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Purpose: Global data mapping access to essential chemotherapeutics for pediatric cancer are scarce. We report a survey of international pediatric cancer care providers' access to these medicines., Methods: A Web-based survey was sent to pediatric oncologists registered on the Cure4Kids Web portal. We queried chemotherapeutics in the WHO Essential Medicines List for Children, from which the average proportional availability was summarized as each country's access score. In addition, we examined availability of drug packages defined by the WHO-sanctioned Expert Committee for eight pediatric cancers. We undertook a sensitivity analysis investigating how regimen access would change if the cytotoxics specified in recent agreements between the Clinton Health Access Initiative, American Cancer Society, and pharmaceutical companies were universally available., Results: There were significant ( P < .001) differences in the median access scores between World Bank income groups, and 42.9% of respondents from low-income and lower middle-income countries reported suboptimal access scores. Our disease-based analysis revealed that 42.1% of patients in low-income and lower middle-income countries lacked full access to chemotherapy packages. Guaranteed availability of the cytotoxics specified in the Clinton Health Access Initiative/American Cancer Society agreements was projected to increase this regimen-based access by 1.6%, although including four additional chemotherapeutics would further increase coverage by 13.9%., Conclusion: This study is the first, to our knowledge, to assess worldwide variation in practical access to pediatric chemotherapy. Although mapping the proportion of available chemotherapeutics is informative, we also developed a meaningful estimate of access using disease-specific drug packages. These data provide an important baseline for continued monitoring and can aid in planning adaptive treatment guidelines that consider the trade-offs between access and outcomes.

Accessibility to immunohistochemistry (IHC) is invaluable to proper diagnosis and treatment of pediatric patients with malignant neoplasms. Whereas IHC is widely available in anatomic pathology laboratories in high-income countries, access to it in anatomic pathology laboratories of low- and middle-income countries remains a struggle, with many limitations. To advance the quality of the pathology service offered to children with cancer in areas with limited resources, a 5-day pathology training workshop was offered to pathologists and histotechnologists from various countries of the Central American and Caribbean region. An initial assessment of the workshop participants' current laboratory capacities was performed, and a regional training center was selected. Didactic and hands-on activities were offered, and review and evaluation of the IHC slides produced during the training course were compared with original slides from the participants' sites. This model of intensive 5-day training appears to be effective and can potentially be used in other budget-constrained regions. Moreover, it can serve as a continuing education activity for pathologists and histotechnologists, and as part of validations and quality improvement projects to build capacity and develop IHC assay proficiency in low- and middle-income countries.

Hodgkin lymphoma (HL) is one of the most curable pediatric and adult cancers, with long-term survival rates now exceeding 90% after treatment with chemotherapy alone or combined with radiotherapy (RT). Of note, global collaboration in clinical trials within cooperative pediatric HL study groups has resulted in continued progress; however, survivors of pediatric HL are at high risk of potentially life-limiting second cancers and treatment-associated cardiovascular disease. Over the last three decades, all major pediatric and several adult HL study groups have followed the paradigm of response-based treatment adaptation and toxicity sparing through the reduction or elimination of RT and tailoring of chemotherapy. High treatment efficacy is achieved using dose-dense chemotherapy. Refinement and reduction of RT have been implemented on the basis of results from collaborative group studies, such that radiation has been completely eliminated for certain subgroups of patients. Because pediatric staging and response criteria are not uniform, comparing the results of trial series among different pediatric and adult study groups remains difficult; thus, initiatives to harmonize criteria are desperately needed. A dynamic harmonization process is of utmost importance to standardize therapeutic risk stratification and response definitions as well as improve the care of children with HL in resource-restricted environments., (© 2015 by American Society of Clinical Oncology.)

Purpose: Hip osteonecrosis frequently complicates treatment with glucocorticoids. When extensive (affecting ≥ 30% of the epiphyseal surface), 80% of joints collapse within 2 years, so interventions are needed to prevent this outcome., Patients and Methods: This prospective cohort magnetic resonance imaging (MRI) screening study included all consecutive children treated for acute lymphoblastic leukemia on a single protocol. Hip MRI was performed at 6.5 and 9 months from diagnosis (early screening) and at completion of chemotherapy (final evaluation) to determine whether screening could identify extensive hip osteonecrosis before symptom development., Results: Of 498 patients, 462 underwent screening MRI. Extensive asymptomatic osteonecrosis was identified by early screening in 26 patients (41 hips); another four patients (seven hips) were detected after the screening period, such that screening sensitivity was 84.1% and specificity was 99.4%. The number of joints screened to detect one lesion was 20.1 joints for all patients, 4.4 joints for patients older than 10 years, and 198 joints for patients ≤ 10 years old (P < .001). Of the 40 extensive lesions in patients older than 10 years, 19 required total hip arthroplasty and none improved. Of eight extensive lesions in younger patients, none required arthroplasty and four improved., Conclusion: In patients age 10 years old or younger who require prolonged glucocorticoid therapy, screening for extensive hip osteonecrosis is unnecessary because their risk is low and lesions tend to heal. In children older than 10 years, early screening successfully identifies extensive asymptomatic lesions in patients who would be eligible for studies of interventions to prevent or delay joint collapse., (© 2015 by American Society of Clinical Oncology.)

Purpose: Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity., Patients and Methods: Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities., Results: Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity., Conclusion: MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.