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Transcatheter hepatic arterial chemoembolization for hepatocellular carcinoma invading the portal veins: therapeutic effects and prognostic factors
European Journal of Radiology 51 (2004) 12–18
Transcatheter hepatic arterial chemoembolization for hepatocellular carcinoma invading the portal veins: therapeutic effects and prognostic factors Junji Uraki, Koichiro Yamakado∗ , Atsuhiro Nakatsuka, Kan Takeda Department of Radiology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8057, Japan Received 27 May 2003; received in revised form 11 July 2003; accepted 15 July 2003
Abstract Purpose: This retrospective study was undertaken to evaluate the therapeutic effects of transcatheter hepatic arterial chemoembolization on hepatocellular carcinoma (HCC) invading the portal veins and to identify prognostic factors. Materials and methods: Sixty-one patients underwent chemoembolization. The HCC had invaded the main portal vein in 23 patients, a first-order branch in 25 patients and a second-order branch in 13 patients. The hepatic arteries feeding the tumors were embolized with gelatin sponge after a mixture of iodized oil and anticancer drugs was injected via these vessels. Tumor response was evaluated by measuring tumor sizes on CT images. A reduction in maximum diameter of 25% or more was considered to indicate response to chemoembolization. Significant prognostic factors were identified by univariate and multivariate analyses. Results: Tumor size was reduced by 25% or more in 26 patients (43%). The 1-, 3- and 5-year survival rates were 42, 11 and 3%, respectively, with mean survival of 15 months in all patients. In the univariate analysis, the following six variables were significantly associated with prognosis: (i) tumor response; (ii) ascites; (iii) accumulation of iodized oil in tumor thrombi; (iv) in main tumors; (v) Okuda classification; and (vi) tumor size. In the multivariate analysis, the first three of these factors showed significantly independent values for patient prognosis. Conclusion: Chemoembolization appears to be an effective treatment for HCCs invading the portal venous system. The prognostic factors identified here are expected to be helpful in classifying patients with HCCs invading the portal veins and should serve as useful guidelines for chemoembolization in clinical practice. © 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Hepatocellular carcinoma; Portal vein; Chemoembolization; Prognosis
1. Introduction Hepatocellular carcinoma (HCC) has a strong propensity to invade the portal vein and portal vein invasion is one of the most important prognostic factors in patients with HCC [1–7]. If invasion of the main portal vein or first-order portal veins has occurred, surgical intervention is contraindicated in most patients. The mean or median survival periods have been reported to be 3 months without treatment [2], 3.9 months after systemic chemotherapy [8], 3.5 months after transcatheter arterial infusion (TAI) [9] and 6 months after intra-arterial hepatic injection of iodine-131-iodized oil [10]. Despite worldwide application of transcatheter arterial chemoembolization for the treatment of unresectable
HCCs, chemoembolization has been considered to be contraindicated in patients with HCCs invading the portal vein because the risk of liver failure increases after obstruction of both the hepatic artery and the portal vein [11]. On the other hand, several studies have demonstrated the clinical utility of chemoembolization in enhancing the survival of such patients [1–3]. Nevertheless, little is known concerning the factors that affect patient prognosis. This retrospective study was undertaken to identify the prognostic factors in patients with HCC invading the portal vein who were treated by chemoembolization.
2. Materials and methods 2.1. Patients
∗
Corresponding author. Tel.: +81-59-231-5029; fax: +81-59-232-8066. E-mail address: [email protected] (K. Yamakado).
Eighty-one patients with HCCs invading the portal veins underwent angiography from September 1991 to September
0720-048X/$ – see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0720-048X(03)00219-5
J. Uraki et al. / European Journal of Radiology 51 (2004) 12–18 Table 1 Patient and tumor characteristics before chemoembolization
13
Table 1(Continued ) Characteristics
No. (%)
23 (38) 38 (62)
Alpha-fetoprotein (ng/dl) < 10,000 ≥ 10,000
42 (69) 19 (31)
Gender Male Female
52 (85) 9 (15)
Previous treatments for primary tumor Yes No
23 (38) 38 (62)
Aspartate aminotransferase (IU/L) < 80 ≥ 80
30 (49) 31 (51)
Portal venous stent placement Yes No
19 (31) 42 (69)
Alanine aminotransferase (IU/L) < 80 ≥ 80
47 (77) 14 (23)
Albumin (g/dl) < 3.0 ≥ 3.0
10 (17) 51 (83)
Bilirubin (mg/dl) < 1.5 ≥ 1.5
54 (89) 7 (11)
Prothrombin time (%) < 80 ≥ 80
16 (26) 45 (74)
Child–Pugh grade Grade-A Grade-B
45 (74) 16 (26)
Ascites (−) (+)
50 (82) 11 (18)
Tumor size (cm) < 10 ≥ 10
21 (34) 40 (66)
Tumor morphology Nodular Infiltrative
11 (18) 50 (82)
Degree of portal venous invasion Main portal vein First order branch Second order branch
23 (38) 25 (41) 13 (21)
Okuda staging Stage-1 Stage-2
16 (26) 45 (74)
Tumor extension (segment) 1 or 2 3 or more
23 (38) 38 (62)
Characteristics
No. (%)
Age (years) < 60 ≥ 60
2001. Chemoembolization was not performed on patients with a Child–Pugh class-C liver profile, hyperbilirubinemia >3 ng/dl or complete obstruction of the main portal vein. However, seven patients with complete obstruction of the main portal vein underwent chemoembolization after metallic stents were placed in the vessel [12]. Chemoembolization was performed in 61 of these 81 patients. Written informed consent was obtained from the patients and their family members. The characteristics of the patients and the tumors are summarized in Table 1. Nine patients were women and 52 patients were men, with a mean age of 63.4 ± 9.6 years (range, 44–79 years). The diagnosis of HCC was mainly established based on the results of radiological diagnostic imaging studies and elevation of ␣ fetoprotein
Fig. 1. Infiltrative hepatocellular carcinoma invading the left and main portal veins in a 59-year-old man. (a) An axial contrast-enhanced computed tomographic (CT) image shows tumor thrombus in the main portal vein (arrow). (b) Frontal left hepatic arteriography shows a hypervascular tumor occupying the left lobe and tumor thrombus (‘thread and streak’ sign) in the left and main portal veins (arrows). Chemoembolization was performed in the left hepatic artery. (c) An axial CT scan obtained 1 month after chemoembolization demonstrates iodized oil accumulation in the main tumor and in the portal tumor thrombus. The patient is still alive more than 5 years after the procedure.
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J. Uraki et al. / European Journal of Radiology 51 (2004) 12–18
Fig. 1. (Continued ).
(AFP) values. The diagnostic imaging studies included ultrasound (US), computed tomography (CT), magnetic resonance (MR) imaging, angiography, CT during arteriography (CTAP) and CT hepatic arteriography (CTHA) (Fig. 1(a, b) and Fig. 2(a)). Portal venous invasion was confirmed in each case by demonstrating the presence of an intraluminal mass extending from the main tumor and expanding the portal vein in US, CT and MR studies, the presence of the ‘thread and streaks’ sign and arterioportal shunting in hepatic arteriograms, and/or the presence of filling defects in the portal vein in transarterial portography and CTAP (Fig. 1(a, b) and Fig. 2(a)). Portal venous invasion was found at the time of diagnosis of HCC and chemoembolization was the initial treatment for HCC in 38 patients. Tumor thrombi developed during the follow-up period in the other 23 patients who had received previous therapy. Fourteen patients had undergone chemoembolization, eight patients had undergone both chemoembolization and percutaneous ethanol injection (PEI) and one patient had undergone hepatic resection before the appearance of portal venous invasion. The tu-
Fig. 2. Infiltrative hepatocellular carcinoma invading the right, left and main portal veins in a 59-year-old man. (a) An axial CT during arterial portography (CTAP) image shows infiltrating tumor occupying the right hepatic lobe. The tumor has invaded the right, left and main portal veins (arrow). Chemoembolization was performed in the right hepatic artery. (b) An axial CTAP image obtained 3 years after initial chemoembolization shows atrophy of the embolized right liver parenchyma including the tumor and hypertrophy of the left hepatic lobe.
mor had invaded the main portal vein in 23 patients (Figs. 1 and 2), a first-order branch in 25 patients and a second-order branch in 13 patients. The mean tumor size was 10.7 ± 3.7 cm (range: 4–19 cm). The maximum tumor size was < 10 cm in 21 patients and 10 cm or more in the other 40 patients. The tumor morphologic type was nodular in 11 patients and infiltrative in 50 patients according to ‘The General Rules for the Clinical and Pathological Study of Primary Liver Cancer’ [13]. Associated liver cirrhosis was observed in all patients. According to the Child–Pugh classification, 45 patients had A grade liver profiles and 16 patients had grade B liver profiles. With regard to the tumor stage based on the Okuda classification [5], 16 patients had stage I disease and 45 patients had stage II disease. 2.2. Chemoembolization Tumor size and number, the feeding arteries and the degree of portal venous thrombosis were evaluated by celiac and superior mesenteric angiography. Chemoembolization
J. Uraki et al. / European Journal of Radiology 51 (2004) 12–18
was performed after a 3F microcatheter (MicroPheret, William Cook Europe, Bjaevevskov, Denmark) was advanced into the feeding arteries. A mixture of iodized oil (Lipiodol, Andre Guerbet, Aulnay-sous-Bois, France) and doxorubicin hydrochloride (Adriacin, Kyowa-Hakko, Tokyo, Japan) was injected into the feeding arteries followed by gelatin sponge (Gelfoam, Pharmacia and Upjohn, Kalamazoo, MI). The injected dose of iodized oil depended on the tumor size, ranging from 1 to 20 ml (mean: 7.6 ml). The gelatin sponge employed consisted of cubes measuring 1–2 mm, which were injected until alternating anterograde and retrograde blood flow was observed in the feeding arteries. Tumor response was evaluated based on CT studies performed 1–3 months after chemoembolization and classified into five grades as follows: complete response (CR) corresponded to total disappearance of the tumor, partial response (PR) to a reduction in maximum tumor size of 50% or more on CT images, minimal response (MR) to a reduction of 25–50%, stable disease (SD) to a change in tumor size of < 25% and progressive disease (PD) to an increase in tumor size of 25% or more [14]. Changes in AFP values were also evaluated in patients with abnormal AFP values at the time of chemoembolization. 2.3. Variables analyzed The 21 variables (Tables 1 and 2) were analyzed to determine their relationship with prognosis by univariate analysis. These variables were selected because possible effects on prognosis had been identified in previous studies [1–3,5,15–21] or were suspected based on our own clinical experience (Table 1). The patients were divided into two subgroups based on each variable. Age and gender were selected to represent individual clinical covariates. With regard to the factors related to the liver profile, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) valTable 2 Therapeutic results Therapeutic results
No. (%)
Iodized oil uptake in main tumor ≥ 80% < 80%
29 (47) 32 (53)
Iodized oil uptake in portal tumor thrombi Yes 33 (54) No 28 (46) Tumor response Yes No
26 (43) 35 (57)
Repeat hepatic arterial infusion chemotherapy after chemoembolization Yes 22 (36) No 39 (64)
15
ues, serum albumin and bilirubin levels, the percent prothrombin time, the Child–Pugh grade and the presence of ascites were included as variables. To represent tumor characteristics, tumor size and morphology, the degree of portal venous invasion, the Okuda classification, tumor extension and AFP values were included. Previous therapy and the combined use of portal venous stent placement were also included as variables. The following post-treatment parameters were also evaluated: iodized-oil uptake in the main tumor and tumor thrombi, tumor response and the subsequent use of repeat hepatic arterial infusion chemotherapy (Table 2). 2.4. Statistical analysis Data are expressed as mean ± S.D. Changes in AFP values were compared before and 1 month after chemoembolization using the paired Student’s t-test. The tumor response rates were compared between subgroups of patients divided according to each factor by the χ2 -test. The estimated survival rates were calculated using the Kaplan–Meier method. The differences in the estimated survival rates between the subgroups divided according to each variable were compared using the log-rank test. In addition to age and gender, variables that achieved statistical significance (P < 0.05) or were close to significance (P < 0.1) in the univariate analysis were subsequently included in a multivariate analysis using a Cox proportional hazards model. A stepwise regression procedure was used to determine which factors were the major independent predictors of prognosis. A P value of < 0.05 was considered to be statistically significant.
3. Results 3.1. Chemoembolization Chemoembolization was performed in a segmental artery in ten patients and in a lobar artery in 51 patients. Patients underwent chemoembolization 132 times (twice for each patient) during the follow-up period. Repeat arterial infusion chemotherapy using an implanted catheter and port system was performed as combination therapy after chemoembolization in 22 patients. 3.2. Therapeutic effects and survival Although both AST and ALT values increased 3- to 10-fold from baseline levels, all but one patient tolerated chemoembolization well. That patient developed massive liver failure and died 1 month after chemoembolization. Follow-up CT showed that the embolized liver parenchyma including the tumor shrank after chemoembolization, with concomitant hypertrophy of the unembolized liver parenchyma (Fig. 2b). Iodized oil accumulation was observed in the main tumor in all patients (Fig. 1c), but the degree of accumulation was < 80% of the tumor volume
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J. Uraki et al. / European Journal of Radiology 51 (2004) 12–18
Table 3 Significant prognostic factors in univariate analysis Variables
n
Mean survival (month)
Estimated survival rate (%) (Kaplan–Meier method) 1-year
2-year
3-year
4-year
5-year
P value < 0.0001
Tumor response Tumor reduction >25% No change or progression
26 35
26.7 6.6
84 9
53 3
26 0
13 0
7 0
Okuda staging Stage-1 Stage-2
16 45
29.2 11.1
67 33
45 17
45 3
30 0
15 0
Iodized oil uptake in tumor Yes No
33 28
19.6 10.3
53 29
39 9
15 9
10 0
5 0
Iodized oil uptake in main tumors >80% < 80%
29 32
20.2 10.5
58 27
38 12
16 6
11 0
5 0
Ascites (−) (+)
50 11
17 7.6
45 27
28 9
14 0
7 0
4 0
Tumor size (cm) < 10 ≥ 10
21 40
21.9 11.6
61 32
33 20
25 4
17 0
4 0
Total
61
15.1
42
25
11
5
3
< 0.002
< 0.005
< 0.006
< 0.02
< 0.02
in more than half of the patients (53%, 32/61). Iodized oil accumulation was also observed in the tumor thrombi in 54% (33/61) of the patients (Fig. 1(c) and Table 2). Although no tumors completely disappeared after chemoembolization, tumor sizes were reduced by 25% or more in 26 patients (43%, 26/61) (Fig. 2b). Tumor size was reduced by 50% or more in eight patients and by 25–50% in 18 patients. Tumor size was unchanged in 16 patients (26%, 16/61) and was increased in the remaining 19 patients (31%, 19/61). The AFP values were abnormal in 17 of 26 responders before chemoembolization and the values fell in all of these patients after chemoembolization. The mean AFP value decreased from 80370 ± 209890 to 7440 ± 13366 ng/dl (P < 0.2). The AFP values were abnormal in 29 of 35 non-responders before chemoembolization and the values decreased in 52% (17/29) of these patients. The mean AFP value increased 1 month after chemoembolization from 34390 ± 78002 to 55960 ± 21392 ng/dl (P < 0.5) in the non-responders.
Repeat hepatic arterial infusion chemotherapy was carried out in 22 patients (Table 2). The estimated 1-, 3- and 5-year survival rates were 42, 11 and 3%, with mean survival of 15.1 ± 2.0 months in all patients. 3.3. Univariate and multivariate analyses The results of the univariate and multivariate analyses are summarized in Tables 3 and 4. In the univariate analysis, the following six variables were significantly associated with prognosis: (i) tumor response; (ii) ascites; (iii) accumulation of iodized oil in tumor thrombi; (iv) in main tumors; (v) Okuda classification; and (vi) tumor size (Table 3). In the multivariate analysis, the first three of these factors were found to show significant independent predictive value for prognosis (Table 4). The degree of portal venous invasion did not have a significant impact on prognosis.
Table 4 Significant prognostic factors in multivariate analysis Variables
Coefficient (β)
S.E.
β/S.E.
χ2
P value
Tumor response Iodized oil accumulation in tumor thrombi Ascites
2.2 0.72 1.2
0.4 0.2 0.4
5.8 2.4 3.3
33.4 5.9 10.7
< 0.0001 0.016 0.011
J. Uraki et al. / European Journal of Radiology 51 (2004) 12–18
4. Discussion 4.1. Therapeutic effects and prognostic factors In the present study, tumor response was achieved in 42% of patients after chemoembolization and tumor response was found to be the most important prognostic factor. It is noteworthy that the mean survival periods were >1 year (15.1 months) in all patients and >2 years (26.7 months) in responders. Few previous studies have evaluated the therapeutic effects of chemoembolization on HCCs invading the portal veins. Chung et al. performed oil-based chemoembolization in 110 patients [1]. The tumor response rate and median survival period were reported to be 35% and 6 months, respectively. They stated that parenchymal tumor extent was the only significant prognostic factor in the univariate analysis. Lee et al. performed chemoembolization in 31 patients with HCCs obstructing the main portal veins [2]. The tumor response rate was 45% and median survival was 5 months. They stated that tumor morphology was the only factor showing significant prognostic value in the multivariate analysis. They speculated that the superior therapeutic effects observed for nodular-type HCCs compared with infiltrative-type HCCs leads to a better prognosis and concluded that patients with infiltrative-type HCCs obstructing the main portal veins are not candidates for chemoembolization. Higashihara et al. performed chemoembolization in 221 patients [3]. The tumor invaded the second-order branch in 77 patients, the first-order branch in 63 and the main trunk in 81 patients. The 5-year survival rates and mean survival periods were 7.7% and 475 days, 8.6% and 406 days, and 6.2% and 350 days, respectively. They have described that an extended survival can be obtained when tumor extent was limited to one lobe and the hepatic function was well preserved. The present study showed the same therapeutic results as those achieved by Higashihara et al. However, neither parenchymal tumor extent nor tumor morphology showed a significant impact on prognosis. In addition to tumor response, iodized oil uptake in tumor thrombi was another independent factor affecting prognosis. Lee et al. also reported that this factor had a significant impact on survival in the univariate analysis [2]. The absence of iodized oil accumulation may suggest the presence of another feeding artery, such as a peribiliary artery or vasa vasorum or the rapid washout of iodized oil from the tumor thrombi, indicating insufficient tumor necrosis. Ascites was the only pre-treatment factor found to affect prognosis in the multivariate analysis. The presence of ascites is a clinical manifestation of poor hepatic reserve and portal hypertension. Chemoembolization increases portal venous pressure and ascites, resulting in exacerbation of the liver profile. In addition to the three factors found to be independent prognostic factors in the multivariate analysis, another
17
three factors were found to be associated with prognosis in the univariate analysis. Two of these were pre-treatment factors (Okuda classification and tumor size) and one was a post-treatment factor (iodized oil uptake in the main tumor). Minagawa et al. performed chemoembolization in 45 patients with HCC and portal vein tumor thrombus and subsequent hepatic resection in 18 of them. They have reported a good 5-year survival as high as 42% in patients who received hepatic resection [22]. They concluded that combination of chemoembolization and hepatic resection enhance patients’ survival when the number of primary nodules is no more than two, the portal trunk is not occluded by tumor thrombus and the indocyanine green retention rate at 15 min (ICGR15) is better than 20%. Hepatic resection following chemoembolization may be an option for further treatment when patients meet their selection criteria for hepatic resection. 4.2. Indications for chemoembolization Considering the fact that post-treatment findings are important prognostic factors, chemoembolization itself appears to be a factor affecting the prognosis of patients with HCCs invading the portal veins. Therefore, It is very important to establish clear selection criteria to ensure safe chemoembolization. With regard to the selection criteria for the chemoembolization of HCCs invading the portal veins, we considered the Child–Pugh class, bilirubin values and patency of the main portal vein. These criteria were considered to be relatively reliable because fatal liver failure developed in only one patient (1/61, 1.6%). However, the limited number of patients and the patient selection bias related to the inclusion criteria in the present study do not allow us to identify good selection criteria to ensure safe chemoembolization. In the near future, appropriate selection criteria for safe chemoembolization should be established. Okamoto et al. have established a safe limit of hepatic resection by measuring the hepatic parenchymal volume excluding tumor volume and ICGR15 [23]. This volumetric analysis may be useful in ensuring safe chemoembolization in patients with HCC invading portal veins.
5. Conclusion Chemoembolization is an effective therapeutic method for HCCs invading the portal venous system. Post-treatment factors and the presence of ascites at the time of chemoembolization are the most important prognostic factors. Although our results should be confirmed in future prospective studies, the factors identified as affecting prognosis in the present study should prove helpful in classifying patients with HCCs invading the portal veins who are treated by chemoembolization and should serve as useful guidelines for chemoembolization in clinical practice.
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References [1] Chung JW, Park JH, Han JK, Choi BI, Han MC. Hepatocellular carcinoma and portal vein invasion: results of treatment with transcatheter oily chemoembolization. Am J Roentgenol 1995;165:315– 21. [2] Lee HS, Kim JS, Choi IJ, Chung JW, Park JH, Kim CY. The safety and efficacy of transcatheter arterial chemoembolization in the treatment of patients with hepatocellular carcinoma and main portal vein obstruction. Cancer 1997;79:2087–94. [3] Higashihara H, Okazaki M. Transcatheter arterial chemoembolization of hepatocellular carcinoma: a Japanese experience. Hepatogastroenterology 2002;49(43):72–8. [4] Katsumori T, Fujita M, Takahashi T, et al. Effective segmental chemoembolization of advanced hepatocellular carcinoma with tumor thrombus in the portal vein. Cardiovasc Intervent Radiol 1995;18:217–21. [5] Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment: study of 850 patients. Cancer 1985;56:918–28. [6] Chen SC, Hsieh MY, Chuang WL, Wang LY, Chang WY. Development of portal vein invasion and its outcome in hepatocellular carcinoma treated by transcatheter arterial chemo-embolization. J Gastroenterol Hepatol 1994;9:1–6. [7] Izumi R, Shimizu K, Ii T, Yagi M, Maatui O, Nonomura A, Miyazaki I. Prognostic factors of hepatocellular carcinoma in patients undergoing hepatic resection. Gastroenterology 1994;106:720–7. [8] Okada S, Okazaki N, Nose H, Yoshimori M, Aoki K. Prognostic factors in patients with hepatocellular carcinoma receiving systemic chemotherapy. Hepatology 1992;16:112–7. [9] Kumagai M. Clinical evaluation of tumor invasion in the portal vein demonstrated by angiography in patients with hepatocellular carcinoma. Kanzou 1985;26(11):1514–21. [10] Raoul JL, Guyader D, Bretagne JF, et al. Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support. J Nucl Med 1994;35:1782–7. [11] Yamada R, Sato M, Kayabata M, Nakatsuka H, Nakamura K, Takashima S. Hepatic artery embolization in 120 patients with unresectable hepatoma. Radiology 1983;148:397–401.
[12] Yamakado K, Nakatsuka A, Tanaka N, Fujii A, Terada N, Takeda K. Malignant portal venous obstructions treated by stent placement: significant factors affecting patency. J Vasc Radiol 2001;12:1407–15. [13] Liver Cancer Study Group of Japan. Macroscopic pattern, In: Liver Cancer Study Group of Japan. The general rules for the clinical and pathological study of primary liver cancer. 4th ed. Tokyo, Japan: Kanehara and Co. Ltd., 2000. p. 13–14. [14] Atiq OT, Kemeny N, Niedzwiecki D, Botet J. Treatment of unresectable primary liver cancer with intrahepatic fluorodeoxyuridine and mitomycin C through an implantable pump. Cancer 1992;69:920– 4. [15] Taniguchi K, Nakata K, Kato Y, et al. Treatment of hepatocellular carcinoma with transcatheter arterial embolization: analysis of prognostic factors. Cancer 1994;73:1341–5. [16] Akashi Y, Koreeda C, Enomoto S, et al. Prognosis of unresectable hepatocellular carcinoma: an evaluation based on multivariate analysis of 90 cases. Hepatology 1991;14:262–8. [17] Sakurai M, Okamura J, Kuroda C. Transcatheter chemo-embolization effective for treating hepatocellular carcinoma: a histopathologic study. Cancer 1984;54:387–92. [18] Nakamura H, Liu T, Hori S, et al. Response to transcatheter oily chemoembolization in hepatocellular carcinoma 3 cm or less: a study in 50 patients who underwent surgery. Hepatogastroenterology 1993;40:6–9. [19] Hashimoto T, Nakamura H, Hori S, et al. Hepatocellular carcinoma: efficacy of transcatheter oily chemoembolization in relation to macroscopic and microscopic patterns of tumor growth among 100 patients with partial hepatectomy. Cardiovasc Intervent Radiol 1995;18:82–6. [20] Sakon M, Monden M, Umeshita K, et al. The prognostic significance of macroscopic growth pattern of hepatocellular carcinoma. Int Surg 1994;79:38–42. [21] Lai EC, Ng IO, You KT, Choi TK, Mok FP, Wong J. Hepatectomy for large hepatocellular carcinoma: the optimal resection margin. World J Surg 1991;15:141–5. [22] Minagawa M, Makuuchi M, Takayama T, Ohtomo K. Selection criteria for hepatectomy in patients with hepatocellular carcinoma and portal vein tumor thrombus. Ann Surg 2001;233(3):379–84. [23] Okamoto E, Kyo A, Yamanaka N, Tanaka N, Kuwata K. Prediction of the safe limits of hepatectomy by combined volumetric and functional measurements in patients with impaired hepatic function. Surgery 1984;95(5):586–92.
Transcatheter hepatic arterial chemoembolization for hepatocellular carcinoma invading the portal veins: therapeutic effects and prognostic factors Junji Uraki, Koichiro Yamakado∗ , Atsuhiro Nakatsuka, Kan Takeda Department of Radiology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8057, Japan Received 27 May 2003; received in revised form 11 July 2003; accepted 15 July 2003
Abstract Purpose: This retrospective study was undertaken to evaluate the therapeutic effects of transcatheter hepatic arterial chemoembolization on hepatocellular carcinoma (HCC) invading the portal veins and to identify prognostic factors. Materials and methods: Sixty-one patients underwent chemoembolization. The HCC had invaded the main portal vein in 23 patients, a first-order branch in 25 patients and a second-order branch in 13 patients. The hepatic arteries feeding the tumors were embolized with gelatin sponge after a mixture of iodized oil and anticancer drugs was injected via these vessels. Tumor response was evaluated by measuring tumor sizes on CT images. A reduction in maximum diameter of 25% or more was considered to indicate response to chemoembolization. Significant prognostic factors were identified by univariate and multivariate analyses. Results: Tumor size was reduced by 25% or more in 26 patients (43%). The 1-, 3- and 5-year survival rates were 42, 11 and 3%, respectively, with mean survival of 15 months in all patients. In the univariate analysis, the following six variables were significantly associated with prognosis: (i) tumor response; (ii) ascites; (iii) accumulation of iodized oil in tumor thrombi; (iv) in main tumors; (v) Okuda classification; and (vi) tumor size. In the multivariate analysis, the first three of these factors showed significantly independent values for patient prognosis. Conclusion: Chemoembolization appears to be an effective treatment for HCCs invading the portal venous system. The prognostic factors identified here are expected to be helpful in classifying patients with HCCs invading the portal veins and should serve as useful guidelines for chemoembolization in clinical practice. © 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Hepatocellular carcinoma; Portal vein; Chemoembolization; Prognosis
1. Introduction Hepatocellular carcinoma (HCC) has a strong propensity to invade the portal vein and portal vein invasion is one of the most important prognostic factors in patients with HCC [1–7]. If invasion of the main portal vein or first-order portal veins has occurred, surgical intervention is contraindicated in most patients. The mean or median survival periods have been reported to be 3 months without treatment [2], 3.9 months after systemic chemotherapy [8], 3.5 months after transcatheter arterial infusion (TAI) [9] and 6 months after intra-arterial hepatic injection of iodine-131-iodized oil [10]. Despite worldwide application of transcatheter arterial chemoembolization for the treatment of unresectable
HCCs, chemoembolization has been considered to be contraindicated in patients with HCCs invading the portal vein because the risk of liver failure increases after obstruction of both the hepatic artery and the portal vein [11]. On the other hand, several studies have demonstrated the clinical utility of chemoembolization in enhancing the survival of such patients [1–3]. Nevertheless, little is known concerning the factors that affect patient prognosis. This retrospective study was undertaken to identify the prognostic factors in patients with HCC invading the portal vein who were treated by chemoembolization.
2. Materials and methods 2.1. Patients
∗
Corresponding author. Tel.: +81-59-231-5029; fax: +81-59-232-8066. E-mail address: [email protected] (K. Yamakado).
Eighty-one patients with HCCs invading the portal veins underwent angiography from September 1991 to September
0720-048X/$ – see front matter © 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0720-048X(03)00219-5
J. Uraki et al. / European Journal of Radiology 51 (2004) 12–18 Table 1 Patient and tumor characteristics before chemoembolization
13
Table 1(Continued ) Characteristics
No. (%)
23 (38) 38 (62)
Alpha-fetoprotein (ng/dl) < 10,000 ≥ 10,000
42 (69) 19 (31)
Gender Male Female
52 (85) 9 (15)
Previous treatments for primary tumor Yes No
23 (38) 38 (62)
Aspartate aminotransferase (IU/L) < 80 ≥ 80
30 (49) 31 (51)
Portal venous stent placement Yes No
19 (31) 42 (69)
Alanine aminotransferase (IU/L) < 80 ≥ 80
47 (77) 14 (23)
Albumin (g/dl) < 3.0 ≥ 3.0
10 (17) 51 (83)
Bilirubin (mg/dl) < 1.5 ≥ 1.5
54 (89) 7 (11)
Prothrombin time (%) < 80 ≥ 80
16 (26) 45 (74)
Child–Pugh grade Grade-A Grade-B
45 (74) 16 (26)
Ascites (−) (+)
50 (82) 11 (18)
Tumor size (cm) < 10 ≥ 10
21 (34) 40 (66)
Tumor morphology Nodular Infiltrative
11 (18) 50 (82)
Degree of portal venous invasion Main portal vein First order branch Second order branch
23 (38) 25 (41) 13 (21)
Okuda staging Stage-1 Stage-2
16 (26) 45 (74)
Tumor extension (segment) 1 or 2 3 or more
23 (38) 38 (62)
Characteristics
No. (%)
Age (years) < 60 ≥ 60
2001. Chemoembolization was not performed on patients with a Child–Pugh class-C liver profile, hyperbilirubinemia >3 ng/dl or complete obstruction of the main portal vein. However, seven patients with complete obstruction of the main portal vein underwent chemoembolization after metallic stents were placed in the vessel [12]. Chemoembolization was performed in 61 of these 81 patients. Written informed consent was obtained from the patients and their family members. The characteristics of the patients and the tumors are summarized in Table 1. Nine patients were women and 52 patients were men, with a mean age of 63.4 ± 9.6 years (range, 44–79 years). The diagnosis of HCC was mainly established based on the results of radiological diagnostic imaging studies and elevation of ␣ fetoprotein
Fig. 1. Infiltrative hepatocellular carcinoma invading the left and main portal veins in a 59-year-old man. (a) An axial contrast-enhanced computed tomographic (CT) image shows tumor thrombus in the main portal vein (arrow). (b) Frontal left hepatic arteriography shows a hypervascular tumor occupying the left lobe and tumor thrombus (‘thread and streak’ sign) in the left and main portal veins (arrows). Chemoembolization was performed in the left hepatic artery. (c) An axial CT scan obtained 1 month after chemoembolization demonstrates iodized oil accumulation in the main tumor and in the portal tumor thrombus. The patient is still alive more than 5 years after the procedure.
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Fig. 1. (Continued ).
(AFP) values. The diagnostic imaging studies included ultrasound (US), computed tomography (CT), magnetic resonance (MR) imaging, angiography, CT during arteriography (CTAP) and CT hepatic arteriography (CTHA) (Fig. 1(a, b) and Fig. 2(a)). Portal venous invasion was confirmed in each case by demonstrating the presence of an intraluminal mass extending from the main tumor and expanding the portal vein in US, CT and MR studies, the presence of the ‘thread and streaks’ sign and arterioportal shunting in hepatic arteriograms, and/or the presence of filling defects in the portal vein in transarterial portography and CTAP (Fig. 1(a, b) and Fig. 2(a)). Portal venous invasion was found at the time of diagnosis of HCC and chemoembolization was the initial treatment for HCC in 38 patients. Tumor thrombi developed during the follow-up period in the other 23 patients who had received previous therapy. Fourteen patients had undergone chemoembolization, eight patients had undergone both chemoembolization and percutaneous ethanol injection (PEI) and one patient had undergone hepatic resection before the appearance of portal venous invasion. The tu-
Fig. 2. Infiltrative hepatocellular carcinoma invading the right, left and main portal veins in a 59-year-old man. (a) An axial CT during arterial portography (CTAP) image shows infiltrating tumor occupying the right hepatic lobe. The tumor has invaded the right, left and main portal veins (arrow). Chemoembolization was performed in the right hepatic artery. (b) An axial CTAP image obtained 3 years after initial chemoembolization shows atrophy of the embolized right liver parenchyma including the tumor and hypertrophy of the left hepatic lobe.
mor had invaded the main portal vein in 23 patients (Figs. 1 and 2), a first-order branch in 25 patients and a second-order branch in 13 patients. The mean tumor size was 10.7 ± 3.7 cm (range: 4–19 cm). The maximum tumor size was < 10 cm in 21 patients and 10 cm or more in the other 40 patients. The tumor morphologic type was nodular in 11 patients and infiltrative in 50 patients according to ‘The General Rules for the Clinical and Pathological Study of Primary Liver Cancer’ [13]. Associated liver cirrhosis was observed in all patients. According to the Child–Pugh classification, 45 patients had A grade liver profiles and 16 patients had grade B liver profiles. With regard to the tumor stage based on the Okuda classification [5], 16 patients had stage I disease and 45 patients had stage II disease. 2.2. Chemoembolization Tumor size and number, the feeding arteries and the degree of portal venous thrombosis were evaluated by celiac and superior mesenteric angiography. Chemoembolization
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was performed after a 3F microcatheter (MicroPheret, William Cook Europe, Bjaevevskov, Denmark) was advanced into the feeding arteries. A mixture of iodized oil (Lipiodol, Andre Guerbet, Aulnay-sous-Bois, France) and doxorubicin hydrochloride (Adriacin, Kyowa-Hakko, Tokyo, Japan) was injected into the feeding arteries followed by gelatin sponge (Gelfoam, Pharmacia and Upjohn, Kalamazoo, MI). The injected dose of iodized oil depended on the tumor size, ranging from 1 to 20 ml (mean: 7.6 ml). The gelatin sponge employed consisted of cubes measuring 1–2 mm, which were injected until alternating anterograde and retrograde blood flow was observed in the feeding arteries. Tumor response was evaluated based on CT studies performed 1–3 months after chemoembolization and classified into five grades as follows: complete response (CR) corresponded to total disappearance of the tumor, partial response (PR) to a reduction in maximum tumor size of 50% or more on CT images, minimal response (MR) to a reduction of 25–50%, stable disease (SD) to a change in tumor size of < 25% and progressive disease (PD) to an increase in tumor size of 25% or more [14]. Changes in AFP values were also evaluated in patients with abnormal AFP values at the time of chemoembolization. 2.3. Variables analyzed The 21 variables (Tables 1 and 2) were analyzed to determine their relationship with prognosis by univariate analysis. These variables were selected because possible effects on prognosis had been identified in previous studies [1–3,5,15–21] or were suspected based on our own clinical experience (Table 1). The patients were divided into two subgroups based on each variable. Age and gender were selected to represent individual clinical covariates. With regard to the factors related to the liver profile, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) valTable 2 Therapeutic results Therapeutic results
No. (%)
Iodized oil uptake in main tumor ≥ 80% < 80%
29 (47) 32 (53)
Iodized oil uptake in portal tumor thrombi Yes 33 (54) No 28 (46) Tumor response Yes No
26 (43) 35 (57)
Repeat hepatic arterial infusion chemotherapy after chemoembolization Yes 22 (36) No 39 (64)
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ues, serum albumin and bilirubin levels, the percent prothrombin time, the Child–Pugh grade and the presence of ascites were included as variables. To represent tumor characteristics, tumor size and morphology, the degree of portal venous invasion, the Okuda classification, tumor extension and AFP values were included. Previous therapy and the combined use of portal venous stent placement were also included as variables. The following post-treatment parameters were also evaluated: iodized-oil uptake in the main tumor and tumor thrombi, tumor response and the subsequent use of repeat hepatic arterial infusion chemotherapy (Table 2). 2.4. Statistical analysis Data are expressed as mean ± S.D. Changes in AFP values were compared before and 1 month after chemoembolization using the paired Student’s t-test. The tumor response rates were compared between subgroups of patients divided according to each factor by the χ2 -test. The estimated survival rates were calculated using the Kaplan–Meier method. The differences in the estimated survival rates between the subgroups divided according to each variable were compared using the log-rank test. In addition to age and gender, variables that achieved statistical significance (P < 0.05) or were close to significance (P < 0.1) in the univariate analysis were subsequently included in a multivariate analysis using a Cox proportional hazards model. A stepwise regression procedure was used to determine which factors were the major independent predictors of prognosis. A P value of < 0.05 was considered to be statistically significant.
3. Results 3.1. Chemoembolization Chemoembolization was performed in a segmental artery in ten patients and in a lobar artery in 51 patients. Patients underwent chemoembolization 132 times (twice for each patient) during the follow-up period. Repeat arterial infusion chemotherapy using an implanted catheter and port system was performed as combination therapy after chemoembolization in 22 patients. 3.2. Therapeutic effects and survival Although both AST and ALT values increased 3- to 10-fold from baseline levels, all but one patient tolerated chemoembolization well. That patient developed massive liver failure and died 1 month after chemoembolization. Follow-up CT showed that the embolized liver parenchyma including the tumor shrank after chemoembolization, with concomitant hypertrophy of the unembolized liver parenchyma (Fig. 2b). Iodized oil accumulation was observed in the main tumor in all patients (Fig. 1c), but the degree of accumulation was < 80% of the tumor volume
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Table 3 Significant prognostic factors in univariate analysis Variables
n
Mean survival (month)
Estimated survival rate (%) (Kaplan–Meier method) 1-year
2-year
3-year
4-year
5-year
P value < 0.0001
Tumor response Tumor reduction >25% No change or progression
26 35
26.7 6.6
84 9
53 3
26 0
13 0
7 0
Okuda staging Stage-1 Stage-2
16 45
29.2 11.1
67 33
45 17
45 3
30 0
15 0
Iodized oil uptake in tumor Yes No
33 28
19.6 10.3
53 29
39 9
15 9
10 0
5 0
Iodized oil uptake in main tumors >80% < 80%
29 32
20.2 10.5
58 27
38 12
16 6
11 0
5 0
Ascites (−) (+)
50 11
17 7.6
45 27
28 9
14 0
7 0
4 0
Tumor size (cm) < 10 ≥ 10
21 40
21.9 11.6
61 32
33 20
25 4
17 0
4 0
Total
61
15.1
42
25
11
5
3
< 0.002
< 0.005
< 0.006
< 0.02
< 0.02
in more than half of the patients (53%, 32/61). Iodized oil accumulation was also observed in the tumor thrombi in 54% (33/61) of the patients (Fig. 1(c) and Table 2). Although no tumors completely disappeared after chemoembolization, tumor sizes were reduced by 25% or more in 26 patients (43%, 26/61) (Fig. 2b). Tumor size was reduced by 50% or more in eight patients and by 25–50% in 18 patients. Tumor size was unchanged in 16 patients (26%, 16/61) and was increased in the remaining 19 patients (31%, 19/61). The AFP values were abnormal in 17 of 26 responders before chemoembolization and the values fell in all of these patients after chemoembolization. The mean AFP value decreased from 80370 ± 209890 to 7440 ± 13366 ng/dl (P < 0.2). The AFP values were abnormal in 29 of 35 non-responders before chemoembolization and the values decreased in 52% (17/29) of these patients. The mean AFP value increased 1 month after chemoembolization from 34390 ± 78002 to 55960 ± 21392 ng/dl (P < 0.5) in the non-responders.
Repeat hepatic arterial infusion chemotherapy was carried out in 22 patients (Table 2). The estimated 1-, 3- and 5-year survival rates were 42, 11 and 3%, with mean survival of 15.1 ± 2.0 months in all patients. 3.3. Univariate and multivariate analyses The results of the univariate and multivariate analyses are summarized in Tables 3 and 4. In the univariate analysis, the following six variables were significantly associated with prognosis: (i) tumor response; (ii) ascites; (iii) accumulation of iodized oil in tumor thrombi; (iv) in main tumors; (v) Okuda classification; and (vi) tumor size (Table 3). In the multivariate analysis, the first three of these factors were found to show significant independent predictive value for prognosis (Table 4). The degree of portal venous invasion did not have a significant impact on prognosis.
Table 4 Significant prognostic factors in multivariate analysis Variables
Coefficient (β)
S.E.
β/S.E.
χ2
P value
Tumor response Iodized oil accumulation in tumor thrombi Ascites
2.2 0.72 1.2
0.4 0.2 0.4
5.8 2.4 3.3
33.4 5.9 10.7
< 0.0001 0.016 0.011
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4. Discussion 4.1. Therapeutic effects and prognostic factors In the present study, tumor response was achieved in 42% of patients after chemoembolization and tumor response was found to be the most important prognostic factor. It is noteworthy that the mean survival periods were >1 year (15.1 months) in all patients and >2 years (26.7 months) in responders. Few previous studies have evaluated the therapeutic effects of chemoembolization on HCCs invading the portal veins. Chung et al. performed oil-based chemoembolization in 110 patients [1]. The tumor response rate and median survival period were reported to be 35% and 6 months, respectively. They stated that parenchymal tumor extent was the only significant prognostic factor in the univariate analysis. Lee et al. performed chemoembolization in 31 patients with HCCs obstructing the main portal veins [2]. The tumor response rate was 45% and median survival was 5 months. They stated that tumor morphology was the only factor showing significant prognostic value in the multivariate analysis. They speculated that the superior therapeutic effects observed for nodular-type HCCs compared with infiltrative-type HCCs leads to a better prognosis and concluded that patients with infiltrative-type HCCs obstructing the main portal veins are not candidates for chemoembolization. Higashihara et al. performed chemoembolization in 221 patients [3]. The tumor invaded the second-order branch in 77 patients, the first-order branch in 63 and the main trunk in 81 patients. The 5-year survival rates and mean survival periods were 7.7% and 475 days, 8.6% and 406 days, and 6.2% and 350 days, respectively. They have described that an extended survival can be obtained when tumor extent was limited to one lobe and the hepatic function was well preserved. The present study showed the same therapeutic results as those achieved by Higashihara et al. However, neither parenchymal tumor extent nor tumor morphology showed a significant impact on prognosis. In addition to tumor response, iodized oil uptake in tumor thrombi was another independent factor affecting prognosis. Lee et al. also reported that this factor had a significant impact on survival in the univariate analysis [2]. The absence of iodized oil accumulation may suggest the presence of another feeding artery, such as a peribiliary artery or vasa vasorum or the rapid washout of iodized oil from the tumor thrombi, indicating insufficient tumor necrosis. Ascites was the only pre-treatment factor found to affect prognosis in the multivariate analysis. The presence of ascites is a clinical manifestation of poor hepatic reserve and portal hypertension. Chemoembolization increases portal venous pressure and ascites, resulting in exacerbation of the liver profile. In addition to the three factors found to be independent prognostic factors in the multivariate analysis, another
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three factors were found to be associated with prognosis in the univariate analysis. Two of these were pre-treatment factors (Okuda classification and tumor size) and one was a post-treatment factor (iodized oil uptake in the main tumor). Minagawa et al. performed chemoembolization in 45 patients with HCC and portal vein tumor thrombus and subsequent hepatic resection in 18 of them. They have reported a good 5-year survival as high as 42% in patients who received hepatic resection [22]. They concluded that combination of chemoembolization and hepatic resection enhance patients’ survival when the number of primary nodules is no more than two, the portal trunk is not occluded by tumor thrombus and the indocyanine green retention rate at 15 min (ICGR15) is better than 20%. Hepatic resection following chemoembolization may be an option for further treatment when patients meet their selection criteria for hepatic resection. 4.2. Indications for chemoembolization Considering the fact that post-treatment findings are important prognostic factors, chemoembolization itself appears to be a factor affecting the prognosis of patients with HCCs invading the portal veins. Therefore, It is very important to establish clear selection criteria to ensure safe chemoembolization. With regard to the selection criteria for the chemoembolization of HCCs invading the portal veins, we considered the Child–Pugh class, bilirubin values and patency of the main portal vein. These criteria were considered to be relatively reliable because fatal liver failure developed in only one patient (1/61, 1.6%). However, the limited number of patients and the patient selection bias related to the inclusion criteria in the present study do not allow us to identify good selection criteria to ensure safe chemoembolization. In the near future, appropriate selection criteria for safe chemoembolization should be established. Okamoto et al. have established a safe limit of hepatic resection by measuring the hepatic parenchymal volume excluding tumor volume and ICGR15 [23]. This volumetric analysis may be useful in ensuring safe chemoembolization in patients with HCC invading portal veins.
5. Conclusion Chemoembolization is an effective therapeutic method for HCCs invading the portal venous system. Post-treatment factors and the presence of ascites at the time of chemoembolization are the most important prognostic factors. Although our results should be confirmed in future prospective studies, the factors identified as affecting prognosis in the present study should prove helpful in classifying patients with HCCs invading the portal veins who are treated by chemoembolization and should serve as useful guidelines for chemoembolization in clinical practice.
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