Efficacy of intracerebral delivery of cisplatin in combination with photon irradiation for treatment of brain tumors

Abstract

We have evaluated the efficacy of intracerebral (i.c.) convection-enhanced delivery (CED) of cisplatin in combination with photon irradiation for the treatment of F98 glioma-bearing rats. One thousand glioma cells were stereotactically implanted into the brains of Fischer rats and 13 days later cisplatin (6 microg/20 microl) was administered i.c. by CED at a flow rate of 0.5 microl/min. On the following day the animals were irradiated with a single 15 Gy dose of X-rays, administered by a linear accelerator (LINAC) or 78.8 keV synchrotron X-rays at the European Synchrotron Radiation Facility (ESRF). Untreated controls had a mean survival time (MST) + or - standard error of 24 + or - 1 days compared to >59 + or - 13 days for rats that received cisplatin alone with 13% of the latter surviving >200 days. Rats that received cisplatin in combination with either 6 MV (LINAC) or 78.8 keV (synchrotron) X-rays had almost identical MSTs of >75 + or - 18 and >74 + or - 19 days, respectively with 17 and 18% long-term survivors. Microscopic examination of the brains of long-term surviving rats revealed an absence of viable tumor cells and cystic areas at the presumptive site of the tumor. Our data demonstrate that i.c. CED of cisplatin in combination with external X-irradiation significantly enhanced the survival of F98 glioma-bearing rats. This was independent of the X-ray beam energy and probably was not due to the production of Auger electrons as we previously had postulated. Our data provide strong support for the approach of concomitantly administering platinum-based chemotherapy in combination with radiotherapy for the treatment of brain tumors. Since a conventional LINAC can be used as the radiation source, this should significantly broaden the clinical applicability of this approach compared to synchrotron radiotherapy, which could only be carried out at a very small number of specialized facilities.

Figure 1

Kaplan-Meier survival curves for F98 glioma-bearing rats after intratumoral radiotherapy alone or intracerebral cisplatin alone. The origin of the x-axis corresponds to tumor implantation. Group 1: untreated controls (◇), Group 2: cisplatin (×, dotted line), Group 3: 6 MV radiotherapy alone (△), Group 5: 78.8 keV radiotherapy alone (□).

Figure 2

Kaplan-Meier survival curves for F98 glioma-bearing rats after intratumoral cisplatin with radiotherapy (6 MV or 78.8 keV photons). Group 1: untreated controls (◇), Group 4: cisplatin combined with 6 MV radiotherapy (▲), Group 6: cisplatin combined with 78.8 keV radiotherapy (■).

Figure 3

A. Histology of the F98 glioma in a rat that received cisplatin and 15 Gy of synchrotron X-irradiation, failed treatment and dies 47 d following tumor implantation The recurrent tumor shows a highly invasive pattern of growth with extensive invasion of white matter (200X). B. Brain of a rat from the same experimental group that was alive at the time of euthanization on d. 200. There was no evidence of viable residual or recurrent tumor. There was a cystic area with a focus of gliosis and fibrosis with mixed infiltrative of lymphocytes, macrophages and scattered pyknotic tumor cells (200X). There also was necrotic cellular debris with some dystrophic calcification (at the time of treatment, the CT images of this rat revealed a large tumor, visible over 6 slices (1mm thickness), data not shown). C. Low power photomicrograph (40X) of a porencephalic cyst measuring 4x5 mm from the right cerebral hemisphere of rat that had received 6 MV X-irradiation and cisplatin. This animal was a long term survivor who has alive at the time of euthanization on d. 200. No residual or recurrent tumor was seen. D. Higher power view (200X) of the wall of the porencephalic cyst. There was mild gliosis and a light scattering of lymphocytes and macrophages immediately adjacent to the cavity.