Int J Gastrointest Interv 2023; 12(2): 75-82
Published online April 30, 2023 https://doi.org/10.18528/ijgii220029
Copyright © International Journal of Gastrointestinal Intervention.
Department of Diagnostic Radiology, Fukui-ken Saiseikai Hospital, Fukui, Japan
Correspondence to:*Department of Diagnostic Radiology, Fukui-ken Saiseikai Hospital, 7-1, Funabashi, Wadanaka-cho, Fukui 918-8503, Japan.
E-mail address: firstname.lastname@example.org (S. Miyayama).
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: To evaluate the outcomes of conventional transarterial chemoembolization (TACE) using guidance software for hepatocellular carcinoma (HCC) in the caudate lobe.
Methods: Seventy-two patients with 79 treatment-naïve caudate lobe HCCs were eligible. TACE was performed through feeders not only identified by automated tumor-feeder detection (AFD) functionality but also detected manually. Technical success of TACE was classified into three grades according to 1-week computed tomography findings: entire tumor embolized with a safety margin (5 mm for tumors < 25 mm and 10 mm for tumors ≥ 25 mm) (grade A); tumor embolized without a margin in parts (grade B); and entire tumor not embolized (grade C). Tumor response was evaluated using the modified Response Evaluation Criteria in Solid Tumors. Tumor-feeder detectability by AFD, technical success of TACE, complete response (CR) at 2–4 months, durable CR, and local tumor progression (LTP) rates calculated by the Kaplan-Meier method were compared in each tumor among three subsegments: the Spiegel lobe (SP); paracaval portion (PC); and caudate process (CP). LTP rates between the grade A and B tumors were also compared.
Results: The mean tumor diameter was 18.6 ± 9.9 mm (range, 6–53 mm), and 111 of 129 (86.0%) tumor feeders were detected by AFD. The rates of feeder detectability by AFD, grade A technical success of TACE, CR at 2–4 months, and durable CR in 30 SP, 38 PC, and 11 CP tumors were 71.4%, 93.3%, 93.1%, and 79.3%; 94.8%, 65.8%, 59.4%, and 34.4%; and 76.5%, 63.6%, 80.0%, and 30.0%, respectively. LTP rates of SP tumors were significantly lower than those of PC tumors (P = 0.0044), and the grade B tumors progressed more frequently (P = 0.0012).
Conclusion: AFD could detect 86.0% of tumor feeders in the caudate lobe; however, the feeder detectability, technical success of TACE, and outcomes differed among the three subsegments.
Keywords: Angiography, Carcinoma, hepatocellular, Chemoembolization, therapeutic, Cone-beam computed tomography, Software
Since the caudate lobe is centrally located in the liver and adjacent to the bare area, hepatocellular carcinoma (HCC) arising in the caudate lobe can receive complex arterial blood supply including from the extrahepatic arteries.1–8 Therefore, transarterial chemoembolization (TACE) can frequently fail to embolize the target HCCs in the caudate lobe completely, mainly because of the difficulty of identifying its feeding arteries and unsuccessful catheterization due to frequent severe angulation of its orifice.1,3,5,6,9
Recently, cone-beam computed tomography (CBCT) and TACE guidance software including automated tumor-feeder detection (AFD) functionality have been introduced to TACE for HCC.10–19 CBCT has a pooled sensitivity of 93%, specificity of 80%–97%, and positive predictive value of 89% for detecting arteries supplying the tumor.20 It can also improve the technical success and early tumor response of TACE.17–19,21 However, the detectability of tumor feeders of HCC in the caudate lobe by AFD and outcomes of TACE are still unknown. The purpose of this study was to evaluate outcomes of TACE using guidance software for HCC in the caudate lobe.
Our institutional review board approved this retrospective study (approval No. 2021-21) and individual patient consent was waived. Written informed consent related to TACE treatment was also obtained from each patient before the procedure.
Between September 2012 and November 2021, transarterial treatment using TACE guidance software was performed for 77 patients with 85 treatment-naïve caudate lobe HCCs. Among them, two tumors in one patient embolized non-selectively without effort to catheterize into the tumor-feeding caudate artery, three ruptured tumors in three patients embolized with gelatin sponge (GS) particles alone, and one huge tumor > 10 cm were excluded. In total, 72 patients with 79 tumors were eligible. The patients’ characteristics are summarized in Table 1.
Table 1 . Patient Characteristics.
|No. of patients||72|
|Mean age (yr)||73.6 ± 8.3 (53–85)|
|Hepatitis B + C||3|
|ECOG performance status|
|Number of tumors in the caudate lobe|
|Mean tumor size (mm)||18.6 ± 9.9 (6–53)|
|Subsegment of the caudate lobe|
|Number of tumors in other sites|
|Conventional TACE alone||37|
|Hepatectomy plus TACE||6|
|Hepatectomy plus HAIC plus TACE||1|
|RFA plus TACE||1|
|Mean AFP level (ng/mL)||527.0 ± 1,866.1 (2–8,240)|
|Mean PIVKA-II level (mAU/mL)||412.3 ± 1,217.0 (10–7,685)|
Values are presented as number only or mean ± standard deviation (range).
ECOG, European Cooperative Oncology Group; HAIC, hepatic arterial infusion chemotherapy; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; AFP, alpha fetoprotein; PIVKA-II, protein induced by absence of vitamin K or antagonist-II.
The diagnosis of HCC was established by imaging findings of CT and/or magnetic resonance imaging (MRI) referencing the serum levels of tumor markers. Histological confirmation was not obtained in any patient. Sixty-eight patients had a single HCC, three had two, and one had four in the caudate lobe.
Twenty-seven (37.5%) patients had naïve HCCs and 45 (62.5%) had a history of TACE (1–11 times, mean: 3.3 ± 2.4) plus other treatments for HCCs. Twenty-four (33.3%) patients only had a single HCC in the caudate lobe. Forty-eight (66.7%) had HCC(s) other than in the caudate lobe.
All CBCT images were obtained with a C-arm angiographic unit (Allura Xper FD20 or AlluraClarity Xper FD20; Philips Healthcare, Best, The Netherlands) with the technique described previously.8,10,11,16–19,21
After CBCT during arterioportography (CBCTAP) and digital subtraction angiography (DSA) of superior mesenteric and celiac arteries, DSA of a common/proper hepatic artery was conducted using a 4-Fr twist catheter (Hanako Medical, Saitama, Japan). Subsequently, dual-phase CBCT during hepatic arteriography (CBCTHA) was performed by injection of 24 mL of contrast material at a rate of 2 mL/s. The 1st scan began 7 seconds after the beginning of the injection of contrast material, and the 2nd scan began 30 seconds after the end of the 1st scan. If DSA of the common/proper hepatic artery using a 4-Fr catheter was not performed because of anatomical difficulties, dual-phase CBCTHA at the proper or left/right hepatic artery was carried out using a microcatheter (Progreat ∑ [1.9-Fr tip]; Terumo Clinical Supply, Kakamigahara, Japan; Asahi Veloute [1.7-Fr tip]; Asahi Intecc, Seto, Japan; or Asahi Veloute Ultra [1.5-Fr tip]; Asahi Intecc) by injecting 12 mL of contrast material at a rate of 1 mL/s.
TACE guidance software (EmboGuide; Philips Healthcare) has been routinely used at a workstation (XtraVision Interventional Workstation; Philips Healthcare) with techniques described previously.8,16–18 First, a virtual target lesion including a safety margin (approximately 5-mm wide for tumors < 25 mm, and 10-mm wide for tumors ≥ 25 mm around the tumor) was created on HCC on the 1st-phase CBCTHA images. After deciding on the start position of vessel tracking using the “Set Catheter” functionality, the “Auto Detect” button was pressed. Then, all potential tumor feeders of all tumors were automatically highlighted within a few seconds on CBCTHA images and a 3D arteriogram. Prototype TACE guidance software (EmboGuide App; Philips Healthcare) has also been used since May 2018.19,21 In this software, the start position was automatically set on the catheter tip and tumor feeders were highlighted instantaneously during creation of the target lesion. The AFD process was usually completed within 2 minutes.
If AFD failed to detect the tumor-feeder, reanalysis was performed after changing the target lesion size. When the target lesion was attached to the large arterial branch, vessel tracking was ended at the attached portion. In such a situation, the target lesion was reduced in size to separate it from the large arterial branches. When AFD could not detect appropriate tumor feeders despite several efforts, the branch in the vicinity of the target lesion was determined as a tumor-feeder and it was clicked on a 3D arteriogram or CBCTHA image. Then, the vessel route was highlighted on the display (manual tumor-feeder detection). This process was the same for both forms of software.
When a microcatheter was advanced into the tumor-feeder, 0.5 mL of 2% lidocaine (Terumo, Tokyo, Japan) was injected through the microcatheter to prevent pain and vasospasm. Then, a mixture of 2–10 mL of iodized oil (Lipiodol 480; Guerbet Japan, Tokyo, Japan) and chemotherapeutics (10–30 mg of epirubicin; [Farmorbicin; Pfizer, Tokyo, Japan] plus 2–6 mg of mitomycin C [Mitomycin; Kyowa Hakko Kirin, Tokyo, Japan]), 10–30 mg of epirubicin, or 50–100 mg of cisplatin (IA Call; Nippon Kayaku, Tokyo, Japan) was slowly injected, followed by an approximately 0.2–0.5-mm diameter GS slurry created from 1-mm-diameter GS particles (Gelpart; Nippon Kayaku) by a pumping method. The ratio of chemotherapeutic solution to iodized oil was 1:3 for epirubicin ± mitomycin C and 1:2 for cisplatin. The total amount of iodized oil was almost equal to the sum of the diameters of the target tumors.
When the branch detected by AFD was determined to be a true tumor-feeder, it was embolized without selective DSA or CBCTHA. The right inferior phrenic artery (RIPA) was also embolized, if necessary, without CBCT and AFD analysis. TACE was finished when all tumor stains disappeared and the tumor feeders were occluded on DSA. CBCT after TACE (LipCBCT) was not performed until May 2018 when accumulation of iodized oil in the target tumor was identified on fluoroscopy. Since May 2018, LipCBCT has been routinely performed at the end of the procedure. When LipCBCT showed incomplete TACE, TACE was added if additional tumor feeders could be identified by manual feeder detection or DSA.
Unenhanced CT was performed 1 week after TACE to check for iodized oil distribution. Dynamic CT and/or MRI was performed every 2–4 months after TACE. When the tumor recurred, additional treatment was performed according to the patient and tumor conditions, if possible.
The tumor location was divided into three subsegments according to Kumon’s classification22 and the tumor diameter of each subsegment was compared by one-factor analysis of variance. When iodized oil accumulation in the tumor and surrounding liver was demonstrated on fluoroscopy and/or LipCBCT, the branch was determined as a tumor-feeder. Although manual feeder detection was used during TACE, the results of AFD were only analyzed at the subsubsegmental hepatic artery level. When the tracing of the tumor-feeder was stopped at a more proximal level, the feeder was judged as “not detected.” When AFD mis-traced the origins of the feeder, but it was easily identified on a 3D arteriogram without additional DSA, the feeder was judged as “detected”. If additional DSA was required to identify the correct origin, the feeder was judged as “not detected”.
The origins of tumor feeders were classified into right proximal (R1), right distal (R2), left proximal (L1), left distal (L2), anterior (A), posterior (P), middle (M), proper hepatic (Ph), common hepatic (Ch), and extrahepatic (Ex) according to the previous definitions (Fig. 1).5
The embolized area was defined as the area where iodized oil was retained on unenhanced CT performed 1 week after TACE. The images were evaluated in 3 dimensions (axial, coronal, and sagittal views) on the image viewer (ShadeQuest/Report; Fujifilm, Tokyo, Japan). The technical success of TACE was classified into three grades: 1) grade A, the entire tumor was embolized with a safety margin (at least 5 mm for tumors < 25 mm and 10 mm for tumors ≥ 25 mm); 2) grade B, the entire tumor was embolized but the safety margin was lacking in parts; and 3) grade C, the entire tumor was not embolized.11
Early tumor response was evaluated on the first follow-up dynamic CT or MRI after TACE using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Local tumor progression (LTP) was also judged by follow-up CT or MRI. The rates of tumor-feeder detection by AFD, grade A success of TACE, complete response (CR) at 2–4 months, and durable CR were compared by the Fisher’s exact test and post-hoc analysis using the Bonferroni's multiple comparison test, and the cumulative LTP rates were calculated by the Kaplan-Meier method and compared by the log-rank test in each subsegment. LTP rates between the grade A and B tumors were also compared by the Fisher’s exact test. Statistical calculations were performed using software (R version 4.1.2, 2021; R Foundation for Statistical Computing, Vienna, Austria) and a
The results are summarized in Table 2.
Table 2 . Tumor Characteristics, Tumor-Feeder Detectability, and Technical Success of TACE in Each Subsegment.
|Characteristic||Spiegel lobe (||Paracaval portion (||Caudate process (|
|Mean diameter (mm) (range)||16.8 ± 9.5 (6–48)||19.6 ± 9.7 (6–53)||21.8 ± 9.9 (9–36)|
|Origins of tumor-feeders||R1, 6; R2, 3; L1, 3; L2, 5; A, 6; P, 3; M, 5; A2, 2; and Ex, 2 (the 3 o’clock artery and RGA)||R1, 3; R2, 6; L1, 2; L2, 6; A, 27; P, 13; M, 11; A2, 1; A3, 1; and A8, 5||R1, 1; R2, 2; A, 5; P, 7; A7, 1; and A6, 1|
|No. of embolized artery||35||77||17|
|No. of embolized artery/per tumor||1.3 ± 0.9/tumor||2.0 ± 0.9/tumor||1.5 ± 0.9/tumor|
|Detectability of tumor-feeders (%)||71.4||94.8||76.5|
|Technical success of TACE (%)|
|CR rate at 2–4 months*||93.1||59.4||80|
|Durable CR rate*||79.3||34.4||30|
Values are presented as mean ± standard deviation or number only.
RGA, right gastric artery; A2, the superior lateral subsegmental artery of the left hepatic artery; A3, the inferior lateral subsegmental artery of the left hepatic artery; A8, the anterior superior subsegmental artery of the right hepatic artery; A7, the posterior superior subsegmental artery of the right hepatic artery; A6, the posterior inferior subsegmental artery of the right hepatic artery; CR, complete response.
*CR rates were evaluated in 29 tumors in the Spiegel lobe, 32 in the paracaval portion, and 10 in the caudate process.
The mean tumor diameter in the caudate lobe was 18.6 ± 9.9 mm (range, 6–53 mm). Thirty (38.0%) tumors were located in the Spiegel lobe (SP) (Fig. 2A, 3A), 38 (48.1%) in the paracaval portion (PC) (Fig. 4A), and 11 (13.9%) in the caudate process (CP). When a tumor was located between two subsegments, it was classified based on the subsegment in which it was dominantly located. There were no significant differences in the tumor diameter among the three subsegments (
In total, 129 arterial branches arising from the common hepatic artery were embolized for HCCs in the caudate lobe. Among them, AFD missed 16 tumor feeders. Additionally, the origins were mis-traced in four tumor feeders, and two feeders were judged as “detected” (Fig. 2C–2E) and the remaining two were judged as “not detected”. In total, 111 (86.0%) tumor feeders were detected by AFD. Moreover, 16 additional branches were misdiagnosed as tumor feeders.
Of 30 SP tumors, three small tumors were supplied by the same feeder of the main tumor; therefore, the detectability and origins of tumor feeders were evaluated in 27 HCCs. Among 35 embolized branches, 25 (71.4%) could be detected by AFD (Fig. 2C), but 10 were misdiagnosed (Fig. 3C). Each tumor-feeder arose from various sites, including two from Ex (the 3 o’clock and right gastric arteries) that could not be detected by AFD, although these branches were opacified on CBCTHA. The ratio of the right to left hepatic artery was 18:15 (6:5). Technically, 34 feeders could be catheterized by a microcatheter, but the remaining feeder arising from L1 could not be catheterized. So, TACE was performed through a microcatheter placed proximal to the orifice of the feeder under blocking the distal flow of the left hepatic artery by a microballoon catheter (Logos; Piolax, Yokohama, Japan) via the additional access route (balloon-assisted TACE7).
For 38 PC tumors, 73 of 77 (94.8%) embolized branches could be corrected by AFD (Fig. 4C). Each tumor-feeder arose from various sites and the ratio of the right to left hepatic artery was 54:21 (≒5:2). Technically, three feeders arising from A could not be catheterized; therefore, two were non-selectively embolized and one was embolized by balloon-assisted TACE.
For 11 CP tumors, 13 of 17 (76.5%) embolized branches were correctly detected by AFD. All branches arose from the right hepatic artery at various sites. Technically, one feeder arising from P was embolized non-selectively due to unsuccessful catheterization.
The tumor-feeder detectability of SP tumors was significantly lower than that of PC tumors (
TACE was performed through the feeders that were detected not only by AFD but also by manual feeder detection and/or selective DSA (Fig. 2F, 3D, 3E, 4D). The RIPA was also embolized in seven tumors, four SP and three CP tumors. Of 79 tumors, 60 (75.9%) were classified into grade A (Fig. 2G, 3F), 11 (13.9%) into grade B (Fig. 4E), and eight (10.1%) into grade C. Regarding the tumor location, grade A was achieved in 28 of 30 (93.3%) tumors in SP, 25 of 38 (65.8%) in PC, and seven of 11 (63.6%) in CP. The rate of grade A technical success of TACE of SP tumors was significantly higher than that of PC tumors (
In six of eight grade C tumors, additional TACE performed 6–34 months (mean, 12.7 ± 10.6 months) later, showing that three residual tumors were supplied by the neighboring hepatic arteries, and two by the previously embolized arteries, including one that had been embolized non-selectively. The remaining tumor was supplied by the RIPA.
Early tumor response was evaluated in 71 tumors using dynamic CT (
Regarding the relationship between technical success of TACE and LTP, 18 of 54 (33.3%) grade A tumors locally progressed 3–51 months (mean, 16.2 ± 39.7 months) after TACE, and 36 (66.7%) showed durable CR 2–105 months (mean, 26.2 ± 22.7 months) after TACE. In contrast, nine of 10 (90.0%) grade B tumors locally progressed 2–22 months (7.1 ± 16.8) after TACE, and only one tumor (10%) showed CR 2 months after TACE. LTP rates of the grade A tumors were significantly lower than those of the grade B tumors (
Surgical resection for HCC in the caudate lobe is associated with a high mortality rate because of marked blood loss and postoperative complications, in addition to a high tumor recurrence rate.23 Percutaneous ablation therapy might also be technically difficult because of the deep tumor location and adjacent large vessels.24–26 Although TACE for HCC in the caudate lobe is also difficult due to complex arterial supply, it has been reported that selective catheterization into the tumor-feeding caudate artery is the most important prognostic factor for a solitary tumor.4,12 Therefore, identification of a tumor-feeding caudate artery is very important to obtain favorable outcomes.
According to previous reports, AFD can detect 85% to 96% of tumor feeders,13–19 and 81% to 87% of tumors can be embolized with a sufficient safety margin.16–19 In the present study, AFD could detect 86% of tumor feeders of HCC in the caudate lobe; however, the detectability differed among the three subsegments. SP is a small area protruding from the right hepatic lobe; therefore, it is difficult to create a virtual target lesion with a sufficient safety margin while separating from the large arteries. Additionally, artifacts from contrast material in the large artery infrequently create “a pseudo-feeder (Fig. 3C).” Moreover, the tumor is infrequently fed by the extrahepatic artery.3,5 These may reduce the detectability of tumor feeders of SP tumors. CP is also a small area and the target lesion is likely to be attached to the right hepatic artery and/or its major branches; therefore, tumor-feeder detectability may also be reduced.
There is a tendency among origins of tumor-feeding caudate arteries according to the tumor location. SP, PC, and CP tumors are fed by the caudate arteries arising from the hepatic artery, with right to left ratios of 3:2, 3:1, and 3:0, respectively.5 This study also showed that ratios of right to left hepatic artery were 6:5 and 5:2 in SP and PC tumors, respectively, and CP tumors were dominantly supplied by the right hepatic artery. This information is helpful to identify a tumor-feeder on DSA when AFD cannot detect it.
In the present study, the outcomes of TACE for HCC in the caudate lobe using guidance software were worse than those of previous reports that included tumors originating at other sites.16–19 Additionally, there was no relationship between the rates of tumor-feeder detection and outcomes of TACE among the three subsegments. The feeder detectability was the highest in PC tumors, but the outcomes of TACE were reduced. In contrast, the feeder detectability was the lowest in SP tumors, but the outcomes of TACE were the best. These suggest that PC tumors might have a potential to be supplied by tiny feeders that could not be detected by guidance software because PC is a watershed area between the bilateral hepatic lobes. Although the feeder detectability in CP tumors was higher than that in tumors in SP, the outcomes were the lowest. This also suggests that CP tumor might be supplied by tiny branches arising from the right hepatic artery and/or its major branches that could not be detected by guidance software. Moreover, complex arterial communications in the hilar plate can promote tumor recurrence.27–30 In contrast, SP tumors might be fed by various branches including extrahepatic arteries;3,5,8 however, SP is “the periphery of the liver.” As a result, favorable outcomes can be achieved when the tumor-feeder is selectively embolized.
There are several limitations of this study. First, selective DSA and/or CBCT was not performed in almost all embolized branches. Additionally, a safety margin was added to the target lesions of most tumors. These might overestimate the number of the tumor-feeder. Second, the anatomical border between PC and the posterior aspect of segment 4, which is frequently supplied by the caudate artery.29 as well as that of CP and segment 6, are unclear on images;31 therefore, some tumors might be extended outside the caudate lobe. Additionally, a tumor located between two subsegments was classified as the subsegment in which it was dominant. These might influence the results of this study. Finally, the prognosis was not evaluated because many patients had multiple tumors outside the caudate lobe, and HCCs in the caudate lobe mainly developed at the end of the treatment course.
In conclusion, AFD could detect 86% of tumor feeders of HCCs in the caudate lobe. However, the detectability of tumor feeders and outcomes differed among the three subsegments. The anatomical location and presence of undetectable tiny tumor feeders may lead to unfavorable outcomes.
The corresponding author received lecture fees from Guerbet Japan, Asahi Intecc, and Philips Healthcare, but other authors have no conflict of interest to disclose with respect to this paper.
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