Joachim Boos

Risk-Adjusted Therapy of Acute Lymphoblastic Leukemia Can Decrease Treatment Burden and Improve Survival: Treatment Results of 2169 Unselected Pediatric and Adolescent Patients Enrolled in the Trial ALL-BFM 95.

The trial ALL-BFM 95 for treatment of childhood acute lymphoblastic leukemia was designed to reduce acute and long-term toxicity in selected patient groups with favorable prognosis and to improve outcome in poor-risk groups by treatment intensification. These aims were pursued through a stratification strategy using white blood cell count, age, immunophenotype, treatment response, and unfavorable genetic aberrations providing an excellent discrimination of risk groups. Estimated 6-year event-free survival (6y-pEFS) for all 2169 patients was 79.6% (+/- 0.9%). The large standard-risk (SR) group (35% of patients) achieved an excellent 6y-EFS of 89.5% (+/- 1.1%) despite significant reduction of anthracyclines. In the medium-risk (MR) group (53% of patients), 6y-pEFS was 79.7% (+/- 1.2%); no improvement was accomplished by the randomized use of additional intermediate-dose cytarabine after consolidation. Omission of preventive cranial irradiation in non-T-ALL MR patients was possible without significant reduction of EFS, although the incidence of central nervous system relapses increased. In the high-risk (HR) group (12% of patients), intensification of consolidation/reinduction treatment led to considerable improvement over the previous ALL-BFM trials yielding a 6y-pEFS of 49.2% (+/- 3.2%). Compared without previous trial ALL-BFM 90, consistently favorable results in non-HR patients were achieved with significant treatment reduction in the majority of these patients.

Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial

BACKGROUNDnMyeloablative megatherapy is commonly used to improve the poor outlook of children with high-risk neuroblastoma, yet its role is poorly defined. We aimed to assess whether megatherapy with autologous stem-cell transplantation could increase event-free survival and overall survival compared with maintenance chemotherapy.nnnMETHODSn295 patients with high-risk neuroblastoma (ie, patients with stage 4 disease aged older than 1 year or those with MYCN-amplified tumours and stage 1, 2, 3, or 4S disease or stage 4 disease and <1 year old) were randomly assigned to myeloablative megatherapy (melphalan, etoposide, and carboplatin) with autologous stem-cell transplantation (n=149) or to oral maintenance chemotherapy with cyclophosphamide (n=146). The primary endpoint was event-free survival. Secondary endpoints were overall survival and the number of treatment-related deaths. Analyses were done by intent to treat, as treated, and treated as randomised.nnnFINDINGSnIntention-to-treat analysis showed that patients allocated megatherapy had increased 3-year event-free survival compared with those allocated maintenance therapy (47% [95% CI 38-55] vs 31% [95% CI 23-39]; hazard ratio 1.404 [95% CI 1.048-1.881], p=0.0221), but did not have significantly increased 3-year overall survival (62% [95% CI 54-70] vs 53% [95% CI 45-62]; 1.329 [0.958-1.843], p=0.0875). Improved 3-year event-free survival and 3-year overall survival were also recorded for patients given megatherapy in the as-treated group (n=212) and in the treated-as-randomised group (n=145). Two patients died from therapy-related complications during induction treatment. No patients given maintenance therapy died from acute treatment-related toxic effects. Five patients given megatherapy died from acute complications related to megatherapy.nnnINTERPRETATIONnMyeloablative chemotherapy with autologous stem-cell transplantation improves the outcome for children with high-risk neuroblastoma despite the raised risk of treatment-associated death.

L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase

Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG‐asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E. coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG‐asparaginase for first‐line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second‐ or third‐line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL. Cancer 2011.

Paediatric and geriatric drug delivery

Age-adapted drug formulations are a challenge in drug development. This paper describes the special requirements of paediatric and geriatric patients, and new ideas to solve the most prominent problems in the application of drugs to these patients. Most requirements are very similar in each subpopulation, but there are also some particularities. In neonates and infants, the immaturity of enzymes may determine the pharmacokinetics of the excipients, which must be carefully selected. Pharmacokinetics in the elderly are strongly influenced by co-morbidity, multiple-drug use or reduced organ functions. The drug handling and the readability of the product information are key issues in both subpopulations. Children and the elderly show difficulties in swallowing solid dosage forms for oral use. In both patient groups, small sized particulates or liquid dosage forms are superior to classic tablets or capsules. The main problem with using liquids is the palatability of the solution, especially when considering that taste sensation differs age-dependently and interindividually. Recent technological developments such as the dose sipping technology, promise improvements. The new EU legislation for the development of new paediatric drugs may also stimulate the research into drug delivery for the elderly.

Level of activity in children undergoing cancer treatment

The diagnosis of cancer bears severe implications for pediatric patients. One immense restriction consists in a reduced level of activity due to different factors. Physical activity affects various aspects of development and can be regarded as an essential part of a childs life. In the present study physical activity in patients undergoing cancer therapy was quantified in order to determine the extent of the restriction and to provide baseline information for the assessment of possible interventions.

Physical activity and childhood cancer.

This review provides a survey of studies investigating physical activity and exercise interventions in patients during tumor treatment and survivors of childhood cancer. PubMed and Medline databases were searched using relevant terms. References of selected papers were tracked. A total of 28 studies could be identified. Seventeen studies investigated physical activity, 11 studies determined the effect of activity enhancing interventions during and after therapy. Even though most studies showed limitations and results were not consistent, considerably reduced physical activity is highly probable in patients during and after therapy. Studies on interventions provided promising results and revealed challenges to be faced. Pediatr Blood Cancer 2010;54:501–510.

Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high dose chemotherapy: Report of the HD CWS-96 trial

We prospectively studied the efficacy of high dose therapy (HDT) versus an oral maintenance treatment (OMT) in patients with stage IV soft tissue sarcoma (STS).

Analytical validation of a microplate reader-based method for the therapeutic drug monitoring of l-asparaginase in human serum

The enzyme L-asparaginase (ASNASE), which hydrolyzes L-asparagine (L-Asn) to ammonia and L-aspartic acid (L-Asp), is commonly used for remission induction in acute lymphoblastic leukemia. To correlate ASNASE activity with L-Asn reduction in human serum, sensitive methods for the determination of ASNASE activity are required. Using L-aspartic beta-hydroxamate (AHA) as substrate we developed a sensitive plate reader-based method for the quantification of ASNASE derived from Escherichia coli and Erwinia chrysanthemi and of pegylated E. coli ASNASE in human serum. ASNASE hydrolyzed AHA to L-Asp and hydroxylamine, which was determined at 710 nm after condensation with 8-hydroxyquinoline and oxidation to indooxine. Measuring the indooxine formation allowed the detection of 2 x 10(-5)U ASNASE in 20 microl serum. Linearity was observed within 2.5-75 and 75-1,250 U/L with coefficients of correlation of r(2)>0.99. The coefficients of variation for intra- and interday variability for the three different ASNASE enzymes were 1.98 to 8.77 and 1.73 to 11.0%. The overall recovery was 101+/-9.92%. The coefficient of correlation for dilution linearity was determined as r(2)=0.986 for dilutions up to 1:20. This method combined with sensitive methods for the quantification of L-Asn will allow bioequivalence studies and individualized therapeutic drug monitoring of different ASNASE preparations.

The role of the Innovative Therapies for Children with Cancer" (ITCC) European consortium

Overall survival from childhood malignancies has dramatically improved, with survival rates now reaching over 70%. Nevertheless, some types of childhood cancer remain a difficult challenge, and for those who survive the burden of treatment can be considerable. The current paradigm for new cancer therapies is to increase our knowledge of the molecular basis of carcinogenesis, followed by the development of cancer-cell specific therapies. Historically, drug development was focused on adult cancers, and the potential efficacy in childhood malignancies was not considered. Recently, a European academic consortium was established, namely innovative therapies for children with cancer (ITCC), to address this unmet need. This initiative is focused on the evaluation of novel agents in pediatric cancer pre-clinical models, and early clinical development of promising new drugs. The number of pediatric patients eligible to participate in such trials is limited, and accurate pre-clinical evaluation may provide evidence-based prioritization for clinical development. Until recently, clinical development of new drugs in childhood cancer was restricted by the limited accessibility of such agents. Recent changes in EU legislation oblige pharmaceutical companies to provide pediatric clinical data for all new drugs relevant to children, including anti-cancer drugs. Pediatric consortiums like ITCC have established networks of expertise with the specific aim of evaluating new drugs for the treatment of childhood cancers. Through proper evaluation in collaborative clinical trials we will learn how best to use these new therapeutic approaches and improve the survival rates and reduce toxicity for children with cancer.

Continuous or repeated prolonged cisplatin infusions in children: A prospective study on ototoxicity, platinum concentrations, and standard serum parameters

To overcome the ototoxicity of cisplatin, single bolus infusions were replaced by repeated prolonged infusions of lower doses or by continuous infusions at still lower infusion rates. However, considering ototoxicity little is, in fact, known about the tolerance of repeated prolonged or continuous infusion in children.