Biology Contribution
Permeability of Brain Tumor Vessels Induced by Uniform or Spatially Microfractionated Synchrotron Radiation Therapies

https://doi.org/10.1016/j.ijrobp.2017.03.025Get rights and content

Purpose

To compare the blood-brain barrier permeability changes induced by synchrotron microbeam radiation therapy (MRT, which relies on spatial fractionation of the incident x-ray beam into parallel micron-wide beams) with changes induced by a spatially uniform synchrotron x-ray radiation therapy.

Methods and Materials

Male rats bearing malignant intracranial F98 gliomas were randomized into 3 groups: untreated, exposed to MRT (peak and valley dose: 241 and 10.5 Gy, respectively), or exposed to broad beam irradiation (BB) delivered at comparable doses (ie, equivalent to MRT valley dose); both applied by 2 arrays, intersecting orthogonally the tumor region. Vessel permeability was monitored in vivo by magnetic resonance imaging 1 day before (T−1) and 1, 2, 7, and 14 days after treatment start. To determine whether physiologic parameters influence vascular permeability, we evaluated vessel integrity in the tumor area with different values for cerebral blood flow, blood volume, edema, and tissue oxygenation.

Results

Microbeam radiation therapy does not modify the vascular permeability of normal brain tissue. Microbeam radiation therapy–induced increase of tumor vascular permeability was detectable from T2 with a maximum at T7 after exposure, whereas BB enhanced vessel permeability only at T7. At this stage MRT was more efficient at increasing tumor vessel permeability (BB vs untreated: +19.1%; P=.0467; MRT vs untreated: +44.8%; P<.0001), and its effects lasted until T14 (MRT vs BB, +22.6%; P=.0199). We also showed that MRT was more efficient at targeting highly oxygenated (high blood volume and flow) and more proliferative parts of the tumor than BB.

Conclusions

Microbeam radiation therapy–induced increased tumor vascular permeability is: (1) significantly greater; (2) earlier and more prolonged than that induced by BB irradiation, especially in highly proliferative tumor areas; and (3) targets all tumor areas discriminated by physiologic characteristics, including those not damaged by homogeneous irradiation.

Introduction

Treatment of high-grade gliomas remains a challenging problem. The median survival time of patients increased only by few months during the last 25 years and now reaches only 16 months after diagnosis (1). Efficiency of intravenous chemotherapies is hampered by a limited exposure of all cells of the tumor mass to a sufficient drug concentration, owing to the anatomic/physiologic characteristics of solid tumors (2). The challenge of drug delivery is increased particularly for brain tumors, owing to the presence of the blood-brain barrier, which is a highly selective physiologic barrier for crossing molecules (3). Even if the integrity of the vascular wall or the blood–brain barrier is altered in some parts of solid tumors, if it is not the case for the entire tumor volume then delivery of molecules to the whole tumor remains a challenge (4). Conventional radiation therapy was reported as an efficient strategy to overcome these physio-anatomic limitations by temporal disruption of the blood–brain barrier in the tumor (5). A clinical study using cumulative doses of 20 Gy delivered in fractions of 2 Gy confirmed that opening of the blood–brain barrier by irradiation optimizes the effects of intracranial chemotherapy (6).

Microbeam radiation therapy (MRT) might enhance vessel permeability specifically in tumors before drug administration 7, 8. Microbeam radiation therapy, developed since the 1990s as a new form of radiation therapy for brain tumors 9, 10, 11, 12, is based on the spatial fractionation of incident synchrotron-generated x-ray beams (characterized by low energy, pulsed high flux, and negligible divergence) into arrays of microns-wide quasi-parallel microbeams, separated by a few hundred microns. High flux synchrotron light allows the delivery of high radiation doses (hundreds of Gy) in the microbeam paths (peak dose). Microbeam radiation therapy has been shown to reduce or even stop the growth of several tumor models and increase animal survival, and a surprisingly high tolerance of normal tissues was observed 11, 12, 13, 14, 15, 16, 17. There were no changes in vascular morphology, density, permeability, or blood volume in normal brain tissue after unidirectional MRT exposure with several hundred Gy 7, 11, 12, 15, 16. Even vessel leakage and damages induced by a 1000-Gy irradiation of normal vessels is rapidly restored 15, 18. Conversely, we demonstrated that MRT has a preferential effect on tumor vessels (for a review see reference 8), leading to radiation-induced decrease of the fractional blood volume in the tumor, reduction of vessel density, and hypoxia progression 7, 19. Further, MRT induced a significant increase in 9L gliosarcoma vessel permeability during the first week after irradiation (7).

We hypothesize that MRT is more efficient in inducing vessel permeability than a spatially homogeneous irradiation. We compared for the first time the effects of MRT and of a spatially uniform irradiation (broad beam irradiation [BB]) on vessel permeability. Using in vivo magnetic resonance imaging (MRI) we have demonstrated that MRT is significantly better than spatially uniform radiation therapy at increasing vascular permeability in a rodent model of intracranial glioblastoma (F98). Glioblastoma are known for their disorganized and chaotic vascular network, leading to nonuniform blood perfusion and microenvironmental heterogeneity characterized by edematous and hypoxic areas (20). This regional heterogeneity is a major clinical hurdle for devising effective therapeutic strategies (20). We therefore sought to determine in a second step whether tissue characteristics influence the vascular permeability induced by radiotherapies and whether they exhibit different response to MRT and BB. To answer these questions, we use a method for evaluation of vessel integrity in tumor regions with different cerebral blood flow (CBF), blood volume (BV), edema (apparent diffusion coefficient [ADC]), and tissue oxygenation values (cerebral metabolic rate of oxygen [CMRO2]). We have thus demonstrated that MRT targets all tumor areas discriminated by physiologic characteristics, including areas not damaged by homogeneous irradiation.

Section snippets

Methods and Materials

All procedures related to animal care conformed to the Guidelines of the French Government with licenses 380325 and 380321 (authorized lab A3818510002 and A3851610004). Rats were anesthetized by isoflurane 5% in air before maintenance by inhalation of isoflurane 2.5% for the tumor implantation, MRI examination, and irradiation.

Treatment effects on F98 brain tumor growth

Tumor volumes measured by MRI (DCE map) are reported in Figure 1c and d. Both BB and MRT significantly slowed tumor growth (P<.0001 for BB and for MRT compared with the untreated group from D25T7). The effects of both irradiations were noticeable from D25T7; tumors were significantly smaller in BB- and MRT-treated rats compared with untreated, by a factor of approximately 3.6 and 7.5, respectively (31.6 ± 10.8 mm3 [BB] and 15.1 ± 7.2 mm3 [MRT] vs 113.4 ± 44.6 mm3 [untreated], P<.0001).

Discussion

Exposure to synchrotron MRT has been described as a modality that enhances vessel permeability, specifically in tumors 7, 8. The present study demonstrated for the first time that MRT more efficiently increases tumor vessel permeability than spatially uniform irradiation (BB). The study of permeability changes in different areas of the tumor characterized by edema, blood volume, cerebral blood flow, or tissue oxygenation revealed that MRT increases tumor vessel permeability in many

Acknowledgment

In fond memory of Régine Farion, who has generously and with heart-warming enthusiasm contributed to this work over many years.

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    This study was funded by the Bernische Krebsliga via grant 37223, as well as the “Conseil Régional Rhône-Alpes,” la “Ligue contre le Cancer, comité de la Drome,” “l'Association pour la Recherche contre le Cancer,” and Imoxy ANR (research funding). The Grenoble MRI facility IRMaGe was partly funded by the French program “Investissement d'Avenir” run by the “Agence Nationale pour la Recherche”; and grant “Infrastructure d'avenir en Biologie Santé” (ANR-11-INBS-0006).

    Conflict of interest: none.

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