Interstitial Photodynamic Therapy for Glioblastomas: A Standardized Procedure for Clinical Use

Abstract

Glioblastomas (GBMs) are high-grade malignancies with a poor prognosis. The current standard of care for GBM is maximal surgical resection followed by radiotherapy and chemotherapy. Despite all these treatments, the overall survival is still limited, with a median of 15 months. For patients harboring inoperable GBM, due to the anatomical location of the tumor or poor general condition of the patient, the life expectancy is even worse. The challenge of managing GBM is therefore to improve the local control especially for non-surgical patients. Interstitial photodynamic therapy (iPDT) is a minimally invasive treatment relying on the interaction of light, a photosensitizer and oxygen. In the case of brain tumors, iPDT consists of introducing one or several optical fibers in the tumor area, without large craniotomy, to illuminate the photosensitized tumor cells. It induces necrosis and/or apoptosis of the tumor cells, and it can destruct the tumor vasculature and produces an acute inflammatory response that attracts leukocytes. Interstitial PDT has already been applied in the treatment of brain tumors with very promising results. However, no standardized procedure has emerged from previous studies. Herein, we propose a standardized and reproducible workflow for the clinical application of iPDT to GBM. This workflow, which involves intraoperative imaging, a dedicated treatment planning system (TPS) and robotic assistance for the implantation of stereotactic optical fibers, represents a key step in the deployment of iPDT for the treatment of GBM. This end-to-end procedure has been validated on a phantom in real operating room conditions. The thorough description of a fully integrated iPDT workflow is an essential step forward to a clinical trial to evaluate iPDT in the treatment of GBM.

Keywords: brain tumor; glioblastoma; interstitial; photodynamic therapy; treatment planning system.

Figure 1

Screenshots from the TPS dedicated to iPDT of GBMs. These screenshots were obtained using a brain phantom (Brain Simulator, Synaptive Resection 750). (A) The first step consists of manually contouring the target volume, which is displayed in green (cm³). (B) Then, an optical fiber trajectory is defined, with an entry point (point of entry into the skull) and a target point (end of the introduced fiber) harboring stereotactic coordinates. The red portion of the fiber corresponds to the diffusing part. (C) The resulting effective volume treated with iPDT is displayed in red. The objective is for the red volume to optimally overlap the target tumor volume in yellow. TPS: treatment planning software. iPDT: interstitial photodynamic therapy. GBMs: glioblastomas.

Figure 2

Screenshots from the iPDT TPS for GBM. (A) Brain MRI, T1 after gadolinium infusion. The green zone corresponds to the target volume. The diffusing part of each fiber is displayed in red. (B) The effective treated volume is displayed in yellow, receiving at least 25 J/cm². The red volume around each fiber corresponds to a volume receiving an energy >250 J/cm². In this snapshot, the optical fibers have a 2 cm diffusing part. Only one fiber is able to cover a volume superior to 1 cm³ (here: 1.166 cm³, taking into account the optical parameters of all brain tissues).

Figure 3

The light emission profile of the 2 cm cylindrical diffusing fiber (represented by red dots), the associated super-Gaussian probability density function (represented by blue dashes) and the distribution of 100,000 positions sampled from this probability density function (represented by magenta dashes).

Figure 4

The brain phantom is fixed in the rigid head holder. (A) A rigid fiducial is fixed on the bone. Then, an ultrasound registration is performed. (B) The registration was performed without any bone anchored fiducial, using the neurolocate^TM module adapted on the robotic arm.

Figure 5

(A) The brain phantom is fixed in the rigid head holder. The CBCT (O-Arm, Medtronic) was performed to obtain the 3D images needed to navigate the robotic arm. The laser at the distal part of the robotic arm is pointing at the skull entry point. (B) A guide was previously introduced into the brain to ensure the right trajectory before inserting the appropriate optical fiber.

Figure 6

A CBCT (O-Arm, Medtronic) was performed after the insertion of the optical fiber through its guide. The planned trajectory is the dotted blue line. The optical fiber appears in white. As the optical fiber is superposed to the blue line, and the accuracy was estimated as satisfying. (A) Coronal plane. (B) Axial plane.