Longitudinal use of patient reported outcomes in pediatric leukemia and lymphoma reveals clinically relevant symptomatic adverse events.

BACKGROUND: Leukemia and lymphoma (LL) are the most common cancer diagnoses of childhood with high survival rates, but not without impact on the child's functioning and quality of life. This study aimed to use patient-reported data to describe the symptomatic adverse event (AE) experiences among children with LL diagnoses. METHODS: Two hundred and fifty seven children and adolescents aged 7-18 years with a first LL diagnosis completed the Pediatric Patient-Reported version of the Common Terminology Criteria for Adverse Events (Ped-PRO-CTCAE) and Patient-Reported Outcome Measurement Information System (PROMIS) Pediatric measures before starting a treatment course (T1) and after the treatment (T2). RESULTS: Fatigue was the most severe AE (68.1% at T1; 67% at T2) and caused the most interference over time. Gastrointestinal AEs were also quite common (e.g., nausea 46.3% at T1 and 48.9% at T2; abdominal pain 42.4% at T1; 46.5% at T2). In general, symptoms were present both at T1 and T2 and did not change significantly in severity or interference. The prevalence of AEs varied by LL disease group (e.g., nausea was most common in acute lymphoblastic leukemia (ALL), fatigue was most severe in ALL and Hodgkin Lymphoma (HL), acute myeloid leukemia had the fewest AEs). CONCLUSION: Despite current supportive care regimens, many children with LL continue to report fatigue, pain, insomnia, and gastrointestinal symptoms as the most frequent or severe symptoms during therapy.

Pharmacogenetic and clinical predictors of ondansetron failure in a diverse pediatric oncology population.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a frequently seen burdensome adverse event of cancer therapy. The 5-HT3 receptor antagonist ondansetron has improved the rates of CINV but, unfortunately, up to 30% of patients do not obtain satisfactory control. This study examined whether genetic variations in a relevant drug-metabolizing enzyme (CYP2D6), transporter (ABCB1), or receptor (5-HT3) were associated with ondansetron failure. METHODS: DNA was extracted from blood and used to genotype: ABCB1 (3435C > T (rs1045642) and G2677A/T (rs2032582)), 5-HT3RB (rs3758987 T > C and rs45460698 (delAAG/dupAAG)), and CYP2D6 variants. Ondansetron failure was determined by review of the medical records and by patient-reported outcomes (PROs). RESULTS: One hundred twenty-nine patients were approached; 103 consented. Participants were less than 1 to 33 years (mean 6.85). A total of 39.8% was female, 58.3% was White (22.3% Black, 19.4% other), and 24.3% was Hispanic. A majority had leukemia or lymphoma, and 41 (39.8%) met the definition of ondansetron failure. Of variants tested, rs45460698 independently showed a significant difference in risk of ondansetron failure between a mutant (any deletion) and normal allele (p = 0.0281, OR 2.67). Age and BMI were both predictive of ondansetron failure (age > 12 (OR 1.12, p = 0.0012) and higher BMI (OR 1.13, p = 0.0119)). In multivariate analysis, age > 12 was highly predictive of ondansetron failure (OR 7.108, p = 0.0008). rs45460698 was predictive when combined with an increased nausea phenotype variant of rs1045642 (OR 3.45, p = 0.0426). CONCLUSION: Select phenotypes of 5-HT3RB and ABCB1, age, and potentially BMI can help predict increased risk for CINV in a diverse pediatric oncology population.

Validation of the caregiver Pediatric Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events measure.

BACKGROUND: Despite improvements in survival rates, cancer treatments have significant side effects that affect the quality of life of children and their families. When an ill child cannot self-report symptoms (eg, he or she is too ill), caregiver (parent) reporting becomes critical. This study evaluates the validity and reliability of the caregiver-reported Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (Ped-PRO-CTCAE [Caregiver]) measure. METHODS: A diverse sample of caregivers with children receiving treatment at 9 oncology centers completed the Ped-PRO-CTCAE [Caregiver] measure, the Patient-Reported Outcomes Measurement Information System® (PROMIS® ) Parent Proxy measures, the Lansky Play-Performance Scale (PPS), medication use questions, and Global Impressions of Change (GIC). Construct validity (including convergent, discriminant, and known groups validity and responsiveness over time) and reliability (stability) were examined. RESULTS: A majority of the 473 caregivers were female (85%), non-Hispanic White (61%), and married (75%). Symptoms assessed with the Ped-PRO-CTCAE [Caregiver] and PROMIS Parent Proxy measures were strongly correlated (e.g., r for pain = 0.78; r for fatigue = 0.78; and r for depression = 0.83). Most of the Ped-PRO-CTCAE [Caregiver] item mean scores distinguished among PPS function levels and between children who did take medications for symptom control and children who did not. Changes in Ped-PRO-CTCAE [Caregiver] item mean scores were responsive to GIC over time. Test-retest evaluation found moderate to high agreement (57.8%-93.3%) over time. CONCLUSIONS: This study found strong evidence for the convergent and discriminant validity, known groups validity, responsiveness, and stability of the Ped-PRO-CTCAE [Caregiver] measure in a large and diverse sample of caregivers. The caregiver perspective provides a valuable and unique insight into the experiences of children and adolescents undergoing cancer treatment. LAY SUMMARY: Despite advances in cancer treatments, children and adolescents continue to suffer from treatment side effects, including pain, nausea, fatigue, and emotional distress, that can adversely affect quality of life for children and their families. Although it is best for children to report how they are feeling, there are times when a child may be too young or too ill to self-report. This study provides critical evidence for a new type of questionnaire that allows the caregiver or parent to report accurately what the child is experiencing. This measure can be used to improve adverse event reporting and child cancer care.

Patients, caregivers, and clinicians differ in performance status ratings: Implications for pediatric cancer clinical trials.

BACKGROUND: The Lansky Play-Performance Scale (LPPS) is often used to determine a child's performance status for cancer clinical trial eligibility. Differences between clinician and caregiver LPPS ratings and their associations with child-reported functioning have not been evaluated. METHODS: Children aged 7 to 18 years who were receiving cancer treatment and their caregivers were recruited from 9 pediatric cancer centers. Caregivers and clinicians reported LPPS scores, and children completed Patient-Reported Outcomes Measurement Information System (PROMIS) pediatric functioning and symptom measures before treatment (time 1 [T1]) and after treatment (time 2 [T2]). t tests and mixed-linear models were used to assess differences in caregiver and clinician LPPS scores; polyserial correlations quantified associations between PROMIS and LPPS scores. RESULTS: Of 482 children, 281 had matched caregiver- and clinician-reported LPPS T1/T2 scores. Caregivers rated children significantly worse on the LPPS than clinicians at both T1 (mean, 73.3 vs 87.4; P < .01) and T2 (mean, 67.9 vs 83.1; P < .01). These differences were not related to a child's age (P = .89), diagnosis (P = .17), or sex (P = .64) or to the time point (P = .45). Small to moderate associations existed between caregiver- and clinician-reported LPPS ratings and child-reported PROMIS scores for mobility (caregiver T1/T2 r = 0.51/0.45; P < .01; clinician T1/T2 r = 0.40/0.35; P < .01), fatigue (caregiver T1/T2 r = -0.46/-0.37; P < .01; clinician T1/T2 r = -0.26/-0.27; P < .01), and pain interference (caregiver T1/T2 r = -0.32/-0.30; P < .01; clinician T1/T2 r = -0.17/-0.31; P < .01). Caregivers and clinicians assigned significantly lower LPPS scores at T2 (caregiver Δ = -5.37; P < .01; clinician Δ = -4.20; P < .01), whereas child-reported PROMIS scores were clinically stable. CONCLUSIONS: Significant differences between clinician and caregiver LPPS ratings of child performance were sustained over time; their associations with child reports were predominantly small to moderate. These data suggest that clinician-reported LPPS ratings by themselves are inadequate for determining clinical trial eligibility and should be supplemented by appropriate measures of a child's functional status reflecting the child and caregiver perspectives.

Mapping child and adolescent self-reported symptom data to clinician-reported adverse event grading to improve pediatric oncology care and research.

BACKGROUND: Clinicians are the standard source for adverse event (AE) reporting in oncology trials, despite the subjective nature of symptomatic AEs. The authors designed a pediatric patient-reported outcome (PRO) instrument for symptomatic AEs to support the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) (the Pediatric PRO-CTCAE). The current study developed a standardized algorithm that maps all possible Pediatric PRO-CTCAE response patterns to recommended CTCAE grades to improve the accuracy of AE reporting in pediatric oncology trials. METHODS: Two rounds of surveys were administered to experienced cancer clinicians across 9 pediatric hospitals. In round 1, pediatric oncologists assigned CTCAE grades to all 101 possible Pediatric PRO-CTCAE response patterns. The authors evaluated clinician agreement of CTCAE grades across response patterns and categorized each response pattern as having high or low agreement. In round 2, a survey was sent to a larger clinician group to examine clinician agreement among a select set of Pediatric PRO-CTCAE response patterns, and the authors examined how clinical context influenced grade assignment. RESULTS: A total of 10 pediatric oncologists participated in round 1. Of the 101 possible patterns, 89 (88%) had high agreement. The Light weighted kappa was averaged across the 10 oncologists (Light kappa = 0.73; 95% CI, 0.66-0.81). A total of 139 clinicians participated in round 2. High clinician agreement remained for the majority of generic response patterns and the clinical context did not typically change grades but rather improved agreement. CONCLUSIONS: The current study provides a framework for integrating child self-reported symptom data directly into mandated AE reporting in oncology trials. Translating Pediatric PRO-CTCAE responses into clinically meaningful metrics will guide future cancer care and toxicity grading.

Expanding construct validity of established and new PROMIS Pediatric measures for children and adolescents receiving cancer treatment.

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric measures were designed to assess symptoms and functioning in children and adolescents. The study goal was to evaluate the validity and responsiveness of the PROMIS Pediatric measures in a diverse cohort of children with cancer. METHODS: Children (7-18 years) from nine pediatric oncology hospitals completed surveys at 72 hours preceding treatment initiation (T1) and at follow-up (T2) approximately 7 to 17 days later for chemotherapy, and 4+ weeks later for radiation. Children completed PROMIS Pediatric measures (Mobility, Pain Interference, Fatigue, Depressive Symptoms, Anxiety, Psychological Stress), Memorial Symptom Assessment Scale (MSAS), and global impressions of change (GIC) questions on their symptoms and functioning at T2 reflecting on T1. Parents completed the Lansky Play-Performance Status (PPS) scale and medication list for their child. RESULTS: The children (n = 482) were average age 12.9 years, 46% female, 60% Caucasian, and had diverse cancers and treatments. There were moderate to strong correlations between PROMIS Pediatric and MSAS, supporting convergent validity. In support for known-groups validity, the PROMIS Pediatric average scores were statistically different (P < 0.05) for most domains by PPS and if the child was on a medication (or not) for controlling a symptom. The PROMIS Pediatric measures were responsive over time in association with the GIC. CONCLUSIONS: In a large, diverse sample of children and adolescents with cancer, there was strong evidence for the construct validity and responsiveness of the PROMIS Pediatric measures. This evidence supports PROMIS Pediatric measure use in pediatric oncology trials.

A Pediatric Case of Transformed Mycosis Fungoides in a BRCA2 Positive Patient.

Cutaneous T-cell lymphomas are very rare in children. Although mycosis fungoides is the most common of these rare cutaneous T-cell lymphomas in children, transformation to an aggressive malignancy remains extremely uncommon, and there are no clear guidelines for clinical management in the pediatric population. In addition, the increased usage of next-generation sequencing for pediatric patients with unusual malignancies may result in the discovery of pathogenic germline mutations, though the association between these mutations and the patient's cancer is not always clear. We present here a unique pediatric case of transformed mycosis fungoides in a patient with BRCA2 mutation.

PROMIS pediatric measures validated in a longitudinal study design in pediatric oncology.

PURPOSE: This study assessed the responsiveness to change over time and theorized associations of Patient-Reported Outcomes Measurement Information System (PROMIS) pediatric measures in children and adolescents in treatment for cancer to determine measure readiness for use in cancer clinical trials. METHODS: We administered eight PROMIS (three symptom, two psychological, and three performance) pediatric short-form measures and the Symptom Distress Scale (SDS) to 96 pediatric oncology patients at three time points during a course of chemotherapy. We assessed responsiveness using paired t tests and generalized estimating equation (GEE) models, calculated standardized response mean (SRM) values for PROMIS measures, and examined scores over three data points (T1-T3). Guided by the theory of unpleasant symptoms (TOUS), we examined associations among the PROMIS measures, the SDS, and other variables using GEE. RESULTS: The paired t tests showed statistically significant changes in two psychological measures and one performance measure from T1 to T2; three symptom, two psychological and two performance measures from T2 to T3; and three symptom and two psychological measures from T1 to T3. Findings from GEE models indicate PROMIS pediatric measures had statistically significant short-term and long-term changes, controlling for demographic and clinical variables. One performance measure did not achieve significant change at any time point. We found positive support for theorized relationships in the TOUS. CONCLUSIONS: Most of the PROMIS pediatric measures demonstrated changes over time and had significant relationships as theorized, thus supporting concurrent and construct validity of these measures when administered to pediatric oncology patients during a course of chemotherapy. This evidence supports the measures' readiness for use in clinical trials.

Profiles of Symptom Suffering and Functioning in Children and Adolescents Receiving Chemotherapy.

BACKGROUND: Some children and adolescents receiving chemotherapy experience few symptom-related adverse events, whereas others experience multiple adverse events. If oncology nurses could identify patients likely to have pronounced chemotherapy-related adverse events, tailored supportive care could be matched to these patients' symptom burdens. OBJECTIVE: The aim of this study was to identify symptom profiles in children and adolescents before and after chemotherapy, and the sociodemographic and psychological factors associated with profile classification and change. METHODS: Participants ranging from 7 to 18 years (n = 436) completed 6 Patient-Reported Outcomes Measurement Information System pediatric symptom measures within 72 hours preceding (T1) and 1 to 2 weeks after (T2) chemotherapy. Profile membership and change were determined by latent profile/latent transition analyses. Associations with profiles and profile transitions were examined using multinomial logit models and logistic regression. RESULTS: Three symptom suffering profiles were identified at T1 and T2: high, medium, and low. The high symptom suffering profile included the fewest participants (T1, n = 70; T2, n = 55); the low symptom suffering profile included the most participants (T1, n = 200; T2, n = 207). Of the participants, 57% remained in the same profile from T1 to T2. Psychological stress was significantly associated with T1 and T2 profile classifications and profile transition; age was associated with profile classification at T1. CONCLUSION: Three symptom suffering profiles existed in a sample of pediatric patients undergoing chemotherapy, indicating that children and adolescents have differing cancer treatment experiences. IMPLICATIONS FOR PRACTICE: Oncology nurses could screen pediatric oncology patients for their symptom suffering profile membership and subsequently prioritize care efforts for those with a high suffering profile.

Profile Comparison of Patient-Reported and Proxy-Reported Symptoms in Pediatric Patients With Cancer Receiving Chemotherapy.

Importance: The variability in individual symptom and adverse event reporting between pediatric patient-reports and proxy-reports is widely reported. However, the question of whether symptom profiles based on reports from children with cancer and their caregivers are similar or disparate have not yet been studied. Objective: To compare proxy symptom reports with patient self-reports to assess alignment. Design, Setting, and Participants: A multicenter cohort study was conducted from October 2016 to December 2018 from data collected at 9 pediatric cancer centers. Participants were a convenience sample of family caregivers or proxies of children aged 7 to 18 years who had received disease-directed oncology treatment in the form of chemotherapy for at least 1 month. Data were analyzed identifying clusters of individuals (ie, latent profiles) based on various responses (ie, indicators) in August 2021. Exposures: The children of proxy participants received upfront chemotherapy. Children and proxies completed Patient-Reported Outcomes Measurement Information System (PROMIS) surveys at 2 time points: within 72 hours preceding treatment initiation and following the course of chemotherapy. Main Outcomes and Measures: The latent profile analysis methods were applied to caregiver-proxy reports of PROMIS Pediatric symptom and function measures (anxiety, depressive symptoms, pain interference, fatigue, psychological stress, and physical function-mobility). The instrument categorized respondents as high symptom suffering, medium symptom suffering, and low symptom suffering (hereafter, high, medium, and low symptom groups, respectively). Results: Of 580 approached proxies, 431 (368 [85.00%] were female) identified as legal guardians of children aged 7 to 18 years with a first cancer diagnosis (mean [SD] age, 13.03 [3.40] years; 235 [54.65%] were male). Proxy reports of children's experiences based on the 5 proxy PROMIS measures comprised 3 distinct symptom profiles. The most common proxy assessments of children's experiences were the moderate symptom groups (45.7% [197 of 431]) and the low symptom groups profiles (40.1% [173 of 431]). A high symptom groups profile emerged which represented 14.2% (61 of 431) of proxy assessments. The number of profiles and observed distribution of profile membership was similar between child and proxy reports. Proxy reports of individual symptoms generally recorded higher scores than child reports; however, no significant difference was observed between proxies and child profile model results for the PROMIS measures. Conclusions and Relevance: Results of this cohort study suggest that, at the level of symptom severity profile, proxy caregiver reports may approximate the children's reports and may serve as a guide to care when the child is not able to self-report.

Lack of Concordance in Symptomatic Adverse Event Reporting by Children, Clinicians, and Caregivers: Implications for Cancer Clinical Trials.

PURPOSE: To examine concordance in symptomatic adverse event (AE) grading using the Common Terminology Criteria for Adverse Events (CTCAE 4.0) for clinicians and its patient-reported outcome (PRO) versions for children (Ped-PRO-CTCAE) and caregivers (Ped-PRO-CTCAE [Caregiver]). METHODS: Children age 7-18 years with a first cancer diagnosis, their clinicians, and caregivers completed CTCAE-based measures before starting a treatment course (T1) and after the treatment (T2). Grades (0-3) were assigned by each reporter for 15 core AEs spanning physical and mental health. Mean grades were compared between reporters using two-sample t-tests; agreement was estimated using weighted kappa (κ) statistics. Multivariable mixed regression models were used to evaluate associations of clinical factors with AE reporting concordance. Significance was set at α = .05 (two-sided). RESULTS: There were 438 child-clinician-caregiver triads with complete data at either T1 or T2. For children, the mean age was 13 years (standard deviation = 3.4), 53.7% were male, 32.6% non-White, and 56.4% had leukemia/lymphoma. At T1, clinician mean AE grades were significantly lower (ie, better) than children for all AEs and remained significantly lower at T2 except for constipation, nausea, anorexia, neuropathy, and anxiety. Caregiver mean AE grades were similar to children at T1 and significantly higher (ie, worse) at T2 for nausea, vomiting, anorexia, pain, fatigue, anxiety, and depression. Agreement for child-clinician grading was poor-to-fair at T1 (κ range, 0.08-0.34) and T2 (0.11-0.35), and for child-caregiver, was fair-to-good at T1 (0.34-0.65) and T2 (0.24-0.60). No factors were consistently associated with reporter concordance across AEs. CONCLUSION: Compared with children, symptomatic AEs were consistently under-reported by clinicians with low agreement and over-reported by caregivers with low-moderate agreement. Direct reporting by children using Ped-PRO-CTCAE or similar measures should be routinely incorporated for toxicity assessment in clinical trials.

Subjective Toxicity Profiles of Children in Treatment for Cancer: A New Guide to Supportive Care?

CONTEXT: Children and adolescents with cancer experience treatment-related, subjective adverse events (AEs). Identifying distinct groups of patients who predictably experience higher prevalence of AEs could guide patient care. OBJECTIVES: Study aims were to 1) identify groups of children and adolescents reporting AEs using the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (Ped-PRO-CTCAE); 2) determine whether demographic and clinical characteristics predict AE group membership; and 3) examine whether AE group membership was related to the distal outcome of psychological stress. METHODS: Four hundred seventy-seven patients self-reported AEs via the Ped-PRO-CTCAE at T1 (beginning of treatment) and the PROMIS Pediatric Psychological Stress measure at T2 (7-28 days later). Latent class analysis was conducted to identify groups of patients and the relationships of the groups with demographic and clinical characteristics, and with stress. RESULTS: Three distinct a priori unknown AE groups were identified (high AE prevalence, moderate AE prevalence, and low AE prevalence). Females, blacks, patients with high psychological stress, and patients more recently diagnosed were more likely to be in the high AE prevalence group. Gender, age, race, and time since diagnosis were associated with psychological stress. CONCLUSION: Children with cancer are heterogeneous in experiencing subjective AEs. Gender, race, and time since diagnosis were significantly associated with higher subjective AE prevalence that may lead to psychological stress.

Agreement Between Child Self-report and Caregiver-Proxy Report for Symptoms and Functioning of Children Undergoing Cancer Treatment.

Importance: Adult patients are considered the best reporters of their own health-related quality of life (HRQOL). Self-report in pediatrics has been challenged by a limited array of valid measures. Caregiver report is therefore often used as a proxy for child report. Objectives: To examine the degree of alignment between child and caregiver proxy report for Patient-Reported Outcomes Measurement Information System (PROMIS) HRQOL domains among children with cancer and to identify factors associated with better child and caregiver-proxy congruence. Design, Setting, and Participants: In this multicenter cohort study, children with a first cancer diagnosis and their caregivers completed surveys at 2 time points: within 72 hours preceding treatment initiation (T1) and during follow-up (T2), when symptom burden was expected to be higher (eg, 7-17 days later for chemotherapy). Data were collected from October 26, 2016, to October 5, 2018, at 9 pediatric oncology hospitals. Five hundred eighty children (aged 7-18 years) and their caregivers were approached; 482 child-caregiver dyads completed surveys at T1 (response rate 83%), and 403 completed surveys at T2 (84% of T1 participants). Data were analyzed from July 1, 2019, to April 22, 2020. Exposures: Participants received up-front cancer treatment, including chemotherapy and radiotherapy. Main Outcomes and Measures: Congruence between child self-report and caregiver-proxy report of PROMIS pediatric domains of mobility (physical functioning), pain interference, fatigue, depressive symptoms, anxiety, and psychological stress. Results: Of the 482 dyads included in the analysis, 262 children (54%) were male (mean [SD] age, 12.9 [3.4] years), 80 (17%) were Black, and 71 (15%) were Hispanic. Intraclass correlations between child self-report and caregiver proxy report showed moderate agreement for mobility (0.57 [95% CI, 0.50-0.63]) and poor agreement for symptoms (range, 0.32 [95% CI, 0.24-0.41] for fatigue to 0.42 [95% CI, 0.34-0.50] for psychological stress). Children reported lower symptom burden and higher mobility than caregivers reported. In a multivariable model adjusted for child and parent sociodemographic factors and the caregiver's own self-reported HRQOL, caregivers reported the child's mobility score 6.00 points worse than the child's self-report at T2 (95% CI, -7.45 to -4.51), exceeding the PROMIS minimally important difference of 3 points. Caregivers overestimated the child's self-reported symptom levels, ranging from 5.79 (95% CI, 3.99-7.60) points for psychological stress to 13.69 (95% CI, 11.60-15.78) points for fatigue. The caregiver's own self-reported HRQOL was associated with the magnitude of difference between child and caregiver scores for all domains except mobility; for example, for fatigue, the magnitude of difference between child and caregiver-proxy scores increased by 0.21 (95% CI, 0.13-0.30) points for each 1-point increase in the caregiver's own fatigue score. Conclusions and Relevance: This study found that caregivers consistently overestimated symptoms and underestimated mobility relative to the children themselves. These results suggest that elicitation of the child's own report should be pursued whenever possible.

Validity and Reliability of the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events.

BACKGROUND: Patient-reported outcome (PRO) measurements linked to Common Terminology Criteria for Adverse Events (CTCAE) grading may improve symptom adverse event (AE) reporting in pediatric oncology trials. We evaluated construct validity, responsiveness, and test-retest reliability of the Ped-PRO-CTCAE measurement system for children and adolescents undergoing cancer care. METHODS: A total of 482 children and adolescents (7-18 years, 41.5% not non-Hispanic white) newly diagnosed with cancer and their caregivers participated from nine pediatric oncology hospitals. Surveys were completed at 72 hours preceding treatment initiation (T1) and at follow-up (T2) approximately 7-17 days later for chemotherapy, and 4+ weeks for radiation. Psychometric analyses examined the relationship of Ped-PRO-CTCAE items (assessing 62 symptom AEs) with Patient-Reported Outcomes Measurement Information System, Memorial Symptom Assessment Scale, Lansky Play-Performance Scale, and medication use. A separate test-retest study included 46 children. RESULTS: Ped-PRO-CTCAE and Memorial Symptom Assessment Scale were strongly correlated across age groups at T2: 7-12 years (r = 0.62-0.80), 13-15 years (r = 0.44-0.94), and 16-18 years (r = 0.65-0.98); and over time. The Ped-PRO-CTCAE was strongly correlated with Patient-Reported Outcomes Measurement Information System Pediatric measures at T2; for example, pain interference (r = 0.70, 95% confidence interval [CI] = 0.64 to 0.76), fatigue severity (r = 0.63, 95% CI = 0.56 to 0.69), and depression severity (r = 0.76, 95% CI = 0.71 to 0.81). Ped-PRO-CTCAE items differentiated children by Lansky Play-Performance Scale and by medication use. Test-retest agreement ranged from 54.3% to 93.5%. CONCLUSIONS: This longitudinal study provided evidence for the construct validity and reliability of the core Ped-PRO-CTCAE symptom AE items relative to several established measures. Additional responsiveness data with clinical anchors are recommended. Incorporation of Ped-PRO-CTCAE in trials may lead to a better understanding of the cancer treatment experience.

Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates.

PURPOSE: Describe and compare the central nervous system pharmacology of the platinum analogues, cisplatin, carboplatin, and oxaliplatin and develop a pharmacokinetic model to distinguish the disposition of active drug from inert platinum species. EXPERIMENTAL DESIGN: Oxaliplatin (7 or 5 mg/kg), cisplatin (2 mg/kg), or carboplatin (10 mg/kg) was given i.v. Serial plasma and cerebrospinal fluid (CSF) samples were collected over 24 hours. Plasma ultrafiltrates were prepared immediately. Platinum concentrations were measured using atomic absorption spectrometry. Areas under the concentration x time curve were derived using the linear trapezoidal method. CSF penetration was defined as the CSF AUC(0-24)/plasma ultrafiltrate AUC(0-24) ratio. A four-compartment model with first-order rate constants was fit to the data to distinguish active drug from inactive metabolites. RESULTS: The mean +/- SD AUCs in plasma ultrafiltrate for oxaliplatin, cisplatin, and carboplatin were 61 +/- 22, 18 +/- 6, and 211 +/- 64 micromol/L hour, respectively. The AUCs in CSF were 1.2 +/- 0.4 micromol/L hour for oxaliplatin, 0.56 +/- 0.08 micromol/L hour for cisplatin, and 8 +/- 2.2 mumol/L hour for carboplatin, and CSF penetration was 2.0%, 3.6%, and 3.8%, respectively. For oxaliplatin, cisplatin, and carboplatin, the pharmacokinetic model estimated that active drug accounted for 29%, 79%, and 81% of platinum in plasma ultrafiltrate, respectively, and 25%, 89%, and 56% of platinum in CSF, respectively. The CSF penetration of active drug was 1.6% for oxaliplatin, 3.7% for cisplatin, and 2.6% for carboplatin. CONCLUSIONS: The CSF penetration of the platinum analogues is limited. The pharmacokinetic model distinguished between active drug and their inactive (inert) metabolites in plasma and CSF.

Integrative Therapy Use for Management of Side Effects and Toxicities Experienced by Pediatric Oncology Patients.

Integrative Therapies (IT), otherwise known as Complementary and Alternative Medicine, are widely used among pediatric oncology patients, despite a paucity of available evidence. This review summarizes surveys that describe the prevalence of IT use by pediatric oncology patients, both during therapy and in survivorship, as well as the modalities being used. Additionally, the evidence that exists for specific treatments that appear to be efficacious in controlling specific symptoms is described. Finally, there are recommendations for practitioners on how to best counsel patients about IT use.

Feasibility and acceptability of the patient-reported outcomes measurement information system measures in children and adolescents in active cancer treatment and survivorship.

BACKGROUND: Patient-reported outcomes related to symptoms, function, and quality of life during and following cancer treatment can guide care for pediatric cancer patients. To advance the science of patient-reported outcomes, the National Institutes of Health funded the Patient-Reported Outcomes Measurement Information System (PROMIS). OBJECTIVE: The objective of this study was to assess feasibility and acceptability of the PROMIS pediatric measures, as defined by enrollment and attrition rates as well as missingness by measure, item, participant, and assessment time point. METHODS: Eight- to 18-year-olds participated in 2 studies: PROMIS I, a cross-sectional study of children in active cancer treatment or survivorship, and PROMIS II, a longitudinal study with 3 assessment time points for children receiving curative treatment. RESULTS: PROMIS I (n = 200) and PROMIS II (n = 94) had enrollment rates of 92.5% and 89.7%, respectively. For PROMIS I, measure missingness was acceptable (8% missed any measures) and was not related to other study variables. For PROMIS II, measure missingness was minimal (0.8%), and item-level missingness was relatively low. In general, items that were skipped asked about experiences that participants had not encountered in the past 7 days. CONCLUSIONS: In both studies, the PROMIS instruments demonstrated good feasibility and acceptability among pediatric cancer patients. Overall, we had high enrollment, low attrition, and acceptable rates of measure and item missingness. IMPLICATIONS FOR PRACTICE: Our results demonstrate that PROMIS measures are acceptable to 8- to 18-year-olds in different points of cancer care and feasible for use in pediatric cancer inpatient and outpatient settings.

Substitution of oral and intravenous thioguanine for mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic leukemia: a collaborative Children's Oncology Group/National Cancer Institute pilot trial (CCG-1942).

BACKGROUND: Although mercaptopurine (MP) is conventionally used to treat childhood acute lymphoblastic leukemia (ALL), thioguanine (TG) is a more potent thiopurine in vitro and, when administered orally to patients, achieves cytotoxic drug concentrations in the cerebrospinal fluid (CSF). We performed a pilot study incorporating oral and 24-hr continuous IV infusion (CIVI) TG in children with newly diagnosed standard-risk ALL. PROCEDURE: Children with newly diagnosed standard-risk ALL (age 1-10 years, WBC<50 k) were eligible. Multi-agent chemotherapy was patterned after the Children's Cancer Group (CCG) 105 trial, with the addition of CIVI-TG (480 mg/m2) during consolidation, interim maintenance and maintenance, and substitution of oral TG (60 mg/m2/day) for oral MP during maintenance. RESULTS: Fifty-eight patients (31 female), median age 4.3 years, were enrolled. At 8 years, the relapse-free and overall survival probabilities were 83% and 88%. There were no CNS relapses. Six patients (five males) experienced reversible veno-occlusive disease (VOD) while receiving oral TG, and the study was amended to discontinue TG, changing all patients to oral MP. Red cell TG nucleotide concentrations during oral TG averaged 95 ng (570 pmol)/8x10(8) RBC, greater than concentrations reported with oral MP. CONCLUSION: Although the absence of CNS relapses in this pilot study suggests that TG may contribute to the prevention of CNS recurrences, the development of VOD negatively impacts the risk:benefit ratio of substituting TG for MP.