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HPB (Oxford). 2012 Apr; 14(4): 247–253.
PMCID: PMC3371211
PMID: 22404263
Rumi Matono, Shohei Yoshiya, Takashi Motomura, Takeo Toshima, Hiroto Kayashima, Toshiro Masuda, Tomoharu Yoshizumi, Akinobu Taketomi, Ken Shirabe, and Yoshihiko Maehara
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Abstract
Objectives
The prognosis in patients with hepatocellular carcinoma (HCC) accompanied by main portal vein tumour thrombus (MPVTT) is poor. The aim of this study was to clarify the factors linked to survival of >5 years after hepatectomy in HCC patients with MPVTT.
Methods
Twenty-nine HCC patients with MPVTT were divided into two groups comprising, respectively, patients who survived >5 years after hepatectomy (survivors, n = 5) and those who did not (non-survivors, n = 24). The two groups were compared.
Results
Overall survival rates at 1, 3 and 5 years were 62.1%, 24.1% and 17.2%, respectively. Four (80.0%) 5-year survivors had recurrences of HCC in which the number of recurrent nodules was under four. Three (21.4%) of the 14 non-survivors who underwent curative resection experienced recurrences of HCC and all of them demonstrated fewer than four recurrent nodules (P = 0.0114). Local therapy, such as radiofrequency ablation and resection of recurrence, had more often been used in survivors than in non-survivors (P = 0.0364).
Conclusions
Although surgical outcomes in patients with HCC accompanied by MPVTT are unsatisfactory, some patients do enjoy longterm survival. When the number of recurrent nodules is less than four, local therapy should be selected with the aim of achieving 5-year survival.
Keywords: hepatocellular carcinoma, main portal vein tumour thrombus, hepatic resection, recurrent pattern, local therapy, longterm survival
Introduction
Hepatocellular carcinoma (HCC) is one of the most malignant diseases in the world.1 In particular, HCC with tumour thrombus in the first branch of the portal vein (Vp3) or with tumour thrombus in the main portal trunk or the opposite side portal branch (Vp4) is considered to represent an end-stage condition with a poor prognosis because tumour cells are likely to have spread throughout the liver.2 In recent reports,3,4 HCC patients with main portal vein tumour thrombus (MPVTT) are described as surviving only 2.7–4.0 months if left untreated. Hepatic resection remains the only potentially curative treatment for such patients. However, in patients who undergo hepatic resection for HCC with MPVTT (Vp3 and Vp4), postoperative 5-year survival rates are only 10–30%.5–9 Nevertheless, there are a few 5-year survivors. Ikai et al.5 reported a 5-year survival rate of 10.9% (four patients) and Le Treut et al.6 reported the 5-year survival of two of 22 patients with HCC accompanied by MPVTT.
This study retrospectively investigated the clinical and pathological characteristics of 29 HCC patients with MPVTT in an attempt to clarify the factors determining 5-year survival in patients with HCC accompanied by MPVTT.
Materials and methods
Patients
This study included 692 HCC patients who underwent liver resection between 1985 and 2005 at the Department of Surgery and Science, Kyushu University Hospital. Preoperative ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), angiography and CT during angiography were performed in all patients. From a retrospective database, 29 patients (4.2%) with tumour invasion of the first branch of the portal vein (Vp3) and tumour in the main portal trunk or the opposite side portal branch (Vp4) were enrolled in this study. These included 25 male and four female patients with a median age of 55 years (range: 29–76 years). Among these patients, 12 (41.4%) were infected with hepatitis C virus (HCV) and 16 (55.2%) with hepatitis B virus (HBV). The median finding on the indocyanine green retention test at 15 min (ICGR15) was 11.4% (range: 1.4–33.6%).
Methods
The 29 patients were divided into two groups consisting of those who survived for >5 years after hepatectomy (5-year survivors, n = 5) and those who did not (non-survivors, n = 24). Possible preoperative prognostic factors investigated in both groups included age, sex, HBV surface antigen, anti-HCV antibody, ICGR15 result, albumin, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alpha fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP). Various cancer-related factors including maximum tumour size, tumour grade (good, moderate or poor) and the presence of intrahepatic metastases were also examined. Our institutional review board approved the study protocol, which conformed to the Helsinki Declaration of 1975.
Operative procedures
Hepatic resection procedures included one trisegmentectomy, 27 lobectomies (11 left, 16 right) and one segmentectomy. There were no significant differences between the two groups in surgical procedures. Curative resection was defined as hepatic resection with no residual HCC. Inoue et al.10 reported no differences in outcome between the peeling-off technique (in which the MPVTT is resected but the portal vein thrombus-bearing territory is preserved) and the en bloc technique (in which the portal veins are reconstructed) when these were performed in association with thrombectomy. All surgery in this study employed the peeling-off technique.
Patient follow-up
Follow-up of patients after hepatectomy followed a strict protocol, which did not change during the study period. Patients were examined for recurrence by US and tumour markers such as AFP and DCP every month and by CT every 3 months.
Recurrence after curative resection
Recurrence of HCC was examined in the 19 patients who had undergone curative resection of primary HCC. Of these 19 patients, 18 had postoperative recurrence of HCC. The recurrence pattern and therapy for recurrence were examined. The recurrence pattern was analysed according to the number of recurrent nodules. This number included metastatic nodules in sites other than the liver. Patients with HCC recurrence were divided into two groups comprising, respectively, those with four or more recurrent nodules and those with fewer than four recurrent nodules.
The therapeutic modalities for recurrent HCC were resection, radiofrequency ablation (RFA), transarterial chemoembolization (TACE), regional chemotherapy and radiation. Repeat hepatectomy for recurrent HCC in the liver was the treatment of choice until recently, when local ablation therapy was recommended as the initial treatment when the recurrent tumour measured <2 cm in diameter and no more than three intrahepatic nodules were found.11 Although all patients in this study had MPVTT, those with intrahepatic recurrence of HCC were treated according to the strategy described above, using local therapy, such as resection and RFA, when possible. In patients with distant metastases, pulmonary and bone metastases were resected if resection was possible, the metastases numbered less than four and intrahepatic recurrence was under control.
Statistical analysis
All data are expressed as median value. Independent chi-squared tests were used for categorical variables. Continuous variables were compared by unpaired Student's t-tests. Cumulative and disease-free survival rates were obtained using the Kaplan–Meier method. Differences in survival between groups were compared for each variable using the log-rank test. The starting point for the calculation of survival time was the date of operation. Death, including deaths that were cancer- or liver-related, represented the end-point. A P-value of <0.05 was considered to indicate statistical significance.
Results
The median length of follow-up was 36 months (range: 18 days to 234 months). One patient died of operative morbidity. Overall survival rates at 1, 3 and 5 years were 62.1%, 24.1% and 17.2%, respectively (Fig. 1). The median survival time in all 29 patients was 16.6 months.
Figure 1
Overall survival rates after hepatic resection in patients with hepatocellular carcinoma accompanied by main portal vein tumour thrombus (n = 29)
Table 1 compares clinical and pathological variables in 5-year survivors (n = 5) and non-survivors (n = 24). Preoperative serum concentrations of DCP in 5-year survivors were significantly lower than in non-survivors (P = 0.0052). In 19 patients, curative resection (no residual HCC nodules) was performed. Non-curative resection with residual HCC was performed in 10 patients. Overall survival rates at 1, 3 and 5 years were 73.4%, 36.8% and 26.3%, respectively, in patients who underwent curative resection and 38.5%, 0% and 0%, respectively, in those who underwent non-curative resection (Fig. 2). All of the 5-year survivors had undergone curative resection. All of the patients who underwent non-curative resection died within 2 years of surgery. The difference in survival rates is not statistically significant (P = 0.1336).
Table 1
Comparison of clinicopathological factors in non-survivors and 5-year survivors
| Factor | Non-survivors (n = 24) | 5-year survivors (n = 5) | P-value |
|---|---|---|---|
| Gender, male, n (%) | 21 (87.5%) | 4 (80.0%) | 0.3896 |
| Age, years, median (range) | 56 (29–76) | 51 (49–63) | 0.3896 |
| Total bilirubin, mg/dl, median (range) | 0.9 (0.4–4.0) | 1.1 (0.5–1.4) | 0.3133 |
| Albumin, g/dl, median (range) | 3.7 (3.1–4.9) | 3.8 (3.1–4.3) | 0.5346 |
| AST, U/l, median (range) | 65 (19–1160) | 36 (22–78) | 0.0365a |
| ALT, U/l, median (range) | 48 (10–338) | 37 (25–300) | 0.5913 |
| Positive HBVs-Ag, n(%) | 13 (54.2%) | 3 (60.0%) | 1.0000 |
| Positive HCV-Ab, n (%) | 9 (37.5%) | 3 (60.0%) | 0.6221 |
| AFP, ng/ml, median (range) | 4 001 (7–422 680) | 2 325 (152.1–98 030) | 0.1914 |
| DCP, mAU/ml, median (range) | 4 240 (24–75 000) | 1 210 (18–2028) | 0.0052a |
| DCP <2200 mAU/ml, n (%) | 10 (41.7%) | 5 (100%) | 0.0421a |
| ICGR15, %, median (range) | 12.0 (5.5–33.6) | 8.7 (1.4–24.5) | 0.1456 |
| Main tumour size, cm, median (range) | 8.5 (2.0–16.0) | 3.9 (2.2–13.0) | 0.1463 |
| Tumour differentiation, moderate, n (%) | 4 (16.7%) | 2 (40.0%) | 0.2709 |
| Intrahepatic metastasis, n (%) | 23 (95.8%) | 3 (60.0%) | 0.0684 |
| Surgical curability, n (%) | 14 (58.3%) | 5 (100%) | 0.1336 |
| Blood loss, ml, median (range) | 1 900 (493–23 000) | 1 800 (1800–12 500) | 0.5198 |
| Transfusion rate, % | 41.7% | 40.0% | 1.0000 |
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aP < 0.05.
AST, aspartate aminotransferase; ALT, alanine aminotransferase; HBVs-Ag, hepatitis B virus surface antigen; HCV-Ab, hepatitis C virus antibody; AFP, alphafetoprotein; DCP, des-γ-carboxy prothrombin; ICGR15, indocyanine green retention test at 15 min.
Figure 2
Comparison of overall survival in patients who underwent curative (n = 19) vs. non-curative (n = 10) resection (P = 0.1336)
Overall survival in patients with high and low serum concentrations of DCP (≥2200 mAU/ml and <2200 mAU/ml, respectively) was examined. The difference was statistically significant (P = 0.0421). Disease-free survival in patients who underwent curative resection is shown in Fig. 3. All except one of the 5-year survivors had postoperative recurrence. There was no significant difference in disease-free survival between 5-year survivors and non-survivors. Recurrence patterns in the two groups are compared in Table 2. Of 18 patients in whom HCC recurred after curative resection, seven (38.8%) patients demonstrated less than four nodules. Clear differences in recurrence patterns were observed between the two groups. All of the 5-year survivors showed fewer than four recurrent nodules, whereas only 21.4% of non-survivors showed fewer than four recurrent nodules (P = 0.0114). The most common organ in which recurrence occurred was the liver; other sites of recurrence included lung, bone, brain and peritoneum.
Figure 3
Comparison of disease-free survival in 5-year survivors (n = 5) and non-survivors (n = 24) after curative resection (P = 0.1134)
Table 2
Comparison of recurrence patterns and therapeutic modalities for recurrent hepatocellular carcinoma in curatively resected patients (n = 19)
| Analysis of recurrence | Non-survivors (n = 14) | 5-year survivors (n = 5) | P-value |
|---|---|---|---|
| Recurrence, n (%) | 14 (100%) | 4 (80.0%) | |
| Number of nodules in recurrence, n (%) | |||
| <4 | 3 (21.4%) | 4 (100%) | 0.0114 |
| ≥4 | 11 (78.6%) | 0 | |
| Sites of recurrence, n | |||
| Liver | 13 | 3 | |
| Lung | 1 | 1 | |
| Bone | 1 | 1 | |
| Brain | 1 | 0 | |
| Peritoneum | 1 | 0 | |
| Treatment for the first recurrence, n | 0.0364 | ||
| Resection | 0 | 2 | |
| Radiofrequency ablation | 3 | 1 | |
| TACE (+ radiation) | 8 | 1 | |
| Best supportive care | 3 | 0 | |
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TACE, transarterial chemoembolization.
Statistically significant differences between the two groups in the therapeutic modalities used for recurrent HCC emerged. Local therapy, such as resection and RFA for recurrent nodules, was performed more commonly in the 5-year survivors than in the non-survivors (P = 0.0364).
Discussion
The prognosis of HCC patients with MPVTT is extremely poor, even after the application of various therapeutic modalities, and the optimal treatment of these patients remains controversial. In previous reports, realistic therapeutic options have included TACE, regional chemotherapy and radiation.12 Mean survival times and response rates are <10 months and ≤40%, respectively, in patients who undergo TACE.13–16 With regional chemotherapy, although much higher response rates, such as 63%, have been reported, mean survival times are <1 year.17–23 Radiation therapy gives much higher response rates, which can reach as much as 100%, but the maximum median survival time reported is 10.7 months.24–29 Thus, median survival time is <12 months in patients who undergo therapeutic modalities other than surgery. In hepatic resection, 5-year survival rates of 0–22.4% (Table 3) and median survival times of 6.4–20.0 months have been reported.5–9 The current study found a 5-year survival rate of 17.4% and a median survival of 16.6 months. These results suggest that hepatic resection may represent the treatment of choice in patients with HCC and MPVTT.
Table 3
Recent reports on outcomes in patients with hepatocellular carcinoma (HCC) accompanied by portal vein tumour thrombus
| Author(s) | Published | Setting | Patients (Vp3 and Vp4), n | Median survival, months | 5-year survival, % (Kaplan-Meier) | 5-year survivors, n |
|---|---|---|---|---|---|---|
| Ikai et al.5 | 2006 | HCC with MPVTT (Vp3 and Vp4) | 78 | 6.9 | 10.9% | 4 |
| Le Treut et al.6 | 2006 | Tumour thrombus in portal and hepatic veins (n = 26) | 22 | 9.0 | 17.0% | 2 |
| Kondo et al.7 | 2009 | HCC with MPVTT (Vp1–4, n = 48) | 29 | 11.3 | 0% (only Vp4) | 0 |
| Ban et al.8 | 2009 | HCC with MPVTT (Vp3 and Vp4) | 45 | 20.0 | 22.4% | 3 |
| Shi et al.9 | 2010 | HCC with MPVTT (Vp1–4, n = 406) | 98 | 6.4 | 0% (only Vp4) | 0 |
| Present study | 2011 | HCC with MPVTT (Vp3 and Vp4) | 29 | 16.9 | 17.2% | 5 |
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Vp3, first branch of the portal vein; Vp4, main portal trunk or the opposite portal branch.
Reports of longterm survival are extremely rare in patients with HCC accompanied by MPVTT. Numbers of 5-year survivors in previous reports are shown in Table 3. These numbers are extremely small and the factors that enable 5-year survival remain unclear. In this study, preoperative serum concentrations of DCP were significantly lower in 5-year survivors and all the 5-year survivors underwent curative resection (no residual HCC). In this study, the crucial cut-off point for serum concentrations of DCP seems to be <2200 mAU/ml. A DCP has been reported to represent a poor prognostic factor in patients with HCC undergoing hepatic resection30,31 or liver transplantation32,33 and is reportedly associated with microvascular invasion by HCC cells.34 In this study, all patients had portal vein invasion; therefore other mechanisms must be presumed to have had effect. Recently, Yue et al.35 showed that DCP induces matrix metalloproteinase activity in HCC cells and Wang et al.36 showed that DCP induces human vascular endothelial cell growth and migration. Fujikawa et al.37 showed that HCC arterial vascularity strongly correlates with expression of serum and tissue DCP, and suggested DCP secreted from HCC cells may not act as a paracrine interaction factor between HCC and vascular endothelial cells, but as an autocrine driver. Recently, Murata et al.38 showed that cytoskeletal changes during epithelial mesenchymal transition serve as a crucial mechanism for DCP production in HCC. These findings suggest that DCP may influence the malignant potential of HCC cells by mechanisms other than vessel invasion.
Recurrence of HCC after hepatectomy and thrombectomy occurs in most patients with MPVTT and is usually difficult to control once it has occurred. The presence of HCC with MPVTT has been considered to represent an end-stage condition with a poor prognosis because tumour cells are likely to have spread throughout the liver. However, the number of recurrent nodules seems to be an important determinant of 5-year survival. In this study, sites of recurrence in 5-year survivors included distant metastatic sites, such as lung and bone. This suggests that the recurrence of fewer than four nodules is not always associated with further multiple recurrences. Therefore, in patients with fewer than four recurrent nodules, local therapy may prolong survival. In this study, two of the 5-year survivors underwent resection of distant metastases, one underwent repeat hepatectomy and one underwent RFA for intrahepatic recurrence. After the local therapy, two patients remained free from HCC recurrence for >5 years. Therefore, in patients with fewer than four recurrent nodules, local therapy such as resection and/or ablation therapy may prolong survival. Thus, when the number of recurrent nodules is under four, local therapy should be selected with the aim of achieving 5-year survival. The effectiveness of surgical resection for pulmonary metastases from HCC after hepatectomy has been shown previously.39 It is crucial to understand that local therapy can be useful for recurrence after curative resection, even in patients with MPVTT.
The prognosis remains extremely poor in patients who undergo non-curative resection and demonstrate four or more recurrent nodules. It is clear that other therapeutic strategies are necessary. Regional chemotherapy, including interferon-α (IFN-α) may be another option for adjuvant therapy after surgery. Nagano40 demonstrated that adjuvant chemotherapy with IFN-α and 5-fluorouracil (5-FU) is useful and prolongs survival. In HCC patients with MPVTT in whom curative resection cannot be performed, IFN-α and 5-FU therapy is effective and curative resection sometimes becomes possible after this therapy.41 The combination of IFN-α and 5-FU therapy and hepatic resection may represent a promising strategy. The effects of sorafenib, a newly developed biologic therapy for non-resectable HCC, should be clarified in these patients.42
In conclusion, factors that relate positively to 5-year survival after hepatic resection seem to be low serum concentrations of DCP and curative resection. In patients who show recurrence of HCC, the presence of fewer than four recurrent nodules seems to be a good predictor of longterm survival. Local therapy, such as surgical resection and/or ablation therapy, may be useful for this type of recurrence. Further therapeutic strategies are necessary in patients with high serum concentrations of DCP, who cannot undergo curative resection and have four or more recurrent nodules.
Conflicts of interest
None declared.
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Articles from HPB : The Official Journal of the International Hepato Pancreato Biliary Association are provided here courtesy of Elsevier
