Appendectomy Versus Observation for Appendicitis in Neutropenic Children With Cancer.

BACKGROUND: Optimal management of neutropenic appendicitis (NA) in children undergoing cancer therapy remains undefined. Management strategies include upfront appendectomy or initial nonoperative management. We aimed to characterize the effect of management strategy on complications and length of stay (LOS) and describe implications for chemotherapy delay or alteration. METHODS: Sites from the Pediatric Surgery Oncology Research Collaborative performed a retrospective review of children with NA over a 6-year period. RESULTS: Sixty-six children, with a median age of 11 years (range 1-17), were identified with NA while undergoing cancer treatment. The most common cancer diagnoses were leukemia (62%) and brain tumor (12%). Upfront appendectomy was performed in 41% of patients; the remainder had initial nonoperative management. Rates of abscess or perforation at diagnosis were equivalent in the groups (30% vs 24%; P = .23). Of patients who had initial nonoperative management, 46% (17 of 37) underwent delayed appendectomy during the same hospitalization. Delayed appendectomy was due to failure of initial nonoperative management in 65% (n = 11) and count recovery in 35% (n = 6). Cancer therapy was delayed in 35% (n = 23). Initial nonoperative management was associated with a delay in cancer treatment (46% vs. 22%, P = .05) and longer LOS (29 vs 12 days; P = .01). Patients who had initial nonoperative management and delayed appendectomy had a higher rate of postoperative complications (P < .01). CONCLUSIONS: In pediatric patients with NA from oncologic treatment, upfront appendectomy resulted in lower complication rates, reduced LOS, and fewer alterations in chemotherapy regimens compared to initial nonoperative management.

Current management of chemotherapy-induced neutropenia in adults: key points and new challenges: Committee of Neoplastic Supportive-Care (CONS), China Anti-Cancer Association Committee of Clinical Chemotherapy, China Anti-Cancer Association.

Chemotherapy-induced neutropenia (CIN) is a potentially fatal and common complication in myelosuppressive chemotherapy. The timing and grade of CIN may play prognostic and predictive roles in cancer therapy. CIN is associated with older age, poor functional and nutritional status, the presence of significant comorbidities, the type of cancer, previous chemotherapy cycles, the stage of the disease, specific chemotherapy regimens, and combined therapies. There are many key points and new challenges in the management of CIN in adults including: (1) Genetic risk factors to evaluate the patient's risk for CIN remain unclear. However, these risk factors urgently need to be identified. (2) Febrile neutropenia (FN) remains one of the most common reasons for oncological emergency. No consensus nomogram for FN risk assessment has been established. (3) Different assessment tools [e.g., Multinational Association for Supportive Care in Cancer (MASCC), the Clinical Index of Stable Febrile Neutropenia (CISNE) score model, and other tools] have been suggested to help stratify the risk of complications in patients with FN. However, current tools have limitations. The CISNE score model is useful to support decision-making, especially for patients with stable FN. (4) There are still some challenges, including the benefits of granulocyte colony stimulating factor treatment and the optimal antibiotic regimen in emergency management of FN. In view of the current reports, our group discusses the key points, new challenges, and management of CIN.

Recent advances in the management of chemotherapy-induced neutropenia: biosimilar granulocyte colony-stimulating factor use in Italy.

During the National Congress of the Italian Association of Medical Oncology, which was held in Rome, Italy, October 2019, experts met to discuss advantages of febrile neutropenia prevention based on biosimilar G-CSF. This issue is of paramount importance in oncology as recent biological products may be of great benefit, provided that costs are sustainable.

Febrile neutropenia-related care and associated costs in elderly patients with breast cancer, lung cancer, or non-Hodgkin lymphoma.

PURPOSE: Limited information is available regarding elderly patients experiencing febrile neutropenia (FN). This study evaluated FN-related care among elderly cancer patients who received high/intermediate FN-risk chemotherapy and experienced ≥ 1 FN episodes. METHODS: We used Medicare data to identify patients aged ≥ 66 years who initiated high/intermediate FN-risk chemotherapy between 1 January 2008 and 31 August 2015 to treat breast cancer (BC), lung cancer (LC), or non-Hodgkin lymphoma (NHL) and had ≥ 1 FN episodes. We identified within-cycle FN episodes for each chemotherapy cycle on Part A inpatient claims or outpatient or Part B claims. We described the FN-related care setting (inpatient hospital, outpatient emergency department [ED], or outpatient non-ED) and reported mean total cost of FN-related care per episode overall and by care setting (adjusted to 2015 US$). RESULTS: We identified 2138, 3521, and 2862 patients with BC, LC, and NHL, respectively, with ≥ 1 FN episodes (total episodes: 2407, 3840, 3587, respectively). Most FN episodes required inpatient care (BC, 88.1%; LC, 93.0%; NHL, 93.2%) with mean hospital length of stay (LOS) 6.2, 6.5, and 6.8 days, respectively. Intensive care unit admission was required for 20.4% of BC, 29.0% of LC, and 25.7% of NHL hospitalizations (mean LOS: 4.7, 4.7, 5.5 days, respectively). The mean total cost of FN care per episode was $11,959 BC, $14,388 LC, and $15,006 NHL, with inpatient admission the costliest care component ($11,826; $14,294; and $14,873; respectively). CONCLUSIONS: Among elderly patients with BC, LC, or NHL who experienced FN, most FN episodes required costly hospital care, highlighting the FN burden on healthcare systems.

Real-world outcomes of FOLFIRINOX vs gemcitabine and nab-paclitaxel in advanced pancreatic cancer: A population-based propensity score-weighted analysis.

BACKGROUND: In Ontario, FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GnP) have been publicly funded for first-line unresectable locally advanced pancreatic cancer (uLAPC) or metastatic pancreatic cancer (mPC) since April 2015. We examined the real-world effectiveness and safety of FFX vs GnP for advanced pancreatic cancer, and in uLAPC and mPC. METHODS: Patients receiving first-line FFX or GnP from April 2015 to March 2017 were identified in the New Drug Funding Program database. Baseline characteristics and outcomes were obtained through the Ontario Cancer Registry and other population-based databases. Overall survival (OS) was assessed using Kaplan-Meier and weighted Cox proportional hazard models, weighted by the inverse propensity score adjusting for baseline characteristics. Weighted odds ratio (OR) for hospitalization and emergency department visits (EDV) were estimated from weighted logistic regression models. RESULTS: For 1130 patients (632 FFX, 498 GnP), crude median OS was 9.6 and 6.1 months for FFX and GnP, respectively. Weighted OS was improved for FFX vs GnP (HR = 0.77, 0.70-0.85). Less frequent EDV and hospitalization were observed in FFX (EDV: 67.8%; Hospitalization: 49.2%) than GnP (EDV: 77.7%; Hospitalization: 59.3%). More frequent febrile neutropenia-related hospitalization was observed in FFX (5.8%) than GnP (3.3%). Risk of EDV and hospitalization were significantly lower for FFX vs GnP (EDV: OR = 0.68, P = .0001; Hospitalization: OR = 0.76, P = .002), whereas the risk of febrile neutropenia-related hospitalization was significantly higher (OR = 2.12, P = .001). Outcomes for uLAPC and mPC were similar. CONCLUSION: In the real world, FFX had longer OS, less frequent all-cause EDV and all-cause hospitalization, but more febrile neutropenia-related hospitalization compared to GnP.

Management of sepsis in neutropenic cancer patients: 2018 guidelines from the Infectious Diseases Working Party (AGIHO) and Intensive Care Working Party (iCHOP) of the German Society of Hematology and Medical Oncology (DGHO).

Sepsis and septic shock are major causes of mortality during chemotherapy-induced neutropenia for malignancies requiring urgent treatment. Thus, awareness of the presenting characteristics and prompt management is most important. Improved management of sepsis during neutropenia may reduce the mortality of cancer therapies. However, optimal management may differ between neutropenic and non-neutropenic patients. The aim of the current guideline is to give evidence-based recommendations for hematologists, oncologists, and intensive care physicians on how to manage adult patients with neutropenia and sepsis.

Development of pediatric oncology supportive care indicators: Evaluation of febrile neutropenia care in the north of the Netherlands.

INTRODUCTION: Febrile neutropenia (FN) is a common complication of the intensive treatment strategies used in pediatric oncology. By close adherence to high-quality guidelines, which can be evaluated by indicators, the burden of FN can potentially be reduced. OBJECTIVES: The aims of this study were tripartite-(1) to develop structure, process, and outcome indicators, (2) to evaluate the implementation of the Dutch Childhood Oncology Group (DCOG) guideline on FN, and (3) to produce baseline measures on local quality of FN care (in the north of the Netherlands). METHODS: Seven indicators derived from the DCOG guideline were developed. Regarding structure indicators, we gathered information from all local centers providing care for children with cancer (n = 9). Regarding process and outcome indicators, we collected individual patient data from one academic and two shared-care hospitals. Children (<18 years) were included if they had been diagnosed with cancer in 2014 or 2015 and had suffered from FN. RESULTS: Six out of nine hospitals used the DCOG guideline on FN and three hospitals used an outdated supportive care handbook. Regarding individual patient data, we included 119 FN episodes in 59 patients. All FN episodes without focus were initially treated with guideline-based antibiotics. Of all FN episodes, 18.5% resulted in intensive care unit (ICU) admittance. Cumulative incidence of death during FN was 1.74%. CONCLUSION: Adherence to the DCOG guideline at the individual patient level was excellent. However, indicators concerning mortality and ICU admittances showed that FN still has devastating consequences. Subsequently, we will implement these indicators nationwide in order to improve FN care.

Daunorubicin during delayed intensification decreases the incidence of infectious complications - a randomized comparison in trial CoALL 08-09.

Anthracyclines are integral components of antileukemic treatment. Apart from cardiotoxicity, myelosuppression and infectious complications have been described for doxorubicin (DOX) and daunorubicin (DNR) as predominant side effects, but little is known about their differential toxicities. To address the question whether DNR is associated with a lower rate of infectious complications compared with DOX, 307 children with newly diagnosed acute lymphoblastic leukemia, enrolled in trial CoALL 08-09, were randomized to receive either DOX 30 mg/m2 (n = 153) or DNR 36 mg/m2 (n = 154) in delayed intensification. Hematologic toxicities and stomatitis were less frequent in the DNR group resulting in a significantly lower rate of infections in the DNR arm (27% vs. 59%, p < .0001). Survival was equal in both arms (95% SE 2%) (p = .55), with an insignificant difference in the relapse rate (RR 0.12 (SE = 0.03) in the DOX arm vs. 0.16 (SE = 0.04) in the DNR arm; p = .37; Hazard ratio 1.3; 95% confidence interval 0.7-2.6). In conclusion, DNR given in delayed intensification is associated with a lower incidence of infectious complications without loss of efficacy.

Retrospective audit of neutropenic fever after chemotherapy: how many patients could benefit from oral antibiotic management?

Guidelines suggest that carefully selected patients with neutropenic fever (NF) may be suitable for early discharge on oral antibiotics. Despite these recommendations, many centres manage NF with intravenous antibiotic protocols and inpatient care. We have conducted a retrospective audit of patients with NF, and found that 12 of 40 (30%) patients were eligible for early discharge on oral antibiotics and ambulatory care. Further studies into the barriers to ambulatory management in NF are warranted.

Validation of the Clinical Index of Stable Febrile Neutropenia (CISNE) model in febrile neutropenia patients visiting the emergency department. Can it guide emergency physicians to a reasonable decision on outpatient vs. inpatient treatment?

Advances in oncology have enabled physicians to treat low-risk febrile neutropenia (FN) in outpatient settings. This study was aimed to explore the usefulness of the CISNE model and identify better triage in the emergency setting. This is a retrospective cohort study on 400 adult FN patients presenting to the Emergency Department of National Cancer Center, Korea from January 2010 to December 2016. All had been treated with cytotoxic chemotherapy for solid tumors in the previous 30 days. The primary outcome was the frequency of any serious complications during the duration of illness. Apparently stable patients numbered 299 (74.8%) of 400, and the remainder comprised clinically unstable patients. The stable patients fell into three cohorts according to the risk scores: CISNE I (low risk), 56 patients (18.7%); CISNE II (intermediate), 124 (41.5%) and CISNE III (high), 119 (39.8%). The primary outcome occurred in 10.7%, 19.4% and 33.6%, respectively, according to the cohort. Compared with the Multinational Association of Supportive Care in Cancer Risk Index Score (MASCC RIS), CISNE I stratum had significantly lower sensitivity (0.22 vs. 0.95 of MASCC low risk) but higher specificity (0.91 vs. 0.17) to predict zero occurrence of the primary outcome. The CISNE model was useful for identifying low-risk FN patients for outpatient treatment. The combination of the CISNE and MASCC RIS may help emergency physicians cope with FN more confidently.

Non-chemotherapy drug-induced neutropenia: key points to manage the challenges.

Non-chemotherapy idiosyncratic drug-induced neutropenia (IDIN) is a relatively rare but potentially fatal disorder that occurs in susceptible individuals, with an incidence of 2.4 to 15.4 cases per million population. Affected patients typically experience severe neutropenia within several weeks to several months after first exposure to a drug, and mortality is ∼5%. The drugs most frequently associated with IDIN include metamizole, clozapine, sulfasalazine, thiamazole, carbimazole, amoxicillin, cotrimoxazole, ticlopidine, and valganciclovir. The idiosyncratic nature of IDIN, the lack of mouse models and diagnostic testing, and its low overall incidence make rigorous studies to elucidate possible mechanisms exceptionally difficult. An immune mechanism for IDIN involving neutrophil destruction by hapten (drug)-specific antibodies and drug-induced autoantibodies is frequently suggested, but strong supporting evidence is lacking. Although laboratory testing for neutrophil drug-dependent antibodies is rarely performed because of the complexity and low sensitivity of tests currently in use, these assays could possibly be enhanced by using reactive drug metabolites in place of the parent drug. Patients typically experience acute, severe neutropenia, or agranulocytosis (<0.5 × 109 neutrophils/L) and symptoms of fever, chills, sore throat, and muscle and joint pain. Diagnosis can be difficult, but timely recognition is critical because if left untreated, there is an increase in mortality. Expanded studies of the production and mechanistic role of reactive drug metabolites, genetic associations, and improved animal models of IDIN are essential to further our understanding of this important disorder.

Incidence and risk factors of bacterial and fungal infection during induction chemotherapy for high-risk neuroblastoma.

High-risk neuroblastoma is an aggressive childhood cancer with poor outcomes. Treatment begins with an induction phase comprised of intense multi-agent chemotherapy with the goal of maximally reducing tumor bulk. Given the high intensity of induction chemotherapy, neutropenic fever and infectious complications are common; however, the actual incidence is difficult to determine from clinical trial reports. We performed a retrospective review of infection-related complications in 76 children treated for high-risk neuroblastoma at Texas Children's Hospital. Medical records were reviewed for demographics, febrile neutropenia (FN) episodes, presence, and type of bacterial and fungal infections, and potential risk factors for infection. Fifty-seven percent of patients developed one or more serious bacterial or fungal infections during induction chemotherapy. Additionally, over 75% of patients had at least one admission for FN. Risk factors for developing any infection included female sex, MYCN amplification, and having Medicaid. Patients with external central venous catheters and those requiring parenteral nutrition had higher rates of bacteremia or fungemia. Each cycle, 50% were readmitted for either FN or infection. The overall burden of infectious complications was high, with 70% having two or more unplanned admissions for infection or FN. The incidence of febrile neutropenia and serious bacterial and fungal infections during induction chemotherapy for high-risk neuroblastoma is high. Most patients had at least two additional hospitalizations for infectious complications. Risk factors including female sex, MYCN amplification, payer status, and type of central access were associated with higher rates of infection in this cohort. ABBREVIATIONS: CLABSI Central line associated blood stream infection; CTCAE Common Terminology Criteria for Adverse Events; FN Febrile neutropenia; ANC Absolute neutrophil count; TPN Total parenteral nutrition.

FACTORS ASSOCIATED WITH TREATMENT OUTCOME OF PEDIATRIC CANCERPATIENTS ADMITTED WITH FEBRILE NEUTROPENIA IN TIKURANBESSA SPECIALIZED TEACHING HOSPITAL, ADDIS ABABA, ETHIOPIA.

Background: Cancer treatment is associated with variable degrees of myelosupression. Infection is often a life-threatening complication of chemotherapy-induced neutropenia, and it is also considered an oncologic emergency. Febrile neutropenia is a common, costly and potentially fatal complication in oncology. Objective: To assess factors affecting treatment outcome of cancer patients with chemotherapy induced febrile neutropenia. Method: We conducted a review of records of pediatric patients hospitalized and treated for chemotherapy-induced febrile neutropenia from January 1, 2013 to December 31, 2013 and met the selection criteria. Result: A total of 60 patients (36 males and 24 females) fulfilled the selection criteria. Twelve of them died while in hospital. The mean (SD) age of patients who died was 4.78 (±2.48) years and the mean (SD) hospital stay before death was 20.2 (±5.26) days. Ten children had hematologic malignancy and two had a solid tumor. Ten of the 12 patients had an absolute neutrophil count of less than 100/mm3 (p=0.008, OR=20.3) and a platelet count of less than 50,000/mm3. Six of the 10 children (10%) had sepsis. Patients with profound neutropenia, platelet count of less than 50,000 and sepsis were more likely to die (P=0.048, OR=7). Conclusion: The result of this study showed that absolute neutrophil count of less than 100/mm3, platelet count of less than 50,000/mm3 and a diagnosis of sepsis were factors affecting outcome patients with febrile neutropenia. Careful evaluation of these factors and assessing severity of patients' clinical condition at time of admission can be useful for triaging children with febrile neutropenia.

Acute Oncology Care: A narrative review of the acute management of neutropenic sepsis and immune-related toxicities of checkpoint inhibitors.

Cancer care has become increasingly specialized and advances in therapy have resulted in a larger number of patients receiving care. There has been a significant increase in the number of patients presenting with cancer related emergencies including treatment toxicities and those directly related to the malignancy. Suspected neutropenic sepsis is an acute medical emergency and empirical antibiotic therapy should be administered immediately. The goal of empirical therapy is to cover the most likely pathogens that will cause life-threatening infections in neutropenic patients. Patients with febrile neutropenia are a heterogeneous group with only a minority of treated patients developing significant medical complications. Outpatient management of low risk febrile neutropenia patients identified by the MASCC score is a safe and effective strategy. Immunotherapy with "checkpoint inhibitors" has significantly improved outcomes for patients with metastatic melanoma and evidence of benefit in a wide range of malignancies is developing. Despite these clinical benefits a number of immune related adverse events have been recognised which can affect virtually all organ systems and are potentially fatal. The timing of the onset of the adverse events is dependent on the organ system affected and unlike anti-neoplastic therapy can be delayed significantly after initiation or completion of therapy. The field of Acute Oncology is changing rapidly. Alongside, the traditional challenge of neutropenic sepsis there are many emerging toxicities. Further research into the optimal management, strategies and pathways of acutely unwell patients with cancer is required.

Human herpesvirus-6 encephalitis following chemotherapy induction for acute myelogenous leukemia.

We report a case of human herpesvirus-6 (HHV-6) encephalitis in a neutropenic patient who had undergone chemotherapy induction for acute myelogenous leukemia while on broad-spectrum antimicrobial therapy. The patient displayed symptoms of confusion, amnesia, and lethargy. Diagnosis was made via polymerase chain reaction analysis of cerebrospinal fluid. Electroencephalogram and magnetic resonance imaging of the brain were unremarkable. Following diagnosis, the patient was successfully treated with ganciclovir. HHV-6 encephalitis should be considered in immunocompromised patients who become encephalopathic.

Management of chemotherapy-induced febrile neutropenia in pediatric oncology patients: A North American survey of pediatric hematology/oncology and pediatric infectious disease physicians.

BACKGROUND: Chemotherapy-induced febrile neutropenia (FN) is traditionally managed with hospital admission for parenteral antibiotics until neutropenia resolves. Recent studies have explored risk stratification and the safety of managing "low-risk" patients as outpatients. Few studies have directly assessed pediatric provider preferences for managing FN. PROCEDURE: We conducted a survey of practicing US and Canadian pediatric hematology/oncology (PHO) and pediatric infectious disease (PID) physicians to assess their FN management preferences using case scenarios with varying risk profiles. RESULTS: Twenty-one percent (n = 186) of PHO and 32% (n = 123) of PID physicians completed the survey. Overall, both groups of providers agreed regarding which patients with FN could be managed outpatient. For a child with acute lymphoblastic leukemia receiving maintenance chemotherapy with an absolute neutrophil count (ANC) of 400 cells/µl, 35% (n = 66) of PHO and 49% (n = 60) of PID physicians would consider outpatient management (P = 0.02). Of those physicians selecting inpatient management, 41% (n = 49) of PHO and 52% (n = 33) of PID physicians would be willing to discharge the patient without an increase in ANC, if afebrile with a negative blood culture (P = 0.16). For a similar patient with an ANC of 100 cells/µl, only 23% (n = 35) of PHO and 42% (n = 39) of PID physicians would consider discharge without an increase in ANC (P = 0.002). CONCLUSIONS: Despite the lack of established guidelines for low-risk pediatric FN, a significant proportion of North American physicians report willingness to modify traditional management. This reinforces the need for evidence-based low-risk criteria and outpatient management guidelines to optimize consistency of care for these patients.

Infection-related complications during treatment for childhood acute lymphoblastic leukemia.

Background: Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking. Patients and methods: We evaluated infection-related complications that were grade ≥3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period. Results: Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n = 389), followed by ear (n = 151), bloodstream (n = 147), and gastrointestinal tract (n = 145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n = 4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1-9.9 years at diagnosis was associated with febrile neutropenia (P = 0.002) during induction and febrile neutropenia and documented infection (both P < 0.001) during later continuation. White race was associated with documented infection (P = 0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P < 0.001) and documented infections (P = 0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P < 0.001). Conclusions: The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients.

Autoimmune and other acquired neutropenias.

This educational review addresses the diagnostic evaluation of patients for autoimmune and other forms of acquired neutropenia, including the futility of deconstructing the overlap of chronic "autoimmune," "benign," and "idiopathic" categories. Isolated neutropenias caused by infection, drugs, and immunologic disorders are also addressed. Discussion of management options emphasizes a conservative approach, with largely supportive care for these mostly benign and self-limited disorders.

Management of infection and febrile neutropenia in patients with solid cancer.

An expert group from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC, for its acronym in Spanish) and the Spanish Society of Medical Oncology (SEOM, for its acronym in Spanish) have reviewed the main aspects to be considered when evaluating patients with solid cancer and infectious complications contained in this article. Recommendations have, therefore, been put forth regarding the prophylaxis of the most prevalent infections in these patients, the use of vaccines, measures to control infection through vascular catheters, and preventing infection in light of certain surgical maneuvers. The following is a revision of the criteria for febrile neutropenia management and the use of colony-stimulating factors and closes with several guidelines for treating the cancer patient with serious infection. The document concludes with a series of measures to control hospital infection.