Chemotherapy-induced nausea and vomiting control in pediatric patients receiving ifosfamide plus etoposide: a prospective, observational study.

PURPOSE: Little evidence exists regarding the emetogenicity of chemotherapy in pediatric patients. This study describes the prevalence of chemotherapy-induced nausea and vomiting (CINV) in pediatric patients receiving etoposide plus ifosfamide over 5 days, a common pediatric regimen. METHODS: English-speaking, non-chemotherapy-naïve patients aged 4 to 18 years about to receive etoposide 100 mg/m2/day plus ifosfamide 1800 mg/m2/day over 5 days participated. Antiemetic prophylaxis was determined by each patient's care team. Emetic episodes were recorded and nausea severity was assessed by patients beginning with the first chemotherapy dose, continuing until 24 h after the last chemotherapy dose (acute phase) and ending 7 days later (delayed phase). The proportion of patients experiencing complete acute CINV control (no nausea, no vomiting, and no retching), the primary study endpoint, was described. The prevalence of complete chemotherapy-induced vomiting (CIV) and chemotherapy-induced nausea (CIN) during the acute, delayed, and overall (acute plus delayed) phases; complete delayed and overall CINV control; and anticipatory CINV were also determined. RESULTS: Twenty-four patients participated; acute CINV was evaluable in 22. Most (75%; 18/24) received a 5-HT3 antagonist plus dexamethasone for antiemetic prophylaxis. Few (23%; 5/22) experienced complete acute CINV control. Complete acute CIV and CIN control were experienced by 57% (13/23) and 27% (6/22) of patients, respectively. Complete delayed CINV, CIV, and CIN control rates were 42% (8/19), 70% (14/20), and 42% (8/19), respectively. CONCLUSIONS: Our findings support the classification of etoposide 100 mg/m2/day plus ifosfamide 1800 mg/m2/day IV over 5 days as highly emetogenic. This information will optimize antiemetic prophylaxis selection and CINV control in pediatric patients.

Fertility Preservation in Pediatric Subspecialties: A Pilot Needs Assessment Beyond Oncology.

Physicians from 6 non-oncology pediatric subspecialties were surveyed about fertility preservation (FP) to assess education/service needs. Almost all (96%; 25 of 26) reported having patients at risk of infertility; however, only 58% (15 of 26) had discussed FP with patients' families. Most subspecialists (92%; 23 of 25) would like access to an FP program. Our data support exploring the expansion of FP programs beyond oncology.

Testicular Biopsy for Fertility Preservation in Prepubertal Boys with Cancer: Identifying Preferences for Procedure and Reactions to Disclosure Practices.

PURPOSE: Fertility preservation options are limited in prepubertal boys with cancer. Worldwide there has been growing interest in testicular tissue cryopreservation as a promising experimental strategy to address future infertility. We measured and compared parent, male cancer survivor and provider willingness to accept the risk of testicular biopsy among prepubertal boys with cancer, and identified reactions to disclosure practices. MATERIALS AND METHODS: We conducted a multicenter study that included 153 parents of prepubertal boys with cancer, 77 male survivors of childhood cancer and 30 oncology providers. The threshold technique was used to measure subject relative willingness to accept risk of testicular biopsy under 4 different aspects of care, ie chance of infertility, complications from biopsy, development of technology to use tissue and tissue storage cost. A total of 47 in-depth interviews were conducted to identify reactions to disclosure practices. RESULTS: A total of 52 survivors (67%), 22 providers (73%) and 110 parents (72%) selected to have testicular biopsy (vs no biopsy). Median minimum infertility risk to make biopsy worthwhile varied from 25% to 30% among the 3 respondent groups. Interviews revealed that some providers would not offer biopsy in cases of greater perceived risk than benefit, that parents preferred having information regardless of risk of infertility and that nondisclosure elicited adverse feelings from some parents. CONCLUSIONS: Parents, survivors and providers were willing to accept risk of prepubertal testicular biopsy. Parental/survivor desire for information and provider decision not to disclose suggest that barriers to information delivery need to be addressed.

Poor chemotherapy-induced nausea and vomiting control in children receiving intermediate or high dose methotrexate.

PURPOSE: Chemotherapy emetogenicity is the most important known determinant of chemotherapy-induced vomiting (CIV) in children. However, direct evidence regarding the emetogenic potential of chemotherapeutic agents in children is limited. This study describes the prevalence of complete control of acute and delayed phase chemotherapy-induced nausea and vomiting (CINV) in children receiving methotrexate. The prevalence of anticipatory CINV is described, and risk factors for CINV are explored. METHODS: English-speaking children (4 to 18 years) receiving intermediate-dose (ID-MTX: >1 to <12 g/m(2)/dose) or high-dose methotrexate (HD-MTX: ≥12 g/m(2)/dose) participated in this prospective study. Emetic episodes, nausea severity, and antiemetic administration were documented for 24 h from the start of the methotrexate infusion (acute phase) and for up to a further 168 h (delayed phase). CINV prophylaxis was provided at the discretion of the treating physician. Anticipatory CINV was assessed in the 24 h preceding chemotherapy. Complete CINV control was defined as no emetic episodes and no nausea. RESULTS: Thirty children (mean age, 11.8 ± 4 years; ID-MTX, 20; HD-MTX, 10) completed the study. CINV prophylaxis included the following: ondansetron/granisetron plus dexamethasone or nabilone. Few patients experienced complete CINV control (ID-MTX: acute phase 20%, delayed phase 5%; HD-MTX: acute phase 0%, delayed phase 30%). Complete emesis control was higher (ID-MTX: acute phase 70%, delayed phase 50%; HD-MTX: acute phase 70%, delayed phase 60%). Anticipatory CINV was reported by 6/28 patients (21%). Patient age, sex, and history of motion sickness were not significant predictors of CINV. CONCLUSIONS: The poor complete CINV control rate in children receiving methotrexate confirms the classification of HD-MTX as highly emetogenic chemotherapy (HEC) and suggests that ID-MTX be reclassified as HEC.

Advanced practice nurses: Improving access to fertility preservation for oncology patients.

Cancer therapies such as chemotherapy, radiation therapy and surgery may place the future fertility of both children and young adults at risk. Oncofertility is a rapidly evolving area that involves increasing access to fertility preservation (FP) information and services. This manuscript aims to: a) highlight the fertility risks associated with cancer therapy and its psychosocial impact, b) describe FP options, c) discuss the unique challenges of FP in distinct cancer populations, and d) illustrate the pivotal role of APNs in oncofertility counselling and education.

An approach to fertility preservation in prepubertal and postpubertal females: a critical review of current literature.

Advancements in childhood cancer treatment have led to increasing survivorship, creating a greater emphasis on long-term management of patients, including quality of life and side effects from therapy; foremost of which is preserving fertility. The American Society of Clinical Oncology (ASCO) recently revised their guidelines and recommend fertility preservation options be discussed at the earliest possible opportunity for newly diagnosed patients, including methods available for children that remain investigational. Herein, we discuss the current barriers to and the impact of these guidelines for pediatric oncologists caring for young female patients, and provide some suggestions on how to approach this complicated topic.

Development and initial evaluation of electronic Children's International Mucositis Evaluation Scale (eChIMES) for children with cancer.

PURPOSE: We previously developed a pediatric-specific measure of oral mucositis named the Children's International Mucositis Evaluation Scale (ChIMES). Availability as an electronic version may improve self-report response rates. The objectives were to develop an electronic version of ChIMES (eChIMES) and to determine whether the instrument is easy to use, understandable, and suitable for measuring mucositis among children and adolescents with cancer. METHODS: Development of eChIMES was on an iPad; the initial version was piloted with ten children to refine instructions for use and presentation. A crosssectional study then was conducted and included English-speaking children and adolescents 8-18 years of age receiving active treatment for cancer. Participants were shown eCHIMES and were asked to complete it. Questions elicited whether they found eChIMES easy or difficult to use, easy or difficult to understand, and suitable (a good way) for children with cancer to monitor mucositis. Outcomes were rated using five-point ordinal scales. RESULTS: Following the development and initial refinement of eChIMES, 40 children were enrolled. Median age was 12.4 (range, 8.0 to 17.8) years. The instrument was found to be easy or very easy to use and understood by 40 (100 %) and 38 (95 %) participants, respectively. The application was considered suitable or very suitable for measuring mucositis by 37 (92 %). CONCLUSIONS: We found that eChIMES was easy to use, understandable, and suitable for monitoring mucositis among children with cancer. Incorporation into clinical trials may improve the ability to compare and evaluate interventions for mucositis.

Development and testing of a multidimensional iPhone pain assessment application for adolescents with cancer.

BACKGROUND: Pain is one of the most common and distressing symptoms reported by adolescents with cancer. Despite advancements in pain assessment and management research, pain due to cancer and/or its treatments continues to be poorly managed. Our research group has developed a native iPhone application (app) called Pain Squad to tackle the problem of poorly managed pain in the adolescent with cancer group. The app functions as an electronic pain diary and is unique in its ability to collect data on pain intensity, duration, location, and the impact pain has on an adolescent's life (ie, relationships, school work, sleep, mood). It also evaluates medications and other physical and psychological pain management strategies used. Users are prompted twice daily at configurable times to complete 20 questions characterizing their pain and the app transmits results to a database for aggregate reporting through a Web interface. Each diary entry represents a pain case filed by an adolescent with cancer and a reward system (ie, moving up through law-enforcement team ranks, built-in videotaped acknowledgements from fictitious officers) encourages consistent use of the diary. OBJECTIVE: Our objective was to design, develop, and test the usability, feasibility, compliance, and satisfaction of a game-based smartphone pain assessment tool for adolescents with cancer. METHODS: We used both low- and high-fidelity qualitative usability testing with qualitative semi-structured, audio-taped interviews and iterative cycles to design and refine the iPhone based Pain Squad app. Qualitative thematic analysis of interviews using constant comparative methodology captured emergent themes related to app usability. Content validity was assessed using question importance-rating surveys completed by participants. Compliance and satisfaction data were collected following a 2-week feasibility trial where users were alarmed to record their pain twice daily on the app. RESULTS: Thematic analysis of usability interviews showed the app to be appealing overall to adolescents. Analyses of both low- and high-fidelity testing resulted in minor revisions to the app to refine the theme and improve its usability. Adolescents resoundingly endorsed the game-based nature of the app and its virtual reward system. The importance of app pain diary questions was established by content validity analysis. Compliance with the app, assessed during feasibility testing, was high (mean 81%, SD 22%) and adolescents from this phase of the study found the app likeable, easy to use, and not bothersome to complete. CONCLUSIONS: A multifaceted usability approach demonstrated how the Pain Squad app could be made more appealing to children and adolescents with cancer. The game-based nature and built-in reward system of the app was appealing to adolescents and may have resulted in the high compliance rates and satisfaction ratings observed during clinical feasibility testing.

Psychometric properties of the Oral Mucositis Daily Questionnaire for child self-report and importance of mucositis in children treated with chemotherapy.

PURPOSE: The objectives of this study were to examine the psychometric properties of the self-report Oral Mucositis Daily Questionnaire (OMDQ) and to measure the importance of mucositis in children receiving intensive chemotherapy. METHODS: Children ≥ 12 years of age receiving intensive chemotherapy for leukemia/lymphoma or undergoing stem cell transplantation were asked to complete the OMDQ daily for 21 days after chemotherapy. Other measures of mucositis obtained concurrently with OMDQ included the World Health Organization (WHO) mucositis scale, the pain visual analog scale (VAS), and the Functional Assessment of Cancer Therapy Esophageal Cancer Sub-scale (FACT-ECS). The importance of mucositis was estimated using a VAS, time trade-off technique, and willingness to pay to avoid mucositis. RESULTS: Fifteen children participated. Test-retest reliability demonstrated at least moderate correlation for all questions within the OMDQ. Assessment of construct validity of the OMDQ revealed at least moderate correlation with WHO, VAS, and FACT-ECS for questions regarding pain, swallowing, drinking, and eating. Effect on sleeping and talking had lower correlations than that expected a priori. The diarrhea question of the OMDQ did not correlate with other measures of mucositis. Severe mucositis is important to children, while mild mucositis is less important to them. Children were willing to pay moderate amounts of money to prevent mucositis. CONCLUSIONS: The OMDQ exhibits test-retest reliability, and most questions show construct validity with the exceptions of the sleep, talking, and diarrhea questions. Therefore, the OMDQ should not be used unmodified as a self-report instrument in children with cancer. Severe mucositis is of importance to these children.

Evaluation of an Educational Whiteboard Video to Introduce Fertility Preservation to Female Adolescents and Young Adults With Cancer.

PURPOSE: Fertility is an important issue for adolescents and young adults with cancer facing potential infertility. Egg cryopreservation options exist, but information is sometimes overwhelming. We evaluated a fertility preservation educational video and assessed patient and family knowledge and impressions at pre- and post-video timepoints. METHODS: We developed a whiteboard video to explain egg cryopreservation to patients and families. The video was evaluated on the basis of patient education best practices (readability, understandability, actionability). Participants were recruited using convenience sampling in oncology clinics. They completed questionnaires before and after watching to assess knowledge and interest. Inclusion criteria were patients age 13-39 years and minimum 1 month from diagnosis. Descriptive statistics, correlation analyses, and mean comparisons were conducted. RESULTS: The video script read at a grade 8 reading level. Average understandability and actionability scores were below the acceptable standard. We recruited 108 patients (mean age, 27 years) and 39 caregivers/partners. Patients' knowledge about fertility preservation increased after viewing the video. Interest was high before and after, and satisfaction was high for both patients and caregivers. Participants appreciated information on process, procedure, and delivery but desired more information on logistics, including cost. CONCLUSION: A targeted patient education video about fertility preservation options can build knowledge and encourage discussions about infertility. The video can be used as a model for videos on related topics to provide accurate information in a youth-friendly medium; however, following patient education best practices for readability, understandability, and actionability may increase video effectiveness. Future research should assess how audiovisual patient education material affects patient behavior.

Understandability, content validity, and overall acceptability of the Children's International Mucositis Evaluation Scale (ChIMES): child and parent reporting.

Mucositis assessment in children has primarily relied on assessment tools that have been developed for an adult population. A mucositis assessment scale for use in children has previously been developed from expert opinion, namely Children's International Mucositis Evaluation Scale (ChIMES). After the development of ChIMES, we aimed to evaluate the user perspective of the scale by testing the understandability, content validity, and overall acceptability of ChIMES working with parents, children, and teenagers as content experts. Overall acceptability of the scale was satisfactory; however, comments provided by the participants questioned several aspects of the initial version of ChIMES. After discussion of the results, a refined version of ChIMES was produced that accounts for the views of the target population.

Designing an oral mucositis assessment instrument for use in children: generating items using a nominal group technique.

GOALS OF WORK: There was a need to develop a mucositis instrument that would be specific for use with children. This paper describes the step of generating items in the process of developing a new instrument for the assessment of oral mucositis in children. MATERIALS AND METHODS: Nine health care professionals with expertise in pediatric cancer, mucositis assessment, and oral assessment in children were invited to participate in a nominal group technique to generate items that should be included in an instrument. RESULTS: Thirty items were generated initially. Voting processes established that six of these items were thought to be necessary for inclusion: (1) presence of ulcers, (2) pain assessment, (3) amount of pain medication received, (4) effect on eating, (5) drooling-pooling of saliva, and (6) effect on drinking. Using these six items, an initial draft of an instrument was developed that could be used to assess oral mucositis in children, namely, the Children's International Mucositis Evaluation Scale. CONCLUSION: The six items generated by this process provided the basis for a simple, feasible, and reliable instrument. With increased clinical research investigating interventions to reduce and prevent oral mucositis, such an instrument will be critical to the effective conduct of this research in children. Further testing of this instrument is necessary.

Challenges of mucositis assessment in children: expert opinion.

Mucositis is a challenging treatment-related complication in children receiving therapy for cancer. The conduct of clinical trials that investigate mucositis prevention and treatment requires adequate evaluation of the oral cavity. However, few instruments to measure mucositis in children have been appropriately developed or evaluated. A focus group of nine health care professionals with expertise in mucositis assessment, oral assessment in children and paediatric cancer aimed to determine the challenges and possible solutions to mucositis assessment in children. The results led to the identification of several areas of concern that included: (1) challenges in oral assessment in children related to age and cooperation, (2) the need for proxy responses while recognizing the challenges of reporting pain and function attributed to oral mucositis, (3) the need for an instrument that is simple, quick to complete, and easy to use in almost all children and (4) educational considerations. The results provide a basis from which guidelines for the oral assessment of mucositis in children can begin. This information could be used to aid in the development of a new scale for the assessment of oral mucositis in children.

Cryopreservation of testicular tissue in pre-pubertal and adolescent boys at risk for infertility: A low risk procedure.

INTRODUCTION: Cryopreservation of testicular tissue (TT) has become an increasingly attractive option for fertility preservation (FP), particularly for pre-pubertal boys at risk for gonadotoxicity from cancer therapy. At our institution, all at-risk families undergo counseling regarding infertility risk and available FP strategies, including this vulnerable patient population. As the technology required to use the acquired tissue is, as yet, unproven, it is paramount to document minimal morbidity and complications from this procedure. Herein, we report these outcomes for all pre-pubertal patients who have undergone TT biopsies for FP. METHODS: We retrospectively reviewed consecutive patients who underwent unilateral open TT biopsies between January 2014 and December 2016. Patient diagnosis, age, concomitant procedures, anesthetic type, complications, procedure times, planned therapy, and bleeding were evaluated. RESULTS: Of a total of 34 patients, mean age at biopsy was 6.9 ± 4.4years. Diagnoses included: leukemia/lymphoma (n = 12), solid tumors (n = 15) and non-neoplastic disorders (hemophagocytic lymphohistiocytosis, aplastic anemia; n = 7). Twenty-two patients (64.7%) were scheduled for stem cell transplantation. Eleven (32.4%) patients had not received any chemotherapy prior to TT biopsy, while all others had exposure preceding the biopsy. Biopsies were performed in conjunction with other procedures (central line placement, bone marrow biopsy, lumbar puncture, lymph node biopsy) in 29 cases (85.3%), with stand-alone procedures performed in the remainder (n = 5). In stand-alone cases, mean anesthetic time was 22 ± 8.7 min. Overall, two (5.9%) patients had complications after biopsy: 1) ipsilateral epididymo-orchitis (resolved with antibiotics) and 2) ipsilateral torsed appendix testis (managed conservatively) (Table). CONCLUSION: In this series, pre-pubertal TT biopsy for cryopreservation was safely performed, and was most often coordinated concomitantly with other medically necessary procedures. The safety profile reported herein supports performing this procedure while technological advances fulfill the requirements to make it a viable option for future fertility.

Efficacy and safety of caspofungin for the empiric management of fever in neutropenic children.

This retrospective review evaluates the response to caspofungin when given to children with febrile neutropenia and describes adverse effects attributable to caspofungin, including risk of hepatotoxicity during concomitant therapy with cyclosporine. Sixty-seven courses of caspofungin administered to 56 patients (1-17 years) were surveyed; 53 (79%) courses resulted in an overall favorable response. Ten children (15% of courses) experienced an adverse drug-related event that was probably or possibly attributable to caspofungin. Rash and hypokalemia were the most commonly identified adverse effects. One of 19 children receiving caspofungin and cyclosporine concurrently developed hepatotoxicity possibly related to caspofungin.

Anti-Müllerian Hormone in Female Adolescent Cancer Patients Before, During, and After Completion of Therapy: A Pilot Feasibility Study.

STUDY OBJECTIVE: Alkylating agents are implicated in premature ovarian insufficiency. To optimize counseling regarding future ovarian function in survivors of adolescent cancer, we describe anti-Müllerian hormone (AMH) levels in female adolescents at diagnosis, during, and shortly after completion of chemotherapy. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: This was a prospective single-institution study. Participants were a mixed population of newly diagnosed postmenarchal female adolescents with malignancy. AMH was performed at diagnosis (T1), 6 months from diagnosis (T2), at end of therapy or 12 months [T3, whichever came first], 1 year after the end of therapy or 24 months from diagnosis [T4, whichever came first], and 18 months from the time of diagnosis (T5). All patients had baseline pelvic ultrasound examinations. Presence of menses and hot flashes were recorded at each time point. RESULTS: Sixteen participants with a median age at diagnosis of 14.3 years (range 12-17 years) were followed for 18.2 months (range, 14-24 months). Oncology diagnoses included leukemia, lymphoma, and sarcoma. Ten patients (62.5%) received alkylating agents with a median cumulative dose of 3041 mg/m2 (range, 2639-6478 mg/m2) of cyclophosphamide. Almost half (n = 7; 44%) experienced amenorrhea during treatment with resumption of menses in 6 of 7 patients (85%). Fifteen of 16 (94%) participants showed a decline in mean AMH levels by 6 months (T2) from diagnosis (15.8 IU/mL at T1 vs 6.5 IU/mL at T2; P = .003) and 12 of 15 (80%) showed at least some recovery of AMH (mean AMH at T4 = 13.2 IU/mL compared with 6.5 IU/mL at T2; P = .02). There was no difference in the mean decline nor recovery of AMH in those who did, vs did not receive cyclophosphamide. CONCLUSION: To our knowledge, this is the largest series to date in adolescents showing that AMH is uniformly suppressed during cancer therapy and short-term recovery occurs in just more than half of the patients by 18-24 months. The contribution of short-term AMH measurements in predicting long-term ovarian function remains to be defined. Long-term follow-up with serial AMH levels is required to help predict those at risk for premature ovarian insufficiency.

Inpatient versus outpatient management of low-risk pediatric febrile neutropenia: measuring parents' and healthcare professionals' preferences.

PURPOSE: Our primary objective was to describe and compare parents' and healthcare professionals' strength of preference scores for outpatient oral antibiotic relative to inpatient parenteral antibiotic treatment for low-risk febrile neutropenic children. Our secondary objective was to identify predictors of strength of preference for oral outpatient treatment. METHODS: Respondents were parents of children receiving cancer chemotherapy, and pediatric oncology healthcare professionals. First, the inpatient and outpatient options were described, and the respondent indicated their initially preferred option. The respondent next ranked how important seven factors (including "fear/anxiety" and "comfort") were in making their initial choice. The threshold technique was then used to elicit the respondent's strength of preference score for oral outpatient, relative to parenteral inpatient management. RESULTS: There were 75 parent and 42 healthcare-professional respondents. There was no significant difference (P =.08) in the proportions of parents (40 of 75; 53%) and healthcare professionals (30 of 42; 71%) who initially would choose outpatient management. For parents, stronger preference for oral outpatient therapy was associated with higher anticipated quality of life for the parent and child at home relative to hospital, lower importance rank for "fear/anxiety," and higher importance rank for "comfort." Conversely, for professionals, only lower importance rank for "fear/anxiety" was associated with higher strength of preference scores for outpatient oral antibiotic management. CONCLUSION: Only 53% of parents would choose outpatient oral antibiotic management for low-risk febrile neutropenia. Predictors of strength of preference scores for outpatient oral antibiotic relative to inpatient parenteral antibiotic treatment differed between parent and professional respondents.

Construct validity and reliability of a real-time multidimensional smartphone app to assess pain in children and adolescents with cancer.

We evaluated the construct validity (including responsiveness), reliability, and feasibility of the Pain Squad multidimensional smartphone-based pain assessment application (app) in children and adolescents with cancer, using 2 descriptive studies with repeated measures. Participants (8-18 years) undergoing cancer treatment were drawn from 4 pediatric cancer centers. In study 1, 92 participants self-reported their level of pain twice daily for 2 weeks using the Pain Squad app to assess app construct validity and reliability. In study 2, 14 participants recorded their level of pain twice a day for 1 week before and 2 weeks after cancer-related surgery to determine app responsiveness. Participants in both studies completed multiple measures to determine the construct validity and feasibility of the Pain Squad app. Correlations between average weekly pain ratings on the Pain Squad app and recalled least, average, and worst weekly pain were moderate to high (0.43-0.68). Correlations with health-related quality of life and pain coping (measured with PedsQL Inventory 4.0, PedsQL Cancer Module, and Pain Coping Questionnaire) were -0.46 to 0.29. The app showed excellent internal consistency (α = 0.96). Pain ratings changed because of surgery with large effect sizes between baseline and the first week postsurgery (>0.85) and small effect sizes between baseline and the second week postsurgery (0.13-0.32). These findings provide evidence of the construct validity, reliability, and feasibility of the Pain Squad app in children and adolescents with cancer. Use of real-time data capture approaches should be considered in future studies of childhood cancer pain. A video accompanying this abstract is available online as Supplemental Digital Content at http://links.lww.com/PAIN/A169.

Non-relapse mortality in pediatric acute lymphoblastic leukemia: a systematic review and meta-analysis.

The primary objective of the study was to describe non-relapse mortality (NRM) and the proportion of first events that are deaths in children with acute lymphoblastic leukemia (ALL). Secondary objectives were to identify groups at higher risk and to determine whether proportions have changed over time. We performed a systematic review of randomized pediatric ALL studies. From 1337 articles, 59 were included, comprising a total of 49 071 patients. The induction death rate was 1.38%, remission death rate was 1.94% and total NRM was 3.60%. Deaths were responsible for 53.84% of first events during induction and 13.03% in total. Standard risk patients had significantly lower NRM during remission. The year of study was not associated with NRM. The results of the study show that the rate of NRM in children with ALL is 3.60% and those with high risk ALL have significantly higher NRM during remission, but NRM has not changed over time. Future research should focus on the exploration of patient-related risk factors for NRM.