Palma Maurizi

Phase II trial of temozolomide in children with recurrent high-grade glioma

SummaryPurposeThe objective of the study was to evaluate the efficacy and toxicity of Temozolomide (TMZ) administered for 5 consecutive days in three daily dosing in children with recurrent or refractory high-grade glioma.Patients and methodsTwenty-four patients with a median age of 10.5xa0years were enrolled onto this open-label, multicenter, phase II study. The patients were previously treated with surgical resection (17 of 24), radiotherapy (19 of 24) and chemotherapy (18 of 24). Therapy was administered orally three times a day for 5 consecutive days at the dose of 200xa0mg/m2/d×5 for chemotherapy naive patients. In patients heavily pretreated with chemotherapy the starting dose was of 150xa0mg/m2/d×5.ResultsA total of 95 cycles were administered. The median progression free-survival (PFS) was 3xa0months for the entire group while disease stabilization was obtained in 7 patients (29.1%), all with supratentorial tumors. No CR or PR was observed. TMZ treatment showed a limited toxicity. Thrombocytopenia was the most common hematological adverse effect.Our data suggest a marginal activity of TMZ in children with recurrent high-grade glioma.

Role of temozolomide in pediatric brain tumors

Features of temozolomideTemozolomide (TMZ) belongs to the imidazotetrazine class and it is a DNA-methylating agent that has a good antitumor activity. Despite of dacarbazine, TMZ is spontaneously converted into its active metabolite 5-(3-methyltriazen-l-yl)imidazole-4-carboxamide at physiologic pH, so it is not required in enzymatic demethylation in the liver. TMZ is able to cross the blood brain barrier and is stable at gastric acid pH so it has almost 100% oral bioavailability and is rapidly absorbed after it is taken orally.Temozolomide in cancer patientsOn the basis of the relatively safe toxicity and the findings achieved in adult malignant gliomas, phase I and II clinical trials were set up to evaluate the opportunity of using this novel drug in pediatric cancer, too. In this review, we evaluate the antitumor activity of TMZ against high-grade gliomas, low-grade-gliomas, and medulloblastoma/primitive neuroectodermal tumors analyzing several phases I and II clinical trials in children.ConclusionsIn spite of the poor activity of TMZ against pediatric brain tumors, the use of the drug in combination with other compounds should be evaluated in phases I and II clinical trials. Moreover, the evaluation of the methylation status of the O6-methylguanine DNA methyltransferase promoter in glioblastoma biopsy specimens could be assayed as a predictive factor of TMZ efficacy.

Severe acute hypertriglyceridemia during acute lymphoblastic leukemia induction successfully treated with plasmapheresis

Children suffering from Acute Lymphoblastic Leukaemia (ALL) treated with asparaginase and corticosteroids are at risk of developing severe lipid abnormalities. The authors report the case of a 10‐year‐old male with extremely high plasma triglyceride concentrations (4,000 mg/dl) during the induction phase of ALL associated with mild pancreatitis. Hypertriglyceridemia was successfully managed with plasmapheresis with a decrease in triglyceride levels to 590 mg/dl. Apheresis appears to be safe and effective in reducing hypertriglyceridemia and preventing related complications. Pediatr Blood Cancer 2008;50:378–380.

Myocardial performance index and biochemical markers for early detection of doxorubicin-induced cardiotoxicity in children with acute lymphoblastic leukaemia

BackgroundDespite significant improvements in the prognosis of childhood acute lymphoblastic leukaemia (ALL), the risk of anthracycline-induced cardiovascular disease remains a major concern. This study was designed to investigate the role of the myocardial performance index (MPI) and serum concentrations of biomarkers (cTnT and NT-pro-BNP) in the early detection of subclinical anthracycline-induced functional alterations in children with ALL.MethodsAll children consecutively admitted to our Pediatric Oncologic Department from January 2009 to October 2010 with a diagnosis of ALL were enrolled in this study. cTnT and NT-pro-BNP were evaluated in all patients at diagnosis, before doxorubicin therapy and 2 and 24xa0h following each anthracycline administration. ECG and echocardiography were performed at diagnosis and 24xa0h after each anthracycline course.ResultsNineteen children with standard-risk ALL were evaluated. The mean age was 6xa0years. The cumulative doxorubicin dosage was 240xa0mg/m2 according to the AIEOP (Associazione Italiana Ematologia Oncologia Pediatrica) ALL 2000 protocol. None of the 19 patients developed congestive heart failure. With increasing cumulative dosages of anthracyclines a significant increase was observed in MPI. This increase was statistically significant starting from the cumulative dosage of 120xa0mg/m2 compared to baseline, while the median NT-pro-BNP level did not change significantly during treatment and cTnT levels never exceeded the cut-off value for cardiac injury.ConclusionMPI value is a sensitive and accurate parameter, allowing subclinical cardiac dysfunction to be detected in children receiving anthracyclines. Lifelong cardiac surveillance of these patients is warranted in order to determine the clinical implications of increased MPI on long-term cardiac status.

Successful treatment with oral valganciclovir in immunocompetent infant with gastrointestinal manifestations of cytomegalovirus infection

A 3-month-old male infant was admitted to hospital with anemia. Follow-up controls revealed the presence of specific cytomegalovirus (CMV) antibodies. Virus was isolated from urine, blood, and saliva. At 7 months of age, he presented with melena. Polymerase chain reaction (PCR) of biopsy samples from the duodenum was positive for CMV. Anemia resolved after starting antiviral therapy with oral valganciclovir.

Hypersensitivity to carboplatin in children

BACKGROUNDnHypersensitivity reactions are rare but at times severe complications to cytostatic drugs.nnnPROCEDUREnThe percentage of allergic reactions to carboplatin and their clinical features were evaluated in 185 children affected by different solid tumors and treated with etoposide-carboplatin chemotherapy. Allergic reactions that occurred during or immediately following etoposide infusion (5 cases, 2.8%) were excluded from the study.nnnRESULTSnSeventeen out of 185 patients (9.2%) suffered from allergic responses to carboplatin. The first of these occurred after an average of 10.1 courses (range, 1-23; median, 9). The risk calculated according to the number of courses is 2% at 6 courses, 11.3% at 12 courses, and 47% at more than 12 courses.nnnCONCLUSIONSnThe high risk of allergic reactions to multiple courses of carboplatin should be kept in mind when developing treatment regimens that include the drug.

Hepatic veno-occlusive disease: A chemotherapy-related toxicity in children with malignancies

Hepatic veno-occlusive disease (VOD) is a major manifestation of liver toxicity associated with conventional and high-dose chemotherapy in children affected by hematologic malignancies and certain solid tumors. Clinically, patients present with jaundice, painful hepatomegaly, and fluid retention, which may evolve into multi-organ failure, a hallmark of severe disease. The pathogenesis is complex and not completely understood, but the damage to sinusoidal endothelium, typically caused by toxic metabolites released from antineoplastic drugs, is thought to play a crucial role, together with cytokine activation, immune deregulation, and coagulopathy.Diagnosis is based on clinical criteria supported by characteristic ultrasound findings, with the gold standard investigation being hepatic-venous pressure gradient measurement and biopsy. Several treatment options have been tested; the most convincing approach to date is the use of defibrotide, a novel oligonucleotide with antithrombotic and antiplatelet aggregating properties, as well as endothelial-stabilizing effects. This agent, together with other specific forms of supportive care, has shown efficacy in the treatment of established VOD and promising results in the prevention of VOD in pediatric patients receiving chemotherapy.

Phase I study of temozolomide combined with oral etoposide in children with recurrent or progressive medulloblastoma

BACKGROUNDnThe prognosis of recurrent or progressive medulloblastoma (MB) is still poor. This study was designed to investigate the potential therapeutic benefit of combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with progressive or relapsed MB. Given the oral administration of both drugs the regimen was administered outpatient.nnnMETHODSnA phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by classical 3+3 design. Cohorts of patients were enrolled at four different levels: (1) TMZ 120 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (2) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (3) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-10; (4) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-12. Therapy was administered in 28-d courses. A total of 66 courses were administered to 14 patients with a median age of 5.7 years.nnnRESULTSnNone of the 3 patients at dose levels 1 and 2 had dose-limiting toxicity (DLT). Of the 6 patients at dose level 3, 1 patient had DLT. At dose level 4, grade 4 thrombocytopaenia and neutropaenia were observed in the first 2 patients enrolled. Therefore, the MTD was established at dose level 3.nnnCONCLUSIONnThe recommended phase II dose in children is TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-10 every 28 d. The combination was well tolerated and demonstrated antitumour activity.

Propofol/alfentanil and propofol/ketamine procedural sedation in children with acute lymphoblastic leukaemia: safety, efficacy and their correlation with pain neuromediator expression.

Invasive procedures, such as the lumbar puncture, can cause anxiety and pain in children undergoing treatment for acute lymphoblastic leukaemia (ALL). We investigated the safety and efficacy of two different protocols for analgo-sedation in 20 children with ALL undergoing lumbar puncture. We have conducted a prospective, cross-over study. Protocol A was composed of an association between propofol and alfentanil. Protocol B consisted in the combination of propofol and ketamine. We also evaluated the levels of nerve growth factor, substance P and enkephalins in the cerebrospinal fluid of these patients. All patients showed a satisfactory sedation and analgesia. We found a statistically significant difference of vital parameters between protocol A and protocol B, while there were no significant differences between sedation scores and the other parameters evaluated. Patients in protocol A showed a higher incidence of major side effects, such as respiratory depression. Pain neuromediator levels did not show any statistical difference between the two groups. This study shows that both protocols are effective to obtain a good sedation and analgesia in children with ALL undergoing lumbar puncture, but the association between propofol and ketamine appears to be safer due to the lower incidence of side effects.

Comparison of propofol versus propofol-ketamine combination in pediatric oncologic procedures performed by non-anesthesiologists.

Limited data are available on the best option (short acting sedatives, opioids, or ketamine) in oncologic procedural sedation performed by non‐anesthesiologists. The aim of the present prospective study is to compare the safety and efficacy of propofol–ketamine versus propofol alone, managed by trained pediatricians, in children with cancer undergoing painful procedures.