Risk factors for bacteremia in children with febrile neutropenia

Background/aim: Bacteremia remains an important cause of morbidity and mortality during febrile neutropenia (FN) episodes. We aimed to define the risk factors for bacteremia in febrile neutropenic children with hemato-oncological malignancies. Materials and methods: The records of 150 patients aged ≤18 years who developed FN in hematology and oncology clinics were retrospectively evaluated. Patients with bacteremia were compared to patients with negative blood cultures. Results: The mean age of the patients was 7.5 ± 4.8 years. Leukemia was more prevalent than solid tumors (61.3% vs. 38.7%). Bacteremia was present in 23.3% of the patients. Coagulase-negative staphylococci were the most frequently isolated microorganism. Leukopenia, severe neutropenia, positive peripheral blood and central line cultures during the previous 3 months, presence of a central line, previous FN episode(s), hypotension, tachycardia, and tachypnea were found to be risk factors for bacteremia. Positive central line cultures during the previous 3 months and presence of previous FN episode(s) were shown to increase bacteremia risk by 2.4-fold and 2.5-fold, respectively. Conclusion: Presence of a bacterial growth in central line cultures during the previous 3 months and presence of any previous FN episode(s) were shown to increase bacteremia risk by 2.4-fold and 2.5-fold, respectively. These factors can predict bacteremia in children with FN.

Weak circadian rhythm increases neutropenia risk among breast cancer patients undergoing adjuvant chemotherapy.

PURPOSE: Severe neutropenia is a common dose-limiting side effect of adjuvant breast cancer chemotherapy. We aimed to test the hypothesis that weak circadian rhythm is associated with an increased risk of neutropenia using a cohort study. METHODS: We consecutively recruited 193 breast cancer patients who received adjuvant chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel; doxorubicin and cyclophosphamide; docetaxel and cyclophosphamide). Participants wore a wrist actigraph continuously for 168 h at the beginning of chemotherapy. Values of percent rhythm and double amplitude below medians represented weak circadian rhythm. Mesor measured the mean activity level and acrophase symboled the peak time of the rhythm. We used Cox proportional hazard regression model to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of grade 4 neutropenia and febrile neutropenia in relation to actigraphy-derived parameters. RESULTS: Low levels of percent rhythm (HR:2.59, 95% CI 1.50-4.72), double amplitude (HR:2.70, 95% CI 1.51-4.85), and mesor (HR: 2.48, 95% CI 1.44-4.29) were positively associated with the risk of grade 4 neutropenia during chemotherapy. Low levels of percent rhythm (HR: 2.41, 95% CI 1.02-5.69) and double amplitude (HR:2.49, 95% CI 1.05-5.90) were also associated with increased risks of febrile neutropenia. The HRs for acrophase were not statistically significant. CONCLUSIONS: This study provides the first epidemiological evidence that increased risks of grade 4 neutropenia and febrile neutropenia are associated with weak circadian rhythm among adjuvant breast cancer patients. The results suggest that circadian rhythm might be one potential target for the prevention of chemotherapy-induced neutropenia among cancer patients.

Impact of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) on cancer treatment outcomes: An overview about well-established and recently emerging clinical data.

Despite the overwhelming evidence for the role of granulocyte colony stimulating factors (G-CSF) in managing febrile neutropenia (FN) risk, chemotherapy-induced neutropenia (CIN) and/or FN still remain the most common reasons for reducing relative dose intensity (RDI) and/or delaying chemotherapy schedule. The need to maintain RDI to ensure optimal clinical outcomes is one of the key rationales for utilizing G-CSF. There is a high incidence of reduced RDI in both curative and palliative settings, and this observation is especially evidenced in retrospective analyses. Reduced RDI leads to significantly decreased survival outcomes and quality of life in various malignancies at various clinical settings and stages. Beyond its role as a surrogate prognostic marker, high-grade CIN may have an unexpected predictive role in clinical practice, as illustrated by several data relating CIN occurrence with favorable survival outcomes; this may be due to the fact that body surface area (BSA) - based calculation of dose may not fully account for the pharmacokinetics (PK) of cytotoxic drugs and the fact that there may be variability in drug metabolism between patients treated with same chemotherapy regimens.

Chemotherapy-Induced Febrile Neutropenia in Solid Tumours.

Febrile neutropaenia (FN) is defined as an oral temperature of >38.3°C or two consecutive readings of >38.0°C for 2 hours and an absolute neutrophil count (ANC) of <0.5 × 109/l, or expected to fall below 0.5 × 109/l. Fever is one of the characteristic symptoms of FN and is usually associated with the presence of an infection caused by various microorganisms. The incidence and epidemiology of FN are variable based on different factors: (type of cancer, the age/sex of the patient, chemotherapy type /number of cycles). FN remains one of the most common and risky complications of chemotherapy which occurred within 6-8 days with standard chemotherapy and it is occurred as about 7-8/1000 patients receiving treatment with chemotherapeutic agents. There is a clear relationship between the severity of neutropaenia (which directly influences the incidence of FN) and the intensity of chemotherapy. Currently, the different regimens are classified as producing a high risk (>20%), an intermediate risk (10%-20%) or a low risk (<10%) of FN. The causative organisms including either bacteria, fungi or viruses. The bacteria Gram-positive (currently dominating) and Gram-negative (Dominant in the 1970s), are usually the main microorganisms responsible for FN and cause complicated infections. Although the morbidity and mortality rates of FN have decreased over the years due to use of proper antibiotic treatment, preventive measures and use the standardrisk management plan as per guidelines but it is still one of oncological emergency. FN is responsible for considerable morbidity as 20%-30% of patient's present complications that require in-hospital management, with an overall in-hospital mortality of ~10%.

Avoidant conversations about death by clinicians cause delays in reporting of neutropenic sepsis: Grounded theory study.

BACKGROUND: Evidence suggests that patients delay reporting symptoms of neutropenic sepsis (NS) despite the risk to their life. This study aimed to elicit factors that contribute to delayed patient reporting of NS symptoms. METHODS: A constructivist grounded theory study used observations of chemotherapy consultations (13 h) and 31 in-depth interviews to explore beliefs, experiences, and behaviors related to NS. Participants included women with breast cancer, their carers (partners, family, or friends), and clinicians. An explanation for patient delays was developed through theoretical sampling of participants to explore emerging areas of interest and through constant comparison of data and their coding. This entailed iterative and concurrent data collection and analysis. Data were collected until saturation. RESULTS: All patients who developed NS-type symptoms delayed presenting to hospital (2.5 h-8 days), sometimes repeatedly. Moderators of delay included metastatic disease, bereavement, fatalism, religious beliefs, and quality of relationships with clinicians. There was an interplay of behaviors between clinicians, patients, and carers where they subconsciously conspired to underplay the seriousness and possibility of NS occurring. CONCLUSIONS: Findings have implications for health risk communication and development of holistic service models.

The signs, symptoms and help-seeking experiences of neutropenic sepsis patients before they reach hospital: a qualitative study.

PURPOSE: Neutropenic sepsis (NS) is a medical emergency in which urgent treatment with antibiotics is known to improve outcomes, yet there are minimal data about what happens to patients with NS before they reach hospital. We aimed to examine the pre-hospital experiences of patients with NS, identifying its early presenting features and exploring the factors potentially delaying patients' arrival at hospital. METHODS: We conducted in-depth, qualitative interviews with 22 cancer patients admitted to hospital for treatment of NS and 10 patient carers. The setting was a tertiary referral centre in Southern England. RESULTS: Thirty seven percent of patients took over 12 h to present to hospital after symptom onset. The mean delay in presentation was 11 h (range 0-68 h). Thematic analysis of the interviews, using grounded theory, revealed wide-ranging, potentially modifiable factors delaying patients' presentation to hospital. For example, information provided to patients about NS from different sources was inconsistent, with 'mixed messages' about urgency triggering delays. All patients self-monitored their temperature and understood the implication of a fever but few appreciated the potential significance of feeling unwell in the absence of fever. Attempts to obtain treatment were sometimes thwarted by nonspecialists' failure to recognise possible neutropenia in a patient with apparently mild signs, and several patients with NS were discharged without treatment. Some patients denied their symptoms to themselves and others to avoid hospital admission; palliative patients seemed particularly prone to these attitudes, while their carers were keen to seek medical attention. CONCLUSIONS: This investigation of patients' and carers' experiences of NS identifies numerous strategies for improving patient education, support and pre-hospital management, all of which may reduce pre-hospital delays and consequently decrease morbidity and mortality from NS.

Reduced-dose (two-thirds) R-CHOP chemotherapy for elderly patients with non-Hodgkin lymphoma.

Elderly patients with non-Hodgkin lymphoma (NHL) have a poor prognosis. Owing to treatment-related toxicities, there is no standard chemotherapy for the elderly patients, especially those aged 70 years or older. In this study, we retrospectively evaluated the efficacy and toxicity of reduced-dose (two-thirds) R-CHOP chemotherapy as an initial chemotherapy for 45 patients aged 70 years or older with B-cell NHL. The WHO classification of NHL included diffuse large B-cell lymphoma (DLBCL) (31), mantle cell lymphoma (5), follicular lymphoma (4), extranodal marginal zone lymphoma (1), Burkitt lymphoma (1), and B-cell lymphoma whose further types were unclassified (3). The incidences of grade 4 neutropenia and febrile neutropenia (FN) were 51.1 and 15.6%, respectively. Efficacy was evaluated in patients with DLBCL. The overall and complete response (CR) rates were 96.7 and 90.0%, respectively. Two-year event-free survival (EFS) and overall survival (OS) were 84.4 and 89.2%, respectively. There was no treatment-related mortality. In conclusion, two-thirds R-CHOP chemotherapy is a promising treatment for elderly patients with B-cell NHL in terms of its efficacy and toxicity.

Risk of febrile neutropenia in patients receiving emerging chemotherapy regimens.

PURPOSE: Considerable evidence exists concerning the risk of febrile neutropenia (FN) associated with well-established, older chemotherapy regimens. Little is known, however, about the risks associated with many regimens that were introduced in the past decade and have become the predominant choice for certain cohorts of patients or are increasingly being used in clinical practice. METHODS: A retrospective cohort design and US healthcare claims data (2006-2011) were employed. Study subjects included adult patients receiving the following: docetaxel + cyclophosphamide (TC), 5-FU + epirubicin + cyclophosphamide (FEC), FEC followed by docetaxel (FEC → D), or docetaxel + carboplatin + trastuzumab (TCH) for non-metastatic breast cancer; TCH for metastatic breast cancer; 5-FU + leucovorin + irinotecan + oxaliplatin (FOLFIRINOX) for metastatic pancreatic cancer; and bendamustine (with rituximab [BR], without rituximab [B-Mono]) for non-Hodgkin's lymphoma (NHL). For each patient, the first qualifying chemotherapy course and each cycle therein were identified, as were the use of supportive care-colony-stimulating factors (CSF) and antimicrobials (AMB)-and unique FN episodes. RESULTS: The crude risk (incidence proportion) of FN during the chemotherapy course ranged from 8.8 (95 % CI 8.3-9.3) to 10.6 % (9.3-12.1) among the breast cancer regimens, was slightly higher for the NHL regimens (BR, 10.5 % [8.9-12.4]; B-Mono, 14.7 % [11.2-18.9]), and was markedly higher for FOLFIRINOX (24.7 % [17.9-33.1]). Most patients developing FN required inpatient care (range, 73-90 %). Use of CSF primary prophylaxis ranged from 17 (B-Mono) to 75 % (FEC → D); use of AMB primary prophylaxis ranged from 6 (FOLFIRINOX) to 13 % (B-Mono). CONCLUSION: The risk of FN among patients receiving selected emerging chemotherapy regimens is considerable, and most cases require inpatient care. Use of CSF and AMB prophylaxis, however, varies substantially across regimens.

Risk factors for febrile neutropenia in patients receiving docetaxel chemotherapy for castration-resistant prostate cancer.

PURPOSE: Docetaxel is a standard therapy for patients with castration-resistant prostate cancer (CRPC). However, docetaxel-associated adverse events (AEs) such as febrile neutropenia (FN) can impair quality of life and may become life-threatening. In this study, we clarified the AEs and risk factors associated with FN in clinical settings. METHODS: This study included 37 Japanese patients with CRPC who were treated with 70-75 mg/m(2) docetaxel and 10 mg prednisone every 3 or 4 weeks between 2008 and 2012. AEs, risk factors for FN, and the prognostic significance of several clinicopathological factors were analyzed. RESULTS: Hematological AEs of ≥grade 3 included neutrocytopenia in 36 patients (97.3 %), leukopenia in 24 patients (64.9 %), lymphopenia in 10 patients (27.0 %), and FN in 4 patients (10.8 %). In addition, severe non-hematological AEs included colonic perforation, interstitial pneumonia, and acute respiratory distress syndrome in 1 patient each. Severe lymphopenia was positively associated with the incidence of FN. Low serum albumin and low lymphocyte count were identified as possible pre-treatment risk factors, while severe lymphopenia was identified as a post-treatment risk factor. CONCLUSIONS: Non-hematological AEs as well as substantial hematological AEs were recognized in the Japanese population treated with docetaxel chemotherapy against CRPC. Pre- and post-treatment lymphopenia and pre-treatment serum albumin should be considered in order to minimize the risk of FN when selecting patients with prostate cancer for docetaxel therapy, and when considering dose modifications, and the prophylactic use of granulocyte colony-stimulating factor.

Phase II multicentre study of efficacy and feasibility of dose-intensified preoperative weekly cisplatin, epirubicin, and paclitaxel (PET) in resectable gastroesophageal cancer.

BACKGROUND: Perioperative chemotherapy improves the overall survival of resectable gastroesophageal adenocarcinoma (GEA) patients. However, more than 40 % of the patients are not healthy enough to complete their post-operative chemotherapy, and the progression-free survival rate is lower than 35 % at 5 years. In order to optimise neoadjuvant chemotherapy regimen, a pilot study of weekly dose-intensified cisplatin, epirubicin, and paclitaxel (PET) was conducted. The primary objective was a complete resection (R0) rate. Then, a R0 rate ≤80 % was considered as uninteresting, with an expected R0 rate of 92 %. Secondary objectives were the feasibility, safety, histological response rate (Becker score), and survival (Trial registration: NCT01830270). METHODS: Patients with >T1N0M0 GEA were included. Treatment consisted of eight preoperative cycles of weekly PET regimen at 30/50/80 mg/m² of cisplatin, epirubicin, and paclitaxel, respectively. Primary prophylaxis by granulocyte colony-stimulating factor was administered. Surgery was performed 4-6 weeks following the last cycle of chemotherapy. Using Fleming two-step design with a unilateral alpha type one error of 5 % and a statistical power of 80 %, it would be required to include 68 patients. At planned interim analysis for futility, it was required to observe at least 25 of 29 patients with R0 resection to pursue inclusion. At the second step, it was required to observe at least 61 of 68 patients with R0 resection to conclude for promising activity of the dose-intensified chemotherapy. RESULTS: Between May 2011 and January 2013, 29 patients were enrolled. Median age was 62 years (range 39-83 years), and seven (24 %) patients presented signet-ring cell histology. Twenty-seven (93 %) patients underwent surgery. Pathological complete responses (Becker score 1a) were observed in four patients, and nearly complete responses (Becker score 1b) for additional three patients. A R0 rate was achieved for 24 of 29 (82.7 %; 95 % CI 64-94 %) patients. No Becker score 1a/1b response was observed among patients with signet-ring cell GEA. Twenty-one (72 %) patients completed all eight cycles, and 86 % received seven or more cycles. Sixteen (56 %) patients experienced grade 3-4 neutropenia, and five patients had febrile neutropenia. Among non-haematological toxicities, mucositis and fatigue were the most frequent ones. The median-delivered relative dose intensity (DI) was 80 % for cisplatin, 75 % for epirubicin, and 79 % for paclitaxel. However, only 45 % of the patients received at least 80 % of the planned median DI for all three drugs. CONCLUSIONS: Despite high R0 and pathological response rates, neoadjuvant PET chemotherapy did not meet the primary end-point and failed to show an acceptable relative DI. PET chemotherapy is not recommended in resectable GEA patients.

Interferon alpha plus 13-cis-retinoic acid modulation of BCL-2 plus paclitaxel for recurrent small-cell lung cancer (SCLC): an Eastern Cooperative Oncology Group study (E6501).

BACKGROUND: Patients with recurrent small-cell lung cancer (SCLC) have dismal outcomes. The failure of salvage therapy is due to the possible development of resistance mechanisms, such as the upregulation of the anti-apoptosis protein, Bcl-2. We conducted a phase II study to evaluate if modulation of Bcl-2 with 13-cis-retinoic acid (13-CRA) and interferon alpha could improve response rates when combined with paclitaxel in patients with recurrent SCLC. METHODS: Patients with recurrent SCLC and measurable disease were treated with interferon alpha at 6 million units/m² subcutaneously and 13-CRA 1 mg/kg orally on days 1 and 2 and paclitaxel 75 mg/m² intravenously on day 2 of each week for 6 weeks of an 8-week treatment cycle. Treatment was continued until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was response rate with secondary endpoints of progression-free survival (PFS) and overall survival (OS). Bcl-2 levels were assessed in peripheral blood mononuclear cells (PBMCs). RESULTS: Thirty-seven patients were enrolled; 34 were included in the intention-to-treat analysis as 3 patients were ineligible for the study. There were 3 partial responses (9 %), and 5 patients had stable disease (15 %) as best response. The median PFS was 2 months, and median OS was 6.2 months. Although mean Bcl-2 protein levels decreased with therapy in PBMCs, there was no association between Bcl-2 levels and response rate or survival. CONCLUSION: Despite sound pre-clinical evidence, the addition of 13-CRA and interferon alpha to paclitaxel did not improve outcomes for recurrent SCLC.

A phase 1 study of linifanib in combination with carboplatin/paclitaxel as first-line treatment of Japanese patients with advanced or metastatic non-small cell lung cancer (NSCLC).

INTRODUCTION: Linifanib is a potent, orally active, and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor kinase activities with clinical efficacy in non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study evaluated the pharmacokinetics, safety, and efficacy of linifanib in combination with carboplatin/paclitaxel in Japanese patients with advanced NSCLC. METHODS: Carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m²) were administered on day 1 of each 21-day cycle up to a maximum of six cycles. Oral linifanib (7.5 mg) was given to six patients once daily throughout all cycles and escalated to 12.5 mg/day in a second cohort of six patients. RESULTS: Twelve patients received at least one dose of linifanib. The most common adverse events were hematologic and consistent with expected toxicities with carboplatin/paclitaxel. With 12.5 mg linifanib, grade 3/4 neutropenia, leukopenia, and thrombocytopenia occurred in 100, 83, and 83 % of patients, respectively. Dose-limiting grade 4 thrombocytopenia occurred in one patient at each dose level. Linifanib pharmacokinetics was similar to that in non-Japanese patients. At 12.5 mg, linifanib Cmax was 0.32 µg/mL and AUC24 was 4.29 µg h/mL. Linifanib Cmax occurred at 2-3 h with both doses and when given alone or in combination with carboplatin/paclitaxel. Exposure to linifanib appeared to be increased by carboplatin/paclitaxel, and exposure to paclitaxel appeared to be increased by linifanib. Partial responses were observed in nine patients. CONCLUSIONS: Linifanib added to carboplatin/paclitaxel is well tolerated in Japanese patients with advanced/metastatic NSCLC. The recommended dose of linifanib with carboplatin/paclitaxel is 12.5 mg, same as for US patients.

A phase 1 and dose-finding study of LY2523355 (litronesib), an Eg5 inhibitor, in Japanese patients with advanced solid tumors.

PURPOSE: Eg5, a mitotic motor kinesin protein, plays an essential role in bipolar spindle formation in the M phase of the cell cycle. LY2523355 (litronesib) is an allosteric inhibitor of Eg5. This phase 1 and dose-finding study aimed to assess the safety, pharmacokinetics (PK), recommended dose for further studies, and preliminary efficacy in Japanese patients with advanced solid tumors. METHODS: LY2523355 was given on days 1, 2, and 3 every 3 weeks at one of three dose levels: 2, 4, and 5 mg/m²/day. Toxicity was assessed according to NCI-CTCAE version 4.0, and tumor response according to RECIST version 1.1. granulocyte colony-stimulating factor (G-CSF) was used only for grade 4 neutropenia or grade 3 febrile neutropenia. RESULTS: Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m²/day. Most frequent treatment-related adverse events were neutropenia and leukopenia (100 %). Grade 4 neutropenia was observed in 83 %, but all recovered to above 500 neutrophils/µl within 7 days. All patients at 4 and 5 mg/m²/day required G-CSF support. No dose-limiting toxicities were reported up to 5 mg/m²/day. In PK analysis, LY2523355 exposure increased in a dose-dependent manner. The PK parameters for LY2523355 were similar to those observed in Western populations. No objective tumor responses were observed. CONCLUSIONS: The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m²/day in Japanese patients with advanced solid tumors.