Abstract
Glioblastoma multiforme (GBM) is a common and aggressive malignant brain cancer with a mean survival time of approximately 15 months after initial diagnosis. Currently, the standard-of-care (SOC) treatment for this disease consists of radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ). We sought to develop an orthotopic preclinical model of GBM and to optimize a protocol for non-invasive monitoring of tumor growth, allowing for determination of the efficacy of SOC therapy using a targeted RT strategy combined with TMZ. A strong correlation (r = 0.80) was observed between contrast-enhanced (CE)-CT-based volume quantification and bioluminescent (BLI)-integrated image intensity when monitoring tumor growth, allowing for BLI imaging as a substitute for CE-CT. An optimized parallel-opposed single-angle RT beam plan delivered on average 96% of the expected RT dose (20, 30 or 60 Gy) to the tumor. Normal tissue on the ipsilateral and contralateral sides of the brain were spared 84% and 99% of the expected dose, respectively. An increase in median survival time was demonstrated for all SOC regimens compared to untreated controls (average 5.2 days, p < 0.05), but treatment was not curative, suggesting the need for novel treatment options to increase therapeutic efficacy.
Highlights
Glioblastoma multiforme (GBM) is an aggressive and frequently occurring primary malignant brain cancer with a mean survival time of less than 15 months after initial diagnosis, regardless of treatment [1]
Both increased exponentially over time (r = 0.88 and 0.96 respectively, Figure 1A,B), and the bioluminescent signal correlated significantly with the tumor volume assessed by Contrast-Enhanced CT (CE-CT) imaging (r = 0.80, p ≤ 0.01, n = 12, Figure 1C)
This correlation allowed for BLI-based signal intensity to be used as a substitute for CE-CT imaging
Summary
Glioblastoma multiforme (GBM) is an aggressive and frequently occurring primary malignant brain cancer with a mean survival time of less than 15 months after initial diagnosis, regardless of treatment [1]. Despite recent advancement in the understanding of the molecular pathogenesis behind the disease and improvement in diagnostic ability, little has changed in terms of prognosis. GBM remains a lethal disease, and most patients (>70%) will die within two years [1,2]. Standard-of-care therapy for newly diagnosed GBM consists of surgical resection, if feasible, and/or regional radiotherapy (RT) with concomitant or adjuvant temozolomide (TMZ), which provides an improvement in median. Cancers 2020, 12, 1585 survival of only 2.5 months [1]. Bevacizumab is approved for patients with recurrent GBM, but only prolongs progression-free survival with no impact on overall survival [3]. Large-field single-beam irradiation was commonplace in preclinical animal studies [4,5]
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