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 year for survival rates and toxicity associated with the sequencing of cranial irradiation and enhanced chemotherapy delivery. Radiation (2000 cGy) was administered as a single fraction, by using parallel opposed portals, 30 days before chemotherapy (Group 1), 24 hours before chemotherapy (Group 2), 30 days after chemotherapy (Group 3), or without chemotherapy or without radiation (control group, Group 4). Five subgroups within each treatment group included rats receiving intra-arterially administered methotrexate (1 g/m²) or intravenously administered etoposide (200 mg/m²) combined with intra-arterially administered carboplatin (200 mg/m²), administered with or without osmotic blood-brain barrier disruption, and a group receiving normal saline solution after blood-brain barrier disruption. RESULTS: There was a significant increase in total toxic effects when the three experimental groups were compared with the control group (P = 0.001, 0.006, and 0.013 for Groups 1, 2, and 3, respectively). All groups receiving radiation and chemotherapy (particularly carboplatin and etoposide) had an increased incidence of hind limb paralysis, resembling experimental allergic neuritis (P = 0.053). Statistical analysis showed a trend toward increased mortality rates in Group 1 (antecedent radiation), compared with the control group (P = 0.082), and an increased incidence of intracerebral calcification (P = 0.019). No differences in mortality rates were observed for Group 2 or 3, compared with the control group. CONCLUSION: Radiation before chemotherapy was a more toxic sequence and, surprisingly, carboplatin/etoposide administered in combination with radiotherapy was more detrimental than methotrexate. Additional studies are in progress to evaluate the toxicity and efficacy of sequences of cranial irradiation and enhanced chemotherapy in tumor-bearing rats.