Critical Reviews in OncologylHematology, 1992; 13: 93-l 05 0 1992 Elsevier Science Publishers B.V. All rights reserved.

ONCHEM

93 lO40-8428/92/$15.00

0003 1

Transcatheter

arterial embolization

of hepatic neoplasms

Keisuke Nakata, Khaleque Newaz Khan and Shigenobu Nagataki The Fir.rt Department oj‘Inrerna1 Medicine, Nagasaki University School qf’ Medicine. Nagusaki. Jqwn (Accepted

10 May

1992)

Contents I.

Introduction

. .._...................................................

II.

Transcatheter

arterial

hepatocellular

carcinoma

embolization

with or without

chemotherapy

in the treatment

of 94

111.

TAE in the treatment

IV.

Transcatheter

oily chemoembolization

V.

Transcatheter

arterial

VI.

Complications A. Hepatic

93

of metastatic

injection

liver tumor (TOCE)

of ‘2’l-labelled

95 in the treatment

of HCC

lipiodol

95 97

of TAE complications

I. Gallbladder and bile duct infarction 2. Infection with abscess and bile cyst formation 3.

Nontumorous

4.

Catheter-related

5.

Complications

B. Extrahepatic

hepatic

tissue damage

complications with specific

not necessarily embolizing

from embolization

agents

complications

1. Gastroduodenal lesions 2. Pancreatic tissue damage VII.

Conclusions

.

.

. . . . .

. .

.

References................................................................

Vascular embolization is a useful therapeutic procedure in many organs of the body. The concept of treating liver tumors by interruption of their arterial supply was first suggested by Markowitz in 1952 [l]. Transcatheter arterial embolization (TAE) has proved particularly valuable in the liver for a number of reasons. Firstly, the liver has a dual blood supply, which miniCorrespondence

10: Dr. Shigenobu

Medicine,

Sakamoto-machi.

Nagasaki

Nagasaki

Nagataki. University

852. Japan.

The First Department School

of Medicine,

101 103

I. Introduction

of Internal

. ..___.....____......__._...._._...

7-l,

mizes the damage of normal liver tissue when the arterial supply is interrupted [2]. Secondly, surgery of the liver can be difficult and often dangerous for the nonspecialist surgeon, especially in the treatment of hepatocellular carcinoma (HCC), because more than 80% of patients with HCC have co-existing cirrhosis [3-71. Thirdly, TAE may be useful in managing complications, such as hemorrhage or arteriovenous fistula, arising from surgical interventions [8&10]. Fourthly, TAE is one of the safest and most effective ways of controlling hepatic arterial bleeding caused by trauma to the liver from penetrating injury or rupture of liver tumor, either as an alternative or as an adjunct to surgery

94

[I I-131. Finally,

the liver is often the site of tumor

posits, and TAE is currently of treatment

in many

the most appropriate

cases [2,13-201.

ingly studied,

liver tumors

and TAE is indicated

prior to surgical cuss the current the management

tumors

resection concept

and disadvan-

have been increasfor palliative

or for possible

[21l24].

reported

treat-

debulking

In this issue, we dis-

and the perspectives

of TAE in

of liver tumor.

by Nilsson

provide ment

Over the past 10 years the advantages tages of TAE in treating ment of unresectable

deform

of a collateral

formed

under

TAE

guidance,

superselectively

artery

is usually

per-

using particles

into the tumor-feeding

to avoid reflux of embolic

cent vessels and to minimize

of

materials

hepatic

to the adja-

the risk of nontumorous

liver tissue damage as well as extrahepatic tissue damage. Likewise, a gelatin sponge seems to be better than Gelfoam

powder

fluoroscopic of a gelatin

have

fluoroscopic

serted

carcinoma studies

effect due to the rapid developcirculation.

gelatin sponge or Gelfoam powder to occlude the feeding arteries of liver tumors. A catheter should be in-

II. Transcatheter arterial embolization with or without chemotherapy in the treatment of hepatocellular

Epidemiological

in 1966 [42], but has been found to

only a transient

demonstrated

that

hepatocellular carcinoma (HCC) is one of the most common fatal malignancies in the world [25]; it is relatively rare in North America, with an incidence of 1 to 3 cases per 100,000 persons per year, whereas annual incidences as high as 50 per 100,000 persons have been reported in several areas of Asia and Africa [26]. The high incidence of HCC among certain Asian populations reflects the incidence of chronic hepatitis B virus (HBV) infection [27-291; however, in Japan, the incidence of HCC steadily increased over the past 10 years, although the age-adjusted mortality rate of HBV-associated HCC was almost unchanged during the same period. In fact, more than 70% of HCC patients who were negative for hepatitis B surface antigen, were positive for anti-hepatitis C virus (HCV) antibody, and the prevalence of HCV-associated HCC has recently increased in Japan [30-331. With the advances in diagnostic facilities such as serum tumor markers, ultrasonography, computed tomography and angiography, HCC can now be detected very early [34]. Even then, however, surgical resection of HCC is usually impossible because of widespread intrahepatic involvement or lack of hepatic reserve resulting from co-existing advanced cirrhosis. Prognosis of untreated patients is very unfavorable; the median survival is less than 6 months [3,18,35,36]. The results of systemic chemotherapy are still disappointing [3,18,37-391. Transcatheter arterial embolization is a useful alternative treatment modality for HCC. The theoretical basis underlying devascularization of hepatic neoplasms is the observation that they receive their blood supply exclusively from the hepatic artery [40.41]. Since normal liver tissue also receives a supply from the portal vein, interruption of hepatic arterial flow should result in selective tumor necrosis. The technique of the hepatic arterial ligation for the treatment of liver tumors was

TAE, therapy,

as an embolic

guidance sponge

material,

because

it is easier to monitor

than of Gelfoam

under

the reflux

powder.

usually combined with intra-arterial has been reported as an effective

chemopalliative

treatment that prolongs the survival of patients with unresectable HCC [ 16-l 9,21-241, although few randomized controlled studies have been carried out [20]. These results are summarized in Table 1. Yamada et al. [ 161 found that 1-year survival after TAE was 5 1.1% in a study of 120 patients with unresectable HCC, whereas the l-year survival rates of patients without surgical resection were less than 20%, irrespective of systemic or intra-arterial chemotherapy [20,37-391. Similarly, Okuda et al. [18] showed that the median survival for TAE was 9.5 months, for intra-arterial chemotherapy 3.7 months, and for systemic chemotherapy 2.5 months, resulting in a better prognosis of patients with TAE

TABLE

1

% survival

No. of patients

of patients cytotoxic

with HCC following agent

TAE

% survival

(months)

Ref.

6

12

24

36

(-)

61%

44%

29%

ND”

16

mitomycin C microcapsule

65%

24%

ND

ND

17

mitomycin mitomycin

C C

78% 64%

43% 40%

25% 15%

0% 15%

18

20’

mitomycin

C

85%

60%

60%

45%

19

42 21 21

(--) 5-fluorouraciP

59% 59%

42% 35%

25% 21%

ND ND

20

120 20

105 Stage I?41 Stage II:64

” Not determined. ’ Okuda’s classification. ’ Tumor sizes were less than 5 cm in diameter in all patients. ‘I Monthly intravenous injection (1.0 g/m’ body surface/day days).

for 5

95

treatment

than intra-arterial

A randomized the l-year

controlled

survival

rates of patients

who received monthly

TAE in the treatment of metastatic

liver tumor

that

who repeatedly

ceived TAE was 42.2%, which was significantly than that of patients

III.

or systemic chemotherapy. trial also demonstrated

re-

higher

chemother-

apy with high doses of 5-fluorouracil [20]. With respect to the histopathologic assessment of resected HCC after

The liver is the site of hematogenous metastases through the portal venous system or the hepatic artery. Since many cases with liver metastases have widespread or multiple intrahepatic involvement, surgical resection is usually

impossible.

Of the cases with liver metastases,

TAE, Sakurai et al. [22] showed that TAE led to immediate necrosis of the tumor and that the secondary gran-

the group who most clearly benefited from therapeutic embolization were those with metastatic endocrine tu-

ulation

mors

tissue around

the tumor caused a collapse

of the

intracapsular veins, tumor emboli, and, hence, capsular invasion. However, several investigators demonstrated that TAE resulted

in massive

tumor

necrosis,

but viable

such as carcinoid,

carcinoma

of the thyroid

that more than 90% of these patients icant alleviation of their symptoms, improvement

was paralleled

tumor cells were also found in more than 50% of cases [43,44]. The failure of complete necrosis of tumor is

dence of reduced

associated

evaluate

with extracapsular

tumor

extension,

liver in-

vasion, satellite nodules. and portal vein involvement, and is probably related to the collateral and portal vein blood supply. The instantaneous occurrence of collaterals also accounts for a residual tumor on the tumor surface or around the tumor vessels in the necrotic tumor mass, and induces resistance to TAE treatment. Repeated embolizations of the extrahepatic and intrahepatic collaterals and redistributed arterial infusion of anticancer drugs may then be necessary in order to provide a more adequate therapy. Recanalization of the embolized artery also contributes to failure; however, the immediate massive necrosis of tumor tissue after TAE [ 161 suggests that the effectiveness of TAE is probably independent of the lasting persistence of the embolus. The extracapsular involvements, including satellite nodules. have been shown to closely correlate with tumor recurrence and the mortality of patients [45,46]. Since the invading tumor tissues and those invading the tumor capsule receive their blood supply from the portal vein, either directly or through diffusion [40.47], TAE has a limited effect in these lesions. These observations therefore argue for the necessity of surgical resection whenever possible in the treatment of HCC [44]. Okuda et al. [ 181 reported in a study of 850 patients with HCC that surgical resection resulted in a more favorable prognosis than did nonsurgical treatments such as TAE and intraarterial and systemic chemotherapy. Thus, TAE is an effective palliative treatment of HCC, and improves the prognosis of patients with unresectable HCC. However, when the tumor tissues are nourished by the portal blood flow, such as satellite nodules and intracapsular tumors, TAE cannot be expected to cause complete tumor necrosis. Although repeated TAE is probably an alternative treatment modality for achieving a complete cure in some patients, surgical resection should be considered whenever it is possible.

glucagonoma

and

[48]. Allison

hormone

the effect of TAE

medullary

et al. [13] revealed experienced signifand this subjective

by the biochemical production.

evi-

It is difficult

on survival

because

to

of the

ethical and practical difficulties in creating a comparable control group. It is, however, noteworthy that TAE can induce alleviation of unpleasant humoral symptoms in patients with endocrine metastases. With regard to non-endocrine metastasis. several investigators reported some beneficial effects of TAE; however, since non-endocrine malignant tumors are detected as hypovascular tumors by hepatic angiography. the therapeutic efficacy of TAE in cases with non-endocrine metastases seems to be lower than that in cases with endocrine metastases or HCC. IV. Transcatheter oily chemoemholization the treatment of HCC

(TOCE)

in

Lipiodol, an ethyl ester of the fatty acid of poppy seed oil with 38% of iodine by weight, has been used as a lymphographic agent. In 1966, Idezuki et al. [49] reported that liver tumor could be detected as a radiolucent mass in uniformly opacified nontumorous liver tissue when lipiodol was injected into the portal vein. On the other hand, in 1979 Nakakuma et al. [50] demonstrated that lipiodol remains selectively in HCC tissues for a long time when injected into the hepatic artery. Since then, intra-arterial injection of lipiodol has proved to be useful not only in detecting small HCCs but also in the treatment of HCC [51-551. The precise mechanism by which lipiodol is selectively retained in HCC tissues remains speculative. Lipiodol has been shown to occlude arteries with a diameter of 25 pm or less in both normal and malignant tissues; however, it is cleared from normal tissue within a few days [55]. In animal experimental models. we demonstrated that radiolabelled lipiodol was found in the vasculature within 6 h after intra-arterial infusion, then extravasated to distribute in HCC tissue as well as in the nontumorous liver tissue, and was predominantly

96

retained in HCC tissue 24 h after infusion. When the disappearance rate of the radiolabelled lipiodol in HCC tissue was compared with that in the nontumorous liver tissue, the half-life of lipiodol in HCC tissue (t,,*=6 ? 1 days) was significantly longer than that in the nontumorous tissue (t,,Z=3 + 1 days). Histochemical analysis showed that lipiodol was exclusively located in the intercellular space in tumor tissue, suggesting a very low uptake of lipiodol by tumor cells [56]. Clearance of lipiodol by normal liver tissue is probably mediated through the reticuloendothelial system including Kupffer cells [57]. Konno et al. [58] have suggested that the lack of a developed reticuloendothelial system in HCC tissue promotes the selective retention of lipiodol in tumor. Lipiodol is accumulated in both the main tumor and the adjacent daughter nodules of HCC, when injected into the hepatic artery. Lipiodol has persisted as a deposit in nodules of HCC for up to a year, but disappears from the nontumorous liver tissue within 2 to 4 weeks [52,53]. Therefore, lipiodol-targeted chemotherapy is expected to greatly enhance the effects of cytotoxic agents on HCC, removing the need for frequent access to the hepatic artery, or minimizing the deteriorative effects of anticancer agents on the nontumorous liver tissue. Target chemotherapy for HCC, using lipiodolmaleic acid neocarzinostatin containing styrene (SMANCS), was carried out by Konno et al. [59]. In a subsequent study of 124 patients with HCC and secondary liver tumors, they demonstrated that the intra-arterial infusion of a combination of lipiodol and SMANCS resulted in a significantly greater survival than the treatments with hepatic arterial ligation and chemotherapy [60]. Good response rates and increased survival for TABLE %

2

survivalof patientswith HCC followingTOCE

No. of patients

cytotoxicagent

% survival

(months)

Ref.

(dose) 12

24

36

doxorubicin 85% (0.6-l .O mg/kg body weight) 85% cisplatin (2 mg/kg body weight)

58%

40%

ND”

70%

45%

ND

100

doxorubicin (4OGlOO mgibody weight)

82%

54%

33%

18%

68

30

doxorubicin (2040 mg/body weight)

82%

59%

30%

ND

69

6 71 25

52

“Not determined.

67

HCC have been also reported using lipiodol in combination with other cytotoxic agents, including doxorubitin, cisplatin and 5-fluorodeoxyuridine-C8 (FUdR-C8) [61-631. Following the selective perfusion of lipiodol in combination with doxorubicin in 149 patients with HCC, Kanematsu et al. [61] demonstrated that lipiodolization caused a much higher concentration of doxorubicin in tumor tissue than in the adjacent nontumorous tissue, and was considerably more effective in patients with Stage I and II (Okuda’s classification), when compared with the results achieved by hepatic arterial ligation and cannulation into the hepatic artery. Shibata et al. [62] reported that the survival rate in the group treated with lipiodol and cisplatin was significantly longer than that in the group treated with lipiodol-containing neocarzinostatin. FUdR-C8 is one of the lipophilic prodrugs of FUdR and has a time-dependent cytotoxic effect, which is considered most suitable for lipiodol-targeted chemotherapy. In a preliminary report, Yamashita et al. [63] showed that the cumulative l-year survival rate in the group treated with lipiodol and FUdR-C8 was 55.1% for HCC and 70.0% for metastatic liver tumors, which is promising for the therapeutic use of FUdR-C8 in combination with lipiodol. Lipiodol-targeted chemotherapy is optimized by coupling it with embolization. This procedure has been called, by some of its supporters, ‘transcatheter oily chemoembolization (TOCE)‘. In TOCE, the hepatic arteries are injected with lipiodol-containing cytotoxic agents, and followed by occlusion of the large feeding vessels with gelatin sponge to prevent ‘wash out’ of the cancer chemotherapeutic agents. Recently, this procedure has been widely used for treating HCC in Japan [64-681, but, as yet, is used little in Western countries [69]. The effects of TOCE on HCC were first reported by Sasaki et al. [64]. They evaluated the anticancer effects of chemoembolization therapy for HCC using lipiodol, cisplatin and gelatin sponge in 20 patients who underwent subsequent hepatic resection. In their study, all main tumors were reduced in size following this therapy, and lesions other than extracapsular invasion were eliminated considerably with this form of therapy. Takayasu et al. [65] also showed that chemoembolization with lipiodol and doxorubicin followed by gelatinsponge particles caused complete necrosis of the main lesion in 83%, daughter tumors in 53%, tumor thrombus in 17%, and foci of intracapsular invasion in 67%. These results were quite superior to those reported previously for chemoembolization without lipiodolization. With respect to the survival rate, several investigators showed that TOCE significantly prolonged the cumulative survival rate when compared with the survival rate in patients who received chemoembolization without

lipiodol infusion. More recently, the clinical trial of intra-arterial injection of a lipiodol-doxorubicin emulsion followed by embolization with gelatin-sponge particles in the management of advanced HCC in cirrhosis was carried out in France [69]. In this study, they suggested that TOCE was an effective palliative treatment even in the Western form of HCC complicating advanced cirrhosis, and indicated that it acts as a locoregional therapy which prevents cancerous invasion of the portal system. The survival rates of patients with HCC following TOCE are summarized in Table 2. Since TOCE dramatically improves its anatomical effects by destroying nearly all of the cancer cells not only in the main tumor but also in the other neoplastic components such as daughter tumors, intracapsular invasion, and even intraportal neoplastic invasion, it is expected that the procedure will become the therapy of choice for preoperative treatment of HCC. Furthermore, previous studies indicated a better survival in the group treated with TOCE than in the control group, even in patients with advanced HCC. Despite the lack of any comparative study between lipiodolization alone and TOCE, the later procedure seems to provide better results. Randomized controlled trials are, however, needed to evaluate the superior effect of TOCE in the management of patients with unresectable HCC. V. Transcatheter lipiodol

arterial injection of ‘311-labelled

The principle of the selective delivery and the retention of lipiodol in hepatic neoplasms have been explained by the developed neovasculature, enhanced permeability, and poor reticuloendothelial system of the tumors [56-581. If a radioactive agent could be combined with lipiodol, prolonged internal radiation therapy may be carried out selectively without side effects. Indeed, 13’1-labelled lipiodol has several potential advantages: (1) It can provide a potentially tumoricidal effect without significant side effects; (2) the retention of ‘3’I-labelled lipiodol in tumor tissues is maintained for a long time, resulting in sustained irradiation of tumor foci: (3) daughter lesions can be treated because lipiodol is retained in both the main tumor and the daughter nodules; and (4) the treatment can be repeated because of minimal vascular damage. Early clinical studies using ‘3’I-labelled lipiodol have focused on the detection of liver tumor by scintigraphy and exhibit a pattern of uptake and retention similar to nonradioactive lipiodol [70,71]. With respect to the therapeutic use of ‘3’I-labelled lipiodol in hepatic neoplasms, we previously studied the effect of intra-arterial infusion of 13’1labelled lipiodol in an animal tumor model [56]. In this

a

1

16‘

O_.

OhTT--

5 days

5

days

Fig. 1. Serial changes of radioactivity in plasma and urine after “‘Ilabelled lipiodol treatment in four cases. (a) Changes in plasma radioactivity (I ml) shown as % of injected dose. (b) Changes in urine radioactivity shown as % of injected dose per day.

study, lipiodol-targeted internal radiation therapy resulted in almost complete necrosis of the tumor without any significant histologic changes in nontumorous liver tissue. In human hepatic neoplasms, seven cases with advanced HCC were studied by Kobayashi et al. [72]. The estimated doses of ‘3’I-labelled lipiodol for tumor ranged from 40 to 190 Gy, and a decrease in tumor size was found in all cases. Bretagne et al. [73] also evaluated the effects of internal radiation therapy with “‘I-labelled lipiodol injection in 15 patients with HCC and eight with hepatic metastases. In patients with HCC, the radiation dose was 12.5-70 Gy for tumors, 2-15 Gy for nontumorous liver, and less than 2.5 Gy for the lungs. Treatment tolerance was excellent, and an average reduction in tumor size of 50% was observed in nine cases. Histological examination of the liver 3 months after injection revealed microscopic features highly suggestive of the effect of radiation in tumor tissue. In contrast, no objective response was noted in cases with widespread metastases. Recently. 20 patients with HCC have been treated in our hospital using ‘3’I-labelled lip-

98

iodol. These included 18 men and two women, with a mean age of 61 years (range: 4476 years). Following selective angiography, ‘311-labelled lipiodol was injected via a hepatic arterial catheter. The injected dose ranged from 230 to 1295 MBq (mean: 836 MBq), which was estimated to deliver less than 30 Gy to nontumorous liver tissue and more than 30 Gy to tumor tissue. Biodistribution of ‘3’I-labelled lipiodol was assayed by scintigraphy, and changes in tumor size were evaluated by follow-up CT scans. In some cases, the serial changes of radioactivity in plasma and urine following ‘3’I-labelled lipiodol injection were also studied. The exposed dose in tumor tissue was 64.5 + 22.7 Gy (mean + SD), whereas the doses in nontumorous liver tissue ranged from 7.9 to 29.0 Gy. The exposure dose in the lung was less than a half of the dose in nontumorous liver tissue in each case (range: 2.2-14.0 Gy). The radioactivity of plasma peaked from 2 to 4 days after treatment and was approximately 10-6-10-7% of the injected dose (Fig. la). Serial changes in the urine radioactivity were closely correlated to those in plasma radioactivity (Fig. lb), and the cumulative urinary excretion of 13’1amounted from 10 to 30% of the injected doses within 8 days following injection (Fig. 2). The effective half-life of “‘I-1abelled lipiodol in tumor tissue was 6.1 & 0.8 days (mean & SD), in contrast to that in nontumorous liver tissue which was 4.1 * 1.2 days (mean k SD). The difference was statistically significant (~~0.01). These findings were almost similar to the previous report using a tracer dose of ‘3’I-labelled lipiodol [74]. When changes in tumor size were analyzed by follow-up CT scans, a decrease in tumor size was found in 18 of 20 cases within 3 months following injection, and tumor sizes were reduced to less than 50% of the pretreatment values within 6 months following injection in 14 of these 18 cases. The representative case is shown in Fig. 3. These decreased tumor sizes were associated with the consequent decline of serum levels of cr-fetoprotein. The histologic examination of the resected specimens in the two cases that underwent surgical resections approximately 2 months after the ‘3’I-labelled lipiodol treatment also revealed complete necrosis of the tumor in one case (as shown in Fig. 4) and nearly complete tumor necrosis in the other. No clinical toxicity to hematopoietic, thyroid, or lung was observed in any patients. Thus, internal radiation therapy with ‘3’I-labelled lipiodol seems quite encouraging in the management of hepatic neoplasms, particularly in treating HCCs. However, it may be important to evaluate the adequate injected dose which induces an utmost tumoricidal effect with minimal toxicity to nontumorous liver tissue and extrahepatic tissues. A multicenter trial should be conducted.

VI. Complications of TAE The promising beneficial art of the embolization technique for the treatment of hepatic neoplasms does not always avoid the associated complications. With the advent of readily available embolization techniques, many patients in the hepatic and extrahepatic area undergo these procedures, displaying moderate to severe hazards of this upcoming therapeutic modality. Although numerous complications of TAE for the treatment of a variety of diseases have already been reported, our purpose here is to summarize the complications of TAE with special emphasis and synthesis of the current state of the art related to the treatment of HCC. TAE or TOCE are mainly indicated for patients with unresectable tumors in whom serious underlying abnormalities are manifest prior to the procedure. In patients with HCC in particular, more than 80% of cases have associated liver cirrhosis. These facts increase the risk of embolization-induced complications. The gelatinsponge particles and lipiodol used for TOCE cause tissue damage through a state of anoxia or hypoxia by occlusion of the vessels [64], whereas the anticancer agents may exert their tissue damage by induced arteritis or a direct toxic effect on the tissue [75]. It is likely that TAE or TOCE cause hepatic or extrahepatic tissue damage by either retrograde flow or scattered distribution of these toxic agents into the adjacent undesired vessels. A number of complications can now be prevented due to the improved techniques available, and the experience and pitfalls previously noted. Complications of TAE for the treatment of HCC during or following the embolization procedure can be categorized as shown in Table 3. VI-A. Hepatic complications VI-A. I. Gallbladder and bile duct infarction Since the cystic artery usually branches off from the hepatic artery, TAE in patients with malignant hepatic tumors can facilitate retrograde embolic occlusion of the cystic artery, causing ischemic necrosis of the gallbladder. Most patients experience post-embolization syndrome characterized by abdominal pain, fever, nausea, vomiting, and/or ileus persisting for 2 to 7 days following TAE [2]. Post-TAE pyrexia is presumed to represent absorption fever associated with the necrosis of tumor tissue [ 161. The cause of abdominal pain may, in part, be due to acute ischemic necrosis of the gallbladder [2]. The uncomplicated post-embolization syndrome can be alleviated by conventional conservative therapy. Infarction of the gallbladder following TAE was confirmed specifying three grades depending on the extent

99

avoid the TAE-induced unwanted hazards to the gallbladder, the hepatic artery should be embolized at the distal portion beyond the junction of the cystic artery using a specially tapered polyethylene catheter for this purpose [80]. Although bile duct necrosis is rarely [2 I,8 1,821 reported, Makuuchi et al. [83] demonstrated proximal bile duct necrosis in 2 of 4 patients where Gelfoam powder was used as the embolus. Therefore, avoidance of the use of Gelfoam powder and the consequent technique of superselective TAE can be suggested.

2

4

6

6

Days

Fig. 2. Summation of urinary excretion of “‘I shown as % of injected dose in four cases. The amount of urinary excretion of “‘I in one case (0) was lowest. whereas % of accumulation of “‘I in tumor was highest in the same case.

of the involved area [76]. Kuruda et al. [77] demonstrated occlusion of the cystic artery or its branches by embolic material in 8 of 16 (50%) patients with HCC as a cause of gallbladder infarction without any evidence of perforation. In another report, Takayasu et al. [78] documented ulceration of the gallbladder with fibrosis of varying degrees following complete or incomplete embolization of the cystic artery in 9 of 10 patients. De Jode et al. [79] reported that necrosis of the gallbladder resembling perforation was particularly dangerous in their patients, but fortunately no evidence of the gallbladder perforation has yet been established [21,76]. To

TABLE

3

Complications

of TAE

Complications

Ref.

1.

Post-embolization

2.

Hepatic complications a.Gallbladder and bile duct infarction b.Infection with abscess and bile cyst formation c. Nontumorous hepatic tissue damage d.Catheter related. not necessarily from embolization e.Complications with specific embolizing agents

3.

syndrome

Extrahepatic complications a. Gastroduodenal lesions b. Pancreatic tissue damage

2.16

21,76,77,78, 79,80,8 1,82,83 82.84.86.88.89 99 95.103,104 95

75,105,106 109

VI-A.2. Infection with abscess and bile cyst formation Even a deliberate peripheral embolization may sometimes be followed by a superimposed bacterial infection, putting the patient at risk of septic complications such as liver abscess and/or recurrent cholangitis [84]. Although Rankin observed no abscess formation in the liver in his 47 patients [85], this complication has been reported elsewhere [86]. Bile cyst formation secondary to liver infarcts as a consequence of TAE has been established. With proximal hepatic artery occlusion, collateral arterial flow develops rapidly [87]; however, peripheral hepatic artery occlusion sometimes induces hepatic infarction leading to bile cyst formation caused by bile duct epithelial necrosis with consequent extravasation of bile [82,84]. Doppman et al. [88] already demonstrated this so-called hepatic biloma in all of 13 experimental female monkeys embolized with silicone. revealing numerous bile-filled cysts scattered throughout the liver. Recently, a sterile hepatic bile cyst in a patient with hepatic tumor was detected in our department by CT scan 24 days after the second TOCE [89]. Careful follow-up using updated imaging techniques, percutaneous drainage under ultrasonographic guidance, and concurrent therapy with antibiotics and hyperoxygenation resulted in successful resolution of these intrahepatic collections. VI-A.3. Nonturnorous hepatic tissue damage Hepatic infarction as a fatal complication of TAE for the treatment of intra- and extrahepatic disease has been extensively studied [81,87.90-941. The exact pathophysiology of liver necrosis is not clearly understood, but it has been proposed that a decreased portal perfusion resulting from recent or ongoing hemorrhagic shock coupled with the transcatheter occlusion of several hepatic arteries by the embolic materials plays a major role [95]. Although an immense number of reports has, so far, indicated the therapeutic efficacy of TAE, inducing tumor necrosis of hepatic neoplasms, both primary and metastatic, by causing tumor devascularization [ 16,2 1.64,76.96,97], however, little atten-

100 S.H 61M.

Fig. 3. A representative case with a marked decrease in tumor size following “‘I-labelled lipiodol treatment. Tumor size was progressively reduced to less than one tenth of the pretreatment value six months after the treatment.

tion was given to the subsequent changes in the associated nontumorous liver tissue which might possibly be affected by TAE due to either retrograde flow or scattered distribution of the embolic materials into the adjacent undesired branches of hepatic arteries. Yoshikawa et al. [98] evaluated the effectiveness of the treatment by the analyses of serial changes in serum hepatic enzymes following TAE, but they overlooked the nontumorous tissue damage by TAE, a possible adverse effect of the procedure in patients with HCC. This hidden damage of nontumorous liver tissue by TAE for HCC has currently been evaluated by Khan et al. [99]. This promising work is based on the facts that TAE induced impaired liver function, sometimes resulting in a state of mild to moderate hepatic failure, and that the subsequent liver atrophy after TAE appears to be responsible for not only tumor tissue necrosis but also for the damage to nontumorous liver tissue caused by TAE. This study is very important in the clinical practice to prevent impeding hepatic failure in patients with HCC. In the study, 17 patients with HCC were divided into two groups, undergoing superselective and nonsuperselective TAE performed from the segmental and the nonsegmental branches of hepatic artery, respectively. The serum levels of relatively tumor and nontumor specific marker fructose 1,6-diphosphate (FDP) aldolase and fructose 1-phosphate (F 1P) aldolase isoenzymes, which were released from the damaged tumor and nontumorous tissue by TAE, respectively, were analyzed to measure the contribution to the value by the damage of tumorous and nontumorous liver tissue induced by TAE. We found that the total enzyme outputs of FDP aldolase and FlP aldolase following TAE correlated

significantly with the tumorous and nontumorous tissue volumes, respectively, and that the FDP/FlP aldolase output ratio in superselective TAE was significantly greater than that in nonsuperselective TAE with coincidental effective decline of serum levels of a-fetoprotein. The serum transaminase activities after TAE were also higher in the nonsuperselective TAE than in the superselective TAE. Moreover, the nonsuperselective TAE caused significant total nontumorous liver atrophy when compared with the superselective TAE; however, there was no difference in liver atrophy between superselective TAE and the natural course of liver cirrhosis. Thus, we advocated in our report [99] that TAE should preferably be done as superselectively as possibly so as to exert effective tumor necrosis and, at the same time, to avoid the untoward hazards of TAE to nontumorous liver tissue. The impaired hepatic arterial oxygen perfusion rather than portal perfusion is responsible for the anoxic or hypoxic damage of nontumorous tissue, although three-fourths of the total hepatic blood supply are provided by portal vein [loo]. Popper et al. [loll reported that the limited oxygen supply to the liver by the portal blood flow is not sufficient to prevent liver necrosis by the interruption of hepatic arterial perfusion. In our study, the occlusion of segmental tumorfeeding vessels by embolic materials was more selective than that of nonsegmental vessels where the embolic materials were distributed in a scattered fashion and entered into the intrahepatic branches of other major hepatic arteries, causing nontumorous tissue damage. VI-A.4. Catheter-related from

complications,

not necessarily

embolization

The introduction of the Seldinger technique of transfemoral catheterization [ 1021initiated the modern era of angiography. As its use became widespread, catheterrelated complications were experienced unexpectedly, which were not necessarily the result of the embolization procedure. The rarely observed catheter-related complications are: intra-arterial hemorrhage leading to the formation of hematoma, arterial obstruction due to angiospasm secondary to damage to the intima, pseudoaneurysm, the perforation of vessels, extravasation of contrast materials, and the formation of arteriovenous fistula [ 103,104]. A skillful technical guarantee and careful studies pinpointing these problems should be encouraged and recommended for increasing patient safety. VI-A.5.

Complications

with speczjic embolizing

agents

The complications due to specific occlusive agents can be better appreciated through a detailed description of these materials [95]. Most of these embolizing agents

Fig. 4. Histological examination of the resected specimen after “‘I-1abelled lipiodol treatment. Macroscopic finding (left) and HE staining of the resected specimen (right, x5) show complete necrosis of the tumor.

have complications based on their chemical or mechanical properties. VI-B. Extruhepatic compkations In addition to effective tumor tissue necrosis and associated hepatic hazards, TAE also exerts its adverse effect on extrahepatic abdominal organs. Some of them are described here. VI-B. 1. Gustroduodenal lesions The gastroduodenal complications of TAE have only rarely been documented [1@5,106].Hirakawa et al. [75], however, demonstrated endoscopic features detailing newly developed or exacerbated gastroduodenal lesions after TAE in 45% of embolization procedures in 25 patients with unresectable HCCs. The lesions vary from multiple ulcers to multiple erosions located from the gastric body to the second portion of the duodenum. These gastroduodenal lesions have been suggested to be due to mucosal ischemia caused by embolic materials, the toxic effect of antineoplastic drugs infused, or to stress. Nakamura et al. [IO51 revealed the histopathological changes in gastroduodenal lesions induced by TAE. Upper gastrointestinal endoscopy should be routinely proposed in patients with abdominal pain after TAE because of the relatively high incidence of TAEassociated gastroduodenal lesions. VI-B. 2. Puncrea tic tissue damage Pancreatic complications of TAE for extrahepatic disease, revealing histopathological evidence of pancreatitis after TAE, have rarely been reported [ 107.108].

Currently, we evaluated the pancreatic tissue damage by TAE for the treatment of HCC by analyzing the serial changes in the serum levels of pancreatic enzymes, such as amylase, elastase 1, trypsin and pancreatic secretory trypsin inhibitor after TAE [109]. In this study, TAE resulted in the elevation of at least more than one serum pancreatic enzyme in 8 (40%) of 20 cases without clinical symptoms related to pancreatitis. This enzyme elevation was observed only in the cases of nonsuperselective TAE. but not in the cases of superselective TAE. Subsequent histological analyses of the pancreatic tissue in autopsy cases with elevated pancreatic enzymes following TAE showed that TAE might contribute to pancreatic damage by microcirculatory disturbance. These observations suggest that the occurrence of severe pancreatic tissue damage by TAE is incidental, but that the TAE frequently causes subclinical pancreatitis. VII. Conclusions

The therapeutic efficacy in cases with hepatic neoplasms remains as yet unsatisfactory. The overall analyses of the merits and demerits of the embolization procedure for the treatment of HCC suggest that selection of the catheter tip, the volume of the embolic materials. and the speed of infusion are mainly responsible. In our previous studies, the volumes of sponge and lipiodol used or the injected doses of anticancer agents were not different between the cases of superselective and nonsuperselective TAE we justified, but the position of the inserted catheter tip and the speed of infusion were closely associated with the major hepatic and extrahepatic complications of TAE. Although the follow-

102

ing criteria of TAE had been proposed by Ishida [I IO], who defined the first branch of the abdominal aorta as selective, and beyond as superselective TAE; however, this selectivity of TAE could not avoid the unpleasant hepatic and extrahepatic complications of TAE as reported by us and others. Our dealings with the superselective TAE from segmental branches of the hepatic arteries are directed to obtain the utmost effect of tumor necrosis and minimize the adverse effect of TAE. In contrast, nonsuperselective TAE from nonsegmental branches of hepatic arteries results in severe hepatic and extrahepatic tissue damage. Therefore we propose the following suggestions to obtain a satisfactory effect and to minimize the hazards of TAE: (1) superselective TAE from the segmental branches of hepatic arteries should be performed using the new and improved materials for embolization; (2) the manual speed of embolic infusions should be strictly controlled under fluoroscopic guidance and reduced in cases of nonsuperselective TAE to minimize reflux of embolic materials into the adjacent vessels; (3) the use of Gelfoam powder which has an easily dislodging property should be avoided and replaced with gelatin sponge particles. Although randomized controlled trials between lipiodolization alone and TOCE. or between TAE and TOCE have not yet been carried out, the percentage of survival of patients with HCC following TOCE is in fact higher than that following TAE with or without chemotherapy. This predominant survival rate by TOCE is possibly due to the added hypoxic or anoxic effect of lipiodol on tumor tissue and the prolonged tumoricidal effect of cytotoxic agents dissolved in lipiodol. However, no detailed information concerning the segmental catheterization during the embolization procedure was demonstrated in the previous reports. The survival rates following either TAE or TOCE can be modulated by the selectivity of TAE. because nonsuperselective TAE subsequently induces impaired liver function in a majority of HCC patients with co-existing advanced cirrhosis. Selectivity of TAE or TOCE, thereby, should be included in the controlled trials. Although these treatment modalities may possibly be a disadvantage to successful chemotherapy, due to the reduction in vascular access [ Ill], the currently developed highly elastic and flexible ‘hi-Ii’ tracker catheter can be used successfully to reach the ultimate goal. Internal radiation therapy using “‘I-labelled lipiodol appears to offer several advantages over current nonsurgical treatments of HCC with respect to both tumoritidal potential and low toxicity to normal tissues. However, a multicenter controlled trial will be necessary to prove its curative treatment for HCC in the cirrhotic liver. In cases with small HCCs, percutaneous ethanol

injection therapy (PEIT) has been performed under ultrasonographic guidance, resulting in a good clinical response in Japan [112,113]. Although an intratumoral injection of ethanol causes immediate coagulative necrosis of the tumor tissue, PEIT is, in general, not indicated for cases with tumors of more than 3 cm in diameter. Liver transplantation has been used as a treatment for selected patients with HCC. The results of liver transplantation are quite promising for the incidental HCC detected as a result of regular clinical monitoring of a cirrhotic patient for the development of HCC. but not for clinically evident HCC [114]. There is a great deal of progress in the imaging technology, including ultrasonography, CT scan and magnetic resonance imaging for the detection of small hepatic neoplasms. Since patients with liver cirrhosis are at substantial risk for HCC, the regular screening program for detecting small HCCs [115] should be indicated for cirrhotic patients, optimizing the therapeutic approach to HCC. Treatment with interferon-a or adoptive immunotherapy with lymphokine-activated killer cells could be of some value to reduce tumor progression [ 116,117]. We also reported that A’*-prostaglandin J-,, an ultimate active metabolite of prostaglandin D1 which can be dissolved in lipid, shows a potent inhibitory effect on the proliferation of tumor cells [118]. It is possible that embolization in combination with these systemic adjuvant therapies or lipiodolization with lipid-soluble new cytotoxic agents have advantages over the current therapies as a preventive, palliative or even curative treatment. This point needs further assessment in prospective, controlled trials. Thus, there is progress in the medical treatment of hepatic neoplasms, and in particular of HCCs. A combination of a variety of treatments in addition to early detection of the tumor should improve the curative rate and the survival in patients with hepatic neoplasms.

Biographies

Keisuke Nukatu received an M.D. degree from Nagasaki University, Japan. He is currently a lecturer at The First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan. Khaleque Newaz Khan recieved an M.D. degree from the University of Dhaka, Bangladesh. He is currently a research fellow of Ph. D. doctoral course at The First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan. Shigerzobu Nagataki received an M.D. degree from the University of Tokyo, Japan. He is currently professor and chairman of The First Department of Internal Medicine, Nagasaki University School of Medicine. Nagasaki. Japan.

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Reviewer This manuscript was reviewed by Stephen Davis, M.D., J.D., Wayne NJ, USA. References

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