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PURPOSE To update a clinical practice guideline (CPG) for the empiric management of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic cell transplantation recipients. METHODS The International Pediatric Fever and Neutropenia Guideline Panel reconvened to conduct the second update of this CPG. We updated the previous systematic review to identify new randomized controlled trials (RCTs) evaluating any strategy for the management of FN in pediatric patients. Using the Grading of Recommendations Assessment, Development and Evaluation framework, evidence quality was classified as high, moderate, low, or very low. The panel updated recommendations related to initial management, ongoing management, and empiric antifungal therapy. Changes from the 2017 CPG were articulated, and good practice statements were considered. RESULTS We identified 10 new RCTs in addition to the 69 RCTs identified in previous FN CPGs to inform the 2023 FN CPG. Changes from the 2017 CPG included two conditional recommendations regarding (1) discontinuation of empiric antibacterial therapy in clinically well and afebrile patients with low-risk FN if blood cultures remain negative at 48 hours despite no evidence of marrow recovery and (2) pre-emptive antifungal therapy for invasive fungal disease in high-risk patients not receiving antimold prophylaxis. The panel created a good practice statement to initiate FN CPG-consistent empiric antibacterial therapy as soon as possible in clinically unstable febrile patients. CONCLUSION The updated FN CPG incorporates important modifications on the basis of recently published trials. Future work should focus on addressing knowledge gaps, improving CPG implementation, and measuring the impact of CPG-consistent care.

Introduction: We aimed to create a Spanish-language version of the Pediatric Nausea Assessment Tool (PeNAT) and examine its understandability among Spanish-speaking, Hispanic American children. Methods: Translation: Forward and backward translations of the PeNAT documents were performed and verified by a bilingual panel. Four monolingual, Spanish-speaking dyads (child/parent) and four bilingual dyads piloted the Spanish-language PeNAT documents. Four additional bilingual dyads read both versions and completed the PeNAT using their preferred version. These were reviewed for errors due to misunderstanding. Understandability: Children aged 4–18 years about to receive chemotherapy who spoke Spanish at home and were without impairments precluding PeNAT use were eligible. Participants used the Spanish-language PeNAT during a chemotherapy block. Parents gave feedback on the PeNAT documents. Recruitment continued until 10 consecutive participants offered no substantive suggestions for revision. Results: Translation: All child/parent dyads completed the PeNAT without errors attributable to misunderstanding. The Spanish-language PeNAT was preferred by three of four bilingual dyads. Understandability: Ten cancer patients (mean age: 10.6 years) used the Spanish-language PeNAT. All parents felt their child understood the PeNAT; none felt the documents were hard or very hard to use. Conclusion: The Spanish-language PeNAT was understood by Spanish-speaking Hispanic American children. Further psychometric testing is warranted.

Les nausées et les vomissements induits par la chimiothérapie (NVIC) nuisent à la qualité de vie tant des adultes que des patients pédiatriques atteints d’un cancer (Dupuis, Milne-Wren, Cassidy et al., 2010; Farrell, Brearley, Pilling et Molassiotic, 2013; Russo, Cinausero, Gerratana et al., 2014; Hinds, Gattuso, Billups et al., 2009; Sommariva, Pongiglione, et Tarricone, 2016). Les vomissements et les haut-le-cœur sont des symptômes qui s’évaluent objectivement, alors que la nausée est subjective et plus difficile à mesurer. En général, l’intensité de la nausée chez les adultes peut être décrite à l’aide d’échelles d’évaluation visuelle analogique ou qualitative. Il existe à cette fin des instruments validés et recommandés par des spécialistes du domaine, comme celui de la Multinational Association of Supportive Care in Cancer (en ligne : www.mascc.org) (Hesketh, Gralla, du Bois et Tonato, 2016).

Chemotherapy-induced nausea and vomiting (CINV) continue to negatively influence the quality of life of both adult and pediatric cancer patients (Dupuis et al., 2010; Farrell et al., 2013; Russo et al., 2014; Hinds et al., 2009; Sommariva et al., 2016). Vomiting and retching are symptoms that can be assessed objectively while nausea, a subjective symptom, is more difficult to quantify. Adult cancer patients can usually describe the severity of the nausea they feel using self-report visual analog or adjectival rating scales. Instruments such as the Multinational Association of Supportive Care in Cancer Antiemesis Tool (available from www.mascc.org) have been validated for this purpose and are recommended by experts in the field (Hesketh et al., 2015).

PURPOSE To develop a clinical practice guideline for systemic antifungal prophylaxis in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients. METHODS Recommendations were developed by an international multidisciplinary panel that included a patient advocate. We conducted a systematic review of systemic antifungal prophylaxis in children and adults with cancer and HSCT recipients. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to make strong or weak recommendations and to classify level of evidence as high, moderate, low, or very low. The panel considered directness of the data to pediatric patients. RESULTS There were 68 randomized trials included in the systematic review, of which 6 (9%) were conducted in a solely pediatric population. Strong recommendations were made to administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. A strong recommendation was made to administer a mold-active agent with an echinocandin or a mold-active azole when systemic antifungal prophylaxis is warranted. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested. Posaconazole may also be used in those age 13 years or older. A strong recommendation against routine administration of amphotericin as systemic antifungal prophylaxis was made. CONCLUSION We developed a clinical practice guideline for systemic antifungal prophylaxis administration in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guideline-concordant rates and impacts are important future steps.

PURPOSE To identify factors associated with chemotherapy-induced vomiting (CIV) control in pediatric patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). MATERIALS AND METHODS An individual, patient‐level, pooled analysis was performed using data from five clinical trials of aprepitant or fosaprepitant in pediatric patients receiving HEC or MEC. The proportion of individuals who experienced no vomiting (complete CIV control) during the phase of interest was the primary study end point. The association of acute-phase complete CIV control (from first chemotherapy dose to 24 hours after the last chemotherapy dose of the chemotherapy block) with age, sex, race, cancer type, acute-phase duration, and antiemetic regimen was examined. Association of the same factors and acute-phase complete CIV control with complete CIV control in the delayed phase (end of acute phase until ≤ 96 hours later) was examined. RESULTS A total of 735 patients (mean age, 8.9 years; range, 0.3 to 17.9 years) were included in the acute-phase analysis. Acute-phase complete CIV control was less likely in older patients (relative risk [RR], 0.97 per year; 95% CI, 0.96 to 0.98 per year) and longer acute-phase duration (RR, 0.89 per day; 95% CI, 0.84 to 0.94 per day). Receipt of ondansetron plus aprepitant or fosaprepitant was associated with a higher likelihood of acute-phase complete CIV control versus ondansetron alone (RR, 1.28; 95% CI, 1.09 to 1.50). Delayed-phase complete CIV control was more likely in patients with acute-phase complete CIV control (RR, 1.19; 95% CI, 1.06 to 1.34) and in those who received aprepitant or fosaprepitant. CONCLUSION Younger age, shorter acute-phase duration, and antiemetic regimen were associated with acute-phase complete CIV control in pediatric patients receiving HEC or MEC. Acute-phase complete CIV control and antiemetic regimen were associated with delayed-phase complete CIV control.

Symptom Screening in Pediatrics Tool (SSPedi) (age 8‐18 years) and mini‐SSPedi (age 4‐7 years) can be used to self‐report and proxy‐report bothersome symptoms in pediatric patients receiving cancer treatments. There are limitations of sole child self‐report or proxy‐report. An approach in which children and parents complete symptom reports together may be useful. The aim of our study was to describe discordance between child self‐report and parent proxy‐report symptom scores, and to determine how these scores compare to an approach in which reporting is performed together (co‐SSPedi). Children and parents completed SSPedi or mini‐SSPedi separately. Discordant symptoms were shared with respondents and discussed. Next, the dyad completed co‐SSPedi together and were asked which approach they preferred. Discordance was evaluated for each symptom and was defined as a difference of at least 2 points on an ordinal scale ranging from 0 (not at all bothered) to 4 (extremely bothered). Of the 48 enrolled dyads (children, median age, 10.8 years; 54.2% male), 41 (85.4%) had discordance in at least one symptom. There was no clear pattern in discordance by age group. When a dyad approach was used, more co‐SSPedi scores agreed with the original child self‐report scores (59 dyads, 56.2%) compared to original parent proxy‐report scores (15 dyads, 14.3%) for discordant symptoms. Forty‐three (89.6%) dyads preferred to complete SSPedi together. Future work should evaluate the psychometric properties of co‐SSPedi., Discordance is common between child self‐report and parent proxy‐report of symptom in children receiving cancer treatments, with no clear pattern in discordance by whether the symptom was subjective or objective, nor was there a clear pattern by age group. When a dyad approach was used, more scores agreed with the original child self‐report scores compared to original parent proxy‐report scores for discordant symptoms.

PURPOSE: Prescribing guideline-recommended anti-emetics is an effective strategy to prevent CINV. However, the rate of guideline-concordant care is not well-understood. The purpose of this study was to describe the proportion of pediatric, adolescent, and young adult patients receiving HEC or MEC who received guideline-concordant antiemetic prophylaxis for acute CINV, and to identify potential predictors of guideline-concordant antiemetic prophylaxis. METHODS: Using electronic health record data from 2016 through 2018, a retrospective single-institution cohort study was conducted to investigate how often patients less than 26 years of age receiving moderately or highly emetogenic chemotherapy receive guideline-concordant prophylaxis for acute CINV. Guideline-concordant care was defined according to guidelines from the Pediatric Oncology Group of Ontario for patients < 18 years and the American Society of Clinical Oncology for those ≥ 18 years. Independent variables included: sex, age, insurance status, race, ethnicity, cancer type, chemotherapy regimen, clinical setting, chemotherapy emetogenicity, and patient location. Predictors of receiving guideline-concordant care were determined using multiple logistic regression. RESULTS: Of 180 eligible patients, 65 (36.1%) received guideline-concordant care. In multivariable analysis, being treated in adult oncology setting (aOR: 14.3, CI(95): 5.3 – 38.6), with a cisplatin-based regimen (aOR: 3.5, CI(95):1.4 – 9.0), solid tumor diagnosis (aOR: 2.2, CI(95): 1.0 – 4.8), and commercial insurance (aOR: 2.4, CI(95): 1.1 – 5.2) were associated with significantly higher likelihood of receiving guideline-concordant care. CONCLUSIONS: Multi-level factors were associated with receiving guideline concordant care for prevention of CINV in children, adolescents, and young adults receiving emetogenic chemotherapy. These findings can inform current efforts to optimize implementation strategies for supportive care guidelines

Background Bacteremia and other invasive bacterial infections are common among children with cancer receiving intensive chemotherapy and in pediatric recipients of hematopoietic stem cell transplantation (HSCT). Systemic antibacterial prophylaxis is one approach that can be used to reduce the risk of these infections. Our purpose was to develop a clinical practice guideline (CPG) for systemic antibacterial prophylaxis administration in pediatric patients with cancer and those undergoing HSCT. Methods An international and multidisciplinary panel was convened with representation from pediatric hematology/oncology and HSCT, pediatric infectious diseases (including antibiotic stewardship), nursing, pharmacy, a patient advocate, and a CPG methodologist. The panel used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to generate recommendations based on the results of a systematic review of the literature. Results The systematic review identified 114 eligible randomized trials of antibiotic prophylaxis. The panel made a weak recommendation for systemic antibacterial prophylaxis for children receiving intensive chemotherapy for acute myeloid leukemia and relapsed acute lymphoblastic leukemia (ALL). Weak recommendations against the routine use of systemic antibacterial prophylaxis were made for children undergoing induction chemotherapy for ALL, autologous HSCT and allogeneic HSCT. A strong recommendation against its routine use was made for children whose therapy is not expected to result in prolonged severe neutropenia. If used, prophylaxis with levofloxacin was recommended during severe neutropenia. Conclusions We present a CPG for systemic antibacterial prophylaxis administration in pediatric cancer and HSCT patients. Future research should evaluate the long-term effectiveness and adverse effects of prophylaxis., This clinical practice guideline presents recommendations for systemic antibacterial prophylaxis administration in pediatric cancer and hematopoietic stem cell transplantation patients. The recommendations were developed by an international panel based on the results of a systematic review of 114 randomized trials.

Background Objectives were to describe barriers to pediatric cancer symptom management care pathway implementation and the impact of the COVID-19 pandemic on clinical research evaluating their implementation. Methods We included 25 pediatric oncology hospitals in the United States that supported a grant submission to perform a cluster randomized trial in which the intervention encompassed care pathways for symptom management. A survey was distributed to site principal investigators prior to randomization to measure contextual elements related to care pathway implementation. Questions included the inner setting measures of the Consolidated Framework for Implementation Research (CFIR), study-specific potential barriers and the impact of the COVID-19 pandemic on clinical research. The Wilcoxon rank sum test was used to compare characteristics of institutions that agreed that their department supported the implementation of symptom management care pathways vs. institutions that did not agree. Results Of the 25 sites, one withdrew because of resource constraints and one did not respond, leaving 23 institutions. Among the seven CFIR constructs, the least supported was implementation climate; 57% agreed there was support, 39% agreed there was recognition and 39% agreed there was prioritization for symptom management care pathway implementation at their institution. Most common barriers were lack of person-time to create care pathways and champion their use (35%), lack of interest from physicians (30%) and lack of information technology resources (26%). Most sites reported no negative impact of the COVID-19 pandemic across research activities. Sites with fewer pediatric cancer patients were more likely to agree that staff are supported to implement symptom management care pathways (P = 0.003). Conclusions The most commonly reported barriers to implementation were lack of support, recognition and prioritization. The COVID-19 pandemic may not be a major barrier to clinical research activities in pediatric oncology.

Background: Features of clinical practice guideline (CPG) recommendations may affect understanding and consequently successful uptake and implementation. We aimed to develop a recommendation format to improve understandability among healthcare professionals involved in pediatric cancer care.Methods: We conducted a multi-center qualitative study of health care professionals at participating pediatric oncology sites. We developed an initial format based on the current literature and used the “think-aloud” technique in multiple rounds of one-on-one cognitive interviews to iteratively improve it. Interviews were conducted until the format was well understood and no new, substantive suggestions for revision were raised. We took a directed (deductive) approach to content analysis of the interview notes to identify concerns related to the understandability of the recommendation. Results: Five investigators interviewed 33 healthcare professionals from multiple disciplines in seven rounds. We identified important factors influencing how to communicate recommendations. Regarding the strength of the recommendation, participants found understanding weak recommendations more challenging than strong. Understanding was improved by using the word ‘conditional’ instead of ‘weak’. Participants believed the inclusion of a rationale section to be very helpful. More information was desirable when a recommendation entailed a practice change. Although participants wanted additional information, they were concerned that there could be too much information. They, therefore, suggested that key words and the studies included in the evidence synthesis be hyperlinked to explanatory data. In the final format, the recommendation strength is clearly indicated in the title, highlighted, and defined within a text box. The rationale for the recommendation is in a column on the left, with supporting evidence on the right. In a bulleted list, the rationale section describes the benefits and harms and additional factors, such as implementation, that were balanced by the CPG developers. Each bullet under the supporting evidence section indicates the level of evidence with an explanation and the supporting studies with hyperlinks when applicable. Conclusions: A well-understood recommendation format to present strong and conditional recommendations was created through an iterative interview process. The format is straightforward, making it easy for organizations and CPG developers to use it to communicate recommendations clearly to intended users.

There is growing recognition of the degree to which symptoms negatively impact on children receiving cancer treatments. A recent study described that almost all inpatient pediatric oncology patients are experiencing at least one bothersome symptom and almost 60% are experiencing at least one severely bothersome symptom. Poor symptom control occurs because of challenges with communication of bothersome symptoms to clinicians, lack of clinical practice guidelines (CPGs) for most of these symptoms, and failure to administer preventative and therapeutic interventions known to be effective for symptom control. This article reviews approaches used to improve symptom control for children receiving cancer treatments. Areas addressed include systematic symptom screening and creation of CPGs for symptom management. Challenges with electronic health integration are also addressed. Several multi-symptom assessment scales have been developed but none have yet been used to directly influence patient management. The number of CPGs applicable to symptom control in pediatric oncology is increasing but remains small. Improving the creation of and adherence to CPGs for symptom management is an important priority. Finally, identifying ways that symptom management systems can be integrated into clinical work flows is essential; these will likely need to focus on electronic health records.

PURPOSE To determine the efficacy and safety of different prophylactic systemic antibiotics in adult and pediatric patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation (HSCT). METHODS We conducted a systematic review and performed searches of Ovid MEDLINE, MEDLINE in-process and Embase; and Cochrane Central Register of Controlled Trials. Studies were included if patients had cancer or were HSCT recipients with anticipated neutropenia, and the intervention was systemic antibacterial prophylaxis. Strategies synthesized included fluoroquinolone vs no antibiotic/nonabsorbable antibiotic; fluoroquinolone vs trimethoprim-sulfamethoxazole; trimethoprim-sulfamethoxazole vs no antibiotic; and cephalosporin vs. no antibiotic. Fluoroquinolone vs cephalosporin and levofloxacin vs ciprofloxacin were compared by network meta-analysis. Primary outcome was bacteremia. RESULTS Of 20 984 citations screened, 113 studies comparing prophylactic antibiotic to control were included. The following were effective in reducing bacteremia: fluoroquinolone vs no antibiotic/nonabsorbable antibiotic (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.41-0.76), trimethoprim-sulfamethoxazole vs no antibiotic (RR 0.59, 95% CI 0.41-0.85) and cephalosporin vs no antibiotic (RR 0.30, 95% CI 0.16-0.58). Fluoroquinolone was not significantly associated with increased Clostridium difficile infection (RR 0.62, 95% CI 0.31-1.24) or invasive fungal disease (RR 1.28, 95% CI 0.79-2.08) but did increase resistance to fluoroquinolone among bacteremia isolates (RR 3.35, 95% CI 1.12 to 10.03). Heterogeneity in fluoroquinolone effect on bacteremia was not explained by evaluated study, population, or methodological factors. Network meta-analysis revealed no direct comparisons for pre-specified analyses; superior regimens were not identified. CONCLUSIONS Fluoroquinolone, trimethoprim-sulfamethoxazole, and cephalosporin prophylaxis reduced bacteremia. A clinical practice guideline to facilitate prophylactic antibiotic decision-making is required.

Purpose To update the 2015 clinical practice guideline for the prevention of oral mucositis in pediatric cancer or hematopoietic stem cell transplant (HSCT) patients. Methods We performed seven systematic reviews of mucositis prevention. Three reviews included randomized controlled trials (RCTs) conducted in pediatric and adult patients evaluating cryotherapy, keratinocyte growth factor (KGF) or photobiomodulation therapy with a focus on efficacy. Three reviews included studies of any design conducted in pediatric patients evaluating these same interventions with a focus on adverse events and feasibility. One review included all RCTs of any intervention for mucositis prevention in pediatric patients. Primary outcome was severe oral mucositis. Results We included 107 unique studies of cryotherapy (22 RCTs and 4 pediatric studies); KGF (15 RCTs and 12 pediatric studies); photobiomodulation therapy (29 RCTs and 8 pediatric studies) and any intervention (31 pediatric RCTs). Effects on severe mucositis reduction from RCTs were cryotherapy risk ratio (RR) 0.49 and 95% confidence interval (CI) 0.31–0.76; palifermin RR 0.81 and 95% CI 0.69–0.95 and photobiomodulation therapy RR 0.40 and 95% CI 0.27–0.60. Cryotherapy was not feasible in young children while photobiomodulation therapy was feasible across age groups. Palifermin was associated with adverse effects. Conclusions Cryotherapy should be used for older cooperative pediatric patients who will receive short infusions of melphalan or 5-fluorouracil. Intraoral photobiomodulation therapy (620–750 nm spectrum) should be used in pediatric patients undergoing autologous or allogeneic HSCT and for pediatric head and neck carcinoma patients undergoing radiotherapy. Palifermin should not be used routinely in pediatric cancer or HSCT patients.

Background Clinical practice guideline (CPG)-consistent care improves patient outcomes, but CPG implementation is poor. Little is known about CPG implementation in pediatric oncology. This study aimed to understand supportive care CPG implementation facilitators and barriers at pediatric oncology National Cancer Institute (NCI) Community Oncology Research Program (NCORP) institutions. Methods Healthcare professionals at 26 pediatric, Children's Oncology Group-member, NCORP institutions were invited to participate in face-to-face focus groups. Serial focus groups were held until saturation of ideas was reached. Supportive care CPG implementation facilitators and barriers were solicited using nominal group technique (NGT), and implementation of specific supportive care CPG recommendations was discussed. Notes from each focus group were analyzed using a directed content analysis. The top five themes arising from an analysis of NGT items were identified, first from each focus group and then across all focus groups. Results Saturation of ideas was reached after seven focus groups involving 35 participants from 18 institutions. The top five facilitators of CPG implementation identified across all focus groups were organizational factors including charging teams with CPG implementation, individual factors including willingness to standardize care, user needs and values including mentorship, system factors including implementation structure, and implementation strategies including a basis in science. The top five barriers of CPG implementation identified were organizational factors including tolerance for inconsistencies, individual factors including lack of trust, system factors including administrative hurdles, user needs and values including lack of inclusivity, and professional including knowledge gaps. Conclusions Healthcare professionals at pediatric NCORP institutions believe that organizational factors are the most important determinants of supportive care CPG implementation. They believe that CPG-consistent supportive care is most likely to be delivered in organizations that prioritize evidence-based care, provide structure and resources to implement CPGs, and eliminate implementation barriers. Trial registration ClinicalTrials.gov Identifier: NCT02847130. Date of registration: July 28, 2016.

Background: To describe barriers to pediatric cancer symptom management care pathway implementation and the impact of the COVID-19 pandemic on clinical research evaluating their implementation. Methods: We included 25 pediatric oncology hospitals in the United States that supported a grant submission to perform a cluster randomized trial in which the intervention encompassed care pathways for symptom management. A survey was distributed to site principal investigators to measure contextual elements related to care pathway implementation. Questions included the inner setting measures of the Consolidated Framework for Implementation Research (CFIR), study-specific potential barriers and the impact of the COVID-19 pandemic on clinical research. The Wilcoxon rank sum test was used to compare characteristics of institutions that agreed that their department supported the implementation of symptom management care pathways vs. institutions that did not agree.Results: Of the 25 sites, one withdrew because of resource constraints and one did not respond, leaving 23 institutions. Among the seven CFIR constructs, the least supported was implementation climate; 57% agreed there was support, 39% agreed there was recognition and 39% agreed there was prioritization for symptom management care pathway implementation at their institution. Most common barriers were lack of person-time to create care pathways and champion their use (35%), lack of interest from physicians (30%) and lack of information technology resources (26%). Most sites reported no negative impact of the COVID-19 pandemic across research activities. Sites with fewer pediatric cancer patients were more likely to agree that staff are supported to implement symptom management care pathways (P=0.003). Conclusions: The most commonly reported barriers to implementation were lack of support, recognition and prioritization. The COVID-19 pandemic was not a major barrier to clinical research activities in pediatric oncology.Clinical Trial Registration: NCT04614662

Our purpose was to compare conventional meta-analysis and network meta-analysis to evaluate the efficacy of different prophylactic systemic antibiotic classes in patients undergoing chemotherapy or haematopoietic stem cell transplant (HSCT). We included randomised trials if patients had cancer or were HSCT recipients and the intervention was systemic antibacterial prophylaxis. Three types of control groups were used: (1) placebo, no antibiotic and non-absorbable antibiotic separately; (2) placebo and no antibiotic combined; and (3) all three combined. These gave different network geometries. Strategies synthesised were fluoroquinolone, trimethoprim-sulfamethoxazole, cephalosporin and parenteral glycopeptide versus control groups. In total 113 trials met the eligibility criteria. Where treatment effects could be estimated with both conventional and network meta-analysis, values were generally similar. However, where events were sparse, network meta-analysis could be more precise. For example, trimethoprim-sulfamethoxazole versus placebo for infection-related mortality showed a relative risk ratio (RR) of 0.55, 95% CI (0.21 to 1.44) with conventional, and RR 0.43, 95% credible region (0.20 to 0.82) with network meta-analysis. Cephalosporin versus fluoroquinolone was comparable only indirectly using the network approach and yielded RR 0.59, 95% credible region (0.28 to 1.20) to reduce bacteraemia. Incoherence (difference between direct and indirect estimates raising concerns about network meta-analysis validity) was observed with network geometry where control groups were separated, but not where control groups were combined. In this situation, conventional and network meta-analysis yielded similar results in general. Network meta-analysis results could be more precise when events were rare. Some analysis could only be performed with the network approach. These results identify scenarios in which network meta-analysis may be advantageous.

Additional file 1. SPARK family member web pages (Final versions)

Background: Children with cancer often undergo long treatment trajectories involving repeated needle procedures that potentially cause pain and distress. As part of a comprehensive effort to develop clinical practice guidelines (CPGs) to address pain prevention and management in children with cancer, we aimed to provide recommendations on the pharmacological and psychological management of procedure-related pain and distress. Methods: Of the international inter-disciplinary CPG development panel (44 individuals), two working groups including 13 healthcare professionals focused on procedural pain and distress. Grading of Recommendations Assessment, Development and Evaluation methodology was used, including the use of systematic literature reviews to inform recommendations and the use of evidence to decision frameworks. At an in-person meeting in February 2018, the guideline panel discussed these frameworks and formulated recommendations which were then discussed with a patient-parent panel consisting of 4 survivors and 5 parents. Results: The systematic reviews led to the inclusion of 48 randomised controlled trials (total number of participants = 2271). Quality of evidence supporting the recommendations ranged from very low to moderate. Strong recommendations were made for the use of topical anesthetics in all needle procedures, for offering deep sedation (DS)/general anesthesia (GA) to all children undergoing lumbar puncture, for the use of DS/GA in major procedures in children of all ages, for the use of hypnosis in all needle procedures and for the use of active distraction in all needle procedures. Conclusion: In this CPG, an evidence-based approach to manage procedure-related pain and distress in children with cancer is presented. As children with cancer often undergo repeated needle procedures during treatment, prevention and alleviation of procedure-related pain and distress is of the utmost importance to increase quality of life in these children and their families. (C) 2020 The Authors. Published by Elsevier Ltd.

Objectives Primary objectives were to evaluate the interrater reliability and validity of proxy-report Symptom Screening in Pediatrics Tool (SSPedi) in children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients. Secondary objective was to describe the interrater reliability of each SSPedi item. Methods Respondents were children aged eight to 18 years with cancer or HSCT recipients, and their parents or guardians. We enrolled two pediatric respondent groups. The more symptomatic group was receiving active treatment for cancer, admitted to hospital, and expected to be in a hospital three days later. The less symptomatic group either was in maintenance therapy for acute lymphoblastic leukemia or had completed cancer treatments. Convergent validity was evaluated by comparing proxy-reported mucositis, nausea and vomiting, pain, and total SSPedi scores, with child self-reported validated scales, and we hypothesized fair correlations. Discriminant validity was evaluated by comparing proxy-reported total SSPedi scores between groups. Interrater reliability of each SSPedi item was evaluated. Results Four hundred thirty-nine child and parent or guardian pairs were recruited. Mean difference in proxy-reported SSPedi scores between the more and less symptomatic groups was 8.2, 95% CI 6.6–9.8. All hypothesized relationships among measures were observed. Intraclass correlation coefficients for SSPedi items ranged from 0.34 (problems with thinking) to 0.80 (diarrhea). Conclusion Proxy-report SSPedi is reliable and valid in children aged 8 years to 18 years with cancer and HSCT recipients. Future work should support proxy-reported symptom assessment in clinical settings where children are not able to self-report or communicate bothersome symptoms.

Background The objective was to evaluate the reliability and validity of the self-report Symptom Screening in Pediatrics Tool (SSPedi) from the perspective of children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients. Methods In this multicenter study, respondents were children age eight to 18 years who had cancer or had received HSCT, and their parents. Two different child respondent populations were targeted. More symptomatic respondents were receiving active treatment for cancer, admitted to the hospital, and expected to be in the hospital three days later. Less symptomatic respondents were in maintenance therapy for acute lymphoblastic leukemia or had completed cancer therapy. Children completed SSPedi and then responded to validated self-report measures of mucositis, nausea, pain, and global quality of life. Children in the more symptomatic group repeated SSPedi and a global symptom change scale three days later. Parent proxy-report was optional. Reliability was evaluated using intraclass correlations while convergent validity was evaluated using Spearman correlations. Results Of 502 children enrolled, 302 were in the more symptomatic group and 200 were in the less symptomatic group. Intraclass correlation coefficients were 0.88 (95% confidence interval [CI] = 0.82 to 0.92) for test-retest reliability and 0.76 (95% CI = 0.71 to 0.80) for inter-rater reliability. The mean difference in SSPedi scores between more and less symptomatic groups was 7.8 (95% CI = 6.4 to 9.2). SSPedi was responsive to change in global symptoms. All hypothesized relationships among measures were observed. Conclusions SSPedi is a self-report symptom bother tool for children with cancer and HSCT recipients that is reliable, valid, and responsive to change. SSPedi can be used for clinical and research purposes. Future work should focus on integration into care delivery.

ObjectivesTo translate a symptom screening tool developed for paediatric patients receiving cancer therapies called Symptom Screening in Pediatrics Tool (SSPedi) into Argentinian Spanish and to evaluate the understandability and cultural relevance of the translated version of SSPedi among children with cancer and paediatric haematopoietic stem cell transplant (HSCT) recipients.MethodsWe conducted a multiphase, descriptive study to translate SSPedi into Argentinian Spanish. Using two translators, forward and backward translations were performed. The translated version was evaluated by Spanish-speaking paediatric patients 8–18 years of age receiving cancer treatments in two centres in Argentina and El Salvador.Primary and secondary outcome measuresThe primary outcome was patient self-reported difficulty with understanding of the SSPedi instructions and each symptom using a 5-point Likert scale. Secondary outcomes were incorrect understanding of the SSPedi instructions, symptoms and response scale determined by cognitive interviews with the patients and rated using a 4-point Likert scale. Cultural relevance was assessed qualitatively.ResultsThere were 30 children enrolled and included in cognitive interviews; 16 lived in Argentina and 14 lived in El Salvador. The most common types of Spanish spoken were Central American (17, 57%) followed by South American (10, 33%) and Castilian (3, 10%). No changes to Argentinian Spanish SSPedi were required based on the outcomes or qualitative comments. No issues with cultural relevance were identified by any of the respondents.ConclusionsWe translated and finalised Argentinian Spanish SSPedi. Future research will focus on its use to describe bothersome symptoms by Argentinian Spanish-speaking children.

Aims Aprepitant and fosaprepitant, commonly used for the prevention of chemotherapy-induced nausea and vomiting, alter cytochrome P450 activity. This systematic review evaluates clinically significant pharmacokinetic drug interactions with aprepitant and fosaprepitant and describes adverse events ascribed to drug interactions with aprepitant or fosaprepitant. Methods We systematically reviewed the literature to September 11, 2016 to identify articles evaluating drug interactions involving aprepitant/fosaprepitant. The clinical significance of each reported pharmacokinetic drug interaction was evaluated based on the United States Food and Drug Administration guidance document on conducting drug interaction studies. The probability of an adverse event reported in case reports being due to a drug interaction with aprepitant/fosaprepitant was determined using the Drug Interaction Probability Scale. Results 4377 publications were identified. Of these, 64 met inclusion eligibility criteria: 34 described pharmacokinetic drug interactions and 30 described adverse events ascribed to a drug interaction. Clinically significant pharmacokinetic interactions between aprepitant/fosaprepitant and bosutinib PO, cabazitaxel IV, cyclophosphamide IV, dexamethasone PO, methylprednisolone IV, midazolam PO/IV, oxycodone PO and tolbutamide PO were identified as were adverse events resulting from an interaction between aprepitant/fosaprepitant and alcohol, anthracyclines, ifosfamide, oxycodone, quetiapine, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors and warfarin. Conclusions The potential for a drug interaction with aprepitant and fosaprepitant should be considered when selecting antiemetic therapy.

Purpose To develop an evidence-based clinical practice guideline for the prevention of oral mucositis in children (0–18 years) receiving treatment for cancer or undergoing haematopoietic stem cell transplantation (HSCT). Methods The Mucositis Prevention Guideline Development Group was interdisciplinary and included internationally recognised experts in paediatric mucositis. For the evidence review, we included randomised controlled trials (RCTs) conducted in either children or adults evaluating the following interventions selected according to prespecified criteria: cryotherapy, low level light therapy (LLLT) and keratinocyte growth factor (KGF). We also examined RCTs of any intervention conducted in children. For all systematic reviews, we synthesised the occurrence of severe oral mucositis. The Grades of Recommendation, Assessment, Development and Evaluation approach was used to describe quality of evidence and strength of recommendations. Results We suggest cryotherapy or LLLT may be offered to cooperative children receiving chemotherapy or HSCT conditioning with regimens associated with a high rate of mucositis. We also suggest KGF may be offered to children receiving HSCT conditioning with regimens associated with a high rate of severe mucositis. However, KGF use merits caution as there is a lack of efficacy and toxicity data in children, and a lack of long-term follow-up data in paediatric cancers. No other interventions were recommended for oral mucositis prevention in children. Conclusions All three specific interventions evaluated in this clinical practice guideline were associated with a weak recommendation for use. There may be important organisational and cost barriers to the adoption of LLLT and KGF. Considerations for implementation and key research gaps are highlighted.

Despite ototoxicity being a prevalent consequence of cisplatin chemotherapy, little guidance exists on interventions to prevent this permanent and progressive adverse event. To develop a clinical practice guideline for the prevention of cisplatin-induced ototoxicity in children and adolescents with cancer, we convened an international, multidisciplinary panel of experts and patient advocates to update a systematic review of randomised trials for the prevention of cisplatin-induced ototoxicity. The systematic review identified 27 eligible adult and paediatric trials that evaluated amifostine, sodium diethyldithiocarbamate or disulfiram, systemic sodium thiosulfate, intratympanic therapies, and cisplatin infusion duration. Regarding systemic sodium thiosulfate, the panel made a strong recommendation for administration in non-metastatic hepatoblastoma, a weak recommendation for administration in other non-metastatic cancers, and a weak recommendation against its routine use in metastatic cancers. Amifostine, sodium diethyldithiocarbamate, and intratympanic therapy should not be routinely used. Cisplatin infusion duration should not be altered as a means to reduce ototoxicity. Further research to determine the safety of sodium thiosulfate in patients with metastatic cancer is encouraged.

Terms used to label types of clinical recommendations and guidance are applied inconsistently and do not reflect the methods used to create each type. Here, the international Pediatric Oncology Supportive Care Guideline Network proposes a lexicon for types of recommendations and guidance documents. A lexicon describing three types of recommendations (clinical practice guideline-derived, good practice statement, and expert opinion statement) and two types of guidance documents (clinical practice guideline and expert opinion) is presented. Consistent use of this lexicon will allow pediatric oncology clinicians to readily appreciate the methods used to create clinical guidance.

Although pain is one of the most prevalent and bothersome symptoms children with cancer experience, evidence-based guidance regarding assessment and management is lacking. With 44 international, multidisciplinary healthcare professionals and nine patient representatives, we aimed to develop a clinical practice guideline (following GRADE methodology), addressing assessment and pharmacological, psychological, and physical management of tumor-, treatment-, and procedure-related pain in children with cancer. In this paper, we present our thorough methodology for this development, including the challenges we faced and how we approached these. This lays the foundation for our clinical practice guideline, for which there is a high clinical demand.

Busulfan therapeutic drug monitoring (TDM) is often used to achieve target plasma exposures. Variability in busulfan plasma exposure units (BPEU) is a potential source for misinterpretation of publications and protocols and is a barrier to data capture by hematopoietic cell transplantation (HCT) registry databases. We sought to harmonize to a single BPEU for international use. Using Delphi consensus methodology, iterative surveys were sent to an increasing number of relevant clinical stakeholders. In survey 1, 14 stakeholders were asked to identify ideal properties of a BPEU. In survey 2, 52 stakeholders were asked (1) to evaluate BPEU candidates according to ideal BPEU properties established by survey 1 and local position statements for TDM and (2) to identify potential facilitators and barriers to adoption of the harmonized BPEU. The most frequently used BPEU identified, in descending order, were area under the curve (AUC) in μM × min, AUC in mg × h/L, concentration at steady state (Css) in ng/mL, AUC in μM × h, and AUC in μg × h/L. All respondents conceptually agreed on the ideal properties of a BPEU and to adopt a harmonized BPEU. Respondents were equally divided between selecting AUC in μM × min versus mg × h/L for harmonization. AUC in mg × h/L was finally selected as the harmonized BPEU, because it satisfied most of the survey-determined ideal properties for the harmonized BPEU and is read easily understood in the clinical practice environment. Furthermore, 10 major professional societies have endorsed AUC in mg × h/L as the harmonized unit for reporting to HCT registry databases and for use in future protocols and publications.

Background Supportive care Prioritization, Assessment and Recommendations for Kids (SPARK) is a web application focused on improving symptom control. It enables pediatric cancer and hematopoietic stem cell transplant (HSCT) patients to self-report and track symptoms, and allows healthcare professionals to access guidelines for symptom management. Objective was to determine the feasibility of longitudinal collection of symptom data. Methods In this longitudinal, single-armed feasibility study, respondents were children 8–18 years of age with cancer or pediatric HSCT recipients. Participants completed symptom reporting daily for 5 days. Cognitive interviews were conducted on day 5. Quantitative evaluation included SPARK ease of use and understandability of SPARK reports. Qualitative feedback on facilitators and barriers to daily symptom screening was solicited. Feasibility was defined as ≥75% of participants completing symptom screening on at least 60% of on-study days during the five-day study. Results Among the 30 children enrolled, the median number of days SSPedi was completed at least once was 5 (range 3 to 5). Overall, 28/29 (96.6%) thought completing symptom screening using SPARK was easy or very easy. All participants understood SPARK symptom reports. Severe symptoms was the most common barrier to daily reporting while an alarm reminder system was the most commonly identified facilitator. Conclusions Daily completion of symptom screening using SPARK over 5 days was feasible in children aged 8 to 18 years with cancer and pediatric HSCT recipients. SPARK is now appropriate for use in randomized trials to evaluate the effect of symptom screening and symptom feedback.