Abstract
Background
Currently, there is no definitive management for hepatocellular carcinoma (HCC) intrahepatic recurrence (IHR) after primary resection (PR). The aim of this study was to analyze the outcomes of three modalities for patients who received curative PR and had IHR within the University of California San Francisco (UCSF) criteria.
Methods
Between 2003 and 2010, patients with IHR after PR were treated with salvage liver transplantation (SLT), re-resection (RR) or local ablation (LA). Clinico-pathological features of primary tumor and recurrent HCC were analyzed to determine the risk factors that adversely affected overall survival (OS) and disease free survival (DFS).
Results
The study included 130 patients with subgroups of SLT (n = 25), RR (n = 31) and LA (n = 74). The 5-year DFS and OS were 75%, 31% and 17% and 80%, 60% and 58% respectively for each subgroup. SLT had a significantly better DFS than other modalities (p < 0.001). There was no difference in OS. In multivariate analysis, two variables adversely affected DFS: microvascular invasion in PR and not treating patients with SLT.
Conclusions
SLT provides better DFS for patients with IHR within the UCSF criteria. However, SLT failed to show the same advantage in OS.
Introduction
Hepatic resection is considered to be a potentially curative treatment for hepatocellular carcinoma (HCC), especially in patients with preserved liver function. However, a high incidence of recurrence remains the main challenge after curative resection of HCC with a 5-year disease-free survival rate (DFS) of 27–42%; with more than 70% of recurrences occurring within the hepatic remnant.1, 2, 3, 4, 5 Successful subsequent management with curative intent has been shown to prolong survival in patients with intrahepatic recurrence (IHR).6, 7 Different modalities have been used for IHR management, including salvage liver transplantation (SLT), re-resection (RR), local ablation (LA) using radiofrequency ablation (RFA) and/or percutaneous ethanol injection (PEI) and trans-arterial embolization/chemo-embolization (TAE/TACE).7, 8, 9, 10, 11, 12, 13, 14 Currently, there are no definitive selection criteria for IHR management other than those applied to the management of primary HCC.13, 15
The pathological features of HCC and non-tumor liver parenchyma (NTLP) are strongly related to recurrence.2, 3, 4, 16 When deciding on therapeutic management options for patients with IHR the pathological features of the primary HCC can also be taken into account. This concept has previously been applied to identify patients at high risk of recurrence and whom would benefit from SLT prior to the diagnosis of recurrence.17
The aim of this study was to analyze the outcomes of three modalities (SLT, RR and LA) used for management of patients who underwent curative primary resection (PR) complicated by IHR that fell within the University of California San Francisco (UCSF) criteria.18 Prognostic factors affecting DFS and overall survival (OS) after IHR management were identified.
Patients and methods
From January 2003 to December 2010, all patients who underwent curative PR complicated by IHR that fell within the UCSF criteria were included for further study. All patients with possible diagnosis of HCC were discussed in a weekly multidisciplinary tumor conference prior to initiating treatment. The BCLC treatment guidelines were used with minor adjustment. The AJCC staging system was used to determine adjuvant treatment. Patients who underwent palliative PR, patients with associated malignancies and patients with recurrence beyond the UCSF criteria were excluded. The UCSF criteria (solitary tumor < or = 6.5 cm, or three or fewer nodules with the largest lesion < or = 4.5 cm and total tumor diameter < or = 8 cm, without gross vascular invasion) was applied because patients listed for liver transplantation (LT) are required to fall within the criteria as determined by the National Health Insurance Administration (NHI), Ministry of Health and Welfare, Taiwan. Histopathological features of PR and clinical data of recurrence were collected from a prospectively maintained database. The study protocol was approved by the hospital's ethics committee (IRB No. 101-2817B).
Primary resection, follow-up and diagnosis of recurrence
Preoperative assessments and the PR operative procedures have been described previously.3 A major resection was defined as a resection of at least three hepatic segments. The features of HCC and NTLP in PR were histopathologically examined. The degree of fibrosis in the NTLP was graded according to an Ishak score.19 Microvascular invasion was defined as tumor emboli within the central vein, a lobar or segmental portal or hepatic vein and large capsular vessels. Patients were followed up regularly at the first month, then every 3 months for 5 years and then every 6 months thereafter. Follow-up comprised serum alpha fetoprotein level (AFP) analysis and abdominal ultrasonography. Patients suspected of having recurrence underwent computed tomography (CT) for confirmation. Diagnosis of primary and recurrent HCC was based on the criteria of practice guidelines of the European Association for the Study of the Liver (EASL) or the American Association for the Study of Liver Disease (AASLD).20, 21
Management of recurrence
The BCLC treatment guidelines were used with minor adjustment. The AJCC staging system was used for possible adjuvant treatment. In general, RR was performed in Child–Pugh score A patients whose future remnant liver volume was >30–40% of the standard liver volume (Appendix Fig. A1). For patients to be eligible for SLT, the UCSF criteria had to be met. Local ablation therapy was considered in Child–Pugh score A patients and selected B patients. Neither number nor size of primary HCC was considered in the UCSF categorization of recurrent HCC, but major vascular invasion and extrahepatic metastasis in PR precluded the patients from the study. Techniques of hepatectomy, SLT and LA have been described elsewhere.3, 22, 23
Follow-up after management of recurrence
Perioperative mortality was defined as a patient's death within 90 days of the procedure. The follow-up protocol after management of recurrence was the same as that after PR. The response for LA was assessed by contrast-enhanced CT 1 month after the procedure. Local ablation therapy was considered complete when it resulted in an area without contrast enhancement that was equal to or larger than the ablated tumor. Normalization of serum AFP, if elevated, was also considered. If LA therapy resulted in an incomplete response, it was repeated until a complete response was achieved, and the date of the complete response was considered to be the date of management. All patients were followed up until the end of December 2015.
Statistical analysis
Continuous variables were expressed as medians and interquartile ranges and were compared using the Kruskal–Wallis test; in cases of significance, the Mann–Whitney U test was used to compare paired groups. Categorical variables were expressed as numbers and percentages and were compared using a χ2 test. DFS and OS rates were estimated via the Kaplan–Meier method, and differences in survival curves between groups were compared using a log-rank test. Histopathological characteristics of PR and features of recurrence were analyzed for their influence on DFS and OS using the Cox proportional hazard model. Variables with p-values <0.1 were used in multivariate analysis by the Cox proportional hazard model with a backward stepwise method. OS was measured from the management of recurrence date until death or last follow-up. DFS was computed from the management of recurrence date until radiological confirmation of re-recurrence, last follow-up or death. Except for univariate analysis, statistical significance was defined as a p-value <0.05. Statistical analysis was performed using SPSS 16 for Windows (SPSS Inc., Chicago, IL, USA).
Results
From a total of 1075 patients who underwent primary resection for HCC 136 (13%) patients were managed for IHR within the UCSF criteria using SLT, RR and LA. After exclusion of six patients who were lost to follow-up, the study group included 130 patients (Fig. 1). The median follow-up length was 56 months (range, 0.6–139 months). At the end of follow up, 75 patients (58%) were still alive and 42 patients (32%) were disease free. The following modalities were used: SLT (n = 25 19%), RR (n = 31 24%) and LA (n = 74 57%). Baseline characteristics of patients and features of recurrent tumors are summarized in Table 1. For the SLT group, all patients were from living donors except for one patient. Postoperative complications and causes of death are enlisted in Appendix Table A1.
Figure 1.
Inclusion and exclusion criteria
Table 1.
Baseline characteristics of the three groups at the time of recurrence
| SLT (n = 25) | RR (n = 31) | LA (n = 74) n, (%) |
p-Value | |
|---|---|---|---|---|
| Gender (Male) | 20 | 20 | 61 (83) | 0.126 |
| Age (years)a,b | 54 (51–56) | 58 (54–62) | 61 (59–64) | 0.007 |
| Time to recurrence (months)c | 13 (5–22) | 21 (10–35) | 17 (8–33) | 0.025 |
| BMI (kg/m2)b | 25 (24–27) | 24 (23–25) | 25 (24–26) | 0.228 |
| Virology | 0.390 | |||
| • HBV | 18 | 22 | 40 (54) | |
| • HCV | 4 | 4 | 24 (32) | |
| • Combined B,C | 1 | 1 | 3 (4) | |
| • NBNC | 2 | 4 | 7 (10) | |
| AFP (ng/ml)c | 10 (4–93) | 13 (3–50) | 10 (4–35) | 0.840 |
| AST (U/L)c | 38 (27–57) | 41 (28–47) | 42 (33–58) | 0.275 |
| ALT (U/L)c | 36 (23–52) | 34 (23–61) | 44 (29–60) | 0.203 |
| Alb (gm/dl)b | 3.9 (3.6–4.1) | 4.2 (4.1–4.3) | 3.9 (3.8–4.0) | 0.010 |
| Bilirubin (mg/dl)c | 1.0 (0.7–1.6) | 0.8 (0.7–1.1) | 0.9 (0.7–1.1) | 0.203 |
| INRb | 1.09 (1.02–1.16) | 1.03 (1.01–1.05) | 1.03 (1.02–1.05) | 0.019 |
| Platelets ×103/mm3b | 163 (110–216) | 197 (172–221) | 175 (158–191) | 0.307 |
| Child–Pugh score | 0.030 | |||
| • A | 20 | 31 | 70 (95) | |
| • B | 4 | 0 | 4 (54) | |
| • C | 1 | 0 | 0 (0) | |
| Size (cm)a,b | 1.9 (1.6–2.2) | 2.1 (1.7–2.5) | 1.8 (1.7–2.0) | 0.199 |
| Numbera | <0.001 | |||
| Single | 9 | 20 | 57 (77) | |
| 2–3 | 8 | 8 | 17 (23) | |
| >3 | 8 | 3 | 0 (0) |
SLT, salvage liver transplantation; RR, re-resection; LA, local ablation; BMI, body mass index; HBV, chronic hepatitis B infection; HCV, chronic hepatitis C infection; NBNC, neither anti-HCV nor HBsAg positive; AFP, serum alpha fetoprotein; AST, serum aspartate aminotransferase; ALT, serum alanine aminotransferase; Alb, serum albumin; Bilirubin, serum total bilirubin.
Imaging findings before treatment of first recurrence.
Mean (95% CI).
Median (IQR).
There was no significant difference among the three groups in terms of clinico-pathological features of PR (Table 2). A total of 88 (68%) patients developed a further recurrence; the breakdown and outcomes are shown in Appendix Table A2.
Table 2.
Features of primary resection
| SLT (n = 25) | RR (n = 31) | LA (n = 74) n, (%) |
p-Value | |
|---|---|---|---|---|
| Major resection | 5 | 7 | 20 (27) | 0.745 |
| Histopathology | ||||
| Resection margin (mm) | 11 (3–20) | 9 (5–15) | 10 (4–20) | 0.930 |
| Size (cm) | 3 (2–6) | 4 (3–6) | 3 (2–5) | 0.050 |
| Tumor number | 0.123 | |||
| • 1 | 9 | 20 | 63 (85) | |
| • 2–3 | 4 | 2 | 6 (8) | |
| • >3 | 3 | 2 | 5 (7) | |
| Histological grading | 0.656 | |||
| Well diff. | 2 | 3 | 6 (9) | |
| Moderately/Poorly diff. | 10 | 19 | 61 (91) | |
| mVI | 5 | 9 | 23 (31) | 0.838 |
| Cirrhosis | 8 | 7 | 31 (42) | 0.379 |
| AJCC stage (7th edition) | 0.417 | |||
| • I | 6 | 14 | 45 (61) | |
| • II | 8 | 8 | 26 (35) | |
| • IIIA | 2 | 2 | 3 (4) | |
SLT, salvage liver transplantation; RR, re-resection; LA, local ablation; Diff., differentiated; mVI, microvascular invasion.
Survival analysis
The actuarial DFS and OS are shown in Fig. 2. The 1-, 3- and 5-year DFS rates were 83%, 75% and 75%, respectively, for the SLT group; 58%, 39% and 31%, respectively, for the RR group; and 63%, 24% and 17%, respectively, for the LA group. SLT had a significantly better DFS rate than other modalities (p < 0.001). The 1-, 3- and 5-year OS rates were 96%, 88% and 80%, respectively, for the SLT group; 97%, 74% and 60%, respectively, for the RR group; and 91%, 70% and 58%, respectively, for the LA group. There were no significant differences in the 3 modalities. The results of the univariable and multivariable analyses by Cox model in DFS and OS are shown in Table 3, Table 4. The results are compatible with results of Kaplan–Meier method.
Figure 2.
Outcomes after management of patients with intrahepatic recurrence after hepatectomy in hepatocellular carcinoma within UCSF criteria. a. Disease-free survival. b. Overall survival
Table 3.
Univariate and multivariate analysis by Cox proportional hazard ratio of clinico-pathological factors affecting disease-free survival rate
| Factors | Comparisons | Univariate |
Multivariate |
||
|---|---|---|---|---|---|
| HR (95% CI) | p-Value | HR (95% CI) | p-Value | ||
| First resection | |||||
| Gender | Male vs. female | 0.79 (0.46–1.36) | 0.399 | ||
| Size of tumor | Per 1 cm increase | 1.00 (0.93–1.08) | 0.995 | ||
| Resection margin | Per 1 mm increase | 0.98 (0.96–1.00) | 0.110 | ||
| Tumor number | Single vs. multiple | 0.77 (0.43–1.36) | 0.361 | ||
| Histological grade | Well diff. vs. moderately and poorly diff. | 0.59 (0.25–1.36) | 0.213 | ||
| mVI | No vs. yes | 0.41 (0.25–0.66) | <0.001 | 0.41 (0.25–0.66) | <0.001 |
| Cirrhosis | No vs. yes | 0.83 (0.51–1.33) | 0.430 | ||
| Recurrence | |||||
| Age | Per 1 year increase | 1.02 (1.00–1.04) | 0.085 | ||
| BMI | Per 1 kg/m2 increase | 1.00 (0.93–1.08) | 0.971 | ||
| Platelets | Per 1 103/mm3 increase | 100 (97–104) | 0.821 | ||
| HBV | No vs. yes | 1.20 (0.72–2.02) | 0.485 | ||
| HCV | No vs. yes | 0.77 (0.45–1.34) | 0.363 | ||
| Combined HBV and HCV | No vs. yes | 1.27 (0.31–5.20) | 0.740 | ||
| AFP | Per 1 ng/mL increase | 1.00 (1.00–1.001) | 0.648 | ||
| ALT | Per 1 U/L increase | 1.00 (1.00–1.01) | 0.777 | ||
| Albumin | Per 1 g/dL increase | 0.86 (0.50–1.47) | 0.579 | ||
| Bilirubin | Per 1 mg/dL increase | 0.66 (0.36–1.21) | 0.181 | ||
| INR | Per 1 s increase | 2.62 (0.12–59.29) | 0.545 | ||
| Child–Pugh score | Per 1 score increase | 1.10 (0.40–3.04) | 0.849 | ||
| Time to recurrence | Per 1 months increase | 1.01 (1.00–1.02) | 0.189 | ||
| Tumor number | Single vs. multiple | 1.43 (0.81–2.53) | 0.219 | ||
| Size of tumor | Per 1 cm increase | 1.12 (0.82–1.55) | 0.479 | ||
| Primary resection | RR vs. SLT | 4.22 (1.19–14.98) | 0.026 | 4.22 (1.19–14.98) | 0.026 |
| LA vs. SLT | 7.34 (2.27–23.68) | 0.001 | 7.34 (2.27–23.68) | 0.001 | |
mVI, microvascular invasion; BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus; AFP, serum alpha feto-protein; ALT, alanine transaminase; INR, international normalized ratio; SLT, salvage liver transplantation; RR, re-resection; LA, local ablation; diff., differentiated.
Table 4.
Univariate and multivariate analysis by Cox proportional hazard ratio of clinico-pathological factors affecting overall survival rate
| Factors | Comparisons | Univariate |
Multivariate |
||
|---|---|---|---|---|---|
| HR (95% CI) | p-Value | HR (95% CI) | p-Value | ||
| First resection | |||||
| Gender | Male vs. female | 1.49 (0.62–3.61) | 0.374 | ||
| Size of tumor | Per 1 cm increase | 1.05 (0.95–1.16) | 0.302 | ||
| Resection margin | Per 1 mm increase | 1.00 (0.97–1.02) | 0.736 | ||
| Tumor number | Single vs. multiple | 2.11 (0.74–5.99) | 0.161 | ||
| Histological grade | Well diff. vs. moderately and poorly diff. | 0.71 (0.22–2.31) | 0.566 | ||
| mVI | No vs. yes | 0.59 (0.30–1.17) | 0.130 | ||
| Cirrhosis | No vs. yes | 0.68 (0.35–1.33) | 0.259 | ||
| Recurrence | |||||
| Age | Per 1 year increase | 0.98 (0.95–1.02) | 0.319 | ||
| BMI | Per 1 kg/m2 increase | 0.98 (0.88–1.09) | 0.713 | ||
| Platelets | Per 1 103/mm3 increase | 98 (93–103) | 0.451 | ||
| HBV | No vs. yes | 0.98 (0.47–2.05) | 0.957 | ||
| HCV | No vs. yes | 0.85 (0.39–1.86) | 0.690 | ||
| Combined HBV and HCV | No vs. yes | 21.40 (0.01–63254.29) | 0.452 | ||
| AFP | Per 1 ng/mL increase | 1.00 (1.00–1.001) | 0.885 | ||
| ALT | Per 1 U/L increase | 1.00 (1.00–1.01) | 0.267 | ||
| Albumin | Per 1 g/dL increase | 0.93 (0.45–1.92) | 0.838 | ||
| Bilirubin | Per 1 mg/dL increase | 0.85 (0.39–1.86) | 0.681 | ||
| INR | Per 1 s increase | 11.55 (0.21–636.92) | 0.232 | ||
| Child–Pugh score | Per 1 score increase | 1.22 (0.29–5.10) | 0.789 | ||
| Time to recurrence | Per 1 months increase | 1.00 (0.99–1.02) | 0.656 | ||
| Tumor number | Single vs. multiple | 1.63 (0.70–3.79) | 0.254 | ||
| Size of tumor | Per 1 cm increase | 1.16 (0.74–1.81) | 0.511 | ||
| Primary resection | RR vs. SLT | 2.40 (0.49–11.91) | 0.283 | ||
| LA vs. SLT | 3.59 (0.85–15.23) | 0.083 | |||
mVI, microvascular invasion; BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus; AFP, serum alpha feto-protein; ALT, alanine transaminase; INR, international normalized ratio; SLT, salvage liver transplantation; RR, re-resection; LA, local ablation; diff., differentiated.
Discussion
A high incidence of IHR remains a challenge after curative PR of HCC, given that subsequent management has been reported to prolong survival in patients with IHR.1, 2, 3, 4, 5, 6, 7 Different modalities are used for IHR management, including SLT, RR, LA and TAE.7, 8, 9, 10, 11, 12, 13 SLT has the lowest potential for re-recurrence, with a 5-year DFS rate of 48–67%.8, 11, 24 A recent report showed a 5-year DFS rate of 60% after living-donor SLT for recurrent HCC within the Milan criteria.15 However, a donor-pool shortage, life-long immunosuppression and the technical demands of the procedure limit its use for all patients. Re-resection has shown good survival outcomes and was considered by Minagawa et al. to be the treatment of choice for patients with a single tumor in the PR, recurrence after 1 year and absent portal vein invasion.12 Re-resection is sometimes limited by functional liver reserve, which makes it inapplicable to all patients. Furthermore, a recent report showed that it has no survival benefit over RFA for IHR management; LA procedures have advantages of repeatability, minimal invasiveness and hepatic parenchyma preservation.13 TACE also showed satisfactory results; it carries the same advantages as LA therapy.10, 25 However, it is usually considered to be a palliative treatment.
From previous discussions, it appears that no single procedure can be considered definitive treatment. Current results showed that SLT had a 5-year DFS rate of 75%; this was significantly better than LA and RR and was comparable to previous reports.8, 11, 15, 24 However, SLT failed to show the same advantage with regards to OS. Liver transplantation, by nature, is a complex and technically demanding procedure, especially SLT. Current results showed a higher incidence of morbidity in the SLT group compared to LA and RR. For the above-mentioned reasons, in addition to organ shortages, offering SLT to all patients with transplantable IHR does not seem to be a practical option. The question is which category of patients can experience the best benefit from SLT. In recurrence management, the pathological criteria of the primary tumor as well as NTLP are available. Sala et al. used pathological features of HCC in PR to identify groups at a high risk for recurrence, offering SLT to the high-risk patients even before recurrence.17 In this study, mVI in the PR specimen was found to be an independent risk factor for re-recurrence. Microvascular invasion is associated with a high potential for recurrence after resection of HCC.2, 3, 16, 26 However, the impact of mVI and resection margin in the PR specimen on the outcome of IHR management has not been widely studied.
Several studies have shown that mVI is a poor prognostic factor for recurrence after LT. In these studies, the explanted liver in the transplant setting rather than the previously resected HCC was the key factor to predict tumor recurrence.26, 27 Meniconi et al. suggested that SLT should not be performed in patients where HCC was observed in the PR with mVI.28 However, this study did not investigate the impact of mVI in PR on the outcome of SLT. In another study, Kluger et al. concluded that tumor biology and NTLP rather than tumor size are the main prognostic factors for recurrence and survival after resection of HCC.29 Microvascular invasion was one of the factors that negatively affected the DFS. A subgroup analysis to study the impact of mVI on outcome of each modality may be helpful, but the small patient numbers in SLT and RR group made this analysis difficult. Further studies with larger cohorts are needed in this context.
The reported 5-year DFS rate after RR is 17–24% and increases to 48% in the subset of patients with recurrence within the Milan criteria.12, 13, 15 Within the current study the 5-year DFS rate after RR of IHR within the UCSF criteria was 31%. The current study also showed a 5-year OS of 60% which is consistent with previous studies.12, 13 However, Minagawa et al. reported a 3-year OS rate of 100% after RR in a highly selected group of patients with single HCC during primary hepatectomy, a DFS more than 1 year after primary hepatectomy and absent portal vein invasion at the second resection.12 This highly selected cohort was similar to the current study with patients limited to those – within the UCSF criteria with absent major vascular invasion in primary and repeat hepatectomies. In addition, patients were subjected to a strict follow-up and were offered potentially curative management for re-recurrence. Eleven patients in the RR group suffered intra-hepatic re-recurrence; 10 of them were offered potentially curative treatment: SLT for one patient, a third hepatectomy for three patients and LA therapy for six patients.
Local ablation therapy had advantages of minimal invasiveness and repeatability and showed satisfactory results in IHR management.7, 13 Current results showed that there was no significant difference in terms of DFS between LA and RR. In a recent study, both modalities had a comparable outcome in a subset of patients with IHR within the Milan criteria.15 It seems that RR loses its rationale in accordance to those results, but LA still cannot be offered to all patients because it is not suitable for patients with superficial lesions, large lesions, coagulopathy and lesions adjacent to major vessels or main biliary radicles.
The yet unanswered question is which to whom? In this report, SLT proved to offer better oncological outcome with less incidence of re-recurrence. However, its benefit has to be weighed wisely to its complexity, higher morbidity and necessity to long-term follow up, especially with the good OS of RR and the minimal accessibility, repeatability and the chance to shift to more invasive procedures which distinguish LA therapies. In selection criteria for LT, the biological behavior of the tumor is replacing the size/number concept used by most of centers.30, 31, 32 This study proved that even the biological behavior of the primary tumor has an impact on the outcome of the management of recurrent HCC. This should be a motive for further studies with larger cohorts of patients to evaluate the impact of pathological criteria of primary resected HCC and the characteristics of NTLP on the outcome of management of IHR, attempting for proper procedure/patient matching.
There are some limitations in the study. The study population in the SLT and RR groups was relatively small. Patients were not prospectively randomized into the three groups. Diagnosis in the SLT and RR groups was confirmed by pathology of a resected specimen, while diagnosis in the LA group was confirmed by imaging studies. However, the authors believe that it may contribute to adopting the concept of using the available data from the PR and the features of recurrence for selection of the appropriate treatment for patients with IHR.
In summary, SLT provides better DFS rates for patients with IHR within the UCSF criteria. Microvascular invasion in the PR specimen and treating patients with modalities other than SLT are independent risk factors adversely affecting DFS. There was no significant factor affecting OS. In the light of the DFS benefit of SLT over other modalities, which is not the same as regards to OS, and the impact of pathological features of primary resected HCC on survival after managing IHR, further studies are needed to determine the subset of patients who benefit the most from each procedure.
Conflict of interest
None declared.
Financial support
None reported.
Footnotes
This article was presented at the 11th World Congress of the International Hepato-Pancreato-Biliary Association, 22–27 March 2014, Seoul, Korea.
Appendix.
Figure A1.
Algorithm of criteria of management for recurrent HCC after primary resection
Table A1.
Complications according to Clavien–Dindo classification and cause of death
| SLT (n = 25) n, (%) |
RR (n = 31) n, (%) |
LA (n = 74) n, (%) |
p-Value | |
|---|---|---|---|---|
| Clavien–Dindo classification | ||||
| No | 12 (48) | 22 (71) | 62 (84) | <0.001 |
| Grade I | 4 (16) | 8 (26) | 12 (16) | |
| Grade II | 5 (20) | 1 (3) | 0 (0) | |
| Grade IIIa | 1 (4) | 0 (0) | 0 (0) | |
| Grade IIIb | 2 (8) | 0 (0) | 0 (0) | |
| Grade V | 1 (4) | 0 (0) | 0 (0) | |
| Cause of death | ||||
| Respiratory | 1 (17) | 1 (8) | 2 (6) | 0.034 |
| Recurrence | 2 (33) | 10 (77) | 20 (56) | |
| End-stage liver disease | 0 (0) | 0 (0) | 3 (8) | |
| End-stage liver disease with recurrence | 0 (0) | 0 (0) | 3 (8) | |
| Intracranial hemorrhage | 0 (0) | 0 (0) | 1 (3) | |
| Hepatic artery thrombosis | 1 (17) | 0 (0) | 0 (0) | |
| Extrahepatic malignancy | 2 (33) | 0 (0) | 0 (0) | |
| Out of hospital cardiac arrest | 0 (0) | 0 (0) | 1 (3) | |
| Post-nephroureterectomy hemorrhagic shock | 0 (0) | 0 (0) | 1 (3) | |
| Sepsis | 0 (0) | 0 (0) | 1 (3) | |
| Unknown | 0 (0) | 2 (15) | 4 (11) | |
Table A2.
Site and management of recurrence of re-recurrence
| SLT (n = 25) n, (%) |
RR (n = 31) n, (%) |
LA (n = 74) n, (%) |
|
|---|---|---|---|
| Site of re-recurrence | |||
| • No | 20 (80) | 15 (48) | 36 (49) |
| • Intrahepatic | 1 (4) | 11 (36) | 27 (37) |
| • Extrahepatic | 2 (8) | 1 (3) | 8 (4) |
| • Combined | 2 (8) | 4 (13) | 3 (11) |
| Management of re-recurrence | |||
| • No treatment | 1 (17) | 1 (5) | 3 (5) |
| • SLT | 0 (0) | 1 (5) | 0 (0) |
| • Re-resection | 0 (0) | 3 (14) | 0 (0) |
| • LA | 0 (0) | 5 (24) | 28 (46) |
| • TAE | 2 (33) | 6 (29) | 14 (23) |
| • Chemotherapy | 3 (50) | 3 (14) | 6 (10) |
| • Resection of EHM | 0 (0) | 0 (0) | 1 (2) |
| • LA + TAE | 0 (0) | 2 (10) | 9 (15) |
SLT, salvage liver transplantation; RR, re-resection; LA, local ablation; TAE, transarterial embolization; EHM, extrahepatic metastasis.
References
- 1.Ercolani G., Grazi G., Ravaioli M., Del Gaudio M., Gardini A., Cescon M. Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg. 2003;237:536–543. doi: 10.1097/01.SLA.0000059988.22416.F2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Shah S., Cleary S., Wei A., Yang I., Taylor B., Hemming A. Recurrence after liver resection for hepatocellular carcinoma: risk factors, treatment, and outcomes. Surgery. 2007;141:330–339. doi: 10.1016/j.surg.2006.06.028. [DOI] [PubMed] [Google Scholar]
- 3.Wang C.C., Iyer S., Low J.K., Lin C.Y., Wang S.H., Lu S.N. Perioperative factors affecting long-term outcomes of 473 consecutive patients undergoing hepatectomy for hepatocellular carcinoma. Ann Surg Oncol. 2009;16:1832–1842. doi: 10.1245/s10434-009-0448-y. [DOI] [PubMed] [Google Scholar]
- 4.Portolani N., Coniglio A., Ghidoni S., Giovanelli M., Benetti A., Tiberio G. Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg. 2006;243:229–235. doi: 10.1097/01.sla.0000197706.21803.a1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Arii S., Teramoto K., Kawamura T., Okamoto H., Kaido T., Mori A. Characteristics of recurrent hepatocellular carcinoma in Japan and our surgical experience. J Hepatobiliary Pancreat Surg. 2001;8:397–403. doi: 10.1007/s005340100000. [DOI] [PubMed] [Google Scholar]
- 6.Lai E.C., Fan S.T., Lo C.M., Chu K.M., Liu C.L., Wong J. Hepatic resection for hepatocellular carcinoma. An audit of 343 patients. Ann Surg. 1995;221:291–298. doi: 10.1097/00000658-199503000-00012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Taura K., Ikai I., Hatano E., Fujii H., Uyama N., Shimahara Y. Implication of frequent local ablation therapy for intrahepatic recurrence in prolonged survival of patients with hepatocellular carcinoma undergoing hepatic resection: an analysis of 610 patients over 16 years old. Ann Surg. 2006;244:265–273. doi: 10.1097/01.sla.0000217921.28563.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Belghiti J., Cortes A., Abdalla E., Regimbeau J., Prakash K., Durand F. Resection prior to liver transplantation for hepatocellular carcinoma. Ann Surg. 2003;238:885–892. doi: 10.1097/01.sla.0000098621.74851.65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Poon R.T., Fan S.T., Lo C.M., Liu C.L., Wong J. Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors. Ann Surg. 1999;229:216–222. doi: 10.1097/00000658-199902000-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Choi J.W., Park J.Y., Ahn S.H., Yoon K.T., Ko H.K., Lee do Y. Efficacy and safety of transarterial chemoembolization in recurrent hepatocellular carcinoma after curative surgical resection. Am J Clin Oncol. 2009;32:564–569. doi: 10.1097/COC.0b013e3181967da0. [DOI] [PubMed] [Google Scholar]
- 11.Moon J.I., Kwon C.H., Joh J.W., Choi G.S., Jung G.O., Kim J.M. Primary versus salvage living donor liver transplantation for patients with hepatocellular carcinoma: impact of microvascular invasion on survival. Transplant Proc. 2012;44:487–493. doi: 10.1016/j.transproceed.2011.11.009. [DOI] [PubMed] [Google Scholar]
- 12.Minagawa M., Makuuchi M., Takayama T., Kokudo N. Selection criteria for repeat hepatectomy in patients with recurrent hepatocellular carcinoma. Ann Surg. 2003;238:703–710. doi: 10.1097/01.sla.0000094549.11754.e6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Chan A.C., Poon R.T., Cheung T.T., Chok K.S., Chan S.C., Fan S.T. Survival analysis of re-resection versus radiofrequency ablation for intrahepatic recurrence after hepatectomy for hepatocellular carcinoma. World J Surg. 2012;36:151–156. doi: 10.1007/s00268-011-1323-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Umeda Y., Matsuda H., Sadamori H., Matsukawa H., Yagi T., Fujiwara T. A prognostic model and treatment strategy for intrahepatic recurrence of hepatocellular carcinoma after curative resection. World J Surg. 2011;35:170–177. doi: 10.1007/s00268-010-0794-8. [DOI] [PubMed] [Google Scholar]
- 15.Chan A.C., Chan S.C., Chok K.S., Cheung T.T., Chiu D.W., Poon R.T. Treatment strategy for recurrent hepatocellular carcinoma: salvage transplantation, repeated resection, or radiofrequency ablation? Liver Transpl. 2013;19:411–419. doi: 10.1002/lt.23605. [DOI] [PubMed] [Google Scholar]
- 16.Vauthey J., Klimstra D., Franceschi D., Tao Y., Fortner J., Blumgart L. Factors affecting long-term outcome after hepatic resection for hepatocellular carcinoma. Am J Surg. 1995;169:28–34. doi: 10.1016/s0002-9610(99)80106-8. [DOI] [PubMed] [Google Scholar]
- 17.Sala M., Fuster J., Llovet J., Navasa M., Sole M., Varela M. High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation. Liver Transpl. 2004;10:1294–1300. doi: 10.1002/lt.20202. [DOI] [PubMed] [Google Scholar]
- 18.Yao F.Y., Ferrell L., Bass N., Watson J., Bacchetti P., Venook A. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001;33:1394–1403. doi: 10.1053/jhep.2001.24563. [DOI] [PubMed] [Google Scholar]
- 19.Ishak K., Baptista A., Bianchi L., Callea F., De Groote J., Gudat F. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22:696–699. doi: 10.1016/0168-8278(95)80226-6. [DOI] [PubMed] [Google Scholar]
- 20.Bruix J., Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–1236. doi: 10.1002/hep.20933. [DOI] [PubMed] [Google Scholar]
- 21.Bruix J., Sherman M., Llovet J., Beaugrand M., Lencioni R., Burroughs A. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001;35:421–430. doi: 10.1016/s0168-8278(01)00130-1. [DOI] [PubMed] [Google Scholar]
- 22.Concejero A., Chen C.L., Wang C.C., Wang S.H., Lin C.C., Liu Y.W. Living donor liver transplantation for hepatocellular carcinoma: a single-center experience in Taiwan. Transplantation. 2008;85:398–406. doi: 10.1097/TP.0b013e3181622ff8. [DOI] [PubMed] [Google Scholar]
- 23.Wang J.H., Wang C.C., Hung C.H., Chen C.L., Lu S.N. Survival comparison between surgical resection and radiofrequency ablation for patients in BCLC very early/early stage hepatocellular carcinoma. J Hepatol. 2012;56:412–418. doi: 10.1016/j.jhep.2011.05.020. [DOI] [PubMed] [Google Scholar]
- 24.Del Gaudio M., Ercolani G., Ravaioli M., Cescon M., Lauro A., Vivarelli M. Liver transplantation for recurrent hepatocellular carcinoma on cirrhosis after liver resection: University of Bologna experience. Am J Transplant. 2008;8:1177–1185. doi: 10.1111/j.1600-6143.2008.02229.x. [DOI] [PubMed] [Google Scholar]
- 25.Shim J.H., Kim K.M., Lee Y.J., Ko G.Y., Yoon H.K., Sung K.B. Complete necrosis after transarterial chemoembolization could predict prolonged survival in patients with recurrent intrahepatic hepatocellular carcinoma after curative resection. Ann Surg Oncol. 2010;17:869–877. doi: 10.1245/s10434-009-0788-7. [DOI] [PubMed] [Google Scholar]
- 26.Agopian V.G., Harlander-Locke M., Zarrinpar A., Kaldas F.M., Farmer D.G., Yersiz H. A novel prognostic nomogram accurately predicts hepatocellular carcinoma recurrence after liver transplantation: analysis of 865 consecutive liver transplant recipients. J Am Coll Surg. 2015;220:416–427. doi: 10.1016/j.jamcollsurg.2014.12.025. [DOI] [PubMed] [Google Scholar]
- 27.Varona M.A., Soriano A., Aguirre-Jaime A., Garrido S., Oton E., Diaz D. Risk factors of hepatocellular carcinoma recurrence after liver transplantation: accuracy of the alpha-fetoprotein model in a single-center experience. Transplant Proc. 2015;47:84–89. doi: 10.1016/j.transproceed.2014.12.013. [DOI] [PubMed] [Google Scholar]
- 28.Meniconi R.L., Komatsu S., Perdigao F., Boëlle P.Y., Soubrane O., Scatton O. Recurrent hepatocellular carcinoma: a Western strategy that emphasizes the impact of pathologic profile of the first resection. Surgery. 2015;157:454–462. doi: 10.1016/j.surg.2014.10.011. [DOI] [PubMed] [Google Scholar]
- 29.Kluger M.D., Salceda J.A., Laurent A., Tayar C., Duvoux C., Decaens T. Liver resection for hepatocellular carcinoma in 313 Western patients: tumor biology and underlying liver rather than tumor size drive prognosis. J Hepatol. 2015;62:1131–1140. doi: 10.1016/j.jhep.2014.12.018. [DOI] [PubMed] [Google Scholar]
- 30.Lai Q., Avolio A.W., Graziadei I., Otto G., Rossi M., Tisone G. Alpha-fetoprotein and mRECIST progression post-locoregional therapy as predictors of hepatocellular cancer recurrence and death after transplantation. Liver Transpl. 2013;19:1108–1118. doi: 10.1002/lt.23706. [DOI] [PubMed] [Google Scholar]
- 31.Duvoux C., Roudot-Thoraval F., Decaens T., Pessione F., Badran H., Piradi T. Liver transplantation for hepatocellular carcinoma: a model including alpha-fetoprotein improves the performance of Milan criteria. Gastroenterology. 2012;143:986–994. doi: 10.1053/j.gastro.2012.05.052. [DOI] [PubMed] [Google Scholar]
- 32.Mehta N., Yao F.Y. Moving past “one size (and number) fits all” in the selection of candidates with hepatocellular carcinoma for liver transplant. Liver Transplant. 2013;19:1055–1058. doi: 10.1002/lt.23730. [Editorial] [DOI] [PubMed] [Google Scholar]