Access to essential anticancer medicines for children and adolescents in Europe.

BACKGROUND: Essential anticancer medicines are an indispensable component of multidisciplinary treatment of paediatric malignancies. A European Society for Medical Oncology (ESMO) study reported inequalities in the availability of anticancer medicines for adult solid tumours and provided a model for the present survey. The aim of this survey was to assess the accessibility of essential medicines used in paediatric cancer patients aged 0 to 18 years across Europe from 2016 to 2018. METHODS: A list of medicines was drawn with input from the European Society for Paediatric Oncology (SIOP Europe) Clinical Research Council referring to the World Health Organization Model List of Essential Medicines for Children (WHO EMLc) 2017. A survey was sent to nominated national clinician and pharmacist rapporteurs and parent associations in up to 37 countries; answers were obtained from 34 countries. RESULTS: The full survey list contained 68 medicines, including 24 on the WHO EMLc 2017. Health professionals reported that 35% of all medicines were prescribed off-label in at least one country and that 44% were always available in >90% of countries. Only 63% of the EMLc 2017 medicines were reported as always available. The main determinant of unavailability was shortages, reported for 72% of medicines in at least one country. Out-of-pocket costs were reported in eight countries. Twenty-seven percent of orally administered medicines were never available in child-friendly formulations. Parents detailed individual efforts and challenges of facilitating ingestion of oral medicines as prescribed. Inequalities in access to pain control during procedures were reported by parents across Europe. CONCLUSIONS: Children and adolescents with cancer in Europe experience lack of access to essential medicines. Urgent actions are needed to address shortages, financial accessibility, availability of safe age-appropriate oral formulations, and pain management across Europe.

Evaluation of the Implementation of the Response Assessment in Neuro-Oncology Criteria in the HERBY Trial of Pediatric Patients with Newly Diagnosed High-Grade Gliomas.

BACKGROUND AND PURPOSE: HERBY was a Phase II multicenter trial setup to establish the efficacy and safety of adding bevacizumab to radiation therapy and temozolomide in pediatric patients with newly diagnosed non-brain stem high-grade gliomas. This study evaluates the implementation of the radiologic aspects of HERBY. MATERIALS AND METHODS: We analyzed multimodal imaging compliance rates and scan quality for participating sites, adjudication rates and reading times for the central review process, the influence of different Response Assessment in Neuro-Oncology criteria in the final response, the incidence of pseudoprogression, and the benefit of incorporating multimodal imaging into the decision process. RESULTS: Multimodal imaging compliance rates were the following: diffusion, 82%; perfusion, 60%; and spectroscopy, 48%. Neuroradiologists' responses differed for 50% of scans, requiring adjudication, with a total average reading time per patient of approximately 3 hours. Pseudoprogression occurred in 10/116 (9%) cases, 8 in the radiation therapy/temozolomide arm and 2 in the bevacizumab arm (P < .01). Increased target enhancing lesion diameter was a reason for progression in 8/86 cases (9.3%) but never the only radiologic or clinical reason. Event-free survival was predicted earlier in 5/86 (5.8%) patients by multimodal imaging (diffusion, n = 4; perfusion, n = 1). CONCLUSIONS: The addition of multimodal imaging to the response criteria modified the assessment in a small number of cases, determining progression earlier than structural imaging alone. Increased target lesion diameter, accounting for a large proportion of reading time, was never the only reason to designate disease progression.

Pathophysiology and therapy of irinotecan-induced delayed-onset diarrhea in patients with advanced colorectal cancer: a prospective assessment.

PURPOSE: Irinotecan (CPT-11), a camptothecin derivative, has shown efficacy against colorectal cancer. Delayed-onset diarrhea is its main limiting toxicity. The aim of this study was to determine the pathophysiology of CPT-11-induced delayed-onset diarrhea and assess the efficacy of combined antidiarrheal medication in a phase II, prospective, successive-cohorts, open study. PATIENTS AND METHODS: Twenty-eight patients with advanced colorectal cancer refractory to fluorouracil (5-FU) therapy received CPT-11 350 mg/m2 every 3 weeks. The first cohort of 14 consecutive patients explored for the mechanism of diarrhea received acetorphan (a new enkephalinase inhibitor) 100 mg three times daily; the second 14-patient cohort received, in addition to acetorphan, loperamide 4 mg three times daily. Before treatment, and if late diarrhea occurred, patients underwent colon mucosal biopsies for CPT-11 and topoisomerase I levels; intestinal transit time; fecalogram; fat and protein excretion; alpha1-antitrypsin clearance; D-xylose test; blood levels for vasoactive intestinal polypeptide, glucagon, gastrin, somatostatin, prostaglandin E2, and carboxylesterase; CPT-11/SN-38 and SN-38 glucuronide pharmacokinetics; and stool cultures. RESULTS: Delayed-onset diarrhea occurred during the first three treatment cycles in 23 patients (82%). Electrolyte fecal measurements showed a negative or small osmotic gap in nine of nine patients and an increased alpha1-antitrypsin clearance in six of six patients. There were no modifications in stool cultures or hormonal dysfunction. Four of 11 patients (36%) with delayed-onset diarrhea in the first cohort responded to acetorphan, whereas nine of 10 patients (90%) responded to the combination of acetorphan and loperamide (P < .02). CONCLUSION: CPT-11-induced delayed-onset diarrhea is caused by a secretory mechanism with an exudative component. Early combined treatment with loperamide and acetorphan seems effective in controlling the diarrheal episodes.

Brain tumours under the age of three. The price of survival. A retrospective study of 20 long-term survivors.

Between 1975 and 1989, 98 children with brain tumours under the age of three at time of diagnosis were entered into a retrospective study. Twenty of them are alive and free of tumour more than five years after treatment and were evaluated in this study. Thirteen tumour localizations were infratentorial and 7 were supratentorial. A histological examination was performed in 15 patients: 5 ependymomas, 6 medulloblastomas and 4 astrocytomas were identified. Fifteen patients underwent surgical removal of tumour, all but one received radiotherapy and 8 were given chemotherapy. Only two children have not late effects. Analysis of long-term sequelae in survivors showed central endocrinopathies in 14 (70%), a neurological handicap in 13 (65%) and impaired cognitive functions in 17 (85%). Irradiation was clearly responsible for mental sequelae in 7 patients and endocrinopathies in 6 patients. The other possible causes are tumour injury, hydrocephalus or surgery. The risks incurred with radiotherapy and advances in infant brain tumour therapy are discussed.