Enhanced survival and cure of F98 glioma-bearing rats following intracerebral delivery of carboplatin in combination with photon irradiation.

PURPOSE: The goal of the present study was to evaluate the efficacy of intracerebral (i.c.) administration of carboplatin by means of convection-enhanced delivery (CED) in combination with fractionated, external beam photon irradiation for the treatment of F98 glioma-bearing rats. EXPERIMENTAL DESIGN: Carboplatin (20 microg/20 microL) was administrated i.c. by CED to F98 glioma-bearing rats, 13 days after stereotactic implantation of 10(3) tumor cells. One day following initiation of CED, a 24-Gy X-ray dose was administered in three daily fractions of 8 Gy each. Photon irradiation was carried out using either a conventional (6 MV) linear accelerator or a monochromatic synchrotron source (80 keV) at the European Synchrotron Radiation Facility. The primary end point of this study was overall survival. RESULTS: The median survival times were 79 and 60 days and the corresponding percent increase in life spans were 182% and 114%, respectively, for the combination of carboplatin chemotherapy and irradiation with either 6-MV or 80-keV photons. A subset of long-term survivors (>200 days) were observed in both chemoradiotherapy groups: 16.6% and 8.3% for 6 MV and 80 keV, respectively. In contrast, the median survival times for 6-MV or 80-keV irradiated controls, chemotherapy alone, and untreated controls were 42, 51, 45, and 28 days, respectively. CONCLUSIONS: Our results convincingly show the therapeutic efficacy of i.c. administration of carboplatin by means of CED in combination with either 6-MV or 80-keV photons. Further studies are warranted to optimize this combination of chemoradiotherapy for malignant gliomas.

Convection-enhanced delivery of an iodine tracer into rat brain for synchrotron stereotactic radiotherapy.

PURPOSE: To evaluate direct intracerebral and intratumoral iodine delivery as means to improve iodine distribution for synchrotron stereotactic radiotherapy (SSR) and to evaluate the corresponding X-ray dose distribution. METHODS AND MATERIALS: Healthy rats and F98 glioma-bearing rats received an iodinated contrast agent (iopamidol) intracerebrally either by bolus injection (5 microL over approximately 1 min) or by convection-enhanced delivery (infusion volumes of 5, 10, and 20 microL at a rate of 0.5 microL/min). We used synchrotron computed tomography (CT) to determine the iodine distribution after completion of infusion and a Monte Carlo code to compute the resulting radiation dose in SSR. RESULTS: Post-infusion CT imaging revealed high iodine concentrations in the perfused area with both injection methods. The iodine concentration remained elevated, with an exponential decay time constant of approximately 50 min, well suited for SSR treatment. Convection-enhanced delivery was shown to provide more uniform and controlled volumes of distribution than bolus injection and was chosen to evaluate the corresponding X-ray dose distribution. Sharp dose gradients around the target and excellent sparing of the contralateral brain were achievable with low iodine concentrations in the surrounding healthy brain tissues and blood vessels. CONCLUSIONS: Convection-enhanced delivery is an effective method to deliver high iodine concentrations and could improve the outcome of iodine-enhanced SSR.

Irradiation in presence of iodinated contrast agent results in radiosensitization of endothelial cells: consequences for computed tomography therapy.

PURPOSE: To date, iodinated contrast agents (ICA) are commonly used in medical imaging to improve tumor visualization by attenuating scanners X-rays. However, some adverse reactions to ICAs are still reported, and their molecular origin remains unclear. In 1983, it was proposed to visualize and treat ICA-loaded tumors by using scanners as therapy machines to enhance X-rays absorption at the iodine atoms. Theoretically, such physical conditions are optimized at 50 keV and can be easily obtained with synchrotrons. METHODS AND MATERIALS: Here, we examined the molecular and cellular responses of mammalian endothelial cells to radiation in the presence of iomeprol, one of the most extensively used ICAs. RESULTS: Irradiation with X-rays at 50 keV in the presence of iomeprol produced a strong radiosensitization effect. The same conclusion was reached with a standard medical irradiator but to a lesser extent. While such treatment did not produce additional DNA double-strand breaks, we observed a dose-dependent production of iodides due to the iomeprol radiolysis that inhibit double-strand break repair rate by decreasing DNA-PK kinase activity. CONCLUSIONS: Our data suggest that the concomitant use of ICA and radiation may be toxic when radiation-produced iodide concentrations and double-strand break yields are sufficient. The potential toxicity of ICAs during X-rays for diagnosis and therapy is discussed.

Monte Carlo dosimetry for synchrotron stereotactic radiotherapy of brain tumours.

A radiation dose enhancement can be obtained in brain tumours after infusion of an iodinated contrast agent and irradiation with kilovoltage x-rays in tomography mode. The aim of this study was to assess dosimetric properties of the synchrotron stereotactic radiotherapy technique applied to humans (SSR) for preparing clinical trials. We designed an interface for dose computation based on a Monte Carlo code (MCNPX). A patient head was constructed from computed tomography (CT) data and a tumour volume was modelled. Dose distributions were calculated in SSR configuration for various energy beam and iodine content in the target volume. From the calculations, it appears that the iodine-filled target (10 mg ml(-1)) can be efficiently irradiated by a monochromatic beam of energy ranging from 50 to 85 keV. This paper demonstrates the feasibility of stereotactic radiotherapy for treating deep-seated brain tumours with monoenergetic x-rays from a synchrotron.

Synchrotron stereotactic radiotherapy: dosimetry by Fricke gel and Monte Carlo simulations.

Synchrotron stereotactic radiotherapy (SSR) consists in loading the tumour with a high atomic number element (Z), and exposing it to monochromatic x-rays from a synchrotron source (50-100 keV), in stereotactic conditions. The dose distribution results from both the stereotactic monochromatic x-ray irradiation and the presence of the high Z element. The purpose of this preliminary study was to evaluate the two-dimensional dose distribution resulting solely from the irradiation geometry, using Monte Carlo simulations and a Fricke gel dosimeter. The verification of a Monte Carlo-based dosimetry was first assessed by depth dose measurements in a water tank. We thereafter used a Fricke dosimeter to compare Monte Carlo simulations with dose measurements. The Fricke dosimeter is a solution containing ferrous ions which are oxidized to ferric ions under ionizing radiation, proportionally to the absorbed dose. A cylindrical phantom filled with Fricke gel was irradiated in stereotactic conditions over several slices with a continuous beam (beam section = 0.1 x 1 cm2). The phantom and calibration vessels were then imaged by nuclear magnetic resonance. The measured doses were fairly consistent with those predicted by Monte Carlo simulations. However, the measured maximum absolute dose was 10% underestimated regarding calculation. The loss of information in the higher region of dose is explained by the diffusion of ferric ions. Monte Carlo simulation is the most accurate tool for dosimetry including complex geometries made of heterogeneous materials. Although the technique requires improvements, gel dosimetry remains an essential tool for the experimental verification of dose distribution in SSR with millimetre precision.

Normoxic polyacrylamide gel doped with iodine: response versus X-ray energy.

The basis of Synchrotron Stereotactic Radio-Therapy (SSRT) is the incorporation of high atomic number atoms (iodine, for example) into the tumour mass followed by an irradiation with a monochromatic, low energy, X-ray beam from a synchrotron source. The purpose of the present study was to determine whether polymer gel dosimetry could be used to measure the enhancement of absorbed energy induced by the iodine in the media. We have used a standard nPAG formulation, loaded with NaI and the irradiations were performed either with monochromatic X-rays at the ESRF medical beamline or with a conventional 6 MV X-ray beam from a linear accelerator at the Grenoble University Hospital. We observed sensitivity increase with iodine loaded gels irradiated at low energies, in good agreement with the theoretical iodine dose-enhancement. As expected, the response of the iodine-doped polymer gel was not increased after irradiation with mega-voltage X-rays. We demonstrate in this study that polymer gel dosimeters can be used for measuring dose-enhancement due to iodine presence in SSR treatment.

Fast dose calculation for stereotactic synchrotron radiotherapy.

A hybrid approach is proposed to compute the dose deposited in cancerous and healthy tissues during stereotactic synchrotron radiotherapy treatment. In this approach the computation is divided into two parts: (1) the primary dose is calculated using a deterministic algorithm based on ray casting; (2) the secondary dose (due to scattering and fluorescence) is computed using a hybrid algorithm combining Monte Carlo and a deterministic method. The results obtained for test cases are compared to those obtained with the Monte Carlo method alone (Geant4 code) and found to be in excellent agreement. The proposed simulation scheme makes it possible to simulate dose maps with a single personal computer, with computation time and statistical fluctuations substantially reduced in comparison with conventional Monte Carlo simulations.