Intra-arterial chemotherapy with osmotic blood-brain barrier disruption for aggressive oligodendroglial tumors: results of a phase I study

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/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.

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/m(2)/d for 2 days) shows acceptable toxicity and encouraging efficacy, especially in patients demonstrating 1p and/or 19q deletion.

Figure 1

Subject #5 was diagnosed with a left frontotemporal AO in 2005, and underwent tumor resection followed by temozolomide (TMZ). After developing progression while on TMZ, the subject declined radiation therapy (RT). (A) T1 weighted (T1W) MRI (axial view, post Gd-DTPA) prior to BBBD protocol demonstrates previous left frontal craniotomy and enhancing mass (arrow). T1W image without contrast (not shown) demonstrated that this was not blood products. (B) T1W MRI (axial, post Gd-DTPA) 3 months after initiating BBBD protocol revealed absence of the previous tumor enhancement (arrow). (C) T1W MRI (axial, post Gd-DTPA) 26 months after initiating BBBD protocol reveals no evidence of tumor progression.

Figure 2

Subject #8 underwent right frontal mass resection at the age of 18. Pathology revealed grade 2 oligodendroglioma. Six years later the tumor progressed, requiring a second resection, followed by 8 courses of procarbazine/BCNU chemotherapy. Four years later, MRI showed recurrence. A third resection revealed grade 3 AO and the patient was treated with a year of TMZ chemotherapy. The tumor progressed 2 years later and RT consultation was obtained. BBBD protocol was initiated. (A) T1W MRI (sagittal view, post Gd-DTPA) prior to BBBD protocol shows right frontal enhancement (arrow). (B) T1W MRI (sagittal, post Gd-DTPA) 11 months after initiating BBBD, shows improvement (arrow). (C) T1W MRI (sagittal, post Gd-DTPA) 19 months after initiating BBBD shows no progression (arrow).

Figure 3

Subject #13 underwent right temporal mass resection; pathology revealed AO. RT consultation was obtained however the subject chose to proceed with TMZ. After one year of TMZ, MRI revealed recurrence. Repeat resection was performed and pathology revealed AO with increased atypia and proliferative activity. The subject began BBBD protocol treatment. (A) T1W MRI (axial view, post Gd-DTPA) obtained prior to BBBD demonstrated postoperative changes and enhancement along the medial margin of the resection cavity (arrow). (B) T1W MRI (axial, post Gd-DTPA) 2 months after initiation of BBBD protocol showed resolution of the abnormal enhancement (arrow). (C) T1W MRI (axial, post Gd-DTPA) 4 months after initiating BBBD revealed evidence of progression (arrow) with an enhancing nodule in the left ventricular trigone (not shown). The subject subsequently received 2 cycles of bevacizumab (IV), carboplatin (IA) and melphalan (IA) before starting RT with TMZ. (D) T1W MRI (axial, post Gd-DTPA) 5 months after RT with TMZ shows resolution of enhancement (arrow).