Intracarotid Chemotherapy with a Combination of 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU), cis-Diaminedichloroplatinum (Cisplatin), and 4'-O-Demethyl-1-O-(4,6-O-2-thenylidene-β-D-glucopyranosyl)epipodophyllotoxin (VM-26) in the Treatment of Primary and Metastatic Brain Tumors

Abstract

Abstract Thirty-seven patients with intracranial primary or metastatic tumors were treated with an intraarterial combination of BCNU, cisplatin, and VM-26 to determine the efficacy, toxicity, and maximal tolerated doses for the combination. A transfemoral fluoroscopic approach was used to catheterize temporarily the internal carotid or vertebral artery. Thirteen of 19 (68%) evaluable primary brain tumors and 9 of 16 (56%) evaluable brain metastases responded. The response rate was lower in patients previously treated with both cranial irradiation and i.v. chemotherapy than in patients less heavily pretreated (54% vs. 82%), although even patients previously treated i.v. with all three of the study drugs responded. All five patients with both extracranial and intracranial evaluable tumor deposits experienced a greater response of their intracranial than of their extracranial tumor. Ipsilateral retinal and neurological toxicity were dose-limiting, with major toxicity (permanent decreased vision or hemiparesis) occurring in five of nine (56%) patients receiving doses of BCNU ≥ 100 mg/m2, plus cisplatin, 60 mg/m2, plus VM-26, 175 mg/m2. Only 9% of the patients treated with a lower VM-26 dose developed permanent severe toxicity, and the doses that we now recommend are: BCNU, 100 mg/m2; cisplatin, 60 mg/m2; and VM-26, 150 mg/m2. The response rate was also dose-related (100% at the highest doses tested vs. 57% at the lower doses). Fully reversible toxicity was also seen, including transient decrease in ipsilateral visual acuity (11%), transient hemiparesis or hemianesthesia (5%), transient increased intracranial pressure (5%), mild ototoxicity (3%), mild to moderate vomiting (80%), severe periorbital pain and erythema during BCNU infusion (94%), and myelosuppression (30%). Vertebral artery infusion must be performed with great caution because infusions of BCNU and VM-26 (but not of cisplatin) were associated with marked but rapidly reversible somnolence and potentially life-threatening cardiac and respiratory depression. No cardiorespiratory depression was seen with carotid artery infusions. The intraarterial infusion of this three-drug regimen is quite effective in reducing the size of the tumor as seen on the computed tomographic scan in this poor prognosis group of patients, but is also potentially quite toxic. We are now initiating other studies adding i.v. drugs to our intracarotid combination.