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Theses

Photodynamic therapies of high-grade gliomas : from theory to clinical perspectives

Abstract : Gliomas are the most common primary brain tumors in adults. Among them, glioblastoma (GBM) represents the most frequent primary brain tumor and have the most dismal prognosis. Its annual incidence is about 3 to 5 cases for 100,000 persons (about 3000 news cases each year in France). Median survival varies between 11 to 13 months according the extent of tumor resection.The standard of care includes surgery and is followed by radiation therapy and chemotherapy. Maximal resection is expected to delay recurrence. Despite of using intraoperative photodynamic diagnosis, or fluorescence guided resection (FGR), which improves the extent of resection, relapse still occurs in these resection margins in 85% of cases.Alternatives therapies have to be developed to enhance patients’ overall survival. In this context, Photodynamic Therapy (PDT) seems relevant. PDT is based on the synergy of three parameters: a photosensitizing molecule, the photosensitizer (PS) that concentrates preferentially into the tumor cells, laser light and oxygen. Laser light induces a reaction between the PS and the oxygen of the cell. This reaction produces highly cytotoxic molecules (including singlet oxygen) and leads to death of tumor cells. Two treatment modalities are investigated: interstitial PDT (iPDT) or intraoperative PDT.The main goal of this thesis is to provide technological tools to develop the PDT for GBM treatment. Thus, the two treatment modalities have been investigated.When tumor resection is non-achievable (about 20% to 30% of cases), iPDT may be preferred. This modality aims to insert optical fibers directly into the target to illuminate tumor tissues. Thus, simulation of light propagation in brain tissues is required to plan the location of optical fibers. Considered as reference method, a Monte-Carlo model accelerated by graphics processing unit was developed. This model computes the light propagation emitted by a cylindrical diffusor inside heterogeneous media. Accuracy of the model was evaluated with experimental measurements. The acceleration provided by the parallelization allows its use in clinical routine.The iPDT has to be planned using a Treatment Planning System (TPS). A proof of concept of a TPS dedicated to the stereotactic iPDT treatment of GBM was developed. This software provides basic tools to plan the stereotactic insertion of cylindrical diffusors in patient’s brain and to compute the associated dosimetry. The stereotactic registration and the dosimetry computation’s accuracy were evaluated with specific methodologies.When tumor resection is achievable, the intraoperative PDT may be applied early after the FGR. It takes advantage of the presence of the PS (the protoporphyrin IX) used for FGR purpose and that is already concentrates into the tumor cells. Thus, the proposed treatment strategy fits into the current standard of care. A medical device was designed to fit to the resection cavity and illuminate homogeneously the cavity’s margins. The device is constituted of two parts: a trocar coupled to an inflatable balloon and a fiber guide developed in the ONCO-THAI laboratory allowing to insert the light source. Specific methodologies were developed to calibrate and assess the device in terms of mechanical properties and dosimetry. The calibration process leaded to a transfer function that provides fast, robust and easy treatment duration prescription to induce a PDT response in cavity margins. Furthermore, a comprehensive experimental design has been worked out prior to the clinical trial that evaluate the safety of the procedure.
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https://tel.archives-ouvertes.fr/tel-01812180
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Submitted on : Monday, June 11, 2018 - 12:40:07 PM
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  • HAL Id : tel-01812180, version 1

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Clément Dupont. Photodynamic therapies of high-grade gliomas : from theory to clinical perspectives. Human health and pathology. Université du Droit et de la Santé - Lille II, 2017. English. ⟨NNT : 2017LIL2S034⟩. ⟨tel-01812180⟩

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