Selective intra-arterial chemotherapy with a combination of etoposide and cisplatin for malignant gliomas: Preliminary report

Surg Neural

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1994 ;41 :19-2ƈ

Selective Intra arterial Chemotherapy with a Combination of Etoposide and Cisplatin for Malignant Gliomas : Preliminary Report Hidemitsu Nakagawa, M .D., Toshiaki Fujita, M .D ., Shigeki Kubo, M .D., Koichiro Tsuruzono, M .D., Masanobu Yamada, M.D., Koji Tokiyoshi, M.D., Youji Miyawaki, M .D., Takuji Kanayama, M .D ., Tsuyoshi Kadota, M.D., and Toru Hayakawa, M .D . Department of Neurosurgery and Radiology, The Center for Adult Diseases, Osaka, Osaka University Medical School, Osaka, Japan

Nakagawa H, Fujita T, Kubo S, Tsuruzono K, Yamada M, Tokiyoshi K, Miyawaki Y, Kanayama T, Kadota T, Hayakawa T . Selective intra-arterial chemotherapy with a combination of etoposide and cisplatin for malignant gliomas : preliminary report . Surg Neurol 1994 ;41 :19-2ƈ . We administered selective intra-arterial chemotherapy consisting of a combination of etoposide and cisplatin to 20 patients with malignant glioma (seven with recurrent and six with enlarged tumors after initial treatment, and seven newly diagnosed patients) . Evaluation of efficacy was based on computed tomographic and magnetic resonance imaging findings . In the process of establishing a safe technique for superselective intra-arterial chemotherapy, we encountered cerebrovascular accidents in two patients (after etoposide in one and after etoposide plus cisplatin in the other) . In these two cases, 100 mg/m2 of etoposide and 100 mg/m 2 of cisplatin were delivered via the horizontal segment of the middle cerebral artery (Ml) or the tip of the basilar artery, with the infusion time reduced to 20 minutes . Thereafter, the etoposide was diluted, and the doses of both drugs were reduced to 80 or ƈ0 mg/m2 , and finally to ƈ0 mg/m 2, and both were infused over ƈ0 minutes . In addition, for prevention of local spasm, papaverine hydrochloride and nicardipine were given via the same catheter at ƈminute intervals during administration of etoposide and cisplatin . No complications developed in the later cases . Thereafter, selective intra-arterial infusion of etoposide and cisplatin into the anterior cerebral artery, middle cerebral artery, posterior cerebral artery, or the basilar artery for malignant gliomas in the basal ganglia, internal capsule, and brainstem-a procedure generally considered risky in terms of potential complications-was performed safely, with tolerable side effects . Computed tomography and magnetic resonance imaging indicated improvement in 13 patients, including four whose tuAddress reprint requests to : Hidemirsu Nakagawa, M .D ., Director, Department of Neurosurgery, The Center for Adult Diseases, Osaka, 3 Nakamichi 1-Chome, Higashinari-ku, Osaka ƈ3ƈ, Japan . Received March 24, 1993 ; accepted June 1, 1993 . © 1994 b, Elscrier Science . .c l

mors completely disappeared . This method of intraarterial chemotherapy may be useful as an adjuvant treatment for malignant glioma . Cisplatin ; Etoposide ; Malignant glioma; Selective intra-arterial chemotherapy KEY WORDS :

In recent years, cisplatin (CDDP), which has attracted attention because of its marked anti-tumor effects, has been administered intra-arterially to patients with malignant glioma [ƈ, ƈ,8,13,18,191. Another agent, VP-1ƈ (etoposide), administered intravenously, has demonstrated antitumor effects in patients with brain tumors in a clinical trial [20], but intracarotid administration showed no superiority over intravenous administration [ƈ] . However, combinations of VP-1ƈ and CDDP have been reported to have synergistic effects [2,3,1ƈ], moreover, VP-1ƈ has also been reported to enhance blood-brain permeability in rats [1ƈ1 . We speculated that infusion of VP-1ƈ and CDDP into a major artery directly feeding the tumor results in high local drug concentrations and free CDDP (nonprotein-bound platinum), reportedly the active form of the drug [9,10] . The drug may thus be delivered to the tumor area in higher amounts than by intravenous administration, and moreover, the drug concentration will be higher than that achieved by intra-arterial infusion of CDDP alone, because the intra-arterial infusion of VP1ƈ modifies the blood-brain barrier . Although selective intra-arterial (IA) chemotherapy has been facilitated by recent improvements in catheter design, the safety of this therapy remains a problem . We describe our experience with selective IA chemotherapy with etoposide and cisplatin and discuss its benefits and drawbacks .

Patients and Methods The study population (Tables 1 and 2) consisted of 20 patients with malignant glioma who had initially received 0090-3019/94/ƈƈ-00



20

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1994 ;41 :19-2ƈ

Table 1 . Study Population Pt. no .

Age/ Se,

Recurrent or enlarged glioma 1 ƈ2/M 2 1ƈ/M ƈƈ/F 3 4 31/F ƈ ƈ ƈ 8 9 10 11 12 13

43/M 20/F 33/F ƈ0/F 4ƈ/M 44/F 48/M ƈƈ/M ƈ1/F

Initially treated glioma 14 ƈƈ/M 1ƈ 1ƈ 1ƈ 18 19 20

ƈ3/M ƈƈ/M 49/F 48/M ƈ01F ƈ2/F

Pathology at study entry

Tumor location

Temporal-parietal-basal ganglia Third ventricle-basal ganglia Temporal-Parietal Frontal-basal ganglia Parietal-basal ganglia Midbrain Frontal-temporal-basal ganglia Splenium-bilateral occipital Midbrain-thalamus Thalamus-midbrain Temporal-parietal-basal ganglia Temporal-parieral-basal ganglia Temporal-basal ganglia

Corpus callosum, temporal Temporal-basal ganglia Temporal-basal ganglia Corpus callosum, temporal Temporal-parietal Temporal-basal ganglia Temporal-basal ganglia

Tumor characteristics

GB GB GB GB GB AA" AA GB GB GB GB

Recurrent Recurrent Recurrent Recurrent Enlarged Enlarged Enlarged

GB GB

Enlarged Recurrent

Enlarged Recurrent Recurrent Enlarged

GB AA AA GB GB GB AA

Abbreviation

GB, glioblastoma ; AA, anaplastic astrocytoma . ' histologic diagnosis was confirmed by autopsy .

intravenous or intracarotid ACNU therapy alone or in combination with radiation therapy, but whose tumors had subsequently enlarged or recurred and seven patients with malignant glioma who had had non pre-adjuvant therapy . Patients who received intra-arterial (IA) chemotherapy are serially numbered in tables (Tables 1-ƈ) . Informed consent was obtained from either the patients or their families . IA infusion ofetoposide [ƈ0 to 100 mg/m 2 (20 mg/mL)] was followed by IA infusion or cisplatin [ƈ0 to 100 mglm 2 (0 .ƈ mg/mL)] via a microcatheter (Tracker18 catheter, Target Therapeutic Co, CA, USA ; Balt Catheter Magic, Japan Mallinkrodt Co, Tokyo) . Details are given in Table 3 . The pulsed injection was given manually rather than with a pump . Heparin was administered just before drug infusion (ƈ000 U) and at 30-minute intervals during infusion (1000 U) ; the drugs were passed through 0.22-/gm filters at the time of infusion . After drug administration, betamethasone (Rinderon ; 24 mg/d) was given for 2 days, with the dosage being gradually reduced over the next ƈ days . In addition, 20% mannitol (200 mL) was infused over a 1ƈ-minute period, and the fluid volume of electrolyte was adjusted so as to maintain a urine output of 100 mL/h for I week . IA chemotherapy was administered twice, at 2-week intervals in the 13 recurrent gliomas . In the three nonrecurrent gliomas (patients 14, 1ƈ, and 18), infusion was performed alternately in two different main feeding arteries at 2-week intervals . The effects of the

treatment were evaluated 2 weeks after the second course of chemotherapy, on the basis of computed tomography (CT) and magnetic resonance imaging (MRI) findings . The response to chemotherapy was rated by changes in size on CT and MRI : complete remission (CR), no evidence of tumor ; partial remission (PR), more than ƈ0% reduction in the sum of the maximum two-dimensional measurements; minor remission (MR), less than ƈ0% reduction in the sum of the maximum two-dimensional measurements ; stable, no change in size . Hematologic analysis was conducted weekly ; standard WHO criteria were used for myelosuppression evaluation . Creatinine was measured weekly and creatinine clearance was measured before and 2 weeks after chemotherapy. Assessment of auditory function was based on the ability to appreciate normal conversational tones ; audiometry was not used. Tinnitus was considered to be a manifestation of ototoxicity.

Results Establishment of Safe Supers elective Intra-arterial Chemotherapy with Etoposide and Cisplatin and Outline of all Intra-arterial Chemotherapy Protocols (Table 3) Drug infusion into the anterior and middle cerebral artery (ACA-MCA) bifurcation was performed in pa-



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Intra-arterial Chemotherapy of Malignant Glioma

Table 2 . History of Treatment of Malignant Glioma Pt . no .

A : Previous chemotherapy/ irradiation

Recurrent or enlarged glioma 1 ACNU 100 mg/m2 i .a . x 4 Liniac ƈ0 Gy (W) 2 ACNU 100 mg/m2 i .a. x 3 Liniac ƈ0 Gy (W) + 20 Gy (L) ACNU 10 mg/kg i .a . + ABMT (b) Liniac ƈ0 Gv (W) MeCCNU 100 mglm2 p .o. x 22 Liniac ƈ0 Gy (W) (c) ACNU 80 mg/m2 i.v . x 4 (c) Liniac 2ƈ Gy (L) ACNU 10 mg/kg i.a. + ABMT (b) ƈ ƈ ACNU 100 mg/m2 i .v . X 2 Liniac ƈ0 Gy ACNLI 100 mg/m2 x 2 Liniac ƈ0 Gy (W) + 20 Gy (L) 8 ACNLI 80 mg/m2 i .a. x 2 9 Liniac ƈ0 Gy (L) (c) ACNU 80 mg/m2 i .v . X 1 (c) ACNU 30 mglm2 i .ai x 3 (c) Liniac 40 Gv (L) (c) Carboplatin 310 mg i .v . X 2 (c) etoposide (ƈ0 mg x ƈ, p .o .) x 2 10 ACNU 80 mg/m2 t .v . X 2 Liniac ƈ0 Gy 11 ACNU 80 rig/m2 Lv . X 2 Liniac 40 Gy (W) + 20 Gy (L) 12 ACNU 80 mg/m2 i .v . x 2 13 ACNLI 80 mg/m2 i .a . X I Initially treated glioma 14 1ƈ 1ƈ 1ƈ

B : Surgery

prior to study

19 20

Interval to study entry from B (weeks)

None ƈ

PR

ƈ

None

ƈ2

PR

2

8

2 2

PR None None

1

48 ƈ

None None

ƈ .ƈ

None

1 .ƈ

PR

2

1

None PR

2

3

PR PR PR BS PR PR PR

18

Abbeviati,oo: (W), whole

Interval to study entry from A (months)

8

3 2 2 2 2 3

brain ; 0.), local ; PR, partial resection ; BS, biopsy ; ABMT, autologous bone marrow transplantation : lc), therapy at first recurrence .

tients 1-4 . There were no ophthalmological, otolaryngological, or other complications in these patients . Patient ƈ had had a recurrence after previous IA infusion of 10 mg/kg of ACNU into the horizontal segment of the MCA (M I) in combination with an autologous bone marrow transplant . He had left hemiplegia when IA chemotherapy with etoposide and cisplatin was performed, and no new neurologic symptoms developed after this chemotherapy . Patient ƈ, who had a rapidly progressing midbrain glioma, received IA infusion into the vertebral artery slightly peripheral to the bifurcation of the posterior inferior cerebellar artery and experienced no complications, including hearing impairment or hemiparalysis . Patient ƈ, whose tumor extended from the temporal

lobe to the cerebral basal ganglia, developed slight dysarthria and right hemiplegia after infusion of 100 mg/M 2 of etoposide into the M1 . Initially, it was thought that these symptoms were the sequelae of an epileptic seizure, because she had had a seizure 2 days previously and the chemotherapy had been completed . Despite treatment with high-dose urokinase and steroids, a lowdensity area persisted on the CT scan in the lenticulostriate area. Because the tumor had infiltrated this area, a cerebral infarction was suspected . The patient's speech was largely restored with rehabilitation . In this case, shortening of the infusion time from 30 to 20 minutes (which had been unavoidable) and the use of an undiluted etoposide solution may have been responsible for the cerebral infarction .



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Table 3 . Acute Complications of Intra-arterial Chemotherapy Pt. no .

Dose (mglmt)

Infusion time (minutes)

Point of catheter insertion

Recurrent or enlarged glioma 1 100 (E, P) 2 100 (E, P) 3 100 (E, P) 4 100 (E, P) ƈ 100 (E, P) ƈ 100 (E, P) ƈ 100 (E, P) 100 (E, P) 8 80 (E, P) 9 10 a 80 (ƈ0) (E, P) 11 ƈ0 (E, P) 12 ƈ0 (E, P) 13 ƈ0 (E, P)

30 each 30 each 30 each 30 each 30 each 30 each 20 (E) 20 each ƈ0 each ƈ0 each ƈ0 each ƈ0 each ƈ0 each

ICA ICA ICA ICA MCA VA MCA BA BA BA MCA MCA MCA

Initially treated glioma 14 ƈ0 (E, P) ƈ0 (E, P) 1ƈ 1ƈ ƈ0 (E, P) 1ƈ ƈ0 (E, P) 18 ƈ0 (E, P) 19 ƈ0 (E, P) 20 ƈ0 (E, P)

ƈ0 ƈ0 ƈ0 ƈ0 ƈ0 ƈ0 ƈ0

ACA (Al), BA MCA (Ml) MCA (Ml) ACA (Al), PCA (P1/2) Ant choroid, BA MCA (MI) MCA (Ml)

each each each each each each each

Complications

None None None None None None CA CA D .O.C . None None None None

(M I) (Ml)

(Ml) (Ml) (Ml)

D .O .C . None None Seizures None None None

Abbrwiation: E, etoposide ; P, cisplatin ; ICA, internal carotid artery ; MCA, middle cerebral artery ; VA, vertebral artery ; BA, basilar artery ; ACA, anterior cerebral artery ; PCA, posterior cerebral artery ; Ant choroid, anterior choroidal artery ; CA, cerebral infarction ; D .O .C., decreased level of consciousness . -Doses of the second infusion were reduced due to myelosuppression .

Table 4 . Response to It ntra-arterial Chemotherapy Pt. no .

Number of chemo. courses

Pre-Post-treatment Pƈ(KS)

CT and MR1 response

Duration of response (months)

Remarks (time is interval from study entry)

Recurrent or enlarged glioma 2 2 2 2 2 1 1 1 2 2 2 2

ƈ0-> ƈ0 ƈ0 , ƈ0 40 -* 40 30-> 30 20 , 20 40-40 ƈ0 -r 40 40-s 20 20-s 20 20-r 20 40 y 40 ƈ0-, ƈ0 40 -+ ƈ0

ST ST PR ST MR ST MR MR CR MR ST ST CR

2 .0 ƈ.0 2 .0 2 .0 ƈ .ƈ 18 .0 14 .0 N.E . 0.ƈ 1 .ƈ 4.0 4 .0 3 .0

died ƈ m regrew at ƈ m died ƈ m died ƈ m died 11 m died 20 m stable 18 m died 4 m (a) died 2 w (b) died 3 w (c) stable 13 m died ƈ .ƈ m died 4 m

Initially treated glioma 14 4 1ƈ 2 1ƈ 3 4 1ƈ 4 18 19 2 20 2

30- 30 ƈ0 -s ƈ0 ƈ0 , ƈ0 ƈ0 , ƈ0 40,40 ƈ0-ƈ0 ƈ0, ƈ0

MR N. E. CR PR MR CR PR

ƈ .0 N .E. ƈ .ƈ ƈ .0 10.0 4 .0 2 .ƈ

died ƈ m (d) died 13 days (e) died 10 m stable for ƈ m stable for 12 m recurred 4 m stable for 4 m

2 3 4 ƈ ƈ ƈ 8 9 10 li 12 13

Abbreviations : PS, performance status ; KS, Karnofsky Scale (percentage) ; CT, computed tomography ; MRI, magnetic resonance imaging; ST, stable disease; PR, partial response ; MR, minor response ; CR, complete response ; N .E., not evaluable ; m, months ; w, weeks; (a), of pneumonia; (b), of pulmonary embolism ; (c), of bemothorax (iatrogenic); (d), of pneumonia due to methydlin resistance staphylococcus aureus; (e), of peritonitis due to perforation of a duodenal ulcer .



Table ƈ . Toxic Pt. no.

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Intra-arterial Chemotherapy of Malignant Glioma

Effects of Intra-arterial Chemotherapy

Nausea and vomiting (WHO grade 0-4)

Myelosuppression grade 0-4)

Otomxicity

(WHO

Renal toxicity

Seizures (pmt-infusion) No

Recurrent or enlarged glioma 1

2

2

3

3 4 ƈ ƈ

1 0 0 1

ƈ

3

8 9 10 11 12 13

1 0 0 0 0 1

Initially treated glioma 14 1ƈ 1ƈ 1ƈ 18 19 20

0 1 1 1 2 0 2

No No N .E. N .E. N .E. No No N .E . N.E . N.E . No No No

Le (2), th (0), an (0) Le (2), rh (0), an (0) Le (3), th (0), an (2) Le (3), th (0), an (3) Le (0), rh (1), an (2) Le (4), th (4), an (3) Le (3), rh (0), an (0) Le (1), th (0), an (0) Le (2), th (1), an (0) Le (4), th (4), an (1) Le (2), th (0), an (2) Le (0), th (0), an (2) Le (2), th (0), an (3)

No No No No No No No No No No No

No No No No No No No

Le Le Le Le Le Le Le

No No No No No No No

(2), th (1), an (0), th (0), an (0), th (0), an (0), th (1), an (0), th (0), an (2), th (0), an (0), rh (0), an

(2) (2) (2) (2) (0) (3) (1)

Yes Yes

Yes No No

Yes No No No No No No No

Yes Yes No

Yes No No No

Yes

Le, Leukopenia ; th, tromhocytopenia; an, anemia. were evaluated after IA chemotherapy and weekly thereafter . Seizures were temporary and well controlled . Myelosuppression was evaluated after two courses of chemotherapy in patients 14, 1ƈ, and 18 . Abbreviations : Toxic effects

Patient 8 had a glioblastoma extending bilaterally from the splenium to the occipital lobe . After IA infusion of both drugs into the basilar artery, this patient showed a slight decrease in the level of consciousness, as well as right hemiplegia . Although a CT scan showed no evidence of infarction, when the patient died 2 months later, an autopsy disclosed an infarction in the perforating branch area in the pons, which was probably due to the IA therapy . In this patient, also, the infusion time had been reduced to 20 minutes, and an undiluted etoposide solution had been used . Because of these two experiences, when we treated patients 9 and 10 whose tumors extended from the left midbrain to the thalamus, we lowered the doses of both drugs to 80 Mg/M2, diluted the etoposide to 1 : 20 with physiologic saline, and conducted the infusion (into the basilar artery) over a ƈ0-minute period . In addition, to prevent the possible induction of vasospasm by the drugs, we prepared 12 mL of a dilute mixture of papaverme hydrochloride (1 ampule : 1 mL) and nicardipine (Perdipine 2 mg: 2 mL) and infused 1 mL of this mixture every ƈ minutes during drug administration . CT scans obtained on the following day showed an increase in low density in the area corresponding to the tumor, but no evidence of infarction . Patients 11 and 12, who had temporoparietal glioblastomas involving the basal gan-

glia, received diluted etoposide and cisplatin (ƈ0 mg/m' each) delivered into the M I over a ƈ0-minute period, along with intermittent spasm prophylaxis, as described above . After treatment, there was an increase in low density in the region of the residual tumor, but there were no complications . Patient 13, who had a temporal tumor extending to the insula and basal ganglia, received the same infusion (ƈ0 mg/m' each of etoposide and cisplatin), also without incident . Selective intra-arterial chemotherapy was then administered to the seven patients undergoing initial treatment of malignant gliomas (patients 14-20). In three of these seven patients, whose tumors had two main feeding arterial trunks, intra-arterial infusion was performed alternately in the two different arteries at 2-week intervals . The first intra-arterial infusion was into the ACA (A1 : the horizontal segment of the ACA) in patients 14 and 1ƈ and the anterior choroidal artery in patient 18 . The second infusion given after a 2-week interval, was into the basilar tip in patients 14 and 18 and into the posterior cerebral artery (P1 : the segment of the PCA from its origin to the posterior communicating artery, and P2 : the portion of the PCA from the posterior communicating artery to the origin of the inferior temporal arteries) in patient 1ƈ . Thus, each intra-arterial infusion was performed twice . These selective intra-arterial chemotherapies were



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Figure 1 . Single intra-arterial infusion of etoposide and cifplatin at the tip of the basilar artery in patient 9 . who bad recurrent glioma, discloses disappearance of the tumor 2 weeks after the chemotherapy . Digital subtraction angiography just before infusion ( ) demonstrates the tip of the microcatheter and tumor shadow .

also performed safely, without production of new neurologic deficits . However, three of the seven patients who had intra-arterial infusion at the basilar tip showed a slight decrease in the level of consciousness that lasted for 2 weeks . Effectiveness of Therapy (Table 4) Performance status, as assessed with the Karnofsky Scale [12] improved in only two patients (numbers 13 and 20). Patient 13, who had a recurrent glioma, became ambulatory to a small extent, for a short period after IA drug infusion . The two patients who had cerebral infarctions during the chemotherapy, and one other patient (number 1ƈ), showed a decrease in performance status . The level of consciousness grossly improved in seven patients, and mild hemiparesis present before treatment improved in five . CT and MRI indicated improvement in 13 patients . The tumor volume decreased by less than ƈ0% in six patients and by ƈ0% or more in three . In patients 9 (Figure 1), 13, 1ƈ, and 19 (Figure 2), the tumor was completely absent on posttreatment

Nakagawa et al

CT scans . In six patients, the tumor size was unchanged 2 weeks after treatment . However, in patient 12, central necrosis was marked, involving all areas except the tumor margins and resulting in alleviation of the compression and deformation of the lateral ventricle . Complications and Side Effects (Tables 3-ƈ) Five of the 20 patients developed neurologic complications (Table 3), and two died as a result of treatment (Table 4) . Moderate, transient myelosuppression occurred in all patients, regardless of drug dosage . Combinations of leukopenia, thrombocytopenia, and anemia were frequently encountered. Leukopenia was marked in the 13 patients with recurrent or enlarged tumors, five of whom had leukocyte counts of less than 2000 cells/mm 3 , and in two patients the platelet count was less than ƈ0,000 cells/mm 3. On the other hand, in the initially treated glioma group, two patient showed leukopenia of less than 3000 cells/mm 3 . Anemia was also a common side effect, observed in eight of the 13 recurrent or enlarged patients and six of the seven initially treated patients . Nausea and vomiting occurred in seven of the 13 patients in the recurrent or enlarged glioma group who received drug doses of ƈ0 to 100 mg/m °. However, neither of the two patients given doses of ƈ0 mg/m' experienced gastrointestinal distress . In the initially



Intra-arterial Chemotherapy of Malignant Glioma

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treated glioma group, five of the seven patients developed slight to moderate nausea and vomiting at the first chemotherapy . However, this side effect was prevented in the second chemotherapy session by intravenous administration of Granisetron Hydrochloride (Kytril ®, SmithKline Beecham-p .l .c.) just before chemotherapy . There was little change in creatinine clearance after IA chemotherapy . One patient, in whom creatinine clearance was decreased before treatment, exhibited mild renal failure and required diuretics after chemotherapy . Ototoxicity was not observed in any of patients . Treatment-related seizures were observed during intraarterial infusion in one patient and after chemotherapy in six patients . However, none showed a persistent convulsion, and seizures were well controlled with anticonvulsants . Discussion Many studies of IA chemotherapy for malignant glioma have been conducted, but none have clearly shown its superiority over IV chemotherapy . Rather, such side effects as ocular toxicity have attracted attention [19] . IA cisplatin therapy for malignant gliomas was first reported in 1982 by Stewart et al [ 191, and its effectiveness was noted by Feun et al [ƈ] in 1984 . The reported response rate varies from about 30% [ƈ] to ƈ0% [13] . Madajewicz et al [1ƈ] treated 20 patients with malignant

Figure 2 . Digital subtraction angiography through a micro catheter placed at the MI portion of the middle cerebral artery just before infra-arterial chemotherapy in patient 19, and CT scans before and 2 weeks after two sessions of intra-arterial chemotherapy with etoposide and cisplatin are shown . Disappearance of the tumor, which extended from the temporal lobe to the basal ganglia, is observed .

glioma with IA etoposide and cisplatin alone and reported positive responses in eight . However, this response rate is no higher than that obtained with conventional therapy with BCNU . In our study, the neurologic grade improved in eight of the 20 patients ; the tumor substantially decreased in size in eight and completely disappeared in four. Despite radiologic evidence of tumor response in 13 of the 20 patients, only two patient displayed improvement on the Karnofsky assessment [12] of performance status . Moreover, tumor regression was not usually accompanied by amelioration of neurologic deficits . In many of our patients, brain damage caused by the tumor had resulted in severe neurologic and emotional impairment prior to IA chemotherapy, so that the tumor reduction was not sufficient to restore the lost functions . This is not uncommon in patients treated for recurrent or enlarging glioma. Nevertheless, we feel that this treatment approach has great potential . After cerebral infarction was identified as a treatment complication, in patient ƈ, we halved the doses of both etoposide and cisplatin (to ƈ0 mg/m2) for infusion into



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the M1 and reduced the dose by 40% (to ƈ0 mg/m 2 ) for infusion into the ACA-MCA bifurcation . The latter reduction was lower because the dose is split at the ACA-MCA bifurcation . Kapp and Sanford [11] asserted that a dose of at least ƈ9 mg/m2 was needed to obtain anti-tumor effects . However, their report described infusion into the internal carotid artery . A dose of ƈ0 mg/ In2 would seem to be adequate for infusion into the MI . For the basilar artery, the dose should be slightly higher, as this artery branches, into two posterior cerebral arteries; however, the dose should be lower than 100 mg/ m2 in the interest of avoiding cerebrovascular complications . Thus, for the basilar artery, we decided on a dose of 80 mg/m2. With our revised doses, we encountered no severe side effects or complications, and these doses also appeared to be optimal in terms of tumor response . Various measures have been taken to prevent complications due to IA chemotherapy, including IA injection of steroids [11) and heparin [19], filtration of the drugs [11,13], and changing the duration of administration according to drug distribution [1) . Kapp and Sanford [11] obtained a response rate of 83% after IA administration of cisplatin (ƈ0 to 200 mg) plus BCNU (300 mg) but observed hemiplegia in 23 % of their patients . Their analysis of risks associated with IA chemotherapy suggested that the incidence of hemiplegia was reduced by filtration and streaming [1,141 and the use of pulsatile bolus infusions to reduce the problem of laminar flow [4], but not by preinfusion of steroids . They also noted that the dose should be reduced in patients with diffuse tumor infiltration of the internal capsule . In our experience, paralysis was not induced by superselective IA therapy with a normal dose of the nitrosourea ACNU (unpublished data) . Thus, we believe that in the patients studied by Kapp and Sanford [11) the paralysis may have been induced not by BCNU but by cisplatin . Their findings, together with our own data, imply that the problem we experienced in our Patient ƈ could have been due to the use of an undiluted etoposide solution, the high dose, the short infusion time, and the fact that the tumor had extended to the cerebral basal ganglia and internal capsule (drug filtration and pulsatile bolus infusion were used in this case) . The posttreatment hemiparesis in patient 8 was also attributed to these treatment conditions . In subsequent patients, drug dilution, lower doses, and longer periods of administration, combined with intermittent IA infusion of nicardipine and papaverine hydrochloride, yielded good results . We feel that the duration of infusion, which is dependent on the drug dose, is particularly important . The usual duration for etoposide and cisplatin is 30 minutes for each agent . In our study, an infusion duration of 20 minutes may have been responsible for serious complications . Cisplatin requires a slower rate of infusion than that required for nitrosourea agents . The reported optimal infusion

Nakagawa et al

rates for cisplatin are about 3 .3 mg/min (12) or 100 mg/ m 2 over 1 hour [ 13,19) . For a combination of ƈ0 to 120 mg/m2 of BCNU and 40-ƈ0 mg/m2 of cisplatin, 30- to ƈ0-minute infusion has been used [8] . The highest reported rate was ƈ0 mg/m2 over about 20 minutes [ 18]. In our study, the five patients who received etoposide and cisplatin over a 1-hour period experienced an increase in edema at the tumor site, but there was no evidence of infarction. We conclude that good results are dependent on a sufficiently long infusion time . Of the various complications that may arise on infusion into the vertebral artery, hearing disturbance [13) and possible cardiovascular effects are of particular concern . We used this route in only one patient, without incident . The prophylaxis described above, except for the intermittent infusion of nicardipine and papaverine hydrochloride, was applied in this case, but it is unclear whether or not the absence of complications was related to these measures . More research on vertebral artery infusion is needed . The incidence of myelosuppression was higher than that caused by administration of cisplatin alone, implying that the addition of etoposide was a significant factor . However, the myelosuppressive effect was milder at the lower doses, especially at ƈ0 mg/ma . Otic, renal, and central nervous system toxicity were minimal and were of concern only in patients with preexisting hearing or renal impairment . This study yielded two major findings . One is that survival time was not prolonged in spite of a high rate of improvement according to CT and/or MRJ . This indicates a need for effective maintenance therapy after intra-arterial chemotherapy . The other is that tumor cells with no sensitivity to etoposide and/or cisplatin do not respond to this therapy, even though higher concentrations of these anti-cancer drugs reach the tumor area. The sensitivity of malignant glioma to anti-cancer drugs must be tested further. We conclude that superselective infusion (into the basilar tip, Al, M1 or Pl/2) of etoposide and cisplatin, each at a dose of ƈ0 to ƈ0 mg/m 2 each, over periods of ƈ0 minutes orlonger is safe, provided that along infusion time is used, the etoposide is diluted, and drug administration is accompanied by intermittent IA infusion of papaverine hydrochloride and nicardipine . With further study and refinement, IA chemotherapy may provide significant benefit to patients with malignant glioma . This work was supported in part by grants-in-aid for scientific research on cancer from the Japanese Ministry of Health and Welfare (2-14).

References 1 . Blacklock JB, Wright DC, Dedrick RL, Blasberg RG, Lutz RJ, Doppman JL, Oldfield EH . Drug streaming during intraarterial chemotherapy . J Neurosurg 198ƈ ;ƈ4 :284-91 .



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