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Background: Red blood cell (RBC) transfusions play an important role in supportive care in children and neonates with cancer. However, in current clinical practice, evidence-based recommendations are lacking on when to administer prophylactic RBC transfusions. To address this gap, a clinical practice guideline (CPG) was developed to systematically review the available evidence and provide recommendations for clinicians., Methods: A systematic literature review in three databases was conducted. The GRADE methodology was used to assess, extract, and summarize the evidence. A multidisciplinary panel of 21 professionals was assembled to ensure comprehensive expertise. If there was insufficient evidence in children with cancer, additional evidence was gathered in general pediatric or adult oncology guidelines, or the panel utilized shared expert opinion to develop a comprehensive CPG. Multiple in-person meetings were conducted to discuss evidence, complete evidence-to-decision frameworks, and formulate recommendations., Results: Four studies including 203 children with all types of cancer, met the inclusion criteria. The expert panel assessed all evidence and translated it into recommendations. In total, 47 recommendations were formulated regarding RBC transfusions in children and neonates with cancer. For instance, specific thresholds for prophylactic RBC transfusions were recommended for children and neonates with cancer who have sepsis, are on ECMO, or are undergoing radiotherapy., Conclusion: This clinical practice guideline presents evidence-based recommendations regarding RBC transfusions in children and neonates with cancer. By providing these recommendations, we aim to guide clinicians and contribute to improving outcomes for children and neonates with cancer., (© 2024. The Author(s).)

Purpose: In current clinical practice, recommendations regarding restrictions in daily life for children with cancer are often lacking or not evidence-based. Critically reviewing the evidence and formulating recommendations are therefore of great importance as social restrictions (e.g., swimming, school attendance, sports) can impair the quality of life of these children severely. Therefore, our aim was to develop a clinical practice guideline for clinicians, children, and their parents regarding social restrictions in children with cancer., Methods: A comprehensive multidisciplinary panel was assembled, comprising 21 professionals and patient representatives. A systematic literature review was performed, including dual appraisal of all citations. The GRADE methodology was used to extract, summarize, and assess the evidence. Multiple in-person meetings were held to rank outcomes, discuss evidence, complete evidence-to-decision frameworks, and formulate recommendations. Final recommendations were unanimously supported by all panel members., Results: Six studies, including 758 children, formed the evidence base for the recommendations. Given the scarcity of the available evidence and various designs of studies in children with cancer, additional evidence was extracted from adult oncology guidelines, and shared expert opinions were utilized. In total, 14 recommendations were formulated of which multiple result in changes in current policy and standard of practice in the Netherlands. Topics covered in this guideline are swimming, having pets, visiting the zoo or farm, performing sports or high-velocity events, attending school or kindergarten, and use of public transport. This guideline is not intended to provide recommendations for patients after end of treatment, for palliative care settings, or for children undergoing a stem cell transplantation., Conclusions: In this clinical practice guideline, we provide recommendations regarding restrictions in daily life in children with cancer. These include evidence-based recommendations and, in the absence of sufficient evidence, recommendations based on expert evidence. With these recommendations, we provide guidance for clinicians, children, and parents and contribute to improving quality of life for children with cancer., (© 2024. The Author(s).)

Background: Fetal and neonatal exposure to antibiotics may contribute to the development of necrotizing enterocolitis (NEC) in preterm infants. This systematic review and meta-analysis investigate whether exposure to third trimester maternal antibiotics (MAB) and/or prolongation of empirical antibiotics (PEAB) are associated with NEC development in preterms., Method: We included observational and randomized controlled studies, including those on preterm or very low birth weight (VLBW) infants, from MEDLINE and EMBASE, published between 1990 and June 2021. Exposure was defined as third trimester MAB and/or PEAB. The two reviewers independently performed study selection, data extraction, and quality assessment., Results: Three cohort studies compared third trimester MAB with no antibiotics. MAB was associated with lower NEC incidence, unadjusted pooled odds ratio (OR) is 0.57 (95% CI: 0.35-0.93). Twelve cohort studies showed that PEAB was associated with an increased risk of NEC. Ten observational cohort studies show an unadjusted OR of 2.72 (1.65-4.47), and two case-control studies show an unadjusted mean difference of 2.31 (0.94-3.68). Moderate to substantial heterogeneity was observed but decreased in studies with low risk of bias and large sample size., Conclusion: Evidence suggests an association between MAB and decreased risk of NEC and an association between PEAB and increased risk of NEC. Further studies should confirm these associations and explore causality., Systematic Review Registration: identifier [CRD42022304937]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Klerk, van Avezaath, Loeffen, Hulscher and Kooi.)

Patients with childhood, adolescent, and young adult cancer who will be treated with gonadotoxic therapies are at increased risk for infertility. Many patients and their families desire biological children but effective communication about treatment-related infertility risk and procedures for fertility preservation does not always happen. The PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group reviewed the literature and developed a clinical practice guideline that provides recommendations for ongoing communication methods for fertility preservation for patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger and their families. Moreover, the guideline panel formulated considerations of the ethical implications that are associated with these procedures. Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the evidence and recommendations. In this clinical practice guideline, existing evidence and international expertise are combined to develop transparent recommendations that are easy to use to facilitate ongoing communication between health-care providers and patients with childhood, adolescent, and young adult cancer who might be at high risk for fertility impairment and their families., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Female patients with childhood, adolescent, and young adult cancer are at increased risk for fertility impairment when treatment adversely affects the function of reproductive organs. Patients and their families desire biological children but substantial variations in clinical practice guidelines reduce consistent and timely implementation of effective interventions for fertility preservation across institutions. As part of the PanCareLIFE Consortium, and in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in female patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. This clinical practice guideline leverages existing evidence and international expertise to develop transparent recommendations that are easy to use to facilitate the care of female patients with childhood, adolescent, and young adult cancer who are at high risk for fertility impairment. A complete review of the existing evidence, including a quality assessment, transparent reporting of the guideline panel's decisions, and achievement of global interdisciplinary consensus, is an important result of this intensive collaboration., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Male patients with childhood, adolescent, and young adult cancer are at an increased risk for infertility if their treatment adversely affects reproductive organ function. Future fertility is a primary concern of patients and their families. Variations in clinical practice are barriers to the timely implementation of interventions that preserve fertility. As part of the PanCareLIFE Consortium, in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in male patients who are diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. Recognising the need for global consensus, this clinical practice guideline used existing evidence and international expertise to rigorously develop transparent recommendations that are easy to use to facilitate the care of male patients with childhood, adolescent, and young adult cancer who are at high risk of fertility impairment and to enhance their quality of life., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Despite advances in personalizing the efficacy of cancer therapy, our ability to identify patients at risk of severe treatment side effects and provide individualized supportive care is limited. This is particularly the case for mucositis (oral and gastrointestinal), with no comprehensive risk evaluation strategies to identify high-risk patients. We, the Multinational Association for Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) Mucositis Study Group, therefore aimed to systematically review current evidence on that factors that influence mucositis risk to provide a foundation upon which future risk prediction studies can be based., Methods: We identified 11,018 papers from PubMed and Web of Science, with 197 records extracted for full review and 113 meeting final eligibility criteria. Data were then synthesized into tables to highlight the level of evidence for each risk predictor., Results: The strongest level of evidence supported dosimetric parameters as key predictors of mucositis risk. Genetic variants in drug-metabolizing pathways, immune signaling, and cell injury/repair mechanisms were also identified to impact mucositis risk. Factors relating to the individual were variably linked to mucositis outcomes, although female sex and smoking status showed some association with mucositis risk., Conclusion: Mucositis risk reflects the complex interplay between the host, tumor microenvironment, and treatment specifications, yet the large majority of studies rely on hypothesis-driven, single-candidate approaches. For significant advances in the provision of personalized supportive care, coordinated research efforts with robust multiplexed approaches are strongly advised.

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., Competing Interests: Conflict of interest statement The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: Intensive treatment regimens have contributed to a marked increase in childhood cancer survival rates. Death due to treatment-related adverse effects becomes an increasingly important area to further improve overall survival. In this study, we examined 5-year survival in children with cancer to identify risk factors for treatment-related mortality (TRM)., Methods: All children (aged <18 years at diagnosis) diagnosed with cancer in 2 Dutch university hospitals between 2003 and 2013 were included, survival status was determined and causes of death were analysed. Various demographic and treatment factors were evaluated, for which a multivariable competing risks analysis was performed., Results: A total of 1764 patients were included; overall 5-year survival was 78.6%. Of all 378 deaths, 81 (21.4%) were treatment-related, with infection being responsible for more than half of these deaths. Forty percent of TRM occurred in the first three months after initial diagnosis. Factors associated with TRM in the multivariable competing risks analysis were diagnosis of a haematological malignancy, age at diagnosis <1 year and receipt of allogeneic haematopoietic stem cell transplantation. In children suffering from haematological malignancies, TRM accounted for 56.3% of 103 deaths., Conclusion: Over one in five deaths in children with cancer death was related to treatment, mostly due to infection. In children suffering from a haematological malignancy, more children died due to their treatment than due to progression of their disease. To further increase overall survival, clinical and research focus should be placed on lowering TRM rates without compromising anti-tumour efficacy. The findings presented in this study might help identifying areas for improvement., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2019 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

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., (© 2018 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

Background: Pain in children and adolescents with cancer has been identified as an area where many healthcare professionals seek guidance. This protocol details a systematic review whose aim is to explore current knowledge regarding measurement instruments to assess pain (and pain-related distress) in children and adolescents with cancer. After completion of the review, the information will be used in the development of a clinical practice guideline., Methods: We will search four electronic databases (MEDLINE via PubMed, CINAHL, PsycINFO and HaPI). Additional relevant studies will be identified by reference checking and expert consultation. All citations will be screened independently by two reviewers in a three-step approach: first selection based on title, second selection based on abstract, third selection based on full-text. Studies in children and adolescents with cancer that aimed to evaluate the clinimetric properties of an existing pain measurement instrument or to develop a new pain measurement instrument and that include at least one relevant outcome (reliability, validity, responsiveness, interpretability, clinical utility) are eligible for inclusion. For all steps of evidence selection, a detailed list with eligibility criteria will be determined a priori. Data extraction and quality assessment of included studies (according to the COnsensus-based Standards for the selection of health Measurement INstruments, COSMIN criteria) will be conducted independently by two authors., Discussion: This systematic review will provide an overview of the current literature regarding measurement instruments to assess pain in children and adolescents with cancer. This knowledge synthesis will be used to formulate recommendations for clinical practice. Also, by synthesizing existing evidence, knowledge gaps will be identified., Systematic Review Registration: PROSPERO CRD42017072879.

Purpose: Only a third of children with cancer and febrile neutropenia (FN) have a proven bacterial infection; nevertheless, most children are hospitalized and treated with intravenous antibiotics. Several biomarkers have been proposed as predictive markers for bacterial infection in this population. We aimed to evaluate the role of interleukin-6 (IL-6) and procalcitonin (PCT) in diagnosing bacterial infection in children with cancer and FN., Methods: The study population was derived from a prospective database (2006-2013, IL-8 study) comprising children with cancer who presented with FN. From stored plasma samples (taken at admission and/or at 12-24 h), we determined the PCT and IL-6 levels. Consequently, we explored their relation with the presence of bacterial infection (positive blood culture, radiologically documented infection or clinical bacterial focus). We predefined cutoff values at 60 ng/L for IL-6 and 0.25 ng/mL for PCT., Results: Seventy-seven FN episodes in 55 children with cancer were included. In 18 episodes (23.4%), a bacterial infection was documented. Both at presentation and after 12-24 h, median values of IL-6 and PCT were significantly higher in patients with a bacterial infection compared to patients without a bacterial infection. With both biomarkers above cutoff values, sensitivity was 93% (with either one, this was even 100%). The identified group at low risk for bacterial infection comprised 41% of the population., Conclusion: PCT and IL-6 are promising markers in identifying bacterial infection in children with cancer and FN. In a subsequent project, we will incorporate these biomarkers in a risk assessment model that we will test prospectively in a clinical trial.

Aims: Survival after cancer diagnosed during childhood or adolescence continues to improve with new treatments and supportive therapies. Optimal long-term care requires that risks to vulnerable organs are clearly defined and translated into guidelines that are implemented into practice. PanCareLIFE is a pan-European consortium that addresses survivorship issues comprising fertility, hearing impairment and quality of life. This article describes the scientific basis of PanCareLIFE's studies., Methods: PanCareLIFE involves 17 partner institutions from eight European countries, with additional 11 data providers from five other countries. Study designs and methods include molecular genetic, cohort and case-control studies, a longitudinal study and an intervention study. Ethics and data protection issues have been taken into account from the beginning., Results: PanCareLIFE will investigate the way that treatment impairs female fertility, by evaluating anti-Müllerian hormone levels and the underlying genetic susceptibility to loss of fertility. For our fertility studies, more than 6000 survivors have completed questionnaires, more than 1500 provided serum samples and more than 400 case-control triads have been identified. Fertility preservation guidelines for boys and girls will be developed. More than 2000 survivors have contributed audiograms for the ototoxicity study. Almost 1000 samples were sent for genetic analysis related to ototoxicity and gonadal reserve. The SF-36 questionnaire will measure quality of life in more than 10,000 survivors., Conclusions: The large number of subjects enrolled in PanCareLIFE and the detailed information accumulated will allow in-depth evaluation of important outcomes. Fertility preservation guidelines will help patients and their families make informed decisions and contribute to their long-term well-being., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: In 2013, the Pediatric Association of the Netherlands launched an evidence-based guideline 'Palliative care for children'. To promote implementation in daily practice and hereby improve quality of paediatric palliative care, we aimed to develop a functional individualised paediatric palliative care plan (IPPCP) that covers physical, psychological, spiritual and social functioning, with great emphasis on the guideline's recommendations, advance care planning and patients' and parents' preferences and desires., Methods: A Dutch working group (28 individuals) with a strong multidisciplinary character developed a draft IPPCP, which was piloted retrospectively and prospectively. In the pilots we completed, the IPPCPs for patients who were recently diagnosed with a life-threatening or life-limiting condition and evaluated completeness, usability and user-friendliness., Results: The final IPPCP comprised five domains: (1) IPPCP data, (2) basics, (3) social, (4) psychosocial and spiritual and (5) physical care. Each domain covered various components. In both pilots, the IPPCP was considered a comprehensive document that covered all areas of paediatric palliative care and was experienced as an improvement to the present situation. However, the current form was regarded to lack user-friendliness., Conclusion: We propose a set of essential components of a comprehensive IPPCP for paediatric palliative care with extra attention for advance care planning and anticipatory action. Patients' and parents' preferences and desires are included next to the recommendations of the evidence-based guideline 'Palliative care for children'., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

We aimed to provide recommendations on the infusion duration of anthracycline chemotherapy agents in children with cancer. This study also serves as a practice example of the essential steps that need to be taken when using a previously published systematic review to develop a high-quality clinical practice guideline. Although evidence was scarce and included adult studies, the panel was able (using the Grading of Recommendations Assessment, Development and Evaluation evidence-to-decision framework) to recommend in favor of an anthracycline infusion duration of at least 1 hr (strong recommendation, very low to moderate quality of evidence). Recommending a precise optimal prolonged infusion duration was currently not possible., (© 2017 Wiley Periodicals, Inc.)

Purpose: Intensive therapies in pediatric malignancies increased survival rates but also occurrence of treatment-related morbidities. Therefore, supportive care fulfills an increasingly important role. In planning development of guidelines with incorporation of shared decision making, we noticed that little is known about the needs and preferences of patients and their parents. Our goals were therefore to investigate (1) which supportive care topics patients and parents regard as most important and (2) the preferred role they wish to fulfill in decision making., Methods: This qualitative study consisted of three focus groups (two traditional, one online) with patients and parents of two Dutch pediatric oncology centers. Data were transcribed as simple verbatim and analyzed using thematic analysis., Results: Eleven adolescent patients and 18 parents shared detailed views on various aspects of supportive care. Themes of major importance were communication between patient and physician (commitment, accessibility, proactive attitude of physicians), well-timed provision of information, and the suitability and accessibility of psychosocial care. In contrast to prioritized supportive care topics by medical professionals, somatic issues (e.g., febrile neutropenia) were infrequently addressed. Patients and parents preferred to be actively involved in decision making in selected topics, such as choice of analgesics and anti-emetics, but not in, e.g., choice of antibiotics., Conclusions: Children with cancer and parents were provided a valuable insight into their views regarding supportive care and shared decision making. These results have important implications towards improving supportive care, both in selecting topics for guideline development and incorporating preferences of patients and parents herein.

As cure rates in pediatric oncology have improved substantially over the last decades, supportive care has become increasingly important to reduce morbidity and mortality and improve quality of life in children with cancer. Currently, large variations exist in pediatric oncology supportive care practice, which might negatively influence care. This plea underlines the importance of development and implementation of trustworthy supportive care clinical practice guidelines, which we believe is the essential next step towards better supportive care practice, and thus a higher quality of care. To facilitate international development and endorsement, the International Pediatric Oncology Guidelines in Supportive Care Network has been established.