Radiofrequency ablation versus open hepatic resection for elderly patients (> 65 years) with very early or early hepatocellular carcinoma

Authors

  • Zhen-Wei Peng MD,

    Corresponding author
    1. Department of Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
    • Corresponding author: Min-Shan Chen, MD, PhD, Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China; Fax: 011 (8620) 8734 3117; Chminsh@mail.sysu.edu.cn. Zhen-Wei Peng, MD, Department of Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Fax: 011 (8620) 8734 3585; pengzhenwei2005@163.com.

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    • The first 2 authors contributed equally to this manuscript.

  • Fu-Rong Liu MD,

    1. Department of General Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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    • The first 2 authors contributed equally to this manuscript.

  • Sheng Ye MD,

    1. Department of Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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  • Li Xu MD,

    1. State Key Laboratory of Oncology in Southern China, Guangzhou, China
    2. Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
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  • Yao-Jun Zhang MD,

    1. State Key Laboratory of Oncology in Southern China, Guangzhou, China
    2. Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
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  • Hui-Hong Liang MD,

    1. State Key Laboratory of Oncology in Southern China, Guangzhou, China
    2. Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
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  • Xiao-Jun Lin MD,

    1. State Key Laboratory of Oncology in Southern China, Guangzhou, China
    2. Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
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  • Wan Yee Lau MD,

    1. Faculty of Medicine, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China
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  • Min-Shan Chen MD, PhD

    Corresponding author
    1. State Key Laboratory of Oncology in Southern China, Guangzhou, China
    2. Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China
    • Corresponding author: Min-Shan Chen, MD, PhD, Department of Hepatobiliary Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China; Fax: 011 (8620) 8734 3117; Chminsh@mail.sysu.edu.cn. Zhen-Wei Peng, MD, Department of Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Fax: 011 (8620) 8734 3585; pengzhenwei2005@163.com.

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Abstract

BACKGROUND

This study retrospectively compared the safety and efficacy of percutaneous radiofrequency ablation (RFA) with open hepatic resection (HR) in elderly patients (age > 65 years) with very early or early hepatocellular carcinoma (HCC).

METHODS

Elderly patients (n = 180) with very early or early HCC were studied. This study was approved by the Ethics Committee of the Cancer Center of Sun Yat-Sen University, Guangzhou, China. Written informed consent was obtained from each patient before treatment. As an initial treatment, 89 patients were treated by RFA and 91 patients by HR. The survival curves were constructed by the Kaplan-Meier method and compared by log-rank test.

RESULTS

The 1-, 3-, and 5-year overall survivals were 93.2%, 71.1%, and 55.2% for the RFA group and 88.8%, 62.8%, and 51.9% for the HR group, respectively (P = .305). The corresponding recurrence-free survivals for these 2 groups were 84.1%, 62.7%, and 35.5% and 76.7%, 39.3%, and 33.1%, respectively (P = .035). On subgroup analysis for tumor ≤ 3 cm, the 1-, 3-, and 5-year overall survivals were 94.2%, 82.6%, and 67.5% for the RFA group and 90.1%, 65.0%, and 55.1% for the HR group, respectively (P = .038). The corresponding recurrence-free survivals for the 2 groups were 85.5%, 69.1%, and 40.7%, and 82.2%, 40.1%, and 31.8%, respectively (P = .049). For tumor > 3 cm, there was no significant difference between these 2 groups for overall survivals and recurrence-free survivals (P = .543, P = .356, respectively). A multivariate regression analysis showed that treatment type was the only significant prognostic factor for recurrence-free survival (P = .039).

CONCLUSIONS

There was no difference between the HR and RFA groups for overall survival, but RFA had better efficacy than HR for elderly patients with HCC ≤ 3 cm. Cancer 2013;119:3812–3820. © 2013 American Cancer Society.

INTRODUCTION

Hepatocellular carcinoma (HCC) is a common cancer, and it is the third most common global cause of cancer-related death.[1] With an increase in life expectancy of the general population, the number of elderly individuals with HCC is expected to increase.[2, 3] Current curative treatment options for HCC include: liver transplantation, hepatic resection (HR), and local ablation therapy. Liver transplantation is a good treatment for HCC within the Milan criteria (single HCC ≤ 5 cm or up to 3 nodules each < 3 cm). As a result of the lack of liver donors, one relative contraindication for liver transplantation is age > 65 years, or the protocol requires elderly patients to have very good general health before they can be put on a transplant list.[4, 5] Transcatheter arterial chemoembolization (TACE) is used more commonly for the treatment of intermediate and advanced-stage HCC,[6] whereas HR and local ablation therapy are used for early-stage HCC.[7-9] Among the local ablative therapies, radiofrequency ablation (RFA) is the most widely used.[10, 11] It has the advantage of minimal invasiveness,[8, 9] making it the first-line treatment for small HCC in patients with compromised liver function or associated severe medical conditions.[12, 13]

Elderly patients are more likely to have poor general conditions and associated medical diseases.[14] RFA has the advantage of being less invasive and it causes less pain, less blood loss, and earlier recovery than HR. On the other hand, incomplete ablation of HCC and tumor track seeding may occur.[15] Several studies have demonstrated the safety of HR for elderly patients.[16-18] There is no good evidence in the medical literature to support whether RFA or HR is the better treatment for elderly patients with HCC, and therefore, we conducted this retrospective comparative study on prospectively collected data.

MATERIALS AND METHODS

Patients

This retrospective comparative study on prospectively collected data in our center was approved by the Ethics Committee of the Cancer Center of Sun Yat-Sen University, Guangzhou, China. Written informed consent was obtained from each patient before treatment. From January 2003 to January 2007, there were 456 patients who were older than 65 years and were diagnosed to have HCC for the first time at the Department of Hepatobiliary Oncology in the Cancer Center of Sun Yat-Sen University. Consecutive patients (n = 180) with very early or early HCC (single HCC ≤ 5 cm or up to 3 nodules each ≤ 3 cm) received either RFA or open HR as an initial therapy (Fig. 1). The treatment for elderly patients with very early or early HCC is still controversial and without a universally accepted protocol. After pretreatment investigations, our multidisciplinary treatment team, which comprised radiologists, surgeons, hepatologists, and oncologists, met and selected patients who were suitable to receive either RFA or HR. These treatment options were then discussed with the patient, who was allowed to choose the treatment.

Figure 1.

Chart shows the treatment strategy. Abbreviations: HCC, hepatocellular carcinoma; HR, hepatic resection; RFA, radiofrequency ablation; TACE, transarterial chemoembolization.

The inclusion criteria were: 1) age > 65 years; 2) a solitary HCC ≤ 5.0 cm in diameter, or multiple HCC ≤ 3 lesions, each ≤ 3.0 cm in diameter; 3) no radiologic evidence of invasion into major portal/hepatic vein branches; 4) no extrahepatic metastases; 5) lesions visible on ultrasound and with an acceptable and safe path between the lesion and the skin on ultrasound; or 6) Child-Pugh class A or B disease.

The exclusion criteria were: 1) severe coagulopathy (prothrombin activity < 40% or a platelet count of < 40,000/mm3); 2) Child-Pugh class C disease or evidence of hepatic decompensation including ascites, esophageal or gastric variceal bleeding, or hepatic encephalopathy; or 3) previous treatment.

Diagnosis of HCC

The diagnosis of HCC was based on the criteria used by the European Association for the Study of the Liver (EASL)[19]: either 2 imaging techniques showing typical features of HCC or positive findings on one imaging study together with an AFP level of > 400 ng/mL (n = 132), or cytological/histological diagnosis of HCC (n = 48).

RFA Procedure

The procedure was done by 2 experienced interventional radiologists, who had 14 and 9 years of experience in interventional therapy at the start of the study in January 2003, respectively. Conscious analgesic sedation by intravenous fentanyl citrate and droperidol was routinely used. Local anesthesia with 1% lidocaine was injected at the skin down to the peritoneum along the planned puncture track. The skin was then incised with a small lancet, and a needle was advanced followed by a RFA electrode into the tumor under real-time ultrasound guidance (EUB-2000, Hitachi Medical Systems). For RFA, we used a commercially available system with a 375-kHz computer-assisted radiofrequency generator (Elektrotom HiTT 106; Berchtold, Medizinelektronik, Germany) and an open-perfused electrode (Berchtold, Tuttlingen, Germany) of 15 cm (or 20 cm), 14 gauge, and a 15 mm (or 20 mm) active electrode tip with microbores. After the 14-gauge needle was introduced into the center of the tumor, 60 W of radiofrequency energy was delivered for 8 minutes in a single energy application. During the RFA application, continuous perfusion of the open-perfused electrode with 0.9% sodium chloride solution was done automatically through a syringe pump (Pilot C; Fresenius Medical Care, Alzenau, Germany) linked to a radiofrequency generator. The saline solution was administered at a basal rate of 120 mL/hour. A bolus of 10 to 20 mL saline was administered for 1 to 2 seconds if the impedance increased for more than 900 Ω. A single applicator position with 1 to 2 cycles was adopted for RFA for a tumor. During RFA, a hyperechoic area on ultrasonic monitoring was observed around the electrode tip. The treatment aimed to have this hyperechoic area cover an area larger than 1 cm around the HCC. At the end of the procedure, the needle track was ablated. The patients were closely monitored after RFA.[20]

The evaluation for complete ablation of the lesions after RFA was done by dynamic computed tomography (CT) at 4 weeks after treatment. Complete ablation was diagnosed when a low-density area in both the arterial and portal venous phases was observed, and the size of the area was bigger than the lesion before treatment.[21]

Open Hepatic Resection

Hepatic resection was carried out under general anesthesia using a right subcostal incision with a midline extension. There was no laparoscopic HR. Four surgeons with 13 to 21 years of experience in HR carried out the operations. Intraoperative ultrasonography was routinely used. We preferred to use anatomic resections in the form of segmentectomy and/or subsegmentectomy as described by Makuuchi et al.[22] In segmentectomy, the hepatic parenchyma was transected at the intersegmental plane as described by Couinaud. If the hepatic parenchymal transection plane needed to go beyond the intersegmental plane to achieve the desired extent of resection margin, the small portal branches supplying the liver parenchyma up to the aimed transection plane were punctured under ultrasound guidance and injected with methylthioninium chloride, and then liver subsegmentectomy was performed either alone or in combination with segmentectomy along the plane of demarcation as delineated by the injected methylthioninium chloride. We always resected the whole liver segment(s) which contained the tumor in anatomic resection. In nonanatomic resection (or wedge resection), the resection was done with no regard to segmental or subsegmental plane. Wedge resection was only performed for a superficial tumor situated at the border of more than one liver segment. Pringle's maneuver was used with cycles of clamp and unclamp time of 10 minutes and 5 minutes, respectively. Hemostasis of the raw liver surface was done with suturing and fibrin glue spray.

The resected specimens were histopathologically examined. According to the guidelines of the International Union Against Cancer (UICC), R0 and R1 resections were defined by the absence (tumor-free margin ≥ 1 mm for all detected lesions) or presence (tumor-free margin of 0 mm) of microscopic tumor invasion of the resection margins.[23]

Follow-Up

A dynamic enhanced CT was done 4 weeks after treatment and thereafter once every 3 to 4 months for the first 2 years. At each follow-up visit, liver function tests and alpha-fetoprotein (AFP) were determined. Chest radiography was performed once every 6 months. If necessary, a CT of the chest and bone scintigraphy were also performed for the diagnosis of extrahepatic metastasis. Follow-up visits were extended to once every 6 months from 2 to 5 years after treatment, then once every 12 months after 5 years. This study was censored on January 1, 2011.

Recurrent/residual tumor was classified as: 1) residual disease: this consisted of incomplete ablation in the RFA group and R1 resection in the HR group; 2) local recurrence: recurrent tumor < 2 cm from the ablated area after RFA or from the resection margin after HR; 3) intrahepatic distant recurrence: recurrent tumor at ≥ 2 cm from the ablated area after RFA or from the resection margin after HR; or 4) extrahepatic metastasis. For very early and early recurrent/residual HCC, either HR or RFA was recommended using the Barcelona Clinic Liver Cancer (BCLC) staging classification.[24] For intermediate-stage HCC, either TACE or systemic chemotherapy was given. For advanced HCC, symptomatic treatment was given. Overall survival was defined as the interval between the time of diagnosis of HCC to death or to the last date of follow-up. Recurrence-free survival time was the time between the treatment of HCC to the time when recurrent/residual tumor was diagnosed or to the time of the last follow-up. Patients lost to follow-up were censored on the date of the last follow-up.

Complications

Complications were reported using National Cancer Institute Common Toxicity Criteria, version 4.0, grading.[25] The observation, determination of complications, and grading of pain were done separately by 2 authors of this study (Y.J.Z and H.H.L). Any disagreements were settled by counsel. All complications were observed clinically when patients were admitted, and by telephone after patients were discharged.

Statistical Analysis

Comparisons were made using the unpaired Student t test for continuous variables and the chi-square test for categorical variables. Survival was calculated using the Kaplan-Meier method and comparison between groups was made using the log-rank test. A prognostic significance of the variables in predicting survival was analyzed by the univariate Cox proportional hazards regression models. Results were given as mean ± standard deviation. All significance tests were 2-tailed, and a P < 0.05 was considered to be significant. Statistical analysis of the data was performed using SPSS version 13.0 statistical software.

RESULTS

Patient Characteristics

The demographic data are shown in Table 1. There were significantly more males than females. The mean age in the RFA group was 70.4 years, compared with 68.7 years in the HR group (P = .012). Extrahepatic comorbidities were significantly more common in the RFA group (P = .029). Hepatitis B viral infection was present in 79.8% of the RFA group and 80.2% in the HR group (P = .544). There was no significant difference in Child-Pugh grade, AFP level, platelet count, alanine transaminase, albumin, total bilirubin, and prothrombin activity levels between the 2 groups. There was no significant difference in the number of patients with HCC with a maximum diameter of > 3 cm (P = .524) or with a single HCC between the 2 groups of patients (P = .079).

Table 1. Clinical Characteristics of Patients.
VariableRFA (n = 89)HR (n = 91)P
  1. Abbreviations: AFP, alpha fetoprotein; ALT, alanine aminotransferase; HBV/HCV, hepatitis B/C virus; HR, hepatic resection; RFA, radiofrequency ablation.

Male sex, n (%)75 (84.3)77 (84.6).999
Age, y (range)70.4 ± 4.9 (66–87)68.7 ± 3.3 (66–80).012
Associated comorbidities, n(%)  .029
Diabetes11 (12.4)8 (8.8) 
Hypertension28 (31.5)10 (11.0) 
History of stoke0 (0)1 (1.1) 
Cardiac dysfunction7 (7.9)6 (6.6) 
Chronic pulmonary disease12 (13.5)12 (13.2) 
Renal dysfunction5 (5.6)0 (0) 
Underlying cirrhosis,n(%)   
HBV71 (79.8)73 (80.2).544
HCV4 (4.45)3 (3.3).488
HBV+HCV0 (0)0 (0).999
Nonviral10 (11.2)15 (16.5).212
Alcoholic4 (4.5)0 (0).121
Child-Pugh grade, n   
A/B/C78/11/086/5/0.087
Laboratory data, mean (range)   
Platelet count (×109/L)112.5 ± 34.0 (42–455)174.0 ± 58.4 (74–341).308
Prothrombin activity (%)90 ± 20.1 (52–117)94 ± 18.0 (72–117).433
Albumin (g/L)39.2 ± 3.4 (28.8–48.9)41.4 ± 5.0.4 (30.3–48.3).194
ALT (IU/L)34 ± 10.4 (12–294)32 ± 9.7 (10–364).568
Total bilirubin (μmol/L)19.9 ± 2.4 (6.6–45)15.9 ± 1.6 (7.9–54.8).221
No. of tumors, n (%)  .079
1 tumor83 (93.3)78 (85.7) 
2 tumors4 (4.5)12 (13.2) 
3 tumors2 (2.2)1 (1.1) 
Tumor size max, n(%)  .524
≤2 cm30 (33.7)28 (30.8) 
2.1–3 cm33 (37.1)32 (35.1) 
3.1–5 cm26 (39.2)31 (34.1) 
Single tumor, n(%)   
≤2 cm30 (33.7)27 (29.7).761
2.1–3 cm32 (36.0)32 (35.1).999
3.1–5 cm21 (23.6)19 (20.9).861
AFP level (ng/mL), n (%)   
≤40068 (76.4)59 (64.8).062
>40021 (23.6)32 (35.2) 

Radiofrequency Ablation

The complete ablation rate was 95.5%. For the 4 patients who had incomplete ablation, 1 patient selected symptomatic treatment, 1 received TACE, and the remaining 2 patients received RFA which resulted in complete ablation of the tumors. For the 2 patients with local recurrence, they were treated with RFA. For the 45 patients who had intrahepatic distant recurrence, 20 received RFA, 12 received TACE, and 13 received symptomatic treatment. Extrahepatic metastasis was diagnosed at the left adrenal in 1 patient who also had intrahepatic distant recurrence. This patient received systemic chemotherapy (Table 2).

Table 2. Treatment of Recurrences
VariableRFA (n = 48)HR (n = 57)P
  1. Abbreviations: HR, hepatic resection; RFA, radiofrequency ablation; TACE, transcatheter arterial chemoembolization.

RFA/HR2210.027
TACE1232.044
Systemic chemotherapy10.462
Symptomatic treatment1315.999

Open Hepatic Resection

The operative variables and perioperative outcomes for the 91 patients in the HR group are shown in Table 3. The diagnosis of HCC was confirmed histopathologically in these patients. R0 resection was achieved in 86 patients. For the 5 patients with R1 resection, they were treated with TACE 4 weeks after HR. One patient who developed a local recurrence received RFA. For the 55 patients with intrahepatic distant recurrence, 2 received repeat HR, 7 received RFA, 32 received TACE, and 14 had symptomatic treatment. Extrahepatic metastasis to the right lung and intrahepatic distant recurrence was diagnosed in 1 patient who was given symptomatic treatment (Table 2).

Table 3. Postoperative Outcomes for the Hepatic Resection (HR) Group
VariableHR (n = 91)
Extent of resection (segments) (1/>1)55/36
Surgical time, min (range)155.2 ± 44.5 (60–240)
Blood loss, mL, median (range)300.0 (50–4000)
Red blood cell transfusion (yes/no)29/62
Time of Pringle maneuver, min (range)11.9 ± 9.2 (0–38)
Hospital stay, d (range)21.7 ± 7.0 (13–47)
R0 resection (yes/no)86/5
Degree of differentiation of tumors 
Well-differentiated23
Intermediate-differentiated38
Poorly-differentiated30

Overall Survival and Recurrence-Free Survival

The median follow-up time was 41 months (range, 2-80 months) in the RFA group and 39 months (range, 1-79 months) in the HR group. During follow-up, 45 patients in the HR group and 30 patients in the RFA group died. Seven patients (15.6% of deaths) in the HR group died of non–tumor related causes, including 1 patient who died of hepatic encephalopathy after surgery. The remaining 38 patients in the HR group died of tumor-related causes. For the RFA group, 30 patients died of tumor-related causes (Table 4). The cumulative overall survivals in the RFA group were 93.2% at 1 year, 71.1% at 3 years, and 55.2% at 5 years, whereas the corresponding figures for the HR group were 88.8%, 62.8%, and 51.9%, respectively (Fig. 2A; P = .305). The 1-, 3-, and 5-year recurrence-free survivals were 84.1%, 62.7%, and 35.5% for the RFA group and 76.7%, 39.3%, and 33.1% for the HR group, respectively (Fig. 2B; P = .035).

Figure 2.

Survival curves are shown for the radiofrequency ablation (RFA) and hepatic (liver) resection (LR) groups. Graphs show (A) overall survivals for the RFA and LR groups, and (B) recurrence-free survivals for the RFA and LR groups.

Table 4. Causes of Death on Follow-Up
VariableRFA (n = 30)HR (n = 45)P
  1. Abbreviations: HR, hepatic resection; RFA, radiofrequency ablation.

Cancer-related3038.735
Liver failure05.151
Gastrointestinal bleeding01.999
Treatment-related01.999

On subgroup analysis for patients with tumor ≤ 3 cm, the 1-, 3-, and 5-year overall survivals were 94.2%, 82.6%, and 67.5% for the RFA group (n = 63) and 90.1%, 65.0%, and 55.1% for the HR group (n = 60), respectively (Fig. 3A; P = .038). The corresponding recurrence-free survivals for the RFA (n = 63) and HR (n = 60) groups were 85.5%, 69.1%, and 40.7% and 82.2%, 40.1%, and 31.8%, respectively (Fig. 3B; P = .049). For patients with tumors > 3 cm, the 1-, 3-, and 5-year overall survival were 91.7%, 53.9%, and 36.6% for the RFA group and 87.1%, 58.8%, and 47.0% for the HR group, respectively (P = .543). The corresponding recurrence-free survivals after RFA and HR were 79.4%, 51.8%, and 30.0% and 62.1%, 38.4%, and 28.8%, respectively (P = .356).

Figure 3.

Subgroup analysis was performed for patients with hepatocellular carcinoma (HCC) ≤ 3 cm. Graphs show (A) overall survivals for patients with HCC ≤ 3 cm who received radiofrequency ablation (RFA) and hepatic (liver) resection (LR), and (B) recurrence-free survivals for patients with HCC ≤ 3 cm who received RFA or LR.

Complications

One patient in the HR group died within the same hospital admission, producing a mortality rate of 1.1%. The in-hospital mortality for the RFA group was 0%. The 90-day mortality rate for the HR group was 1.1%. The corresponding figure for the RFA group was 0%. Fever and pain were the most commonly seen minor complications after treatments. Posttreatment fever with an axillary temperature > 38.5°C, was observed in 26 patients in the RFA group and 42 patients in the HR group (P = .014). Analgesics were required in 33 patients in the RFA group and 48 patients in the HR group (P = .025) (Table 5). In the RFA group, skin burn occurred in 1 patient. There was no tumor track seeding or no local hematoma in the RFA group. Other more significant complications included ascites, cardiac disorder, hepatic failure, transient ischemic attack, lung infection, hepatobiliary disorder, pleural effusion, postoperative hemorrhage, acute kidney injury in the HR group, and pleural effusion and hepatobiliary disorder in 1 patient in the RFA group (Table 4). The hospital stay for the RFA group was significantly shorter than that of the HR group (8.01 days ± 2.70 days versus 13.50 days ± 4.05 days, P < .001).

Table 5. Complications After Treatment
VariableRFA (n = 89)HR (n = 91)P
  1. Abbreviations: HR, hepatic resection; RFA, radiofrequency ablation.

Pain  .025
Grade 11910 
Grade 21329 
Grade 319 
Fever (temperature >38.5°C)  .014
Grade 12425 
Grade 2217 
Ascites  <.001
Grade 105 
Grade 208 
Skin burn  .999
Grade 110 
Cardiac disorder  .999
Grade 201 
Hepatic failure  .004
Grade 308 
Grade 401 
Transient ischemic attack  .122
Grade 104 
Lung infection  .999
Grade 201 
Hepatobiliary disorders  .999
Grade 110 
Grade 201 
Pleural effusion  .004
Grade 112 
Grade 2113 
Postoperative hemorrhage  .497
Grade 201 
Grade 301 
Acute kidney injury  .999
Grade 201 
Death01.999

Univariate and Multivariate Analyses

By univariate analysis, prothrombin activity (P = .002) and tumor size (P < .001) were associated with overall survival. Multivariate Cox proportional hazards regression analysis showed that tumor size (hazard ratio = 1.875; 95% confidence interval [CI] = 1.91-2.951; P = .007) was the only significant prognostic factor for overall survival. By univariate analysis, tumor size (P = .01), prothrombin activity (P = .02), and treatment type (P = .001) were associated with recurrence-free survival. Multivariate Cox proportional hazards ratio analysis showed treatment type (hazard regression = 1.502; 95% CI = 1.021-2.209; P = .039) was the only significant prognostic factor for recurrence-free survival.

DISCUSSION

As the life expectancy of the population is getting longer, the incidence of HCC rises in the elderly.[26, 27] We chose 65 years as the cutoff age for elderly patients in this study because a British study reported patients aged 65 years and above received less active treatment and had poorer survival than younger patients.[28] A Korean study also showed patients with HCC who were older than 65 years had more morbidities, poor performance status, smaller tumor area, and multinodular disease.[14] Besides, age older than 65 years is a relative contraindication for liver transplantation, according to some guidelines.[4, 5]

Studies have shown that surgery is effective and safe in selected elderly patients with HCC,[16-18] and the survival and postoperative complication are not significantly different from that of younger patients. However, there are few reports that compare RFA with HR in elderly patients with HCC. Takahashi et al[29] compared elderly and younger patients who received RFA, and they concluded that RFA was efficient and safe in the elderly patient, but they did not compare RFA with HR in the elderly. There are several randomized controlled trials that compared RFA with HR in the treatment of small HCC. Chen et al[8] claimed RFA was as effective as HR for solitary and small HCC, but it was less invasive. On the other hand, Huang et al[9] showed HR to result in better survival and less recurrence than RFA for patients with HCC within the Milan criteria. However, this study included both younger and elderly patients. Our study is the first study to compare the efficacy and safety between RFA and open HR for elderly patients with HCC. This study shows there was no difference in overall survival between RFA and HR in elderly patients who had HCC within the Milan criteria, but RFA had better recurrence-free survival than HR. On subgroup analysis, the overall and recurrence-free survivals were significantly better for patients with tumor ≤ 3 cm who received RFA than those who had HR. The results are not surprising for the following reasons: First, several studies have shown that RFA can achieve similar survival outcomes as HR for early-stage HCC.[13, 30] Current technologies allow RFA to produce a necrotic area of 5 cm or more in diameter in one treatment session, thus allowing full ablation of a 3-cm tumor plus a 1.0-cm margin, making RFA suitable for treatment of HCC ≤ 3 cm in diameter. Microvascular invasion with satellite lesions is an important poor prognostic factor for HCC,[31] and a larger safety ablation margin theoretically allows a higher potential to cure a HCC ≤ 3 cm. Second, because RFA causes less deteriorative effects on the patient's liver function than HR, patients who receive RFA are more likely to receive repeated curative treatment when HCC recurs.[32] In our study, approximately 45.8% (22 of 48 patients) in the RFA group received RFA or HR for recurrent HCC, whereas only 17.5% (10 of 57 patients) in the HR group received these treatments (P = .027). Third, elderly patients with associated comorbidities have a higher perioperative risk for HR than with RFA. Furthermore, blood loss and blood transfusion, which are more likely to be required in HR than in RFA, are associated with increased recurrence rates and worse survivals.[33, 34] In addition, there was a study which indicated that RFA could exert an activating effect on the immune system, thus favoring trafficking of lymphocyte subsets and enhancing tumor antigen-specific cellular immune responses, and the local necrosis of tumor cells produced by RFA was involved in immune regulation.[35] Our results suggested that RFA is a good treatment for a solitary HCC ≤ 3 cm or up to 3 nodules each of < 3 cm. For tumors 3.1 to 5.0 cm in size, there is no evidence that RFA is better than HR. Regarding complications of treatment, RFA is unlikely to result in major complications,[8, 9, 13] whereas elderly patients are prone to develop complications following HR. Thus, RFA is safer than HR in these patients.

There are limitations of our study. This study is retrospective and it is likely that there is a bias in selecting patients to receive either RFA or open HR. Another limitation is that the location of the tumors in the 2 groups of patients had not been taken into consideration during the analysis of our data. Third, the 2 groups of patients were extremely well matched. We believe this happened partly by chance, and partly because of the large number of patients with HCC we treat per year. During the study period, we treated on average 600 patients with hepatic resection, 800 patients with TACE, and 240 patients with RFA per year. A randomized study comparing these 2 groups of patients is now ongoing in our department, and the study has been registered with Clinicaltrials.gov (NCT01570075). Fourth, we did not carry out biopsy of the lesions for the patients who received RFA. Noninvasive diagnosis of HCC based on a combination of imaging and laboratory finding was first established by the EASL in Barcelona, Spain, in 2001.[19] In 2005, a new HCC radiological hallmark, ie, contrast uptake in the arterial phase and washout in the venous/late phase, was adopted by the EASL panel of experts and by the American Association for the Study of Liver Diseases (AASLD) guidelines to establish a new noninvasive diagnostic criteria of HCC.[36] In this criteria, diagnosis was established by 1 imaging technique in nodules > 2 cm showing the HCC radiological hallmark and 2 coincidental techniques with nodules of 1 to 2 cm in diameter. AFP levels were dropped from the diagnostic scheme.[36] This noninvasive diagnosis has been shown to achieve high positive predictive value and specificity in several prospectively conducted studies,[37, 38] although the diagnostic rate is not 100%.

In conclusion, RFA was efficacious and safe for elderly patients with HCC within the very early or early stage. The results were especially good for patients with HCC smaller than 3 cm.

FUNDING SOURCES

This work is supported by a grant from the National Natural Science Foundation of China (NSFC, grant 30872995), the State Key Project on Infectious Diseases of China (grant 2012ZX10002-016) and the 5010 Foundation of Sun Yat-sen University, grant 2007043.

CONFLICT OF INTEREST DISCLOSURE

The authors made no disclosure.

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