Abstract
Background: The number of elderly patients with hepatocellular carcinoma (HCC) has increased in Japan. Patients and Methods: A total of 280 patients with HCC treated with endoscopic radiofrequency ablation (ERFA) were enrolled in the present study. The patients were divided into two groups, an elderly group (≥70 years) and a non-elderly group (<70 years) and their clinical and survival data were compared. Results: The cumulative overall survival rates in the elderly and non-elderly groups were equivalent: 73% and 70% at three years and 57% and 52% at five years, respectively (p=0.900). The disease-free survival rates were 21% and 23% at three years and 17% and 14% at five years, respectively (p=0.628). No significant effects were observed between the two groups due to any of the covariates in the survival analysis (all p-values for interaction ≥0.19). The complication rates were also comparable: 5.1% in the elderly group and 8.6% in the non-elderly group. Conclusion: ERFA is safe and provides excellent therapeutic effects in elderly as well as non-elderly patients with HCC.
Thermal ablation, including microwave coagulation therapy and radiofrequency ablation (RFA), was recently developed as a less invasive and curative treatment for small-sized hepatocellular carcinoma (HCC) (1-3). The percutaneous approach is primarily used in association with a wide range of indications. However, if the tumor exists on the liver surface or is close to the digestive organs, thermal ablation must be performed under direct observation in order to prevent neoplastic seeding and thermal injury to the adjacent organ (4-6). In addition, we have consistently recommended the use of thoracoscopic ablation if the tumor exists in the hepatic dome and the tumor image is not visible on percutaneous ultrasonography due to the presence of lung artifacts (6). However, endoscopic treatment requires for general anesthesia and occasionally lung deflation or the creation of a pneumoperitoneum. Furthermore, endoscopic ablation may be more invasive in elderly patients than in younger patients with HCC.
With the aging of society, the number of elderly patients with HCC has increased in Japan (7). Elderly patients have a high incidence of comorbid illnesses and are usually considered to be a high-risk group for major surgery (8, 9). Few studies have shown that percutaneous ablation therapy with local anesthesia provides similar outcomes in both elderly and non-elderly patients with HCC (10-12). In contrast, the utility of endoscopic ablation in elderly patients has not been fully clarified (13).
In the present study, we evaluated the value of endoscopic radiofrequency ablation (ERFA) with respect to safety, invasiveness and survival benefits of this treatment in elderly patients with HCC in comparison to non-elderly patients.
Patients and Methods
Patients. Between February 2000 and December 2009, 280 patients with HCC were treated with ERFA at the Department of Gastroenterological Surgery, Kumamoto University Hospital and the Department of Surgery, Miyazaki Prefectural Nobeoka Hospital. The patients were divided into two groups, an elderly group (≥70 years) and a non-elderly group (<70 years), based on age at the time of initial ERFA procedure. We analyzed information in the prospectively collected clinical database, including that related to recurrence and survival. The diagnosis of HCC was made based on pathological findings or typical HCC findings observed on imaging modalities including dynamic computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography or angiography, and the levels of tumor markers, including that of α-fetoprotein (AFP), lens culinaris agglutinin-reactive α-fetoprotein (AFP-L3) and protein-induced vitamin K antagonist-II (PIVKA-II).
Patients' characteristics.
Indications for ERFA. Percutaneous, endoscopic and open approaches were selected according to size, number and localization of the tumors to be treated (6, 14). The indications for ERFA to treat HCC were as follows: an initially unresectable and superficial location; a location that was inaccessible percutaneously; the presence of three or fewer nodules; a maximal diameter less than 30 mm (≤40 mm for extrahepatic growth type tumors); and no distinct vascular invasion. An essential liver function was defined as a total bilirubin level of ≤3 mg/dl, a prothrombin activity level of ≥40% and no uncontrollable ascites. A pre-treatment performance status level between 0 and 2 was required.
RFA procedure. RFA was performed using the cooled tip RF electronic system (Radionics, Burlington, MA, USA). A 17-gauge cooled-tip electrode with a 2- or 3-cm metallic tip was inserted into the tumor and surrounding liver tissue. The power application was increased to 60 and 80 W for three minutes using a hand-piece with a 2- and 3-cm length of metal tip, respectively, in the impedance control mode. The electrode was left in the tumor for six to 10 minutes for five rounds of impedance-out while refluxing cold water inside the needle.
Postoperative assessment. Dynamic CT was performed seven days after ERFA. Complete ablation was confirmed when the tumor and a 5-mm width of surrounding live parenchyma were detected as a low-density area without enhancement in the arterial phase. If the ablation was judged to be incomplete, an additional round of ablation was performed. Monthly blood tests were regularly performed to evaluate the liver function and levels of tumor marker (AFP, AFP-L3 and PIVKA-II), in addition to dynamic CT or dynamic MRI every three to four months. Local recurrence was defined as reappearance of tumor progression either within the ablation site or outside the ablation site on contrast enhanced CT or MRI scans during follow-up (15, 16).
Statistical analysis. Comparisons of the patients' characteristics were made using Student's t-test for continuous variables and the chi-square test for categorical variables. The cumulative disease-free survival (DFS) and overall survival (OS) were calculated from the time of ERFA according to the Kaplan–Meier method and compared between the groups using the log-rank test. The prognostic relevance of 17 baseline variables to survival was analyzed using a univariate Cox proportional hazard regression model. All variables with a p-value of less than 0.1 in the univariate analyses were included in the Cox regression model for the multivariate analysis. The results of the univariate and multivariate analyses are presented as relative risks with p-values obtained from the Wald test. Interactions were assessed by including the age variable and another variable of interest (without cases with missing data) in a multivariate Cox model, followed by the WALD test. All significance tests were two-tailed, and a p-value of <0.05 was considered to be statistically significant.
Results
The preoperative clinical profiles and operative data are shown in Table I. The mean age was 74.7±2.7 years (range=70-87 years) in the elderly group and 61.7±6.5 years (range=40-69 years) in the non-elderly group. There were no significant differences in gender, etiology of hepatitis, liver function parameters, tumor stage, tumor marker levels or operative data between the two groups.
Survival analysis. There were no differences in DFS: the 3- and 5-year rates were 23% and 14% in the non-elderly group and 21% and 17% in the elderly group, respectively (p=0.628) (Figure 1A). Similarly, there were no differences in OS: the 3- and 5-year rates were 70% and 52% in the non-elderly group and 73% and 57% in the elderly group, respectively (p=0.900) (Figure 1B).
The rates of local tumor progression were 5.5% after one year and 20.4% after three years in the elderly group and 2.7% after one year and 8.6% after three years in the non-elderly group, with no significant differences among the groups (p=0.068) (Figure 1C).
Disease-free (A) and cumulative overall (B) survival and local recurrence (C) rates after endoscopic radiofrequency ablation for hepatocellular carcinoma. The rates were determined according to the Kaplan–Meier method in the elderly (n=112) and non-elderly groups (n=168) of patients. There were no significant differences in the disease-free or overall survival rates, nor for local recurrence rate between the two groups (p=0.628, p=0.900, p=0.068, respectively).
In multivariate analysis, the independent factors affecting the OS were identified to be PIVKA-II (HR=1.604, p=0.028) and albumin (HR=1.686, p=0.021) levels (Table II). Limited to the elderly patients, a high AFP level (HR=3.999, p=0.030) was found to be independently associated with a worse survival rate after ERFA (Table III). In the multivariate analysis for DFS, the independent factors were an AFP of 400 ng/ml (HR=1.938, p=0.016) and an albumin level of<3.5 g/dl (HR=1.487, p=0.022). Among the elderly patients, only a high AFP level 400 ng/ml (HR=2.286, p=0.035) was found to be independently associated with a worse survival rate after ERFA (data not shown).
Interaction between age and other variables in the survival analyses. We also examined whether the influence of age at surgery on the OS was modified by any of the clinical or pathological variables. No significant effects were observed for any of the covariates in the survival analysis (all p value for interaction ≥0.19). Notably, there were no significant interactions between age at surgery and the platelet level, tumor number or clinical stage (p value for interaction ≥0.19) (Figure 2).
Postoperative morbidity and mortality. Postoperative complications were observed after ERFA in 6/118 (5.1%) patients in the elderly group. On the other hand, complications occurred in 14/162 (8.7%) patients in the non-elderly group (p=0.258). The overall mortality rate within 90 days was quite low in both groups: 0.8% in the elderly group and 0.6% in the non-elderly group (p=0.659).
Postoperative hospital stay. The length of postoperative hospital stay after ERFA was significantly shorter in the elderly group (10.2±0.4 days) than in the non elderly group (11.5±0.5 days) (<0.001).
The findings of a univariate and multivariate analysis in relation to the overall survival for all patients (n=280).
Discussion
The present study demonstrated that operative outcomes, including the cumulative OS and DFS, are equivalent in elderly (≥70 years) and non-elderly (<70 years) patients with HCC treated with ERFA. Only a few reports have assessed the efficacy and safety of percutaneous RFA in elderly patients with HCC (10-12). One report demonstrated similar 3-year survival rates between patients over 69 years of age (76%) and those under 68 years of age (79.2%) among 1,000 patients with HCC treated with percutaneous RFA (10). In that study, the cumulative OS rate in the elderly group was 82% at three years and 61% at five years, which is equivalent to that observed in the non-elderly group in our study. Similarly, in that study, no differences were observed in the recurrence rate. In the multivariate analysis, the Child-Pugh grade, AFP level and tumor size were found to be significantly associated with OS; however, age was not determined to be a prognostic factor. Although the elderly patients had more extrahepatic comorbidities, the presence of comorbidities did not influence the rate of survival or postoperative complications (11). Another report suggested that elderly patients with HCC should be treated with percutaneous RFA in the same manner and with the same strategy as non-elderly patients. In that study, the 3- and 5-year cumulative OS rates were similar: 82.5% and 49.7% in the elderly patients and 78.3% and 57.5% in the non-elderly patients, respectively. There were no specific severe complications among the elderly patients (12). In our Department, ERFA is primarily applied for HCC that is difficult to treat percutaneously or which is superficial. If HCC is a contraindication for both for percutaneous and endoscopic approaches, an open approach is selected. Therefore, it is not appropriate to compare the surgical outcomes and complications of RFA according to the approach.
On the other hand, ERFA may be more risky and invasive compared to percutaneous RFA in elderly patients with HCC. In the present study, all of the patients treated with ERFA required general anesthesia, and the conditions of some patients necessitated lung deflation or the additional creation of a pneumoperitoneum. However, there are some advantages to performing endoscopic treatment under general anesthesia. For example, the development of neoplastic seeding after RFA is a serious problem. It has been reported that the rate of neoplastic seeding after percutaneous RFA is 0.9~12.5% (17-19). If tumor tissue spreads during ERFA, the tissue can be aspirated and washed with saline containing anticancer drugs, therefore, neoplastic seeding can be prevented (6). In fact, no cases of neoplastic seeding were observed in this study. It is important to freeze the patient's breath in order to accurately puncture the tumor using the hand-piece during RFA. It is quite easy to freeze the patient's breath under general anesthesia compared to local anesthesia. In this study, sufficient coagulation was not always completed under local anesthesia due to pain, especially in cases involving multiple tumors. Indeed, local anesthesia was described as being an independent factor conferring poor prognosis for OS following ERFA treatment in a multivariate analysis (20). Another advantage of ERFA is the ability to perform endoscopic high-frequency ultrasonography in order to detect new lesions that were not observed on preoperative imaging (21, 22). It has been reported that ERFA allows for the treatment of lesions that are not treatable using the percutaneous approach, as well as the detection of new HCC nodules detecting 27% of all lesions observed on intraoperative endoscopic ultrasonography (23).
Forest plot for overall survival according to the interactions between age and other variables. The influence of age at surgery with respect to modification by any of the clinical or pathological variables was analyzed. No significant effects of any of the covariates were observed in the survival analysis (all p-values for interaction ≥0.19).
Recently, the efficacy and safety of ERFA in patients with HCC over 60 years of age were reported (13). In that study, the 2-year OS rate in the patients undergoing laparoscopic RFA was 75%, while the complication rate was 10%, with one death. The overall mortality rate was 19% at one year and factors associated with mortality did not include the patient's age, but rather the number of ablated lesions, the platelet count and an AFP level greater than 400 ng/ml, based on a multivariate analysis. Compared to that report, our results in elderly patients demonstrate a favorable 3-year OS rate (73%), a lower complication rate (5.0%) and a lower overall mortality rate (0.8%) within one year.
Another report demonstrated that elderly patients (≥70 years) exhibit significantly low local recurrence rates and similar OS rates compared to non-elderly patients following endoscopic thermal ablation for small HCC (20). In a multivariate analysis, local anesthesia and a high Child-Pugh score were found to be independent prognostic factors for poor survival. In the current study, ERFA for elderly patients (≥70 years) was found to result in an excellent and equivalent OS (73% at three years and 57% at five years) and DFS rate (21% at three years and 17% at five years) rates compared to those observed in non-elderly patients. Furthermore, the background characteristics of both groups were quite similar (Table I).
Poor prognostic factors affecting overall survival after ERFA have been reported in previous reports to be a Child-Pugh classification of non-A, a high AFP level and the use of local anesthesia (20, 24). In our study, the prognostic factors for OS after in ERFA among all patients were the PIVKA II level (≥40 IU) and the albumin level (<3.5 g/dl). Additionally, the only prognostic factor for OS identified among the elderly patients was the AFP level (≥400 mg/ml). Importantly, age was not detected as a prognostic factor affecting OS in any previous reports. In the current study, we additionally demonstrated that there were no significant interactions between age and any of the clinical or pathological factors for OS.
The findings of a univariate and multivariate analysis in relation to the overall survival for elderly group (n=118).
It has been reported that the mortality rates after hepatic resection in elderly patients of 65 years of age or older is greater than that observed in younger patients (11.3% versus 2.0%) (25). However, with suitable patient selection and due to the advancement of surgical techniques and perioperative management, there are no significant differences in complication rates between the elderly and younger patients groups (26, 27). The operative mortality rate associated with liver resection in elderly patients has improved from 2% to 3% (26, 28). In addition, hepatectomy-associated complication rates are not significantly different between elderly patients and younger patients (21.7% versus 26.0%). However, the incidence of systematic complications, such as cardiovascular and pulmonary disease, is significantly more common in patients 70 years of age or older (27). In our study of endoscopic RFA for HCC, the morbidity rate was 5.0% in the elderly group, versus 8.7% in the younger group. The overall mortality rate within one year was 0.8% in the elderly group.
There were no differences found in the 4-year OS or DFS rates in a prospective randomized trial comparing percutaneous RFA and partial hepatectomy to treat small and single HCC (28). In that study, RFA for small HCC was performed more safely and with similar effects to those of surgical resection, although the proportion of patients with Child-Pugh B class liver cirrhosis among those treated with RFA was larger than that observed among the patients treated with surgical resection (29, 30). Therefore, it may be possible to safely treat elderly patients with a poor liver function using RFA in addition to non-elderly patients.
Recently, the operative and oncological short-term outcomes of laparoscopic liver resections in elderly patients (≥70 years old) with malignancy have been reported (31). In that study, there existed no differences in the operative time, median amount of blood loss, or blood transfusion rate between the elderly and non-elderly patients. The morbidity (12% versus 20%, p=0.797) and perioperative mortality (0% versus 3%, p=0.868) were also similar between the two groups. At a median follow-up of 18 months, 12% of the elderly patients and 26% of non-elderly patients experienced a disease recurrence (p=0.163). In our Department, we performed endoscopic hepatectomy in 89 patients with HCC who met the Milan Criteria from 1999 to 2011 (unpublished data). The OS rates for patients in the elderly (n=34) and non-elderly (n=55) groups were both excellent [78% and 89% at three years and 46% and 89% at five years, respectively (p=0.012)], while the DFS rate was 33% and 50% at three years and 11% and 36% at five years, respectively (p=0.056). Interestingly, among the patients who underwent endoscopic hepatectomy, the OS and DFS rates were worse in the elderly group. The reduced invasiveness of ERFA may result in excellent DFS and OS rates, even among elderly patients with HCC.
We conclude that, even in elderly patients (≥70 years), ERFA should be recommended for the treatment of HCC, if the patient meets the criteria of a suitable tumor stage and tumor location as well as the liver function.
Footnotes
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Conflicts of Interest
No conflicts of interest.
- Received January 23, 2015.
- Revision received February 9, 2015.
- Accepted February 12, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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