Scandinavian Journal of Gastroenterology. 2015; 50: 567–576
ORIGINAL ARTICLE
Radiofrequency ablation versus resection for the treatment of early stage hepatocellular carcinoma: a multicenter Australian study
ILANA GORY1, MICHAEL FINK2, SALLY BELL3, PAUL GOW2, AMANDA NICOLL4, VIRGINIA KNIGHT5, ANOUK DEV5, ANTHONY RODE4, MICHAEL BAILEY6, WA CHEUNG1, WILLIAM KEMP1 & STUART K. ROBERTS1, ON BEHALF OF THE MELBOURNE LIVER GROUP 1
The Alfred Hospital, Melbourne, Australia, 2University of Melbourne Department of Surgery, Austin Health, Melbourne, Australia, 3St. Vincent’s Hospital, Melbourne, Australia, 4Royal Melbourne Hospital, Melbourne, Australia, 5Monash Medical Centre, Monash University, Melbourne, Australia, and 6Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
Abstract Objectives. It remains unclear whether radiofrequency ablation (RFA) provides comparable outcomes to surgical resection (SR). We, therefore, compared survival outcomes of RFA to SR in patients with early stage and very early stage hepatocellular carcinoma (HCC). Methods. A multicenter retrospective analysis was performed in patients from five academic hospitals with Barcelona Cancer of the Liver Clinic (BCLC) stages 0–A HCC having RFA or SR as primary therapy. Results. From 2000– 2010, 146 patients who received treatment with RFA (n = 96) or SR (n = 52) were identified. In BCLC A patients with £5 cm HCC, there was a trend of lower overall survival after RFA compared with SR (3- and 5-year survival: 62% and 37% vs. 66% and 62% respectively; p = 0.11). By multivariate analysis, RFA was an independent predictor of poor survival (hazard ratio = 2.26; 95% confidence interval: 1.02–5.03; p = 0.04). In £3 cm HCC (n = 109), the 3- and 5-year survivals in RFA and SR groups were 66% and 39%, and 69% and 59%, respectively, with no difference in the median survival (p = 0.41). Local recurrence was significantly higher after RFA compared to SR in HCC £5 cm (p = 0.006) with a trend of lower recurrence-free survival (p = 0.06) after RFA in HCC £3 cm. There were fewer major complications after RFA (2% vs. 8%). Conclusion. While SR is superior to RFA for the management of early stage BCLC A disease with £5 cm HCC, both appear effective as firstline treatment options for Western patients with small £3 cm tumors. Although safer than SR, RFA is associated with higher rates of tumor recurrence and local disease progression. Further prospective randomized controlled trials are warranted to compare these two modalities.
Key Words: Hepatocellular carcinoma, radiofrequency ablation, surgical resection, survival
Introduction Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide with more than 500,000 deaths occurring annually from this disease [1–3]. Moreover, HCC incidence rates are rising in several developed countries [4–7]. In response, HCC screening programs have been widely implemented in at-risk populations to reduce the mortality of HCC.
As a consequence, an increasing number of patients are diagnosed with early stage HCC and are now eligible for curative therapies including surgery and local ablation [8,9]. Although liver transplantation is the optimal curative therapy for early stage HCC, access to this modality is limited due to donor shortage. Further, surgical resection (SR) as the next best option is only applicable to around 10–20% patients [2,10–14]. In
Correspondence: Stuart Roberts, Department of Gastroenterology, The Alfred Hospital, 55 Commercial Rd, Melbourne, 3004, Australia. Tel: +61 3 9076 3375. Fax: +61 3 9076 2194. E-mail: [email protected]
(Received 1 June 2014; revised 4 August 2014; accepted 5 August 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2014.953572
568
I. Gory et al.
contrast, significantly more patients are candidates for curative therapy with radiofrequency ablation (RFA) that is considered a safe and effective modality for patients with cirrhosis and small HCC [15–20]. Recently, there has been much interest and debate regarding the relative efficacy of RFA versus SR as first-line therapy in patients with small HCC [21–38]. Although learned societies recommend SR as the preferred modality for small HCC, the results of comparative studies to date have been far from conclusive. One randomized controlled trial (RCT) and two meta-analyses found SR was associated with better overall survival (OS) compared to RFA [21,36,37]. However, two other RCTs and several retrospective studies found equivalent survival outcomes for resection and ablation [22–35]. Also, as most of the evidence to date has been derived from Eastern countries, it is unclear as to whether these data can be extrapolated to Western patients. Thus, we conducted a retrospective, multicenter study comparing outcomes of RFA and SR across five Australian tertiary referral centers in patients with early or very early stage HCC.
Radiofrequency ablation RFA procedures were performed laparoscopically or percutaneously using commercially available systems and needle electrodes at all sites. The response to RFA was assessed by contrast-enhanced triphasic CT or MRI 1 month post-procedure. Complete response was defined as absence of enhancing tumor areas. Incomplete response defined as residual enhancing tumor after two RFA sessions was assessed as treatment failure. Subjects with treatment failure were managed with other therapeutic modalities. Local recurrence was defined as tumor recurrence at or adjacent to the ablated site and intrahepatic distal recurrence at a site other than the original tumor site. Surgical resection The extent of hepatic resection performed was at the discretion of the treating surgeon and included anatomical resections depending on the size and location of the tumor(s) and the degree of hepatic dysfunction. Statistics
Methods Patients We included patients diagnosed with very early or early stage (Barcelona Cancer of the Liver Clinic [BCLC] 0/ A) HCC at five large tertiary academic hospitals in Melbourne during the period between 2000 and 2010 who had undergone initial treatment with either RFA or SR. The diagnosis of HCC was made according to practice guidelines being either with positive histocytopathology (n = 84) or standard noninvasive criteria on contrast-enhanced liver imaging with triphasic computed tomography (CT) and/or magnetic resonance imaging (MRI) (n = 64). Study inclusion criteria included: i) clinically compensated liver disease; ii) presence of a single nodule £5 cm or up to 3 nodules with each nodule £3 cm. Patients were managed at all academic centers by the Gastroenterology units and hepatobiliary surgical units. The initial choice of therapy with RFA or surgery was at the discretion of the physicians and surgeons managing the patients. Data Detailed information was retrieved from HCC databases, medical histories, and national death registries. Data collected included patient demographics; etiology and severity of liver disease; tumor characteristics; and patient outcomes. All patients were followed up until death or May 2010.
Data were assessed for normality and presented as mean ± standard deviation (SD) for normally distributed quantitative variables, as median (interquartile range) for non-normally distributed variables, and as frequencies and percentages for qualitative variables. Comparisons between treatment cohorts were analyzed using the Pearson’s chi-squared test for categorical data, Student’s t-tests for parametric data and the Mann– Whitney U test for nonparametric continuous data. Kaplan–Meier survival curves were generated and compared using log-rank test. Univariate and multivariate Cox proportional hazards regression models were used to analyze the prognostic relevance of baseline and treatment covariates. Multivariate models were constructed using both stepwise selection and backward elimination procedures before undergoing a final assessment for clinical and biological plausibility. Variables with a p-Value of 90%) of patients had cirrhosis and had HCC detected via screening. Of the 148 patients, 96 had initial therapy with RFA to 109 tumor nodules, whereas 52 underwent SR. In comparison to those undergoing SR, patients treated with RFA were older and had more severe liver disease including a higher frequency of cirrhosis and portal hypertension, and higher Model of End Stage Liver Disease (MELD) score. However, mean tumor size was lower in the RFA group although the distribution of BCLC stage 0/A disease and median serum a-fetoprotein levels were similar between the two groups (Table I).
Hepatic resection. Among the 52 patients having SR, there was 1 (2%) surgery-related death due to hemorrhage and 3 (6%) other major complications, including a bile leak, subphrenic abscess, and wound dehiscence. Overall survival The median duration of follow up of the overall cohort (i.e. HCC £5 cm) was 2.3 (1.0–3.8) years and was significantly longer in the resection group than the RFA group (3.5 vs. 2.2 years; p = 0.01)
Table I. Baseline characteristics of the overall and treatment groups.
Gender male, n (%) Age (years), mean ± SD Cirrhosis, n (%)* Detection by screening, n (%) Etiology of liver disease, n (%) Hepatitis C Hepatitis B Alcohol Other Child–Pugh class (A/B) MELD score, mean ± SD Bilirubin (mmol/l), mean ± SD Albumin (g/dl), mean ± SD INR, mean ± SD Creatinine (mmol/l), mean ± SD Platelets (109/l), mean ± SD BCLC stage (0/A) Tumor size (mm), mean ± SD Tumor no., median (IQR) AFP (ng/ml), median (IQR) Portal hypertension, n (%)# Follow up (years), median
Overall (n = 148)
RFA (n = 96)
Resection (n = 52)
113 (76) 63.1 ± 10.6 132 (92) 107 (76)
71 (74) 65.1 ± 10.0 91 (97) 74 (78)
42 (81) 59.3 ± 10.7 41 (84) 33 (72)
52 (35) 41 (28) 18 (12) 36 (25) 121/27 9.6 ± 3.0 21.0 ± 14.1 36.8 ± 6.2 1.2 ± 0.2 84.1 ± 25.8 147 ± 62 50/98 25.6 ± 10.6 1 (1–3) 10.8 (5–65) 77 (59) 2.3 (1–3.8)
39 (41) 19 (20) 15 (16) 22 (23) 75/21 10.1 ± 3.2 23.8 ± 16.3 35.4 ± 6.2 1.2 ± 0.2 82.5 ± 23.7 136 ± 61 36/60 23.0 ± 9.6 1 (1–3) 10.1 (5–39) 45 (54) 2.2(1–3.5)
13 (25) 22 (42) 3 (6) 14 (27) 46/6 8.4 ± 2.1 15.9 ± 6.5 39.4 ± 5.4 1.1 ± 0.1 87.3 ± 29.5 168 ± 61 14/38 30.3 ± 10.8 1 (1–2) 16 (5–168) 9 (18) 3.5(1.3–7.3)
p-Value 0.35 0.001 0.005 0.42 0.01
0.12 0.002 0.0005 0.0002 0.0005 0.33 0.006 0.19 < 0.0001 0.19 0.40 < 0.0001 0.01
p-Values given are for comparison between RFA and resection groups. *Cirrhosis status was available for 143 patients. # Portal hypertension data were available for 131 patients. Abbreviations: RFA = Radiofrequency ablation; MELD = Model of End Stage Liver Disease; INR = International normalized ratio; BCLC = Barcelona Cancer of the Liver Clinic; AFP = a-fetoprotein level.
570
I. Gory et al.
(Table I). There were 56 deaths in follow up, including 38 (40%) in the RFA group and 18 (35%) in the resection group. As seen in Figure 1A, the 3- and 5-year OS of patients with HCC £5 cm were 62% and 37% in the RFA group compared to 66% and 62% in the SR group (p = 0.11). In patients with tumors >3 cm and
ORIGINAL ARTICLE
Radiofrequency ablation versus resection for the treatment of early stage hepatocellular carcinoma: a multicenter Australian study
ILANA GORY1, MICHAEL FINK2, SALLY BELL3, PAUL GOW2, AMANDA NICOLL4, VIRGINIA KNIGHT5, ANOUK DEV5, ANTHONY RODE4, MICHAEL BAILEY6, WA CHEUNG1, WILLIAM KEMP1 & STUART K. ROBERTS1, ON BEHALF OF THE MELBOURNE LIVER GROUP 1
The Alfred Hospital, Melbourne, Australia, 2University of Melbourne Department of Surgery, Austin Health, Melbourne, Australia, 3St. Vincent’s Hospital, Melbourne, Australia, 4Royal Melbourne Hospital, Melbourne, Australia, 5Monash Medical Centre, Monash University, Melbourne, Australia, and 6Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
Abstract Objectives. It remains unclear whether radiofrequency ablation (RFA) provides comparable outcomes to surgical resection (SR). We, therefore, compared survival outcomes of RFA to SR in patients with early stage and very early stage hepatocellular carcinoma (HCC). Methods. A multicenter retrospective analysis was performed in patients from five academic hospitals with Barcelona Cancer of the Liver Clinic (BCLC) stages 0–A HCC having RFA or SR as primary therapy. Results. From 2000– 2010, 146 patients who received treatment with RFA (n = 96) or SR (n = 52) were identified. In BCLC A patients with £5 cm HCC, there was a trend of lower overall survival after RFA compared with SR (3- and 5-year survival: 62% and 37% vs. 66% and 62% respectively; p = 0.11). By multivariate analysis, RFA was an independent predictor of poor survival (hazard ratio = 2.26; 95% confidence interval: 1.02–5.03; p = 0.04). In £3 cm HCC (n = 109), the 3- and 5-year survivals in RFA and SR groups were 66% and 39%, and 69% and 59%, respectively, with no difference in the median survival (p = 0.41). Local recurrence was significantly higher after RFA compared to SR in HCC £5 cm (p = 0.006) with a trend of lower recurrence-free survival (p = 0.06) after RFA in HCC £3 cm. There were fewer major complications after RFA (2% vs. 8%). Conclusion. While SR is superior to RFA for the management of early stage BCLC A disease with £5 cm HCC, both appear effective as firstline treatment options for Western patients with small £3 cm tumors. Although safer than SR, RFA is associated with higher rates of tumor recurrence and local disease progression. Further prospective randomized controlled trials are warranted to compare these two modalities.
Key Words: Hepatocellular carcinoma, radiofrequency ablation, surgical resection, survival
Introduction Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide with more than 500,000 deaths occurring annually from this disease [1–3]. Moreover, HCC incidence rates are rising in several developed countries [4–7]. In response, HCC screening programs have been widely implemented in at-risk populations to reduce the mortality of HCC.
As a consequence, an increasing number of patients are diagnosed with early stage HCC and are now eligible for curative therapies including surgery and local ablation [8,9]. Although liver transplantation is the optimal curative therapy for early stage HCC, access to this modality is limited due to donor shortage. Further, surgical resection (SR) as the next best option is only applicable to around 10–20% patients [2,10–14]. In
Correspondence: Stuart Roberts, Department of Gastroenterology, The Alfred Hospital, 55 Commercial Rd, Melbourne, 3004, Australia. Tel: +61 3 9076 3375. Fax: +61 3 9076 2194. E-mail: [email protected]
(Received 1 June 2014; revised 4 August 2014; accepted 5 August 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2015 Informa Healthcare DOI: 10.3109/00365521.2014.953572
568
I. Gory et al.
contrast, significantly more patients are candidates for curative therapy with radiofrequency ablation (RFA) that is considered a safe and effective modality for patients with cirrhosis and small HCC [15–20]. Recently, there has been much interest and debate regarding the relative efficacy of RFA versus SR as first-line therapy in patients with small HCC [21–38]. Although learned societies recommend SR as the preferred modality for small HCC, the results of comparative studies to date have been far from conclusive. One randomized controlled trial (RCT) and two meta-analyses found SR was associated with better overall survival (OS) compared to RFA [21,36,37]. However, two other RCTs and several retrospective studies found equivalent survival outcomes for resection and ablation [22–35]. Also, as most of the evidence to date has been derived from Eastern countries, it is unclear as to whether these data can be extrapolated to Western patients. Thus, we conducted a retrospective, multicenter study comparing outcomes of RFA and SR across five Australian tertiary referral centers in patients with early or very early stage HCC.
Radiofrequency ablation RFA procedures were performed laparoscopically or percutaneously using commercially available systems and needle electrodes at all sites. The response to RFA was assessed by contrast-enhanced triphasic CT or MRI 1 month post-procedure. Complete response was defined as absence of enhancing tumor areas. Incomplete response defined as residual enhancing tumor after two RFA sessions was assessed as treatment failure. Subjects with treatment failure were managed with other therapeutic modalities. Local recurrence was defined as tumor recurrence at or adjacent to the ablated site and intrahepatic distal recurrence at a site other than the original tumor site. Surgical resection The extent of hepatic resection performed was at the discretion of the treating surgeon and included anatomical resections depending on the size and location of the tumor(s) and the degree of hepatic dysfunction. Statistics
Methods Patients We included patients diagnosed with very early or early stage (Barcelona Cancer of the Liver Clinic [BCLC] 0/ A) HCC at five large tertiary academic hospitals in Melbourne during the period between 2000 and 2010 who had undergone initial treatment with either RFA or SR. The diagnosis of HCC was made according to practice guidelines being either with positive histocytopathology (n = 84) or standard noninvasive criteria on contrast-enhanced liver imaging with triphasic computed tomography (CT) and/or magnetic resonance imaging (MRI) (n = 64). Study inclusion criteria included: i) clinically compensated liver disease; ii) presence of a single nodule £5 cm or up to 3 nodules with each nodule £3 cm. Patients were managed at all academic centers by the Gastroenterology units and hepatobiliary surgical units. The initial choice of therapy with RFA or surgery was at the discretion of the physicians and surgeons managing the patients. Data Detailed information was retrieved from HCC databases, medical histories, and national death registries. Data collected included patient demographics; etiology and severity of liver disease; tumor characteristics; and patient outcomes. All patients were followed up until death or May 2010.
Data were assessed for normality and presented as mean ± standard deviation (SD) for normally distributed quantitative variables, as median (interquartile range) for non-normally distributed variables, and as frequencies and percentages for qualitative variables. Comparisons between treatment cohorts were analyzed using the Pearson’s chi-squared test for categorical data, Student’s t-tests for parametric data and the Mann– Whitney U test for nonparametric continuous data. Kaplan–Meier survival curves were generated and compared using log-rank test. Univariate and multivariate Cox proportional hazards regression models were used to analyze the prognostic relevance of baseline and treatment covariates. Multivariate models were constructed using both stepwise selection and backward elimination procedures before undergoing a final assessment for clinical and biological plausibility. Variables with a p-Value of 90%) of patients had cirrhosis and had HCC detected via screening. Of the 148 patients, 96 had initial therapy with RFA to 109 tumor nodules, whereas 52 underwent SR. In comparison to those undergoing SR, patients treated with RFA were older and had more severe liver disease including a higher frequency of cirrhosis and portal hypertension, and higher Model of End Stage Liver Disease (MELD) score. However, mean tumor size was lower in the RFA group although the distribution of BCLC stage 0/A disease and median serum a-fetoprotein levels were similar between the two groups (Table I).
Hepatic resection. Among the 52 patients having SR, there was 1 (2%) surgery-related death due to hemorrhage and 3 (6%) other major complications, including a bile leak, subphrenic abscess, and wound dehiscence. Overall survival The median duration of follow up of the overall cohort (i.e. HCC £5 cm) was 2.3 (1.0–3.8) years and was significantly longer in the resection group than the RFA group (3.5 vs. 2.2 years; p = 0.01)
Table I. Baseline characteristics of the overall and treatment groups.
Gender male, n (%) Age (years), mean ± SD Cirrhosis, n (%)* Detection by screening, n (%) Etiology of liver disease, n (%) Hepatitis C Hepatitis B Alcohol Other Child–Pugh class (A/B) MELD score, mean ± SD Bilirubin (mmol/l), mean ± SD Albumin (g/dl), mean ± SD INR, mean ± SD Creatinine (mmol/l), mean ± SD Platelets (109/l), mean ± SD BCLC stage (0/A) Tumor size (mm), mean ± SD Tumor no., median (IQR) AFP (ng/ml), median (IQR) Portal hypertension, n (%)# Follow up (years), median
Overall (n = 148)
RFA (n = 96)
Resection (n = 52)
113 (76) 63.1 ± 10.6 132 (92) 107 (76)
71 (74) 65.1 ± 10.0 91 (97) 74 (78)
42 (81) 59.3 ± 10.7 41 (84) 33 (72)
52 (35) 41 (28) 18 (12) 36 (25) 121/27 9.6 ± 3.0 21.0 ± 14.1 36.8 ± 6.2 1.2 ± 0.2 84.1 ± 25.8 147 ± 62 50/98 25.6 ± 10.6 1 (1–3) 10.8 (5–65) 77 (59) 2.3 (1–3.8)
39 (41) 19 (20) 15 (16) 22 (23) 75/21 10.1 ± 3.2 23.8 ± 16.3 35.4 ± 6.2 1.2 ± 0.2 82.5 ± 23.7 136 ± 61 36/60 23.0 ± 9.6 1 (1–3) 10.1 (5–39) 45 (54) 2.2(1–3.5)
13 (25) 22 (42) 3 (6) 14 (27) 46/6 8.4 ± 2.1 15.9 ± 6.5 39.4 ± 5.4 1.1 ± 0.1 87.3 ± 29.5 168 ± 61 14/38 30.3 ± 10.8 1 (1–2) 16 (5–168) 9 (18) 3.5(1.3–7.3)
p-Value 0.35 0.001 0.005 0.42 0.01
0.12 0.002 0.0005 0.0002 0.0005 0.33 0.006 0.19 < 0.0001 0.19 0.40 < 0.0001 0.01
p-Values given are for comparison between RFA and resection groups. *Cirrhosis status was available for 143 patients. # Portal hypertension data were available for 131 patients. Abbreviations: RFA = Radiofrequency ablation; MELD = Model of End Stage Liver Disease; INR = International normalized ratio; BCLC = Barcelona Cancer of the Liver Clinic; AFP = a-fetoprotein level.
570
I. Gory et al.
(Table I). There were 56 deaths in follow up, including 38 (40%) in the RFA group and 18 (35%) in the resection group. As seen in Figure 1A, the 3- and 5-year OS of patients with HCC £5 cm were 62% and 37% in the RFA group compared to 66% and 62% in the SR group (p = 0.11). In patients with tumors >3 cm and
