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Hepatology Research 2014; 44: E335–E345
doi: 10.1111/hepr.12313
Original Article
Salvage treatment for local recurrence of hepatocellular carcinoma after local ablation therapy Katsunori Imai,1 Toru Beppu,1,2 Akira Chikamoto,1 Kosuke Mima,1 Hirohisa Okabe,1 Hiromitsu Hayashi,1 Hidetoshi Nitta,1 Takatoshi Ishiko1 and Hideo Baba1 1
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, and Department of Multidisciplinary Treatment for Gastroenterological Cancer, Kumamoto University Hospital, Kumamoto, Japan 2
Aim: Local recurrence of hepatocellular carcinoma (HCC) after local ablation therapy (LAT) is a serious problem; however, the optimal treatment strategy remains unclear. Methods: A retrospective analysis was conducted of 50 patients with local recurrence of HCC after LAT that underwent either salvage hepatectomy (n = 23) or radiofrequency ablation (RFA; n = 27). Their background characteristics, intraoperative data, and postoperative short- and long-term outcome were analyzed. Results: The RFA group was found to be significantly associated with an impaired liver functional reserve, smaller number and size of tumors. The hepatectomy group showed a significantly longer operation time, greater intraoperative blood loss and more frequent red blood cell transfusion. In-hospital stay mortality and morbidity rate did not significantly differ. The disease-free and overall survival showed no
INTRODUCTION
H
EPATOCELLULAR CARCINOMA (HCC) is the fifth most common malignancy and the third most common cause of cancer-related death in the world.1 Two treatment modalities, hepatectomy and liver transplantation (LT), are considered to be potentially curative. The optimal therapy depends on each patient’s general condition, medical status including associated liver dysfunction, and the clinical characteristics of the tumors. Out of these, LT achieves the best Correspondence: Professor Hideo Baba, Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Email: [email protected] Conflict of interest: None of the authors has any conflict of interest. Received 16 December 2013; revision 4 February 2014; accepted 12 February 2014.
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significant difference between the groups. Although local recurrence after salvage treatment was found in zero (0%) for hepatectomy and in seven (25.9%) for RFA, that did not affect the overall survival. The tumor size at the prior LAT was identified as an independent prognostic factor for disease-free survival and serum albumin for overall survival.
Conclusion: Whereas salvage hepatectomy for local recurrent HCC is recommended for selected patients in terms of its good local control effect, salvage RFA is also acceptable because it is less invasive and also has a reasonable long-term outcome. Key words: hepatocellular carcinoma, local ablation therapy, local recurrence, radiofrequency ablation, salvage treatment
results from the aspect of offering the potential to remove the entire tumor-bearing liver and eliminate the cirrhosis as a field of de novo carcinogenesis. However, its feasibility has been restricted by organ donor shortage and high cost.2 Hepatectomy is considered to be the next curative treatment but is suitable for only a small percentage of patients because of their poor liver function reserve caused by the underlying liver disease.3,4 Local ablation therapy (LAT) such as radiofrequency ablation (RFA), microwave coagulation (MCT), percutaneous ethanol injection (PEI) or cryoablation plays a key role in the management of small HCC.5–8 Despite the reports of its excellent efficacy, safety and minimal invasiveness, local tumor recurrence after LAT remains a serious problem. The local tumor recurrence rates have been reported to range 17–38% after PEI,9–13 3.2–26% after RFA,14–17 5.9–19% after MCT18–20 and 8.0–24% after cryoablation.21,22 The treatment modalities for
© 2014 The Japan Society of Hepatology
Hepatology Research 2014; 44: E335–E345
these locally recurrent tumors include iterative LAT, transcatheter arterial chemoembolization (TACE), hepatectomy and LT. Salvage hepatectomy for locally recurrent tumors after LAT has been reported to be an acceptable treatment despite the added surgical difficulty.23,24 However, patients that undergo initial LAT tend to have a more impaired liver functional reserve in comparison with those referred for hepatectomy. Therefore, it is sometimes difficult to select a salvage hepatectomy when tumor regrowth is detected in those patients. The objective of this study was to evaluate the role of salvage hepatectomy and RFA for local regrowth of HCC after LAT.
METHODS Patients
S
IXTY CONSECUTIVE PATIENTS underwent either salvage hepatectomy or RFA for the local regrowth of HCC after LAT at the Department of Gastroenterological Surgery, Kumamoto University Hospital (Kumamoto, Japan), from June 2000 to February 2012. The patients who had local recurrent HCC with an obvious residual tumor after LAT on the postoperative diagnostic imaging were not enrolled in this study. Ten of those patients had intrahepatic dissemination in synchronization with local recurrence. These patients were excluded from this study because these tumors were more advanced and aggressive.25 The remaining 50 patients were enrolled in this study. Local recurrence after LAT was defined as tumor recurrence within or at the periphery of the original ablated lesion based on routine imaging modalities, including ultrasonography (US), enhanced computed tomography (CT) and magnetic resonance imaging (MRI). Meanwhile, local recurrence after salvage hepatectomy was defined as tumor recurrence at the resection margin. All patients underwent liver function tests before treatment, including bilirubin, albumin, prothrombin activity, indocyanine green retention rate at 15 min (ICG-R15) and technetium99m galactosyl human serum albumin (99mTc-GSA) scintigraphy. Written informed consent was obtained from all patients before treatment.
Treatment modalities as a salvage treatment The surgical procedure was selected based on the tumor location, extent of the tumor, parenchymal liver function and the patient’s general condition. In general, hepatectomy was considered as the treatment of first choice for patients with good liver functional reserve,
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and anatomical resection was employed if the liver function allowed. The reasons for undergoing RFA rather than hepatectomy included deeply located tumors requiring major hepatic resection leading to insufficient remnant liver volume, insufficient liver function reserve, high operative risk associated with general condition and refusal of hepatectomy, as described previously.26 For local recurrent HCC after LAT, if the liver function and general condition were good enough, hepatectomy was performed as a first choice, because the local regrowth of a tumor after LAT is often associated with a more aggressive phenotype, such as high-frequency vascular invasion or sarcomatous changes.24,27,28 Salvage RFA was offered with an appropriate approach because hepatectomy was thought to be unsafe, because of the parenchymal liver dysfunction, patient’s poor general condition or the anatomical position of the tumor. A total of 23 hepatectomies were successfully performed, including six non-anatomical partial hepatectomies, four segmentectomies, eight sectionectomies, three left hepatectomies and two right hepatectomies. All hepatectomies were considered to be radical with tumor-free resection margins. Twenty-seven patients were treated with salvage RFA for local tumor recurrence of HCC after LAT. RFA was performed via a percutaneous approach in 11 patients, a laparoscopic approach in nine, a thoracoscopic approach in four patients and via laparotomy in three patients under general anesthesia. RFA was conducted using a cooled-tip electrode with a length of 2–3 cm (Radionics, Burlington, MA, USA) and was connected to a 500-kHz RF generator (Radionics) under the programmed cyclic impedance control condition as described previously.29 A 17-G electrode was inserted into the lesion under either US guidance or direct visual guidance, ablation was initiated and the power was increased to 60 W at a 2-cm length and 80 W in 3-cm length needle. The duration of maximum ablation was 8–10 min and the impedance was closely monitored. The aim of salvage RFA was to ablate all detected tumor with curative intent. All ablations aimed at achieving at least a 0.5-cm margin of nontumorous liver parenchyma, if possible, in a single session. Multiple overlapping ablations were performed in a positive manner as appropriate. Enhanced CT was performed 7 days after RFA to evaluate the tumor response to RFA in all patients. Complete ablation was defined as the absence of contrast enhancement within the entire tumor. The procedure was repeated if an unablated tumor remnant was suspected to remain.
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Postoperative morbidity and mortality Postoperative morbidity and mortality were defined as complications or death, respectively, occurring either within 30 days following surgery or during hospital stay, even when longer than 30 days. Postoperative morbidities were graded using validated classification criteria as described by Dindo et al.,30 and any postoperative complication worse than grade I were considered to be positive.
Follow up All of the patients underwent regular follow up of their serum α-fetoprotein (AFP) level, Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-γcarboxy prothrombin (DCP) levels, and US and CT scans or MRI were taken every 2–4 months to detect any intrahepatic recurrence or distant metastasis, as described previously.31 Recurrence was defined as the appearance of a lesion with radiological features typical of HCC, as confirmed by US, CT, MRI or sometimes tumor biopsy.
Statistical analysis Continuous variables are expressed as the means 1 standard deviation (SD), and compared using the Mann–Whitney U-test. Categorical variables were compared using the χ2-test. The disease-free survival and overall survival after treatment were computed using the Kaplan–Meier method, and then were compared using the log–rank test. Survival time was calculated from the date of the salvage treatment to the time of interest. A Cox regression model was utilized for the multivariate analysis. Only variables of P 2 0.10 in the univariate analysis were subjected to multivariate analysis. P 2 0.05 was considered to be statistically significant.
RESULTS Patient characteristics
A
TOTAL OF 50 patients (36 men and 14 women) were enrolled in this study, with a median age of 71 years (range, 41–82). The mean tumor size at the prior LAT was 20.9 1 8.8 mm (median, 20 mm; range, 10–65 mm) and the mean tumor size at salvage treatment was 24.2 1 14.8 mm (median, 20 mm; range, 8–110 mm). The mean number of tumors at the time of salvage treatment was 1.7 1 1.2 (median, 1; range, 1–5). The mean time interval between prior LAT and salvage treatment was 20.2 1 22.5 months (median, 10.9 months; range, 2.3–108 months). The mean follow-up
© 2014 The Japan Society of Hepatology
Hepatology Research 2014; 44: E335–E345
periods were 52.5 months after prior LAT and 32.3 months after salvage treatment. The clinical characteristics of the patients according to the salvage treatment modality are summarized in Table 1. The patients in the RFA group were characterized primarily with a lower frequency of Child–Pugh classification A, with an increased serum concentration of aspartate aminotransferase, decreased serum concentration of albumin level and prothrombin activity, and an impaired ICG-R15 and uptake ratio of the liver to the liver plus heart at 15 min as determined by 99mTc-GSA scintigraphy in comparison with the hepatectomy group, suggesting that there was impaired liver functional reserve. The patients that received salvage hepatectomy had a larger number and size of HCC with a higher DCP level than those who received RFA. Visible vascular invasion in the preoperative diagnostic imaging findings was identified in only one patient in the hepatectomy group and in none of the patients in the RFA group.
Perioperative short-term outcome The intraoperative and postoperative outcomes are summarized in Table 2. The operation time was significantly longer (401.0 1 87.6 vs 161.9 1 86.9 min, P < 0.0001), and the intraoperative blood loss was also significantly greater in the hepatectomy group than in the RFA group (870.7 1 1336.4 vs 27.6 1 88.4 mL, P < 0.0001). In addition, blood transfusion of red blood cells was more frequent in the hepatectomy group than in the RFA group (17.4% vs 0%, P = 0.024), and length of the hospital stay after operation was significantly longer in the hepatectomy group in comparison with the RFA group (22.1 1 21.6 vs 10.5 1 7.6 days, P < 0.0001). Postoperative major complications occurred in five patients (21.7%) in the hepatectomy group, and in two patients in the RFA group (7.4%), as detailed in Table 2; there was no significant difference between the two groups (P = 0.15). Although the 30-day mortality was nil in the two groups, one patient in the hepatectomy group died from sepsis 87 days after surgery, during the same hospital stay. Therefore, in-hospital mortality was 4.3% in the hepatectomy group and 0% in the RFA group (P = 0.27). One other patient in the hepatectomy group died of rapid regrowth recurrent HCC in the remnant liver 86 days after surgery, after re-admission to our hospital.
Tumor recurrence and survival analysis Forty patients (80%) experienced tumor recurrence within a mean follow-up period of 32.3 months after
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Salvage for local recurrence of HCC E338
Table 1 Clinical characteristics of the patients according to the salvage treatment modality for the local recurrence of HCC after LAT RFA (n = 27)
P-value
71.0 1 7.7 18/9
0.10 0.36
6 (26.1%) 14 (60.9%) 33.5 1 16.4 34.0 1 18.3 0.81 1 0.35 3.98 1 0.45 92.0 1 11.7 14.4 1 4.6 13.0 1 6.0 0.91 1 0.03 23/0 7.6 1 1.2 508.2 1 1574.7 7 (30.4%) 1598.4 1 5971.1 15/8 19.0 1 18.0 19.5 1 6.5 31.7 1 23.8 2.3 1 1.4
4 (11.1%) 22 (81.5%) 48.7 1 26.6 41.3 1 27.0 0.96 1 0.38 3.60 1 0.58 84.4 1 12.7 12.7 1 8.0 24.0 1 17.1 0.87 1 0.07 21/6 8.1 1 1.5 922.8 1 4464.0 4 (14.8%) 52.9 1 67.4 22/5 21.2 1 26.1 22.1 1 10.4 17.8 1 5.0 1.2 1 0.6
0.17 0.10 0.0054 0.44 0.094 0.034 0.034 0.089 0.0040 0.0041 0.02 0.19 0.69 0.18 0.037 0.19 0.76 0.65 0.0072 0.0029 0.18
16 7 28.7 1 29.2
23 4 35.3 1 25.4
Hepatectomy (n = 23) Age Sex (male/female) Etiology HBsAg positive HCVAb positive AST (IU/L) ALT (IU/L) Total bilirubin (mg/dL) Albumin (IU/L) Prothrombin activity (%) Platelet count (104/μL) ICG-R15 (%) 99m Tc-GSA LHL15 Child–Pugh classification (A/B) MELD score AFP (ng/mL) AFP-L3 >10 (%) DCP (mAU/mL) Tumor location (right liver/left liver) Time interval from prior LAT (months) Tumor size at prior LAT (mm) Tumor size at salvage treatment (mm) Tumor number at salvage treatment Treatment method of prior LAT RFA PEI Follow-up period (months)
67.2 1 9.5 18/5
0.16
Values are the means 1 standard deviations. 99m Tc-GSA, technetium-99m galactosyl human serum albumin; AFP, α-fetoprotein; AFP-L3, Lens culinaris agglutinin-reactive fraction of AFP; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DCP, des-γ-carboxy prothrombin; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HCVAb, anti-hepatitis C antibody; ICG-R15, indocyanine green retention rate at 15 min; LAT, local ablation therapy; LHL15, the liver to the liver plus heart at 15 min; MELD, Model for End-Stage Liver Disease; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation.
salvage treatment. The cumulative disease-free survival rates at 1, 3 and 5 years were 51.0%, 15.3% and nil in the hepatectomy group and 57.2%, 13.2% and 8.8% in the RFA group (P = 0.99; Fig. 1a). In the hepatectomy group, the tumor recurrence was found in 16 of 23 patients; the recurrence sites were liver (n = 12), lung (n = 1), liver + lung (n = 1), lymph node (n = 1) and bone (n = 1). In the RFA group, the tumor recurrence was found in 24 of 27 patients in the follow-up period; the recurrence site was only liver, of which, seven patients had local recurrence at the ablated sites. The cumulative overall survival rates at 1, 3 and 5 years were 84.0%, 70.0% and 58.3% in the hepatectomy group and 100%, 68.1% and 60.5% in the RFA group (P = 0.22;
Fig. 1b), respectively. Eight of 23 patients (34.8%) in the hepatectomy group and six of 27 patients in the RFA group (22.2%) died during the observation period. In the hepatectomy group, seven patients died from HCC recurrence and one patient died from postoperative complication from 87 days after surgery. In the RFA group, all six patients died from HCC recurrence. Local tumor recurrence after salvage treatment was found in zero (0%) in the hepatectomy group and in seven (25.9%) in the RFA group (P = 0.011; Table 2). Of these seven patients, five had local recurrence only and two had local recurrence with other intrahepatic metastasis; the mean time interval to develop local recurrence after salvage treatment was 12.8 months
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Table 2 Perioperative short-term outcome
Operation time (min) Blood loss (mL) Laparoscopic approach (%) Red blood cell transfusion (%) Hospital stay after operation (days) No. of patients with complication (%) Bile leakage Duodenal ulcer bleeding Wound infection Sepsis Intra-abdominal abscess Hemobilia 30-day mortality (%) In-hospital stay mortality (%) Local tumor recurrence (%)
Hepatectomy (n = 23)
RFA (n = 27)
P-value
401.0 1 87.6 870.7 1 1336.4 5 (21.7%) 4 (17.4%) 22.1 1 21.6 5 (21.7%) 3 (13.0%) 1 (4.3%) 1 (4.3%) 1 (4.3%) 0 (0%) 0 (0%) 0 (0%) 1 (4.3%) 0 (0%)
161.9 1 86.9 27.6 1 88.4 11 (40.7%) 0 (0%) 10.5 1 7.6 2 (7.4%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (3.7%) 1 (3.7%) 0 (0%) 0 (0%) 7 (25.9%)
35 vs 235) (IU/L) ALT (>35 vs 235) (IU/L) Total bilirubin (>1.0 vs 21.0) (mg/dL) Albumin (23.5 vs >3.5) (mg/dL) Prothrombin activity (>80 vs 280) (%) Platelet counts (>10 vs 210) (104/μL) ICG-R15 (>10 vs 210) (%) 99m Tc-GSA LHL15 (>0.9 vs 20.9) AFP (>20 vs 220) (ng/mL) AFP-L3 (>10 vs 210) (%) DCP (>40 vs 240) (mAU/mL) Tumor location (Right liver vs Left liver) Operation time (>263 vs 2263†) (min) Blood loss (>20 vs 220†) (g) Red blood cell transfusion (presence vs absence) Complication (presence vs absence) Time interval from prior LAT (>10.9 vs 210.9†) (months) Tumor size at prior LAT (>20 vs 220†) (mm) Tumor size at salvage treatment (>20 vs 220†) (mm) Tumor number at salvage treatment Salvage treatment modality (hepatectomy vs RFA) Local recurrence after salvage treatment (yes vs no)
0.67 0.22 0.68 0.075 0.49 0.74 0.51 0.17 0.85 0.97 0.77 0.87 0.11 0.27 0.089 0.75 0.24 0.13 0.66
Multivariate P-value
0.12
0.063
HR
1.93
2.05
95% CI
0.84–4.44
0.96–4.37
0.27 0.59 0.015
Overall survival Univariate P-value 0.17 0.50 0.22 0.062 0.3 0.86 0.7 0.069 0.42 0.57 0.19 0.45 0.007 0.028 0.10 0.72 0.22 0.33 0.075 0.019 0.21
0.0068
2.85
1.33–6.10
Multivariate P-value
HR
95% CI
0.46
1.74
0.40–7.54
0.05
4.11
1.00–16.94
0.42 0.61 0.16
1.75 1.74 2.77
0.44–6.87 0.21–14.32 0.66–11.62
0.67
1.64
0.17–16.24
0.40
3.36
0.20–56.32
0.19
0.35
0.25
0.20 0.99
0.11 0.22
0.22
0.33
†Median. 95% CI, 95% confidence interval; 99mTc-GSA, technetium-99m galactosyl human serum albumin; AFP, α-fetoprotein; AFP-L3, Lens culinaris agglutinin-reactive fraction of AFP; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DCP, des-γ-carboxy prothrombin; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HCVAb, anti-hepatitis C antibody; HR, hazard ratio; ICG-R15, indocyanine green retention rate at 15 min; LAT, local ablation therapy; LHL15, the liver to the liver plus heart at 15 min; MELD, Model for End-Stage Liver Disease; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation.
and less invasiveness with a mortality rate of 0–0.5% and a complication rate of 1.8–9.6%.17,32–35 On the other hand, local recurrence at an ablated site after LAT is a serious problem; the rates have varied 17–38% after PEI9–13 and 3.2–26% after RFA.14–17 Local recurrence after LAT may be attributable to insufficient ablation of the primary tumor and/or the presence of tumor venous
© 2014 The Japan Society of Hepatology
invasion in the adjacent liver. The risk factors for local recurrence after LAT include a large tumor size,13,16,36,37 the serum DCP level,17 multiple tumor nodules,38 an insufficient tumor margin,39 the tumor location relative to the liver surface40 and the presence of a perivascular tumor.41,42 In the current study, a percutaneous approach had a high local recurrence rate (5/11, 45.4%)
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Table 4 Postoperative macroscopic and histopathological characteristics of the 23 patients who underwent salvage hepatectomy n = 23 Gross type Single nodular type Single nodular type with extranodular growth Confluent multinodular type Invasive type Tumor differentiation Well Moderate Poor Sarcomatous change Growth type Extensive growth Invasive growth fc positive (%) fc infiltration positive (%) Septum formation positive (%) Portal vein invasion positive (%) Hepatic vein invasion positive (%)
12 2 8 1 1 14 7 1 20 3 18 (78.3%) 17 (94.4%) 17 (73.9%) 11 (47.8%) 3 (13.0%)
fc, fibrous capsule.
than laparoscopic (1/9, 11.1%), thoracoscopic (1/4, 25.0%) and via laparotomy (0/3, 0%). Although the sample size is too small to validate precisely, a percutaneous approach has the potential to be one of the risk factors for local tumor recurrence after salvage RFA in comparison with other approaches. Although it goes without saying that the possibility of complete tumor eradication is one of the most important issues for the selection of further treatment for local tumor recurrence, the strategy of additional treatment for local recurrence after LAT is still unclear. The prognosis of HCC is influenced by several factors related to both the extent of the tumor and parenchymal liver function.43 However, there is no evidence of the prognostic significance of local recurrence after LAT for HCC in the published work. Previous studies demonstrated that there was no notable difference in overall survival between patients with and without local recurrence after RFA.16,24,44 They had postulated that this may be explained by an aggressive treatment strategy such as hepatectomy, repeated RFA, or LT in patients with local recurrence after LAT. Sugo et al. reported that hepatectomy as a salvage treatment for local recurrence after LAT was associated with low mortality and morbidity (0% and 13%, respectively), and yielded overall survival benefits; the 5-year
overall survival rate was 67%.24 They concluded that salvage hepatectomy is an acceptable treatment for the patients with local recurrence of HCC after LAT, in spite of the added surgical difficulty. The current study showed similar results; 30-day mortality, in-hospital mortality and morbidity rate was 0%, 4.3% and 21.7%, respectively, and 5-year overall survival rate was 58.3%. In addition, these results achieved an outcome equivalent to those of the American College of Surgeon National Surgical Quality Improvement Program database after hepatectomy in the USA (the mortality and morbidity rates are 2.3% and 19.0%, respectively)45 and the nationwide survey of HCC in Japan (the mortality and morbidity rates are 2.6% and 14.5%, respectively,46 and the 5-year overall survival rate is 53.4% after hepatectomy).4 These results suggest that salvage hepatectomy is an acceptable treatment for the local recurrence of HCC after LAT in terms of its safety and efficacy. In the current study, local tumor recurrence after salvage treatment was observed more frequently in the RFA group than in the hepatectomy group (25.9% and 0%, respectively, Table 2). The re-local recurrence or incomplete response rates after salvage RFA have been reported to range 23.1–36.4%; the results of the current study are similar to these previous results.16,47 This re-local recurrence rate after salvage RFA is relatively higher than the local recurrence rate after initial RFA.14–17 In addition, we recently reported that local recurrent HCC after LAT had more aggressive potential via epithelial–mesenchymal transition compared to initial HCC.48 A Japanese large-scale nationwide survey of primary liver cancer reported that fc infiltration and portal vein invasion were detected in 68.9% and 29.4%, respectively, of patients with primary HCC in an assessment of more than 4000 cases.4 In the current study, the histopathological analysis of the resected specimens by salvage hepatectomy revealed that fc infiltration and portal vein invasion of locally recurrent tumors were detected more frequently than for primary (non-locally recurrent) HCC, where the incidence of fc infiltration and portal vein invasion were 94.4% and 47.8%, respectively. These findings suggest that locally recurrent HCC after LAT has more malignant behavior than primary HCC. Based on these matters, we believe that salvage hepatectomy for local tumor recurrence after LAT is indicated for the patients with good liver function reserve in terms of its good local control effect. However, the current study revealed that the RFA group was primarily characterized to have impaired liver functional reserve at the salvage treatment (Table 1) and was associated with shorter operation time, less blood loss,
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lower frequency of red blood cell transfusion and shorter hospital stay after the operation, in comparison with the hepatectomy group (Table 2). Furthermore, additional radical treatment was performed in all seven patients with local tumor recurrence after salvage RFA, and the complete eradication of local recurrent tumors could be achieved in all patients. As a result, local tumor recurrence after salvage RFA did not affect the overall survival (Fig. 2). As with the previous reports,16,24,44 this result may support an aggressive treatment policy for local recurrent tumor after LAT. These results suggest that salvage RFA is less invasive and an acceptable treatment strategy, especially for patients with an impaired liver function reserve. There are some limitations in this study. First, this is a retrospective data analysis from one single institution and the number of cases is relatively small. Second, some bias could be present due to patients’ selections and choices of treatment. In this study, the patients in the RFA group were characterized primarily by their impaired liver function reserve in comparison with the hepatectomy group. However, the patients in the hepatectomy group had more advanced and aggressive tumors, characterized by larger numbers and sizes, and a higher DCP level. These differences might have affected the short- and long-term outcome of the patients with locally recurrent HCC after LAT. In addition, the patients might have received prior LAT, rather than hepatectomy, due to a variety of reasons even when they were suitable for hepatectomy at the point of initial treatment. In the current study, 14 of 23 patients (60.9%) in the hepatectomy group and eight of 27 patients (30.0%) in the RFA group had received prior LAT before salvage treatment in the other institutions, and then were referred to our department after being diagnosed with local recurrence of HCC. Therefore, it could not be analyzed and explained exactly why the patients who received salvage hepatectomy were not resected at the instant of initial treatment. Because of the low local tumor recurrence rate after LAT in most centers, the pooling of data from multiple centers may be needed to provide a large enough sample size for a further study to clarify the optimal treatment strategy for local tumor recurrence after LAT. In conclusion, salvage hepatectomy for local recurrent HCC after LAT is indicated for selected patients, in terms of its good local control effect. However, its feasibility is restricted by the surgical difficulty and the patient’s liver functional reserve. Salvage RFA for local tumor recurrence is an acceptable treatment in such cases because of its less invasive and the reasonably long-term outcome.
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of hepatocellular carcinoma. J Am Coll Surg 2008; 207: 20–9. Shiina S, Tateishi R, Arano T et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am J Gastroenterol 2012; 107: 569–77; quiz 578. Takami Y, Ryu T, Wada Y, Saitsu H. Evaluation of intraoperative microwave coagulo-necrotic therapy (MCN) for hepatocellular carcinoma: a single center experience of 719 consecutive cases. J Hepatobiliary Pancreat Surg 2013; 20: 332–41. Itoh S, Ikeda Y, Kawanaka H et al. Efficacy of surgical microwave therapy in patients with unresectable hepatocellular carcinoma. Ann Surg 2011; 18: 3650–6. Ohmoto K, Yoshioka N, Tomiyama Y et al. Comparison of therapeutic effects between radiofrequency ablation and percutaneous microwave coagulation therapy for small hepatocellular carcinomas. J Gastroenterol Hepatol 2009; 24: 223–7. Lee SM, Won JY, Lee DY et al. Percutaneous cryoablation of small hepatocellular carcinomas using a 17-gauge ultrathin probe. Clin radiol 2011; 66: 752–9. Xu KC, Niu LZ, Zhou Q et al. Sequential use of transarterial chemoembolization and percutaneous cryosurgery for hepatocellular carcinoma. World J Gastroenterol 2009; 15: 3664–9. Torzilli G, Del Fabbro D, Palmisano A, Marconi M, Makuuchi M, Montorsi M. Salvage hepatic resection after incomplete interstitial therapy for primary and secondary liver tumours. Br J Surg 2007; 94: 208–13. Sugo H, Ishizaki Y, Yoshimoto J, Imamura H, Kawasaki S. Salvage hepatectomy for local recurrent hepatocellular carcinoma after ablation therapy. Ann Surg Oncol 2012; 19: 2238–45. Masuda T, Beppu T, Ishiko T et al. Intrahepatic dissemination of hepatocellular carcinoma after local ablation therapy. J Hepatobiliary Pancreat Surg 2008; 15: 589–95. Imai K, Beppu T, Chikamoto A et al. Comparison between hepatic resection and radiofrequency ablation as first-line treatment for solitary small-sized hepatocellular carcinoma of 3 cm or less. Hepatol Res 2013; 43: 853–64. Kong J, Pan B, Ke S et al. Insufficient radiofrequency ablation promotes angiogenesis of residual hepatocellular carcinoma via HIF-1alpha/VEGFA. PloS One 2012; 7: e37266. Koda M, Maeda Y, Matsunaga Y, Mimura K, Murawaki Y, Horie Y. Hepatocellular carcinoma with sarcomatous change arising after radiofrequency ablation for welldifferentiated hepatocellular carcinoma. Hepatol Res 2003; 27: 163–7. Ishiko T, Beppu T, Sugiyama S et al. Radiofrequency ablation with hand-assisted laparoscopic surgery for the treatment of hepatocellular carcinoma in the caudate lobe. Surg Laparosc Endosc Percutan Tech 2008; 18: 272–6. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a
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cohort of 6336 patients and results of a survey. Ann Surg 2004; 240: 205–13. Imai K, Beppu T, Nakayama Y et al. Preoperative prediction of poorly differentiated components in small-sized hepatocellular carcinoma for safe local ablation therapy. J Surg Oncol 2009; 100: 121–6. Livraghi T, Meloni F, Di Stasi M et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice? Hepatology 2008; 47: 82–9. Koda M, Murawaki Y, Hirooka Y et al. Complications of radiofrequency ablation for hepatocellular carcinoma in a multicenter study: an analysis of 16 346 treated nodules in 13 283 patients. Hepatol Res 2012; 42: 1058–64. Mulier S, Mulier P, Ni Y et al. Complications of radiofrequency coagulation of liver tumours. Br J Surg 2002; 89: 1206–22. Zhou Y, Zhao Y, Li B et al. Meta-analysis of radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma. BMC Gastroenterol 2010; 10: 78. Mulier S, Ni Y, Jamart J, Ruers T, Marchal G, Michel L. Local recurrence after hepatic radiofrequency coagulation: multivariate meta-analysis and review of contributing factors. Ann Surg 2005; 242: 158–71. Komorizono Y, Oketani M, Sako K et al. Risk factors for local recurrence of small hepatocellular carcinoma tumors after a single session, single application of percutaneous radiofrequency ablation. Cancer 2003; 97: 1253–62. Yamanaka Y, Shiraki K, Miyashita K et al. Risk factors for the recurrence of hepatocellular carcinoma after radiofrequency ablation of hepatocellular carcinoma in patients with hepatitis C. World J Gastroenterol 2005; 11: 2174–8. Kei SK, Rhim H, Choi D, Lee WJ, Lim HK, Kim YS. Local tumor progression after radiofrequency ablation of liver tumors: analysis of morphologic pattern and site of recurrence. AJR Am J Roentgenol 2008; 190: 1544–51. Hori T, Nagata K, Hasuike S et al. Risk factors for the local recurrence of hepatocellular carcinoma after a single session of percutaneous radiofrequency ablation. J Gastroenterol 2003; 38: 977–81. Lu DS, Raman SS, Limanond P et al. Influence of large peritumoral vessels on outcome of radiofrequency ablation of liver tumors. J Vasc Interv Radiol 2003; 14: 1267–74. Patterson EJ, Scudamore CH, Owen DA, Nagy AG, Buczkowski AK. Radiofrequency ablation of porcine liver in vivo: effects of blood flow and treatment time on lesion size. Ann Surg 1998; 227: 559–65. Predictive factors for long term prognosis after partial hepatectomy for patients with hepatocellular carcinoma in Japan. The Liver Cancer Study Group of Japan. Cancer 1994; 74: 2772–80. N’Kontchou G, Mahamoudi A, Aout M et al. Radiofrequency ablation of hepatocellular carcinoma:
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long-term results and prognostic factors in 235 Western patients with cirrhosis. Hepatology 2009; 50: 1475–83. Tzeng CW, Cooper AB, Vauthey JN, Curley SA, Aloia TA. Predictors of morbidity and mortality after hepatectomy in elderly patients: analysis of 7621 NSQIP patients. HPB (Oxford) 2013. [Epub ahead of print.] Sato M, Tateishi R, Yasunaga H et al. Mortality and morbidity of hepatectomy, radiofrequency ablation, and embolization for hepatocellular carcinoma: a national survey of 54,145 patients. J Gastroenterol 2012; 47: 1125– 33. Lam VW, Ng KK, Chok KS et al. Incomplete ablation after radiofrequency ablation of hepatocellular carcinoma: analysis of risk factors and prognostic factors. Ann Surg Oncol 2008; 15: 782–90. Mima K, Hayashi H, Imai K et al. High CD44s expression is associated with the EMT expression profile and intrahepatic dissemination of hepatocellular carcinoma after local ablation therapy. J Hepatobiliary Pancreat Sci 2013; 20: 429–34.
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SUPPORTING INFORMATION
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DDITIONAL SUPPORTING INFORMATION may be found in the online version of this article at the publisher’s website: Figure S1 The cumulative disease-free survival and overall survival curve of the patients with local recurrent HCC tumors
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doi: 10.1111/hepr.12313
Original Article
Salvage treatment for local recurrence of hepatocellular carcinoma after local ablation therapy Katsunori Imai,1 Toru Beppu,1,2 Akira Chikamoto,1 Kosuke Mima,1 Hirohisa Okabe,1 Hiromitsu Hayashi,1 Hidetoshi Nitta,1 Takatoshi Ishiko1 and Hideo Baba1 1
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, and Department of Multidisciplinary Treatment for Gastroenterological Cancer, Kumamoto University Hospital, Kumamoto, Japan 2
Aim: Local recurrence of hepatocellular carcinoma (HCC) after local ablation therapy (LAT) is a serious problem; however, the optimal treatment strategy remains unclear. Methods: A retrospective analysis was conducted of 50 patients with local recurrence of HCC after LAT that underwent either salvage hepatectomy (n = 23) or radiofrequency ablation (RFA; n = 27). Their background characteristics, intraoperative data, and postoperative short- and long-term outcome were analyzed. Results: The RFA group was found to be significantly associated with an impaired liver functional reserve, smaller number and size of tumors. The hepatectomy group showed a significantly longer operation time, greater intraoperative blood loss and more frequent red blood cell transfusion. In-hospital stay mortality and morbidity rate did not significantly differ. The disease-free and overall survival showed no
INTRODUCTION
H
EPATOCELLULAR CARCINOMA (HCC) is the fifth most common malignancy and the third most common cause of cancer-related death in the world.1 Two treatment modalities, hepatectomy and liver transplantation (LT), are considered to be potentially curative. The optimal therapy depends on each patient’s general condition, medical status including associated liver dysfunction, and the clinical characteristics of the tumors. Out of these, LT achieves the best Correspondence: Professor Hideo Baba, Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Email: [email protected] Conflict of interest: None of the authors has any conflict of interest. Received 16 December 2013; revision 4 February 2014; accepted 12 February 2014.
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significant difference between the groups. Although local recurrence after salvage treatment was found in zero (0%) for hepatectomy and in seven (25.9%) for RFA, that did not affect the overall survival. The tumor size at the prior LAT was identified as an independent prognostic factor for disease-free survival and serum albumin for overall survival.
Conclusion: Whereas salvage hepatectomy for local recurrent HCC is recommended for selected patients in terms of its good local control effect, salvage RFA is also acceptable because it is less invasive and also has a reasonable long-term outcome. Key words: hepatocellular carcinoma, local ablation therapy, local recurrence, radiofrequency ablation, salvage treatment
results from the aspect of offering the potential to remove the entire tumor-bearing liver and eliminate the cirrhosis as a field of de novo carcinogenesis. However, its feasibility has been restricted by organ donor shortage and high cost.2 Hepatectomy is considered to be the next curative treatment but is suitable for only a small percentage of patients because of their poor liver function reserve caused by the underlying liver disease.3,4 Local ablation therapy (LAT) such as radiofrequency ablation (RFA), microwave coagulation (MCT), percutaneous ethanol injection (PEI) or cryoablation plays a key role in the management of small HCC.5–8 Despite the reports of its excellent efficacy, safety and minimal invasiveness, local tumor recurrence after LAT remains a serious problem. The local tumor recurrence rates have been reported to range 17–38% after PEI,9–13 3.2–26% after RFA,14–17 5.9–19% after MCT18–20 and 8.0–24% after cryoablation.21,22 The treatment modalities for
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these locally recurrent tumors include iterative LAT, transcatheter arterial chemoembolization (TACE), hepatectomy and LT. Salvage hepatectomy for locally recurrent tumors after LAT has been reported to be an acceptable treatment despite the added surgical difficulty.23,24 However, patients that undergo initial LAT tend to have a more impaired liver functional reserve in comparison with those referred for hepatectomy. Therefore, it is sometimes difficult to select a salvage hepatectomy when tumor regrowth is detected in those patients. The objective of this study was to evaluate the role of salvage hepatectomy and RFA for local regrowth of HCC after LAT.
METHODS Patients
S
IXTY CONSECUTIVE PATIENTS underwent either salvage hepatectomy or RFA for the local regrowth of HCC after LAT at the Department of Gastroenterological Surgery, Kumamoto University Hospital (Kumamoto, Japan), from June 2000 to February 2012. The patients who had local recurrent HCC with an obvious residual tumor after LAT on the postoperative diagnostic imaging were not enrolled in this study. Ten of those patients had intrahepatic dissemination in synchronization with local recurrence. These patients were excluded from this study because these tumors were more advanced and aggressive.25 The remaining 50 patients were enrolled in this study. Local recurrence after LAT was defined as tumor recurrence within or at the periphery of the original ablated lesion based on routine imaging modalities, including ultrasonography (US), enhanced computed tomography (CT) and magnetic resonance imaging (MRI). Meanwhile, local recurrence after salvage hepatectomy was defined as tumor recurrence at the resection margin. All patients underwent liver function tests before treatment, including bilirubin, albumin, prothrombin activity, indocyanine green retention rate at 15 min (ICG-R15) and technetium99m galactosyl human serum albumin (99mTc-GSA) scintigraphy. Written informed consent was obtained from all patients before treatment.
Treatment modalities as a salvage treatment The surgical procedure was selected based on the tumor location, extent of the tumor, parenchymal liver function and the patient’s general condition. In general, hepatectomy was considered as the treatment of first choice for patients with good liver functional reserve,
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and anatomical resection was employed if the liver function allowed. The reasons for undergoing RFA rather than hepatectomy included deeply located tumors requiring major hepatic resection leading to insufficient remnant liver volume, insufficient liver function reserve, high operative risk associated with general condition and refusal of hepatectomy, as described previously.26 For local recurrent HCC after LAT, if the liver function and general condition were good enough, hepatectomy was performed as a first choice, because the local regrowth of a tumor after LAT is often associated with a more aggressive phenotype, such as high-frequency vascular invasion or sarcomatous changes.24,27,28 Salvage RFA was offered with an appropriate approach because hepatectomy was thought to be unsafe, because of the parenchymal liver dysfunction, patient’s poor general condition or the anatomical position of the tumor. A total of 23 hepatectomies were successfully performed, including six non-anatomical partial hepatectomies, four segmentectomies, eight sectionectomies, three left hepatectomies and two right hepatectomies. All hepatectomies were considered to be radical with tumor-free resection margins. Twenty-seven patients were treated with salvage RFA for local tumor recurrence of HCC after LAT. RFA was performed via a percutaneous approach in 11 patients, a laparoscopic approach in nine, a thoracoscopic approach in four patients and via laparotomy in three patients under general anesthesia. RFA was conducted using a cooled-tip electrode with a length of 2–3 cm (Radionics, Burlington, MA, USA) and was connected to a 500-kHz RF generator (Radionics) under the programmed cyclic impedance control condition as described previously.29 A 17-G electrode was inserted into the lesion under either US guidance or direct visual guidance, ablation was initiated and the power was increased to 60 W at a 2-cm length and 80 W in 3-cm length needle. The duration of maximum ablation was 8–10 min and the impedance was closely monitored. The aim of salvage RFA was to ablate all detected tumor with curative intent. All ablations aimed at achieving at least a 0.5-cm margin of nontumorous liver parenchyma, if possible, in a single session. Multiple overlapping ablations were performed in a positive manner as appropriate. Enhanced CT was performed 7 days after RFA to evaluate the tumor response to RFA in all patients. Complete ablation was defined as the absence of contrast enhancement within the entire tumor. The procedure was repeated if an unablated tumor remnant was suspected to remain.
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Postoperative morbidity and mortality Postoperative morbidity and mortality were defined as complications or death, respectively, occurring either within 30 days following surgery or during hospital stay, even when longer than 30 days. Postoperative morbidities were graded using validated classification criteria as described by Dindo et al.,30 and any postoperative complication worse than grade I were considered to be positive.
Follow up All of the patients underwent regular follow up of their serum α-fetoprotein (AFP) level, Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-γcarboxy prothrombin (DCP) levels, and US and CT scans or MRI were taken every 2–4 months to detect any intrahepatic recurrence or distant metastasis, as described previously.31 Recurrence was defined as the appearance of a lesion with radiological features typical of HCC, as confirmed by US, CT, MRI or sometimes tumor biopsy.
Statistical analysis Continuous variables are expressed as the means 1 standard deviation (SD), and compared using the Mann–Whitney U-test. Categorical variables were compared using the χ2-test. The disease-free survival and overall survival after treatment were computed using the Kaplan–Meier method, and then were compared using the log–rank test. Survival time was calculated from the date of the salvage treatment to the time of interest. A Cox regression model was utilized for the multivariate analysis. Only variables of P 2 0.10 in the univariate analysis were subjected to multivariate analysis. P 2 0.05 was considered to be statistically significant.
RESULTS Patient characteristics
A
TOTAL OF 50 patients (36 men and 14 women) were enrolled in this study, with a median age of 71 years (range, 41–82). The mean tumor size at the prior LAT was 20.9 1 8.8 mm (median, 20 mm; range, 10–65 mm) and the mean tumor size at salvage treatment was 24.2 1 14.8 mm (median, 20 mm; range, 8–110 mm). The mean number of tumors at the time of salvage treatment was 1.7 1 1.2 (median, 1; range, 1–5). The mean time interval between prior LAT and salvage treatment was 20.2 1 22.5 months (median, 10.9 months; range, 2.3–108 months). The mean follow-up
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periods were 52.5 months after prior LAT and 32.3 months after salvage treatment. The clinical characteristics of the patients according to the salvage treatment modality are summarized in Table 1. The patients in the RFA group were characterized primarily with a lower frequency of Child–Pugh classification A, with an increased serum concentration of aspartate aminotransferase, decreased serum concentration of albumin level and prothrombin activity, and an impaired ICG-R15 and uptake ratio of the liver to the liver plus heart at 15 min as determined by 99mTc-GSA scintigraphy in comparison with the hepatectomy group, suggesting that there was impaired liver functional reserve. The patients that received salvage hepatectomy had a larger number and size of HCC with a higher DCP level than those who received RFA. Visible vascular invasion in the preoperative diagnostic imaging findings was identified in only one patient in the hepatectomy group and in none of the patients in the RFA group.
Perioperative short-term outcome The intraoperative and postoperative outcomes are summarized in Table 2. The operation time was significantly longer (401.0 1 87.6 vs 161.9 1 86.9 min, P < 0.0001), and the intraoperative blood loss was also significantly greater in the hepatectomy group than in the RFA group (870.7 1 1336.4 vs 27.6 1 88.4 mL, P < 0.0001). In addition, blood transfusion of red blood cells was more frequent in the hepatectomy group than in the RFA group (17.4% vs 0%, P = 0.024), and length of the hospital stay after operation was significantly longer in the hepatectomy group in comparison with the RFA group (22.1 1 21.6 vs 10.5 1 7.6 days, P < 0.0001). Postoperative major complications occurred in five patients (21.7%) in the hepatectomy group, and in two patients in the RFA group (7.4%), as detailed in Table 2; there was no significant difference between the two groups (P = 0.15). Although the 30-day mortality was nil in the two groups, one patient in the hepatectomy group died from sepsis 87 days after surgery, during the same hospital stay. Therefore, in-hospital mortality was 4.3% in the hepatectomy group and 0% in the RFA group (P = 0.27). One other patient in the hepatectomy group died of rapid regrowth recurrent HCC in the remnant liver 86 days after surgery, after re-admission to our hospital.
Tumor recurrence and survival analysis Forty patients (80%) experienced tumor recurrence within a mean follow-up period of 32.3 months after
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Table 1 Clinical characteristics of the patients according to the salvage treatment modality for the local recurrence of HCC after LAT RFA (n = 27)
P-value
71.0 1 7.7 18/9
0.10 0.36
6 (26.1%) 14 (60.9%) 33.5 1 16.4 34.0 1 18.3 0.81 1 0.35 3.98 1 0.45 92.0 1 11.7 14.4 1 4.6 13.0 1 6.0 0.91 1 0.03 23/0 7.6 1 1.2 508.2 1 1574.7 7 (30.4%) 1598.4 1 5971.1 15/8 19.0 1 18.0 19.5 1 6.5 31.7 1 23.8 2.3 1 1.4
4 (11.1%) 22 (81.5%) 48.7 1 26.6 41.3 1 27.0 0.96 1 0.38 3.60 1 0.58 84.4 1 12.7 12.7 1 8.0 24.0 1 17.1 0.87 1 0.07 21/6 8.1 1 1.5 922.8 1 4464.0 4 (14.8%) 52.9 1 67.4 22/5 21.2 1 26.1 22.1 1 10.4 17.8 1 5.0 1.2 1 0.6
0.17 0.10 0.0054 0.44 0.094 0.034 0.034 0.089 0.0040 0.0041 0.02 0.19 0.69 0.18 0.037 0.19 0.76 0.65 0.0072 0.0029 0.18
16 7 28.7 1 29.2
23 4 35.3 1 25.4
Hepatectomy (n = 23) Age Sex (male/female) Etiology HBsAg positive HCVAb positive AST (IU/L) ALT (IU/L) Total bilirubin (mg/dL) Albumin (IU/L) Prothrombin activity (%) Platelet count (104/μL) ICG-R15 (%) 99m Tc-GSA LHL15 Child–Pugh classification (A/B) MELD score AFP (ng/mL) AFP-L3 >10 (%) DCP (mAU/mL) Tumor location (right liver/left liver) Time interval from prior LAT (months) Tumor size at prior LAT (mm) Tumor size at salvage treatment (mm) Tumor number at salvage treatment Treatment method of prior LAT RFA PEI Follow-up period (months)
67.2 1 9.5 18/5
0.16
Values are the means 1 standard deviations. 99m Tc-GSA, technetium-99m galactosyl human serum albumin; AFP, α-fetoprotein; AFP-L3, Lens culinaris agglutinin-reactive fraction of AFP; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DCP, des-γ-carboxy prothrombin; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HCVAb, anti-hepatitis C antibody; ICG-R15, indocyanine green retention rate at 15 min; LAT, local ablation therapy; LHL15, the liver to the liver plus heart at 15 min; MELD, Model for End-Stage Liver Disease; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation.
salvage treatment. The cumulative disease-free survival rates at 1, 3 and 5 years were 51.0%, 15.3% and nil in the hepatectomy group and 57.2%, 13.2% and 8.8% in the RFA group (P = 0.99; Fig. 1a). In the hepatectomy group, the tumor recurrence was found in 16 of 23 patients; the recurrence sites were liver (n = 12), lung (n = 1), liver + lung (n = 1), lymph node (n = 1) and bone (n = 1). In the RFA group, the tumor recurrence was found in 24 of 27 patients in the follow-up period; the recurrence site was only liver, of which, seven patients had local recurrence at the ablated sites. The cumulative overall survival rates at 1, 3 and 5 years were 84.0%, 70.0% and 58.3% in the hepatectomy group and 100%, 68.1% and 60.5% in the RFA group (P = 0.22;
Fig. 1b), respectively. Eight of 23 patients (34.8%) in the hepatectomy group and six of 27 patients in the RFA group (22.2%) died during the observation period. In the hepatectomy group, seven patients died from HCC recurrence and one patient died from postoperative complication from 87 days after surgery. In the RFA group, all six patients died from HCC recurrence. Local tumor recurrence after salvage treatment was found in zero (0%) in the hepatectomy group and in seven (25.9%) in the RFA group (P = 0.011; Table 2). Of these seven patients, five had local recurrence only and two had local recurrence with other intrahepatic metastasis; the mean time interval to develop local recurrence after salvage treatment was 12.8 months
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Table 2 Perioperative short-term outcome
Operation time (min) Blood loss (mL) Laparoscopic approach (%) Red blood cell transfusion (%) Hospital stay after operation (days) No. of patients with complication (%) Bile leakage Duodenal ulcer bleeding Wound infection Sepsis Intra-abdominal abscess Hemobilia 30-day mortality (%) In-hospital stay mortality (%) Local tumor recurrence (%)
Hepatectomy (n = 23)
RFA (n = 27)
P-value
401.0 1 87.6 870.7 1 1336.4 5 (21.7%) 4 (17.4%) 22.1 1 21.6 5 (21.7%) 3 (13.0%) 1 (4.3%) 1 (4.3%) 1 (4.3%) 0 (0%) 0 (0%) 0 (0%) 1 (4.3%) 0 (0%)
161.9 1 86.9 27.6 1 88.4 11 (40.7%) 0 (0%) 10.5 1 7.6 2 (7.4%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (3.7%) 1 (3.7%) 0 (0%) 0 (0%) 7 (25.9%)
35 vs 235) (IU/L) ALT (>35 vs 235) (IU/L) Total bilirubin (>1.0 vs 21.0) (mg/dL) Albumin (23.5 vs >3.5) (mg/dL) Prothrombin activity (>80 vs 280) (%) Platelet counts (>10 vs 210) (104/μL) ICG-R15 (>10 vs 210) (%) 99m Tc-GSA LHL15 (>0.9 vs 20.9) AFP (>20 vs 220) (ng/mL) AFP-L3 (>10 vs 210) (%) DCP (>40 vs 240) (mAU/mL) Tumor location (Right liver vs Left liver) Operation time (>263 vs 2263†) (min) Blood loss (>20 vs 220†) (g) Red blood cell transfusion (presence vs absence) Complication (presence vs absence) Time interval from prior LAT (>10.9 vs 210.9†) (months) Tumor size at prior LAT (>20 vs 220†) (mm) Tumor size at salvage treatment (>20 vs 220†) (mm) Tumor number at salvage treatment Salvage treatment modality (hepatectomy vs RFA) Local recurrence after salvage treatment (yes vs no)
0.67 0.22 0.68 0.075 0.49 0.74 0.51 0.17 0.85 0.97 0.77 0.87 0.11 0.27 0.089 0.75 0.24 0.13 0.66
Multivariate P-value
0.12
0.063
HR
1.93
2.05
95% CI
0.84–4.44
0.96–4.37
0.27 0.59 0.015
Overall survival Univariate P-value 0.17 0.50 0.22 0.062 0.3 0.86 0.7 0.069 0.42 0.57 0.19 0.45 0.007 0.028 0.10 0.72 0.22 0.33 0.075 0.019 0.21
0.0068
2.85
1.33–6.10
Multivariate P-value
HR
95% CI
0.46
1.74
0.40–7.54
0.05
4.11
1.00–16.94
0.42 0.61 0.16
1.75 1.74 2.77
0.44–6.87 0.21–14.32 0.66–11.62
0.67
1.64
0.17–16.24
0.40
3.36
0.20–56.32
0.19
0.35
0.25
0.20 0.99
0.11 0.22
0.22
0.33
†Median. 95% CI, 95% confidence interval; 99mTc-GSA, technetium-99m galactosyl human serum albumin; AFP, α-fetoprotein; AFP-L3, Lens culinaris agglutinin-reactive fraction of AFP; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DCP, des-γ-carboxy prothrombin; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HCVAb, anti-hepatitis C antibody; HR, hazard ratio; ICG-R15, indocyanine green retention rate at 15 min; LAT, local ablation therapy; LHL15, the liver to the liver plus heart at 15 min; MELD, Model for End-Stage Liver Disease; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation.
and less invasiveness with a mortality rate of 0–0.5% and a complication rate of 1.8–9.6%.17,32–35 On the other hand, local recurrence at an ablated site after LAT is a serious problem; the rates have varied 17–38% after PEI9–13 and 3.2–26% after RFA.14–17 Local recurrence after LAT may be attributable to insufficient ablation of the primary tumor and/or the presence of tumor venous
© 2014 The Japan Society of Hepatology
invasion in the adjacent liver. The risk factors for local recurrence after LAT include a large tumor size,13,16,36,37 the serum DCP level,17 multiple tumor nodules,38 an insufficient tumor margin,39 the tumor location relative to the liver surface40 and the presence of a perivascular tumor.41,42 In the current study, a percutaneous approach had a high local recurrence rate (5/11, 45.4%)
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Table 4 Postoperative macroscopic and histopathological characteristics of the 23 patients who underwent salvage hepatectomy n = 23 Gross type Single nodular type Single nodular type with extranodular growth Confluent multinodular type Invasive type Tumor differentiation Well Moderate Poor Sarcomatous change Growth type Extensive growth Invasive growth fc positive (%) fc infiltration positive (%) Septum formation positive (%) Portal vein invasion positive (%) Hepatic vein invasion positive (%)
12 2 8 1 1 14 7 1 20 3 18 (78.3%) 17 (94.4%) 17 (73.9%) 11 (47.8%) 3 (13.0%)
fc, fibrous capsule.
than laparoscopic (1/9, 11.1%), thoracoscopic (1/4, 25.0%) and via laparotomy (0/3, 0%). Although the sample size is too small to validate precisely, a percutaneous approach has the potential to be one of the risk factors for local tumor recurrence after salvage RFA in comparison with other approaches. Although it goes without saying that the possibility of complete tumor eradication is one of the most important issues for the selection of further treatment for local tumor recurrence, the strategy of additional treatment for local recurrence after LAT is still unclear. The prognosis of HCC is influenced by several factors related to both the extent of the tumor and parenchymal liver function.43 However, there is no evidence of the prognostic significance of local recurrence after LAT for HCC in the published work. Previous studies demonstrated that there was no notable difference in overall survival between patients with and without local recurrence after RFA.16,24,44 They had postulated that this may be explained by an aggressive treatment strategy such as hepatectomy, repeated RFA, or LT in patients with local recurrence after LAT. Sugo et al. reported that hepatectomy as a salvage treatment for local recurrence after LAT was associated with low mortality and morbidity (0% and 13%, respectively), and yielded overall survival benefits; the 5-year
overall survival rate was 67%.24 They concluded that salvage hepatectomy is an acceptable treatment for the patients with local recurrence of HCC after LAT, in spite of the added surgical difficulty. The current study showed similar results; 30-day mortality, in-hospital mortality and morbidity rate was 0%, 4.3% and 21.7%, respectively, and 5-year overall survival rate was 58.3%. In addition, these results achieved an outcome equivalent to those of the American College of Surgeon National Surgical Quality Improvement Program database after hepatectomy in the USA (the mortality and morbidity rates are 2.3% and 19.0%, respectively)45 and the nationwide survey of HCC in Japan (the mortality and morbidity rates are 2.6% and 14.5%, respectively,46 and the 5-year overall survival rate is 53.4% after hepatectomy).4 These results suggest that salvage hepatectomy is an acceptable treatment for the local recurrence of HCC after LAT in terms of its safety and efficacy. In the current study, local tumor recurrence after salvage treatment was observed more frequently in the RFA group than in the hepatectomy group (25.9% and 0%, respectively, Table 2). The re-local recurrence or incomplete response rates after salvage RFA have been reported to range 23.1–36.4%; the results of the current study are similar to these previous results.16,47 This re-local recurrence rate after salvage RFA is relatively higher than the local recurrence rate after initial RFA.14–17 In addition, we recently reported that local recurrent HCC after LAT had more aggressive potential via epithelial–mesenchymal transition compared to initial HCC.48 A Japanese large-scale nationwide survey of primary liver cancer reported that fc infiltration and portal vein invasion were detected in 68.9% and 29.4%, respectively, of patients with primary HCC in an assessment of more than 4000 cases.4 In the current study, the histopathological analysis of the resected specimens by salvage hepatectomy revealed that fc infiltration and portal vein invasion of locally recurrent tumors were detected more frequently than for primary (non-locally recurrent) HCC, where the incidence of fc infiltration and portal vein invasion were 94.4% and 47.8%, respectively. These findings suggest that locally recurrent HCC after LAT has more malignant behavior than primary HCC. Based on these matters, we believe that salvage hepatectomy for local tumor recurrence after LAT is indicated for the patients with good liver function reserve in terms of its good local control effect. However, the current study revealed that the RFA group was primarily characterized to have impaired liver functional reserve at the salvage treatment (Table 1) and was associated with shorter operation time, less blood loss,
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lower frequency of red blood cell transfusion and shorter hospital stay after the operation, in comparison with the hepatectomy group (Table 2). Furthermore, additional radical treatment was performed in all seven patients with local tumor recurrence after salvage RFA, and the complete eradication of local recurrent tumors could be achieved in all patients. As a result, local tumor recurrence after salvage RFA did not affect the overall survival (Fig. 2). As with the previous reports,16,24,44 this result may support an aggressive treatment policy for local recurrent tumor after LAT. These results suggest that salvage RFA is less invasive and an acceptable treatment strategy, especially for patients with an impaired liver function reserve. There are some limitations in this study. First, this is a retrospective data analysis from one single institution and the number of cases is relatively small. Second, some bias could be present due to patients’ selections and choices of treatment. In this study, the patients in the RFA group were characterized primarily by their impaired liver function reserve in comparison with the hepatectomy group. However, the patients in the hepatectomy group had more advanced and aggressive tumors, characterized by larger numbers and sizes, and a higher DCP level. These differences might have affected the short- and long-term outcome of the patients with locally recurrent HCC after LAT. In addition, the patients might have received prior LAT, rather than hepatectomy, due to a variety of reasons even when they were suitable for hepatectomy at the point of initial treatment. In the current study, 14 of 23 patients (60.9%) in the hepatectomy group and eight of 27 patients (30.0%) in the RFA group had received prior LAT before salvage treatment in the other institutions, and then were referred to our department after being diagnosed with local recurrence of HCC. Therefore, it could not be analyzed and explained exactly why the patients who received salvage hepatectomy were not resected at the instant of initial treatment. Because of the low local tumor recurrence rate after LAT in most centers, the pooling of data from multiple centers may be needed to provide a large enough sample size for a further study to clarify the optimal treatment strategy for local tumor recurrence after LAT. In conclusion, salvage hepatectomy for local recurrent HCC after LAT is indicated for selected patients, in terms of its good local control effect. However, its feasibility is restricted by the surgical difficulty and the patient’s liver functional reserve. Salvage RFA for local tumor recurrence is an acceptable treatment in such cases because of its less invasive and the reasonably long-term outcome.
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SUPPORTING INFORMATION
A
DDITIONAL SUPPORTING INFORMATION may be found in the online version of this article at the publisher’s website: Figure S1 The cumulative disease-free survival and overall survival curve of the patients with local recurrent HCC tumors
