Abstract
Objectives:
This study aimed to compare survival outcomes after hepatic resection (HR) and radiofrequency ablation (RFA) in early-stage hepatocellular carcinoma (HCC) at a Western hepatobiliary centre.
Methods:
Demographic details, clinicopathologic tumour characteristics and survival outcomes were compared among non-transplant candidate patients undergoing HR (n= 50) and RFA (n= 60) for early-stage HCC during 2001–2011.
Results:
Patients who underwent HR had larger tumours, a longer length of stay and a higher rate of postoperative complications. After a median follow-up of 29 months, there were no significant differences between the treatment groups in 1-, 3- and 5-year overall survival (OS) [RFA group: 86%, 50%, 35%, respectively; HR group: 88%, 68%, 47%, respectively (P= 0.222)] or disease-free survival (DFS) [RFA group: 68%, 42%, 28%, respectively; HR group: 66%, 42%, 34%, respectively (P= 0.823)]. The 58 patients who underwent RFA demonstrated ablation success on follow-up computed tomography at 3 months. Of these, 96.5% of patients showed sustained ablation success over the entire follow-up period. In a subgroup analysis of patients with tumours measuring 2–5 cm, no differences in OS or DFS emerged between the HR and RFA groups. Similarly, no significant differences in outcomes in patients with Child–Pugh class A cirrhosis were seen between the RFA and HR groups.
Conclusions:
Radiofrequency ablation is comparable with HR in terms of OS and DFS. It is a reasonable alternative as a first-line treatment for HCC in well-selected patients who are not candidates for transplant.
Introduction
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third most common cause of cancer-related death; an estimated 500 000 deaths from HCC occur per year.1 It is less common in the western hemisphere; however, its incidence is increasing.2 The implementation of early screening guidelines has increased the number of patients diagnosed with early-stage HCC.3 For patients who are candidates, liver transplantation guarantees the best longterm overall survival (OS) and disease-free survival (DFS) as it removes both the tumour and the cirrhotic background liver. However, its use is limited by shortages in donor organ supply and high costs. For these reasons, limited hepatic resection (HR), for which 5-year survival rates range from 41% to 72%, has traditionally been seen as the next best treatment for patients with HCC.4 Unfortunately, surgical resection is often limited by the degree of liver cirrhosis and resection rates range between 10% and 37%, even in highly specialized centres.5
Multiple local ablative treatments have been developed to treat HCC. These include transarterial chemoembolization, percutaneous ethanol injection and radiofrequency ablation (RFA). The last of these has been increasingly used as a second-line alternative to surgery for primary and metastatic hepatic malignancies because it is superior to other locally ablative modalities, safer and provides more consistent results in local tumour control.6–8 Its major usage has been in patients with early-stage HCC and limited liver reserve, who are unsuitable for surgical resection. Most of the guidelines for the treatment of HCC recommend HR and RFA as first- and second-line treatments, respectively, in patients with good liver function (classified as Child–Pugh class A or B cirrhosis) and a single tumour or no more than three tumours each measuring ≤3 cm.9–11 These guidelines were based on the assumption that surgical resection achieves complete tumour ablation with a safety margin, although there is no evidence supported by randomized controlled trials (RCTs) for this.
Whether RFA provides longterm OS and DFS equivalent to those of HR when it is used as a first-line treatment remains unclear in cohort studies.12–14 Two RCTs have been performed, but gave contradictory conclusions.15,16 A recent meta-analysis showed that HR was superior to RFA, especially for HCC tumours measuring >3 cm, although the low level of evidence in the studies enrolled in this meta-analysis limits its conclusions. Therefore, the optimal first-line treatment for early-stage HCC, whether it be HR or RFA, in patients with well-preserved liver function remains insufficiently established. Although many studies conducted in Asia and Europe have compared outcomes between HR and RFA, this type of comparison has not been properly performed in the USA. This study sought to retrospectively analyse longterm OS and DFS in 110 patients with early-stage HCC who were not listed for liver transplant and who received either RFA or HR as a first-line treatment.
Materials and methods
Patients
Between January 2000 and September 2011, 1010 patients diagnosed with HCC were evaluated at the University of Pittsburgh Medical Center (UPMC) Liver Cancer Center in Pittsburgh, Pennsylvania. A total of 110 patients with newly diagnosed HCC classified according to the Barcelona Clinic Liver Cancer (BCLC) system11 as very early/early-stage HCC and in receipt of either HR (n= 50) or RFA (n= 60) as a first-line treatment were included in this study. Patients who received or were listed for liver transplantation during the study period were excluded. Patients were not listed for liver transplant for reasons of active alcohol or illicit drug abuse, age, severe comorbidities, psychosocial factors, absence of liver cirrhosis or patient preference. Data were analysed retrospectively from a prospective institutional review board-approved hepatic cancer registry. Factors examined included patient demographics, presence of cirrhosis, aetiology of hepatitis, Child–Pugh classification, tumour characteristics, treatment modality and survival outcome.
The diagnosis of HCC was based on the criteria defined in the practice guidelines of the European Association for the Study of Liver (EASL) or the American Association for the Study of Liver Disease (AASLD).10,11 Evaluation included clinical laboratory values (complete blood count, basic metabolic panel, coagulation studies, liver function tests), hepatitis screening, analysis for tumour markers [alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9)], and radiographic studies including triphasic helical axial computed tomography (CT) and magnetic resonance imaging (MRI). Liver biopsy was performed when diagnosis could not be determined according to laboratory (AFP ≥ 400 ng/ml) and radiographic data alone. Diagnosis and treatment recommendations for all patients were made at a weekly multidisciplinary liver tumour conference.
Treatment of HCC
All patients were reviewed by a multidisciplinary liver tumour board comprised of specialists in transplant surgery, surgical and medical oncology, hepatology and interventional radiology. All procedures were performed at a single institution (UPMC). In patients scheduled to undergo HR, the extent of resection was determined by an experienced surgical team based on the severity of liver disease, the location of the tumour, and the anticipation of an adequate non-tumour margin. All RFA procedures were performed in the operating room under general anaesthesia. Open and laparoscopic approaches were used. Laparoscopic ablation was usually performed via three laparoscopic ports. Intraoperative ultrasound was uniformly used to assess the placement of the RFA probe. Standard protocols for ablation time and power were used. Tissue biopsy was always obtained from the tumours intraoperatively prior to ablation.
Surveillance
All patients were surveyed closely in clinic according to imaging studies and AFP levels at intervals of 3–6 months. The effect of RFA was evaluated with contrast-enhanced CT or MRI at 1–3 months after the procedure. Ablation success was defined according to the appearance of an area equal to or larger than that of the ablated tumour without contrast enhancement at 3 months after RFA. Local recurrence was defined as tumour recurrence at the treated site. A new tumour that appeared elsewhere in the hepatic parenchyma was defined as a new intrahepatic recurrence. Recurrences were treated using modalities selected according to the preference of the patient and the clinical practice of treating surgeons and clinicians.
Statistics
All patients were followed until death or September 2011. Statistical analysis was performed using spss Version 17.0 for Windows (SPSS, Inc., Chicago, IL, USA). Descriptive statistics were used to analyse sociodemographic and disease-specific variables. Intergroup comparisons on disease-specific variables were performed using chi-squared analyses for categorical variables. Rates of OS and DFS were obtained using Kaplan–Meier survival analyses (log-rank). In all comparisons, a P-value of 0.05 was considered to indicate statistical significance.
Results
Patient demographics
Of the 1010 consecutive patients treated for HCC at the UPMC Liver Cancer Center, 110 patients presented with early-stage HCC and were treated with either HR or RFA as first-line therapy. Patients who received or were listed for liver transplantation or had Child–Pugh class C cirrhosis were excluded. Demographic characteristics are summarized in Table 1. There were no significant differences between the HR and RFA groups in age, gender, preoperative AFP level or aetiology of cirrhosis. However, patients who underwent RFA had significantly smaller tumours and worse underlying liver function according to Child–Pugh class; however, there was no difference in Model for End-stage Liver Disease (MELD) scores between the groups. Cirrhosis was identified in 66.0% of patients in the HR group and 93.3% of patients in the RFA group. The majority of patients receiving either HR or RFA were treated for a single tumour nodule (HR group, n= 39; RFA group, n= 47).
Table 1.
Patient characteristics
| RFA group (n= 60) | HR group (n= 50) | P-value | |
|---|---|---|---|
| Age, years, mean ± SD | 65.6 ± 12 | 66.3 ± 1 | 0.723 |
| Male gender, n (%) | 38 (63.3%) | 31 (62.0%) | 0.942 |
| AFP, ng/ml, mean ± SD | 141 ± 507 | 2730 ± 9991 | 0.116 |
| Aetiology of cirrhosis | 0.853 | ||
| Hepatitis B only | 5.2% | 6.4% | |
| Hepatitis C only | 48.3% | 38.7% | |
| Hepatitis B and C | 12.1% | 12.9% | |
| Non-viral | 34.4% | 41.9% | |
| Child–Pugh class | 0.03 | ||
| No cirrhosis | 4 (6.7%) | 17 (34.0%) | |
| Class A | 40 (66.7%) | 27 (54.0%) | |
| Class B | 16 (26.7%) | 6 (12.0%) | |
| MELD score in cirrhosis | 8 ± 2 | 8 ± 3 | 0.929 |
| Tumour size, cm, mean ± SD | 2.36 ± 0.94 | 3.07 ± 1.17 | 0.001 |
| Number of nodules, n (%) | 0.851 | ||
| 1 | 47 (78.3%) | 39 (78.0%) | |
| 2 | 11 (18.3%) | 10 (20.0%) | |
| 3 | 2 (3.3%) | 1 (2.0%) | |
| Hospital LoS, days, mean ± SD | 2.2 ± 1.85 | 5.36 ± 2.9 | < 0.01 |
| 90-day complications, n (%) | 9 (14.7%) | 15 (30.0%) | 0.04 |
| 90-day mortality, n (%) | 2 (3.3%) | 0 |
RFA, radiofrequency ablation; HR, hepatic resection; SD, standard deviation; AFP, alpha-fetoprotein; MELD, Model for End-stage Liver Disease; LoS, length of stay.
Treatment results
Surgical resection for early-stage HCC was performed in 50 patients and consisted of anatomic lobectomy (n= 8), segmentectomy/bisegmentectomy (n= 36) or non-anatomic resection (n= 6). Surgery was performed using an open procedure in 32 (64.0%) patients and as a minimally invasive laparoscopic or hand-assisted procedure in 18 (36.0%) patients. Histopathological examination showed six (12.0%) poorly differentiated, 27 (54.0%) moderately differentiated and 17 (34.0%) well-differentiated tumours. Eight (16.0%) specimens had microsatellites and 24 (48.0%) specimens showed microvascular invasion.
Sixty patients with early-stage HCC received RFA as first-line therapy. The vast majority (95.0%) of RFA procedures were performed laparoscopically. Three (5.0%) patients underwent an open RFA procedure. Biopsy specimens in the RFA group showed five (8.3%) poorly differentiated, 36 (60.0%) moderately differentiated and 19 (31.7%) well-differentiated tumours.
The hospital length of stay (LoS) was significantly longer in the HR group (5.36 ± 2.9 days) than in the RFA group (2.2 ± 1.85 days) (Table 1). A comparison of patients who underwent minimally invasive (laparoscopic) RFA (n= 57) with those subjected to minimally invasive HR (n= 17) showed that hospital LoS was significantly shorter in the laparoscopic RFA subgroup (2.07 ± 1.32 days vs. 3.61 ± 1.33 days; P < 0.001). Two deaths within the first 90 days after surgery occurred in the HR group, both in patients with Child–Pugh class B cirrhosis. No patients in the RFA group died within 90 days of treatment. The frequency of complications was significantly higher in the HR group (n= 15, 30.0%) than in the RFA group (n= 9, 15.0%) (P= 0.04) (Table 1). A comparison of complications classified according to the Clavien–Dindo system showed the occurrence of six and three Grade IIIa complications, four and two Grade II complications, and five and four Grade I complications in the HR and RFA groups, respectively. Complications in the HR group included pleural effusion (n= 3), pneumonia (n= 1), myocardial infarction (n= 1), biloma (n= 2), ileus (n= 2), ascites (n= 1), hyperbilirubinaemia >6 (n= 1), renal insufficiency (n= 1) and encephalopathy (n= 2). Complications in the RFA group included severe oesophagitis (n= 1), encephalopathy (n= 3), cholangitis (n= 1), ascites (n= 2), renal insufficiency (n= 1) and pneumonia (n= 1).
Recurrence of HCC
Follow-up at a median of 29 months showed tumour recurrences in 21 (35.0%) RFA-treated patients and 23 (46.0%) HR-treated patients (P= 0.249). There were no significant differences in the location of disease recurrence between the treatment groups. In the HR group, 18 patients had new intrahepatic lesions, two patients had extrahepatic recurrence, and three patients had both. In the RFA group, 16 patients had new intrahepatic lesions (two of which recurred at sites of prior ablation), two patients had extrahepatic recurrence, and three patients had both. Treatment of recurrences included surgical resection, ablation, systemic chemotherapy, radiation therapy and chemoembolization (Table 2).
Table 2.
Treatment of recurrences in the hepatic resection (HR) and radiofrequency ablation (RFA) groups
| Treatment | HR group (n= 23), n (% ) | RFA group (n= 21), n (% ) |
|---|---|---|
| None | 7 (30.5%) | 5 (23.8%) |
| TACE alone (range: 1–13 treatments) | 8 (34.8%) | 4 (19.1%) |
| Yttrium-90 alone (range: 1–2 treatments) | 3 (13.1%) | 4 (19.1%) |
| Resection | 1 (4.3%) | 2 (9.5%) |
| Systemic chemotherapy | 2 (8.7%) | 1 (4.8%) |
| Radiofrequency ablation | 1 (4.3%) | 3 (14.2%) |
| Combination/sequential treatments (TACE ± yttrium-90 ± resection ± chemotherapy) | 1 (4.3%) | 2 (9.5%) |
TACE, transarterial chemoembolization.
Ablation success as defined in follow-up imaging at 3 months was achieved in 58 (96.7%) of the patients who received RFA. During the follow-up, local recurrence at the ablation site was observed in two of the 58 patients (3.4%). Thus, ablation success was sustained throughout the follow-up period in 56 of 58 patients (96.6%) and treatment was deemed to have failed in four of 60 patients (6.7%).
Survival analyses
Overall survival at 1 year, 3 years and 5 years did not differ between the HR and RFA groups (RFA group: 86%, 50%, 35%, respectively; HR group: 88%, 68%, 47%, respectively) (Fig. 1). The median OS was 42 months in RFA-treated patients and 65 months in HR-treated patients (P= 0.222). Similarly, there were no significant differences between the groups in 1-, 3- and 5-year DFS (RFA group: 68%, 42%, 28%, respectively; HR group: 66%, 42%, 34%, respectively) (Fig. 2). Median DFS was 27 months in the RFA group and 28 months in the HR group (P= 0.823). A subgroup analysis of patients with tumours measuring ≥2 cm (excluding very early-stage HCC) showed no significant difference in OS and DFS between the treatment groups (Table 3, Figs 3 and 4). Likewise, there was no significant difference in OS and DFS in the subgroups of patients with Child–Pugh class A cirrhosis (Table 3, Figs 5 and 6). Similarly, no significant difference in OS and DFS emerged between patients without cirrhosis and patients with Child–Pugh class B cirrhosis (data not shown).
Figure 1.
Kaplan–Meier curves showing overall survival in the hepatic resection (HR) and radiofrequency ablation (RFA) treatment groups
Figure 2.
Kaplan–Meier curves showing disease-free survival in the hepatic resection (HR) and radiofrequency ablation (RFA) treatment groups
Table 3.
Overall and disease-free survival subgroup analysis based on tumour size and degree of cirrhosis
| HR group, tumours of ≥2 cm | RFA group, tumours of ≥2 cm | P-value | HR group, Child–Pugh class A | RFA group, Child–Pugh class A | P-value | |
|---|---|---|---|---|---|---|
| Patients, n | 36 | 36 | 27 | 40 | ||
| Overall survival | NS | NS | ||||
| 1-year | 88% | 82% | 92% | 92% | ||
| 3-year | 68% | 54% | 64% | 60% | ||
| 5-year | 52% | 42% | 52% | 42% | ||
| Median survival, months | 58 | 42 | 65 | 52 | ||
| Disease-free survival | NS | NS | ||||
| 1-year | 50% | 52% | 48% | 54% | ||
| 3-year | 38% | 39% | 32% | 37% | ||
| 5-year | 28% | 24% | 24% | 18% | ||
| Median survival, months | 28 | 24 | 12 | 11.5 |
HR, hepatic resection; RFA, radiofrequency ablation; NS, not significant.
Figure 3.
Kaplan–Meier curves showing overall survival in subgroups of patients with hepatocellular carcinoma tumours measuring ≥2 cm in the hepatic resection (HR) and radiofrequency ablation (RFA) treatment groups
Figure 4.
Kaplan–Meier curves showing disease-free survival in subgroups of patients with hepatocellular carcinoma tumours measuring ≥2 cm in the hepatic resection (HR) and radiofrequency ablation (RFA) treatment groups
Figure 5.
Kaplan–Meier curves showing overall survival in subgroups of patients with Child–Pugh class A cirrhosis in the hepatic resection (HR) and radiofrequency ablation (RFA) treatment groups
Figure 6.
Kaplan–Meier curves showing disease-free survival in subgroups of patients with Child–Pugh class A cirrhosis in the hepatic resection (HR) and radiofrequency ablation (RFA) treatment groups
Discussion
Liver transplantation has been shown to be the ideal treatment for HCC in terms of longterm outcomes.17 However, its application is limited by organ shortages and lengthy waiting times. Hepatic resection is still considered the most effective treatment in patients with resectable HCC and preserved liver function who are not candidates for liver transplantation. Assessing which therapy is optimal is not always easy. In clinical practice, demographics, tumour size, tumour location, underlying liver disease and comorbidities influence the surgeon's decision on whether to offer RFA or HR to a patient with early HCC. Whether the first-line treatment for these patients should comprise HR or RFA remains a matter of debate in which there are no clear guidelines. Two randomized trials addressing this issue have been published. However, one trial concluded that there was no difference in patient survival between HR and RFA, whereas the other demonstrated that HR may provide better survival and lower recurrence than RFA.15,16 Both studies were criticized for their study design, small sample sizes, differences in baseline characteristics between groups and high rates of conversion from ablation to surgery.
In the present study, HR and RFA were used as first-line treatments for patients with early-stage HCC who were not candidates for liver transplantation. Reasons for excluding patients from liver transplant included active alcohol or illicit drug abuse, age, the presence of severe comorbidities, psychosocial factors and patient preferences. Rates of local control efficacy and longterm survival did not differ statistically between patients undergoing HR and RFA, respectively, with curative intent. Furthermore, complete local responses were sustained throughout follow-up (median: 29 months) in 96.5% of patients treated with RFA. Interestingly, survival rates in the present patients with early-stage HCC were lower than those reported in previously published studies.18 This difference may reflect the fact that patients in the Asian studies were younger and were more likely to have hepatitis B than hepatitis C. In addition, the present study analysed only patients not listed for transplant and thus possibly selected patients with poorer upfront prognoses.
A major determinant of survival in patients with HCC refers to the underlying liver disease.19 As a result, comparisons of the outcomes of HR and RFA in different studies are potentially undermined by selection bias because RFA is usually reserved for patients with worse underlying liver function. This was also noted in the present study, in which patients in the RFA group were more often cirrhotic or had Child–Pugh class B cirrhosis. In an attempt to eliminate this discrepancy, a subgroup analysis of outcomes in patients with similar background liver disease was performed. This found no statistically significant difference between outcomes after RFA and HR, respectively, in terms of OS and DFS in patients with Child–Pugh class A cirrhosis.
Radiofrequency ablation has been recommended for the treatment of patients with smaller tumours because it was previously considered to be less efficacious for bigger HCCs.20 Over the course of this study, RFA technology has improved with the development of newer and larger 5–7-cm probes, which allow the treatment of larger tumours. It has also been shown to be efficacious in both tumours measuring <3 cm and HCC tumours of 5 cm.21,22 The present study included a subgroup analysis to investigate how RFA compares with HR in patients with tumours of ≥2 cm. This analysis found no difference in OS and DFS subsequent to RFA and HR, respectively, in patients with larger tumours (2–5 cm), although it did note a trend towards higher OS after HR. Figure 5 shows outcomes in patients with Child–Pugh class A cirrhosis and indicates little separation between the groups. The space between the curves in Fig. 3 may reflect the fact that baseline liver function was better in the HR group and thus patients in this group would expect to achieve better survival. In addition, the analysis may not have reached statistical significance because the number of patients in the group was limited.
Radiofrequency ablation is not without limitations and specific risks should be considered before this technique is employed. Lesions must be visible by ultrasound and should be remote from large blood vessels as the heat sink effect may hinder appropriate tumour control. In addition, care must be taken to avoid thermal injury to adjacent bile ducts. Furthermore, tumour seeding was observed in 1.8% of patients in a series by Livraghi et al.12 In the present study, microsatellite disease next to the primary tumour was detected on final pathology, but not on preoperative imaging, in 16.0% of the HR group. It has been proposed that HR is advantageous because it allows for the complete resection of tumour tissue along with adjacent territory that might harbour microsatellite disease and venous tumour thrombi and thus may lead to a lower frequency of intrahepatic recurrence.23 However, the present study found no significant difference in intrahepatic recurrences between the HR and RFA patient groups.
The limitations of this study include its retrospective nature and the bias inherent in decisions on which treatment should be given to each patient. In addition, the analysis of OS does not take into account effects accomplished by subsequent multimodal treatments. Further, the study sample represented a highly selected small number of patients. However, although this study does not define an algorithm for the use of these two modalities, it does indicate that RFA should be considered as a primary treatment option or as an alternative to surgery in early-stage HCC because it is minimally invasive, allows for excellent local tumour control, and incurs a lower rate of complications and a shorter hospital LoS than HR. Furthermore, Ikeda et al. 24 demonstrated that RFA is more cost-effective than surgery in the treatment of small HCCs. Unfortunately, patients affected by HCC will undergo several treatments during their lives because the recurrence rate at 5 years is close to 70%. As a result, minimally invasive procedures such as RFA are desirable. Patients in whom RFA fails can be reassessed for HR because survival rates in patients undergoing HR after initial RFA failure and patients undergoing HR as initial treatment have been found to be identical.25 In conclusion, the present study finds that RFA is comparable with HR in terms of OS and DFS. Radiofrequency ablation is a reasonable option as a first-line treatment for early-stage HCC in well-selected patients who are not listed for transplantation.
Conflicts of interest
None declared.
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