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 (2,000 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-rain 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.


CONCLUSIONS
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.
Remsen
L G
LG
Department of Neurology, Oregon Health Sciences University, Portland, USA.
McCormick
C I
CI
Sexton
G
G
Pearse
H D
HD
Garcia
R
R
Mass
M
M
Roman-Goldstein
S
S
Neuwelt
E A
EA
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D016190:Carboplatin / Q000633:toxicity; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D016371:Cranial Irradiation; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D005047:Etoposide / Q000633:toxicity; D008353:Mannitol / Q000494:pharmacology; D008727:Methotrexate / Q000633:toxicity; D011833:Radiation Injuries, Experimental / Q000473:pathology*; D018714:Radiotherapy, Adjuvant; D051381:Rats; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D008353:Mannitol; D005047:Etoposide; D016190:Carboplatin; D008727:Methotrexate