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Efficacy of surgical microwave ablation for recurrent hepatocellular carcinoma after curative hepatectomy
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https://doi.org/10.1016/j.hpb.2019.08.001
ORIGINAL ARTICLE
Efficacy of surgical microwave ablation for recurrent hepatocellular carcinoma after curative hepatectomy Tomoki Ryu, Yuko Takami, Yoshiyuki Wada, Takanobu Hara, Shin Sasaki & Hideki Saitsu Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
Abstract Background: Little evidence exists regarding postrecurrence survival after microwave ablation for recurrent hepatocellular carcinoma (HCC) after curative hepatectomy; we aimed to evaluate the feasibility of surgical microwave ablation. Methods: In this retrospective review, we enrolled patients who underwent curative hepatectomy for primary HCC in our department and had intrahepatic recurrence. We analyzed overall survival according to treatment modality to clarify the prognostic factors for survival. Results: Of 257 patients, 119 had intrahepatic recurrence. Three patients underwent repeat hepatectomy; 75 patients underwent surgical microwave ablation, and 34 patients underwent transcatheter arterial chemoembolization or hepatic arterial infusion chemotherapy. The median postrecurrence survival time and 5-year postrecurrence survival after surgical microwave ablation were 37.4 months and 55.4%, respectively. The major complication rate (Clavien–Dindo classification IIIa or above) after surgical microwave ablation was 5.3% with no mortality. Multivariate analysis showed that microvascular invasion at primary tumors, and recurrent tumors within 3 cm and 3 nodules were independent prognostic factors for overall survival after surgical microwave ablation for recurrent HCC. Conclusion: Our results suggested that surgical microwave ablation is safe and feasible for recurrent intrahepatic HCC after curative hepatectomy. Close follow-up and further curative treatment could be important for improving postrecurrence survival. Received 4 April 2019; accepted 6 August 2019
Correspondence Tomoki Ryu, Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama Chuo-ku, Fukuoka 810-8563, Japan. E-mail: ryu.tomoki.mq@mail. hosp.go.jp
Introduction Hepatic resection is considered as the first line of curative treatment for hepatocellular carcinoma (HCC).1 Nevertheless, the recurrence rate after curative hepatectomy is high, with cumulative 5-year recurrence rates >60%.2 Therefore, we must understand how to manage and treat recurrent HCC for improving survival in patients with HCC after curative hepatectomy. Salvage liver transplantation is theoretically recognized the best choice for recurrent HCC, as it removes both recurrent tumors and the cirrhotic liver.3 However, its application has been limited by the shortage of donors, especially in some countries
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with limited availability of livers for transplantation. Repeat hepatectomy is also reported as an effective approach for recurrent HCC,4 although only about 20% of patients with recurrent HCC are eligible for repeat hepatectomy, because of small liver volume, poor liver function reserve, the multiple recurrent tumors, and the presence of postoperative adhesion.5 Given the small population of patients with recurrent HCC who are suitable for repeat hepatectomy, alternative treatment options are required. In recent years, local ablation therapy, such as radiofrequency ablation (RFA) and microwave ablation, has been attracting attention as a therapeutic strategy for small primary HCC or liver cirrhosis.6–8 In addition to a large number of studies about local
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ablation therapy for primary HCC, a recent systematic review focused on local ablation therapy for recurrent HCC have reported that RFA was an effective option for patients with recurrent HCC.9 However, little evidence is available regarding long-term outcomes after microwave ablation for recurrent HCC after curative hepatectomy. The aim of this study was to assess the safety and efficacy of microwave ablation for recurrent HCC and to identify the prognostic factors of intrahepatic recurrent HCC after initial hepatectomy.
Methods Patients In this study, we retrospectively analyzed a total of 257 consecutive patients who underwent curative hepatectomy for primary HCC from July 1994 to December 2017 in our department. Patients with recurrent HCC were selected for further analysis. Curative hepatectomy was defined as complete macroscopic removal of the tumor, where the resection margin was negative and no detectable intrahepatic or extrahepatic metastatic lesions remained. At the time of the data analysis, 118 patients remained free of recurrence, and 139 patients had recurrence postoperatively. Of the 139 patients who recurred, 20 patients had developed extrahepatic recurrence, and the remaining 119 patients who had developed intrahepatic recurrence were enrolled in this study. Among the 119 patients with intrahepatic recurrence, three patients underwent repeat hepatectomy, 75 patients
underwent surgical microwave ablation [microwave coagulonecrotic therapy (MCN)], and 34 patients underwent transcatheter arterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) as the secondary treatment for the recurrent tumors (Fig. 1). Prospectively collected data on patient characteristics, clinicopathologic features, and survival outcomes were reviewed. The diagnosis of HCC was confirmed according to histopathological diagnosis after initial hepatectomy. Gross classification of the nodular type and tumor differentiation were defined based on the General Rules for the Clinical and Pathological Study of Primary Liver Cancer developed by the Liver Cancer Study Group of Japan.10 Liver cirrhosis was defined as grade 4 fibrosis on specimen pathology. All patients were followed until death or March 2019. This study was conducted in accordance with the Declaration of Helsinki and the ethical guidelines for clinical studies of the Ministry of Health, Labour, and Welfare in Japan. The study protocol was approved by the Ethics Committee on Clinical Investigations of Kyushu Medical Center. Follow-up and diagnosis for recurrent HCC All patients received contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the liver within one months after initial hepatectomy for primary HCC to confirm macroscopic tumor clearance. Thereafter, patients were followed postoperatively every 2–3 months with ultrasound and blood chemistry evaluations, including three tumor markers:
Figure 1 Flowchart of patients included in this study. HCC, hepatocellular carcinoma; MCN, microwave coagulo-necrotic therapy; TACE,
transcatheter arterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy
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alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-g-carboxy prothrombin (DCP). Contrast-enhanced CT or MRI was performed every 4–6 months. Intrahepatic recurrence was defined as a new lesion with arterial contrast enhancement and portal venous washout on contrast-enhanced CT or MRI scans with or without elevated serum tumor markers. Treatment strategy for recurrent HCC When recurrent tumors were found, repeat hepatectomy or MCN was again attempted after considering liver function, and tumor status (i.e. the size, number, and location) of each patient.
Both repeat hepatectomy and MCN were performed by the same surgical team of dedicated liver surgeons led by at least one consultant specialist. In our hospital, MCN was preferentially considered to treat for recurrent HCC 3 cm, whereas repeat hepatectomy was performed in selected patients only when recurrent tumors were located on surface or edge of the liver. Repeat hepatectomy was attempted for recurrent HCC >3 cm, although MCN was a secondary consideration for patients with small liver volume, poor liver function reserve, or poor performance status. As for the number of recurrent tumors, we usually attempted MCN for five tumors or fewer, and we also considered MCN for tumors that were more than 5 mm away from the
Table 1 Clinicopathological characteristics at initial hepatectomy
Characteristic
HCC recurrence (n [ 139)
No recurrence (n [ 118)
P-value
70 (42–88)
73 (42–87)
0.056
Background characteristics Age, years, median (range) Sex, male, n (%)
109 (78%)
86 (73%)
0.302
Hepatitis B virus infection, n (%)
19 (14%)
22 (18%)
0.279
Hepatitis C virus infection, n (%)
78 (56%)
45 (38%)
0.004
Albumin, g/dL, median (range)
4.0 (3.0–5.5)
4.1 (2.5–5.0)
0.005
Total bilirubin, mg/dL, median (range)
0.7 (0.3–2.3)
0.7 (0.1–2.3)
0.068
Prothrombin activity, %, median (range)
88 (18–137)
92 (12–139)
0.059
ICGR15, %, median (range)
18.9 (0.6–66.4)
16.6 (0.6–91.8)
0.046
Platelets, × 10 /mL, median (range)
16.6 (4.9–27.8)
18.6 (4.5–49.9)
0.057
Child-Pugh class, A, n (%)
135 (97%)
110 (93%)
0.138
AFP, ng/mL, median (range)
12 (0–89437)
7 (0.9–71771)
0.030
DCP, mAU/mL, median (range)
497 (0–1623100)
60 (0–349000)
<0.001
Tumor Size, mm, median (range)
49.4 (10.4–180)
35.1 (14.2–250)
<0.001
Number of tumors, single, n (%)
115 (83%)
110 (95%)
0.003
Macroscopic vascular invasion, n (%)
10 (7%)
2 (2%)
0.044
102 (74%)
87 (73%)
0.950 0.690
4
Tumor related factors
Surgical factors Type of hepatectomy, anatomical, n (%) Operating time, min, median (range)
198 (51–425)
198 (49–511)
Blood loss, g, median (range)
251 (1–6235)
210 (1–7900)
0.117
Intraoperative blood transfusion, n (%)
15 (11%)
6 (5%)
0.094
Morbidity, n (%)
33 (24%)
10 (9%)
<0.001
Complication of Clavien-Dindo grade IIIA or above, n (%)
16 (12%)
6 (5%)
0.044
Postoperative hospital stays, days, median (range)
14 (7–77)
12 (8–75)
0.010
Pathological factors Gross type, SN with EG or CM, n (%)
82 (59%)
54 (46%)
0.028
Histological grade, poorly differentiated, n (%)
31 (22%)
30 (25%)
0.547
Microscopic vascular invasion, n (%)
82 (60%)
61 (52%)
0.245
Intrahepatic metastasis, n (%)
34 (25%)
2 (2%)
<0.001
Liver cirrhosis, n, (%)
34 (24%)
21 (18%)
0.223
ICGR15, indocyanine green retention rate at 15 min; AFP, alpha fetoprotein; DCP, des-gamma carboxyprothrombin; SN, simple nodular type; SN with EG, simple nodular with extranodular growth type; CM, confluent multinodular type.
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major Glissonean pedicles. If MCN or repeat hepatectomy was considered unsuitable to treat because of impaired liver function, multiple recurrences, or the risk of bile duct injury, we performed TACE or HAIC.
ablation area was evaluated by dynamic CT 1–2 weeks after treatment. Perioperative morbidities were stratified by severity based on the Clavien–Dindo classification13; major complications were considered grade III or above.
MCN procedures MCN procedures were performed as previously reported.11,12 We have performed MCN as curative surgical microwave ablation for primary or recurrent HCC since 1994, and the procedure is wellestablished. We used a 2450-MHz system microwave generator (Alfresa Pharma, Osaka, Japan). MCN repeats electrode insertion and irradiation from the tumor edge to the tumor center to avoid increasing intratumoral pressure and to obtain an adequate ablation margin of 10 mm outside the tumor margin. We performed MCN for recurrent HCC as an open approach, such as laparotomy or thoracotomy, with routine intraoperative ultrasound to identify lesions and monitor treatment effect. The
Statistical analysis Continuous variables were presented as median (range) and compared using the Mann–Whitney U test. Categorical variables were compared using Fisher’s exact probability method or c2 tests. Overall survival was defined as the interval from surgery to death or the date of the last or most recent follow-up visit. Recurrence-free survival was defined as the interval from surgery to the date of diagnosis of the first recurrence or last follow-up. Overall survival after recurrence was defined as the period from the date of treatment for the recurrence to the date of death or the date of the last or most recent follow-up visit. All patients were followed until death or March 2019. Overall survival and
Figure 2 Long-term survival outcomes after curative hepatectomy; (a) overall survival and (b) recurrence-free survival rates
Figure 3 Overall survival rates after recurrence (a) all 119 patients with intrahepatic recurrence, (b) according to treatment for recurrent tumors.
MCN, microwave coagulo-necrotic therapy; TACE, transcatheter arterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy
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Table 2 Comparison of clinical characteristics among MCN, and TACE or HAIC groups
MCN (n [ 75)
TACE or HAIC (n [ 34)
P-value
Age, years, median (range)
69 (42–86)
70 (51–84)
0.384
Hepatitis B virus infection, n (%)
14 (19%)
4 (12%)
0.356
Hepatitis C virus infection, n (%)
43 (57%)
24 (70%)
0.183
ICGR15, %, median (range)
20.3 (0.6–66.4)
16.4 (6.4–49.5)
0.648
AFP, ng/mL, median (range)
12 (0–25314)
15 (1.7–89437)
0.412
DCP, mAU/mL, median (range)
478 (0–62000)
468 (0–140000)
0.609
Maximum tumor size, mm, median (range)
44.8 (15.0–180)
60.5 (10.4–180)
0.031
Number of tumors, single, n (%)
63 (84%)
25 (76%)
0.319
Macroscopic vascular invasion, n (%)
5 (7%)
2 (2%)
0.986
Type of hepatectomy, anatomical, n (%)
49 (65%)
29 (85%)
0.026
Gross type, SN with EG or CM, n (%)
38 (51%)
15 (44%)
0.746
Histological grade, poorly differentiated, n (%)
10 (13%)
8 (25%)
0.178
Microscopic vascular invasion, n (%)
39 (52%)
26 (76%)
0.040
Intrahepatic metastasis, n (%)
15 (21%)
12 (35%)
0.141
Liver cirrhosis, n, (%)
17 (23%)
9 (26%)
0.253
Early recurrence (2 years), n (%)
33 (44%)
26 (76%)
0.001
Albumin, g/dL, median (range)
3.9 (2.4–5.2)
3.8 (3.0–4.5)
0.066
Total bilirubin, mg/dL, median (range)
0.8 (0.3–2.3)
0.7 (0.3–2.5)
0.342
Prothrombin activity, %, median (range)
88 (40–117)
85 (52–111)
0.269
Platelets, × 104/mL, median (range)
15.2 (4.0–30.4)
14.8 (5.5–34.0)
0.269
Child-Pugh class, A, n (%)
62 (84%)
27 (79%)
0.537
Maximum tumor size, mm, median (range)
22 (10–53)
16 (10–35)
0.001
62 (83%)
30 (88%)
0.107
Single
35 (47%)
3 (9%)
2-3
26 (34%)
6 (15%)
>3
14 (19%)
26 (76%)
Within 3 cm and 3 nodules
50 (67%)
6 (18%)
<0.001
AFP, ng/mL, median (range)
7.2 (0.9–8554)
14 (1.6–970112)
0.007
DCP, mAU/mL, median (range)
31 (9–53100)
83 (10–65400)
0.093
Local recurrence, n (%)
5 (4%)
2 (6%)
0.493
Characteristic Factors at initial resection
Factors at recurrence
3 cm, n (%) Number of tumors, n (%)
<0.001
MCN, microwave coagulo-necrotic therapy; TACE, transcatheter arterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy; AFP, alpha fetoprotein; DCP, des-gamma carboxyprothrombin.
recurrence-free survival curves were calculated using the Kaplan–Meier method and compared using the log-rank test. We used a Cox proportional hazards model for univariate and multivariate analyses of the prognostic factors related to survival after treatment for recurrence. All P-values were derived from two-tailed tests, with P < 0.05 considered statistically significant. All statistical analyses were performed using JMP 12 software (SAS Institute, Inc., Cary, NC, USA).
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Results During the study period, 257 patients underwent curative hepatectomy for primary HCC. Clinicopathological data at initial hepatectomy for the entire cohort are listed in Table 1. The median follow-up time was 54.1 months (range, 5.2–259.4) and Kaplan–Meier analysis showed that the 5-, and 10-year overall survivals after initial hepatectomy were 68.6%, and 53.4%, respectively (Fig. 2a). Of the 257 patients resected, 139 (54%)
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developed recurrence. The 5-, and 10-year recurrence-free survivals after initial hepatectomy were 44.5%, and 34.3%, respectively (Fig. 2b). The median time from initial hepatectomy to recurrence was 24.5 months. Among patients who had recurrence, 119 patients (86%) had intrahepatic recurrences and 20 patients (14%) had isolated extrahepatic recurrences. In the 119 patients who had intrahepatic recurrences, the median survival time after recurrence was 26.1 months. The 1-, 3-, and 5-year survivals after recurrence were 81.0%, 52.1%, and 41.6%, respectively (Fig. 3a). Among the 119 patients with intrahepatic recurrence, 75 patients (63%) underwent MCN, 34 patients (28%) underwent TACE or HAIC, three patients (3%) underwent repeat hepatectomy, and seven patients (6%) underwent other therapies for recurrent HCC. Clinicopathological characteristics of the MCN group and the TACE or HAIC group are listed in Table 2. In the MCN group, 33 patients (44%) experienced early recurrence (within 2 years after surgery). Median recurrent tumor size was 22 mm (range, 10–53), and 83% of the recurrent tumor size were 3 cm or smaller in the MCN group. In the MCN group, 35 patients (47%) had a single tumor, and the proportion of patients with recurrent tumor within 3 cm and 3 nodules was 67% in the MCN group. Overall survival rates after recurrence according to the treatment modalities for recurrent HCC were shown in Fig. 3b. The median survival time, and the 1-, 3-, and 5-year overall survival
rates after recurrence were 37.4 months, and 93.1%, 68.5%, and 55.4%, respectively in the MCN group. The median survival time, and the 1-, 3-, and 5-year overall survival rates after recurrence were 17.5 months, and 61.8%, 25.0%, and 21.4%, respectively in the TACE or HAIC group (P < 0.001). Perioperative outcomes of patients who underwent MCN for recurrent HCC are summarized in Table 3. Among the 75 patients who underwent MCN, 40 patients (53%) underwent MCN via laparotomy, with 35 patients (47%) via thoracotomy. Two patient required intraoperative platelet transfusion: patients with a platelet count <4.0 × 104/mL secondary to severe liver cirrhosis. No patients required red blood cell transfusions for intraoperative blood loss. Major complications were experienced by four patients (5.3%; two wound infection, one pleural effusion, and one intra-abdominal abscesses), though Clavien–Dindo grade IV or V complications did not occur. The univariate and multivariate analyses we used to identify prognostic factors affecting overall survival after MCN for recurrent HCC are shown in Table 4. Multivariate analyses showed that microvascular invasion at the primary tumor (hazard ratio [HR]: 3.50, 95% confidence interval [95% CI]: 1.41–9.29; P = 0.007), and recurrent tumors within 3 cm and 3 nodules (HR: 0.41, 95% CI: 0.17–0.92; P = 0.050), were independent prognostic factors for overall survival after MCN for recurrent HCC.
Discussion Table 3 Perioperative characteristics of 75 patients who underwent
MCN for recurrent HCC n [ 75
Characteristics Approach Laparotomy, n (%)
40 (53%)
Thoracotomy, n (%)
35 (47%)
Operating time, min, median (range)
89 (46–232)
Blood loss, g, median (range)
5 (1–461)
Intraoperative blood transfusion, n (%)
2 (3%)
Postoperative morbidities, n (%)
8 (11%)
Wound infection
2
Pleural effusion
2
Intra-abdominal abscess
1
Ascites
1
Hepatic infarction
1
Portal thrombosis
1
Clavien-Dindo classification II
4
IIIa
4
IIIb
0
IV
0
V
0
Postoperative hospital stays, days, median (range)
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11 (4–42)
This study investigated the feasibility of surgical microwave ablation for recurrent HCC after curative hepatectomy. Our study revealed that majority (63%) of patients with intrahepatic recurrence after initial hepatectomy were eligible for surgical microwave ablation, with the 5-year post-recurrence survival rate of 55%. We suggest that long-term survival is possible with microwave ablation for recurrent HCC after curative hepatectomy. Few studies are large enough and include long-term outcome of microwave ablation for recurrent HCC after hepatectomy. To the best of our knowledge, the current study is one of the largest cohort studies to evaluate the long-term outcome of microwave ablation for recurrent HCC after curative hepatectomy. No consensus has been reached as to the most appropriate treatment for recurrent HCC after curative treatment, while the treatment strategy for recurrent HCC varies from center to center all over the world. Though there are no randomized control trials comparing the various treatment modalities for recurrent HCC, retrospective cohort studies of comparing repeat hepatectomy and RFA have been increasing in recent years.14–17 In the majority of studies, no significant differences have been reported between the two groups, with the reported 5-year survival after repeat hepatectomy and RFA for recurrent HCC of 28–72% and 29–83%, respectively.14–17 A recent systematic review of 19 retrospective series that focused on ablation for
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Table 4 Univariate and multivariate analyses of survival after MCN for recurrent HCC (n = 75)
Variables
Univariate analysis HR
Multivariate analysis
95% CI
P-value
HR
95% CI
P-value
1.86
0.87–4.22
0.114
1.37
0.64–2.92
0.415
3.50
1.41–9.29
0.007
1.66
0.63–4.52
0.307
Factors at initial resection Age 70 years
1.31
0.67–2.54
0.422
Hepatitis C virus
2.24
1.12–4.75
0.021
Child-Pugh B
1.07
0.06–5.12
0.944
Platelet count < 10 × 104/mL
1.23
0.32–8.07
0.781
ICGR15 15%
1.26
0.63–2.45
0.505
Maximum tumor size 5 cm
1.85
0.96–3.55
0.065
Multiple nodule
1.26
0.51–2.70
0.598
Anatomical hepatectomy
1.03
0.52–1.98
0.928
SN with EG or CM
1.25
0.64–2.50
0.518
Poorly differentiated
2.58
0.78–15.9
0.132
Microscopic vascular invasion
3.29
1.58–7.14
0.001
Liver cirrhosis
1.18
0.55–2.95
0.684
Time to recurrence <2 years
2.77
1.43–5.53
0.002
Child-Pugh B
1.90
0.81–3.99
0.133
Platelet count < 10 × 104/mL
2.07
0.88–4.37
0.092
Within 3 cm and 3 nodules
0.35
0.18–0.69
0.002
0.41
0.17–0.92
0.032
AFP 20 ng/mL
2.14
1.05–4.21
0.037
2.18
0.92–5.09
0.077
DCP 40 mAU/mL
2.04
1.06–3.94
0.032
1.37
0.52–3.61
0.518
Factors at recurrence
HR, hazards ratio; CI, confidence interval; ICGR15, indocyanine green retention rate at 15 min. AFP, alpha fetoprotein; DCP, des-gamma carboxyprothrombin.
recurrent HCC revealed that 5-year survival rates after RFA for recurrent HCC was 40% (range 23–83%).9 However, they also concluded that there was insufficient date to analyze survival outcomes after microwave ablation. In addition, there have been no studies comparing RFA and microwave ablation for recurrent HCC to date. In this study, the 5-year post-recurrence survival after microwave ablation for recurrent HCC was 55.4%, which is comparable to results reported previously for both repeat hepatectomy and RFA. Microwave ablation has received attention as a curative treatment for HCC in recent years.8,18 There are theoretically some advantages to microwave ablation over RFA; faster ablation times, larger ablation zones, higher intratumoral temperature, and more complete coagulative necrosis.18 Several previous studies have reported microwave ablation was as effective as RFA for primary HCC when comparing local recurrence rates and long-term survival,19,20 with the reported 5-year overall survival of 43%–60%.21–25 We have performed surgical microwave ablation, termed microwave coagulo-necrotic therapy (MCN), for both primary and recurrent HCC for more than 20 years, and previously reported its feasibility and oncological long-term outcomes.11,26,27 Our previous report of the 5-year overall survival rate was 62% in 719 patients who underwent MCN for primary HCC.11 The 5-year survival of 55% in this study is
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comparable to that reported after microwave ablation for primary HCC. We also analyzed the perioperative outcome of MCN for recurrent HCC after initial hepatectomy. The major complication rate was 5.3%, with no procedure-related deaths in MCN for recurrent HCC in this study. These findings suggest that MCN is safe and feasible procedure for patients with recurrent HCC after curative hepatectomy. Another important finding in this study was that we sought to determine the prognostic factors that associated with overall survival after MCN for recurrent HCC. In our multivariate analysis, microvascular invasion at primary tumors, and recurrent tumors within 3 cm and 3 nodules were independent prognostic factors for survival after MCN for recurrent HCC. Intrahepatic recurrence after curative hepatectomy is generally classified into two types: intrahepatic metastasis from primary tumors or multicentric carcinogenesis of new tumors resulting from chronic hepatitis or cirrhosis.28 In previous studies, intrahepatic metastasis occurred mainly within 2 years after surgery, while multicentric carcinogenesis mainly occurred more than 2 years after surgery.29 Microvascular invasion is recognized as a risk factor for early recurrence (i.e., intrahepatic metastasis), after curative hepatectomy.30 In this study, TACE or HAIC tended to be chosen for recurrent HCC with early recurrence or microvascular invasion at primary tumors, which were thought
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to be intrahepatic metastasis from primary tumors. On the other hand, a recent single-center cohort study reported that recurrent HCC more than 18 months after hepatectomy is mainly a result of multicentric carcinogenesis, and repeat hepatectomy in such cases yielded favorable survival.31 Nevertheless, only about 20% of patients with recurrent HCC are eligible for repeat hepatectomy, because of small liver volume, poor liver function reserve, the multiple recurrent tumors, and the presence of postoperative adhesion.5 In this study, we performed surgical microwave ablation in more than 60% of patients with intrahepatic recurrence after initial hepatectomy. It must be emphasized that more than 80% of recurrent tumors could be detected less than 3 cm in this study. These findings suggest that primary tumors without microvascular invasion and recurrent tumors within 3 cm and three nodules can be good indications for surgical microwave ablation for recurrent HCC. Although further studies are needed to precisely determine the indication for surgical microwave ablation for recurrent HCC, close follow-up and early detection in the early stage of recurrence could be important for patients to undergo curative treatment for recurrent HCC. There were some limitations in this study. First, the retrospective study is prone to potential bias. Second, this study was based on a review from a single-institution and might not represent findings in other centers. Third, the study included a limited number of patients who performed repeat hepatectomy for recurrent HCC, meaning that we could not compare perioperative and oncological outcomes between repeat hepatectomy and MCN for recurrent HCC. Despite these limitations, we believe that our results may be clinically informative and could be an indicator for the future analysis of microwave ablation for recurrent HCC. In conclusion, this study investigated the feasibility of surgical microwave ablation for recurrent HCC after curative hepatectomy. Our results suggested that surgical microwave ablation was safe and feasible treatment for recurrent HCC after curative hepatectomy. In particular, primary tumors without microvascular invasion and recurrent tumors within 3 cm and three nodules were good indications for surgical microwave ablation for recurrent HCC. Close follow-up and further curative treatment for recurrent HCC could be important for improving post-recurrence survival in patients with HCC after curative hepatectomy.
Analysis and interpretation of data: Ryu, Takami, and Saitsu. Drafting of manuscript: Ryu. Critical revision: Takami, and Saitsu. Grant support None. Conflict of interest statement None declared. References 1. Takayama T, Makuuchi M, Hirohashi S, Sakamoto M, Yamamoto J, Shimada K et al. (1998) Early hepatocellular carcinoma as an entity with a high cure rate of surgical cure. Hepatology 28:1241–1246. 2. Llovet JM, Schwartz M, Mazzaferro V. (2005) Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis 25: 181–200. 3. Hwang S, Lee SG, Moon DB, Ahn CS, Kim KH, Lee YJ et al. (2007) Salvage living donor liver transplantation after prior liver resection for hepatocellular carcinoma. Liver Transplant 13:741–746. 4. Minagawa M, Makuuchi M, Takayama T, Kokudo N. (2003) Selection criteria for repeat hepatectomy in patients with recurrent hepatocellular carcinoma. Ann Surg 238:703–710. 5. Chan DL, Morris DL, Chua TC. (2013) Clinical efficacy and predictors of outcomes of repeat hepatectomy for recurrent hepatocellular carcinoma—a systematic review. Surg Oncol 22:23–30. 6. Tateishi R, Shiina S, Teratani T, Obi S, Sato S, Koike Y et al. (2005) Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases. Cancer 103:1201–1209. 7. Lau WY, Lai EC. (2009) The current role of radiofrequency ablation in the management of hepatocellular carcinoma: a systematic review. Ann Surg 249:20–25. 8. Liang P, Wang Y. (2007) Microwave ablation of hepatocellular carcinoma. Oncology 72:124–131. 9. Thomasset SC, Dennison AR, Garcea G. (2015) Ablation for recurrent hepatocellular carcinoma: a systematic review of clinical efficacy and prognostic factors. World J Surg 39:1150–1160. 10. Liver Cancer Study Group of Japan. (2010) General Rules for the clinical and pathological study of primary liver cancer, 3rd English ed. Tokyo: Kanehara Shuppan. 11. Takami Y, Ryu T, Wada Y, Saitsu H. (2013) Evaluation of intraoperative microwave coagulo-necrotic therapy (MCN) for hepatocellular carcinoma: a single center experience of 719 consecutive cases. J HepatoBiliary-Pancreatic Sci 20:332–341. 12. Ryu T, Takami Y, Tsutsumi N, Tateishi M, Mikagi K, Wada Y et al. (2017) Simultaneous microwave coagulo-necrotic therapy (MCN) and laparo-
Acknowledgments We thank Andrea Baird, MD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
scopic splenectomy for the treatment of hepatocellular carcinoma with cirrhotic hypersplenism. Surg Today 47:548–554. 13. Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD et al. (2006) The Clavien-Dindo classification of surgical complications:
Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
five-year experience. Ann Surg 250:187–196. 14. Chan AC, Poon RT, Cheung TT, Chok KS, Chan SC, Fan ST et al. (2012) Survival analysis of re-resection versus radiofrequency ablation for intrahepatic recurrence after hepatectomy for hepatocellular carcinoma.
Authors’ contributions
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Study conception and design: Ryu, Takami, and Saitsu. Acquisition of data: Ryu, Wada, Hara, and Sasaki.
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15. Liang HH, Chen MS, Peng ZW, Zhang YJ, Zhang YQ, Li JQ et al. (2008) Percutaneous radiofrequency ablation versus repeat hepatectomy for
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recurrent hepatocellular carcinoma: a retrospective study. Ann Surg Oncol 15:3484–3493.
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https://doi.org/10.1016/j.hpb.2019.08.001
ORIGINAL ARTICLE
Efficacy of surgical microwave ablation for recurrent hepatocellular carcinoma after curative hepatectomy Tomoki Ryu, Yuko Takami, Yoshiyuki Wada, Takanobu Hara, Shin Sasaki & Hideki Saitsu Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
Abstract Background: Little evidence exists regarding postrecurrence survival after microwave ablation for recurrent hepatocellular carcinoma (HCC) after curative hepatectomy; we aimed to evaluate the feasibility of surgical microwave ablation. Methods: In this retrospective review, we enrolled patients who underwent curative hepatectomy for primary HCC in our department and had intrahepatic recurrence. We analyzed overall survival according to treatment modality to clarify the prognostic factors for survival. Results: Of 257 patients, 119 had intrahepatic recurrence. Three patients underwent repeat hepatectomy; 75 patients underwent surgical microwave ablation, and 34 patients underwent transcatheter arterial chemoembolization or hepatic arterial infusion chemotherapy. The median postrecurrence survival time and 5-year postrecurrence survival after surgical microwave ablation were 37.4 months and 55.4%, respectively. The major complication rate (Clavien–Dindo classification IIIa or above) after surgical microwave ablation was 5.3% with no mortality. Multivariate analysis showed that microvascular invasion at primary tumors, and recurrent tumors within 3 cm and 3 nodules were independent prognostic factors for overall survival after surgical microwave ablation for recurrent HCC. Conclusion: Our results suggested that surgical microwave ablation is safe and feasible for recurrent intrahepatic HCC after curative hepatectomy. Close follow-up and further curative treatment could be important for improving postrecurrence survival. Received 4 April 2019; accepted 6 August 2019
Correspondence Tomoki Ryu, Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama Chuo-ku, Fukuoka 810-8563, Japan. E-mail: ryu.tomoki.mq@mail. hosp.go.jp
Introduction Hepatic resection is considered as the first line of curative treatment for hepatocellular carcinoma (HCC).1 Nevertheless, the recurrence rate after curative hepatectomy is high, with cumulative 5-year recurrence rates >60%.2 Therefore, we must understand how to manage and treat recurrent HCC for improving survival in patients with HCC after curative hepatectomy. Salvage liver transplantation is theoretically recognized the best choice for recurrent HCC, as it removes both recurrent tumors and the cirrhotic liver.3 However, its application has been limited by the shortage of donors, especially in some countries
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with limited availability of livers for transplantation. Repeat hepatectomy is also reported as an effective approach for recurrent HCC,4 although only about 20% of patients with recurrent HCC are eligible for repeat hepatectomy, because of small liver volume, poor liver function reserve, the multiple recurrent tumors, and the presence of postoperative adhesion.5 Given the small population of patients with recurrent HCC who are suitable for repeat hepatectomy, alternative treatment options are required. In recent years, local ablation therapy, such as radiofrequency ablation (RFA) and microwave ablation, has been attracting attention as a therapeutic strategy for small primary HCC or liver cirrhosis.6–8 In addition to a large number of studies about local
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ablation therapy for primary HCC, a recent systematic review focused on local ablation therapy for recurrent HCC have reported that RFA was an effective option for patients with recurrent HCC.9 However, little evidence is available regarding long-term outcomes after microwave ablation for recurrent HCC after curative hepatectomy. The aim of this study was to assess the safety and efficacy of microwave ablation for recurrent HCC and to identify the prognostic factors of intrahepatic recurrent HCC after initial hepatectomy.
Methods Patients In this study, we retrospectively analyzed a total of 257 consecutive patients who underwent curative hepatectomy for primary HCC from July 1994 to December 2017 in our department. Patients with recurrent HCC were selected for further analysis. Curative hepatectomy was defined as complete macroscopic removal of the tumor, where the resection margin was negative and no detectable intrahepatic or extrahepatic metastatic lesions remained. At the time of the data analysis, 118 patients remained free of recurrence, and 139 patients had recurrence postoperatively. Of the 139 patients who recurred, 20 patients had developed extrahepatic recurrence, and the remaining 119 patients who had developed intrahepatic recurrence were enrolled in this study. Among the 119 patients with intrahepatic recurrence, three patients underwent repeat hepatectomy, 75 patients
underwent surgical microwave ablation [microwave coagulonecrotic therapy (MCN)], and 34 patients underwent transcatheter arterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) as the secondary treatment for the recurrent tumors (Fig. 1). Prospectively collected data on patient characteristics, clinicopathologic features, and survival outcomes were reviewed. The diagnosis of HCC was confirmed according to histopathological diagnosis after initial hepatectomy. Gross classification of the nodular type and tumor differentiation were defined based on the General Rules for the Clinical and Pathological Study of Primary Liver Cancer developed by the Liver Cancer Study Group of Japan.10 Liver cirrhosis was defined as grade 4 fibrosis on specimen pathology. All patients were followed until death or March 2019. This study was conducted in accordance with the Declaration of Helsinki and the ethical guidelines for clinical studies of the Ministry of Health, Labour, and Welfare in Japan. The study protocol was approved by the Ethics Committee on Clinical Investigations of Kyushu Medical Center. Follow-up and diagnosis for recurrent HCC All patients received contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the liver within one months after initial hepatectomy for primary HCC to confirm macroscopic tumor clearance. Thereafter, patients were followed postoperatively every 2–3 months with ultrasound and blood chemistry evaluations, including three tumor markers:
Figure 1 Flowchart of patients included in this study. HCC, hepatocellular carcinoma; MCN, microwave coagulo-necrotic therapy; TACE,
transcatheter arterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy
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alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-g-carboxy prothrombin (DCP). Contrast-enhanced CT or MRI was performed every 4–6 months. Intrahepatic recurrence was defined as a new lesion with arterial contrast enhancement and portal venous washout on contrast-enhanced CT or MRI scans with or without elevated serum tumor markers. Treatment strategy for recurrent HCC When recurrent tumors were found, repeat hepatectomy or MCN was again attempted after considering liver function, and tumor status (i.e. the size, number, and location) of each patient.
Both repeat hepatectomy and MCN were performed by the same surgical team of dedicated liver surgeons led by at least one consultant specialist. In our hospital, MCN was preferentially considered to treat for recurrent HCC 3 cm, whereas repeat hepatectomy was performed in selected patients only when recurrent tumors were located on surface or edge of the liver. Repeat hepatectomy was attempted for recurrent HCC >3 cm, although MCN was a secondary consideration for patients with small liver volume, poor liver function reserve, or poor performance status. As for the number of recurrent tumors, we usually attempted MCN for five tumors or fewer, and we also considered MCN for tumors that were more than 5 mm away from the
Table 1 Clinicopathological characteristics at initial hepatectomy
Characteristic
HCC recurrence (n [ 139)
No recurrence (n [ 118)
P-value
70 (42–88)
73 (42–87)
0.056
Background characteristics Age, years, median (range) Sex, male, n (%)
109 (78%)
86 (73%)
0.302
Hepatitis B virus infection, n (%)
19 (14%)
22 (18%)
0.279
Hepatitis C virus infection, n (%)
78 (56%)
45 (38%)
0.004
Albumin, g/dL, median (range)
4.0 (3.0–5.5)
4.1 (2.5–5.0)
0.005
Total bilirubin, mg/dL, median (range)
0.7 (0.3–2.3)
0.7 (0.1–2.3)
0.068
Prothrombin activity, %, median (range)
88 (18–137)
92 (12–139)
0.059
ICGR15, %, median (range)
18.9 (0.6–66.4)
16.6 (0.6–91.8)
0.046
Platelets, × 10 /mL, median (range)
16.6 (4.9–27.8)
18.6 (4.5–49.9)
0.057
Child-Pugh class, A, n (%)
135 (97%)
110 (93%)
0.138
AFP, ng/mL, median (range)
12 (0–89437)
7 (0.9–71771)
0.030
DCP, mAU/mL, median (range)
497 (0–1623100)
60 (0–349000)
<0.001
Tumor Size, mm, median (range)
49.4 (10.4–180)
35.1 (14.2–250)
<0.001
Number of tumors, single, n (%)
115 (83%)
110 (95%)
0.003
Macroscopic vascular invasion, n (%)
10 (7%)
2 (2%)
0.044
102 (74%)
87 (73%)
0.950 0.690
4
Tumor related factors
Surgical factors Type of hepatectomy, anatomical, n (%) Operating time, min, median (range)
198 (51–425)
198 (49–511)
Blood loss, g, median (range)
251 (1–6235)
210 (1–7900)
0.117
Intraoperative blood transfusion, n (%)
15 (11%)
6 (5%)
0.094
Morbidity, n (%)
33 (24%)
10 (9%)
<0.001
Complication of Clavien-Dindo grade IIIA or above, n (%)
16 (12%)
6 (5%)
0.044
Postoperative hospital stays, days, median (range)
14 (7–77)
12 (8–75)
0.010
Pathological factors Gross type, SN with EG or CM, n (%)
82 (59%)
54 (46%)
0.028
Histological grade, poorly differentiated, n (%)
31 (22%)
30 (25%)
0.547
Microscopic vascular invasion, n (%)
82 (60%)
61 (52%)
0.245
Intrahepatic metastasis, n (%)
34 (25%)
2 (2%)
<0.001
Liver cirrhosis, n, (%)
34 (24%)
21 (18%)
0.223
ICGR15, indocyanine green retention rate at 15 min; AFP, alpha fetoprotein; DCP, des-gamma carboxyprothrombin; SN, simple nodular type; SN with EG, simple nodular with extranodular growth type; CM, confluent multinodular type.
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major Glissonean pedicles. If MCN or repeat hepatectomy was considered unsuitable to treat because of impaired liver function, multiple recurrences, or the risk of bile duct injury, we performed TACE or HAIC.
ablation area was evaluated by dynamic CT 1–2 weeks after treatment. Perioperative morbidities were stratified by severity based on the Clavien–Dindo classification13; major complications were considered grade III or above.
MCN procedures MCN procedures were performed as previously reported.11,12 We have performed MCN as curative surgical microwave ablation for primary or recurrent HCC since 1994, and the procedure is wellestablished. We used a 2450-MHz system microwave generator (Alfresa Pharma, Osaka, Japan). MCN repeats electrode insertion and irradiation from the tumor edge to the tumor center to avoid increasing intratumoral pressure and to obtain an adequate ablation margin of 10 mm outside the tumor margin. We performed MCN for recurrent HCC as an open approach, such as laparotomy or thoracotomy, with routine intraoperative ultrasound to identify lesions and monitor treatment effect. The
Statistical analysis Continuous variables were presented as median (range) and compared using the Mann–Whitney U test. Categorical variables were compared using Fisher’s exact probability method or c2 tests. Overall survival was defined as the interval from surgery to death or the date of the last or most recent follow-up visit. Recurrence-free survival was defined as the interval from surgery to the date of diagnosis of the first recurrence or last follow-up. Overall survival after recurrence was defined as the period from the date of treatment for the recurrence to the date of death or the date of the last or most recent follow-up visit. All patients were followed until death or March 2019. Overall survival and
Figure 2 Long-term survival outcomes after curative hepatectomy; (a) overall survival and (b) recurrence-free survival rates
Figure 3 Overall survival rates after recurrence (a) all 119 patients with intrahepatic recurrence, (b) according to treatment for recurrent tumors.
MCN, microwave coagulo-necrotic therapy; TACE, transcatheter arterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy
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Table 2 Comparison of clinical characteristics among MCN, and TACE or HAIC groups
MCN (n [ 75)
TACE or HAIC (n [ 34)
P-value
Age, years, median (range)
69 (42–86)
70 (51–84)
0.384
Hepatitis B virus infection, n (%)
14 (19%)
4 (12%)
0.356
Hepatitis C virus infection, n (%)
43 (57%)
24 (70%)
0.183
ICGR15, %, median (range)
20.3 (0.6–66.4)
16.4 (6.4–49.5)
0.648
AFP, ng/mL, median (range)
12 (0–25314)
15 (1.7–89437)
0.412
DCP, mAU/mL, median (range)
478 (0–62000)
468 (0–140000)
0.609
Maximum tumor size, mm, median (range)
44.8 (15.0–180)
60.5 (10.4–180)
0.031
Number of tumors, single, n (%)
63 (84%)
25 (76%)
0.319
Macroscopic vascular invasion, n (%)
5 (7%)
2 (2%)
0.986
Type of hepatectomy, anatomical, n (%)
49 (65%)
29 (85%)
0.026
Gross type, SN with EG or CM, n (%)
38 (51%)
15 (44%)
0.746
Histological grade, poorly differentiated, n (%)
10 (13%)
8 (25%)
0.178
Microscopic vascular invasion, n (%)
39 (52%)
26 (76%)
0.040
Intrahepatic metastasis, n (%)
15 (21%)
12 (35%)
0.141
Liver cirrhosis, n, (%)
17 (23%)
9 (26%)
0.253
Early recurrence (2 years), n (%)
33 (44%)
26 (76%)
0.001
Albumin, g/dL, median (range)
3.9 (2.4–5.2)
3.8 (3.0–4.5)
0.066
Total bilirubin, mg/dL, median (range)
0.8 (0.3–2.3)
0.7 (0.3–2.5)
0.342
Prothrombin activity, %, median (range)
88 (40–117)
85 (52–111)
0.269
Platelets, × 104/mL, median (range)
15.2 (4.0–30.4)
14.8 (5.5–34.0)
0.269
Child-Pugh class, A, n (%)
62 (84%)
27 (79%)
0.537
Maximum tumor size, mm, median (range)
22 (10–53)
16 (10–35)
0.001
62 (83%)
30 (88%)
0.107
Single
35 (47%)
3 (9%)
2-3
26 (34%)
6 (15%)
>3
14 (19%)
26 (76%)
Within 3 cm and 3 nodules
50 (67%)
6 (18%)
<0.001
AFP, ng/mL, median (range)
7.2 (0.9–8554)
14 (1.6–970112)
0.007
DCP, mAU/mL, median (range)
31 (9–53100)
83 (10–65400)
0.093
Local recurrence, n (%)
5 (4%)
2 (6%)
0.493
Characteristic Factors at initial resection
Factors at recurrence
3 cm, n (%) Number of tumors, n (%)
<0.001
MCN, microwave coagulo-necrotic therapy; TACE, transcatheter arterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy; AFP, alpha fetoprotein; DCP, des-gamma carboxyprothrombin.
recurrence-free survival curves were calculated using the Kaplan–Meier method and compared using the log-rank test. We used a Cox proportional hazards model for univariate and multivariate analyses of the prognostic factors related to survival after treatment for recurrence. All P-values were derived from two-tailed tests, with P < 0.05 considered statistically significant. All statistical analyses were performed using JMP 12 software (SAS Institute, Inc., Cary, NC, USA).
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Results During the study period, 257 patients underwent curative hepatectomy for primary HCC. Clinicopathological data at initial hepatectomy for the entire cohort are listed in Table 1. The median follow-up time was 54.1 months (range, 5.2–259.4) and Kaplan–Meier analysis showed that the 5-, and 10-year overall survivals after initial hepatectomy were 68.6%, and 53.4%, respectively (Fig. 2a). Of the 257 patients resected, 139 (54%)
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developed recurrence. The 5-, and 10-year recurrence-free survivals after initial hepatectomy were 44.5%, and 34.3%, respectively (Fig. 2b). The median time from initial hepatectomy to recurrence was 24.5 months. Among patients who had recurrence, 119 patients (86%) had intrahepatic recurrences and 20 patients (14%) had isolated extrahepatic recurrences. In the 119 patients who had intrahepatic recurrences, the median survival time after recurrence was 26.1 months. The 1-, 3-, and 5-year survivals after recurrence were 81.0%, 52.1%, and 41.6%, respectively (Fig. 3a). Among the 119 patients with intrahepatic recurrence, 75 patients (63%) underwent MCN, 34 patients (28%) underwent TACE or HAIC, three patients (3%) underwent repeat hepatectomy, and seven patients (6%) underwent other therapies for recurrent HCC. Clinicopathological characteristics of the MCN group and the TACE or HAIC group are listed in Table 2. In the MCN group, 33 patients (44%) experienced early recurrence (within 2 years after surgery). Median recurrent tumor size was 22 mm (range, 10–53), and 83% of the recurrent tumor size were 3 cm or smaller in the MCN group. In the MCN group, 35 patients (47%) had a single tumor, and the proportion of patients with recurrent tumor within 3 cm and 3 nodules was 67% in the MCN group. Overall survival rates after recurrence according to the treatment modalities for recurrent HCC were shown in Fig. 3b. The median survival time, and the 1-, 3-, and 5-year overall survival
rates after recurrence were 37.4 months, and 93.1%, 68.5%, and 55.4%, respectively in the MCN group. The median survival time, and the 1-, 3-, and 5-year overall survival rates after recurrence were 17.5 months, and 61.8%, 25.0%, and 21.4%, respectively in the TACE or HAIC group (P < 0.001). Perioperative outcomes of patients who underwent MCN for recurrent HCC are summarized in Table 3. Among the 75 patients who underwent MCN, 40 patients (53%) underwent MCN via laparotomy, with 35 patients (47%) via thoracotomy. Two patient required intraoperative platelet transfusion: patients with a platelet count <4.0 × 104/mL secondary to severe liver cirrhosis. No patients required red blood cell transfusions for intraoperative blood loss. Major complications were experienced by four patients (5.3%; two wound infection, one pleural effusion, and one intra-abdominal abscesses), though Clavien–Dindo grade IV or V complications did not occur. The univariate and multivariate analyses we used to identify prognostic factors affecting overall survival after MCN for recurrent HCC are shown in Table 4. Multivariate analyses showed that microvascular invasion at the primary tumor (hazard ratio [HR]: 3.50, 95% confidence interval [95% CI]: 1.41–9.29; P = 0.007), and recurrent tumors within 3 cm and 3 nodules (HR: 0.41, 95% CI: 0.17–0.92; P = 0.050), were independent prognostic factors for overall survival after MCN for recurrent HCC.
Discussion Table 3 Perioperative characteristics of 75 patients who underwent
MCN for recurrent HCC n [ 75
Characteristics Approach Laparotomy, n (%)
40 (53%)
Thoracotomy, n (%)
35 (47%)
Operating time, min, median (range)
89 (46–232)
Blood loss, g, median (range)
5 (1–461)
Intraoperative blood transfusion, n (%)
2 (3%)
Postoperative morbidities, n (%)
8 (11%)
Wound infection
2
Pleural effusion
2
Intra-abdominal abscess
1
Ascites
1
Hepatic infarction
1
Portal thrombosis
1
Clavien-Dindo classification II
4
IIIa
4
IIIb
0
IV
0
V
0
Postoperative hospital stays, days, median (range)
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11 (4–42)
This study investigated the feasibility of surgical microwave ablation for recurrent HCC after curative hepatectomy. Our study revealed that majority (63%) of patients with intrahepatic recurrence after initial hepatectomy were eligible for surgical microwave ablation, with the 5-year post-recurrence survival rate of 55%. We suggest that long-term survival is possible with microwave ablation for recurrent HCC after curative hepatectomy. Few studies are large enough and include long-term outcome of microwave ablation for recurrent HCC after hepatectomy. To the best of our knowledge, the current study is one of the largest cohort studies to evaluate the long-term outcome of microwave ablation for recurrent HCC after curative hepatectomy. No consensus has been reached as to the most appropriate treatment for recurrent HCC after curative treatment, while the treatment strategy for recurrent HCC varies from center to center all over the world. Though there are no randomized control trials comparing the various treatment modalities for recurrent HCC, retrospective cohort studies of comparing repeat hepatectomy and RFA have been increasing in recent years.14–17 In the majority of studies, no significant differences have been reported between the two groups, with the reported 5-year survival after repeat hepatectomy and RFA for recurrent HCC of 28–72% and 29–83%, respectively.14–17 A recent systematic review of 19 retrospective series that focused on ablation for
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Table 4 Univariate and multivariate analyses of survival after MCN for recurrent HCC (n = 75)
Variables
Univariate analysis HR
Multivariate analysis
95% CI
P-value
HR
95% CI
P-value
1.86
0.87–4.22
0.114
1.37
0.64–2.92
0.415
3.50
1.41–9.29
0.007
1.66
0.63–4.52
0.307
Factors at initial resection Age 70 years
1.31
0.67–2.54
0.422
Hepatitis C virus
2.24
1.12–4.75
0.021
Child-Pugh B
1.07
0.06–5.12
0.944
Platelet count < 10 × 104/mL
1.23
0.32–8.07
0.781
ICGR15 15%
1.26
0.63–2.45
0.505
Maximum tumor size 5 cm
1.85
0.96–3.55
0.065
Multiple nodule
1.26
0.51–2.70
0.598
Anatomical hepatectomy
1.03
0.52–1.98
0.928
SN with EG or CM
1.25
0.64–2.50
0.518
Poorly differentiated
2.58
0.78–15.9
0.132
Microscopic vascular invasion
3.29
1.58–7.14
0.001
Liver cirrhosis
1.18
0.55–2.95
0.684
Time to recurrence <2 years
2.77
1.43–5.53
0.002
Child-Pugh B
1.90
0.81–3.99
0.133
Platelet count < 10 × 104/mL
2.07
0.88–4.37
0.092
Within 3 cm and 3 nodules
0.35
0.18–0.69
0.002
0.41
0.17–0.92
0.032
AFP 20 ng/mL
2.14
1.05–4.21
0.037
2.18
0.92–5.09
0.077
DCP 40 mAU/mL
2.04
1.06–3.94
0.032
1.37
0.52–3.61
0.518
Factors at recurrence
HR, hazards ratio; CI, confidence interval; ICGR15, indocyanine green retention rate at 15 min. AFP, alpha fetoprotein; DCP, des-gamma carboxyprothrombin.
recurrent HCC revealed that 5-year survival rates after RFA for recurrent HCC was 40% (range 23–83%).9 However, they also concluded that there was insufficient date to analyze survival outcomes after microwave ablation. In addition, there have been no studies comparing RFA and microwave ablation for recurrent HCC to date. In this study, the 5-year post-recurrence survival after microwave ablation for recurrent HCC was 55.4%, which is comparable to results reported previously for both repeat hepatectomy and RFA. Microwave ablation has received attention as a curative treatment for HCC in recent years.8,18 There are theoretically some advantages to microwave ablation over RFA; faster ablation times, larger ablation zones, higher intratumoral temperature, and more complete coagulative necrosis.18 Several previous studies have reported microwave ablation was as effective as RFA for primary HCC when comparing local recurrence rates and long-term survival,19,20 with the reported 5-year overall survival of 43%–60%.21–25 We have performed surgical microwave ablation, termed microwave coagulo-necrotic therapy (MCN), for both primary and recurrent HCC for more than 20 years, and previously reported its feasibility and oncological long-term outcomes.11,26,27 Our previous report of the 5-year overall survival rate was 62% in 719 patients who underwent MCN for primary HCC.11 The 5-year survival of 55% in this study is
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comparable to that reported after microwave ablation for primary HCC. We also analyzed the perioperative outcome of MCN for recurrent HCC after initial hepatectomy. The major complication rate was 5.3%, with no procedure-related deaths in MCN for recurrent HCC in this study. These findings suggest that MCN is safe and feasible procedure for patients with recurrent HCC after curative hepatectomy. Another important finding in this study was that we sought to determine the prognostic factors that associated with overall survival after MCN for recurrent HCC. In our multivariate analysis, microvascular invasion at primary tumors, and recurrent tumors within 3 cm and 3 nodules were independent prognostic factors for survival after MCN for recurrent HCC. Intrahepatic recurrence after curative hepatectomy is generally classified into two types: intrahepatic metastasis from primary tumors or multicentric carcinogenesis of new tumors resulting from chronic hepatitis or cirrhosis.28 In previous studies, intrahepatic metastasis occurred mainly within 2 years after surgery, while multicentric carcinogenesis mainly occurred more than 2 years after surgery.29 Microvascular invasion is recognized as a risk factor for early recurrence (i.e., intrahepatic metastasis), after curative hepatectomy.30 In this study, TACE or HAIC tended to be chosen for recurrent HCC with early recurrence or microvascular invasion at primary tumors, which were thought
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to be intrahepatic metastasis from primary tumors. On the other hand, a recent single-center cohort study reported that recurrent HCC more than 18 months after hepatectomy is mainly a result of multicentric carcinogenesis, and repeat hepatectomy in such cases yielded favorable survival.31 Nevertheless, only about 20% of patients with recurrent HCC are eligible for repeat hepatectomy, because of small liver volume, poor liver function reserve, the multiple recurrent tumors, and the presence of postoperative adhesion.5 In this study, we performed surgical microwave ablation in more than 60% of patients with intrahepatic recurrence after initial hepatectomy. It must be emphasized that more than 80% of recurrent tumors could be detected less than 3 cm in this study. These findings suggest that primary tumors without microvascular invasion and recurrent tumors within 3 cm and three nodules can be good indications for surgical microwave ablation for recurrent HCC. Although further studies are needed to precisely determine the indication for surgical microwave ablation for recurrent HCC, close follow-up and early detection in the early stage of recurrence could be important for patients to undergo curative treatment for recurrent HCC. There were some limitations in this study. First, the retrospective study is prone to potential bias. Second, this study was based on a review from a single-institution and might not represent findings in other centers. Third, the study included a limited number of patients who performed repeat hepatectomy for recurrent HCC, meaning that we could not compare perioperative and oncological outcomes between repeat hepatectomy and MCN for recurrent HCC. Despite these limitations, we believe that our results may be clinically informative and could be an indicator for the future analysis of microwave ablation for recurrent HCC. In conclusion, this study investigated the feasibility of surgical microwave ablation for recurrent HCC after curative hepatectomy. Our results suggested that surgical microwave ablation was safe and feasible treatment for recurrent HCC after curative hepatectomy. In particular, primary tumors without microvascular invasion and recurrent tumors within 3 cm and three nodules were good indications for surgical microwave ablation for recurrent HCC. Close follow-up and further curative treatment for recurrent HCC could be important for improving post-recurrence survival in patients with HCC after curative hepatectomy.
Analysis and interpretation of data: Ryu, Takami, and Saitsu. Drafting of manuscript: Ryu. Critical revision: Takami, and Saitsu. Grant support None. Conflict of interest statement None declared. References 1. Takayama T, Makuuchi M, Hirohashi S, Sakamoto M, Yamamoto J, Shimada K et al. (1998) Early hepatocellular carcinoma as an entity with a high cure rate of surgical cure. Hepatology 28:1241–1246. 2. Llovet JM, Schwartz M, Mazzaferro V. (2005) Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis 25: 181–200. 3. Hwang S, Lee SG, Moon DB, Ahn CS, Kim KH, Lee YJ et al. (2007) Salvage living donor liver transplantation after prior liver resection for hepatocellular carcinoma. Liver Transplant 13:741–746. 4. Minagawa M, Makuuchi M, Takayama T, Kokudo N. (2003) Selection criteria for repeat hepatectomy in patients with recurrent hepatocellular carcinoma. Ann Surg 238:703–710. 5. Chan DL, Morris DL, Chua TC. (2013) Clinical efficacy and predictors of outcomes of repeat hepatectomy for recurrent hepatocellular carcinoma—a systematic review. Surg Oncol 22:23–30. 6. Tateishi R, Shiina S, Teratani T, Obi S, Sato S, Koike Y et al. (2005) Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases. Cancer 103:1201–1209. 7. Lau WY, Lai EC. (2009) The current role of radiofrequency ablation in the management of hepatocellular carcinoma: a systematic review. Ann Surg 249:20–25. 8. Liang P, Wang Y. (2007) Microwave ablation of hepatocellular carcinoma. Oncology 72:124–131. 9. Thomasset SC, Dennison AR, Garcea G. (2015) Ablation for recurrent hepatocellular carcinoma: a systematic review of clinical efficacy and prognostic factors. World J Surg 39:1150–1160. 10. Liver Cancer Study Group of Japan. (2010) General Rules for the clinical and pathological study of primary liver cancer, 3rd English ed. Tokyo: Kanehara Shuppan. 11. Takami Y, Ryu T, Wada Y, Saitsu H. (2013) Evaluation of intraoperative microwave coagulo-necrotic therapy (MCN) for hepatocellular carcinoma: a single center experience of 719 consecutive cases. J HepatoBiliary-Pancreatic Sci 20:332–341. 12. Ryu T, Takami Y, Tsutsumi N, Tateishi M, Mikagi K, Wada Y et al. (2017) Simultaneous microwave coagulo-necrotic therapy (MCN) and laparo-
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© 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.
Please cite this article as: Ryu T et al., Efficacy of surgical microwave ablation for recurrent hepatocellular carcinoma after curative hepatectomy, HPB, https:// doi.org/10.1016/j.hpb.2019.08.001