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Background: Primary objective was to describe the proportion of children newly diagnosed with cancer enrolled on a therapeutic clinical trial. Secondary objectives were to describe reasons for non-enrollment and factors associated with enrollment on trials.Methods: In this retrospective cohort study, we included children newly diagnosed with cancer between 0 and 14 years of age and diagnosed from 2001 to 2012. We used data from the Cancer in Young People in Canada (CYP-C) national pediatric cancer population-based database. CYP-C captures all cases of pediatric cancer (0-14 years) diagnosed and treated at one of the 17 tertiary pediatric oncology centers in Canada. Non-enrollment was evaluated using univariate and multiple logistic regression analysis.Results: There were 9204 children with cancer included, of whom 2533 (27.5%) were enrolled on a clinical trial. The most common reasons cited for non-enrollment were lack of an available trial (52.2%) and physician choice (11.2%). In multiple regression, Asian and Arab/west Asian race were associated with lower enrollment (P = 0.006 and P = 0.032 respectively). All cancer diagnoses were more likely to be enrolled compared to astrocytoma and children with acute lymphoblastic leukemia had an almost 18-fold increased odds of enrollment compared to astrocytoma (P < 0.0001). Greater distance from the tertiary care center was independently associated with non-enrollment (P < 0.0001).Conclusions: In Canada, 27.5% of children with cancer are enrolled onto therapeutic clinical trials and lack of an available trial is the most common reason contributing to non-enrollment. Future research should better understand reasons for lack of trial availability and physician preferences to not offer trials. [ABSTRACT FROM AUTHOR]

Background Fatigue is an important problem in paediatric cancer patients and yoga may be an effective intervention. The primary objective was to determine the feasibility of individualized yoga for hospitalized children receiving intensive chemotherapy. Methods We included English-speaking children and adolescents aged 7-18 years receiving intensive chemotherapy or haematopoietic stem cell transplantation (HSCT). Yoga was conducted three times weekly for three weeks. The primary outcome was feasibility, defined as ability to deliver at least 60% of planned sessions. Secondary outcomes were parent-reported Pediatric Quality of Life Inventory (PedsQL) Multidimensional Fatigue Scale, Fatigue Scale-Parent, PedsQL Generic Core Scales and PedsQL Acute Cancer Module. Results Between January and October 2013, 11 patients were enrolled. Median age was 14.0 (range 7.7-16.4) years and 6 (55%) were boys. Yoga was feasible with 10/11 participants meeting the threshold for feasibility. The median number of yoga sessions was 9 (range 3-13). No adverse events were attributed to yoga. Mean ± standard deviation for the day 21 proxy-reported PedsQL general fatigue scores was 55.6 ± 15.5. Qualitative comments suggested design changes for future yoga studies. Conclusions Individualized yoga is feasible for inpatient children receiving intensive chemotherapy. Future work will include development and conduct of a randomized trial for fatigue amelioration. [ABSTRACT FROM AUTHOR]

Background: It is not known whether children with acute promyelocytic leukemia (APL) have an infection risk similar to non- APL acute myeloid leukemia. The objective was to describe infectious risk in children with newly diagnosed APL and to describe factors associated with these infections. Methods: We conducted a retrospective, population-based cohort study that included children = 18 years of age with de novo APL treated at 15 Canadian centers. Thirty-three children with APL were included; 78.8% were treated with APL -specific protocols. Results: Bacterial sterile site infection occurred in 12 (36.4%) and fungal sterile site infection occurred in 2 (6.1%) children. Of the 127 chemotherapy courses, 101 (79.5%) were classified as intensive and among these, the proportion in which a sterile site microbiologically documented infection occurred was 14/101 (13.9%). There was one infection-related death. Conclusions: One third of children with APL experienced at least one sterile site bacterial infection throughout treatment and 14% of intensive chemotherapy courses were associated with a microbiologically documented sterile site infection. Infection rates in pediatric APL may be lower compared to non- APL acute myeloid leukemia although these children may still benefit from aggressive supportive care during intensive chemotherapy. [ABSTRACT FROM AUTHOR]

Background Accrual to Cancer Control and Supportive Care (CCL) studies can be challenging. Our objective was to identify facilitators and perceived barriers to successful Children's Oncology Group (COG) CCL accrual from the clinical research associate (CRA) perspective. Methods A survey was developed that focused on the following features from the institutional perspective: (1) Components of successful accrual; (2) Barriers to accrual; (3) Institutional changes that could enhance accrual; and (4) How COG could facilitate accrual. The survey was distributed to the lead CRA at each COG site with at least 2 CCL accruals within the previous year. The written responses were classified into themes and sub-themes. Results 57 sites in the United States (n = 52) and Canada (n = 5) were contacted; 34 (60%) responded. The four major themes were: (1) Staff presence and dynamics; (2) Logistics including adequate numbers of eligible patients; (3) Interests and priorities; and (4) Resources. Suggestions for improvement began at the study design/conception stage, and included ongoing training/support and increased reimbursement or credit for successful CCL enrollment. Conclusions The comments resulted in suggestions to facilitate CCL trials in the future. Soliciting input from key team members in the clinical trials process is important to maximizing accrual rates. [ABSTRACT FROM AUTHOR]

Background: Children with Down syndrome (DS) are at high risk of infectious toxicity when treated with acute lymphoblastic leukemia chemotherapy protocols optimized in children without DS. Our objective was to determine if children with DS and acute myeloid leukemia (AML) have a different risk of infection when treated with chemotherapy protocols developed for children with DS compared to AML treatment protocols developed for children without DS. Methods: We conducted a retrospective, population-based cohort study that included DS children ? 18 years of age with de novo, non-M3 AML diagnosed between January 1995 and December 2004, and treated at 15 Canadian centers. Patients were monitored for infection from initiation of AML treatment until recovery from the last cycle of chemotherapy, conditioning for hematopoietic stem cell transplantation, relapse, persistent disease or death (whichever occurred first). Trained research associates abstracted all information from each site. Results: There were 31 children with DS included; median age was 1.7 (range 0.1-11.1) years. Eleven were treated according to a DS-specific protocol while 20 were treated with non-DS specific protocols. A total of 157 courses of chemotherapy were delivered. Microbiologically documented sterile site infection occurred in 11.9% and 14.3% of DS-specific and non-DS specific AML treatment courses respectively. Sepsis was rare and there were no infection-related deaths. In multiple regression, treatment with a DS-specific protocol was independently associated with a reduction in microbiologically documented sterile site infection (adjusted odds ratio (OR) 0.65, 95% confidence interval (CI) 0.42-0.99; P = 0.044), and clinically documented infection (adjusted OR 0.36, 95% CI 0.14-0.91; P = 0.031) but not bacteremia (adjusted OR 0.73, 95% CI 0.44-1.22; P = 0.231). Conclusions: Our study suggests that children with DS do not experience excessive infectious toxicity during treatment for AML compared to children without DS. Incorporation of DS-specific AML treatment protocols is associated with a more favorable infection profile for children with DS-AML. [ABSTRACT FROM AUTHOR]

Background: The objective was to describe symptom assessment scales that have been used in children with cancer. Methods: We conducted electronic searches of OVID Medline and EMBASE in order to identify all symptom assessment scales that have been used in pediatric cancer. Two reviewers abstracted information from each identified study. Data collected included study demographics and information related to the instrument and children enrolled. We also collected information about the purpose of instrument administration and whether treatment was altered as a result of this information. Results: Fourteen studies were identified which evaluated eight different symptom assessment scales. Eight studies used child self-report and all studies included children on active treatment for cancer although 4 studies also included children following completion of treatment. The most common purpose of instrument administration was to measure the prevalence of symptom burden (n = 8). None of the 14 studies used the scale to screen for symptoms and none changed patient management on the basis of identified symptoms. Conclusions: We failed to identify any symptom assessment scales that were used as a symptom screening tool. There is a need to develop such a tool for use in children with cancer. [ABSTRACT FROM AUTHOR]

Background: Fever and neutropenia (FN) is a common complication of chemotherapy for cancer. Prompt empiric broad-spectrum antibiotic therapy in FN is typically considered standard of care, but the definition of prompt is not clear. We seek to systematically review the available data on the association between time to antibiotics (TTA) administration and clinical outcomes in patients with FN being treated with chemotherapy. There have been several efforts to reduce TTA in patients with FN, by implementing specific interventions, presuming there will be a beneficial effect on patient-important outcomes. This systematic review will also collect data on such interventions and their effect to reduce TTA and potentially change clinical outcomes. Methods/design: The search will cover MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, CINAHL, CDSR, CENTRAL, and LILACS. A full-search strategy is provided. Lists of studies identified by references cited and forward citation searching of included articles will also be reviewed. Studies will be screened, and data extracted by one researcher and independently checked by a second. Confounding biases and quality of studies will be assessed with the risk of bias in non-randomised studies-of interventions (ROBINS-I) tool. Data will be presented in narrative and tabular forms; in addition, if appropriate data is available, random effects meta-analysis will be used to examine TTA. A detailed analysis plan, including an assessment of heterogeneity and publication bias, is provided. Discussion: This study aims to evaluate the association between TTA and patient-important clinical outcomes. Additionally, it will identify, critically appraise, and synthesise information on performed interventions and its effect to reduce TTA as a way of gaining insight into the potential use of these approaches. This will provide better knowledge for an adjusted treatment approach of FN. Systematic review registration: PROSPERO [CRD42018092948] [ABSTRACT FROM AUTHOR]

Background: There is a lack of standardized definition for treatment-related mortality (TRM), which represents an important endpoint in cancer. Our objective was to describe TRM definitions used in studies of children, adolescents and young adults with lymphomas, solid tumors and brain tumors.Methods: We conducted a systematic review of studies enrolling children, adolescents and young adults with lymphomas, solid tumors and brain tumors in which an anti-cancer intervention was randomized, or all study designs in which TRM was a primary or secondary outcome. We searched Ovid MEDLINE, EMBASE and Evidence-Based Medicine Reviews from 1980 to June 2013. Two reviewers evaluated study eligibility and abstracted data.Results: In total, 67 studies were included and consisted of 62 randomized therapeutic trials and 5 TRM studies. None of the studies (0/67) provided a definition for TRM. Only one randomized trial of rhabdomyosarcoma provided a definition of early death.Conclusions: We were unable to identify any TRM definitions used in studies of children, adolescents and young adults with lymphomas, solid tumors and brain tumors. Given that a proportion of this patient population may receive intensive treatment, there is an urgent need for consensus-based definitions of TRM for use across clinical trials. [ABSTRACT FROM AUTHOR]

Background: Administrative databases and cancer registries are frequently used to conduct population-based research, but often lack clinical data necessary for risk stratification. Our objective was to determine the criterion validity of a risk-stratification algorithm based on treatment characteristics available from a pediatric cancer registry as a proxy for disease risk, by comparing it to traditional biology-based risk classifications.Methods: We identified all children with acute lymphoblastic leukemia diagnosed at a single institution between January 2000 and June 2011, and linked them to a population-based cancer registry. Several risk algorithms were then constructed using disease risk variables collected through chart review by a pediatric oncologist, and compared to a risk algorithm based on treatment protocol name and age, available from the registry.Results: Of 596 patients identified, 579 (97.1%) met inclusion criteria and were successfully linked. The registry-based algorithm showed almost perfect agreement with a biology-based algorithm based on age, initial white blood cell count, immunophenotype and cytogenetics (kappa=0.85, 95th confidence interval 0.81-0.90). Discrepant cases were often due to the presence of unusual high risk features not captured by standard disease-risk variables but reflected in clinicians' choices of higher intensity treatment protocols.Conclusions: Protocol name represents a valid proxy of disease risk, allowing for risk stratification while conducting comparative effectiveness research using cancer registries and health services data. Future studies should examine the validity of treatment-based risk algorithms in other malignancies and using other treatment characteristics commonly found in health services data, such as the receipt of specific chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Background: Children with Down syndrome (DS) are at high risk of infectious toxicity when treated with acute lymphoblastic leukemia chemotherapy protocols optimized in children without DS. Our objective was to determine if children with DS and acute myeloid leukemia (AML) have a different risk of infection when treated with chemotherapy protocols developed for children with DS compared to AML treatment protocols developed for children without DS., Methods: We conducted a retrospective, population-based cohort study that included DS children ≤ 18 years of age with de novo, non-M3 AML diagnosed between January 1995 and December 2004, and treated at 15 Canadian centers. Patients were monitored for infection from initiation of AML treatment until recovery from the last cycle of chemotherapy, conditioning for hematopoietic stem cell transplantation, relapse, persistent disease or death (whichever occurred first). Trained research associates abstracted all information from each site., Results: There were 31 children with DS included; median age was 1.7 (range 0.1-11.1) years. Eleven were treated according to a DS-specific protocol while 20 were treated with non-DS specific protocols. A total of 157 courses of chemotherapy were delivered. Microbiologically documented sterile site infection occurred in 11.9% and 14.3% of DS-specific and non-DS specific AML treatment courses respectively. Sepsis was rare and there were no infection-related deaths. In multiple regression, treatment with a DS-specific protocol was independently associated with a reduction in microbiologically documented sterile site infection (adjusted odds ratio (OR) 0.65, 95% confidence interval (CI) 0.42-0.99; P = 0.044), and clinically documented infection (adjusted OR 0.36, 95% CI 0.14-0.91; P = 0.031) but not bacteremia (adjusted OR 0.73, 95% CI 0.44-1.22; P = 0.231)., Conclusions: Our study suggests that children with DS do not experience excessive infectious toxicity during treatment for AML compared to children without DS. Incorporation of DS-specific AML treatment protocols is associated with a more favorable infection profile for children with DS-AML.

Background: Multiple regression models are used in a wide range of scientific disciplines and automated model selection procedures are frequently used to identify independent predictors. However, determination of relative importance of potential predictors and validating the fitted models for their stability, predictive accuracy and generalizability are often overlooked or not done thoroughly., Methods: Using a case study aimed at predicting children with acute lymphoblastic leukemia (ALL) who are at low risk of Tumor Lysis Syndrome (TLS), we propose and compare two strategies, bootstrapping and random split of data, for ordering potential predictors according to their relative importance with respect to model stability and generalizability. We also propose an approach based on relative increase in percentage of explained variation and area under the Receiver Operating Characteristic (ROC) curve for developing models where variables from our ordered list enter the model according to their importance. An additional data set aimed at identifying predictors of prostate cancer penetration is also used for illustrative purposes., Results: Age is chosen to be the most important predictor of TLS. It is selected 100% of the time using the bootstrapping approach. Using the random split method, it is selected 99% of the time in the training data and is significant (at 5% level) 98% of the time in the validation data set. This indicates that age is a stable predictor of TLS with good generalizability. The second most important variable is white blood cell count (WBC). Our methods also identified an important predictor of TLS that was otherwise omitted if relying on any of the automated model selection procedures alone. A group at low risk of TLS consists of children younger than 10 years of age, without T-cell immunophenotype, whose baseline WBC is < 20 x 10(9)/L and palpable spleen is < 2 cm. For the prostate cancer data set, the Gleason score and digital rectal exam are identified to be the most important indicators of whether tumor has penetrated the prostate capsule., Conclusion: Our model selection procedures based on bootstrap re-sampling and repeated random split techniques can be used to assess the strength of evidence that a variable is truly an independent and reproducible predictor. Our methods, therefore, can be used for developing stable and reproducible models with good performances. Moreover, our methods can serve as a good tool for validating a predictive model. Previous biological and clinical studies support the findings based on our selection and validation strategies. However, extensive simulations may be required to assess the performance of our methods under different scenarios as well as check their sensitivity to a random fluctuation in the data.

Background: The primary objective of this meta-analytic study was to determine the impact of RSV-IGIV and palivizumab on risk of respiratory syncytial virus (RSV)-related hospitalization. Secondary objectives were to determine if antibody therapy decreases the risk of RSV infection, intensive care admission, mechanical ventilation, and mortality in high risk infant populations., Methods: We performed searches of electronic data bases from 1966 to April 2009. Inclusion and exclusion criteria were defined a priori. Inclusion criteria were as follows: 1) There was randomization between polyclonal or monoclonal antibodies and placebo or no therapy, and 2) Polyclonal or monoclonal antibodies were given as prophylaxis., Results: Of the six included studies, three utilized RSV-IGIV (total of 533 randomized to treatment groups) and three utilized palivizumab (total of 1,663 randomized to treatment groups). The absolute risk of hospitalization in the control arms was 12% and overall RR for all 2,196 children who received one of the antibody products was 0.53 (95% CI 0.43, 0.66), P < 0.00001. When looking only at the children who received palivizumab, the RR for hospitalization was 0.50 (95% CI 0.38, 0.66), P < 0.00001. For the children receiving RSV-IGIV, the RR for hospitalization was 0.59 (95% CI 0.42, 0.83, P < 0.002). The use of palivizumab resulted in a significant decrease in admission to the ICU (RR 0.29 (95% CI 0.14, 0.59; P = 0.0007). There was no significant reduction in the risk of mechanical ventilation or mortality with the use of antibody prophylaxis. Infants born at less than 35 weeks gestational age, and those with chronic lung and congenital heart disease all had a significant reduction in the risk of RSV hospitalization with children born under 35 weeks gestational age showing a trend towards the greatest benefit., Conclusion: Both palivizumab and RSV-IGIV decrease the incidence of RSV hospitalization and ICU admission and their effect appears to be qualitatively similarly. There was neither a statistically significant reduction in the incidence of mechanical ventilation nor in all cause mortality. This meta-analysis separately quantifies the impact of RSV-IGIV and palivizumab on various measures of severe RSV disease and builds upon a previous study that was only able to examine the pooled effect of all antibody products together.