Abstract #5591: Intracerebral delivery of cisplatin enhances the effect of radiotherapy in an experimental glioma model.
Authors: Julia Rousseau, Rolf Barth, Manuel Fernandez, Jean-François Adam, Jacques Balosso, François Esteve, Hélène Elleaume
Journal: Cancer Research (2009)

Platinated drugs, such as cisplatin, represent an important class of antitumor agents that are widely used to treat various malignancies. However, their clinical use for treating patients with brain tumors has been limited by their systemic toxicity and their decreased ability to cross the blood brain barrier (BBB) in areas where there are microinvasive deposits of tumor. Intratumoral delivery can obviate both of these problems by producing much higher tumor drug concentrations and concomitantly reducing systemic toxicity. We previously have reported on the efficacy of intracerebral (i.c.) administration of cisplatin in combination with monochromatic synchrotron X-irradiation for the treatment of F98 glioma bearing rats (Cancer Res. 64:2317-2323, 2004). This treatment resulted in 35% long-term survivors at 1 year, and at the time were the best survival data ever reported using the F98 glioma model. Our initial hypothesis was that therapeutic efficacy was related to the production of Auger electrons, emitted by relaxation of excited Pt atoms following irradiation with monochromatic X-rays, tuned just above the Pt K-edge energy (78.4 keV). In order to validate or refute this hypothesis, in the present study we have compared the efficacy of i.c. convection enhanced delivery (CED) of cisplatin in combination with either 6 MV photons or synchrotron X-rays. Cisplatin (6 µg/20 µl) was administered i.c. by CED over 40 min to F98 glioma bearing rats, 13 d. after stereotactic implantation of 1000 F98 cells. One day following CED, a 15 Gy X-ray dose was administered using either a 6-MV linear accelerator (LINAC) or a monochromatic synchrotron source (78.8-keV) at the European Synchrotron Radiation Facility (ESRF). Untreated rats had a mean survival time (MST) ± standard error (SE) of 24 ± 1 d. compared to >59 ± 13 d. for cisplatin-treated rats with 3 of 23 surviving >200 d. Rats treated with cisplatin plus 6-MV or 78.8-keV photons had equivalent MSTs of >75 ± 18 d. and >74 ± 19 d., respectively, with subsets of long-term survivors in both groups. The corresponding percent increase in lifespan, based on the MSTs, were 212 % and 205 %, respectively. Similar results have been reported by us using the combination of carboplatin and photon irradiation (Clin. Cancer Res. 13:5195-5201, 2007). Our data demonstrate that i.c. CED of cisplatin or carboplatin in combination with photon irradiation is highly effective for the treatment of the F98 glioma, and that this is independent of their energy since equivalent results were obtained with both types of X-irradiation, thereby refuting our original hypothesis. However, this broadens the applicability of this chemo-radiotherapeutic approach for the treatment of patients with malignant brain tumors, since it could be more easily translated into a clinical trial using a 6-MV LINAC instead of a synchrotron as an X-ray source.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5591.