DECREASED DELIVERY AND ACUTE TOXICITY OF CRANIAL IRRADIATION AND CHEMOTHERAPY GIVEN WITH OSMOTIC BLOOD-BRAIN-BARRIER DISRUPTION IN A RODENTMODEL - THE ISSUE OF SEQUENCE

The sequence of chemotherapy administered prior to cranial irradiation rather than the more traditional order of radiation followed by chemo therapy is currently being evaluated, This rodent study was designed t o assess the sequencing of radiation therapy and chemotherapy administ ered with osmotic blood-brain barrier disruption (BBBD). Drug delivery and acute toxicity were evaluated. Two clinically relevant chemothera py regimens were given with BBBD: intraarterial methotrexate (MTX, 1 g /m(2)), or a combination of intraarterial carboplatin (200 mg/m(2)) an d i.v. etoposide (200 mg/m(2)). In a randomized protocol, the standard rodent model of 2000 cGy as a single fraction using parallel opposed portals was administered 30 days prior to, concurrent dth (24 h prior) , or 30 days after these two chemotherapeutic regimens, A total of 72 animals was evaluated in this study, The administration of external be am radiation therapy either prior to or concurrent with the administra tion of a high molecular weight marker C-14-labeled dextran 70 (M(r) 7 0,000), or a low molecular weight marker H-3-labeled MTX (M(r) 456) re sulted in a statistically significant (P < 0.01) decrease in drug deli very when compared to animals not receiving cranial irradiation. Seizu res were observed in 26% of the animals that received radiation prior to the administration of intraarterial MTX after BBBD. It did not matt er whether the radiotherapy was administered 30 days prior to or concu rrent with MTX. Seizures were not seen in any other group, The mortali ty in animals receiving radiotherapy 30 days prior to chemotherapy was significantly (P = 0.03) higher than the mortality in control animals receiving chemotherapy after osmotic BBBD, but no radiation. Drug del ivery was significantly decreased when the animals received prior radi otherapy; the administration of radiation prior to MTX with BBBD resul ted in an increased incidence of seizures, and there was a significant increase in mortality when cranial irradiation was given 30 days prio r to chemotherapy administered with BBBD. With regard to delivery and toxicity, chemotherapy with BBBD administered prior to radiotherapy ma y have advantages over the other sequences utilizing chemotherapy and cranial irradiation.