Abstract
Purpose
Transarterial chemoembolization (TACE) is highly effective and safe therapeutic modality for unresectable hepatocellular carcinoma (HCC). However, the role of TACE for infiltrative HCC has never been elucidated owing to the concern about hepatic failure and subsequent mortality after the procedure. In this study, we aimed to document whether patients with infiltrative HCC would benefit from TACE.
Methods
Child-Pugh class A/B patients who were newly diagnosed as infiltrative HCC and treated with curative-intent TACE were enrolled. All radiological images were reviewed by a radiologist with more than 20 years of experience in TACE.
Results
Among 1,184 patients newly diagnosed as HCC, 233 (19.7 %) had infiltrative-type tumors and 128 (54.9 %) underwent curative-intent TACE. Although the median overall survival was 5.4 months (IQR 3.1–13.9 months) and 16 (12.5 %) patients had experienced significant complications, 19 (15.9 %) patients survived more than 2 years after the first diagnosis. In multivariable analysis, age >60 years old (HR 0.54, 95 % CI 0.31–0.92), Child-Pugh class A (HR 0.48, 95 % CI 0.30–0.76), and a major PVT without parasitic supply (HR 0.66, 95 % CI 0.44–0.99) were independent favorable prognostic factors. Development of significant complication after TACE was a significant hazard factor of survival (HR 1.99, 95 % CI 1.09–3.62).
Conclusions
In carefully selected patients with preserved hepatic function and good performance, TACE may achieve long-term survival of infiltrative HCC patients with major PVT without parasitic supply. However, the risk of morbidity and immediate mortality after TACE should be considered to select subjects for the procedure.
Keywords: Carcinoma, Hepatocellular, Chemoembolization, Therapeutic, Portal vein/pathology, Survival rate, Risk factors
Introduction
Morphologic types of hepatocellular carcinoma (HCC) can be classified into focal/nodular, massive, and diffuse/infiltrative (Baer et al. 1989; Stroffolini et al. 1999; Okuda et al. 1981; Trevisani et al. 1993). Although the development of therapeutic modalities for HCC has progressed rapidly in recent decades, most physicians still tend to avoid aggressive treatments for infiltrative-type HCC patients due to their grave prognosis. Because most of diffuse infiltrative HCCs that involve portal veins are classified as being at an advanced stage, they are not good candidates for curative treatments such as liver transplantation or local ablation. Although systemic targeted therapy with sorafenib is recommended for advanced unresectable HCC (Forner et al. 2010), the mean survival improvement from sorafenib was merely 3 months in the SHARP trial, which focused on advanced HCC patients (Llovet et al. 2008). Moreover, infiltrative HCC patients had been excluded from previous clinical studies using systemic therapy because they did not have a measurable lesion.
Currently, transarterial chemoembolization (TACE) is regarded as one of the standard treatments for patients with unresectable HCC. According to the previous randomized controlled studies, TACE showed clear survival benefits and improvements of quality of life in unresectable HCC patients compared to symptomatic supportive care (Lo et al. 2002; Llovet et al. 2002). On the contrary, some studies had failed to demonstrate any improvement of patient’s overall survival (Geschwind et al. 2003). The reason why many studies showed inconsistent results was that the eligible patients of these studies were very heterogeneous: ‘unresectable HCC’ was defined as numerous tumor nodules or any stage of HCC with portal vein invasion or metastatic disease. Recently, several studies in which subjects were confined to the patients with portal vein thrombosis (PVT) have revealed that TACE can prolong survival despite an advanced Barcelona Clinic Liver Cancer (BCLC) stage (Chung et al. 2011; Yoon et al. 2010). Nevertheless, patients with infiltrative HCC have seldom been studied as candidates for TACE.
Infiltrative HCC accounts for about 7–15 % of all types of HCC (Kanematsu et al. 2003; Demirjian et al. 2011). A previous prospective comparative study documented that infiltrative HCC shows poor prognosis rather than those with focal nodular HCC and TACE for patients with infiltrative HCC has no apparent benefit (Lopez et al. 2002). However, the infiltrative HCC group of that study included more Child-Pugh class C patients compared to the focal HCC group. Therefore, we aimed in this study to document whether patients with infiltrative HCC would benefit from curative-intent TACE.
Methods
Patients
This retrospective study was approved by the Institutional Review Board, and informed consents were waived by Institutional Review Board after a full explanation about this study protocol. Child-Pugh class A or B patients who were newly diagnosed as infiltrative HCC and who were treated with curative-intent TACE between January 2005 and December 2006 at a tertiary hospital were included in this retrospective cohort study. The diagnosis of HCC was based on the recommendation of the American Association for the Study of Liver Diseases (Bruix and Sherman 2011). We defined the ‘curative-intent’ TACE as a procedure performed to eradicate viable HCC in patients with preserved hepatic function (Child-Pugh class A or B) and with good performance status (Eastern Cooperative Oncology Group (ECOG) performance scale (Conill et al. 1990) 0–2). Among patients treated for infiltrative HCC, those who underwent ‘palliative TACE’ were excluded. Palliative TACE was defined as a procedure (1) to control active tumor bleeding (i.e., hemoperitoneum or hemobilia) or intractable pain, (2) which was performed in those with poor hepatic function (Child-Pugh class C) or with poor performance (ECOG >2).
Among 1,184 patients who were newly diagnosed as HCC, 233 (19.7 %) had infiltrative tumors and 146 underwent TACE. Of the 233 infiltrative HCC patients, 8 underwent surgical resection, 8 were treated with systemic chemotherapy using cytotoxic agents, and 71 were managed conservatively because of their poor performance status/hepatic function (n = 39) or rejection of the curative-intent treatment (n = 32). Of the 146 patients who underwent TACE, we excluded 18 palliative TACE cases: 4 patients with Child-Pugh class C, 10 with poor performance status underwent TACE due to the patient’s strong desire to be treated, and 4 undergone TACE to treat hemoperitoneum. Finally, 128 infiltrative HCC patients who were treated with curative-intent TACE were enrolled and analyzed (Fig. 1).
Fig. 1.
Flowchart of patient selection. Among 1,184 patients who were newly diagnosed as HCC, 233 (19.7 %) had infiltrative tumors and 146 underwent TACE. After exclusion of 18 patients undergone palliative TACE, 128 infiltrative HCC patients who were treated with curative-intent TACE were enrolled and analyzed in this study
Radiologic findings and procedures of TACE
All radiological images were reviewed by a radiologist with more than 20 years of experience in TACE (JWC). Tumors which showed an infiltrative growth without a distinct margination on any portion of the tumor on any sequence of enhanced computed tomography (CT) images were classified as the infiltrative-type HCC (Myung et al. 2006; Kanematsu et al. 2003). The presence of PVT was confirmed by lesions in the portal vein that were enhanced at the arterial phase and revealed early washout at the portal or delayed phase of the dynamic CT protocol. The locations of PVT were described as main, first order, second order, or segmental branch. A main or first-order branch PVT was considered to be a major PVT. Cavernous transformation was defined as multiple periportal collateral vessels.
Selective TACE was performed in all subjects using an iodized oil emulsion (2–3 mL) + doxorubicin (10–60 mg) mixture and gelatin sponge particles (0–2,000 pieces) + mitomycin (0–4 mg). During the procedure, parasitic supplies from inferior phrenic, internal mammary, gastroduodenal, omental, or other possible arteries were studied using angiography according to the location of the tumor. Depending on the judgment of the interventional radiologist, hepatic arterial chemoinfusion with cisplatin (0–100 mg) was performed.
Statistical analysis
The cumulative overall survival rate was analyzed by Kaplan–Meier methods and the log-rank tests which compared the differences between subgroups. To elucidate independent predictors of prolonged overall survival after TACE, Cox regression analysis was carried out with adjustment for factors that affected overall survival significantly in univariable analyses. All statistical evaluations were performed using SPSS version 19.0 [SPSS Inc., Chicago, IL, USA]. p values of <.05 were considered statistically significant.
Results
Baseline characteristics of infiltrative HCC patients who underwent curative-intent TACE
The mean age of enrolled patients was 53.4 years old (standard deviation, 8.6). Patients more than 60 years of age accounted for 21.9 % (Table 1), and the number of male patients was 114 (89.1 %). The most common etiology of chronic liver disease was hepatitis B virus (HBV) infection (85.9 %, Table 1). A total of 96 (75 %) patients had preserved underlying hepatic function (Child-Pugh class A, Table 1). Elevated α-fetoprotein (AFP) greater than 200 ng/mL was detected in 83 (65.4 %) patients. The median serum alkaline phosphatase (ALP) level was 161 IU/L (interquartile range, IQR 111–255), and 80 (62.5 %) patients had elevated serum ALP levels greater than 130 IU/L (Table 1).
Table 1.
Baseline characteristics of study population
| Variable | N = 128 |
|---|---|
| Agea (years old) | 53.4 ± 8.6 |
| >60 years old (no (%)) | 28 (21.9) |
| Male (no (%)) | 114 (89.1) |
| Etiology of liver diseases (no (%)) | |
| HBV | 110 (85.9) |
| HCV | 4 (3.1) |
| Alcohol | 6 (4.7) |
| Cryptogenic | 8 (6.3) |
| Performance status (no (%)) | |
| ECOG 0 | 82 (64.1) |
| ECOG 1 | 17 (13.3) |
| ECOG 2 | 29 (22.7) |
| Child-Pugh class A (no (%)) | 96 (75.0) |
| Laboratory findings | |
| α-Fetoprotein (AFP)b (ng/mL) | 2250 (71–34,100) |
| AFP ≥200 ng/mL (no (%)) | 83 (65.4) |
| Alanine aminotransferase (ALT)b (IU/L) | 48 (33–72.5) |
| Alkaline phosphatase (ALP)b (IU/L) | 161 (111–255) |
| ALP ≥130 IU/L (no (%)) | 80 (62.5) |
| Radiologic findings (no (%)) | |
| Occupying >50 % of the liver | 65 (50.8) |
| Portal vein thrombosis (PVT) | 107 (83.6) |
| Parasitic supply | 24 (18.8) |
| Major PVT without parasitic supply | 72 (56.3) |
| Cavernous transformation | 22 (17.2) |
| TACE procedures | |
| Lipiodola (mL) | 6.6 ± 2.9 |
| Doxorubicina (mg) | 37.0 ± 14.1 |
| Intra-arterial chemotherapy (no (%)) | 94 (73.4) |
| Number of TACEb | 2 (1–4) |
HBV hepatitis B virus, HCV hepatitis C virus, ECOG Eastern Cooperative Oncology Group performance scale, AFP α-fetoprotein, ALT alanine aminotransferase, ALP alkaline phosphatase, PVT portal vein thrombosis, TACE transarterial chemoembolization
aMean ± standard deviation
bMedian (interquartile range)
Tumor characteristics and TACE procedures for infiltrative HCC patients
Extensive tumors which occupied more than 50 % of the liver were detected in 65 (50.8 %) patients (Table 1). A total of 107 (83.6 %) patients had portal vein thromboses (Table 1): 18 (14.1 %) were segmental or second-order branch PVTs and 89 (69.5 %) were main or first-order branch PVTs. Cavernous transformations were found in 22 (17.2 %) patients (Table 1). Parasitic supplying arteries were detected in 24 (18.8 %) patients and 22 (91.7 %) of them were right inferior phrenic arteries. Eligible patients underwent a median of 2 sessions of TACE (IQR 1–4, Table 1). Intra-arterial chemoinfusions using cisplatin were performed in 94 (73.4 %) patients who had a PVT or a supplying vessel that was hard to be selected technically during TACE (Table 1).
Predictors of overall survival after curative-intent TACE in infiltrative HCC patients
After a curative-intent TACE, the median overall survival of infiltrative HCC patients was 5.4 months (IQR 3.1–13.9 months). The 1-year survival rate was 29.4 %, and the 2-year survival rate was 15.9 % (Fig. 2). In particular, 19 patients survived >2 years after the first diagnosis (long-term survivors), and there was no more mortality after the third year since the first TACE for infiltrative HCC (Fig. 2).
Fig. 2.
Cumulative overall survival rates of infiltrative HCC patients treated with curative-intent TACE. All subjects had preserved hepatic function (Child-Pugh class A or B) and good performance status (ECOG 0–2). The median survival of 128 eligible patients was 5.4 months (interquartile range 3.1–13.9 months). The 1-year survival rate was 29.4 %, and the 2-year survival rate was 15.9 %
According to the results from subgroup analyses, preserved hepatic function was an important predictive factor for prolonged survival after TACE among infiltrative HCC patients (Child-Pugh class A vs. B, p < .001, Fig. 3a). Interestingly, patients who were diagnosed with infiltrative HCC after age 60 showed better survival compared to those under 60 years of age (p = .001, Fig. 3b). Those with tumor occupying >50 % of the liver or with a serum ALP level (Sakar et al. 2004) >130 IU/L, which reflected a large tumor extent better than AFP (Kanematsu et al. 2003) in infiltrative HCC, revealed a poorer prognosis after TACE for infiltrative HCC than those with a small tumor extent or a low ALP level (p = .001, Fig. 3c, d).
Fig. 3.
Comparisons of cumulative survival rates of patients with infiltrative HCC according to their Child-Pugh class (a), age (b), tumor extent (c), or serum alkaline phosphatase (ALP) level (d) a Child-Pugh class A patients (solid line) survived significantly longer than those with Child-Pugh class B (dotted line, p < .001). b Infiltrative HCC patients diagnosed after age 60 (solid line) showed better overall survival compared to those aged ≤60 (dotted line, p = .001). c Patients with large infiltrative HCC which replaced more than 50 % of the liver (dotted line) revealed a poorer prognosis after TACE than those with a small tumor extent (≤50 % of the liver, solid line, p = .001). d A high ALP level more than 130 IU/L (dotted line) was a poor prognostic factor after TACE compared to a low serum ALP level (<130 IU/L, solid line, p = .001) in patients with infiltrative HCC
Unlike nodular HCC, a major PVT tended to be related with a good prognosis in curative-treatable infiltrative HCC patients. Eighty-nine patients with a major PVT showed better survival compared with 18 with a non-major PVT or 21 without any PVT, but the statistical significance was borderline (p = .09, Fig. 4a). As a next step, we categorized the subjects, again depending on the presence of a major PVT and parasitic supplies. As a result, patients with a tumor with a major PVT without a parasitic supply showed the best prognosis after curative-intent TACE compared with those without a major PVT or those with a parasitic supply (p = .04, Fig. 4b).
Fig. 4.
A major portal vein thrombosis (PVT) was related with a good prognosis in curative-treatable infiltrative HCC patients. a Eighty-nine patients with a major PVT (solid line) showed better survival compared with 18 with a non-major PVT (dot-and-dash line) or 21 without any PVT (dotted line), but the statistical significance was borderline (p = .09). b Infiltrative HCC patients with a major PVT without a parasitic supply (solid line) showed the best prognosis after curative-intent TACE compared with those without a major PVT (dash-and-dot line, dotted line) or those with a parasitic supply (two-point chain line, p = .04)
Safety of curative-intent TACE for infiltrative HCC patients
As shown in Table 2, the most common adverse event after TACE for infiltrative HCC was fever, which developed in 51 (39.8 %) patients. Of them, 22 (43.1 %) had persistent fever for more than 2 weeks, although 29 (56.9 %) were transient (Table 2). Newly developed or aggravated ascites were detected in 9 (7.0 %) patients. Among the 9 patients, spontaneous bacterial peritonitis developed in 3 (33.3 %) patients, and all were Child-Pugh class B patients (Table 2). Paralytic ileus was detected in 1 patient (0.8 %). Variceal bleeding during the hospital stay was documented in 4 (3.1 %) patients, and hepatic function deterioration, which was defined as an increase in the Child-Pugh score of more than 1 point, was found in 11 (8.6 %) patients (Table 2). Both of these adverse events were detected more frequently in Child-Pugh class B patients compared to class A (variceal bleeding, 9.4 % in Child-Pugh class B vs. 1.0 % in class A, p = .034; hepatic function deterioration, 18.8 % in Child-Pugh class B vs. 5.2 % in class A, p = .028, Table 2).
Table 2.
Adverse events developed after curative-intent transarterial chemoembolization for infiltrative hepatocellular carcinoma patients
| Total N = 128 | Child-Pugh class A, n = 96 | Child-Pugh class B, n = 32 | p value | |
|---|---|---|---|---|
| Fever | 51 (39.8) | 35 (36.5) | 16 (50.0) | .175 |
| Transient | 29 (22.7) | 18 (18.8) | 11 (34.4) | .067 |
| Persistent | 22 (17.2) | 17 (17.7) | 5 (15.6) | .787 |
| Ascites | 7 (5.5) | 5 (5.2) | 2 (6.3) | 1.000 |
| Spontaneous bacterial peritonitis | 3 (2.3) | 0 (0.0) | 3 (9.4) | .015 |
| Ileus | 1 (0.8) | 1 (1.0) | 0 (0.0) | 1.000 |
| Variceal bleeding | 4 (3.1) | 1 (1.0) | 3 (9.4) | .034 |
| Hepatic function deterioration | 11 (8.6) | 5 (5.2) | 6 (18.8) | .028 |
| Overall complication | 74 (57.8) | 51 (53.1) | 23 (71.9) | .052 |
| Significant complication (>2 weeks of in-hospital treatment) | 16 (12.5) | 8 (8.3) | 8 (25.0) | .019 |
| In-hospital mortality | 4 (3.1) | 0 (0.0) | 4 (12.0) | .002 |
Overall, 16 (12.5 %) patients experienced severe complications that prolonged hospitalization more than 2 weeks and it was more common in Child-Pugh class B patients (25 % in Child-Pugh class B vs. 8.3 % in class A, p = .019, Table 2). There were 4 (3.1 %) in-hospital mortalities (Table 2): 2 died from variceal bleeding at the second week, and 2 died from progressive hepatic failure the second month after TACE.
Independent prognostic factors after curative-intent TACE for infiltrative HCC patients
As shown in Table 3, age (>60 years old, HR 0.42, 95 % CI 0.25–0.70), Child-Pugh class (class A, HR 0.38, 95 % CI 0.25–0.59), tumor extent (occupying >50 % of the liver, HR 1.86, 95 % CI 1.27–2.71; serum ALP ≥130 IU/L, HR 1.95, 95 % CI 1.31–2.91), the presence of major PVT without a parasitic supply (HR 0.59, 95 % CI 0.40–0.86), baseline AFP level (AFP ≥200 ng/mL, HR 1.67, 95 % CI 1.11–2.49), and development of significant complications after TACE (HR 3.48, 95 % CI 2.01–6.03) affected overall survival significantly, according to the univariable analyses (Table 3).
Table 3.
Univariate and multivariate analyses of prognostic factors after curative-intent transarterial chemoembolization for infiltrative hepatocellular carcinoma patients
| Univariable analysis | Multivariable analysis | |||||
|---|---|---|---|---|---|---|
| Hazard ratioa | 95 % CIb | p value | Hazard ratioa | 95 % CIb | p value | |
| Age >60 years old | 0.42 | 0.25–0.70 | .001 | 0.54 | 0.31–0.92 | .025 |
| Male | 1.68 | 0.87–3.23 | .12 | 1.11 | 0.56–2.19 | .775 |
| Child-Pugh class A | 0.38 | 0.25–0.59 | <.001 | 0.48 | 0.30–0.76 | .002 |
| Performance scale | – | |||||
| ECOG 0 | 1 | – | – | – | ||
| ECOG 1 | 1.19 | 0.68–2.09 | .537 | – | ||
| ECOG 2 | 1.55 | 0.99–2.43 | .055 | – | ||
| Tumor extent | – | |||||
| Occupying >50 % of the liver | 1.86 | 1.27–2.71 | .001 | – | ||
| Serum ALP ≥130 IU/L | 1.95 | 1.31–2.91 | .001 | 1.38 | 0.89–2.13 | .152 |
| PVT | .068 | |||||
| No | 1 | – | – | – | ||
| Segmental, second-order branch | 1.1 | 0.58–2.11 | – | – | ||
| First-order branch, main | 0.69 | 0.42–1.13 | – | – | ||
| Major PVT without parasitic supply | 0.59 | 0.40–0.86 | .006 | 0.66 | 0.44–0.99 | .044 |
| α-Fetoprotein ≥200 ng/mL | 1.67 | 1.11–2.49 | .013 | 1.50 | 0.98–2.29 | .063 |
| Significant complication after TACE | 3.48 | 2.01–6.03 | <.001 | 1.99 | 1.09–3.62 | .024 |
ECOG Eastern Cooperative Oncology Group performance scale, ALP alkaline phosphatase, PVT portal vein thrombosis, TACE transarterial chemoembolization
aHazard ratio was calculated by using the multivariate Cox proportional hazard model
bConfidence interval
In multivariable Cox regression analysis, old age (age >60 years old, HR 0.54, 95 % CI 0.31–0.92), preserved hepatic function (Child-Pugh class A, HR 0.48, 95 % CI 0.30–0.76), and a major PVT without a parasitic supply (HR 0.66, 95 % CI 0.44–0.99, p = .044) were independent favorable predictors of survival of treated infiltrative HCC patients after adjustment for gender, tumor extent, and pretreatment AFP level (Table 3). Having one or more significant complications after TACE was an independent hazard factor of survival (HR 1.99, 95 % CI 1.09–3.62, Table 3).
Discussion
In the present study, we demonstrated that about 15.9 % of infiltrative HCC patients endured curative-intent TACE repeatedly and survived more than 2 years. Those long-term survivors were more than 60 years old, had preserved hepatic function at the initial diagnosis, had tumors with a major PVT without parasitic supply, and experienced no significant complication after TACE. To the best of our knowledge, this is the first study to suggest the possibility of long-term survival after TACE in infiltrative HCC patients.
Infiltrative HCC has rarely been studied, because it is difficult to diagnose and measure on cross-sectional images. Even in the modified RECIST criteria, infiltrative HCC is mentioned as a non-measurable, non-target lesion. However, infiltrative HCC is not a rare type (Trevisani et al. 1993; Kanematsu et al. 2003), especially in HBV-predominant regions. Similar with previous studies (Benvegnu et al. 2001; Myung et al. 2006), our results showed that 19.7 % of newly diagnosed cases of HCC were infiltrative types (Fig. 1) and most infiltrative HCCs (85.9 %, Table 1) arose from a chronic HBV infection.
According to a previous prospective surveillance study, the cumulative survival rates of patients with infiltrative HCC were 33.3 % at 1 year and 13.6 % at 3 years, independent of the treatment received (Benvegnu et al. 2001). Although similar survival rates were demonstrated at 1 year (29.7 %) and 2 years (16.7 %) in our study, the previous study did not describe the prognostic factors of long-term survival after the first diagnosis of infiltrative HCC. In the same context as recent studies that dealt with unresectable HCCs (Chung et al. 2011; Yoon et al. 2010), our study suggested that TACE can be useful for the treatment of at least well-selected infiltrative HCC patients.
According to subgroup analyses to define long-term survivors, the underlying hepatic function (Fig. 3a; Table 3) and the tumor extent (Fig. 3c, d; Table 3) were important prognostic factors of survival after TACE for infiltrative HCC, similar with the nodular type (Okuda et al. 1985; Marrero et al. 2005). Moreover, patients who were diagnosed with infiltrative HCC at age >60 showed better survival (Fig. 3b; Table 3) than younger patients (≤60 years old). In other words, the less aggressive tumor which was diagnosed in the elderly was more treatable than the highly aggressive one in young patients with infiltrative HCC. Therefore, the curative-intent treatment for an infiltrative tumor in an elderly patient is worth a try if the subject has preserved hepatic function and a non-massive tumor extent.
The most unique finding of this study was that the presence of a major PVT was not a significant hazard factor on survival of infiltrative HCC patients, and patients with infiltrative tumors with a major PVT tended to survive longer than those without a PVT (Fig. 4a). Generally, focal/nodular HCCs with PVT have been thought of as a contraindication for TACE until quite recently because of a poor prognosis and an increased complication risk following TACE (Chung et al. 1996; Savastano et al. 1999; Kiely et al. 2006). On the contrary, our subgroup analysis demonstrated that tumors with a major PVT without parasitic supply showed good prognosis after curative-intent TACE (Fig. 4b; Table 3). From this finding, it might be inferred that a near-complete block of blood supplies to the tumor would be necessary to control the infiltrative HCC successfully. So far, the precise mechanism of this phenomenon seems hard to elucidate. However, some HCC cells are nourished by the portal blood flow after TACE (Goseki et al. 1995) and may retain viable tumor. Moreover, HCC supplied by portal blood flow after repeated TACE has been reported (Choi et al. 2003). Those findings support that the dual block of arterial and portal blood supplies to a tumor and adjacent hepatic tissue by TACE would be more effective than simple arterial embolization without obliteration of a portal vein. This concept has not been tried in previous studies and should be tested in a future study.
When a physician encounters infiltrative HCC patients with PVT, fear of a severe post-procedural complication arising from extensive tumor necrosis is a barrier to aggressive treatment (Lopez et al. 2002). Indeed, development of significant complications after TACE was an independent hazard factor in the present study (Table 3). However, the frequencies of major and all complications did not significantly differ among the groups classified by the presence of a major PVT and parasitic supply (data not shown). The more important determinant of the risk of post-TACE complications was the underlying hepatic function rather than the blood flow obliteration from both hepatic artery and portal vein (Table 2). Significant complications developed in only 8.3 %, and there was no procedure-related mortality of Child-Pugh class A patients. Thus, curative-intent TACE can be performed safely in patients with preserved liver function as the initial treatment.
The principle limitation of this study was the retrospective non-randomized design, and thus, several confounding factors might affect our findings. Since there were no relevant tools for measuring the extent of infiltrative tumor, we defined the large tumor extent using the largest cross-sectional area of tumor (>50 % of the liver) (Okuda et al. 1985) or serum ALP levels (>130 IU/L) (Sakar et al. 2004). In our study population, serum ALP level was a better prognostic marker with area under operating characteristic curve (AUROC) analysis of 0.66 (95 % CI 0.51–0.80) than cross-sectional image findings (tumor occupying area >50 % of the liver, AUROC 0.35, 95 % CI 0.21–0.48, data not shown). Although the proportions of patient with high ALP (>130 IU/L) level were similar between those with major PVT without parasitic supply (58.3 %) and the others (67.9 %, p = .120, data not shown), it could not reflect the true tumor extent of infiltrative HCC. Additionally, the tumor biology could be a major confounding factor. The infiltrative tumor which made PVT without parasitic supply might grow more modestly than it without PVT. Although we attempted to reduce the bias by subgroup and multivariable analyses, a prospective study is needed to confirm our findings.
In conclusion, the present study demonstrated that TACE may achieve long-term survival of infiltrative HCC patients with preserved hepatic function and tumor supplied mostly by hepatic arteries, not by parasitic supplying vessels. However, the subjects should be carefully selected to minimize immediate morbidity after TACE. Further prospective studies are warranted to confirm the efficacy and safety of TACE for infiltrative HCC.
Acknowledgments
This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065) and by a grant from the Liver Research Foundation of Korea.
Conflict of interest
We declare that we have no conflict of interest.
Abbreviations
- HCC
Hepatocellular carcinoma
- TACE
Transarterial chemoembolization
- PVT
Portal vein thrombosis
- BCLC
Barcelona Clinic Liver Cancer
- ECOG
Eastern Cooperative Oncology Group
- HBV
Hepatitis B virus
- AFP
α-Fetoprotein
- ALP
Alkaline phosphatase
- IQR
Interquartile range
- CT
Computed tomography
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