Intra-arterial chemotherapy with osmotic blood-brain barrier disruption for aggressive oligodendroglial tumors: results of a phase I study.
OBJECTIVE
Refractory anaplastic oligodendroglioma and oligoastrocytoma tumors are challenging to treat. This trial primarily evaluated toxicity and estimated the maximum tolerated dose of intra-arterial (IA) melphalan, IA carboplatin, and intravenous (IV) etoposide phosphate in conjunction with blood-brain barrier disruption in these tumors. The secondary measure was efficacy.


METHODS
Thirteen patients with temozolomide-refractory anaplastic oligodendroglioma (11 patients) or oligoastrocytoma (2 patients) underwent blood-brain barrier disruption with carboplatin (IA, 200 mg/m(2)/d), etoposide phosphate (IV, 200 mg/m(2)/d), and melphalan (IA, dose escalation) every 4 weeks, for up to 1 year. Patients underwent melphalan dose escalation (4, 8, 12, 16, and 20 mg/m(2)/d) until the maximum tolerated dose (1 level below that producing grade 4 toxicity) was determined. Toxicity and efficacy were assessed.


RESULTS
Two of 4 patients receiving IA melphalan at 8 mg/m(2)/d developed grade 4 thrombocytopenia; thus, the melphalan maximum tolerated dose was 4 mg/m/d. Adverse events included asymptomatic subintimal tear (1 patient) and grade 4 thrombocytopenia (3 patients). Two patients demonstrated complete response, 3 had partial responses, 5 demonstrated stable disease, and 3 progressed. Median overall progression-free survival was 11 months. Patients with complete or partial response demonstrated deletion of chromosomes 1p and 19q. In the 5 patients with stable disease, 2 demonstrated 1p and 19q deletion, and 3 demonstrated 19q deletion only.


CONCLUSIONS
In patients with anaplastic oligodendroglioma or oligoastrocytoma tumors in whom temozolomide treatment has failed, osmotic blood-brain barrier disruption with IA carboplatin, IV etoposide phosphate, and IA melphalan (4 mg/m(2)/d for 2 days) shows acceptable toxicity and encouraging efficacy, especially in patients demonstrating 1p and/or 19q deletion.
Guillaume
Daniel J
DJ
Department of Neurosurgery, Oregon Health & Science University, Portland, Oregon, USA.
Doolittle
Nancy D
ND
Gahramanov
Seymur
S
Hedrick
Nancy A
NA
Delashaw
Johnny B
JB
Neuwelt
Edward A
EA
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy*; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use; D003432:Cross-Linking Reagents / Q000494:pharmacology / Q000627:therapeutic use; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007269:Injections, Intra-Arterial / Q000379:methods; D008130:Lomustine / Q000627:therapeutic use; D008297:Male; D008558:Melphalan / Q000627:therapeutic use; D008875:Middle Aged; D009837:Oligodendroglioma / Q000188:drug therapy*; D009997:Osmotic Pressure / Q000187:drug effects; D011344:Procarbazine / Q000627:therapeutic use; D000077204:Temozolomide; D014750:Vincristine / Q000627:therapeutic use; D055815:Young Adult
D003432:Cross-Linking Reagents; D011344:Procarbazine; D014750:Vincristine; D008130:Lomustine; D003606:Dacarbazine; D016190:Carboplatin; D008558:Melphalan; D000077204:Temozolomide