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Please indicate author’s corrections in blue, setting errors in red133477 NEON ART.NO 851-96 (657) ORD.NO 234657Journal of Neuro-Oncology 35: 121–131, 1997. 1997 Kluwer Academic Publishers. Printed in the Netherlands.Clinical StudyIntra-arterial carboplatin chemotherapy for brain tumors: A dose escalationstudy based on cerebral blood flowTimothy F. Cloughesy,1,2Y. Pierre Gobin,3Keith L. Black,1,2,4Fernando Vin˜uela,3Foster Taft,2BehdadKadkhoda,2and Fairooz Kabbinavar1,51Jonsson Comprehensive Cancer Center, Departments of 2Neurology, 3Radiology, 4Surgery, and 5Medicine,UCLA School of Medicine, Los Angeles, California, USAKey words: intraarterial, carboplatin, blood flow, glioma, brain tumorSummaryPurpose. To perform an intra-arterial dose escalation study of carboplatin based on hemispheric blood-flowestimation in patients with recurrent malignant glioma. The primary purpose was to determine the maximallytolerated intra-arterial dose. Methods and patients. Methods included: 1) selective intra-arterial delivery per-formed with modern microcatheters, 2) pulsatile infusion, and 3) dosage based on local cerebral blood-flowestimation (middle cerebral artery 60%, anterior cerebral artery 20%, posterior cerebral artery 15%, andanterior choroidal artery 5% of the hemispheric blood-flow). The deliveries were performed above the oph-thalmic artery in the anterior circulation, or above the anterior inferior cerebellar arteries in the posteriorcirculation. The doses were escalated from 200 mg/hemisphere at 50 mg increments. Twenty-one patientswere studied (14 with glioblastoma multiforme, five anaplastic astrocytoma, one aggressive low-grade glioma,one metastasis). Patients had recurrent glioma limited to one hemisphere and Karnofsky score of 50 orgreater. Concomitant therapies were allowed. Results. Carboplatin was escalated to a dose of 1400 mg/hemi-sphere. One patient had a permanent neuromotor decline. The predominant toxicity was hematopoietic. Themedian time to tumor progression was 22 weeks, median survival 39 weeks, and the response rate 70% (50%SD and 20% PR) of 19 patients. Conclusions. Hemispheric blood-flow estimation allowed us to escalate thedose of intra-arterial carboplatin to twice what was previously considered safe. Responses compared favor-ably to previous studies. Further studies are needed to determine if this method will provide improved anddurable responses.IntroductionThe prognosis of malignant glioma is extremelypoor even with therapy using maximal surgical re-section, radiation therapy, and chemotherapy.Many investigators have concluded that the efficacyof chemotherapy in malignant glioma is extremelylimited, as confirmed in a recent meta-analysis [1].Extensive research into the causes of drug resist-ance have found molecular resistance induced bymultiple drug resistance genes such as the O6-me-thylguanine-DNA methyltransferase [2]. As hy-pothesized, dose intensification of chemotherapymay overcome molecular resistance and improvesurvival. This dose intensification can be obtainedby high-dose intravenous chemotherapy whiletreating hematopoietic toxicity with granulocytecolony-stimulating factors or autologous bone mar-row transplant [3]. However, these studies showedsignificant toxicity and mortality with large varia-tion in response rates [3].Another method of dose intensification for brainPlease indicate author’s corrections in blue, setting errors in red133477 NEON ART.NO 851-96 (657) ORD.NO 234657122tumors employs intra-arterial therapy. In theory, in-tra-arterial therapy is at its greatest advantage whenfirst-pass extraction is significant (lipid-solubledrugs) and when the drug has a rapid systemic clear-ance [4]. However, even agents like cisplatin, whichdoes not meet all these characteristics, have shownsome advantages [4–9]. Intra-arterial chemother-apy can have neurologic, ophthalmologic, and ot-ologic complications [10–15]. These complicationsmay be due to: 1) improper technique and improperplacement of the microcatheter, 2) slow infusion ofthe drug and laminar flow, with high concentrationsof chemotherapy perfusing certain areas of thebrain, and 3) improper basis of delivery (mg/m2orAUC vs. blood flow). To exploit the possibility ofintra-arterial chemotherapy we associated the fol-lowing factors: 1) selective intra-arterial deliveryperformed with modern microcatheters, 2) pulsa-tile infusion to overcome streamlining and hetero-geneous delivery, 3) dosage based according to esti-mated local cerebral blood-flow (neither body sur-face area nor area-under-the-curve measurement).These factors allowed us, in a dose escalation study,to infuse very high doses of carboplatin while main-taining low toxicity.MethodsThis study was performed at the University of Cali-fornia, Los Angeles, with the first patient starting inJanuary of 1994 and the last in August of 1995. Thestudy was approved by the UCLA Human SubjectsProtection Committee. The eligibility criteria in-cluded patients who were 18-year of age or olderand had a malignant brain tumor with the contrastenhancement on MRI limited to one hemisphere.Only patients with recurrent or progressive diseasewere included. Recurrent or progressive diseaseswere defined by pathology obtained from a debulk-ing surgery, or by tumor enlargement demonstratedon imaging studies.The primary end-points were the dose escalationand the determination of toxicity. The secondaryend-points included measurements of efficacy. Thedose escalation of carboplatin started at 200 mg perhemisphere and reached 1400 mg per hemisphere.Pre-therapy evaluation included: history and phys-ical, neurologic examination, Karnofsky score,magnetic resonance imaging, audiogram, completeblood count, liver function test, blood urea nitro-gen, creatinine, lytes, magnesium, and routine uri-nalysis.ProceduresEach procedure required a 2-day hospital stay. Theevening prior to treatment, the patient was admit-ted, interim history and physical exam were ob-tained, and hydratation was started at 100 cc/hr.The next morning a foley or condom catheter wasplaced, ondansetron 30 mg intravenously was givenfor antiemitic prophylaxy, and the patient wastransported to the angiosuite. In the angiographicsuite, conscious sedation was given, and one fem-oral artery (alternatively right and left) was punc-tured and catheterized in a standard fashion. Five-thousand units of heparin were given intravenously.A 5 F guiding catheter (Medtronic-MIS, Sunnyvale,CA) was placed


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