-stimulating factors against FN. The accuracy of methods previously used to identify FN in such databases has not been formally evaluated.
Data comprised linked electronic medical records from Geisinger Health System and healthcare claims data from Geisinger Health Plan. Subjects were classified into subgroups based on whether or not they were hospitalized for FN per the presumptive “gold standard” (ANC <1.0×109/L, and body temperature ≥38.3°C or receipt of antibiotics) and claims-based definition (diagnosis codes for neutropenia, fever, and/or infection). Accuracy was evaluated principally based on positive predictive value (PPV) and sensitivity.
Among 357 study subjects, 82 (23%) met the gold standard for hospitalized FN. For the claims-based definition including diagnosis codes for neutropenia plus fever in any position (n=28), PPV was 100% and sensitivity was 34% (95% CI: 24–45). For the definition including neutropenia in the primary position (n=54), PPV was 87% (78–95) and sensitivity was 57% (46–68). For the definition including neutropenia in any position (n=71), PPV was 77% (68–87) and sensitivity was 67% (56–77).
Patients hospitalized for chemotherapy-induced FN can be identified in healthcare claims databases--with an acceptable level of mis-classification--using diagnosis codes for neutropenia, or neutropenia plus fever.
PMCID: PMC3576237  PMID: 23406481
Febrile neutropenia; Neutropenia; Diagnosis; Classification; Sensitivity and specificity; Predictive value of tests

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