Portal vein invasion (PVI) is a poor prognostic factor in patients with hepatocellular carcinoma (HCC). We intended to compare the effects of surgical resection and transarterial chemoembolization (TACE) with additional radiation therapy (RT) in HCC patients with PVI.
The subjects comprised 43 patients who underwent surgical resection for HCC with PVI without previous treatment and another 43 patients who received TACE followed by RT (TACE+RT) as initial treatment who were matched for Child-Pugh class, tumor size, and extent of PVI. Disease progression and death after the treatment were examined, and progression-free survival (PFS) and overall survival (OS) were compared between groups. Predisposing factors affecting OS were analyzed using univariate and multivariate analyses in HCC patients with PVI.
The subjects (Age [51, 24-74; median, range], Sex [81/13; male/female], Etiology [78/1/15; hepatitis B virus {HBV}/ hepatitis C virus {HCV}/non-HBV and non-HCV]) were followed for a median of 17 (2-68) months. There were no differences in clinical or tumor characteristics between the resection and TACE+RT groups. The cumulative PFS was not significantly different between groups. The median PFS was 5.6 and 4.0 months in the resection and TACE+RT groups, respectively. However, the cumulative OS was significantly longer in patients treated with resection than in those treated with TACE+RT (
Surgical resection might be an effective treatment in HCC patients with PVI.
Hepatocellular carcinoma (HCC) is the third major cause of malignant tumor-related death worldwide [
The current treatment guideline from the Barcelona Clinic Liver Cancer system recommends palliative systemic therapy such as sorafenib for HCC with PVI [
Moreover, owing to the challenge for more aggressive treatment and advances in medical techniques, TACE or surgical resection are no longer contraindications for HCC with PVI [
The optimal treatment in HCC patients with PVI is still controversial. Thus, in this study, we aimed to compare and analyze the treatment efficacy between TACE with additional RT (TACE+RT) and resection in HCC patients with PVI.
The subjects comprised a total of 86 HCC patients with PVI (43 in resection group vs. 43 in TACE+RT group). In order to recruit resection group, 54 patients who underwent surgical resection for HCC with PVI between 2005 and 2008 at Asan Medical Center were screened. Of them, 43 patients who received surgical resection as a primary treatment were subjected. Three hundred eighty one patients who received TACE+RT for HCC with PVI during the same period were also screened. And then, 43 patients initially treated with TACE+RT were selected with matching Child-Pugh class (A vs. B), tumor size, and extent of PVI (main or bilateral vs. unilateral). In all patients, HCC was radiologically or histologically diagnosed on the basis of the practice guidelines of the American Association for the Study of Liver Diseases [
The clinical information of patients including demographics, etiologies of liver disease, and laboratory data were obtained at the time of diagnosis. Tumor characteristics such as the extent of PVI, radiologic morphology, and number of tumors were also evaluated initially. The patients were followed at intervals of 1-3 months, and recurrence, progression, and patients’ survival were evaluated through history taking, physical examination, laboratory findings, and imaging modalities such as a dynamic computed tomography (CT) scan or magnetic resonance images (MRI) at each visit. For patients in the TACE+RT group, repeated TACEs were performed based on the findings of CT or MRI, patients’ performance status, and hepatic reserves.
Progressive disease was included under the following conditions: recurrence defined as new detection of HCC in the liver or extrahepatic lesions in the resection group, or an increase of at least 20% in the diameter of viable tumor or newly developed HCC according to the modified Response Evaluation Criteria in Solid Tumors criteria in the TACE+RT group. Progression-free survival (PFS) and overall survival (OS) were measured from the time of diagnosis of HCC with PVI to the date of HCC progression and death or last visit, respectively. The study endpoints were progression of HCC and the OS.
The variables were compared using the chi-square test, Fisher’s exact test, or Student’s
The baseline characteristics of the resection and TACE+RT groups are shown in
There was no treatment-related mortality in both the resection and the TACE+RT groups. However, in the resection group, one patient suffered from pleural effusion within one month after surgery. In the TACE+RT group, chronic hepatitis B flare-up and the complications of cirrhosis such as jaundice and spontaneous bacterial peritonitis were developed in 3 and 2 patients, respectively. All of the patients who had treatment-related complications were improved after proper management.
During the follow-up, the proportion of patients who achieved progressive disease was 86% (n=37) for the resection group and 81% (n=35) for the TACE+RT group. Intrahepatic progression was identified in 62 patients (72%), and extrahepatic metastasis was found in 52 patients (61%). There were no significant differences in intrahepatic and extrahepatic progression between the two groups. The common metastatic sites were the lungs (n=40), lymph nodes (n=9), and bones (n=5). Of the entire patients, 27 (63%) in the resection group and 32 (74%) in the TACE+RT group have died during the follow-up period.
Among the patients with progressive disease, 34 and 35 patients were received the salvage treatment in the resection and the TACE+RT groups, respectively. In the resection group, most common method of salvage treatment was TACE (n=26), followed by RT (n=3), systemic chemotherapy (n=3), RFA (n=1), and surgery (n=1). Similarly, in the TACE+RT group, TACE (n=28) was most common, followed by surgery (n=4) and RT (n=3).
The PFS rates did not show significant differences between the resection and the TACE+RT groups. The 1- and 3-year PFS rates were 23% and 16%, respectively, in the resection group. Similarly, patients in the TACE+RT group showed the 1-year PFS rate of 26% and 3-year PFS rate of 15% (
Out of the patients treated by surgery, 27 (63%) died and 32 patients (74%) died in the TACE+RT group during the follow-up. The OS was significantly longer in the resection group than in the TACE+RT group (
Factors affecting PFS were evaluated using univariate analyses in HCC patients with PVI. However, the initial treatment modalities did not affect PFS. Moreover other characteristics also did not influence PFS (
We also evaluated the predictors affecting OS rates in HCC patients with PVI. On univariate analyses, surgical resection was a significant predictive factor associated with longer survival rates [hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.346-0.979;
In this study, we compared the treatment efficacy between surgical resection and TACE followed by RT in patients with HCC and PVI. Our study demonstrated that patients who received surgical resection achieved higher survival rates than those treated with TACE+RT.
PVI is one of the most common complications of HCC. The presence of PVI in HCC is classified as Barcelona Clinic Liver Cancer stage C, and sorafenib has been recently recommended as a treatment for patients with this condition [
However, in Asian-Pacific countries where the HCC prevalence is high, variable treatment options were attempted before sorafenib was approved. Surgical resection for HCC with PVI was initially reported in 1990 [
Traditionally, TACE has been widely performed for HCC treatment, regardless if the tumor is in the very early or advanced stage. However, the therapeutic effects of TACE have not been satisfactory for HCC with PVI although this procedure has been generally and safely applied. For this reason, the addition of RT to TACE has been attempted for these patients. RT for HCC was previously used restrictively owing to the limitation of poor radiation tolerance and, consequently, the small effects of RT [
Practically, we have attempted TACE+RT or surgical resection for patients with HCC and PVI when sorafenib was not available in Korea. Nowadays we still frequently considered these treatment options as well as sorafenib as an initial treatment. However, there were no data to compare the effects between surgical resection and TACE followed by RT in HCC patients with PVI. Our present study showed that surgical resection was more effective than TACE+RT in improving patient survival. Our study did not reveal a significant difference of PFS between the resection group and the TACE+RT group. As expected, the tumor recurrence or progression rates were still high in patients with advanced HCC regardless of treatment modalities. In the resection group, however, recurrence especially intrahepatic recurrence might be more controllable than those in TACE+RT group due to the relatively small extent of recurred tumor. Moreover, TACE was continuously performed in considerable number of patients in the TACE+RT group, although they had the progressive disease after TACE and RT. Thus the response of salvage treatment may also be better in resection group than those of TACE+RT group. Actually, some of the patients achieved the complete remission after salvage treatment in the resection group (not shown data). Consequently, we could suggest that this effective control of recurred tumor might result in a survival benefit in patients treated by resection.
Although we found that resection for HCC with PVI was superior over TACE+RT, the choice of surgical indication should be made carefully. According to previous reports, the surgical indications for these patients are still controversial [
Our study has potential limitations. The data were analyzed retrospectively and the sample size was relatively small. Thus, to minimize the selection bias and overcome these shortcomings, the subjects of each group were enrolled by matching for underlying liver function, tumor size, and PVI extent. Despite our efforts, the possibility of other unconsidered might exist. Thus, we agree that a further large-scale study is needed prospectively. In conclusion, surgical resection might be associated with better survival outcome than TACE and additional RT in HCC patients with PVI.
Study conception and design: Han Chu Lee
Acquisition of data: Danbi Lee and Jihyun An
Analysis and interpretation of data: Danbi Lee and Han Chu Lee
Drafting of manuscript: Danbi Lee and Han Chu Lee
Critical revision: Han Chu Lee, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Young-Hwa Chung and Yung Sang Lee
The authors have no conflicts to disclose.
alpha-fetoprotein
hepatocellular carcinoma
overall survival
progression-free survival
portal vein invasion
radiation therapy
transarterial chemoembolization
Kaplan-Meier estimates for progression-free survival in relation to treatment group. TACE, transarterial chemoembolization; RT, radiation therapy.
Kaplan-Meier estimates for overall survival in the resection and TACE+RT groups. TACE, transarterial chemoembolization; RT, radiation therapy.
Baseline characteristics
Variables | Resection (n=43) | TACE+RT (n=43) | |
---|---|---|---|
Age |
49 (24-63) | 52 (30-67) | 0.06 |
Sex (male/female) (n) | 36/7 | 35/8 | 1.00 |
Etiology (HBV/HCV/NBNC) (n) | 34/0/9 | 40-1-2 | 0.12 |
Platelet |
185 (79-608) | 149 (35-460) | 0.57 |
Serum ALT |
36 (10-108) | 42 (10-173) | 0.08 |
Serum AFP |
2095 (1.4-612,000) | 312 (1.0-260,000) | 0.46 |
Child-Pugh classification (A/B) (n) | 42/1 | 42/1 | 1.00 |
mUICC stage III/IVA (n) | 23/20 | 28/15 | 0.38 |
Imaging finding (nodular/massive) (n) | 30/13 | 25/18 | 0.37 |
Extent of PVI, main or bilateral/right unilateral/left unilateral (n) | 5/32/6 | 5/32/6 | 1.00 |
Number of tumor (single/multiple) (n) | 23/20 | 25/18 | 0.83 |
Size of tumor |
10 (4.2-18) | 10 (3.0-17) | 0.65 |
ECOG performance status 0/1/2 (n) | 11/32/0 | 15/27/1 | 0.35 |
Comorbidities |
9 | 11 | 0.80 |
TACE, transarterial chemoembolization; RT, radiation therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; NBNC, non-HBV and non-HCV; ALT, alanine aminotransferase; AFP, alpha-fetoprotein; mUICC, modified the Union for International Cancer Control; PVI, portal vein invasion; ECOG, the Eastern Cooperative Oncology Group.
Median (range).
Comorbidities include diabetes mellitus, hypertension, cardiovascular disease, and pulmonary disease.
Univariate analysis of factors affecting progression-free survival
Variables | HR | 95% CI | |
---|---|---|---|
Age | 0.993 | 0.967–1.020 | 0.63 |
Male | 0.721 | 0.379–1.372 | 0.32 |
Resection group | 1.045 | 0.656–1.663 | 0.85 |
Etiology (HBV) | 0.818 | 0.429–0.560 | 0.54 |
Main portal vein invasion | 0.791 | 0.362–1.728 | 0.56 |
Segmental portal branch invasion | 1.518 | 0.927–2.485 | 0.10 |
Multiple tumor | 1.399 | 0.875–0.236 | 0.16 |
Massive type of tumor | 1.232 | 0.763–1.988 | 0.39 |
mUICC stage (III) | 0.783 | 0.490–1.250 | 0.31 |
AFP > 200 ng/mL | 1.203 | 0.735–1.970 | 0.46 |
Thrombocytopenia | 0.931 | 0.583–1.485 | 0.76 |
Size > 5 cm | 1.409 | 0.675–2.942 | 0.36 |
HR, hazard ratio; CI, confidence interval; HBV, hepatitis B virus; mUICC, modified the Union for International Cancer Control; AFP, alpha-fetoprotein.
Univariate and multivariate analyses of predictive factors for overall survival
Variables | Univariate analyses |
Multivariate analyses |
||||
---|---|---|---|---|---|---|
HR | 95% CI | HR | 95% CI | |||
Age | 0.996 | 0.967–1.026 | 0.81 | 0.983 | 0.955–1.012 | 0.26 |
Male | 0.627 | 0.297–1.321 | 0.22 | 1.714 | 0.803–3.661 | 0.16 |
Resection group | 0.582 | 0.346–0.979 | 0.04 | 0.541 | 0.317–0.922 | 0.02 |
Etiology (HBV) | 0.414 | 0.165–14.731 | 0.06 | - | - | - |
Main portal vein invasion | 3.578 | 0.869–2.530 | 0.14 | - | - | - |
Segmental portal branch invasion | 1.462 | 0.845–2.530 | 0.18 | - | - | - |
Multiple tumor | 1.581 | 0.948–2.635 | 0.08 | - | - | - |
Massive type of tumor | 1.258 | 0.742–2.133 | 0.39 | - | - | - |
mUICC stage (III) | 0.731 | 0.438–1.220 | 0.23 | - | - | - |
AFP > 200 ng/mL | 1.148 | 0.660–1.997 | 0.63 | - | - | - |
Thrombocytopenia | 1.038 | 0.621–1.738 | 0.89 | - | - | - |
Size > 5 cm | 1.621 | 0.696–3.776 | 0.26 | - | - | - |
HR, hazard ratio; CI, confidence interval; HBV, hepatitis B virus; mUICC, modified the Union for International Cancer Control; AFP, alpha-fetoprotein.