Cost-Effectiveness Analysis of a Three-Drug Regimen Containing Bevacizumab for the Treatment of Recurrent Pediatric Medulloblastoma in China: Based on a COG Randomized Phase II Screening Trial.

Background: Medulloblastoma is the most common malignant brain tumor of childhood, accounting for 6 to 7 percent of all childhood CNS tumors. The purpose of this study was to evaluate the economic efficacy of a bevacizumab combined with temozolomide + irinotecan regimen for the treatment of recurrent pediatric medulloblastoma in China. Methods: The data analyzed were from a randomized phase II screening trial that showed an improved survival benefit in child patients with recurrent medulloblastoma treated with a T+I+B combination regimen. A Markov model is constructed to estimate the incremental cost-effectiveness ratio (ICER) from the perspective of Chinese society. The uncertainty in the model is solved by one-way certainty and probabilistic sensitivity analysis. Results: Our base case analysis showed that the total costs of treatment increased from $8,786.403 to $27,603.420 with the combination bevacizumab vs. the two-agent chemotherapy regimen. Treatment with T+I+B combination therapy was associated with an increase in effectiveness of 0.280 QALYs from 0.867 to 1.147 QALYs T+I regimen. The incremental cost-effectiveness ratio was $67,203.632/QALY, which exceeded our pre-specified willingness-to-pay threshold ($38,136.26/QALY). Cost changes associated with grade 3-4 AE management, tests used, or hospitalization costs had little effect on the ICER values predicted by sensitivity analysis. Conclusions: Taken together, the results of this study suggest that the combination of bevacizumab with temozolomide and irinotecan is not a cost-effective option from the perspective of Chinese payers as a first-line treatment option for children with recurrent medulloblastoma in China.

Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury.

BACKGROUND: Central nervous system (CNS) injury is a rare complication of radiation therapy for pediatric brain tumors, but its incidence with proton radiation therapy (PRT) is less well defined. Increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the distal end of proton beams may influence this risk. We report the incidence of CNS injury in medulloblastoma patients treated with PRT and investigate correlations with LET and RBE values. METHODS AND MATERIALS: We reviewed 111 consecutive patients treated with PRT for medulloblastoma between 2002 and 2011 and selected patients with clinical symptoms of CNS injury. Magnetic resonance imaging (MRI) findings for all patients were contoured on original planning scans (treatment change areas [TCA]). Dose and LET distributions were calculated for the treated plans using Monte Carlo system. RBE values were estimated based on LET-based published models. RESULTS: At a median follow-up of 4.2 years, the 5-year cumulative incidence of CNS injury was 3.6% for any grade and 2.7% for grade 3+. Three of 4 symptomatic patients were treated with a whole posterior fossa boost. Eight of 10 defined TCAs had higher LET values than the target but statistically nonsignificant differences in RBE values (P=.12). CONCLUSIONS: Central nervous system and brainstem injury incidence for PRT in this series is similar to that reported for photon radiation therapy. The risk of CNS injury was higher for whole posterior fossa boost than for involved field. Although no clear correlation with RBE values was found, numbers were small and additional investigation is warranted to better determine the relationship between injury and LET.

Functional evaluation of therapeutic response for a mouse model of medulloblastoma.

Medulloblastoma is an aggressive childhood cerebellar tumor. We recently reported a mouse model with conditional deletion of Patched1 gene that recapitulates many characteristics of the human medulloblastoma. Qualitative symptoms observed in the mouse model include irregular stride length, impaired cranial nerve function and decreased motor coordination and performance. In our current study, several quantitative behavioral assays including a mouse rotarod, a forced air challenge, a screen inversion test, a horizontal wire test, and stride length analysis were evaluated to determine the most sensitive and cost-effective functional assay for impaired neuromotor behavior associated with disease progression. Magnetic resonance imaging (MRI) was used to confirm and monitor tumor growth and as an anatomical biomarker for therapeutic response. Wild type mice or medulloblastoma-prone, conditional Patched1 knockout mice were observed by behavioral assays and MRI from postnatal weeks 3-6. Bortezomib treatment was administered during this period and therapeutic response was assessed using cerebellar volumes at the end of treatment. Of the behavioral tests assessed in this study, stride length analysis was best able to detect differences between tumor-prone mice and wild type mice as early as postnatal day 37 (P=0.003). Significant differences between stride lengths of bortezomib treated and control tumor-bearing mice could be detected as early as postnatal day 42 (P=0.020). Cerebellar volumes measured by MRI at the end of treatment validated the therapeutic effects seen by behavioral tests (P=0.03). These findings suggest that stride length analysis may serve as one of the more sensitive and cost-effective method for assessing new therapeutic compounds in this and other preclinical model of brain tumors.

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.

Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations.

PURPOSE: Traditional genetic approaches to identify gene mutations in cancer are expensive and laborious. Nonetheless, if we are to avoid rejecting effective molecular targeted therapies, we must test these drugs in patients whose tumors harbor mutations in the drug target. We hypothesized that gene expression profiling might be a more rapid and cost-effective method of identifying tumors that contain specific genetic abnormalities. MATERIALS AND METHODS: Gene expression profiles of 46 samples of medulloblastoma were generated using the U133av2 Affymetrix oligonucleotide array and validated using real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Genetic abnormalities were confirmed using fluorescence in situ hybridization (FISH) and direct sequencing. RESULTS: Unsupervised analysis of gene expression profiles partitioned medulloblastomas into five distinct subgroups (subgroups A to E). Gene expression signatures that distinguished these subgroups predicted the presence of key molecular alterations that we subsequently confirmed by gene sequence analysis and FISH. Subgroup-specific abnormalities included mutations in the Wingless (WNT) pathway and deletion of chromosome 6 (subgroup B) and mutations in the Sonic Hedgehog (SHH) pathway (subgroup D). Real-time RT-PCR analysis of gene expression profiles was then used to predict accurately the presence of mutations in the WNT and SHH pathways in a separate group of 31 medulloblastomas. CONCLUSION: Genome-wide expression profiles can partition large tumor cohorts into subgroups that are enriched for specific genetic alterations. This approach may assist ultimately in the selection of patients for future clinical trials of molecular targeted therapies.

Mapping radiation dose distribution on the fractional anisotropy map: applications in the assessment of treatment-induced white matter injury.

We describe a method to map whole brain radiation dose distribution on to diffusion tensor MR (DT-MR) fractional anisotropy (FA) images and illustrate its applications for studying dose-effect relationships and regional susceptibility in two childhood medulloblastoma survivors. To determine the FA changes voxel-by-voxel in white matter, the post-treatment follow-up FA maps were coregistered to baseline pre-treatment FA maps and automatic segmentation for white matter was carried out. DeltaFA maps representing relative FA change in white matter were hence generated for visual inspection and quantitative analysis. The radiation dose distribution, calculated from radiotherapy plan and exported as images, was coregistered to baseline FA images. DT-MR imaging and processing noise was small with root mean square value of 1.49% for mean DeltaFA. We evaluated the mean DeltaFA changes of regions-of-interest according to radiation dose regions to provide an estimate of the dose-response and found increasing reduction in mean DeltaFA with increasing radiation dose up to 45 Gy after which there was a reversal in the mean FA trend and mean FA approached baseline value. We also found more severe mean FA reduction in the frontal lobes compared to the parietal lobes despite the same radiation dose, suggesting regional susceptibility in the frontal lobe, and mean FA increase in the brainstem after radiation in both patients. We conclude that the method described may be useful in estimating dose-effect relationships and studying regional susceptibility of the brain to radiation in medulloblastoma survivors.