Radiochemotherapy directed at malignancies within the central nervous system (CNS) is frequently used in the treatment of leukemia, non-Hodgkin's lymphoma, brain tumor and certain forms of lung cancer, and this group of malignancies represent approximately half of all childhood neoplasms and more than 10 percent of adult cancers. When the drug most widely used for intrathecal chemotherapy, methotrexate (MTX), is used in the radiochemotherapy combination, the therapy-limiting toxicities are delayed adverse neurologic sequelae - either leukoencephalopathy, myelopathy, intellectual/cognitive deficits, or specific neurologic dysfunctions - depending on which part of the CNS is irradiated.
The specific aims of this project are to identify and characterize radiochemotherapy interactions in the CNS which result in these sequelae. The approach is to use a rat model established by the investigators to study MTX and ionizing radiation. Sprague-Dawley rats are implanted with a miniature osmotic pump connected to a cannula, the tip of which is stereotaxically inserted into the lateral cerebral ventricle. The CNS is infused for 14 days with a constant infusion of either MTX at the maximally-tolerated dose or physiological saline. The cervical cord is irradiated with various doses from a cesium-137 source administered during, before, or after the drug infusion, and with one, two, or multiple fractions of radiation. The end-points are forelimb paralysis and histologic evidence for white matter necrosis in the spiral cord. The paralytic ED50 was 2125 rads for a single fraction and 2850 rads for split fractions. There was no evidence that mature CNS tissue was sensitized to single-fraction or split-dose radiation with either simultaneous or post-radiation exposure to high concentrations of MTX. On the other hand, there was evidence that preradiation MTX protected against both histopathologic (white matter necrosis) and functional (paralysis) neurotoxicities of radiation. The research plan is now focused on determining whether 1) MTX sensitizes mature neural tissue to multiple fractions of radiation in comparison to one or two fractions; 2) immature neural tissue is more susceptible to the radiochemotherapy interactions; 3) evoked potentials are a more sensitive, faster, and less expensive method of radiomyelopathy detection; 4) preradiation MTX can be documented to be significantly radioprotective; and 5) antidotes of MTX or radiation can prevent the adverse neurologic sequelae without compromising therapeutic benefit.
| Taylor, E M; Geyer, J R; Milstein, J M et al. (1988) Rodent model of chemoradiotherapy-induced white matter necrosis. NCI Monogr :59-64 |
