The Path Toward PET-Guided Radiation Therapy for Glioblastoma in Laboratory Animals: A Mini Review

Abstract

Glioblastoma is the most aggressive and malignant primary brain tumor in adults. Despite the current state-of-the-art treatment, which consists of maximal surgical resection followed by radiation therapy, concomitant, and adjuvant chemotherapy, progression remains rapid due to aggressive tumor characteristics. Several new therapeutic targets have been investigated using chemotherapeutics and targeted molecular drugs, however, the intrinsic resistance to induced cell death of brain cells impede the effectiveness of systemic therapies. Also, the unique immune environment of the central nervous system imposes challenges for immune-based therapeutics. Therefore, it is important to consider other approaches to treat these tumors. There is a well-known dose-response relationship for glioblastoma with increased survival with increasing doses, but this effect seems to cap around 60 Gy, due to increased toxicity to the normal brain. Currently, radiation treatment planning of glioblastoma patients relies on CT and MRI that does not visualize the heterogeneous nature of the tumor, and consequently, a homogenous dose is delivered to the entire tumor. Metabolic imaging, such as positron-emission tomography, allows to visualize the heterogeneous tumor environment. Using these metabolic imaging techniques, an approach called dose painting can be used to deliver a higher dose to the tumor regions with high malignancy and/or radiation resistance. Preclinical studies are required for evaluating the benefits of novel radiation treatment strategies, such as PET-based dose painting. The aim of this review is to give a brief overview of promising PET tracers that can be evaluated in laboratory animals to bridge the gap between PET-based dose painting in glioblastoma patients.

Keywords: PET; dose painting; glioblastoma; laboratory animals; radiation therapy; tumor heterogeneity.

Figure 1

The concept of dose painting. Schematic representation of the two dose painting methods: dose painting by contours (DPBC) and dose painting by numbers (DPBN). The image and color bar on the left show the PET tracer uptake. The images and color scales on the right display a discrete fictive dose distribution for radiation therapy.

Figure 2

[¹⁸F]FET time-activity curves for tumor grade assessment. These simulated data show typical examples for diffuse astrocytoma (WHO II, blue), anaplastic astrocytoma (WHO III, red), and glioblastoma (WHO IV, green) on dynamic [¹⁸F]FET PET scans. This illustrates the discrepancy between LGG, which typically show a steadily increasing time-activity curve, and HGG (WHO III-IV), which typically show an early peak followed by a washout period.