Journal of Neuro-Oncology, 1:211 218 (1983) © Martinus Nijhoff Publishers. Printed in the Netherlands

Intra-arterial B C N U in the treatment o f metastatic brain t u m o r s Terrence L. Cascino,J Thomas N. Byrne, Michael D. F. Deck & Jerome B. Posner

Departments of Neurology and Radiology, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York City, New York, USA ~Present address: Mayo Clinic, Rochester, Minnesota, USA

Keywords: metastasis, brain tumor, chemotherapy, intra-arterial chemotherapy

Abstract Thirty-one patients with metastatic brain tumors that either failed to respond or recurred after conventional therapy were treated by intra-arterial infusion of 100 m g / m 2 of 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) into either a carotid or vertebral artery. Five patients (three with lung cancer, one with breast cancer and one with melanoma) had a partial response of the tumor(s) in the distribution of the injected artery. In two patients, brain metastases not in the distribution of the injected artery enlarged, while the tumors perfused by the injected artery responded. In one of these patients, subsequent infusion of BCNU to the enlarging tumor resulted in a partial response. A m o n g responders, the median survival following onset of BCNU was 17 weeks. One patient remains alive and well at 30 weeks. No permanent neurological, retinal or systemic toxicity was observed.

Introduction Conventional therapy of metastatic brain tumors is often unsatisfactory. Metastatic brain tumors often are multiple and occur late in the course of systemic cancer when widespread metastases outside the nervous system are also present. These two facts eliminate most patients from consideration for surgical extirpation. Radiation therapy is effective palliation for some patients with metastatic brain tumors, but in some the tumors either fail to respond or recur in weeks to months. Chemotherapy by the oral or intravenous route is generally considered to be ineffective, although there are few data in the literature supporting this widely held belief. If, in fact, metastatic brain tumors are resistant to conventional chemotherapy, inadequate drug delivery may be one potential cause (1). In order to improve drug delivery, several investigators have undertaken studies of intra-arterial infusions of chemotherapeutic agents for malignant

brain tumors (2 5). These trials were prompted by the predictions of enhanced tumor drug exposure in the mathematical model reported by Fenstermacher and Cowles (6) and the observed increase in BCNU uptake in the brain of squirrel monkeys after the intracarotid administration of drug as compared to intravenous infusion (7). Based on the studies of intracarotid administration of 1,3-bis (2-chloroethyl)-l-nitrosourea (BCNU) in monkeys (7, 8) and the preliminary results in humans treated for metastatic brain tumors (9), we undertook a study of intra-arterial BCNU for the treatment of brain metastases that had failed to respond or recurred following conventional therapy.

Methods Patients with metastatic brain tumors seen between March 1979 and June 1982 at Memorial

Addressfor reprints: Dr. Jerome B. Posner, 1275 York Avenue, New York, NY 10021, USA

212 Sloan-Kettering Cancer Center (MSKCC) who had failed conventional therapy, including radiation therapy (RT) a n d / o r systemic chemotherapy, were eligible for protocol. All patients had increasing neurological symptoms and signs due to residual a n d / o r recurrent brain metastasis. Intra-arterial chemotherapy was administered via the carotid or vertebral artery, depending on the arterial distribution of the single brain metastasis selected for treatment. In cases where the patient had multiple brain metastases, the largest a n d / o r the most symptomatic brain metastasis was treated. BCNU was administered at a dose of 100 m g / m 2 by infusion. The drug was dissolved in 1.5 ml of absolute ethanol per 100 mg and then added to normal saline to make a total volume of 50 ml. The internal carotid or vertebral artery was catheterized under fluoroscopic control via the femoral artery. (In some patients arteriography was performed prior to drug infusion.) The effect of the contrast agent on the blood brain barrier and its potential effect on distribution of the chemotherapeutic agent in tumor and normal brain are unknown.) The drug was infused by way of a Medrad injector (Medrad Corp., Pittsburgh, Pa.) at a rate of 3-4 ml/min for the carotid artery and a rate of 2 ml/min for the vertebral artery. Complete blood counts were measured prior to each injection. Only patients with WBC > 3000 and platelets > 100000 were treated. Follow-up CT scans of the head and clinical examinations were performed 4-5 weeks post-treatment. Patients were eligible for repeat injection every 5 6 weeks. A CT scan of the head, clinical examination and blood count were performed prior to each injection.

Results Intra-arterial BCNU was administered to 31 patients. Patients ranged in age from 26 to 75 yrs (median 53 yrs). There were 18 men and 13 women. In all patients except one, the primary cancer had been identified at the time of neurological presentation. One patient had biopsy proved adenocarcin o m a in the brain of unknown primary origin. The underlying primary cancers in the other 30 patients varied, with the majority (52%) harboring non-oat cell carcinoma of the lung (Table 1). All patients had failed previous treatment for

Table l

Primary tumor Number of patients

Lung cancer (non-oat cell) Breast cancer Melanoma Genitourinary cancer Colon cancer Esophageal cancer Unknown primary Total

16 3 5 3 2 1 1 31

brain metastasis. Twenty-six patients had been treated with whole-brain RT (3000 rad in 6 fractions) prior to receiving intra-arterial chemotherapy. Thirteen of the 26 (50%) patients were judged by CT scan and clinical examination to have no response to RT. Six patients (23%) were judged to have more than a 50% decrease in the size of the brain metastasis on CT scan. An additional seven patients (27%) had a complete response on CT scan after RT. Patients were then begun on intra-arterial chemotherapy for residual symptomatic disease or, in the cases of RT responders, for recurrent disease. Surgical extirpation was performed in five patients as the initial therapy. Three of these patients received subsequent RT. All patients were thought to have an initial good response to extirpation. Three of the five patients later had t u m o r recurrence at the surgical site and were then begun on intraarterial chemotherapy. One patient developed a second brain metastasis in a site different from the surgical site. The fifth patient was judged by surgical observation and CT scan to have residual postoperative tumor and was begun on chemotherapy for this purpose. T w o patients with colon carcinoma were t r e a t e d with systemic chemotherapy alone as the initial treatment for their brain metastasis. Both were begun on methotrexate, oncovin, 5-FU and streptozotocin but neither patient responded. In all, 12 of 31 patients had previous chemotherapy (nine patients for advancing systemic disease). CNS response to systemic chemotherapy was not demonstrated in any patient. All patients had been off chemotherapy for several months prior to the institution of intra-arterial chemotherapy. The median time from the institution of initial therapy to recurrence and institution of intra-arterial BCNU was 31 weeks (range 2-104 weeks).

213 Intracarotid BCNU was administered to 27 patients for a total of 42 treatments. Intravertebral drug was given to four patients for a total of six treatments. A single dose of BCNU was administered in 20 patients, while 11 patients received multiple doses. The various reasons for patients receiving only one dose are outlined in Table 2. The most c o m m o n reason for halting therapy after one dose was rapidly advancing systemic disease. Four of these patients were taken off protocol due to rapidly progressing symptoms from a brain metastasis. Two of these patients elected to undergo surgical extirpation rather than to continue with intra-arterial chemotherapy. Follow-up CT scans were done in 23 of the 31 patients. The remaining patients either died or were

Table2. Reasons for receiving only one intra-arterial treatment. N u m b e r of patients Increasing systemic disease Did not return (no improvement) Increased CNS disease (surgical extirpation in two patients) Side effects (transient deficits) Died Refused On study

Total

7 4 4

2 1 1 1 20

too ill from systemic disease to return for follow-up scan. Of the 23 patients who had follow-up scans, five patients were judged to have a definite response following intra-arterial chemotherapy ( > 50% decrease in the size of the tumor) (Figs. ! & 2). Two of these patients had adenocarcinoma of the lung, one anaplastic large cell carcinoma of the lung, one breast cancer and one melanoma (Table 3). All those who responded (responders) had significant reduction in the size of the tumor on CT scan one month after the initial injection of BCNU. The CT scan improvement continued while treatment continued. Definite clinical improvement was seen in four of the five patients. One patient with multiple bilateral lesions was not clearly improved clinically. All were on stable or decreasing dosages of dexamethasone at the time of follow-up CT scan. All those who responded to the intra-arterial therapy had undergone RT as their initial treatment. One patient had had a complete response to RT, three patients partial responses and one patient no response. All were deteriorating both by CT scan and on clinical examination prior to intra-arterial BCNU. The median time from RT to BCNU infusion was 26 weeks (16-104 weeks). None of the responding patients were on any other form of treatment which would account for tumor response. Only one patient had had prior chemotherapy and that for breast cancer with minimal effect. Responders lived a median of 17 weeks after

Table 3. Responders to BCNU. Primary tumor

Previous treatment a and response b

1. A d e n o c a r c i n o m a (lung) 2. A d e n o c a r c i n o m a (lung) 3, Breast cancer 4. Large cell (Ca lung) 5. M e l a n o m a

a b c d e

Interval: treatment to BCNU

Metastases'. no. c and site

BCNU infusions: no. and sited

Interval: BCNU to death

CT response b Clinical to BCNU response b to BCNU

RT-PR

30 weeks

M-bifrontal

5-1CA

alive

PR

PR

RT PR

23 weeks

S-cerebral

2-1CA

17 weeks

PR

PR

RT-CR RT PR

104 weeks 26 weeks

S-cerebellar M-cerebral

I-IVA 4-1CA

12 weeks 14 weeks

PR PR

PR PR

16 weeks

M-cerebral

2-1CA

20 weeks

PR

none

RT-none

Whole-brain radiation therapy. C R - complete response; P R - partial response. M = multiple; S = single. I C A = intracarotid artery; IVA = intravertebral artery. Responses only occurred in t u m o r s perfused by injected artery.

214

Fig. 1. A 45-year-old w o m a n (patient #4 of Table 3) with large cell carcinoma of the lung and brain metastases treated with whole-brain radiation therapy. Twenty weeks after RT she developed symptoms and CT evidence of a left recurrent frontal tumor, a) (top, left) CT scan prior to first left internal carotid infusion of BCNU; b) (top, right) CT scan six weeks later and prior to second BCNU infusion; c) (bottom, left) CT scan four weeks after the second infusion.

intra-arterial BCNU therapy (range 14 30+ weeks). One patient died of a combination of systemic cancer and meningeal metastasis. One patient who responded to ipsilateral injection died from cerebral herniation secondary to contralateral brain metastasis.

Two of the five responders had bilateral cerebral metastases (patients #1 and #5 of Table 3). In both there was regression of the t u m o r ipsilateral to the infusion only. Both patients over the course of treatment developed increasing tumor on the contralateral side. Both patients were then treated on the contralateral side with intra-arterial injection. One patient died before a definite response could be seen on the contralateral side (patient #5). The remaining patient (patient # 1) had a definite response after treatment of the contralateral tumor by intracarotid infusion of that side (Fig. 2). Complications of the treatment included pain in the distribution of the injected vessel. In the case of intracarotid injection, ipsilateral eye pain occurred during the time of injection only. This pain disappeared 30-60 sec after the injection was completed. Patients who received an intravertebral injection developed neck and occipital pain which also dis-

215 appeared a brief time after the injection was stopped. The pain was controlled with intravenous morphine (10-20 mg). Two patients developed transient neurological deficits while the injection was underway. In both patients the deficits resolved after the injection was completed. One patient developed bone marrow toxicity (thrombocytopenia, leukopenia and anemia) three weeks after treatment. This patient had had previous~ treatment with cyclophosphamide, methotrexate and 5-FU for breast cancer. In addition, she was found to have metastatic tumor in her bone marrow. This patient was taken off protocol due to her pancytopenia. No patient suffered either blindness or retinopathy (2).

Discussion

Intra-arterial infusion of chemotherapy for primary and metastatic brain tumors were performed with a variety of chemotherapeutic agents in the 1950's and 1960's (10). The results of these studies were not encouraging. Most of the agents that were available and studied at that time, however, have been superceded by more effective drugs and this fact has prompted a re-evaluation of intra-arterial infusions of chemotherapy. The theoretical advantages of intra-arterial chemotherapy for brain tumors have been studied by Fenstermacher & Cowles (6) using a computer model. These investigators found that drug delivery to the brain could be significantly enhanced by intra-arterial infusion as compared to intravenous infusion of the same dose of drug. The bone marrow, considered to be the most frequent site of systemic toxicity, experienced essentially identical drug exposures by the two routes of drug administration, resulting in a marked improvement in the predicted therapeutic index. (The contralateral brain, like the bone marrow, receives an exposure similar to an intravenous injection.) When the drug metabolism a n d / o r excretion was rapid, the predicted advantage of intracarotid infusions was even further enhanced. Since BCNU has a brief plasma half-life (11), it was considered suitable for intra-arterial infusion. Intra-arterial infusion of BCNU has been performed in monkeys (7, 8). Using 14C-labeled BCNU, these investigators found intracarotid administra-

tion achieved 190% to 280% higher brain nucleicacid-bound drug as compared with intravenous infusion of the same drug dosage. They also found that the infusion was well-tolerated by the animals and recommended a dose of 115 m g / m : or less for human studies. Madajewicz et al. (3) performed a Phase II study of intra-arterial BCNU (100 rag/m 2) for metastatic brain tumors arising from carcinoma of the lung and melanoma. Of 25 evaluable patients with metastatic lung cancer, 12 patients had a complete or partial response lasting from I to 14 months. Of the patients who showed responses, five had small carcinoma of the lung. Only five of the 25 evaluable patients had been previously treated with cranial RT, although all had been on systemic chemotherapy at the time they were referred for intraarterial chemotherapy. None of the ten evaluable patients with metastatic melanoma to the brain responded to intra-arterial chemotherapy. Our own results are less promising then the 50% response rate for metastatic lung cancer obtained by Madajewicz et al. (3). The most likely explanation for this pertains to the cell type being treated. While our own series contains no cases of small cell carcinoma of the lung, that of Madajewicz showed responses in each of the five patients with this type of tumor. This observation is consistent with the responsiveness of this tumor in other sites in the body (12). Of the five patients in the present series who responded to intra-arterial BCNU, four had previously responded to RT. These four patients represent 31% of the cohort of 13 patients who had responded to RT. In comparison, of the 13 patients who did not show a response to RT, only one patient (8%) responded to intra-arterial BCNU. Since tumor cell cross resistance has been shown between BCNU and ionizing radiation (13), it appears that the clones of cells which repopulate a tumor after effective RT do not always represent cells resistant to alkylating agents. None of the previous studies address the question of whether intra-arterial infusion is of greater benefit than intravenous administration. Although it is conventional wisdom that metastatic brain tumors respond poorly to intravenous chemotherapy, there is no theoretical reason why a metastasis in the brain should be less responsive than one elsewhere in the body. (The view that the blood-brain

216

Fig. 2a, b, c, d.

217

Fig. 2. A 53-year-old man (patient # 1 of Table 3) with adenocarcinoma of the lung and brain metastases. Seven months after RT he developed symptoms and CT evidence of recurrent tumors in the frontal lobes (a, b: facing page, top left and top right). He was treated with three left internal carotid infusions of BCNU. One

month after the third infusion, there was marked reduction in left frontal tumor enhancement (c, d: facing page, bottom left and bottom right) but growth of the right frontal lesion. He then received two infusions of his right internal carotid artery with BCNU. The CT response is shown (e, f: above, left and right).

b a r r i e r excludes effective p a r e n t e r a l c h e m o t h e r a p y is n o t t e n a b l e in patients with c o n t r a s t - e n h a n c i n g m e t a s t a t i c lesions.) O u r own experience has been t h a t s o m e m e t a s t a t i c b r a i n t u m o r s are quite sensitive to p a r e n t e r a l c h e m o t h e r a p y . We have seen c o m p l e t e C T d i s a p p e a r a n c e of m e t a s t a t i c breast a n d o a t cell c a r c i n o m a s with c o n v e n t i o n a l p a r e n teral c h e m o t h e r a p y . Thus, there is a practical reason to raise the q u e s t i o n of whether i n t r a - a r t e r i a l infusion c h e m o t h e r a p y , which is m o r e difficult to p e r f o r m a n d p o t e n t i a l l y m o r e h a z a r d o u s to the central n e r v o u s system, is of g r e a t e r benefit t h a n int r a v e n o u s t h e r a p y . N o w e l l - c o n t r o l l e d trial c o m p a r i n g the two m o d a l i t i e s has been carried out, b u t o u r two p a t i e n t s with b i l a t e r a l metastases r e p r e s e n t an i n t e r n a l c o n t r o l ; the m e t a s t a s i s on the side of the i n t r a - a r t e r i a l infusion being t r e a t e d i n t r a - a r t e r i a l l y a n d the c o n t r a l a t e r a l metastasis being t r e a t e d int r a v e n o u s l y by the i n t r a - a r t e r i a l d r u g t h a t bypasses the brain. Both patients r e s p o n d e d to u n i l a t e r a l c a r o t i d injection on the ipsilateral side only, with the c o n t r a l a t e r a l t u m o r c o n t i n u i n g to enlarge. This finding p r o v i d e s s o m e evidence t h a t i n t r a - a r t e r i a l

t h e r a p y was s u p e r i o r to i n t r a v e n o u s t h e r a p y in these patients. H o w e v e r , it c o u l d have been t h a t the m e t a s t a t i c t u m o r on the i p s i l a t e r a l side consisted of clones of cells m o r e sensitive to B C N U t h a n on the c o n t r a l a t e r a l side. This seems unlikely because in the one e v a l u a b l e patient ( P a t i e n t #1) there was an u n e q u i v o c a l response on the c o n t r a l a t e r a l side when t h a t side was injected. P r i o r to d r u g infusion, b o t h patients u n d e r w e n t c e r e b r a l a n g i o g r a p h y which s h o w e d no c r o s s - o v e r filling to the region of the c o n t r a l a t e r a l tumor. F r o m these results it w o u l d a p p e a r t h a t the e n h a n c e d d r u g e x p o s u r e achieved by i n t r a - a r t e r i a l injection over i n t r a v e n o u s infusion is r e s p o n s i b l e for the r e s p o n s e of the ipsilateral tumor. T h e r e was no p e r m a n e n t acute or d e l a y e d t o x i c i ty f r o m i n t r a - a r t e r i a l t h e r a p y at the doses we used. The only p r e d i c t a b l e side effect which occurred in all of o u r patients was m o d e r a t e to severe p a i n in the d i s t r i b u t i o n of the injected artery. A t higher doses there m a y be toxicity. G r e e n b e r g et ah (2) r e p o r t e d on the a d m i n i s t r a t i o n of 200 m g / m 2 of B C N U every six weeks. The only significant toxici-

218 ty was d e l a y e d i p s i l a t e r a l r e t i n a l d a m a g e , w h i c h has n o t o c c u r r e d w h e n t h e y e m p l o y e d less d i l u e n t e t h a n o l (14). T h e s e studies a n d the results of o u r o w n i n d i c a t e t h a t i n t r a - a r t e r i a l B C N U c a n be g i v e n w i t h o u t s i g n i f i c a n t m o r b i d i t y or m o r t a l i t y . B u r g e r et al. (15) h a v e r e p o r t e d e n c e p h a l o m y e l o p a t h y in several p a t i e n t s b e i n g t r e a t e d w i t h h i g h - d o s e B C N U as well as o t h e r c h e m o t h e r a p e u t i c agents, a n d this r e m a i n s a p o t e n t i a l d a n g e r of h i g h - d o s e i n t r a - a r t e rial t h e r a p y . W e a r e c u r r e n t l y u n d e r t a k i n g a s t u d y o f i n t r a - a r t e r i a l B C N U at a d o s e o f 200 m g / m 2 f o r metastatic brain tumors.

References 1. Tator CH: Retention of tritiated methotrexate in a transplantable mouse glioma. Cancer Res 36:3058-3066, 1976. 2. Greenberg HS, Ensminger WD, Seeger JF et ah Intra-arterial BCNU chemotherapy for the treatment of malignant gliomas of the central nervous system: a preliminary report. Cancer Treat Rep 65:803-810, 1981. 3. Madajewicz S, West CR, Park HC et ah Phase II study intra-arterial BCNU therapy for metastatic brain tumors. Cancer 47:653-657, 1981. 4. Stewart D J, Wallace S, Feun, L e t al: A phase I study of intracarotid artery infusion of cis-diamminedichloroplatinum (I1) in patients with recurrent malignant intracerebral tumors. Cancer Res 42:2059-2062, 1982. 5. Phillios TW, Chandler WF, Kindt GW et ah New impIantable continuous administration and bolus dose intracarotid drug delivery system for the treatment of malignant gliomas. Neurosurgery 11:213-218, 1982. 6. Fenstermacher JD, Cowles AL: Theoretic limitations of intracarotid infusions in brain tumor chemotherapy. Cancer Treat Rep 61:519-526, 1977. 7. Levin, VA, Kabra PM, Freeman-Dove MA: Pharmacokinetics of intracarotid artery J4C-BCNU in the squirrel monkey. J Neurosurg 48:587-593, 1978.

8. Crafts DC, Levin VA, Nielsen SL: Intracarotid BCNU (NSC-409962): a toxicity study in six rhesus monkeys. Cancer Treat Rep 50:541-545, 1976. 9. Yamada K, Bremer AM, West CR et al: Intra-arterial BCNU in the treatment of metastatic brain tumor from lung carcinoma: a preliminary report. Cancer 44:2000-2007, 1979. 10. Shapiro WR, Ausman JI: The chemotherapy of brain tumors: a clinical and experimental review. In: Plum F (ed) Recent advances in neurology. FA Davis, Philadelphia, 1969, pp 149 237. l 1. Reed D J: Metabolism of nitrosoureas. In: Prestayk0 AW, Crooke ST, Baker LH et al (eds) Nitrosoureas, current status and new developments. Academic Press, New York, 198 l, pp 51 68. 12. Minna JD, Higgins GA, Glatstein ES: Cancer of the lung. In: De Vita VT, Hellman S, Rosenberg SA (eds) Cancer, principles and practice of ontology. J B Lippincott, Philadelphia, 1982, pp 396-474. 13. Pratt WB, Ruddon RW: The anticancer drugs. Oxford University Press, London, 1979, pp 79-80. 14. Greenberg HS: Personal communication. 15. Burger PC, Kamenar E, Schold DC et al: Encephalomyelopathy following high-dose BCNU therapy. Cancer 48: 1318-1327, 1981. 16. Ross RL, Kapp JP, Hochberg F et al: Solvent systems for intracarotid 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) infusion. Neurosurgery 12:512-514, 1983.

Note added in press S i n c e this p a p e r was s u b m i t t e d , R o s s et al. (16) have reported that with low quantities of alcohol a n d a saline s o l v e n t , t h e r e is a d e c r e a s e in the a m o u n t o f B C N U a v a i l a b l e to t h e p a t i e n t . W e h a v e c o n f i r m e d t h e s e o b s e r v a t i o n s . A c c o r d i n g l y , we n o w d i l u t e e a c h 100 m g of B C N U in 3 cc of a l c o h o l a n d t a k e to v o l u m e w i t h sterile water.