Children's Oncology Group 2023 blueprint for research: Cancer care delivery research.

The National Cancer Institute (NCI) has a 40-year history of initiatives to encourage the participation of community oncology sites into clinical trials research and clinical care. In 2014, the NCI re-organized to form the NCI Community Oncology Research Program (NCORP) network across seven research bases, including the Children's Oncology Group (COG), and numerous community sites. The COG portfolio for Cancer Care Delivery Research (CCDR), mirroring the larger NCORP network, has included two studies addressing guideline congruence, as an important marker of quality cancer care, and another focusing on financial toxicity, addressing the pervasive problems of healthcare cost. CCDR is a cross-cutting field that frequently examines intersectional aspects of healthcare delivery. With that in mind, we explicitly define domains of CCDR to propel our research agenda into the next phase of the NCORP CCDR program while acknowledging the complex and dynamic fields of clinical care, policy level decisions, research findings, and needs of communities served by the NCORP network that will inform the subsequent research questions. To ensure programmatic success, we will engage a broad interdisciplinary group of investigators and clinicians with expertise and dedication to community oncology and the populations they serve.

Clostridioides difficile infection in paediatric patients with cancer and haematopoietic stem cell transplant recipients.

BACKGROUND: Epidemiology of Clostridioides difficile infection (CDI) in paediatric cancer patients is uncertain. The primary objective was to describe the prevalence of CDI outcomes among paediatric patients receiving cancer treatments. Secondary objectives were to describe clinical features of CDI, propose a definition of severe CDI and to determine risk factors for CDI clinical outcomes. METHODS: A multi-centre retrospective cohort study that included paediatric patients (1-18 years of age) receiving cancer treatments with CDI. Severe CDI definition was achieved by consensus. Univariable and multivariable regression was conducted to evaluate risk factors for CDI outcomes. RESULTS: There were 627 eligible patients who experienced 721 CDI episodes. The prevalence of clinical cure was 82.9%, recurrence was 9.6%, global cure was 75.0% and repeated new CDI episode was 12.8%. The proposed definition of severe CDI was the presence of colitis, pneumatosis intestinalis, pseudomembranous colitis, ileus or surgery for CDI, occurring in 70 (9.7%) episodes. In univariable regression, initial oral metronidazole or initial oral vancomycin were not significantly associated with failure to achieve clinical cure or CDI recurrence. In multiple regression, oral metronidazole was significantly associated with higher odds (odds ratio (OR) 1.7, 95% confidence interval (CI) 1.0-2.7) and oral vancomycin was significantly associated with lower odds (OR 0.4, 95% CI 0.2-0.8) of repeated new episodes. CONCLUSION: The prevalence of clinical cure was 82.9% and recurrence was 9.6% in pediatric patients receiving cancer treatments. Severe CDI, as per our proposed definition, occurred in 9.7% episodes. Initial oral vancomycin was significantly associated with a reduction in repeated new CDI episodes.

Clinical practice guideline for the prevention of oral and oropharyngeal mucositis in pediatric cancer and hematopoietic stem cell transplant patients: 2021 update.

PURPOSE: To update the 2015 clinical practice guideline for the prevention of oral mucositis in pediatric cancer or hematopoietic stem cell transplant (HSCT) patients. METHODS: We performed seven systematic reviews of mucositis prevention. Three reviews included randomized controlled trials (RCTs) conducted in pediatric and adult patients evaluating cryotherapy, keratinocyte growth factor (KGF) or photobiomodulation therapy with a focus on efficacy. Three reviews included studies of any design conducted in pediatric patients evaluating these same interventions with a focus on adverse events and feasibility. One review included all RCTs of any intervention for mucositis prevention in pediatric patients. Primary outcome was severe oral mucositis. RESULTS: We included 107 unique studies of cryotherapy (22 RCTs and 4 pediatric studies); KGF (15 RCTs and 12 pediatric studies); photobiomodulation therapy (29 RCTs and 8 pediatric studies) and any intervention (31 pediatric RCTs). Effects on severe mucositis reduction from RCTs were cryotherapy risk ratio (RR) 0.49 and 95% confidence interval (CI) 0.31-0.76; palifermin RR 0.81 and 95% CI 0.69-0.95 and photobiomodulation therapy RR 0.40 and 95% CI 0.27-0.60. Cryotherapy was not feasible in young children while photobiomodulation therapy was feasible across age groups. Palifermin was associated with adverse effects. CONCLUSIONS: Cryotherapy should be used for older cooperative pediatric patients who will receive short infusions of melphalan or 5-fluorouracil. Intraoral photobiomodulation therapy (620-750 nm spectrum) should be used in pediatric patients undergoing autologous or allogeneic HSCT and for pediatric head and neck carcinoma patients undergoing radiotherapy. Palifermin should not be used routinely in pediatric cancer or HSCT patients.

Translating the Symptom Screening in Pediatrics Tool (SSPedi) into Argentinian Spanish for paediatric patients receiving cancer treatments, and evaluating understandability and cultural relevance in a multiple-phase descriptive study.

OBJECTIVES: To translate a symptom screening tool developed for paediatric patients receiving cancer therapies called Symptom Screening in Pediatrics Tool (SSPedi) into Argentinian Spanish and to evaluate the understandability and cultural relevance of the translated version of SSPedi among children with cancer and paediatric haematopoietic stem cell transplant (HSCT) recipients. METHODS: We conducted a multiphase, descriptive study to translate SSPedi into Argentinian Spanish. Using two translators, forward and backward translations were performed. The translated version was evaluated by Spanish-speaking paediatric patients 8-18 years of age receiving cancer treatments in two centres in Argentina and El Salvador. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was patient self-reported difficulty with understanding of the SSPedi instructions and each symptom using a 5-point Likert scale. Secondary outcomes were incorrect understanding of the SSPedi instructions, symptoms and response scale determined by cognitive interviews with the patients and rated using a 4-point Likert scale. Cultural relevance was assessed qualitatively. RESULTS: There were 30 children enrolled and included in cognitive interviews; 16 lived in Argentina and 14 lived in El Salvador. The most common types of Spanish spoken were Central American (17, 57%) followed by South American (10, 33%) and Castilian (3, 10%). No changes to Argentinian Spanish SSPedi were required based on the outcomes or qualitative comments. No issues with cultural relevance were identified by any of the respondents. CONCLUSIONS: We translated and finalised Argentinian Spanish SSPedi. Future research will focus on its use to describe bothersome symptoms by Argentinian Spanish-speaking children.

Translating the Symptom Screening in Paediatrics Tool (SSPedi) into North American Spanish and Among Spanish-speaking children receiving cancer treatments: evaluating understandability and cultural relevance in a multiple-phase descriptive study.

OBJECTIVES: Symptom screening is important to achieving symptom control. Symptom Screening in Paediatrics Tool (SSPedi) is validated for English-speaking children. Objectives were to translate SSPedi into Spanish, and to evaluate the understandability and cultural relevance of the translated version among Spanish-speaking children with cancer and paediatric haematopoietic stem cell transplant recipients. METHODS: We conducted a multiphase, descriptive study to translate SSPedi into Spanish. The first step was to determine whether one Spanish version would be appropriate for both North America and Argentina. Once this decision was made, forward and backward translations were performed. The translated version was evaluated by Spanish-speaking children 8-18 years of age receiving cancer treatments. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was child self-reported difficulty with understanding of the entire instrument and each symptom using a 5-point Likert scale. Secondary outcomes were incorrect understanding of SSPedi items identified by cognitive interviews with the children using a 4-point Likert scale and cultural relevance, which was assessed qualitatively. RESULTS: This report focuses on North American Spanish as a separate version will be required for Argentinian Spanish SSPedi based on different common vocabulary and grammatical structure. There were 20 children from Toronto and San Antonio included in cognitive interviews. The most common types of Spanish spoken were Mexican (13, 65%), Central American (2, 10%) and South American (2, 10%). No child reported that it was hard or very hard to complete Spanish SSPedi. Changes to the instrument itself were not required based on understanding or cultural relevance. CONCLUSIONS: We translated and finalised Spanish SSPedi appropriate for use in North America. Future research will translate and evaluate SSPedi for use in Argentina and other Spanish-speaking countries.

Translating the Symptom Screening in Pediatrics Tool (SSPedi) into French and among French-speaking children receiving cancer treatments, evaluating understandability and cultural relevance in a multiple-phase descriptive study.

OBJECTIVES: Symptom Screening in Pediatrics Tool (SSPedi) is a validated approach to measuring bothersome symptoms for English-speaking and Spanish-speaking children with cancer and paediatric haematopoietic stem cell transplantation (HSCT) recipients. Objectives were to translate SSPedi into French, and among French-speaking children receiving cancer treatments, to evaluate understandability and cultural relevance. METHODS: We conducted a multiphase, descriptive study to translate SSPedi into French. Forward translation was performed by four medical translators. After confirming that back translation was satisfactory, we enrolled French-speaking children with cancer and paediatric HSCT recipients at four centres in France and Canada. PRIMARY AND SECONDARY OUTCOME MEASURES: Understandability was evaluated by children themselves who self-reported degree of difficulty, and by two adjudicators who rated incorrectness. Assessment of cultural relevance was qualitative. Participants were enrolled in cohorts of 10. RESULTS: There were 30 children enrolled. Participants were enrolled from Marseille (n=10, 33%), Ottawa (n=1, 3%), Quebec City (n=11, 37%) and Toronto (n=8, 27%). No child reported that it was hard or very hard to complete French SSPedi in the last cohort of 10 participants. Changes to the instrument itself were not required. After enrolment of 30 respondents, the French translation of SSPedi was considered finalised based on self-reported difficulty with understanding, adjudicated incorrect understanding and cultural relevance. CONCLUSIONS: We translated and finalised SSPedi for use by French-speaking children and adolescents receiving cancer treatments. Future work should begin to use the translated version to conduct research and to facilitate clinical care.

Reducing pain in children with cancer: Methodology for the development of a clinical practice guideline.

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.

GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study.

Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p<0.001) supporting their importance in capturing PK variability. Four GSTA1 diplotype groups that significantly correlated with clearance (p=0.009) were distinguished. Diplotypes underlying fast and slow metabolizing capacity showed higher and lower BU clearance (ml/min/kg), respectively. GSTA1 diplotypes with slow metabolizing capacity were associated with higher incidence of sinusoidal obstruction syndrome, acute graft versus host disease and combined treatment-related toxicity (p<0.0005). Among other GST genes investigated, GSTP1 313GG correlated with acute graft versus host disease grade 1-4 (p=0.01) and GSTM1 non-null genotype was associated with hemorrhagic cystitis (p=0.003). This study further strengthens the hypothesis that GST diplotypes/genotypes could be incorporated into already existing population pharmacokinetic models for improving first BU dose prediction and HSCT outcomes. (No Clinicaltrials.gov identifier: NCT01257854. Registered 8 December 2010, retrospectively registered).

Parent Attributions About Child Symptoms Related to Cancer Therapy.

PURPOSE: Symptom assessment is an emergent area of research in pediatric cancer. Our team previously reported on the development of a questionnaire to be completed by parents to determine symptom prevalence and bother. This exploratory study examined parental nonprobed, free-text comments about their child's treatment-related symptoms reported on the questionnaire. METHOD: Participants were parents of children aged 4 to 18 years who had been diagnosed with cancer at least 2 months prior to enrolment and had received intravenous chemotherapy within the past month at 1 of 5 pediatric cancer centers. The questionnaire consisted of 69 or 71 items (based on child's age) addressing physical and psychological sequelae. Each symptom query was accompanied by a blank space in which parents could comment on their response. Comments were analyzed guided by content analysis methodology. RESULTS: Five major themes emerged: parental attributions for the symptoms experienced in their child; coping patterns and communication styles within the family; evidence of anticipatory, procedural, and other anxieties; interruption of daily life; and changes in the child's physical appearance. CONCLUSIONS: These exploratory findings provide context to parental perception of their child's treatment-related symptoms and may contribute to a better understanding of parental perception of child and the family coping and communicating style. These findings may assist in the development of psychoeducational interventions aimed at promoting open communication styles within the family and reducing child and parent burden during treatment procedures.

Strategies facilitating practice change in pediatric cancer: a systematic review.

PURPOSE: By conducting a systematic review, we describe strategies to actively disseminate knowledge or facilitate practice change among healthcare providers caring for children with cancer and we evaluate the effectiveness of these strategies. DATA SOURCES: We searched Ovid Medline, EMBASE and PsychINFO. STUDY SELECTION: Fully published primary studies were included if they evaluated one or more professional intervention strategies to actively disseminate knowledge or facilitate practice change in pediatric cancer or hematopoietic stem cell transplantation. DATA EXTRACTION: Data extracted included study characteristics and strategies evaluated. In studies with a quantitative analysis of patient outcomes, the relationship between study-level characteristics and statistically significant primary analyses was evaluated. RESULTS OF DATA SYNTHESIS: Of 20 644 titles and abstracts screened, 146 studies were retrieved in full and 60 were included. In 20 studies, quantitative evaluation of patient outcomes was examined and a primary outcome was stated. Eighteen studies were 'before and after' design; there were no randomized studies. All studies were at risk for bias. Interrupted time series was never the primary analytic approach. No specific strategy type was successful at improving patient outcomes. CONCLUSIONS: Literature describing strategies to facilitate practice change in pediatric cancer is emerging. However, major methodological limitations exist. Studies with robust designs are required to identify effective strategies to effect practice change.

A Feasibility Pilot Trial of Individualized Homeopathic Treatment of Fatigue in Children Receiving Chemotherapy.

BACKGROUND: Fatigue is a major problem in children with cancer. The objective was to examine the feasibility of performing a clinical trial of homeopathic treatment for fatigue in children receiving chemotherapy. MATERIALS: This was a single-institution, open-label, pilot study. Children 2 to 18 years old, diagnosed with cancer, and receiving chemotherapy were eligible. Participants were given individualized homeopathic treatment for a maximum of 14 days. In-home or clinic assessments were conducted up to 3 times weekly. Feasibility was defined as the ability to recruit and administer homeopathy to 10 participants within 1 year. Fatigue was measured using the Symptom Distress Scale daily and the PedsQL Multidimensional Fatigue Module weekly. RESULTS: Between April 2012 and April 2014, 155 potential participants were identified. There were 45 eligible and contacted patients; 36 declined participation, 30 because they were not interested; 9 agreed to participate, but 1 participant withdrew prior to treatment initiation. Median length of homeopathic treatment was 10.5 (range = 6 to 14) days. All parents found homeopathic treatment to be easy or very easy to follow. CONCLUSIONS: Trials of individualized homeopathy for fatigue reduction in pediatric cancer are not feasible in this context; lack of interest was a primary reason. Alternative approaches to evaluating homeopathy efficacy are needed.

The clinical relevance of pre-formed anti-HLA and anti-MICA antibodies after cord blood transplantation in children.

Preformed anti-HLA antibodies (AHA) are known to be associated with delayed engraftment and reduced overall survival after adult hematopoietic stem cell transplantation. However, limited data is available in pediatric patients. In this study, we explored the role of AHA on clinical outcomes in 70 pediatric patients who received a single unit of HLA mismatch cord blood for hematologic malignancies, immunodeficiencies or metabolic diseases. The presence of AHA was detected in 44% (31/70) of the patients. Preformed class I AHA was associated with an increased occurrence of grade 1-4 acute graft-versus host disease (p<0.05). The presence of anti- major-histocompatibility-complex class I-related chain A antigens (MICA) antibodies was significantly associated with a reduced platelet recovery after transplantation (p<0.05). AHA of class II with the strength of antibody titer measured as the mean fluorescence intensity above 2000 was associated with reduced event-free survival (p<0.05). A reduction of high titer of AHA and anti-MICA antibodies might have to be considered before cord blood transplantation in pediatric patients for better outcomes.

Children's Oncology Group's 2013 blueprint for research: cancer control and supportive care.

In cancer control research, the objective is to reduce overall morbidity and mortality by decreasing acute and delayed treatment-related toxicities in all children with cancer. To date, the Children's Oncology Group (COG) has focused on infection, neurocognition, quality of life (QoL), and nutrition/antiemetics. COG is conducting randomized controlled trials (RCTs) to determine prophylaxis strategies that will reduce infections in high-risk populations. Two RCTs are determining if modafinil or computerized cognitive training improve cognitive functioning in pediatric brain tumor patients. QoL is being assessed in acute leukemia patients. Improved supportive care outcomes will only occur when the most effective interventions are established.

Outcome and toxicity of chemotherapy for acute lymphoblastic leukemia in children with Down syndrome.

BACKGROUND: Acute lymphoblastic leukemia (ALL) in children with Down syndrome (DS) presents with an increased incidence, higher frequency of adverse effects and inferior probability of survival. Attempts at improving outcomes face the dilemma posed by the need to avoid excessive toxicity while maintaining the efficacy of treatment. Dose reductions and avoidance of infusions of intermediate and high-dose methotrexate are common in this group. PROCEDURE: In a matched pair analysis we compared adverse effects and survival after ALL chemotherapy using intermediate and high doses of methotrexate in children with and without Down syndrome. RESULTS: Following intermediate and high doses of methotrexate to treat primary ALL, children with DS did not require opiate analgesia and parenteral nutrition for severe mucositis more often than children without DS. Children with DS spent more days in hospital and missed more doses of maintenance chemotherapy. Chemotherapy dose reductions were common and in this study had no detectable adverse impact. Event-free and overall survival (OS) of children with ALL was lower in the DS than the non-Down syndrome (NDS) control group. The difference, however, was no longer significant during the recent treatment era. CONCLUSIONS: The feasibility of all treatment elements that are efficacious in pediatric ALL needs to be carefully considered in children with DS. In addition to survival data, the prospective collection of data on both adverse events and treatment modifications is essential to strike a balance between the avoidance of adverse effects and the need for intensive therapy that will safely improve ALL outcomes in this group.

Documentation of pediatric drug safety in manufacturers' product monographs: a cross-sectional evaluation of the canadian compendium of pharmaceuticals and specialities.

OBJECTIVE: To describe the provision of pediatric drug safety information in a national formulary of manufacturers' drug product monographs. METHODS: We performed a cross-sectional evaluation of comprehensive product monographs contained in the 2005 Canadian Compendium of Pharmaceuticals and Specialities (CPS). We abstracted data describing indications for prescription, statements about pediatric safety, available preparations, and provision of dosing guidelines. For each monograph we classified pediatric safety data as either present, present but limited or absent. We then described the pediatric safety data in CPS monographs for drugs listed in the published formulary of the Hospital for Sick Children, Toronto, Ontario, Canada. RESULTS: A total of 2232 product monographs were screened; 684 were excluded and 1548 (66%) were further analyzed. 1462 (94%) had indications that did not exclude children. Pediatric safety information was present in 592 (38%), present but limited in 148 (10%), and absent in 808 (52%) drug monographs. Safety statements were absent in 224 (14%) drug monographs that provided both dosing guidelines and formulations suitable for administration to children, and in 214 (52%) of 411 drugs in the pediatric hospital formulary. CONCLUSION: We evaluated a widely available national source of pediatric prescribing information. Safety data for children was not mentioned in more than half of the product monographs. Moreover, the provision of safety data was discordant with indications for prescription, the availability of pediatric formulations, and dosing guidelines within the monographs, and with inclusion in a pediatric hospital formulary. Our study suggests that the presentation of pediatric safety data in drug product monographs can be improved to better inform prescribing and to optimize pharmacotherapy in children.