A d a Radiologica 34 (1993) Fax. 4 Printed in Denmark . All rights reserved

Copyright 0 Arta Radiologica 1993

A C T A R A D I 0 LO G I C A ISSN 0248-1851

FROM THE DEPARTMENT OF RADIOLOGY, ZHONG SHAN HOSPITAL, SHANGHAI MEDICAL UNIVERSITY, SHANGHAI, P. R. CHINA.

YTTRIUM-90 GLASS MICROSPHERES INJECTED VIA THE PORTAL VEIN

An experimental study

Z. P. YAN, G. LIN, H. Y. ZHAO and Y. H. DONG

Abstract Nondegradable glass microspheres (35 p) were injected into the

portal vein for toxicity test in 15 rabbits. In 10 animals the micro- spheres were loaded with wY, giving liver absorbed doses between 24.6 and 437.4 Gy, and’in 5 with *’Y (control group). The total amount of microspheres injected in each animal varied between 35 and 140 mg. The rabbits in the experimental group tolerated the effect of radioembolization in a dose 4 times higher than the upper limit of the clinical dose (100 Gy). After injection of wY glass microspheres into the portal veid of rats with diethylnitrosamine (DEN)-induced hepatic carcinoma, the microspheres, in addition to the liver parenchyma, accumulated in central and peripheral parts of the cancer nodules, causing necrosis. The internal radiation therapy of ’OY glass microspheres delivered via the portal vein may be an effective nonsurgical method for the treatment of liver cancer, especially in small nodules.

Key words; Liver neoplasms, therapy; yttrium, radioactive; mi- crospheres, radioactive; portal vein, therapeutic embolization; inter- ventional procedures, experimental.

The internal radiation therapy of radiating microspheres is one of the nonsurgical modalities for treatment of liver cancer (2, 8, 13, 14). 90Y is the nuclide of choice. It is a pure beta-emitter with a half-life of 64.5 hours, and a mean beta- particle energy of 0.93 MeV (maximum 2.27 MeV). The average penetration in tissue is 2.’5 mm (maximum 10.3 mm) and thus causes a high radiation region around the microspheres without damage to adjacent organs (3). The “bremsstrahlung” can be detected by external survey to confirm the localization of radiation and is no hazard to attendants (14). The commonly used microspheres are obtained by absorbing 90Y onto the surface of plastic resin- based microspheres. This absorption is not permanent and

the resin microsphere itself is degradable. Therefore 9 can leak and cause severe complications such as myelo- suppression and pulmonary fibrosis (7, 8, 13, 16). The only way to solve the problems is to incorporate wY into a nondegradable matrix. Therefore wY glass microspheres were developed (Theraspheres, Theragenic Corporations, Atlanta): the s9Y is incorporated and activated by neutron bombardment to wY with stable properties (7). Animal experiments (16) and clinical pilot trials (10, 1 1) have shown that it is safe, effective and applicable to administrate a large dose of wY glass microspheres via the hepatic artery in the treatment of primary liver cancer.

Since liver tumors in addition to arterial blood supply also have portal blood supply (1, 6, 12), 90y glass micro- spheres were administered in the portal vein. The aims of the study were to observe the toxicity effect on the liver and hematopoietic system after administration of the glass microspheres via the portal vein and the effect on experi- mental hepatoma.

Material and Methods

I. Effect of microspheres in rabbits. Thirty p to 50 p (mean 35 p, density 3.27 g/ml) ”Y glass microspheres were manufactured (Shanghai Institute of Building Materials) and activated (Isotope Institute of the Chinese Academy of Atomic Energy Sciences) to

Fifteen New Zealand white rabbits weighing 2.0 to 3.0 kg were used. After a middle abdominal incision a branch

glass microspheres.

Accepted for publication 4 November 1992.

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Table

Dose of glass microspheres and followup time

Z. P. YAN ET AL.

Rabbit Weight n9Y Absorbed Follow-up kg mg dose in time

liver, Gy

Group 1 P I P 2 P 3 P 4 P 5 P 6 P 7 P 8 P 9 P 10

Group 2 P 1 1 P 12 P 13 P 14 P 15

2.0 2.5 2.0 2.0 2.2 3.0 3.0 2.9 2.9 3.0

2.0 2.5 2.9 3.0 2.5

370 185 222 I48 185 185 185 46.3 99.9

85 I

76 35 70

I40 I40

258.4 114.1 171.2 114.1 129.7 95.1 95.1 24.6 53.1

437.4

1 month 3 weeks 2 weeks 1 week 2 weeks 5 months 5 months 1 month 2 days 2 months

4 months 2 weeks 2 weeks 3 months 1 month

of the jejunal vein was punctured and microspheres were slowly injected using a 10-ml disposable syringe. Ten rabbits received 90Y (46-851 MBq; Group 1) and 5 "Y (35-140 mg; Group 2) (Table). Complete blood counts and liver routine function tests were obtained before and 2 days, 1, 2, 3 weeks, and 1 month after injection. In a few rabbits these parameters were followed a further 2 to 5 months (Table). After the follow-up period the' rabbits were sacrificed with pentobarbital sodium and histopathologically examined. All examined tissues were stained with hematoxylin and eosin.

II. Effect of 90Y glass microspheres in experimental rat hepatoma. Four Wistar rats were given water containing diethylnitrosamine (DEN) (80 ppm) for 14 weeks and a hepatoma was induced in all of them. 90Y glass microspheres were given using the same technique: 142 MBq %Y glass microspheres were slowly injected using a 2-ml disposable syringe. The rats were sacrificed with pentobarbital sodium 2 weeks later and liver and tumor were examined histopath- ologically.

Results

I. Blood parameters were normal in both rabbit groups studied. Of the liver function tests, bilirubin and alkaline phosphatase were normal. Glutamic pyruvic transaminase (S-GPT) was slightly elevated in both groups, but became normal in 2 weeks. Elevation of globulin was only found in Group 1, where it returned to normal in one week. Emission computed tomography (ECT) showed a homogeneous dis- tribution of 90Y in the liver. On gross examination, in one rabbit (P 11) the liver was firm, shrunken and dark-brown with fine nodules. There was 200 ml ascites. In the remaining 14 rabbits no macroscopic lesion was observed in the stom- ach, duodenum or liver. Histologically, Group 1 (90Y) ani-

Fig. 1. Rabbit P 3; histopathology of liver specimen 2 weeks after injection of 90Y microspheres (hematoxylin eosin x 20). Vacuolar degeneration of hepatocytes.

Fig. 2. Rabbit P 11; histopathology of liver specimen 4 months after injection of 89Y microspheres (hematoxylin eosin x 4). Obvious portal fibrosis extending between hepatic lobules and surrounding the hepatic lobules.

mals showed cloudy swelling and vacuolar degeneration in some of the hepatocytes (Fig. 1) within 3 weeks. Focal necroses of hepatocytes with infiltration of lymphocytes and neutrophils were observed in 2 liver specimens. Invasion of lymphocytes and portal fibrosis with proliferation of bile ducts were also found in portal areas. The portal fibrosis increased in severity from one month on, extending between the hepatic lobules with tendency to surround them 5 months after operation (P 6, P 7). The same changes were also observed in Group 2 (8q). In P 1 1 the portal fibrosis was even more severe surrounding the hepatic lobules (Fig. 2) and glass microspheres were observed in portal areas (Fig. 3).

11. Twenty tumor nodules (7-8 mm in diameter) were examined under microscopy. In 14 nodules there was obvi- ous necrosis with residual vital tumor cells in the periphery of the tumors (Fig. 4). Fibrosis between the tumor and liver tissue, and a large number of strong light-reflecting microspheres were seen in necrotic and peripheral regions of the tumor nodule.

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YTTRIUM-90 GLASS MICROSPHERES VIA THE PORTAL VEIN 397

Fig. 3. Rabbit P 14; liver specimen obtained 3 months after injection of "Y microspheres (hematoxylin eosin x 20). Glass microspheres in portal areas.

Fig. 4. Liver specimen with experimental hepatoma in a rat 2 weeks after injection of "Y microspheres (hematoxylin eosin x 4). Necrosis of tumor nodule with few residual cancer cells in tumor periphery.

Discussion

BREEDIS & YOUNG (4) concluded that liver neoplasms, both primary and metastatic, receive their blood supply only from the hepatic artery. Transarterial infusion and embolization via the hepatic artery has therefore con- tributed to improvements in the treatment of liver cancer (5, 17). ACKERMAN ( I ) , LIN et al. (12), and CONWAY et al. (6), however, showed that liver cancer also is supplied from the portal vein, especially the small nodules (< 2 cm), but also the peripheral parts of large tumors. The finding that 90Y glass microspheres delivered via the portal vein accum- ulated in DEN-treated tumors also proved this conclusion. Therefore, treatment via the portal vein may be helpful in controlling liver cancer (especially the intrahepatic small nodules) and may be important in patients with liver cancer after treatment with transarterial embolization.

There is' no previous report concerning the liver tolerance to 'OY microspheres injected via the portal vein. In our study, we delivered 46.3 to 851 MBq of 90y glass micro-

spheres in Group 1, and the absorbed doses were 24.6 to 437.4 Gy (mean 152.0+ 122.7). All rabbits appeared clinical- ly normal with the exception of a transient elevation of S- GPT and globulin. We found that the liver could tolerate 90y glass microspheres in large doses injected via the portal vein. Previously we observed the same when they were injec- ted into the hepatic artery in rabbits and in 24 patients (unpublished data). The pathologic changes were more pro- nounced when they were delivered via the portal vein: a) degeneration of hepatocytes was more obvious and exten- sive; b) portal fibrosis appeared earlier and more extensive- ly; c) fibrosis was present in Group 1 as well as in Group 2 (controls). In 2 rabbits (P 11 and P 15) of Group 2 the fibrosis surrounded the hepatic lobules. We also found similar portal fibrosis when Lipiodol was administered via the portal vein (unpublished data). Portal fibrosis after in- jection of 'OY glass microspheres via the portal vein is related not only to absorbed radiation dose to the liver, but also to terminal embolization of the portal vein, a common finding after microembolization of the portal vein (9, 15). Patients with severe portal hypertension and esophageal and gastric fundus varices should be disqualified from the therapy.

There are no reports on the effect of 9oY glass micro- spheres in the treatment of liver cancer via the portal vein. Our results in 4 experimental liver cancers demonstrated that glass microspheres delivered via the portal vein can accumulate in the tumor nodule. They cause necrosis of the tumor with residual tumor cells remaining only in the peripheral parts of the nodule. Thus, it may be effective to deliver 'OY glass microspheres via the portal vein for treat- ment of liver cancer, especially in small intrahepatic tumor nodules which have a rich supply from the portal vein.

Request for reprints: Dr. Zhi Ping Yan, Department of Radiology, Zhong Shan Hospital, Shanghai Medical University, 136 Yi Xue Yuan Road, Shanghai 200032, P. R. China.

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