Challenges in prescribing drugs for children with cancer

Paediatric oncology has achieved high cure rates despite the limited availability of drugs that have been specifically studied for use in children with cancer. Efficacy of these drugs has received more attention than their safety, but permanent side-effects in growing children need to be considered. An absence of pharmacokinetic data, dose-defining studies, schedules defined by age, and appropriate formulations can lead to underdosing or overdosing in specific age groups, resulting in a potential lack of benefit, development of resistance, and increased adverse drug reactions. These major clinical concerns have promoted initiatives in Europe since 2003 regarding the need for a Paediatric Regulation, aimed at improving the risk-benefit ratio of such drugs in children and providing the legal framework to overcome the limitations of the past. However, to undertake the appropriate studies of these drugs in this setting, financial support is essential. Europe is now showing its commitment to overcome the present difficulties of drug prescribing for children with cancer by introducing measures that will encourage new public-private partnerships. All those involved, including researchers, paediatric oncologists, learned societies, regulatory agencies, national agencies, and pharmaceutical companies, need to become more familiar with the opportunities opened up by the new regulation, which is aimed at providing an increased cooperation between researchers and drug developers for the benefit of children.     

Kyprolis gains accelerated approval for multiple myeloma

Onyx Pharmaceuticals' second-generation proteasome inhibitor Kyprolis (carfilzomib) has been approved for treating patients with multiple myeloma who have received at least 2 prior therapies.     

New drugs for the treatment of metastatic or refractory soft tissue sarcomas in children

Children with relapsed, recurrent or metastatic sarcomas represent a therapeutic challenge for the pediatric oncologist. Strategies for the development of newer therapies for children with these sarcomas have, in the past, been histology-specific. For example, drug development in rhabdomyosarcoma has relied upon the preclinical xenograft model, whereas therapies for pediatric nonrhabdomyosarcomatous soft tissue sarcomas have mostly been derived from adult trials. The progress to date and the tools used in the treatment of advanced pediatric sarcomas will be summarized in this review.     

Survival among children with medulloblastoma in Greece: gains from transition to chemotherapy and socio-economic differentials.

The objective of this study was to quantify improvements in survival due to chemotherapy among children with medulloblastoma treated during the last three decades at a university unit in Greece, compare these gains with figures derived from a specialized unit in the United States and explore the role of extrinsic factors affecting survival. The records of all children with medulloblastoma (n=50) treated at the University Childhood Oncology Unit in Athens, Greece during the period 1973-2003 were reviewed. The role on survival of socio-demographic factors was studied by modeling the data through Cox's proportional-hazards regression, controlling for the mode of treatment (chemotherapy, yes vs. no), whereas survival of children with medulloblastoma treated in Greece was compared with that of 76 children treated in a specialized center in the United States during a respective period. After adjustment for demographic factors, children with medulloblastoma who received adjuvant therapy in Greece had an approximately four times higher instantaneous rate of remaining alive than those who did not (P=0.05). The 5-year survival of children with medulloblastoma treated at specialized medical centers in Greece and the United States was 66 and 63%, respectively. Despite the comparable figure with that of an acceptable standard, however, there was a suggestion (P=0.07) that a rural place of residence in Greece is a poor prognostic indicator. Assuming inherently similar age of occurrence in urban and rural areas, children from rural areas in this study had a more advanced age at diagnosis than those residing in urban Greece (mean age: 7.9 vs. 6.6 years) with a 5-year survival of 57 and 73%, respectively. As expected, incorporation of adjuvant chemotherapy in the treatment of Greek children with medulloblastoma has yielded remarkable improvement in 5-year survival, comparable to that of technologically advanced countries. On the contrary, children residing in rural areas of the country seem to enjoy less favorable prognosis, possibly owing to delays in diagnosis or limited access to optimal treatment facilities.     

Potential gains using high-energy protons for therapy of malignant tumours

High-energy protons have physical properties that virtually always will result in geometrically better dose distributions than can be achieved using photons or electrons. The clinical gains in terms of the probability of higher tumour control and/or the reduced probability of normal tissue complications are, however, not completely known. Comparative model dose planning studies using real patients offer the possibility of estimating the potential gains using a new technique. Several recently completed model studies, including clinically relevant endpoints, indicate that protons may have advantages, even when compared with the conventional treatment that is likely to be introduced at the most advanced hospitals world-wide within the next decade. These advantages can be seen not only in well-demarcated targets close to risk organs, but also when irradiating extended irregular tissue volumes at risk of containing tumour cells.     

A randomized controlled trial of financial incentives for smoking cessation.

BACKGROUND: Although 435,000 Americans die each year of tobacco-related illness, only approximately 3% of smokers quit each year. Financial incentives have been shown to be effective in modifying behavior within highly structured settings, such as drug treatment programs, but this has not been shown in treating chronic disease in less structured settings. The objective of this study was to determine whether modest financial incentives increase the rate of smoking cessation program enrollment, completion, and quit rates in a outpatient clinical setting.METHODS: 179 smokers at the Philadelphia Veterans Affairs Medical Center who reported smoking at least 10 cigarettes per day were randomized into incentive and non-incentive groups. Both groups were offered a free five-class smoking cessation program at the Philadelphia Veterans Affairs Medical Center. The incentive group was also offered $20 for each class attended and $100 if they quit smoking 30 days post program completion. Self-reported smoking cessation was confirmed with urine cotinine tests.RESULTS: The incentive group had higher rates of program enrollment (43.3% versus 20.2%; P<0.001) and completion (25.8% versus 12.2%; P=0.02). Quit rates at 75 days were 16.3% in the incentive group versus 4.6% in the control group (P=0.01). At 6 months, quit rates in the incentive group were not significantly higher (6.5%) than in the control group (4.6%; P>0.20).CONCLUSION: Modest financial incentives are associated with significantly higher rates of smoking cessation program enrollment and completion and short-term quit rates. Future studies should consider including an incentive for longer-term cessation.     

Eight drugs in one day chemotherapy for brain tumors: experience in 107 children and rationale for preradiation chemotherapy

The development of a new multidrug chemotherapy regimen for primary brain tumors was based upon the cellular heterogeneity within individual tumors, the Goldie-Coldman and Price-Goldie-Hill hypotheses, and known agonistic effects of certain drug combinations and sequences. Eight drugs (vincristine [VCR], hydroxyurea, procarbazine, CCNU, cisplatin, cytosine arabinoside [Ara-C] high-dose methylprednisolone, and either cyclophosphamide or dacarbazine) were administered within 12 hours in an attempt to minimize myelosuppression. Courses were repeated at 2- to 4-week intervals. The regimen was devised to include lipid and water soluble drugs, polar and nonpolar agents, phase-specific and cell-cycle independent agents, and antineoplastics with different mechanisms of action. More than 330 courses of the regimen were administered to 107 children with brain tumors whose tumor had recurred or had been incompletely resected at diagnosis. Tumor response according to protocol-specified criteria and independent review was evaluable in 78% of the patients. After just two cycles of chemotherapy and within a 4- to 6-week interval, 50% had an objective tumor response including 15.5% who had a complete response (CR). Nephrotoxicity and high-frequency hearing losses were noted after three to five courses of therapy in approximately half of the patients. Transfusions with red cells or platelets and use of antibiotics for fever and neutropenia were required in 10% to 25% of patients. The regimen appears satisfactory for preradiation chemotherapy in newly diagnosed patients with residual tumor after surgery, but it must be compared with standard therapeutic approaches in prospective controlled trials before its relative value can be established.     

New drugs for myeloma

Although multiple myeloma remains incurable with conventional treatments, management of the disease has recently been transformed with the introduction of three novel agents, bortezomib, thalidomide, and lenalidomide. The proteasome inhibitor bortezomib is approved for the treatment of patients who have received one prior therapy; there is a growing body of clinical evidence showing its effectiveness alone and in combination in the frontline setting, with high response rates and consistently high rates of complete response. Thalidomide plus dexamethasone is approved as frontline treatment of multiple myeloma. Other combination regimens including thalidomide have demonstrated substantial activity in both relapsed and frontline settings. Recently, the thalidomide analogue lenalidomide has been approved, in combination with dexamethasone, for the treatment of patients who have received one prior therapy; this regimen has shown promising results in the frontline setting. These agents represent a new generation of treatments for multiple myeloma that affect both specific intracellular signaling pathways and the tumor microenvironment. Other novel, targeted therapies are also being evaluated in preclinical and clinical studies. Regimens incorporating bortezomib, thalidomide, lenalidomide, and other novel agents, together with commonly used conventional drugs, represent a promising future direction in myeloma treatment. At present, further investigation is required to assess the safety and activity of combinations integrating these other novel agents. However, bortezomib, thalidomide, and lenalidomide are now in widespread clinical use. This review therefore focuses on the extensive clinical data available from studies of these drugs in the treatment of newly diagnosed and advanced multiple myeloma.     

TuBaFrost 4: access rules and incentives for a European tumour bank

When designing infrastructure for a networked virtual tumour bank (samples remain at the collector institutes and sample data are collected in a searchable central database), it is apparent that this can only function properly after developing an adequate set of rules for use and access. These rules must include sufficient incentives for the tissue sample collectors to remain active within the network and maintain sufficient sample levels in the local bank. These requirements resulted in a key TuBaFrost rule, stating that the custodianship of the samples remains under the authority of the local collector. As a consequence, the samples and the decision to issue the samples to a requestor are not transferred to a large organisation but instead remain with the collector, thus allowing autonomous negotiation between collector and requestor, potential co-authorship in publications or compensation for collection and processing costs. Furthermore, it realises a streamlined cost effective network, ensuring tissue visibility and accessibility thereby improving the availability of large amounts of samples of highly specific or rare tumour types as well as providing contact opportunities for collaboration between scientists with cutting edge technology and tissue collectors. With this general purpose in mind, the rules and responsibilities for collectors, requestors and central office were generated.     

CHART in lung cancer: economic evaluation and incentives for implementation.

BACKGROUND AND PURPOSE: To investigate the financial consequences and the impact on daily implementation of CHART in lung cancer. PATIENTS AND METHODS: A cost-effectiveness and cost-utility analysis were performed using Markov models, comparing the early and delayed costs and effects of CHART for NSCLC over a 4-year time span from a societal viewpoint. The outcome estimates were based on the CHART literature, the cost estimates on the standard practice of the Leuven University Hospitals, the radiotherapy costs being derived from an activity-based costing (ABC) programme developed in the department. RESULTS: The additional societal cost per life-year gained was 9164 Euro, the incremental cost per quality-adjusted life-year 11,576 Euro. Sensitivity analyses confirmed the robustness of these results, the incremental cost-utility ratio remaining well under 20,000 Euro/QALY in all tested circumstances. The threshold analyses found the results of the study to be sensitive to the cost of CHART and to the quality of life after treatment. More specifically, standard treatment would become the optimal treatment if CHART would have a higher cost or would result in more long-term side effects. CONCLUSION: CHART should not be denied to patients with NSCLC on the basis of clinical or economic arguments. Other factors such as socio-economical, institutional, practical departmental and physician-bound barriers most probably explain the lack of implementation into daily practice.