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Liver Resection versus Radiofrequency Ablation plus Transcatheter Arterial Chemoembolization in Cirrhotic Patients with Solitary Large Hepatocellular Carcinoma
CLINICAL STUDY
Liver Resection versus Radiofrequency Ablation plus Transcatheter Arterial Chemoembolization in Cirrhotic Patients with Solitary Large Hepatocellular Carcinoma Antonio Saviano, MD, Roberto Iezzi, MD, Felice Giuliante, MD, Lucia Salvatore, MD, Caterina Mele, MD, Alessandro Posa, MD, Francesco Ardito, MD, Anna Maria De Gaetano, MD, and Maurizio Pompili, MD; HepatoCATT Study Group ABSTRACT Purpose: To compare liver resection (LR) with single-step, balloon-occluded RF ablation plus drug-eluting embolics transarterial chemoembolization in cirrhotic patients with single hepatocellular carcinoma (HCC) 3 cm. Materials and Methods: From 2010 to 2014, 25 patients with compensated cirrhosis and single HCC 3 cm (median size 4.5 cm; range, 3.0–6.8 cm) not suitable for LR or liver transplantation were treated with RF ablation plus transarterial chemoembolization in a prospective observational single-center pilot study; all patients had complete tumor necrosis after treatment. A retrospective control group included 29 patients (median HCC size 4.0 cm; range, 3.0–7.4 cm) who underwent LR. RF ablation plus transarterial chemoembolization group included more patients with severe portal hypertension (65.5% vs 35.0%, P ¼ .017). Primary endpoints were overall survival (OS) and tumor recurrence (TR) rates. Results: One death and 1 major complication (4%) were observed in LR group. No major complications were reported in RF ablation plus transarterial chemoembolization group (P ¼ .463). OS rates at 1 and 3 years were 91.8% and 79.3% in LR group and 89.4% and 48.2% in RF ablation plus transarterial chemoembolization group (P ¼ 0.117). TR rates at 1 and 3 years were 29.5% and 45.0% in LR group and 42.4% and 76.0% in RF ablation plus transarterial chemoembolization group (P ¼ .034). Local tumor progression (LTP) rates at 3 years were significantly lower in LR group (21.8% vs 58.1%, P ¼ .005). Similar results were found in patients with HCC 5 cm (TR rates 35.4% vs 75.1%, P ¼ .016; LTP 16.0% vs 55.7%, P ¼ .013). Conclusions: LR achieved lower TR and LTP rates than RF ablation plus transarterial chemoembolization, but 3-years OS rates were not statistically different between the 2 groups. RF ablation plus transarterial chemoembolization is an effective treatment option in patients with compensated cirrhosis and solitary HCC 3 cm unsuitable for LR.
ABBREVIATIONS HCC ¼ hepatocellular carcinoma, LR ¼ liver resection, LTP ¼ local tumor progression, MW ¼ microwave, OS ¼ overall survival
Liver resection (LR) represents the mainstay of treatment for solitary hepatocellular carcinoma (HCC) > 3 cm unsuitable for liver transplantation (1). However, the feasibility and long-term effectiveness of LR are affected by liver function From the Department of Internal Medicine and Gastroenterology (A.S., L.S., M.P.), Department of Bioimaging and Radiological Sciences (R.I., A.P., A.M.D.), Institute of Radiology, and Hepatobiliary Surgery Unit (F.G., C.M., F.A.), Department of Surgical Sciences, “A. Gemelli” Hospital, Catholic University of Rome, Largo F. Vito 1, Rome 00168, Italy. Received January 18, 2017; final revision received and accepted June 9, 2017. Address correspondence to M.P.; E-mail: [email protected]
and alternative therapies are needed for patients with compensated cirrhosis and contraindication to surgery (1,2). Radiofrequency (RF) ablation provides excellent results in lesions up to 3 cm in size but is less effective in larger None of the authors have identified a conflict of interest. © SIR, 2017 J Vasc Interv Radiol 2017; ▪:1–8 http://dx.doi.org/10.1016/j.jvir.2017.06.016
2 ▪ Liver Resection vs RF Ablation plus Chemoembolization in HCC
lesions (3,4). Transarterial chemoembolization is considered a palliative treatment, as complete tumor necrosis is rarely attained—as shown in explants analysis of HCC treated before liver transplantation—and it is associated with high tumor recurrence rates (5). This is the reason why combinations of these techniques have been used, showing better results than RF ablation or transarterial chemoembolization alone in achieving tumor necrosis and higher survival rates (6–8). The efficacy of the combination of RF ablation plus transarterial chemoembolization compared with LR in patients with cirrhosis and single HCC 3 cm is still a matter of debate, as only a few studies addressing this issue with controversial results are available (9,10). Hence, the aim of this study was to evaluate the effectiveness and the safety of LR versus single-step, balloon-occluded RF ablation plus transarterial chemoembolization in patients with cirrhosis and single HCC 3 cm.
MATERIALS AND METHODS Study Design This study was approved by the institutional review board and was performed in agreement with the 1990 Declaration of Helsinki and subsequent amendments. Written informed consent was obtained from all patients. The study enrolled patients with cirrhosis and single HCC 3 cm who were included in an observational prospective single-center pilot study designed to assess effectiveness and safety of singlestep combined therapy of RF ablation plus drug-eluting embolics transarterial chemoembolization. A cohort of cirrhotic patients who underwent LR whose data were collected retrospectively served as control group. All patients were > 18 years old and fulfilled the following inclusion criteria: (a) liver cirrhosis classified as Child-Pugh score A, (b) single large HCC 3–8 cm, (c) no vascular invasion or extrahepatic metastases on sectional studies performed before treatment, (d) detection of complete tumor necrosis 1 month after RF ablation plus transarterial chemoembolization session. Exclusion criteria were the following: (a) liver cirrhosis classified as Child-Pugh score B or C, (b) diuretic-resistant ascites, (c) platelet count < 40,000/μL for LR group, (d) platelet count < 40,000/μL for RF ablation plus transarterial chemoembolization group if a prophylactic platelet transfusion before treatment was not able to raise the platelet count to 40,000/μL, and (e) chronic kidney disease stage 4 or stage 5 not on hemodialysis for RF ablation plus transarterial chemoembolization group. All patients who underwent RF ablation plus transarterial chemoembolization had been excluded from LR after multidisciplinary evaluation because of 1 of the following reasons: requirement of major resection in patients with severe portal hypertension (defined as presence of esophageal varices F2 or gastric varices, splenomegaly with platelet count < 100,000/mL, or actual ascites or previous ascites successfully treated with diuretics), surgery unfeasible or hazardous owing to lesion location, concurrent severe comorbidities, or patient refusal.
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Workup before Treatment and Patients’ Clinical and Demographic Characteristics The workup before treatment in both RF ablation plus transarterial chemoembolization and LR groups consisted of physical examination; laboratory tests; and imaging studies including liver ultrasound (US), radionuclide bone scan, and dynamic contrast-enhanced computed tomography (CT) of thorax and abdomen. Cirrhosis was diagnosed by histologic and/or clinical criteria (laboratory parameters, US and/or CT signs). Severe portal hypertension was diagnosed in the presence of 1 of the above-mentioned criteria excluding patients from major LR. Diagnosis of HCC was based on the guidelines in force at the time of study enrollment (1). Patients were treated between January 2010 and December 2014. The LR group included 25 patients. During the enrollment period, 33 patients with compensated cirrhosis and solitary HCC 3 cm were treated with RF ablation plus transarterial chemoembolization; 4 patients (12.1%) were excluded because complete tumor necrosis was not achieved. Hence, the RF ablation plus transarterial chemoembolization group included 29 patients. Clinical features of patients are listed in Table 1. All patients with mild ascites were treated successfully with diuretic therapy before treatment. The RF ablation plus transarterial chemoembolization group also included 1 patient on hemodialysis and 1 patient with a platelet count of 19,000/μL who underwent platelet transfusion before the treatment. Eight patients in the RF ablation plus transarterial chemoembolization group (24.2%) and 6 patients in the LR group (20.6%) had been previously treated with other locoregional procedures (ie, transarterial chemoembolization, RF ablation, and percutaneous ethanol injection) without achieving complete necrosis (P ¼ .121).
RF Ablation plus Transarterial Chemoembolization Protocol All combined treatments were performed by the same interventional radiologist (R.I.) with 14 years of experience. A single-step combination approach was used (11). Hepatic angiography using a 6-F guiding catheter (curved C1 or C2, 65 cm in length) was performed through a right common femoral approach to map liver vascular anatomy, arterial tumor supply, and eventual arteriovenous shunts. A 0.014-inch guide wire (ChoICE; Boston Scientific, Marlborough, Massachusetts) and a low-profile monorail percutaneous transluminal angioplasty balloon (4–5 20 mm, Muso; Terumo Corp, Tokyo, Japan) were advanced into the segmental hepatic artery feeding the lesion. An internally cooled RF electrode with a 3-cm exposed tip (Cool-tip RF Ablation System; Medtronic, Minneapolis, Minnesota) was introduced into the nodule using US guidance. The angioplasty balloon in the segmental hepatic artery was filled with saline solution and contrast material until vascular occlusion was achieved. The RF generator was activated to maintain a temperature of 90 –115 C at the exposed tip for 12 minutes. At the end of the procedure, the RF electrode was withdrawn, the occlusion
Volume ▪ ▪ Number ▪ ▪ Month ▪ 2017
3
Table 1. Demographic and Clinical Characteristics of Enrolled Patients Variable
LR (n ¼ 25)
RF Ablation plus Transarterial Chemoembolization (n ¼ 29)
P Value
Age, y
72 (45–80)
67 (47–83)
Male sex (%)
22 (88.0)
25 (86.2)
1.000
.184
Anti-HCV positive (%)
.106
15 (60.0)
11 (37.9)
HBsAg positive (%)
2 (8.0)
5 (17.2)
.431
Alcohol abuse (%) Other etiology of cirrhosis (%)
4 (16.0) 4 (16.0)
11 (37.9) 4 (13.8)
.073 1.000
Portal hypertension (%)
8 (32.0)
19 (65.5)
.017
Portal vein thrombosis (%)
1 (4.0)
4 (13.8)
.358
Platelet count, 109/L Mild ascites (%)
121 (60–312) 0 (0.0)
107 (19–294)
.286
4 (13.8)
.115
Total bilirubin, mg/dL
0.8 (0.29–1.33)
0.84 (0.20–2.21)
.572
Albumin, g/dL
4.0 (3.1–4.8)
3.85 (2.8–4.7)
.093
0.87 (0.40–11.00) 9 (6–20)
.456 .252
Creatinine, mg/dL MELD score ALT, IU/L AFP, ng/mL
0.94 (0.64–1.52) 8 (6–18) 35 (22–136)
27 (8–162)
.010
8 (3–6,235)
8 (2–378)
.725
Tumor size, cm
4.5 (3.0–7.4)
4.0 (3.0–6.8)
HCC > 5 cm (%)
.121
10 (40.0)
6 (20.7)
.138
Previous HCC treatment (%)
10 (40.0)
6 (20.7)
.121
Note–Continuous variables were reported as median (range). AFP ¼ alpha fetoprotein; ALT ¼ alanine aminotransferase; Anti-HCV ¼ antibody to hepatitis C virus; HBsAg ¼ hepatitis B virus surface antigen; HCC ¼ hepatocellular carcinoma; LR ¼ liver resection; MELD ¼ Model for End-Stage Liver Disease.
balloon was deflated and removed, and the immediate results were evaluated by angiography. Superselective transarterial chemoembolization using 100–300 μm drug-eluting embolics (DC-Bead; Terumo Corp) loaded with doxorubicin 50 mg was performed using a coaxial technique and a 2.7-F microcatheter (Progreat; Terumo Corp). The time elapsed between RF ablation and drug-eluting embolics transarterial chemoembolization was < 5 minutes. Endpoints for the transarterial chemoembolization procedure alone were the delivery of the full planned drug-eluting embolics dose and the achievement of complete tumor arterial devascularization. Procedure-related complications were reported according to the current classification scale of interventional radiology complications (12).
LR Treatment Workup before treatment for patients selected for LR also included indocyanine green clearance test and remnant liver volumetry, which was performed by CT with the semiautomatic GE ADW 4.5 software (GE Healthcare, Chicago, Illinois) according to our previous published protocol (13). Patients with 15-minute retention rates of indocyanine green 10% were excluded from major resection; patients with a remnant liver volume < 40% underwent preoperative portal vein embolization (2). Resection of 3 segments was classified as major hepatectomy. The surgical technique for LR used was previously described (14). Complications were assessed according to Clavien-Dindo classification (15). Perioperative mortality was defined as death occurring within 90 days from treatment.
Follow-up Effectiveness of RF ablation plus transarterial chemoembolization was assessed 1 month after ablation using dynamic CT or magnetic resonance imaging. The presence of tumor arterial enhancement indicated partial necrosis, and patients were retreated to achieve complete necrosis with either RF ablation plus transarterial chemoembolization or transarterial chemoembolization alone if the residual tumor was peripheral and < 2 cm. Follow-up started from the day of complete necrosis or LR and was based on 3-month US and serum alpha fetoprotein assay. All patients underwent a dynamic CT study within 6 months after treatment. Local tumor progression (LTP) was diagnosed when neoplastic viable tissue was detected within 2 cm from the ablation site (RF ablation plus transarterial chemoembolization patients) or at the resection margin (LR patients) (16,17). All other cases of intrahepatic recurrence were defined as intrahepatic distant recurrence, whereas extrahepatic recurrence included all HCC lesions diagnosed outside the liver. Each recurrent HCC lesion was managed according to guidelines available at the time of diagnosis (1).
Statistical Analysis Survival rates were calculated from the first treatment session, whereas tumor recurrence rates were calculated from surgical procedure in the LR group and from the achievement of complete necrosis in the RF ablation plus transarterial chemoembolization group. Follow-up ended at the last clinical visit or death. Continuous variables were tested for normality using Kolmogorov-Smirnov test and were
4 ▪ Liver Resection vs RF Ablation plus Chemoembolization in HCC
reported as median and range. Comparisons between groups were performed using Mann-Whitney test for continuous variables and c2 or Fisher exact test for categorical data. Cumulative HCC recurrence and survival rates were estimated with the Kaplan-Meier method and compared using the log-rank test. Results with P < .05 were considered significant. Data were analyzed with R v3.3.1 (R Foundation for Statistical Computing, Vienna, Austria).
Saviano et al ▪ JVIR
Table 2. Overall Survival and Tumor Recurrence Rates (Kaplan-Meier Method) in Patients with Hepatocellular Carcinoma 3 cm LR (n ¼ 25)
RF Ablation plus Transarterial Chemoembolization (n ¼ 29)
P Value
Overall survival 1–3 y, %
91.8–79.3
89.4–48.2
.117
RESULTS
Tumor recurrence 1–3 y, %
29.5–45.0
42.4–76.0
.034
In the LR group, 5 patients (20.0%) were treated with major hepatectomy (right hepatectomy in 3 cases and left hepatectomy in 2 cases); 2 of these patients underwent portal vein embolization before surgical resection. Among the 20 patients treated with minor hepatectomy, 10 were treated with wedge resection, 2 with segmentectomy, and 8 with bisegmentectomy. In the RF ablation plus transarterial chemoembolization group, 6 patients (20.7%) underwent a second treatment to achieve complete necrosis within 3 months from the first session. One death as a result of liver failure occurred early after treatment in the LR group in a patient who underwent left hepatectomy without a prior portal vein embolization. No deaths occurring after the procedure were reported in the RF ablation plus transarterial chemoembolization group. In the LR group, 1 major complication (4%; pleural effusion requiring surgical drainage) and 2 minor complications (8%; 1 reversible liver failure and 1 partial bowel obstruction) were also recorded. No major complications and 4 minor complications (16%; 3 occurrences of liver decompensation with ascites and 1 perihepatic hematoma) were observed in the RF ablation plus transarterial chemoembolization group (P ¼ .463 and P ¼ .675, respectively).
Local tumor progression 1–3 y, %
9.4–21.8
42.4–58.1
.005
Intrahepatic recurrence 1–3 y, %
29.7–39.1
29.8–58.5
.446
Overall Survival and Tumor Recurrence Rates Median follow-up was 34 months (range, 3–71 months) in the LR group and 26 months (range, 1–59 months) in the RF ablation plus transarterial chemoembolization group (P ¼ .108). During the follow-up period, 8 patients in the LR group (32.0%) and 12 patients in the RF ablation plus transarterial chemoembolization group (41.4%) died; deaths as a result of tumor progression were reported in 6 patients (24%) in the LR group and 7 patients (24.1%) in the RF ablation plus transarterial chemoembolization group. Overall survival (OS) rates at 1 and 3 years were not statistically different between the 2 groups (Table 2 and Fig 1a). HCC recurred in 11 patients (44.0%) in the LR group and in 19 patients (65.5%) in the RF ablation plus transarterial chemoembolization group. The median time to recurrence was 37 months in the LR group and 17 months in the RF ablation plus transarterial chemoembolization group. The tumor recurrence (TR) and LTP rates at 1 and 3 years were higher in the RF ablation plus transarterial chemoembolization group (P ¼ .034 and P ¼ .005, respectively) (Table 2 and Fig 1b–c). Intrahepatic distant
LR ¼ liver resection.
recurrence rates are reported in Table 2 and Figure 1d. The detailed recurrence pattern at the end of follow-up is presented in Table 3. In the LR group, LTP and intrahepatic recurrence without extrahepatic involvement were treated with transarterial chemoembolization (n ¼ 5), LR (n ¼ 2), or RF ablation (n ¼ 1). In RF ablation plus transarterial chemoembolization group, LTP and intrahepatic recurrence without extrahepatic spread were treated with transarterial chemoembolization (n ¼ 11), RF ablation plus transarterial chemoembolization (n ¼ 3), RF ablation (n ¼ 1), and sorafenib administration (n ¼ 1). Extrahepatic metastases occurred in 3 patients (12.0%) in the LR group and in 3 patients (10.3%) in the RF ablation plus transarterial chemoembolization group and were always associated with LTP or intrahepatic recurrence; considering liver function and patients’ comorbidities and preferences, sorafenib treatment was started in 2 patients in the RF ablation plus transarterial chemoembolization group and 1 patient in the LR group, and the remaining patients were assigned to receive best supportive care. A subgroup analysis of patients with HCC 5 cm showed results similar to the overall population (Table 4 and Fig 2a–d). Non–statistically significant differences in terms of OS and TR between the 2 treatment groups were found in the subset of patients with HCC > 5 cm (Table 4 and Fig 3a–d).
DISCUSSION For patients with compensated cirrhosis and single HCC 3 cm unsuitable for liver transplantation or LR, the best therapeutic approach is still a matter of debate, and different percutaneous or intravascular techniques have been used and combined (8). A common combination approach is transarterial chemoembolization followed by RF ablation, as transarterial chemoembolization could reduce the cooling effect of hepatic blood flow and increase the necrotizing effect of RF ablation (8). A second option is to combine
100 80 40
60
RF+Chemoembolization
0
20
LR
0
12
24
36
Months After Treatment
25 LR RF+Chemoemb. 29
19 14
13 9
b
100 80
25 LR RF+Chemoemb. 29
36
17 14
7 3
11 8
p=0.446 RF+Chemoembolization
LR
0
Patients at risk 9 2
24
100
12 8
p=0.005
Patients at risk
12
Months After Treatment
80
16 20
22 24
a Local Recurrence Rates (%)
0 Patients at risk
60
25 29
60
36
40
LR RF+Chemoemb.
24
Months After Treatment
20
12
LR
0
0 Patients at risk
Intrahepatic Distant Recurrence Rates (%)
20
p=0.117
p=0.034
40
40
RF+Chemoembolization
RF+Chemoembolization
20
60
80
LR
0
100
Tumour Recurrence Rates (%)
5
0
Overall Survival Rates (%)
Volume ▪ ▪ Number ▪ ▪ Month ▪ 2017
25 LR RF+Chemoemb. 29
12
24
36
Months After Treatment 17 19
11 12
8 3
Figure 1. Survival and tumor recurrence curves (Kaplan-Meier method) in patients with cirrhosis and single HCC 3 cm treated with LR or RF ablation plus drug-eluting embolics transarterial chemoembolization. Survival rates (a) were not significantly different in the 2 groups. Cumulative (b) and local tumor recurrence (c) rates were significantly higher in RF ablation plus transarterial chemoembolization group than in LR group. Intrahepatic distant recurrence rates (d) were not significantly different in the 2 treatment groups.
Table 3. Recurrence Prevalence and Pattern According to Treatment Group
No recurrence
LR (n ¼ 25)
RF Ablation plus Transarterial Chemoembolization (n ¼ 29)
14 (56.0%)
10 (30.3%)
Isolated LTP
1 (4.0%)
6 (18.2%)
Isolated IDR
5 (20.0%)
3 (9.1%)
LTP þ IDR
2 (8.0%)
7 (24.1%)
IDR þ extrahepatic recurrence LTP þ IDR þ extrahepatic recurrence
2 (8.0%)
1 (3.4%)
1 (4.0%)
2 (6.9%)
IDR ¼ intrahepatic distant recurrence; LR ¼ liver resection; LTP ¼ local tumor progression.
transarterial chemoembolization with microwave (MW) ablation, which has the theoretical advantages of achieving higher intratumoral temperatures, achieving larger ablation areas, and being less susceptible to the heat sink effect (18). However, in a retrospective study by Ginsburg et al (19)
comparing RF ablation plus transarterial chemoembolization versus MW ablation plus transarterial chemoembolization in patients with unresectable HCC with median size of 3 cm (range, 1.6–12.5 cm), no differences in terms of OS or tumor progression–free survival were found between the 2 techniques. Another therapeutic approach for unresectable HCC is transarterial yttrium-90 radiation segmentectomy, which was shown to achieve high degrees of necrosis in solitary HCC excluded from thermal ablation or LR (20,21) and to obtain results comparable to MW ablation plus transarterial chemoembolization in HCC nodules up to 3 cm in terms of OS and time to progression (22). The efficacy of these therapeutic strategies compared with LR—which is the current standard of care—is still unclear, as no robust data comparing RF ablation plus transarterial chemoembolization, MW ablation plus transarterial chemoembolization, and radiation segmentectomy versus LR are available. Three retrospective studies comparing sequential RF ablation plus transarterial chemoembolization and LR in patients with single HCC 2–5 cm or no more than 3 tumors < 3 cm showed that RF ablation plus transarterial chemoembolization provided OS rates similar to LR (9,23,24), whereas a randomized trial of HCC within Milan
6 ▪ Liver Resection vs RF Ablation plus Chemoembolization in HCC
Saviano et al ▪ JVIR
Table 4. Overall Survival and Tumor Recurrence Rates (Kaplan-Meier Method) in Subgroup of Patients with Hepatocellular Carcinoma 5 cm and > 5 cm HCC ≤ 3 cm to ≤ 5 cm LR (n ¼ 15)
HCC > 5 cm P Value
RF Ablation plus Transarterial Chemoembolization (n ¼ 23)
LR (n ¼ 10)
RF Ablation plus Transarterial Chemoembolization (n ¼ 6)
P Value
OS 1–3 y, %
100–86.7
91.1–54.2
.113
78.7–83.3
83.3–31.2
.589
TR 1–3 y %
20.0–35.4
43.0–75.1
.016
46.7–60.0
37.5–68.8
.827
LTP 1–3 y %
6.7–16.0
43.0–55.7
.013
16.7–33.3
37.5–68.8
.169
IDR 1–3 y %
20.0–27.3
19.0–62.1
.109
46.7–60
20.0–46.7
.730
9 6
12 16
80
p=0.013
40
60
RF+Chemoembolization
0
20
LR
0 Patients at risk 15 LR RF+Chemoemb. 23
12
24
36
Months After Treatment 13 12
11 8
100 80 60 40 20 0
15 LR RF+Chemoemb. 23
12 12
b
36
10 7
6 3
p=0.109 RF+Chemoembolization
LR
0
Patients at risk 7 2
24
100
15 20
12
Months After Treatment
80
15 23
0 Patients at risk
100
a
36
60
LR RF+Chemoemb.
24
LR
40
12
Months After Treatment
Intrahepatic Distant Recurrence Rates (%)
0
p=0.016
20
20
p=0.113
Patients at risk
Local Recurrence Rates (%)
Tumour Recurrence Rates (%)
40
RF+Chemoembolization
RF+Chemoembolization
0
100 60
80
LR
0
Overall Survival Rates (%)
HCC ¼ hepatocellular carcinoma; IDR ¼ intrahepatic distant recurrence; LR ¼ liver resection; LTP ¼ local tumor progression; OS ¼ overall survival; TR ¼ tumor recurrence.
15 LR RF+Chemoemb. 23
12
24
36
Months After Treatment 12 16
10 10
7 2
Figure 2. Survival and tumor recurrence curves (Kaplan-Meier method) in the subgroup of patients with single HCC 3–5 cm treated with LR or RF ablation plus drug-eluting embolics transarterial chemoembolization. The results were similar to the overall population. Survival rates (a) were higher in LR group, but the difference was not statistically significant. Cumulative (b) and local (c), but not intrahepatic distant recurrence (d), rates were significantly higher in RF ablation plus transarterial chemoembolization group.
criteria showed that surgery was associated with better OS and recurrence-free survival (10). Moreover, the comparison of these studies is difficult because of the heterogeneity in combination policy, HCC stage, and management of residual disease. In the present study, RF ablation and transarterial chemoembolization were combined in a single-step procedure
with RF ablation performed during balloon occlusion of the segmental hepatic artery to enhance the RF ablation necrosis; RF ablation was then followed by transarterial chemoembolization to take advantage of the vascular response induced by the thermal damage enhancing the cytotoxic effect at the tumor boundary (8,25). Although the singlestep procedure provides better local disease control than
p=0.589
100 80 40
60
RF+Chemoembolization
20
LR
0
Local Recurrence Rates (%)
p=0.169
Patients at risk 10 LR RF+Chemoemb. 6
24
36
Months After Treatment 6 2
2 1
100 80
p=0.730
24
36
1 1
1 0
LR
RF+Chemoembolization
0
Patients at risk 2 0
5 2
10 LR RF+Chemoemb. 6
b
12
60
Patients at risk 3 2
4 4
a
0
12
Months After Treatment
100
7 4
40 0
80
10 6
20
36
60
Patients at risk LR RF+Chemoemb.
24
Months After Treatment
40
12
LR
20
0
p=0.827
0
20
RF+Chemoembolization
RF+Chemoembolization
0
40
60
LR
Intrahepatic Distant Recurrence Rates (%)
80
100
Tumour Recurrence Rates (%)
7
0
Overall Survival Rates (%)
Volume ▪ ▪ Number ▪ ▪ Month ▪ 2017
10 LR RF+Chemoemb. 6
12
24
36
Months After Treatment 5 3
1 2
1 1
Figure 3. Survival and tumor recurrence curves (Kaplan-Meier method) in the subgroup of patients with single HCC > 5 cm treated with LR or RF ablation plus drug-eluting embolics transarterial chemoembolization. No differences were found regarding overall survival rates (a), cumulative tumor recurrence (b), local tumor progression (c), or intrahepatic distant recurrence (d) rates between the 2 treatment groups.
transarterial chemoembolization alone in single HCC up to 7 cm and entails some theoretical advantages, such as the reduction of hospital length of stay, patient discomfort, and overall costs, the demonstration of superiority of this approach over the sequential procedure is not possible owing to the lack of comparative randomized studies (8,25). This study involving patients with compensated cirrhosis and single HCC 3–8 cm shows that RF ablation plus transarterial chemoembolization treatment is associated with higher 3-year TR and LTP rates than LR in both the overall population (TR 45.0% vs 76%, P ¼ .034; LTP 21.8% vs 58.1%, P ¼ .005) and the subgroup of patients with HCC 5 cm (TR 35.4% vs 75.1%, P ¼ .016; LTP 16.0% vs 55.7%, P ¼.013). Similar results were found by Kagawa et al (9) and by Takuma et al (23), who showed that patients who underwent RF ablation plus transarterial chemoembolization had significantly lower disease-free survival rates compared with patients who underwent LR. These findings could be explained by the persistence, in tumors treated with nonsurgical approaches, of small foci of viable neoplastic cells that cannot be detected on short-term dynamic imaging and are responsible for delayed tumor recurrence (26). The higher recurrence rates in the RF ablation plus transarterial chemoembolization group were not confirmed in the subgroup of
patients with HCC > 5 cm. This finding was due to a higher rate of TR in patients with HCC > 5 cm who underwent LR compared with patients with HCC 5 cm who underwent LR (3-y TR 60% vs 35.4%), whereas TR rates in the corresponding RF ablation plus transarterial chemoembolization subgroups were similar (3-y TR 68.8% vs 75.1%). In terms of OS, no statistical differences were found between LR and RF ablation plus transarterial chemoembolization with 3-year rates of 79.3% and 48.2%, respectively (P ¼ .117). The survival data in this study seem to be comparable to data reported in other studies evaluating LR versus RF ablation plus transarterial chemoembolization and RF ablation plus transarterial chemoembolization versus MW ablation plus transarterial chemoembolization or radiation segmentectomy alone in similar cohorts of patients with a 3-year OS of approximately 80% and a median OS of 23.3– 42.6 months (9,19,20,22,23). Thus, the higher rates of TR in the RF ablation plus transarterial chemoembolization group were not associated with a significant reduction in patient survival—as already reported in other studies evaluating percutaneous ablation techniques—probably because TR was promptly treated with the most effective therapy after multidisciplinary evaluation (27). Concerning the safety analysis, major and minor complications rates were similar in the 2
8 ▪ Liver Resection vs RF Ablation plus Chemoembolization in HCC
groups (P ¼.463 and P ¼.675), although the RF ablation plus transarterial chemoembolization group included more patients with severe portal hypertension, and 1 postoperative death in a high-risk patient was reported in the LR group. This study has some limitations. This is a single-center experience including a limited number of patients. Data for the LR group were collected retrospectively owing to the practical and ethical issues that a randomized controlled study could raise. Only patients with complete necrosis after RF ablation plus transarterial chemoembolization were included, selecting a population with a higher probability of achieving long-term favorable results. However, this per-protocol strategy allows better comparison of the efficacy of RF ablation plus transarterial chemoembolization with LR, which is a curative approach completely removing the tumor tissue. Moreover, only 4 patients of 33 (12.1%) treated with RF ablation plus transarterial chemoembolization were excluded because of incomplete tumor necrosis, and in intention-totreat studies with this technique, complete necrosis was obtained in approximately 80% of the cases, suggesting that it is achievable in a high percentage of treated patients (11,19). In conclusion, in patients with compensated liver cirrhosis and single HCC > 3 cm, LR and RF ablation plus transarterial chemoembolization have similar OS rates, but RF ablation plus transarterial chemoembolization is associated with higher TR and LTP rates; these results were also confirmed in the subgroup of patients with HCC 5 cm. When surgery is not feasible because of patient refusal, comorbidities, tumor location, or high risk of complications or death, an optimal treatment approach is not yet available. In this setting, RF ablation plus transarterial chemoembolization is a safe and effective option that needs further investigation in a larger number of patients.
ACKNOWLEDGMENTS HepatoCATT Study Group: Emanuele Rinninella, MD, Maria Assunta Zocco, MD, Laura Riccardi, MD, Brigida Eleonora Annicchiarico, MD, Massimo Siciliano, MD, Nicoletta De Matthaeis, MD, Antonio Grieco, MD, Gian Ludovico Rapaccini, MD, and Antonio Gasbarrini, MD, Department of Internal Medicine and Gastroenterology, “A. Gemelli” Hospital, Catholic University of Rome, Rome, Italy.
REFERENCES 1. European Association for the Study of the Liver. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56:908–943. 2. Shindoh J, D Tzeng CW, Vauthey JN. Portal vein embolization for hepatocellular carcinoma. Liver Cancer 2012; 1:159–167. 3. Francica G, Saviano A, De Sio I, et al. Long-term effectiveness of radiofrequency ablation for solitary small hepatocellular carcinoma: a retrospective analysis of 363 patients. Dig Liver Dis 2013; 45:336–341. 4. Shiina S, Tateishi R, Arano T, et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am J Gastroenterol 2012; 107:569–577; quiz 578. 5. Tsochatzis E, Garcovich M, Marelli L, et al. Transarterial embolization as neo-adjuvant therapy pretransplantation in patients with hepatocellular carcinoma. Liver Int 2013; 33:944–949.
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6. Ni JY, Liu SS, Xu LF, Al E. Meta-analysis of radiofrequency ablation in combination with transarterial chemoembolization for hepatocellular carcinoma. World J Gastroenterol 2013; 19:3872–3882. 7. Yang D, Luo K, Liu H, et al. Meta-analysis of transcatheter arterial chemoembolization plus radiofrequency ablation versus transcatheter arterial chemoembolization alone for hepatocellular carcinoma. Oncotarget 2016; 8:2960–2970. 8. Iezzi R, Pompili M, Posa A, Coppola G, Gasbarrini A, Bonomo L. Combined locoregional treatment of patients with hepatocellular carcinoma: state of the art. World J Gastroenterol 2016; 22:1935–1942. 9. Kagawa T, Koizumi J, Kojima S, et al. Transcatheter arterial chemoembolization plus radiofrequency ablation therapy for early stage hepatocellular carcinoma: comparison with surgical resection. Cancer 2010; 116:3638–3644. 10. Liu H, Wang ZG, Fu SY, et al. Randomized clinical trial of chemoembolization plus radiofrequency ablation versus partial hepatectomy for hepatocellular carcinoma within the Milan criteria. Br J Surg 2016; 103:348–356. 11. Iezzi R, Cesario V, Siciliani L, et al. Single-step multimodal locoregional treatment for unresectable hepatocellular carcinoma: balloon-occluded percutaneous radiofrequency thermal ablation (BO-RFA) plus transcatheter arterial chemoembolization (TACE). Radiol Med 2013; 118:555–569. 12. Sacks D, Mcclenny TE, Cardella JF, Lewis CA. Society of Interventional Radiology clinical practice guidelines. J Vasc Interv Radiol 2003; 14: 199–202. 13. Ardito F, Vellone M, Barbaro B, et al. Right and extended-right hepatectomies for unilobar colorectal metastases: impact of portal vein embolization on long-term outcome and liver recurrence. Surgery 2013; 153: 801–810. 14. Giuliante F, Nuzzo G, Ardito F, Vellone M, De Cosmo G, Giovannini I. Extraparenchymal control of hepatic veins during mesohepatectomy. J Am Coll Surg 2008; 206:496–502. 15. Dindo D, Demartines N, Clavien PA. Classification of surgical complications. Ann Surg 2004; 240:205–213. 16. Rossi S, Ravetta V, Rosa L, et al. Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular carcinomas: a long-term cohort study. Hepatology 2011; 53:136–147. 17. Ahmed M, Solbiati L, Brace CL, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria—a 10-year update. J Vasc Interv Radiol 2014; 25:1691–1705.e4. 18. Lubner MG, Brace CL, Hinshaw JL, Lee FT. Microwave tumor ablation: mechanism of action, clinical results, and devices. J Vasc Interv Radiol 2010; 21:S192–S203. 19. Ginsburg M, Zivin SP, Wroblewski K, Doshi T, Vasnani RJ, Van Ha TG. Comparison of combination therapies in the management of hepatocellular carcinoma: transarterial chemoembolization with radiofrequency ablation versus microwave ablation. J Vasc Interv Radiol 2015; 26:330–341. 20. Vouche M, Habib A, Ward TJ, et al. Unresectable solitary hepatocellular carcinoma not amenable to radiofrequency ablation: multicenter radiology-pathology correlation and survival of radiation segmentectomy. Hepatology 2014; 60:192–201. 21. Padia SA, Kwan SW, Roudsari B, Monsky WL, Coveler A, Harris WP. Superselective yttrium-90 radioembolization for hepatocellular carcinoma yields high response rates with minimal toxicity. J Vasc Interv Radiol 2014; 25:1067–1073. 22. Biederman DM, Titano JJ, Bishay VL, et al. Radiation segmentectomy versus TACE combined with microwave ablation for unresectable solitary hepatocellular carcinoma up to 3 cm: a propensity score matching study. Radiology 2017; 283:895–905. 23. Takuma Y, Takabatake H, Morimoto Y, et al. Comparison of combined transcatheter arterial chemoembolization and radiofrequency ablation with surgical resection by using propensity score matching in patients with hepatocellular carcinoma within Milan criteria. Radiology 2013; 269: 927–937. 24. Kim JW, Shin SS, Kim JK, et al. Radiofrequency ablation combined with transcatheter arterial chemoembolization for the treatment of single hepatocellular carcinoma of 2 to 5 cm in diameter: comparison with surgical resection. Korean J Radiol 2013; 14:626–635. 25. Iezzi R, Pompili M, La Torre MF, et al. Radiofrequency ablation plus drugeluting beads transcatheter arterial chemoembolization for the treatment of single large hepatocellular carcinoma. Dig Liver Dis 2015; 47:242–248. 26. Mazzaferro V, Battiston C, Perrone S, et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann Surg 2004; 240:900–909. 27. Pompili M, Saviano A, De Matthaeis N, et al. Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma 3 cm. Results of a multicenter Italian survey. J Hepatol 2013; 59:89–97.
Liver Resection versus Radiofrequency Ablation plus Transcatheter Arterial Chemoembolization in Cirrhotic Patients with Solitary Large Hepatocellular Carcinoma Antonio Saviano, MD, Roberto Iezzi, MD, Felice Giuliante, MD, Lucia Salvatore, MD, Caterina Mele, MD, Alessandro Posa, MD, Francesco Ardito, MD, Anna Maria De Gaetano, MD, and Maurizio Pompili, MD; HepatoCATT Study Group ABSTRACT Purpose: To compare liver resection (LR) with single-step, balloon-occluded RF ablation plus drug-eluting embolics transarterial chemoembolization in cirrhotic patients with single hepatocellular carcinoma (HCC) 3 cm. Materials and Methods: From 2010 to 2014, 25 patients with compensated cirrhosis and single HCC 3 cm (median size 4.5 cm; range, 3.0–6.8 cm) not suitable for LR or liver transplantation were treated with RF ablation plus transarterial chemoembolization in a prospective observational single-center pilot study; all patients had complete tumor necrosis after treatment. A retrospective control group included 29 patients (median HCC size 4.0 cm; range, 3.0–7.4 cm) who underwent LR. RF ablation plus transarterial chemoembolization group included more patients with severe portal hypertension (65.5% vs 35.0%, P ¼ .017). Primary endpoints were overall survival (OS) and tumor recurrence (TR) rates. Results: One death and 1 major complication (4%) were observed in LR group. No major complications were reported in RF ablation plus transarterial chemoembolization group (P ¼ .463). OS rates at 1 and 3 years were 91.8% and 79.3% in LR group and 89.4% and 48.2% in RF ablation plus transarterial chemoembolization group (P ¼ 0.117). TR rates at 1 and 3 years were 29.5% and 45.0% in LR group and 42.4% and 76.0% in RF ablation plus transarterial chemoembolization group (P ¼ .034). Local tumor progression (LTP) rates at 3 years were significantly lower in LR group (21.8% vs 58.1%, P ¼ .005). Similar results were found in patients with HCC 5 cm (TR rates 35.4% vs 75.1%, P ¼ .016; LTP 16.0% vs 55.7%, P ¼ .013). Conclusions: LR achieved lower TR and LTP rates than RF ablation plus transarterial chemoembolization, but 3-years OS rates were not statistically different between the 2 groups. RF ablation plus transarterial chemoembolization is an effective treatment option in patients with compensated cirrhosis and solitary HCC 3 cm unsuitable for LR.
ABBREVIATIONS HCC ¼ hepatocellular carcinoma, LR ¼ liver resection, LTP ¼ local tumor progression, MW ¼ microwave, OS ¼ overall survival
Liver resection (LR) represents the mainstay of treatment for solitary hepatocellular carcinoma (HCC) > 3 cm unsuitable for liver transplantation (1). However, the feasibility and long-term effectiveness of LR are affected by liver function From the Department of Internal Medicine and Gastroenterology (A.S., L.S., M.P.), Department of Bioimaging and Radiological Sciences (R.I., A.P., A.M.D.), Institute of Radiology, and Hepatobiliary Surgery Unit (F.G., C.M., F.A.), Department of Surgical Sciences, “A. Gemelli” Hospital, Catholic University of Rome, Largo F. Vito 1, Rome 00168, Italy. Received January 18, 2017; final revision received and accepted June 9, 2017. Address correspondence to M.P.; E-mail: [email protected]
and alternative therapies are needed for patients with compensated cirrhosis and contraindication to surgery (1,2). Radiofrequency (RF) ablation provides excellent results in lesions up to 3 cm in size but is less effective in larger None of the authors have identified a conflict of interest. © SIR, 2017 J Vasc Interv Radiol 2017; ▪:1–8 http://dx.doi.org/10.1016/j.jvir.2017.06.016
2 ▪ Liver Resection vs RF Ablation plus Chemoembolization in HCC
lesions (3,4). Transarterial chemoembolization is considered a palliative treatment, as complete tumor necrosis is rarely attained—as shown in explants analysis of HCC treated before liver transplantation—and it is associated with high tumor recurrence rates (5). This is the reason why combinations of these techniques have been used, showing better results than RF ablation or transarterial chemoembolization alone in achieving tumor necrosis and higher survival rates (6–8). The efficacy of the combination of RF ablation plus transarterial chemoembolization compared with LR in patients with cirrhosis and single HCC 3 cm is still a matter of debate, as only a few studies addressing this issue with controversial results are available (9,10). Hence, the aim of this study was to evaluate the effectiveness and the safety of LR versus single-step, balloon-occluded RF ablation plus transarterial chemoembolization in patients with cirrhosis and single HCC 3 cm.
MATERIALS AND METHODS Study Design This study was approved by the institutional review board and was performed in agreement with the 1990 Declaration of Helsinki and subsequent amendments. Written informed consent was obtained from all patients. The study enrolled patients with cirrhosis and single HCC 3 cm who were included in an observational prospective single-center pilot study designed to assess effectiveness and safety of singlestep combined therapy of RF ablation plus drug-eluting embolics transarterial chemoembolization. A cohort of cirrhotic patients who underwent LR whose data were collected retrospectively served as control group. All patients were > 18 years old and fulfilled the following inclusion criteria: (a) liver cirrhosis classified as Child-Pugh score A, (b) single large HCC 3–8 cm, (c) no vascular invasion or extrahepatic metastases on sectional studies performed before treatment, (d) detection of complete tumor necrosis 1 month after RF ablation plus transarterial chemoembolization session. Exclusion criteria were the following: (a) liver cirrhosis classified as Child-Pugh score B or C, (b) diuretic-resistant ascites, (c) platelet count < 40,000/μL for LR group, (d) platelet count < 40,000/μL for RF ablation plus transarterial chemoembolization group if a prophylactic platelet transfusion before treatment was not able to raise the platelet count to 40,000/μL, and (e) chronic kidney disease stage 4 or stage 5 not on hemodialysis for RF ablation plus transarterial chemoembolization group. All patients who underwent RF ablation plus transarterial chemoembolization had been excluded from LR after multidisciplinary evaluation because of 1 of the following reasons: requirement of major resection in patients with severe portal hypertension (defined as presence of esophageal varices F2 or gastric varices, splenomegaly with platelet count < 100,000/mL, or actual ascites or previous ascites successfully treated with diuretics), surgery unfeasible or hazardous owing to lesion location, concurrent severe comorbidities, or patient refusal.
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Workup before Treatment and Patients’ Clinical and Demographic Characteristics The workup before treatment in both RF ablation plus transarterial chemoembolization and LR groups consisted of physical examination; laboratory tests; and imaging studies including liver ultrasound (US), radionuclide bone scan, and dynamic contrast-enhanced computed tomography (CT) of thorax and abdomen. Cirrhosis was diagnosed by histologic and/or clinical criteria (laboratory parameters, US and/or CT signs). Severe portal hypertension was diagnosed in the presence of 1 of the above-mentioned criteria excluding patients from major LR. Diagnosis of HCC was based on the guidelines in force at the time of study enrollment (1). Patients were treated between January 2010 and December 2014. The LR group included 25 patients. During the enrollment period, 33 patients with compensated cirrhosis and solitary HCC 3 cm were treated with RF ablation plus transarterial chemoembolization; 4 patients (12.1%) were excluded because complete tumor necrosis was not achieved. Hence, the RF ablation plus transarterial chemoembolization group included 29 patients. Clinical features of patients are listed in Table 1. All patients with mild ascites were treated successfully with diuretic therapy before treatment. The RF ablation plus transarterial chemoembolization group also included 1 patient on hemodialysis and 1 patient with a platelet count of 19,000/μL who underwent platelet transfusion before the treatment. Eight patients in the RF ablation plus transarterial chemoembolization group (24.2%) and 6 patients in the LR group (20.6%) had been previously treated with other locoregional procedures (ie, transarterial chemoembolization, RF ablation, and percutaneous ethanol injection) without achieving complete necrosis (P ¼ .121).
RF Ablation plus Transarterial Chemoembolization Protocol All combined treatments were performed by the same interventional radiologist (R.I.) with 14 years of experience. A single-step combination approach was used (11). Hepatic angiography using a 6-F guiding catheter (curved C1 or C2, 65 cm in length) was performed through a right common femoral approach to map liver vascular anatomy, arterial tumor supply, and eventual arteriovenous shunts. A 0.014-inch guide wire (ChoICE; Boston Scientific, Marlborough, Massachusetts) and a low-profile monorail percutaneous transluminal angioplasty balloon (4–5 20 mm, Muso; Terumo Corp, Tokyo, Japan) were advanced into the segmental hepatic artery feeding the lesion. An internally cooled RF electrode with a 3-cm exposed tip (Cool-tip RF Ablation System; Medtronic, Minneapolis, Minnesota) was introduced into the nodule using US guidance. The angioplasty balloon in the segmental hepatic artery was filled with saline solution and contrast material until vascular occlusion was achieved. The RF generator was activated to maintain a temperature of 90 –115 C at the exposed tip for 12 minutes. At the end of the procedure, the RF electrode was withdrawn, the occlusion
Volume ▪ ▪ Number ▪ ▪ Month ▪ 2017
3
Table 1. Demographic and Clinical Characteristics of Enrolled Patients Variable
LR (n ¼ 25)
RF Ablation plus Transarterial Chemoembolization (n ¼ 29)
P Value
Age, y
72 (45–80)
67 (47–83)
Male sex (%)
22 (88.0)
25 (86.2)
1.000
.184
Anti-HCV positive (%)
.106
15 (60.0)
11 (37.9)
HBsAg positive (%)
2 (8.0)
5 (17.2)
.431
Alcohol abuse (%) Other etiology of cirrhosis (%)
4 (16.0) 4 (16.0)
11 (37.9) 4 (13.8)
.073 1.000
Portal hypertension (%)
8 (32.0)
19 (65.5)
.017
Portal vein thrombosis (%)
1 (4.0)
4 (13.8)
.358
Platelet count, 109/L Mild ascites (%)
121 (60–312) 0 (0.0)
107 (19–294)
.286
4 (13.8)
.115
Total bilirubin, mg/dL
0.8 (0.29–1.33)
0.84 (0.20–2.21)
.572
Albumin, g/dL
4.0 (3.1–4.8)
3.85 (2.8–4.7)
.093
0.87 (0.40–11.00) 9 (6–20)
.456 .252
Creatinine, mg/dL MELD score ALT, IU/L AFP, ng/mL
0.94 (0.64–1.52) 8 (6–18) 35 (22–136)
27 (8–162)
.010
8 (3–6,235)
8 (2–378)
.725
Tumor size, cm
4.5 (3.0–7.4)
4.0 (3.0–6.8)
HCC > 5 cm (%)
.121
10 (40.0)
6 (20.7)
.138
Previous HCC treatment (%)
10 (40.0)
6 (20.7)
.121
Note–Continuous variables were reported as median (range). AFP ¼ alpha fetoprotein; ALT ¼ alanine aminotransferase; Anti-HCV ¼ antibody to hepatitis C virus; HBsAg ¼ hepatitis B virus surface antigen; HCC ¼ hepatocellular carcinoma; LR ¼ liver resection; MELD ¼ Model for End-Stage Liver Disease.
balloon was deflated and removed, and the immediate results were evaluated by angiography. Superselective transarterial chemoembolization using 100–300 μm drug-eluting embolics (DC-Bead; Terumo Corp) loaded with doxorubicin 50 mg was performed using a coaxial technique and a 2.7-F microcatheter (Progreat; Terumo Corp). The time elapsed between RF ablation and drug-eluting embolics transarterial chemoembolization was < 5 minutes. Endpoints for the transarterial chemoembolization procedure alone were the delivery of the full planned drug-eluting embolics dose and the achievement of complete tumor arterial devascularization. Procedure-related complications were reported according to the current classification scale of interventional radiology complications (12).
LR Treatment Workup before treatment for patients selected for LR also included indocyanine green clearance test and remnant liver volumetry, which was performed by CT with the semiautomatic GE ADW 4.5 software (GE Healthcare, Chicago, Illinois) according to our previous published protocol (13). Patients with 15-minute retention rates of indocyanine green 10% were excluded from major resection; patients with a remnant liver volume < 40% underwent preoperative portal vein embolization (2). Resection of 3 segments was classified as major hepatectomy. The surgical technique for LR used was previously described (14). Complications were assessed according to Clavien-Dindo classification (15). Perioperative mortality was defined as death occurring within 90 days from treatment.
Follow-up Effectiveness of RF ablation plus transarterial chemoembolization was assessed 1 month after ablation using dynamic CT or magnetic resonance imaging. The presence of tumor arterial enhancement indicated partial necrosis, and patients were retreated to achieve complete necrosis with either RF ablation plus transarterial chemoembolization or transarterial chemoembolization alone if the residual tumor was peripheral and < 2 cm. Follow-up started from the day of complete necrosis or LR and was based on 3-month US and serum alpha fetoprotein assay. All patients underwent a dynamic CT study within 6 months after treatment. Local tumor progression (LTP) was diagnosed when neoplastic viable tissue was detected within 2 cm from the ablation site (RF ablation plus transarterial chemoembolization patients) or at the resection margin (LR patients) (16,17). All other cases of intrahepatic recurrence were defined as intrahepatic distant recurrence, whereas extrahepatic recurrence included all HCC lesions diagnosed outside the liver. Each recurrent HCC lesion was managed according to guidelines available at the time of diagnosis (1).
Statistical Analysis Survival rates were calculated from the first treatment session, whereas tumor recurrence rates were calculated from surgical procedure in the LR group and from the achievement of complete necrosis in the RF ablation plus transarterial chemoembolization group. Follow-up ended at the last clinical visit or death. Continuous variables were tested for normality using Kolmogorov-Smirnov test and were
4 ▪ Liver Resection vs RF Ablation plus Chemoembolization in HCC
reported as median and range. Comparisons between groups were performed using Mann-Whitney test for continuous variables and c2 or Fisher exact test for categorical data. Cumulative HCC recurrence and survival rates were estimated with the Kaplan-Meier method and compared using the log-rank test. Results with P < .05 were considered significant. Data were analyzed with R v3.3.1 (R Foundation for Statistical Computing, Vienna, Austria).
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Table 2. Overall Survival and Tumor Recurrence Rates (Kaplan-Meier Method) in Patients with Hepatocellular Carcinoma 3 cm LR (n ¼ 25)
RF Ablation plus Transarterial Chemoembolization (n ¼ 29)
P Value
Overall survival 1–3 y, %
91.8–79.3
89.4–48.2
.117
RESULTS
Tumor recurrence 1–3 y, %
29.5–45.0
42.4–76.0
.034
In the LR group, 5 patients (20.0%) were treated with major hepatectomy (right hepatectomy in 3 cases and left hepatectomy in 2 cases); 2 of these patients underwent portal vein embolization before surgical resection. Among the 20 patients treated with minor hepatectomy, 10 were treated with wedge resection, 2 with segmentectomy, and 8 with bisegmentectomy. In the RF ablation plus transarterial chemoembolization group, 6 patients (20.7%) underwent a second treatment to achieve complete necrosis within 3 months from the first session. One death as a result of liver failure occurred early after treatment in the LR group in a patient who underwent left hepatectomy without a prior portal vein embolization. No deaths occurring after the procedure were reported in the RF ablation plus transarterial chemoembolization group. In the LR group, 1 major complication (4%; pleural effusion requiring surgical drainage) and 2 minor complications (8%; 1 reversible liver failure and 1 partial bowel obstruction) were also recorded. No major complications and 4 minor complications (16%; 3 occurrences of liver decompensation with ascites and 1 perihepatic hematoma) were observed in the RF ablation plus transarterial chemoembolization group (P ¼ .463 and P ¼ .675, respectively).
Local tumor progression 1–3 y, %
9.4–21.8
42.4–58.1
.005
Intrahepatic recurrence 1–3 y, %
29.7–39.1
29.8–58.5
.446
Overall Survival and Tumor Recurrence Rates Median follow-up was 34 months (range, 3–71 months) in the LR group and 26 months (range, 1–59 months) in the RF ablation plus transarterial chemoembolization group (P ¼ .108). During the follow-up period, 8 patients in the LR group (32.0%) and 12 patients in the RF ablation plus transarterial chemoembolization group (41.4%) died; deaths as a result of tumor progression were reported in 6 patients (24%) in the LR group and 7 patients (24.1%) in the RF ablation plus transarterial chemoembolization group. Overall survival (OS) rates at 1 and 3 years were not statistically different between the 2 groups (Table 2 and Fig 1a). HCC recurred in 11 patients (44.0%) in the LR group and in 19 patients (65.5%) in the RF ablation plus transarterial chemoembolization group. The median time to recurrence was 37 months in the LR group and 17 months in the RF ablation plus transarterial chemoembolization group. The tumor recurrence (TR) and LTP rates at 1 and 3 years were higher in the RF ablation plus transarterial chemoembolization group (P ¼ .034 and P ¼ .005, respectively) (Table 2 and Fig 1b–c). Intrahepatic distant
LR ¼ liver resection.
recurrence rates are reported in Table 2 and Figure 1d. The detailed recurrence pattern at the end of follow-up is presented in Table 3. In the LR group, LTP and intrahepatic recurrence without extrahepatic involvement were treated with transarterial chemoembolization (n ¼ 5), LR (n ¼ 2), or RF ablation (n ¼ 1). In RF ablation plus transarterial chemoembolization group, LTP and intrahepatic recurrence without extrahepatic spread were treated with transarterial chemoembolization (n ¼ 11), RF ablation plus transarterial chemoembolization (n ¼ 3), RF ablation (n ¼ 1), and sorafenib administration (n ¼ 1). Extrahepatic metastases occurred in 3 patients (12.0%) in the LR group and in 3 patients (10.3%) in the RF ablation plus transarterial chemoembolization group and were always associated with LTP or intrahepatic recurrence; considering liver function and patients’ comorbidities and preferences, sorafenib treatment was started in 2 patients in the RF ablation plus transarterial chemoembolization group and 1 patient in the LR group, and the remaining patients were assigned to receive best supportive care. A subgroup analysis of patients with HCC 5 cm showed results similar to the overall population (Table 4 and Fig 2a–d). Non–statistically significant differences in terms of OS and TR between the 2 treatment groups were found in the subset of patients with HCC > 5 cm (Table 4 and Fig 3a–d).
DISCUSSION For patients with compensated cirrhosis and single HCC 3 cm unsuitable for liver transplantation or LR, the best therapeutic approach is still a matter of debate, and different percutaneous or intravascular techniques have been used and combined (8). A common combination approach is transarterial chemoembolization followed by RF ablation, as transarterial chemoembolization could reduce the cooling effect of hepatic blood flow and increase the necrotizing effect of RF ablation (8). A second option is to combine
100 80 40
60
RF+Chemoembolization
0
20
LR
0
12
24
36
Months After Treatment
25 LR RF+Chemoemb. 29
19 14
13 9
b
100 80
25 LR RF+Chemoemb. 29
36
17 14
7 3
11 8
p=0.446 RF+Chemoembolization
LR
0
Patients at risk 9 2
24
100
12 8
p=0.005
Patients at risk
12
Months After Treatment
80
16 20
22 24
a Local Recurrence Rates (%)
0 Patients at risk
60
25 29
60
36
40
LR RF+Chemoemb.
24
Months After Treatment
20
12
LR
0
0 Patients at risk
Intrahepatic Distant Recurrence Rates (%)
20
p=0.117
p=0.034
40
40
RF+Chemoembolization
RF+Chemoembolization
20
60
80
LR
0
100
Tumour Recurrence Rates (%)
5
0
Overall Survival Rates (%)
Volume ▪ ▪ Number ▪ ▪ Month ▪ 2017
25 LR RF+Chemoemb. 29
12
24
36
Months After Treatment 17 19
11 12
8 3
Figure 1. Survival and tumor recurrence curves (Kaplan-Meier method) in patients with cirrhosis and single HCC 3 cm treated with LR or RF ablation plus drug-eluting embolics transarterial chemoembolization. Survival rates (a) were not significantly different in the 2 groups. Cumulative (b) and local tumor recurrence (c) rates were significantly higher in RF ablation plus transarterial chemoembolization group than in LR group. Intrahepatic distant recurrence rates (d) were not significantly different in the 2 treatment groups.
Table 3. Recurrence Prevalence and Pattern According to Treatment Group
No recurrence
LR (n ¼ 25)
RF Ablation plus Transarterial Chemoembolization (n ¼ 29)
14 (56.0%)
10 (30.3%)
Isolated LTP
1 (4.0%)
6 (18.2%)
Isolated IDR
5 (20.0%)
3 (9.1%)
LTP þ IDR
2 (8.0%)
7 (24.1%)
IDR þ extrahepatic recurrence LTP þ IDR þ extrahepatic recurrence
2 (8.0%)
1 (3.4%)
1 (4.0%)
2 (6.9%)
IDR ¼ intrahepatic distant recurrence; LR ¼ liver resection; LTP ¼ local tumor progression.
transarterial chemoembolization with microwave (MW) ablation, which has the theoretical advantages of achieving higher intratumoral temperatures, achieving larger ablation areas, and being less susceptible to the heat sink effect (18). However, in a retrospective study by Ginsburg et al (19)
comparing RF ablation plus transarterial chemoembolization versus MW ablation plus transarterial chemoembolization in patients with unresectable HCC with median size of 3 cm (range, 1.6–12.5 cm), no differences in terms of OS or tumor progression–free survival were found between the 2 techniques. Another therapeutic approach for unresectable HCC is transarterial yttrium-90 radiation segmentectomy, which was shown to achieve high degrees of necrosis in solitary HCC excluded from thermal ablation or LR (20,21) and to obtain results comparable to MW ablation plus transarterial chemoembolization in HCC nodules up to 3 cm in terms of OS and time to progression (22). The efficacy of these therapeutic strategies compared with LR—which is the current standard of care—is still unclear, as no robust data comparing RF ablation plus transarterial chemoembolization, MW ablation plus transarterial chemoembolization, and radiation segmentectomy versus LR are available. Three retrospective studies comparing sequential RF ablation plus transarterial chemoembolization and LR in patients with single HCC 2–5 cm or no more than 3 tumors < 3 cm showed that RF ablation plus transarterial chemoembolization provided OS rates similar to LR (9,23,24), whereas a randomized trial of HCC within Milan
6 ▪ Liver Resection vs RF Ablation plus Chemoembolization in HCC
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Table 4. Overall Survival and Tumor Recurrence Rates (Kaplan-Meier Method) in Subgroup of Patients with Hepatocellular Carcinoma 5 cm and > 5 cm HCC ≤ 3 cm to ≤ 5 cm LR (n ¼ 15)
HCC > 5 cm P Value
RF Ablation plus Transarterial Chemoembolization (n ¼ 23)
LR (n ¼ 10)
RF Ablation plus Transarterial Chemoembolization (n ¼ 6)
P Value
OS 1–3 y, %
100–86.7
91.1–54.2
.113
78.7–83.3
83.3–31.2
.589
TR 1–3 y %
20.0–35.4
43.0–75.1
.016
46.7–60.0
37.5–68.8
.827
LTP 1–3 y %
6.7–16.0
43.0–55.7
.013
16.7–33.3
37.5–68.8
.169
IDR 1–3 y %
20.0–27.3
19.0–62.1
.109
46.7–60
20.0–46.7
.730
9 6
12 16
80
p=0.013
40
60
RF+Chemoembolization
0
20
LR
0 Patients at risk 15 LR RF+Chemoemb. 23
12
24
36
Months After Treatment 13 12
11 8
100 80 60 40 20 0
15 LR RF+Chemoemb. 23
12 12
b
36
10 7
6 3
p=0.109 RF+Chemoembolization
LR
0
Patients at risk 7 2
24
100
15 20
12
Months After Treatment
80
15 23
0 Patients at risk
100
a
36
60
LR RF+Chemoemb.
24
LR
40
12
Months After Treatment
Intrahepatic Distant Recurrence Rates (%)
0
p=0.016
20
20
p=0.113
Patients at risk
Local Recurrence Rates (%)
Tumour Recurrence Rates (%)
40
RF+Chemoembolization
RF+Chemoembolization
0
100 60
80
LR
0
Overall Survival Rates (%)
HCC ¼ hepatocellular carcinoma; IDR ¼ intrahepatic distant recurrence; LR ¼ liver resection; LTP ¼ local tumor progression; OS ¼ overall survival; TR ¼ tumor recurrence.
15 LR RF+Chemoemb. 23
12
24
36
Months After Treatment 12 16
10 10
7 2
Figure 2. Survival and tumor recurrence curves (Kaplan-Meier method) in the subgroup of patients with single HCC 3–5 cm treated with LR or RF ablation plus drug-eluting embolics transarterial chemoembolization. The results were similar to the overall population. Survival rates (a) were higher in LR group, but the difference was not statistically significant. Cumulative (b) and local (c), but not intrahepatic distant recurrence (d), rates were significantly higher in RF ablation plus transarterial chemoembolization group.
criteria showed that surgery was associated with better OS and recurrence-free survival (10). Moreover, the comparison of these studies is difficult because of the heterogeneity in combination policy, HCC stage, and management of residual disease. In the present study, RF ablation and transarterial chemoembolization were combined in a single-step procedure
with RF ablation performed during balloon occlusion of the segmental hepatic artery to enhance the RF ablation necrosis; RF ablation was then followed by transarterial chemoembolization to take advantage of the vascular response induced by the thermal damage enhancing the cytotoxic effect at the tumor boundary (8,25). Although the singlestep procedure provides better local disease control than
p=0.589
100 80 40
60
RF+Chemoembolization
20
LR
0
Local Recurrence Rates (%)
p=0.169
Patients at risk 10 LR RF+Chemoemb. 6
24
36
Months After Treatment 6 2
2 1
100 80
p=0.730
24
36
1 1
1 0
LR
RF+Chemoembolization
0
Patients at risk 2 0
5 2
10 LR RF+Chemoemb. 6
b
12
60
Patients at risk 3 2
4 4
a
0
12
Months After Treatment
100
7 4
40 0
80
10 6
20
36
60
Patients at risk LR RF+Chemoemb.
24
Months After Treatment
40
12
LR
20
0
p=0.827
0
20
RF+Chemoembolization
RF+Chemoembolization
0
40
60
LR
Intrahepatic Distant Recurrence Rates (%)
80
100
Tumour Recurrence Rates (%)
7
0
Overall Survival Rates (%)
Volume ▪ ▪ Number ▪ ▪ Month ▪ 2017
10 LR RF+Chemoemb. 6
12
24
36
Months After Treatment 5 3
1 2
1 1
Figure 3. Survival and tumor recurrence curves (Kaplan-Meier method) in the subgroup of patients with single HCC > 5 cm treated with LR or RF ablation plus drug-eluting embolics transarterial chemoembolization. No differences were found regarding overall survival rates (a), cumulative tumor recurrence (b), local tumor progression (c), or intrahepatic distant recurrence (d) rates between the 2 treatment groups.
transarterial chemoembolization alone in single HCC up to 7 cm and entails some theoretical advantages, such as the reduction of hospital length of stay, patient discomfort, and overall costs, the demonstration of superiority of this approach over the sequential procedure is not possible owing to the lack of comparative randomized studies (8,25). This study involving patients with compensated cirrhosis and single HCC 3–8 cm shows that RF ablation plus transarterial chemoembolization treatment is associated with higher 3-year TR and LTP rates than LR in both the overall population (TR 45.0% vs 76%, P ¼ .034; LTP 21.8% vs 58.1%, P ¼ .005) and the subgroup of patients with HCC 5 cm (TR 35.4% vs 75.1%, P ¼ .016; LTP 16.0% vs 55.7%, P ¼.013). Similar results were found by Kagawa et al (9) and by Takuma et al (23), who showed that patients who underwent RF ablation plus transarterial chemoembolization had significantly lower disease-free survival rates compared with patients who underwent LR. These findings could be explained by the persistence, in tumors treated with nonsurgical approaches, of small foci of viable neoplastic cells that cannot be detected on short-term dynamic imaging and are responsible for delayed tumor recurrence (26). The higher recurrence rates in the RF ablation plus transarterial chemoembolization group were not confirmed in the subgroup of
patients with HCC > 5 cm. This finding was due to a higher rate of TR in patients with HCC > 5 cm who underwent LR compared with patients with HCC 5 cm who underwent LR (3-y TR 60% vs 35.4%), whereas TR rates in the corresponding RF ablation plus transarterial chemoembolization subgroups were similar (3-y TR 68.8% vs 75.1%). In terms of OS, no statistical differences were found between LR and RF ablation plus transarterial chemoembolization with 3-year rates of 79.3% and 48.2%, respectively (P ¼ .117). The survival data in this study seem to be comparable to data reported in other studies evaluating LR versus RF ablation plus transarterial chemoembolization and RF ablation plus transarterial chemoembolization versus MW ablation plus transarterial chemoembolization or radiation segmentectomy alone in similar cohorts of patients with a 3-year OS of approximately 80% and a median OS of 23.3– 42.6 months (9,19,20,22,23). Thus, the higher rates of TR in the RF ablation plus transarterial chemoembolization group were not associated with a significant reduction in patient survival—as already reported in other studies evaluating percutaneous ablation techniques—probably because TR was promptly treated with the most effective therapy after multidisciplinary evaluation (27). Concerning the safety analysis, major and minor complications rates were similar in the 2
8 ▪ Liver Resection vs RF Ablation plus Chemoembolization in HCC
groups (P ¼.463 and P ¼.675), although the RF ablation plus transarterial chemoembolization group included more patients with severe portal hypertension, and 1 postoperative death in a high-risk patient was reported in the LR group. This study has some limitations. This is a single-center experience including a limited number of patients. Data for the LR group were collected retrospectively owing to the practical and ethical issues that a randomized controlled study could raise. Only patients with complete necrosis after RF ablation plus transarterial chemoembolization were included, selecting a population with a higher probability of achieving long-term favorable results. However, this per-protocol strategy allows better comparison of the efficacy of RF ablation plus transarterial chemoembolization with LR, which is a curative approach completely removing the tumor tissue. Moreover, only 4 patients of 33 (12.1%) treated with RF ablation plus transarterial chemoembolization were excluded because of incomplete tumor necrosis, and in intention-totreat studies with this technique, complete necrosis was obtained in approximately 80% of the cases, suggesting that it is achievable in a high percentage of treated patients (11,19). In conclusion, in patients with compensated liver cirrhosis and single HCC > 3 cm, LR and RF ablation plus transarterial chemoembolization have similar OS rates, but RF ablation plus transarterial chemoembolization is associated with higher TR and LTP rates; these results were also confirmed in the subgroup of patients with HCC 5 cm. When surgery is not feasible because of patient refusal, comorbidities, tumor location, or high risk of complications or death, an optimal treatment approach is not yet available. In this setting, RF ablation plus transarterial chemoembolization is a safe and effective option that needs further investigation in a larger number of patients.
ACKNOWLEDGMENTS HepatoCATT Study Group: Emanuele Rinninella, MD, Maria Assunta Zocco, MD, Laura Riccardi, MD, Brigida Eleonora Annicchiarico, MD, Massimo Siciliano, MD, Nicoletta De Matthaeis, MD, Antonio Grieco, MD, Gian Ludovico Rapaccini, MD, and Antonio Gasbarrini, MD, Department of Internal Medicine and Gastroenterology, “A. Gemelli” Hospital, Catholic University of Rome, Rome, Italy.
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