Intra-arterial chemotherapy with osmotic blood-brain barrier disruption for aggressive oligodendroglial tumors

Results of a phase i study

Daniel J. Guillaume, Nancy Doolittle, Seymur Gahramanov, Nancy A. Hedrick, Johnny B. Delashaw, Edward Neuwelt

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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/m2/d), etoposide phosphate (IV, 200 mg/m2/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/m2/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/m2/d developed grade 4 thrombocytopenia; thus, the melphalan maximum tolerated dose was 4 mg/m2/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. CONCLUSION: 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/m2/d for 2 days) shows acceptable toxicity and encouraging efficacy, especially in patients demonstrating 1p and/or 19q deletion.

Original languageEnglish (US)
Pages (from-to)48-58
Number of pages11
JournalNeurosurgery
Volume66
Issue number1
DOIs
StatePublished - Jan 2010

Fingerprint

Blood-Brain Barrier
Drug Therapy
Melphalan
Neoplasms
temozolomide
Oligodendroglioma
Maximum Tolerated Dose
Carboplatin
Tears
Disease-Free Survival

Keywords

  • Anaplastic oligodendroglioma
  • Blood-brain barrier
  • Chemotherapy
  • Intra-arterial chemotherapy
  • Oligoastrocytoma
  • Oligodendroglial tumors

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery

Cite this

Intra-arterial chemotherapy with osmotic blood-brain barrier disruption for aggressive oligodendroglial tumors : Results of a phase i study. / Guillaume, Daniel J.; Doolittle, Nancy; Gahramanov, Seymur; Hedrick, Nancy A.; Delashaw, Johnny B.; Neuwelt, Edward.

In: Neurosurgery, Vol. 66, No. 1, 01.2010, p. 48-58.

Research output: Contribution to journalArticle

Guillaume, Daniel J. ; Doolittle, Nancy ; Gahramanov, Seymur ; Hedrick, Nancy A. ; Delashaw, Johnny B. ; Neuwelt, Edward. / Intra-arterial chemotherapy with osmotic blood-brain barrier disruption for aggressive oligodendroglial tumors : Results of a phase i study. In: Neurosurgery. 2010 ; Vol. 66, No. 1. pp. 48-58.
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AU - Hedrick, Nancy A.

AU - Delashaw, Johnny B.

AU - Neuwelt, Edward

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N2 - 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/m2/d), etoposide phosphate (IV, 200 mg/m2/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/m2/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/m2/d developed grade 4 thrombocytopenia; thus, the melphalan maximum tolerated dose was 4 mg/m2/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. CONCLUSION: 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/m2/d for 2 days) shows acceptable toxicity and encouraging efficacy, especially in patients demonstrating 1p and/or 19q deletion.

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