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Background: Pediatric cancer leads to reduced participation in exercise and only few patients comply with national physical activity recommendations. Physically inactive behavior hinders motor development and increases physical and psychological adverse effects of therapy and incidence of sequelae. Currently, there is neither nationwide coverage nor uniform level of knowledge regarding exercise promotion. The objective of the guideline is to facilitate qualified exercise interventions through standardized procedures in addition to regular physiotherapy and overall avoid physical inactivity in pediatric cancer patients., Methods: This guideline addresses the multidisciplinary treatment team and informs physiotherapists and decision-makers in tertiary care hospitals and health insurance companies. The requirements of the Association of the Scientific Medical Societies in Germany were followed. Contents were based on best practice experience of experts, patient advocates, as well as on scientific evidence., Results: The guideline includes 11 recommendations. Recommendations 1-4 declare the relevance of implementing exercise interventions and address general framework conditions. Recommendations 5-11 focus on the design of exercise programs, prevention and safety issues, relative contraindications for specific training loads, and options to overcome barriers to exercise., Conclusion: This guideline summarizes existing and established structures and evidence in the context of movement and exercise in pediatric oncology. It takes into consideration the rights, varying needs, and characteristics of children and adolescents as well as national and international experience in this field. In the future, relevant research gaps need to be addressed by high-quality intervention studies to provide the scientific background for a stronger evidence-based guideline., (© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Resumption of physical activity and reintegration into social surroundings after treatment for pediatric cancer is of high importance to recover from the burden of disease and treatment and to positively influence long-term health outcomes. Eighty-three children who had completed intensive treatment for pediatric cancer were surveyed regarding their participation in physical education at school (PES). The results show a concerning low rate of participation, particularly in children treated for pediatric bone tumors, and associated barriers. Reported reasons for quitting PES seem to be conquerable by individual and entity-related support to enable participation according to the children's desire., (© 2015 Wiley Periodicals, Inc.)

Background: Due to growing evidence about the value of exercise in pediatric cancer patients, the purpose of this study was to determine factors that influence participation in physical activities and exercise in children and adolescents during treatment., Procedure: This cross-sectional qualitative study included 40 pediatric cancer patients during intensive treatment. Patients were recruited at the Department for Pediatric Hematology and Oncology, University Hospital of Muenster where a supervised exercise program has been implemented for hospital stays. The qualitative approach included semi-structured guideline interviews, transcription and coding based on grounded theory. Four major topics were discussed in the interviews: (1) values and beliefs, (2) barriers to exercise, (3) motivations to exercise, and (4) encouragement from parents and physicians., Results: Patients reported mainly positive attitudes toward physical activities during treatment and the local exercise program was desired and valued as essential for engaging in exercise during in-patient stays. Identified barriers included physical, psychological, and organizational aspects. Motivational aspects were based on improvements in physical fitness and mental well-being. Parents' behavior related to physical activities of their children differed between being supportive, inhibiting, and inert. Few patients received information about exercise during treatment by their physicians., Conclusions: Interventions that aim at maintaining physical activities during treatment and eliminating exercise barriers are required due to the patients' positive attitudes and multiple motivations toward exercise. These interventions need to be supervised and should include health-counseling programs for patients, parents, and physicians to underline the importance of physical activities in childhood cancer patients., (© 2014 Wiley Periodicals, Inc.)

Background: Physical activities are important for the development of children and increasing evidence suggests beneficial effects of physical activity promotion during cancer treatment as well. The present study aimed at evaluating the current need of exercise interventions in pediatric cancer patients undergoing acute treatment and identifying risk factors for inactivity., Procedure: Data about self-reported physical activity before and during treatment was collected in a cross-sectional design with the physical activity questionnaire from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) in a modified cancer specific version., Results: One hundred thirty pediatric cancer patients with various entities were questioned 3.0 ± 1.6 months since diagnosis. Patients' activity levels before diagnosis mainly matched reference values for healthy children in Germany. Reductions during treatment affected all dimensions of daily physical activities and minutes of exercise per week decreased significantly (P < 0.001). Largest reductions of physical activities during treatment were identified for bone tumor patients and in-patient stays., Conclusions: Due to the well known importance of physical activity during childhood and the identified risk of inactivity during cancer treatment, supervised exercise interventions should be implemented into acute treatment phase to enhance activity levels and ensure a continuously support by qualified exercise professionals., (© 2013 Wiley Periodicals, Inc.)

Background: Busulfan (Bu) is a DNA-alkylating agent used for myeloablative conditioning in stem cell transplantation in children and adults. While the use of intravenous rather than oral administration of Bu has reduced inter-individual variability in plasma levels, toxicity still occurs frequently after hematopoietic stem cell transplantation (HSCT). Toxicity (especially hepatotoxic effects) of intravenous (IV) Bu may be related to both Bu and/or N,N-dimethylacetamide (DMA), the solvent of Bu. In this study, we assessed the relation between the exposure of Bu and DMA with regards to the clinical outcome in children from two cohorts., Methods: In a two-centre study Bu and DMA AUC (area under the curve) were correlated in pediatric stem cell recipients to the risk of developing SOS and to the clinical outcome., Result: In patients receiving Bu four times per day Bu levels >1,500 µmol/L minute correlate to an increased risk of developing a SOS. In the collective cohort, summarizing data of all 53 patients of this study, neither high area under the curve (AUC) of Bu nor high AUC of DMA appears to be an independent risk factor for the development of SOS in children., Conclusion: In this study neither Bu nor DMA was observed as an independent risk factor for the development of SOS. To identify subgroups (e.g., infants), in which Bu or DMA might be risk factors for the induction of SOS, larger cohorts have to be evaluated., (© 2013 Wiley Periodicals, Inc.)

Background: Mesenchymal cells (MSCs) in bone marrow (BM) may produce asparagine and form protective niches for leukemic cells. In vitro, this led to high levels of asparagine and conferred asparaginase resistance to acute lymphoblastic leukemia (ALL) cells. The aim of this study was to investigate whether MSCs or other cells in BM indeed produce such significant amounts of asparagine in vivo as to result in clinical asparaginase resistance., Procedure: Twenty-six patients with newly diagnosed ALL were enrolled. All children received induction chemotherapy according to the Dutch Childhood Oncology Group (DCOG) ALL-10 protocol. Asparaginase was administered from days 12-33. Asparaginase, asparagine, aspartic acid, glutamine, and glutamic acid levels were measured in BM and blood at diagnosis, days 15, 33, and 79., Results: Median asparaginase trough levels were not significantly different at days 15 and 33. Only at diagnosis, asparagine level was significantly higher in BM than in blood (P = 0.001). Asparagine levels were all below the lower limit of quantification in BM and blood at days 15 and 33. However, aspartic acid level in BM was significantly higher than in blood (P < 0.001) at diagnosis, and also at days 15, 33, and 79., Conclusions: We demonstrate higher aspartic acid levels in BM compared to blood; however, no increased asparagine levels were seen during induction therapy containing asparaginase in BM when compared to blood. Therefore, increased asparagine synthesis by MSCs is of relevance for resistance to asparaginase of leukemic cells in vitro, but it is questionable whether this leads to asparaginase resistance in childhood ALL patients., (Copyright © 2012 Wiley Periodicals, Inc.)

We report for the first time the impact of neoadjuvant oral low-dose chemotherapy consisting of oral trofosfamide, idarubicin, and etoposide (O-TIE) in the case of alveolar rhabdomyosarcoma (RMS) in the lower jaw of an 18-year-old woman at 27 weeks of gestation, without fetal complications and a highly efficient anti-tumor response. Our study suggests the possible application of O-TIE treatment in a neoadjuvant setting during pregnancy and recommends a schedule that can be considered for the treatment of patients with high-risk sarcomas who cannot be treated with intensive chemotherapy for various reasons., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Due to the new European regulations for pediatric medications, future clinical trials will include an increasing number of minors. It is therefore important to reconsider and evaluate recent methodological and ethical aspects of clinical trials in minors., Procedure: The following questions were investigated: How are randomized controlled clinical trials (RCTs) performed in practice? Do investigators take into consideration biomedical ethical principles, explicated for example by Beauchamp and Childress, when planning and conducting a trial? The study was conducted in a descriptive manner. A systematic, algorithm-guided search focusing on RCTs in minors with malignant diseases was carried out in PubMed. One-thousand-nine-hundred-sixty-two publications from 2001 to 2005 were randomized in sequence. The first 1,000 publications were screened according to a priori defined inclusion criteria. One hundred seventy-five publications met the criteria and were reviewed using the SIGN methodological checklist (2004), the CONSORT Statement (2001, section Methods, items 3-12) and indicators for ethical aspects. Seventeen publications were checked by two raters., Results: Information on randomization and blinding was often equivocal. The publications were mainly rated positive for the criteria of the SIGN checklist, and mostly rated negative for the additional items of the CONSORT Statement. Regarding the ethical principles, only few contributions were found in the publications. Inter-rater reliability was good., Conclusions: In the publications analyzed, we found only limited information concerning methods and reflections on ethical principles of the trials. Improvements are thus necessary and possible. We suggest how such trials and their respective publications can be optimized for these aspects., (Copyright © 2011 Wiley-Liss, Inc.)

Background: Therapeutic drug monitoring (TDM) of asparaginase (ASNase), a fundamental element of acute lymphoblastic leukemia treatment, was integrated in the ALL-BFM 2000 protocol on a voluntary basis., Methods: Over a 5-year period, 127 patients (1,355 samples) were monitored for asparaginase activity in a single-center setting. We report monitoring data from throughout the ASNase containing treatment elements. Additional information obtained on risk stratification, minimal residual disease (MRD), steroid randomization and relapse is discussed in relation to ASNase activity., Results: At completion of the induction phase 93% (115/124) of patients showed sufficient ASNase activity (5,000 U/m(2) Escherichia coli ASNase), 77 of 86 (90%) monitored patients finished the first re-intensification element without requiring Erwinia ASNase. MRD, risk stratification and steroid randomization were not associated with significant differences in ASNase activity. Of patients who relapsed, only 25% (3/12) were able to maintain sufficient ASNase activity after E. coli ASNase., Conclusion: This single-center data set gives a true and unbiased insight into clinical reality of ASNase therapy. It shows no significant relationship between MRD positivity or risk stratification and ASNase treatment intensity. Overall, within the ALL-BFM 2000 trial, 90% of patients completed first re-intensification without requiring third-line Erwinia ASNase., (Copyright © 2011 Wiley-Liss, Inc.)

Background: On a voluntary basis therapeutic drug monitoring (TDM) was implemented in the ALL-BFM 2000 protocol for the three currently used asparaginase (ASNase) preparations (first line: native Escherichia coli ASNase; second line: pegylated ASNase and third line: Erwinia chrysanthemi ASNase)., Procedure: Between 2000 and 2007, 2,074 ASNase samples from 763 patients out of 114 hospitals were evaluated (5,000 U/m2 E. coli ASNase (n = 318), 1,000 U/m2 pegylated ASNase (n = 416) and 10,000 U/m2 Erwinia chrysanthemi ASNase (n = 29))., Results: First-line therapy with 5,000 U/m2 E. coli ASNase resulted in an ASNase activity of <100 U/L in 10% of all samples from day +3 after administration. Second-line treatment with 1,000 U/m2 PEG ASNase led to activity values below 100 U/L in approximately 30% of all samples taken +7 days. Relating ASNase activity to route of administration, 10,000 U/m2 Erwinia ASNase IM compared to IV as third-line treatment, led to a higher median activity (IM: median 151.5 U/L, range (0-750 U/L); IV: median 115 U/L, range (0-884 U/L), P = 0.3) and fewer samples below 100 U/L (IM: 15% vs. IV: 45%) at day +2., Conclusion: The reduced dose of 5,000 U/m2 E. coli ASNase for induction treatment succeeded to achieve an activity level above 100 U/L in more than 90% of all samples. They confirm that dose reduction is reasonable and provide the basis for future treatment strategies employing ASNase., (Copyright 2010 Wiley-Liss, Inc.)

This review provides a survey of studies investigating physical activity and exercise interventions in patients during tumor treatment and survivors of childhood cancer. PubMed and Medline databases were searched using relevant terms. References of selected papers were tracked. A total of 28 studies could be identified. Seventeen studies investigated physical activity, 11 studies determined the effect of activity enhancing interventions during and after therapy. Even though most studies showed limitations and results were not consistent, considerably reduced physical activity is highly probable in patients during and after therapy. Studies on interventions provided promising results and revealed challenges to be faced.

Background: There is an extreme paucity of pharmacokinetic data for anticancer agents in infants. Therefore, we aimed at characterizing the pharmacokinetics for daunorubicin in infants and examined their relationship to age, body weight, and body surface area., Procedure: Leukemia patients treated according to the Interfant 99 protocol received 30 mg/m(2) daunorubicin, with dose reduction to 3/4 for patients 6-12 months old and 2/3 for patients <6 months, respectively. Plasma samples from 21 patients (aged 0.05-1.88 years) were collected and analyzed for daunorubicin and daunorubicinol. Samples from 12 children (age 1.6-18.8 years), who received daunorubicin in an earlier investigation, were used for pharmacokinetic model building using the software NONMEM., Results: Plasma concentration time profiles could be described using a two compartment model. Daunorubicin clearance was 43.9 L hr(-1) m(-2) +/- 65% and central volume of distribution 16.4 L m(-2) +/- 46%, whereas apparent clearance of daunorubicinol was 19.1 L hr(-1) m(-2) +/- 32% and apparent volume of distribution 228 L m(-2) +/- 80% (mean +/- interindividual variability). No age-dependency in any of the BSA-normalized pharmacokinetic parameters was observed. Consequently, due to the empirical dose reduction in infants the overall exposure to daunorubicinol in infants was smaller than would be expected from older children. Patients aged <6 months experienced more infections in the induction phase than the group aged 6-12 months at diagnosis. Other toxicities were similar in both groups., Conclusion: We observed no indication of an age-dependency in the pharmacokinetics of daunorubicin. Pediatr Blood Cancer 2010;54:355-360., (Copyright 2009 Wiley-Liss, Inc.)

Background: The diagnosis of cancer bears severe implications for pediatric patients. One immense restriction consists in a reduced level of activity due to different factors. Physical activity affects various aspects of development and can be regarded as an essential part of a child's life. In the present study physical activity in patients undergoing cancer therapy was quantified in order to determine the extent of the restriction and to provide baseline information for the assessment of possible interventions., Procedure: Physical activity in 80 patients and 45 healthy children matched for age and gender was measured using the StepWatch 3 Activity Monitor (SAM, OrthoCare Innovations)., Results: Pediatric cancer patients, at 2,787 gait cycles (gcs) per day, were significantly less active than their healthy counterparts (8,096 gcs). Patients were significantly more active at home than during inpatient stays (3,185 gcs compared to 1,830 gcs), and patients with bone tumors were less active than those with leukemia regarding both, the amount (1,849 gcs vs. 2,992 gcs) and the intensity of activity., Conclusion: The present study quantified an often observed but so far hardly assessable problem. Activity in cancer patients is considerably reduced and patients with bone tumors are at increased risk from the detrimental effects of prolonged inactivity. Both our findings and the accepted fact that activity is an essential element of child development confirm the need for interventions tailored to a patient's needs and abilities during the course of treatment., ((c) 2009 Wiley-Liss, Inc.)

Purpose: We prospectively studied the efficacy of high dose therapy (HDT) versus an oral maintenance treatment (OMT) in patients with stage IV soft tissue sarcoma (STS)., Patients and Methods: Both groups were pretreated with the CEVAIE combination consisting of carboplatin, etoposide, vincristine, actinomycin D, ifosfamide, and epirubicin. HDT consisted of a tandem cycle of thiotepa (600 mg/m(2)) plus cyclophosphamide (4,500 mg/m(2)) and melphalan (120 mg/m(2)) plus etoposide (1,800 mg/m(2)). This treatment was compared with OMT, consisting of four cycles trofosfamide (10 days 2 x 75 mg/m(2)/day) plus etoposide (10 days 2 x 25 mg/m(2)/day), and 4 cycles trofosfamide (10 days 2 x 75 mg/m(2)/day) plus idarubicin (10 days 4 x 5 mg/m(2)). Eligibility criteria were: diagnosis confirmed by reference pathology, primary stage IV, below 22 years of age, and having completed the study therapy., Results: From 96 patients 45 were treated with HDT and 51 with OMT. The main risk parameters were equally distributed in both arms. After a median follow-up of 57.4 months, 11/45 (24.4%) patients in the HDT-arm and 26/51 (57.8%) patients in OMT-arm were alive. Kaplan-Meier analysis demonstrated an overall survival for the whole group of 0.27 (OMT group: 0.52, HDT group 0.27, log rank P = 0.03). The proportional hazard analysis for patients with rhabdomyosarcoma (RMS) or "RMS-like" tumors (77.1% of all patients) demonstrated an independent benefit of OMT on outcome., Conclusion: Oral maintenance therapy seems to be a promising option for patients with RMS-like stage IV tumors., ((c) 2008 Wiley-Liss, Inc.)