PURPOSE:Fever in neutropenia (FN) is a potentially lethal complication of chemotherapy for cancer. Prompt administration of broad-spectrum antibiotics is standard of care. Despite conflicting results on the association of time to antibiotics (TTA) with outcomes, TTA limits are used as FN quality measure both in adult and pediatric oncology. This individual patient data (IPD) meta-analysis studied the association between TTA and outcomes in pediatric patients with FN. PATIENTS AND METHODS:IPD on TTA in pediatric patients with FN receiving chemotherapy for any malignancy was collected internationally. Three-level mixed binomial logistic regression analyzed the association of TTA with safety relevant events (SRE; death, admission to intensive care unit [ICU], bacteremia), primarily in patients with severe disease at presentation and secondarily in all patients. RESULTS:Data on 4006 FN episodes in 2073 patients, diagnosed 2016-2023, were reported from 15 study sites in eight countries. Median TTA was 61 min overall and 53 min in the 345 (8.6%) episodes with severe disease at presentation. Among these with severe disease, an SRE was reported in 119 (34%) episodes. Longer TTA (> 60 vs. ≤ 60 min) was associated with less SRE (odds ratio, 0.41; 95% CI, 0.24-0.70). This primary finding was confirmed in secondary and additional exploratory analyses. CONCLUSION:This large, international and adequately powered IPD meta-analysis found no association between shorter TTA and improved clinical outcomes in pediatric patients with FN. This finding was consistent across analyses. These results challenge the continued use of TTA limits as a quality measure for pediatric oncology centers.

INTRODUCTION:While clinical practice guidelines (CPGs) for pediatric oncology infection prophylaxis and management exist, few data describe actual management occurring at pediatric oncology centers. METHODS:An electronic survey querying infection management practices in nontransplant pediatric oncology patients was iteratively created by the Children's Oncology Group (COG) Cancer Control and Supportive Care Infectious Diseases Subcommittee and sent to leaders at all COG institutions, limiting each site to one response to represent their institution. RESULTS:The response rate was 57% (129/227 institutions). Many sites reported utilizing COG-endorsed CPGs for antibacterial (76%) and antifungal prophylaxis (74%), and fever and neutropenia (FN, 64%). Most institutions reported using antimicrobial prophylaxis for patients with acute myeloid leukemia (88% antibacterial, 100% antifungal) and relapsed acute lymphoblastic leukemia (82% antibacterial, 95% antifungal). Definitions of fever, phagocyte recovery, and antibiotic duration in febrile patients varied. Most institutions administer empiric broad-spectrum antibiotics for nonneutropenic fever, although 14% reported withholding antibiotics based on initial clinical status or risk stratification tools. Most respondents reported (70%) admitting FN patients for at least 48 h, however 15% have low-risk FN protocols allowing outpatient management. FN patients remain admitted on antibiotics through count recovery in 50% of institutions, whereas the others employed various early discharge/early antibiotic discontinuation strategies. CONCLUSIONS:There is often consistency but also substantial variability in reported antimicrobial prophylaxis strategies and management of patients with fever and represents an opportunity for implementation studies to standardize application of CPG recommendations and randomized trials to advance evidence where knowledge gaps exist.

The primary objective is to identify which observational research methods have been used in the last 5 years in rare disease drug evaluation and how they are applied to generate adequate evidence regarding the real-world effectiveness or safety of rare disease drugs. Rare disease is an umbrella term for a condition which affects < 200,000 people each year and despite the rarity of these conditions, collectively they encompass approximately 7000 different conditions. With the striking number of rare conditions, many pharmaceutical manufacturers are introducing an increased number of drugs to treat them. However, due to small patient populations, heterogeneity and other factors related to rare diseases, there are feasibility concerns regarding the generation of adequate efficacy and safety evidence using conventional randomized controlled trials (RCTs). Recently, real-world evidence generated through observational (or real-world) studies has been proposed to address some of the feasibility concerns with RCTs by measuring drug effectiveness or safety in the real-world setting. However, there remain methodological concerns due to a lack of randomization/masking. This proposed scoping review aims to identify which observational research methods in the last 5 years are used in rare disease drug evaluation to address methodological concerns and how they are applied to generate evidence on drug effectiveness or safety. Articles must be primary observational or real-world studies reporting rare disease drug effectiveness or safety published within the five years preceding this review. Literature reviews, meta-analyses, randomized control trials, case series, case reports, opinion pieces, conference abstracts, and studies with unavailable full-text articles will be excluded. The search strategy will combine the following key search concepts: rare disease, drugs for rare disease and observational/real-world studies. The search will be conducted in MEDLINE and EMBASE. Review registration number: Open Science Framework, https://osf.io/f3wpv.

PURPOSE:Ten pediatric cancer treatment sites previously implemented site-specific symptom management care pathways for 15 symptoms, which were based upon clinical practice guidelines (CPGs). The primary objective of this analysis was to describe the prevalence of care pathway- and CPG-consistent care for symptom management. The secondary objective was to identify factors associated with care pathway-consistent care. METHODS:Participants were patients age 8-18 years diagnosed with cancer within the previous 4 weeks. We identified any intervention to manage each of 15 symptoms during a 3-day period 8 weeks after enrollment. We determined whether the intervention appeared in that site's care pathway and whether it was recommended in the CPG. We determined whether type of symptom (observable v nonobservable) or patient characteristics were associated with care pathway-consistent care. RESULTS:Two hundred twenty participants were analyzed. The prevalence of care pathway-consistent care for each symptom ranged from 0% (problems thinking, body or face changes, and diarrhea) to 52.3% (throwing up) and was <27% for 14 of 15 symptoms. Similarly, the prevalence of CPG-consistent care was <50% across all symptoms. Participants received significantly more care pathway-consistent interventions for observable symptoms compared with nonobservable symptoms (difference 30% [95% CI, 3 to 54]). Factors associated with receipt of at least one care pathway-consistent intervention were age group, race, ethnicity, and cancer type. CONCLUSION:Care pathway- and CPG-consistent care were surprisingly uncommon. Care pathway-consistent interventions were more common for observable than nonobservable symptoms and were associated with patient characteristics. Future work should identify approaches to improve care pathway-consistent care delivery.

Background:Food restrictions during periods of neutropenia have been widely used in oncology settings to prevent infections. As there is a lack of clearly demonstrated effectiveness, this strategy is being increasingly questioned. Methods:A multi-national panel of 23 individuals was convened to develop a clinical practice guideline (CPG) on the use of food restrictions to prevent infections in paediatric patients with cancer and haematopoietic cell transplantation (HCT) recipients. It included representation from persons with lived experience and physicians, dieticians, nurses, pharmacists and guideline methodologists working in paediatric oncology/HCT or infectious diseases. Panel members (female n = 15; 65%) were from North America (12, 52%), Europe (8, 35%), South America (2, 9%) and Australia (1, 4%). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to formulate the CPG recommendations based on a systematic review of randomised controlled trials (RCTs). MEDLINE, MEDLINE in-Process and Embase databases were searched from January 1, 1980, to May 7, 2024, with a broad strategy which combined subject headings and text words relating to neutropenia, infection and diet. Findings:The systematic review, which provided the evidence base for the CPG recommendations, identified 4312 unique citations, of which 52 were retrieved for full-text evaluation. Eight RCTs met the eligibility criteria and informed panel deliberations. Although there was clinical heterogeneity in the food restrictions evaluated, data were consistent in suggesting that food restrictions lack clinically significant benefit in preventing infections. The panel made two conditional recommendations against the use of food restrictions in a) paediatric patients with cancer receiving chemotherapy and b) in the setting of allogeneic and autologous HCT. The panel developed a good practice statement to emphasise the importance of health care organisations and families adhering to local food safety practices. Interpretation:This CPG provides the first evidence-based recommendations on use of food restrictions to prevent infections in children and adolescents undergoing chemotherapy and paediatric haematopoietic cell transplant recipients. Funding:This CPG was funded and developed through the POGO Guidelines Program.

Chemotherapy-induced peripheral neuropathy (CIPN) affects > 78

PURPOSE:Care pathways are an implementation tool to help bridge the gap between evidence-based clinical practice guidelines and clinical practice. At four pediatric cancer institutions in Ontario, Canada, institution-specific care pathways for the management of infection complications in pediatric oncology were created. To standardize care delivery approaches across institutions, a project to harmonize the institution-specific care pathways was undertaken. METHODS:The institution-specific infection care pathways were compared. Discrepancies between the pathways were identified, and 33 care pathway components covering 10 clinical actions were prioritized for harmonization. An in-person harmonization meeting with representatives from all institutions was convened, where potential areas for harmonization were identified. At the end of the discussion of each clinical action, the institutional representatives gauged the feasibility of harmonization on a five-point Likert scale. A second virtual meeting was then held to finalize the harmonization plan. RESULTS:Of the 33 care pathway components, harmonization was achieved for 25. Of the 10 components related to antibacterial and antifungal prophylaxis choice, timing, and indications, eight were harmonized. Harmonization was reached for 11 of 16 components related to the initial and ongoing management of febrile neutropenia. Harmonization was achieved for six of the seven components related to prolonged fever. CONCLUSION:Harmonization of infection care pathways across institutions was achieved. However, certain care pathway elements may not be amenable to harmonization due to differences in institutional resources, cultures, and priorities.

INTRODUCTION:Objective was to describe the association between baseline characteristics and the number of Symptom Screening in Pediatrics Tool (SSPedi) assessments completed over an 8-week period. METHODS:This was a sub-analysis of a cluster randomized controlled trial among 10 sites that were randomized to the intervention group. Participants were English- or Spanish-speaking pediatric patients 8-18 years of age newly diagnosed with cancer. Participants were prompted to complete SSPedi three times weekly for 8 weeks. The outcome was the number of SSPedi assessments completed during the 8-week period. Factors associated with the number of assessments were determined using mixed effects Poisson regression. RESULTS:At the 10 intervention sites, 216 patients were included in the analysis. Among these participants, 129 (59.7%) were male, 112 (51.9%) were white, and 83 (38.4%) were Hispanic. The number of SSPedi assessments was significantly higher for participants 11-14 years (rate ratio (RR) 1.13, 95% confidence interval (CI) 1.02-1.25) and 15-18 years (RR 1.15, 95% CI 1.04-1.27) compared to 8-10 years. Participants completed more SSPedi assessments if they were Asian compared to white (RR 1.27, 95% CI 1.10-1.46), non-Hispanic compared to Hispanic (RR 1.15, 95% CI 1.04-1.28) and from families with a household income ≥$60,000 (RR 1.12, 95% CI 1.03-1.21). Participants completed fewer SSPedi assessments if they had solid tumors compared to leukemia (RR 0.91, 95% CI 0.84-0.99). CONCLUSION:Adherence to three-times weekly SSPedi varied by age, race, ethnicity, cancer diagnosis, and family income. This information may facilitate interventions to support routine symptom screening in clinical practice. TRIAL REGISTRATION:NCT04614662.

PURPOSE:The objective was to identify factors associated with self-reported symptom burden measured using Symptom Screening in Pediatrics Tool (SSPedi) in pediatric patients with cancer. METHODS:This was a secondary analysis of a cluster randomized trial enrolling pediatric patients newly diagnosed with cancer. Twenty sites were randomized to routine symptom screening versus usual care. Intervention included thrice-weekly symptom screening with SSPedi, delivery of severely bothersome scores to health care teams, and implementation of locally adapted symptom management care pathways. Primary outcome was total SSPedi scores, 0 (no bothersome symptoms) to 60 (worst bothersome symptoms), obtained at baseline, week four, and week eight in 430 patients (n = 217 intervention and n = 213 usual care). We created a mixed linear regression model evaluating design (including time point), patient/guardian, and site characteristics for their associations with symptom burden after controlling for treatment assignment. RESULTS:SSPedi scores were significantly lower at weeks 4 and 8 compared with baseline (P < .0001 overall), and at intervention versus control sites (P < .0001). In the full model, males (estimate, -3.3 [95% CI, -4.6 to -2.0]; P < .0001) and sites with higher physician staffing ratios (each physician full-time equivalent per 100 new diagnoses estimate -0.20 [95% CI, -0.5 to 0.0]; P = .024) had significantly lower total SSPedi scores. CONCLUSION:Total symptom burden was reduced by time, intervention (symptom screening and care pathways), and greater physician staffing ratio. Females had higher symptom burden. These data may inform programmatic implementation of routine symptom screening in pediatric patients with cancer.

Impact of infection management care pathway implementation is uncertain in pediatric cancer. Objective was to determine whether fewer patients received clinical practice guideline (CPG)- and care pathway-inconsistent care after implementation of an adapted infection management care pathway compared to pre-implementation. We implemented adapted infection management care pathways based on CPGs for prophylaxis, and initial, ongoing, and prolonged fever and neutropenia (FN) management in three centers. We conducted a retrospective chart review, sampling patients with episodes of high- and low-risk FN, pre- and post-implementation of the care pathway. Up to five chemotherapy cycles per patient were adjudicated for antibacterial and antifungal prophylaxis care pathway inconsistency. Among these cycles, FN episodes were identified, and one was randomly chosen per patient. CPG- and care pathway-inconsistent actions were adjudicated. Three hundred seventy-five patients were assessed for eligibility, and 272 were included. For prophylaxis, 115 pre-implementation and 57 post-implementation high-risk cycles were evaluated. For FN, 82 pre-implementation and 42 post-implementation episodes were evaluated. Antifungal prophylaxis inconsistency decreased in the post-implementation period compared with the pre-implementation period (P = 0.023). However, there were no other significant differences in CPG- or care pathway-inconsistent actions by period. In both periods, CPG- and care pathway-inconsistent actions were common. Implementation of adapted care pathways for infection management was associated with fewer patients receiving care pathway-inconsistent antifungal prophylaxis. However, it did not reduce other CPG- or care pathway-inconsistent actions. Inconsistent actions for FN management were common in both periods. Targeted approaches are required to improve care pathway-consistent infection management in pediatric cancer patients.

Importance:Pediatric patients with cancer experience severely bothersome symptoms during treatment. It was hypothesized that symptom screening and provision of symptom reports to the health care team would reduce symptom burden in pediatric patients with cancer. Objective:To determine if daily symptom screening and provision of symptom reports to the health care team was associated with lower total symptom burden as measured by the Symptom Screening in Pediatrics Tool (SSPedi) compared to usual care among pediatric patients with cancer admitted to a hospital or seen in a clinic daily for at least 5 days. Design, Setting, and Participants:This randomized clinical trial enrolled participants from July 2018 to September 2023 from 8 Canadian tertiary care centers that diagnose and treat pediatric patients with cancer. Patients aged 8 to 18 years with cancer expected to be in a hospital or clinic daily for at least 5 consecutive days were eligible for inclusion. Participants were randomized to intervention (n = 176) vs control (n = 169) groups. Data were analyzed from November 2023 to December 2023. Intervention:Intervention participants completed the SSPedi once daily for 5 days. Printed symptom reports were provided daily to the health care team, and email alerts were distributed for severely bothersome symptoms. Control participants received usual care. Main Outcomes and Measures:The primary outcome was self-reported total SSPedi score on day 5. Secondary outcomes were individual SSPedi symptoms, pain, quality of life, symptom documentation, and intervention provision. The primary analysis compared the day 5 total SSPedi scores between randomized groups using a multiple linear regression model. For the secondary analysis comparing individual SSPedi symptom scores, the odds ratio for the intervention was estimated using a proportional odds model. Pain and quality of life were analyzed using the same approach as the primary outcome. Fisher exact test was used to compare symptom documentation, any intervention, and symptom-specific intervention between groups. Results:A total of 345 participants were enrolled; median (range) participant age was 13.8 (8.0-18.8) years, and 150 participants (43.5%) were female. Day 5 SSPedi score was significantly better with symptom screening compared to usual care (adjusted mean difference, -2.5; 95% CI, -3.8 to -1.2). Symptom screening reduced the odds of higher individual symptom scores; 8 of 15 symptom reductions were statistically significant. There were no significant differences in pain or quality of life scores between groups. Five symptoms were documented or treated significantly more often with symptom screening than usual care. Conclusions and Relevance:In this randomized clinical trial, among pediatric patients with cancer admitted to a hospital or seen in a clinic daily for at least 5 days, symptom screening with SSPedi improved total symptom scores compared to usual care. Trial Registration:ClinicalTrials.gov Identifier: NCT03593525.

Objective: Progress toward incorporating patient-reported outcomes (PROs) into the routine clinical care of pediatric cancer patients has accelerated over the last decade. Objective was to review general PRO considerations for pediatric cancer patients, describe the impact of PROs from adult cancer trials, summarize Symptom Screening in Pediatrics Tool (SSPedi) suite development and validation, and highlight recent clinical trials evaluating SSPedi implementation. Methods: This review addressed the following topics: instrument choice, respondent type, lessons learned from adult oncology trials, SSPedi tools, recent randomized controlled trials (RCTs) of symptoms screening using SSPedi, and future directions. Results: Instrument choice should be guided by the purpose of the assessment, where reasons include monitoring for adverse effects during cancer treatment clinical trials, choice as primary or secondary outcomes for supportive care clinical trials, and enabling routine symptom screening to enhance clinical care. While pediatric patient self-report of subjective symptoms is ideal, it may not always be feasible and careful consideration of respondent type is required. Instruments developed for use by different respondent types will likely be required for clinical implementation. Both adult and pediatric trials have demonstrated the value of symptom screening and support its adoption into routine clinical care. Two recent RCTs have shown that administration of SSPedi can improve symptom control in pediatric cancer patients. Conclusions: There have been many advancements in PROs for pediatric cancer patients. Identifying approaches to feasibly implement symptom screening into routine clinical care is required. In the future, routine monitoring of symptoms should be a measure of quality of care.

The Symptom Screening in Pediatrics Tool (SSPedi) was developed to facilitate symptom assessment among pediatric patients receiving cancer treatments; limited translations are available. The objective was to describe, among non-English pediatric patients receiving cancer treatments and non-English guardians, the language in which they understood symptoms and their language preferences for SSPedi completion. In this single-center study, we included patients receiving cancer treatments aged 8–18 years or guardians of patients 2–18 years with non-English first languages. A single interview was conducted where participants were asked whether they understood the words for each of the 15 SSPedi symptoms in their first language, English, or both. We also asked about the importance of SSPedi translation in their first language. We included 50 pediatric patients and 155 guardians speaking 49 unique first languages. The number who knew a symptom only in their first language ranged from 2/50 (4.0

BACKGROUND:Supportive care clinical practice guidelines (CPGs) facilitate the incorporation of the best available evidence into pediatric cancer care. We aimed to assess the impact of the work of the Children's Oncology Group (COG) Supportive Care Guideline Task Force on institutional supportive care practices. PROCEDURE:An online survey was distributed to representatives at 209 COG sites to assess the awareness, use, and helpfulness of COG-endorsed supportive care CPGs. Availability of institutional policies regarding 13 topics addressed by current COG-endorsed CPGs was also assessed. Respondents described their institutional processes for developing supportive care policies. RESULTS:Representatives from 92 COG sites responded to the survey, and 78% (72/92) were "very aware" of the COG-endorsed supportive care CPGs. On average, sites had policies that addressed seven COG-endorsed supportive care CPG topics (median = 7, range: 0-12). Only 45% (41/92) of sites reported having institutional processes for developing supportive care policies. Of these, most (76%, 31/41) reported that the COG-endorsed CPGs have a medium or large impact on policy development. Compared with sites without processes for supportive care policy development, sites with established processes had policies on a greater number of topics aligned with current COG-endorsed CPG topics (mean = 6.6, range: 0-12 vs mean = 7.9, range: 2-12; p = 0.027). CONCLUSIONS:Most site respondents were aware of the COG-endorsed supportive care CPGs. Less than half of the COG sites represented in the survey have processes in place to implement supportive care policies. Improvement in local implementation is required to ensure that patients at COG sites receive evidence-based supportive care.

Importance:Pediatric patients with cancer commonly experience severely bothersome symptoms. The effectiveness of routine symptom screening with symptom feedback and symptom management care pathways is unknown. Objective:To determine whether thrice-weekly symptom screening with symptom feedback and management care pathways, compared with usual care, improves overall self-reported symptom scores measured by the Symptom Screening in Pediatrics Tool (SSPedi) in pediatric patients with cancer. Design, Setting, and Participants:This cluster randomized trial enrolled participants between July 2021 and August 2023 from 20 pediatric cancer centers in the US. Patients newly diagnosed with cancer aged 8 to 18 years receiving any cancer treatment were included. Twenty sites were randomized to provide symptom screening (n = 10) vs usual care (n = 10); 221 participants were enrolled at intervention sites and 224 participants at control sites. The date of final follow-up was October 18, 2023. Intervention:Symptom screening included providing thrice-weekly symptom screening prompts to participants, email alerts to the health care team, and locally adapted symptom management care pathway implementation. Main Outcomes and Measures:The primary outcome was self-reported total SSPedi score at week 8 (range, 0-60; higher scores indicate more bothersome). Secondary outcomes were Patient-Reported Outcomes Measurement Information System Fatigue score (mean [SD] score, 50 [10]; higher scores indicate more fatigue), Pediatric Quality of Life 3.0 Acute Cancer Module scores (range, 0-100; higher scores indicate better health), symptom documentation and interventions at week 8, and unplanned health care encounters. Results:A total of 445 participants (median [range] age, 14.8 [8.1-18.9] years; 58.9% males) were enrolled. The mean (SD) 8-week SSPedi score was 7.9 (7.2) in the symptom screening group vs 11.4 (8.7) in the usual care group. Symptom screening was associated with significantly better 8-week total SSPedi scores (adjusted mean difference, -3.8 [95% CI, -6.4 to -1.2]) and less bothersome individual symptoms, with 12 of 15 symptoms being statistically significantly reduced. There was no difference in fatigue or quality of life. The mean (SD) number of emergency department visits was 0.77 (1.12) in the symptom screening group and 0.45 (0.81) in the usual care group. There were significantly more emergency department visits in the symptom screening group (rate ratio, 1.72 [95% CI, 1.03-2.87]). Conclusions:Symptom screening with symptom feedback and symptom management care pathways was associated with improved symptom scores and increased symptom-specific interventions. Future work should integrate symptom screening into routine clinical care. Trial Registration:ClinicalTrials.gov Identifier: NCT04614662.

ImportancePediatric patients with cancer commonly experience severely bothersome symptoms. The effectiveness of routine symptom screening with symptom feedback and symptom management care pathways is unknown.ObjectiveTo determine whether thrice-weekly symptom screening with symptom feedback and management care pathways, compared with usual care, improves overall self-reported symptom scores measured by the Symptom Screening in Pediatrics Tool (SSPedi) in pediatric patients with cancer.Design, Setting, and ParticipantsThis cluster randomized trial enrolled participants between July 2021 and August 2023 from 20 pediatric cancer centers in the US. Patients newly diagnosed with cancer aged 8 to 18 years receiving any cancer treatment were included. Twenty sites were randomized to provide symptom screening (n = 10) vs usual care (n = 10); 221 participants were enrolled at intervention sites and 224 participants at control sites. The date of final follow-up was October 18, 2023.InterventionSymptom screening included providing thrice-weekly symptom screening prompts to participants, email alerts to the health care team, and locally adapted symptom management care pathway implementation.Main Outcomes and MeasuresThe primary outcome was self-reported total SSPedi score at week 8 (range, 0-60; higher scores indicate more bothersome). Secondary outcomes were Patient-Reported Outcomes Measurement Information System Fatigue score (mean [SD] score, 50 [10]; higher scores indicate more fatigue), Pediatric Quality of Life 3.0 Acute Cancer Module scores (range, 0-100; higher scores indicate better health), symptom documentation and interventions at week 8, and unplanned health care encounters.ResultsA total of 445 participants (median [range] age, 14.8 [8.1-18.9] years; 58.9% males) were enrolled. The mean (SD) 8-week SSPedi score was 7.9 (7.2) in the symptom screening group vs 11.4 (8.7) in the usual care group. Symptom screening was associated with significantly better 8-week total SSPedi scores (adjusted mean difference, −3.8 [95% CI, −6.4 to −1.2]) and less bothersome individual symptoms, with 12 of 15 symptoms being statistically significantly reduced. There was no difference in fatigue or quality of life. The mean (SD) number of emergency department visits was 0.77 (1.12) in the symptom screening group and 0.45 (0.81) in the usual care group. There were significantly more emergency department visits in the symptom screening group (rate ratio, 1.72 [95% CI, 1.03-2.87]).ConclusionsSymptom screening with symptom feedback and symptom management care pathways was associated with improved symptom scores and increased symptom-specific interventions. Future work should integrate symptom screening into routine clinical care.Trial RegistrationClinicalTrials.gov Identifier: NCT04614662