PURPOSE Chemotherapy ordering errors can have serious safety implications in pediatric oncology. Computerized provider order entry systems may reduce chemotherapy ordering errors. Crisantaspase recombinant (crisantaspase) is a chemotherapy drug used in pediatric leukemia that poses significant safety risk when ordering because of complex dosing and monitoring. The aim of this study was to compare errors, satisfaction, and efficiency between two approaches to ordering in our electronic health record: namely, the standard treatment plan order group (OG) and a novel supportive care plan (SCP). METHODS We recruited oncology providers and nurses at an academic pediatric institution. Providers were asked to complete two simulated chemotherapy ordering sessions using the treatment plan OG and the SCP. Order entry errors were assessed in seven domains, and the total number of order entry errors was calculated. Satisfaction was assessed using a five-point Likert scale, and satisfaction was defined as answering “Agree” or “Strongly Agree” to all five satisfaction questions. Efficiency was compared by measuring the time to complete the task. Errors, satisfaction, and efficiency were compared between the two tools. RESULTS We enrolled 14 providers and five nurses. The proportion of chemotherapy ordering errors was significantly lower with the SCP (5 of 98, 5.1%) compared with the treatment plan OG (11 of 98, 11.2%; P < .01). The SCP significantly improved provider efficiency, reducing the time taken to complete order entry from 16.3 minutes with the OG to 7.7 minutes with the SCP (mean difference, 8.6 minutes; P < .001). Provider satisfaction was significantly higher with the SCP (12 of 14, 85.7%) compared with the treatment plan OG (2 of 14, 14.2%; P < .001). CONCLUSION Use of a novel SCP instead of a tradition treatment plan OG improved provider efficiency and satisfaction while decreasing order entry errors. Thoughtful design and usability testing of chemotherapy order tools is needed to maximize their utility.

Abstract BACKGROUND Craniopharyngiomas (CP) is a life-long chronic disease predominantly affecting young children. Consequently, the developing brain is particularly sensitive to therapies such as surgery or radiotherapy. Hence, therapies allowing to avoid or delay intensive therapies provide substantial benefit. Intracystic injection of interferon alfa-2a or -2 has emerged as frequently applied treatment based on advantageous risk-benefit ratio with good effects leading to cyst shrinkage. Unfortunately, the original drug is worldwide no longer available. To overcome this shortage we performed an elaborate pharmacological review, identifying peginterferon alfa-2a (Pegasys®) as best currently available alternative drug for intracystic treatment of CP patients. METHODS Within an international collaboration we set up a novel protocol for intracystic peginterferon treatment. Based on the protocol five patients were treated with intracystic peginterferon alfa-2a for cystic CP. After initial CP cyst-aspiration peginterferon alfa-2a was injected once per week via an Ommaya reservoir. One treatment course was six weeks accompanied by regular response assessment with MRI (3-6 weeks). Side effect, safety and therapeutic effects were analyzed. RESULTS Age of patients ranged from 4 to 54 years (4 pediatric patients <12 years, 1 adult patient). Intracystic therapy with peginterferon alfa-2a was generally well tolerated throughout the treatment course and resulted in cyst shrinkage in all cases. Cyst leakage was observed in one case highlighting the importance of testing cyst permeability before starting intracystic treatment courses. CONCLUSIONS Taken together, intracystic treatment with peginterferon alfa-2a was feasible and effective being comparable to prior intracystic interferon protocols for cystic CP being of potential clinical benefit for this severely affected patient cohort. Our experience in this small cohort indicated the potential of this treatment modality, which should be further investigated within a larger trial cohort.

BackgroundChildren with craniopharyngiomas (CPs) typically suffer from a life-long chronic disease. The younger the child, the more vulnerable the maturing brain is to invasive therapies such as surgery or radiotherapy. Therefore, treatment modalities facilitating avoidance or delay of invasive therapies are beneficial for these patients. In the last decade, intracystic injection of interferon alfa-2a or alfa-2b evolved as a treatment of choice based on efficacy and minor toxicity. However, the drug is no longer available internationally. After an extensive pharmacological review, peginterferon alfa-2a was identified as the agent with closest similarity.MethodsA retrospective case series is described, including five patients treated with intracystic peginterferon alfa-2a for cystic CP according to an innovative care protocol. After initial CP cyst aspiration, peginterferon alfa-2a was injected once per week via an Ommaya reservoir for 6 weeks followed by response assessment with MRI.ResultsPatients’ age ranged from 4 to 54 years (four patients <12 years, one adult patient). Intracystic therapy with peginterferon alfa-2a was tolerated well by all five individuals without any major toxicities and resulted in cyst shrinkage in all of the five patients. The importance of a permeability study prior to commencing intracystic therapy became apparent in one patient who suffered from cyst leakage.ConclusionsIntracystic treatment with peginterferon alfa-2a was found to be a tolerable and efficacious treatment modality in patients with cystic CP. This experience warrants further research with a larger number of patients with measurement of long-term efficacy and safety outcomes.

Little evidence exists regarding the emetogenicity of chemotherapy in pediatric patients. This study describes the prevalence of chemotherapy-induced nausea and vomiting (CINV) in pediatric patients receiving etoposide plus ifosfamide over 5 days, a common pediatric regimen.

Objectives: To characterize the drug-related needs of ambulatory HO patients identified by a pharmacist; describe the role of the pharmacist in a pediatric hematology/oncology (HO) clinic; assess the impact of clinical pharmacy services in a pediatric HO clinic on patient care; and make recommendations for the future provision of clinical pharmacy services to patients attending the HO clinic. Design: Prospective descriptive study over 12 weeks. Setting: Hematology/oncology clinic in a 411 bed tertiary/quarternary, university-affiliated pediatric hospital. Patients: Thirty-one children who attended a clinic post-bone marrow transplant (BMT) and 27 children who attended an oncology clinic. Methods: Actual or potential drug-related problems (DRPs) were identified or verified by patient/parent dialogue and interventions were made by the pharmacist in consultation with the responsible physician and/or patient/parent. The impact of a subset of these interventions was assessed by two physicians and two pharmacists. Results: 165 DRPs were identified in 31 BMT and 27 ONC patients. The mean number of DRPs identified per patient was 4.8 in BMT patients and 0.6 in ONC patients. The most frequently identified DRP was too high a (35%) in BMT patients and ''inappropriate medication administration (35%) in ONC patients. 177 interventions were made by the pharmacist; 81 % were accepted by the physician and/or patient/parent. The review panel deemed 83.5% of the subset of interventions to have had a positive impact. Conclusions: Children attending the HO clinic have drug-related needs. BMT patients would benefit from dialogue with a pharmacist for assessment, prevention, and resolution of their DRPs while the primary need for newly diagnosed ONC patients is education regarding antineoplastic and supportive therapy. RESUME Objectifs : Determiner les besoins pharmacotherapeutiques des patients ambulatoires en HO (hematologie/oncologie) qu'a identifies le pharmacien; decrier le role du pharmacien au sein d'une clinique d'hematologie/oncologie pour enfants; evaluer l'impact des services de pharmacie clinique dans une clinique d'HO pour enfants sur les soins apportes aux patients; et formuler des recommandations pour la planification de la fourniture des services de pharmacie clinique aux patients qui frequent une clinique d'HO. Plan : etude prospective de prevalence d'une duree de 12 semaines. Milieu : clinique d'hematologie/oncologie dans un hopital pour enfants affilie a une universite, de 411 lits de soins tertiaires/quaternaires. Patients : Trente et un enfants qui ont frequente une clinique apres une greffe de moelle osseuse (GMO) et 27 autres enfants qui ont frequente une clinique d'oncologie (CO). Methodes : Les problemes pharmacotherapeutiques (PP) reels ou potentiels ont ete identifies ou verifies au moyen d'une discussion avec le patient/parent et des interventions ont ete portees par le pharmacien apres consultation avec le medecin traitant et/ou le patient/parent. L’impact d'un sous-groupe de ces interventions a ete evalue par deux medecins et deux pharmaciens. Resultats : 165 PP ont ete identifies chez 31 patients GMO et 27 patients CO. Le nombre moyen de PP identifies par patient etait de 4,8 chez les patients GMO et de 0,6 chez les patients CO. Le PP qui a ete le plus souvent identifie etait «une dose trop elevee» (35 %) chez les patients GMO et «l'administration d'un medicament inadequat» (35 %) chez les patients CO. Un total de 177 interventions ont ete realisees par le pharmacien et 81 % de ces dernieres ont ete acceptees par le medecin et/ou le patient/parent. Le comite de revision a juge que 83,5 % du sous-groupe d'interventions avait eu un impact positif. Conclusions : Les enfants qui frequentent une clinique d'HO ont des besoins pharmacotherapeutiques. Les patients GMO tireraient profit d'une discussion avec le pharmacien pour evaluer, prevenir et resoudre leurs PP, alors que les patients CO qui viennent d'etre diagnostiques ont d'abord un besoin d'education en ce qui a trait aux traitements antineoplasiques et de soutien.

Background: High-dose methotrexate (HD MTX) is usually administered as an inpatient to those with osteosarcoma. We prospectively tested the safety and feasibility of administering HD MTX in the ambulatory setting. Materials and Methods: In this single arm prospective observational study, eligible patients had previously completed 2 courses of HD MTX as an inpatient. On study, patients received MTX in hospital, discharged home and returned for daily assessment. Criteria to determine safety and feasibility included: (1) parent compliance with home instructions, (2) pump functioning/failure, and/or (3) admission for toxicity/noncompliance. Outpatient therapy was deemed feasible if <25% courses resulted in study event. Patient satisfaction was assessed. Results: Six patients (median age, 13.5 y) with extremity osteosarcoma completed 35 courses of MTX. There were no study events—no hospitalizations or pump failures and all parents were compliant. The Data and Safety Committee concluded that with zero events in 35 courses, it was unlikely for outpatient MTX to be infeasible; study was thus terminated early. Participants reported value to stay out of hospital, permitted life to feel “more normal”; however, burden of daily commute to hospital was cited. Conclusions: The delivery of HD MTX is safe and feasible in patients with osteosarcoma.

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

Achievement of target trough cyclosporine whole blood concentrations after hematopoietic stem cell transplant (HSCT) reduces the risk of acute graft versus host disease (aGvHD). In solid organ transplant, prevention of acute graft rejection correlates with achievement of target area under the whole blood concentration versus time curve during the 12-hour dosing interval (AUC-12) after oral administration. This study describes a limited sampling strategy for determination of cyclosporine AUC-12 after administration of the first intravenous (IV) dose in children undergoing HSCT and explores the relationships between individual whole blood concentrations during the dosing interval and the AUC. Children undergoing HSCT and receiving cyclosporine prophylaxis were eligible to participate. The first cyclosporine dose was given as a 2 hour infusion, and eight cyclosporine concentrations were determined at 2 (end of the infusion), 2.5, 3, 4, 6, 8, 10, and 12 hours after the start of the IV infusion. The relationship between AUC-12 and whole blood cyclosporine concentrations at individual time points after IV administration was assessed by the Spearman rho correlation coefficient. Limited sampling strategies were developed using three to six time points by way of multiple linear regression analysis. The agreement between the AUC-12 calculated using all eight data points and the limited sampling strategies was assessed by intraclass coefficient and Bland-Altman analysis. Twenty-four children (0.5-16.9 yr) participated. The mean AUC-12 calculated using all eight concentration versus time points was 2793 ± 1165.6 μg/L·hr. Whole blood cyclosporine concentrations obtained within the first 4 hours from the start of the infusion correlated strongly with AUC-12 (Spearman rho coefficient, 0.717-0.868). Limited sampling strategies were developed to estimate AUC-12 with adjusted r2 of 0.955 to 0.998, mean bias of 0% to 0.93%, and precision of 1.6% to 8.1%. The actual AUC-12 and predicted AUC-12 values agreed strongly (intraclass coefficient, 0.981-0.999). Limited sampling strategies using three to six data points have been developed that will estimate cyclosporine AUC-12 after administration of the first IV dose given over 2 hours. Information regarding the possible association between aGvHD and cyclosporine AUC-12 is not available. The limited sampling strategies described here will facilitate the prospective evaluation of the clinical importance of cyclosporine AUC-12 in the prevention of aGvHD.

Study Objectives. To compare the disposition of cyclosporine after the administration of two oral formulations to children undergoing hematopoietic stem cell transplantation, and to evaluate the relationship between whole blood cyclosporine concentrations during the dosing interval and the area under the whole blood concentration‐time curve.Design. Prospective, descriptive, crossover study.Setting. Hematopoietic stem cell transplantation unit in a tertiary‐quaternary university‐affiliated pediatric hospital.Patients. Twenty‐four pediatric patients aged 0.5–16.9 years undergoing allogeneic hematopoietic stem cell transplantation.Intervention. The modified oral formulation of cyclosporine was given on the first day (divided as two doses), and a single identical dose of the original oral formulation was given on the morning of the second day.Measurements and Main Results. Blood samples were obtained at 0, 0.5, 1.25, 2, 4, 6, 9, and 12 hours after the morning dose from the lumen of the central venous catheter not previously used for intravenous cyclosporine administration. Cyclosporine concentration‐time data were analyzed by using noncompartmental methods. Mean ± SD maximum concentrations were significantly higher after administration of the modified form than after administration of the original form (594.9 ± 349.7 vs 483.0 ± 363.0 μg/L, p=0.003), as was the area under the concentration‐time curve from 0–12 hours (AUC0–12; 3432 ± 1563 vs 3144 ± 1780 μg/L•hr, p=0.022). For both formulations, cyclosporine concentrations at 4 hours after administration were most strongly correlated with the AUC0–12. Unlike that of the original formulation, the trough cyclosporine concentration of the modified form had the weakest relationship with AUC (Spearman ρ coefficient 0.584, p=0.003).Conclusion. Cyclosporine absorption is lower in children undergoing hematopoietic stem cell transplantation than in children receiving solid organ transplants. Dosage adjustment for the modified formulation based on trough concentration may not be appropriate because its relationship with the AUC was weak. The link between pharmacokinetic parameters and clinical outcomes, such as graft‐versus‐host disease, must be further studied.

This study describes the disposition of cyclosporine in 24 children undergoing HSCT after IV administration and oral administration of 2 different formulations: Neoral® and Sandimmune®. Whole-blood samples for cyclosporine measurement were obtained after the first IV cyclosporine dose on day −1 and after the morning dose on each of the first 2 days of oral cyclosporine administration. Neoral® was given on the first day of oral cyclosporine administration, and a single dose of Sandimmune® was given in the morning of the second day. Oral cyclosporine doses were identical and were given on an empty stomach. Cyclosporine concentration-time data were analyzed by noncompartmental methods. A total of 24 children completed the study. After IV administration of 1.5± 0.07 mg/kg, the mean cyclosporine maximum concentration (Cmax), volume of distribution at steady state, elimination half-life, clearance, and area under the concentration-versus-time curve (AUC) were 1103.4± 787.71 μg/L, 2.6± 1.52 L/kg, 4.2± 2.49 hours, 0.56± 0.255 L/hr/kg, and 2852± 1198 μg· hr· L−1, respectively. Children took their first oral cyclosporine dose on average 29.4± 6.88 days after their first IV dose. The mean Cmax observed after Neoral® administration was significantly higher than after Sandimmune® administration (595 ±349.7 vs 486± 363.0 μg/L; P= .043), as was AUC 0–12 hr (3432± 1563 vs 3144± 1780 μg· hr· L−1; P= .022). There was no difference in time to reach Cmax (tmax) between the formulations. The coefficients of variation in Cmax, tmax, and AUC were all lower with Neoral® than with Sandimmune®, but remained substantial. The cyclosporine concentration at hour 4 after oral Neoral® and Sandimmune® administration exhibited the strongest correlation with AUC0–12 hr. However, unlike Sandimmune®, the trough cyclosporine concentration after Neoral® administration showed the weakest relationship with AUC (Spearman's ρ coefficient= 0.568; P= .027). In children undergoing HSCT, cyclosporine absorption is lower than that usually seen in children who have undergone solid organ transplantations. The relationship between cyclosporine concentrations during the dosing interval and AUC differs depending on the oral formulation administered. Thus, Neoral® dose adjustment based on trough concentration may not be appropriate. The link between pharmacokinetic parameters and clinical outcomes such as GvHD must be studied further.

Study Objectives. To describe the pharmacokinetic disposition of tobramycin in children undergoing stem cell transplantation (SCT) after intravenous administration either every 24 hours or every 8 hours, and to use this information to create initial dosing guidelines for administration every 24 hours in this patient population.Design. Pharmacokinetic analysis of a randomized controlled trial.Setting. The Hospital for Sick Children, Toronto, Ontario, Canada.Patients. Sixty children (< 18 yrs) with febrile neutropenia undergoing stem cell transplantation.Intervention. Patients were randomized to receive intravenous tobramycin either every 24 hours (29 patients) or every 8 hours (31 patients). Initially, they received either 2.5 mg/kg/dose every 8 hours or weight‐based doses by age group (< 5 yrs, 9 mg/kg/dose; 5 to < 12 yrs, 8 mg/kg/dose; ≥ 12 yrs, 7 mg/kg/dose) every 24 hours.Measurements and Main Results. Serum tobramycin concentrations were obtained at 2 and 8 hours after the first dose. Initial guidelines for dosing every 24 hours were derived using the parameters from all patients to achieve a maximum serum concentration (Cmax) of 20–22.5 mg/L and a drug‐free interval (time during dosing interval when the tobramycin concentration was < 1 mg/L) of at least 4 hours. After the first tobramycin dose, the elimination rate constant (kel) and volume of distribution (Vd) observed in the every‐8‐hour group (23 patients) were 0.34 ± 0.09 hours−1 and 0.48 ± 0.21 L/kg, respectively. The kel and Vd in the every‐24‐hour group (22 patients) were 0.43 ± 0.12 hr−1 and 0.43 ± 0.26 L/kg, respectively. Tobramycin Vd varied with age. Initial doses of tobramycin every 24 hours recommended to achieve the target parameters are 10 mg/kg/dose for patients aged 6 months to less than 9 years, 8 mg/kg/dose for those aged 9 to less than 12 years, and 6 mg/kg/dose for those aged 12 years or older.Conclusion. Children undergoing SCT who receive tobramycin every 24 hours should receive an initial dose based on age. Further validation of the proposed dosing guidelines is required.

BACKGROUNDThe benefits of aminoglycoside antibiotics, such as tobramycin, administered as a once-daily dose to manage febrile neutropenia, have been demonstrated in many patient populations. However, toxicity and safety data are lacking for pediatric stem cell transplant recipients, who are at especially high risk for aminoglycoside-related toxicity and infectious morbidity. In particular, the relative nephrotoxicity and efficacy of tobramycin administered as a single daily dose or as three daily doses among this patient population is not known.METHODSWe conducted a randomized, double-blind controlled study of tobramycin dosing among children 18 years or younger who had fever and neutropenia while undergoing stem cell transplantation. From October 2000 through November 2002, 60 children were randomly assigned to receive intravenous tobramycin, as either a single daily dose (n = 29) or every 8 hours (n = 31), in combination with either piperacillin or ceftazidime (intravenous). Tobramycin doses were adjusted to achieve pharmacokinetic targets. The primary outcome was nephrotoxicity, as represented by the maximal percent increase in serum creatinine concentration throughout the episode of febrile neutropenia relative to the baseline serum creatinine concentration. Efficacy was a secondary outcome and was defined as survival of the episode without modification of the antibacterial regimen. All statistical tests were two-sided.RESULTSIn a modified intent-to-treat analysis, the mean maximal percent increase in serum creatinine concentration was 32% (N = 26) in the once daily dose group and 51% (N = 28) in the every 8 hours dose group (difference = 19%, 95% confidence interval [CI] = 0% to 38%; P =.054). Among patients evaluable for efficacy, 12 (46%) of 26 patients in the once daily dose group and five (19%) of 27 patients in the every 8 hours dose group survived the episode of febrile neutropenia without requiring antibacterial treatment modification (difference = 27%, 95% CI = 4% to 52%; P =.03). There was one death in each group.CONCLUSIONSIn febrile neutropenic children undergoing stem cell transplantation, tobramycin may be less nephrotoxic and more efficacious when administered as a once daily dose than when administered every 8 hours.