LONG-TERM TOXICITY AND NEUROPATHOLOGY ASSOCIATED WITH THE SEQUENCING OF CRANIAL IRRADIATION AND ENHANCED CHEMOTHERAPY DELIVERY

OBJECTIVE: The goal was to evaluate, at 1 year, 75 Long-Evans rats for survival rates and toxicity associated with the sequencing of cranial irradiation and enhanced chemotherapy delivery. METHODS: Seventy-five Long-Evans rats were randomized into four groups and evaluated at 1 y ear for survival rates and toxicity associated with the sequencing of cranial irradiation and enhanced chemotherapy delivery. Radiation (200 0 cGy) was administered as a single fraction, by using parallel oppose d portals, 30 days before chemotherapy (Group 1), 24 hours before chem otherapy (Group 2), 30 days after chemotherapy (Group 3), or without c hemotherapy or without radiation (control group, Group 4). Five subgro ups within each treatment group included rats receiving intra-arterial ly administered methotrexate (1 g/m(2)) or intravenously administered etoposide (200 mg/m(2)) combined with intra-arterially administered ca rboplatin (200 mg/m(2)), administered with or without osmotic blood-br ain barrier disruption, and a group receiving normal saline solution a fter brood-brain barrier disruption. RESULTS: There was a significant increase in total toxic effects when the three experimental groups wer e compared with the control group (P = 0.001, 0.006, and 0.013 for Gro ups 1, 2, and 3, respectively). All groups receiving radiation and che motherapy (particularly carboplatin and etoposide) had an increased in cidence of hind limb paralysis, resembling experimental allergic neuri tis (P = 0.053). Statistical analysis showed a trend toward increased mortality rates in Group 1 (antecedent radiation), compared with the c ontrol group (P = 0.082), and an increased incidence of intracerebral calcification (P = 0.019). No differences in mortality rates were obse rved for Group 2 or 3, compared with the control group. CONCLUSION: Ra diation before chemotherapy was a more toxic sequence and, surprisingl y, carboplatin/etoposide administered in combination with radiotherapy was more detrimental than methotrexate. Additional studies are in pro gress to evaluate the toxicity and efficacy of sequences of cranial ir radiation and enhanced chemotherapy in tumor-bearing rats.