Ethnic-specific predictors of neurotoxicity among patients with pediatric acute lymphoblastic leukemia after high-dose methotrexate.

BACKGROUND: High-dose methotrexate (HD-MTX; 5000 mg/m2 ) is an important component of curative therapy in many treatment regimens for high-risk pediatric acute lymphoblastic leukemia (ALL). However, methotrexate therapy can result in dose-limiting neurotoxicity, which may disproportionately affect Latino children. This study evaluated risk factors for neurotoxicity after HD-MTX in an ethnically diverse population of patients with ALL. METHODS: The authors retrospectively reviewed the medical records of patients who were diagnosed with ALL and treated with HD-MTX at Texas Children's Cancer Center (2010-2017). Methotrexate neurotoxicity was defined as a neurologic episode (e.g., seizures or stroke-like symptoms) occurring within 21 days of HD-MTX that resulted in methotrexate treatment modifications. Mixed effects multivariable logistic regression was used to estimate the odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between clinical factors and neurotoxicity. RESULTS: Overall, 351 patients (58.1% Latino) who received 1183 HD-MTX infusions were evaluated. Thirty-five patients (10%) experienced neurotoxicity, 71% of whom were Latino. After adjusting for clinical risk factors, the authors observed that serum creatinine elevations ≥50% of baseline were associated with a three-fold increased odds (OR, 3.32; 95% CI, 0.98-11.21; p = .05) for neurotoxicity compared with creatinine elevation <25%. Notably, predictors of neurotoxicity differed by ethnicity. Specifically, Latino children experienced a nearly six-fold increase in neurotoxicity odds (OR, 5.80; 95% CI, 1.39-24.17; p = .02) with serum creatinine elevation ≥50% compared with creatinine elevation <25%. CONCLUSIONS: The current findings indicate that serum creatinine elevations ≥50% may be associated with an increased risk for neurotoxicity among Latino children with ALL and may identify potential candidates for therapeutic or supportive care interventions.

Prospective patient-reported symptom profiles associated with pediatric acute lymphoblastic leukemia relapse.

PURPOSE: Despite improvements in frontline pediatric acute lymphoblastic leukemia (ALL) treatment, relapse remains a concern. Research in adult cancer patients suggests that patient-reported symptoms may predict survival, but the relationship between symptoms and relapse for pediatric ALL has received little attention. METHODS: Pediatric patients with ALL (age 2-18 years) and/or their primary caregivers completed symptom surveys at the end of induction, start of delayed intensification (DI), start of maintenance cycle 1 (MC1), and start of maintenance cycle 2 (MC2). Symptom clusters for co-occurring fatigue, pain, sleep disruptions, and nausea were defined using latent profile analysis. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between symptom clusters, individual symptoms, and subsequent relapse were calculated using multivariable Cox proportional hazards models, adjusting for clinical and demographic factors. RESULTS: Eligible patients (n = 208) were followed an average of 2.6 years for the incidence of relapse (n = 22). Associations between relapse and symptoms were identified for fatigue at DI (HR = 1.83, 95%CI 1.23-2.73) and MC1 (HR = 2.14, 95%CI 1.62-2.84), pain at DI (HR = 1.80, 95%CI 1.19-2.72), nausea at the end of induction (HR = 1.19, 95%CI 1.01-1.39), and sleep disturbances at the end of induction (HR = 2.00, 95%CI 1.11-3.62), DI (HR = 1.73, 95%CI 1.01-2.96), and MC1 (HR = 2.19, 95%CI 1.10-4.35). Symptom clusters comprised of individuals with a higher average symptom burden at DI were significantly (p < 0.05) associated with relapse. CONCLUSION: Patient-reported symptoms may provide prognostic information to aid in the identification of pediatric ALL patients at increased risk of relapse.

Review of nutritional status, body composition, and effects of antineoplastic drug disposition.

The overall survival for children with cancer in high income countries is excellent. However, there are many disparities that may negatively affect survival, which are particularly problematic in low income countries, such as nutritional status at diagnosis and throughout therapy. Nutritional status as well as concomitant foods, supplements, and medications may play a role in overall exposure and response to chemotherapy. Emerging science around the microbiome may also play a role and should be further explored as a contributor to disease progression and therapeutic response. This article highlights some of these issues and proposes additional areas of research relevant to nutritional status and pharmacology that are needed in pediatric oncology.

A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group.

BACKGROUND: We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors. METHODS: Patients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed. RESULTS: Forty-one patients, median (range) age 13 (4-18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m2 /day. At 40 mg/m2 /d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m2 /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma). CONCLUSIONS: A protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m2 /day. A phase 2 study of cabozantinib is being conducted.

Efficacy of liposomal bupivacaine in pediatric patients undergoing spine surgery.

BACKGROUND: Liposomal bupivacaine may be an option for reducing opioid utilization in pediatric scoliosis surgery. The use of liposomal bupivacaine in this patient population has not been previously described. METHODS: Patients who underwent posterior spinal fusion surgery at our institution from 2011-2016 were identified. We performed a retrospective matched cohort study, matching patients who received intraoperative liposomal bupivacaine by age, gender, and extent of surgery to patients who did not. The primary endpoint was the use of morphine equivalents in the first 72 hours after surgery. Data collection included demographic and surgical data, pain medication utilization, and pain scores. Area under the curve (AUC) for pain scores was calculated. Descriptive statistical methods and univariable analysis were used to compare patients who received liposomal bupivacaine to patients who did not. RESULTS: One hundred and forty-one patients met study criteria; 47 patients who received liposomal bupivacaine were matched to 94 control patients who did not receive liposomal bupivacaine. No significant differences were noted in the patient population with the patients requiring a median of 11 segments (range 10-13 segments) fused. Patients received a mean of 56.6 ± 37.4 mg/kg of intravenous acetaminophen, a mean of 3.4 ± 2.1 mg/kg of intravenous ketorolac, and 1.9 ± 0.93 mg/kg of morphine equivalents in the first 72 hours after surgery. On univariable analysis, no differences were noted in intravenous acetaminophen use, pain score AUC, intravenous ketorolac use, or morphine equivalents (2.0 ± 98 vs 1.8 ± 0.82) in patients who did not receive liposomal bupivacaine as compared to those patient who did received liposomal bupivacaine. CONCLUSION: Liposomal bupivacaine was not associated with reductions in postoperative opioid use in pediatric spinal surgery.

Race and ethnicity: Not factors in the prescribing of hydrocodone and codeine-containing products in two pediatric emergency departments.

OBJECTIVE: To describe the prescription of hydrocodone-containing products (HCPs) and codeine-containing products (CCPs) by patient and provider race and ethnicity at two pediatric emergency departments (EDs) before and after the US Drug Enforcement Administration (DEA) rescheduling of HCPs in 2014. DESIGN AND SETTING: The authors performed a secondary analysis of data describing the prescription of HCPs and CCPs for 6 months before and after the DEA rescheduling of HCPs in two academic, urban pediatric EDs. PATIENTS, PARTICIPANTS: The authors included all children for whom race and ethnicity data were available and who were prescribed HCPs or CCPs at the time of discharge from the ED during a 12-month period (n = 1,246). The authors sent a three-question survey soliciting name, race, and ethnicity to all providers who prescribed an HCP or a CCP during the study period. MAIN OUTCOME MEASURES: Chi-square comparisons were made between the number of HCP and CCP prescriptions for primary ED diagnosis and patient ethnicity or race. The number of HCP and CCP prescriptions before and after the DEA rescheduling were compared to patient and provider race and ethnicity using the Breslow-Day test for homogeneity. RESULTS: There were no significant differences in the number of HCP and CCP prescriptions between the pre- and post-DEA rescheduling periods across all racial and ethnic groups. When comparing the number of HCP and CCP prescriptions to patient race, Caucasian patients (84.4 percent) were prescribed more HCPs and CCPs than African Americans (15.6 percent) for abdominal pain (p value = 0.02). Non-Hispanic providers prescribed CCPs more often (n = 38, 55.2 percent) than Hispanic providers (n = 0, 0.0 percent) after DEA rescheduling (Breslow-Day p value = 0.01). Providers of all races wrote similar numbers of HCP and CCP prescriptions before and after the DEA rescheduling (Breslow-Day p value = 0.99). CONCLUSIONS: Pediatric patients of all races and ethnicities received fewer HCP prescriptions after the 2014 DEA rescheduling of HCPs. However, Caucasian patients were prescribed HCPs and CCPs for abdominal pain more frequently than African American patients. There were no significant differences in the number of prescriptions of HCPs and CCPs by provider race.

Chemotherapy and Supportive Care Agents as Essential Medicines for Children With Cancer.

In resource-rich countries, 5-year survival rates for children with cancer approach 85%. This impressive statistic is largely the result of integrating research with clinical care. At the core of this endeavor are multiagent combination chemotherapy and supportive care agents (CASCA). Most CASCAs belong to the class of sterile injectable drugs, which make up the backbone of many proven and life-saving pediatric oncology regimens. There are few if any alternative agents available to treat most life-threatening childhood cancers. In the United States, shortages of CASCAs are now commonplace. The consequences of drug shortages are far reaching. Beyond the economic costs, these shortages directly affect patients' lives, and this is especially true for children with cancer. Drug shortages in general and shortages of CASCAs specifically result in increased medication errors, delayed administration of life-saving therapy, inferior outcomes, and patient deaths. One way to mitigate drug shortages is to adopt an essential medicines list and ensure that these medications remain in adequate supply at all times. We argue for creation of a CASCA-specific essential medicines list for childhood cancer and provide ethical and policy-based reasoning for this approach. We recognize that such a call has implications beyond pediatric cancer, in that children with other serious disease should have an equal claim to access to guaranteed evidence-based medicines. We provide these arguments as an example of what should be claimed for medical indications that are deemed essential to preserve life and function.