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Preclinical Modeling of Image-Guided Craniospinal Irradiation for Very-High-Risk Medulloblastoma.

ABSTRACT: PURPOSE:Craniospinal irradiation (CSI) is a crucial component of treatment for medulloblastoma (MB), a brain tumor clinically stratified into prognostically distinct molecular subgroups. Preclinical models of clinically relevant CSI offer the potential to study radiation dose and volume effects in these subgroups and to identify subgroup-specific combination adjuvant therapies, particularly for very-high-risk MB in which treatments are often unsuccessful. METHODS AND MATERIALS:The commercially available Small Animal Radiation Research Platform equipped with a motorized variable collimator was used for image-guided CSI. Mice were implanted in brain cortices with patient-derived orthotopic xenografts (PDOXs) of very-high-risk Group 3 (G3) or Sonic Hedgehog (SHH) MB and were treated with fully fractionated CSI at 2 Gy/fraction for a cumulative 36 Gy. Radiation therapy dose response effects on tumor burden and overall survival were assessed. The pattern of treatment failure was determined using bioluminescence and then confirmed histologically. Acute toxicity was appraised by body weight measurements and blood work. RESULTS:We established an accurate and efficient preclinical protocol to administer CSI reproducibly to mice harboring MB. CSI improved the survival of mice bearing very-high-risk G3 or SHH MB PDOXs. However, radiation therapy dose responses across models suggested significant radio-responsiveness to conventionally fractionated CSI ?20 Gy. CSI was well tolerated; mice had no significant changes in body weight, and acute leukopenia developed but resolved soon after therapy completion. CONCLUSIONS:Our protocol for preclinical CSI delivery was effective and well tolerated, and it can be readily integrated into preclinical pipelines for MB and other central nervous system-seeding tumors.

SUBMITTER: Smith SMC

PROVIDER: S-EPMC6421074 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Preclinical Modeling of Image-Guided Craniospinal Irradiation for Very-High-Risk Medulloblastoma.

Smith Stephanie M C SMC Bianski Brandon M BM Orr Brent A BA Harknett Gretchen G Onar-Thomas Arzu A Gilbertson Richard J RJ Merchant Thomas E TE Roussel Martine F MF Tinkle Christopher L CL

International journal of radiation oncology, biology, physics 20181023 3

<h4>Purpose</h4>Craniospinal irradiation (CSI) is a crucial component of treatment for medulloblastoma (MB), a brain tumor clinically stratified into prognostically distinct molecular subgroups. Preclinical models of clinically relevant CSI offer the potential to study radiation dose and volume effects in these subgroups and to identify subgroup-specific combination adjuvant therapies, particularly for very-high-risk MB in which treatments are often unsuccessful.<h4>Methods and materials</h4>The ...[more]

PMID: 30366006

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Project description:PurposeWidely used cone beam computed tomography (CBCT)-guided irradiators in preclinical radiation research are limited to localize soft tissue target because of low imaging contrast. Knowledge of target volume is a fundamental need for radiation therapy (RT). Without such information to guide radiation, normal tissue can be overirradiated, introducing experimental uncertainties. This led us to develop high-contrast quantitative bioluminescence tomography (QBLT) for guidance. The use of a 3-dimensional bioluminescence signal, related to cell viability, for preclinical radiation research is one step toward biology-guided RT.Methods and materialsOur QBLT system enables multiprojection and multispectral bioluminescence imaging to maximize input data for the tomographic reconstruction. Accurate quantification of spectrum and dynamic change of in vivo signal were also accounted for the QBLT. A spectral-derivative method was implemented to eliminate the modeling of the light propagation from animal surface to detector. We demonstrated the QBLT capability of guiding conformal RT using a bioluminescent glioblastoma (GBM) model in vivo. A threshold was determined to delineate QBLT reconstructed gross target volume (GTVQBLT), which provides the best overlap between the GTVQBLT and CBCT contrast labeled GBM (GTV), used as the ground truth for GBM volume. To account for the uncertainty of GTVQBLT in target positioning and volume delineation, a margin was determined and added to the GTVQBLT to form a QBLT planning target volume (PTVQBLT) for guidance.ResultsThe QBLT can reconstruct in vivo GBM with localization accuracy within 1 mm. A 0.5-mm margin was determined and added to GTVQBLT to form PTVQBLT, largely improving tumor coverage from 75.0% (0 mm margin) to 97.9% in average, while minimizing normal tissue toxicity. With the goal of prescribed dose 5 Gy covering 95% of PTVQBLT, QBLT-guided 7-field conformal RT can effectively irradiate 99.4 ± 1.0% of GTV.ConclusionsThe QBLT provides a unique opportunity for investigators to use biologic information for target delineation, guiding conformal irradiation, and reducing normal tissue involvement, which is expected to increase reproducibility of scientific discovery.

Dataset Information

Preclinical Modeling of Image-Guided Craniospinal Irradiation for Very-High-Risk Medulloblastoma.

Publications

Preclinical Modeling of Image-Guided Craniospinal Irradiation for Very-High-Risk Medulloblastoma.

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