Abstract
Background: The number of elderly patients who undergo hepatectomy for hepatocellular carcinoma (HCC) has been increasing. Therefore, criteria for selection of an appropriate hepatectomy procedure are required. Patients and Methods: Two hundred and twenty-nine HCC patients undergoing hepatectomy were enrolled in the present study. Patients were classified into two groups: the elderly group (age ≥75 years, n=34) and the non-elderly group (age <75 years, n=195). The hepatectomy procedure was selected based on the prognostic score (PS) formula, that includes patient age as a variable. Results: The incidence of non-anatomical resection was higher (p=0.015) and the weight of resected specimens was lower (p=0.019) in the elderly group than in the non-elderly group. No significant difference was observed in the postoperative complication rate between the two groups. The 5-year survival rates were comparable between the two groups. Conclusion: Favorable short- and long-term outcomes can be obtained based on cautious selection criteria for hepatectomy procedures, while considering patient age, in the treatment of elderly patients with HCC.
Improvement in the social conditions and the enhancement of medical knowledge and techniques have led to a progressive increase in the average life expectancy worldwide (1-3). Moreover, cholecystectomy and gastrointestinal resection have become routine procedures for elderly individuals, and even extensive procedures such as cardiovascular and hepatobiliary pancreatic operations can be performed with a relatively low mortality (4, 5).
Hepatocellular carcinoma (HCC) is the fourth most-common malignancy and third most-common cause of mortality worldwide, and its incidence is gradually increasing (6, 7). Hepatic resection is an effective treatment modality for HCC, and with improvements in surgical techniques, perioperative management, and anesthesia (8, 9), it is increasingly becoming a safe procedure. Thus, elderly patients are more frequently becoming candidates for hepatic resection for HCC.
Although several studies have reported on clinical outcomes of hepatic resection of HCC in elderly patients (3, 4, 8, 10-16), feasibility of the operation and the long-term outcomes remain controversial. Moreover, suitable criteria for the selection of hepatectomy procedures in elderly patients are still being investigated. Therefore, in the present study, we aimed to evaluate the efficacy of hepatectomy for elderly HCC patients and assess the validity of the selection criteria of hepatectomy procedures, including patient age as a variable.
Patients and Methods
Patients. From January 2000 to December 2010, 299 patients with HCC underwent initial curative hepatic resection at the Department of Gastroenterological Surgery, Yokohama City University. Patients aged ≥75 years were assigned to the elderly group (n=34), whereas those aged <75 years were assigned to the non-elderly group (n=195); data between these two groups were compared.
Operative procedures. Patients with HCC were treated according to clinical practice guidelines for HCC established by the Japanese Society of Hepatology, 2009 (17). We used the prediction score (PS) developed by Yamanaka et al. (18) to determine the resection fraction limit. PS was calculated using the formula PS=-84.6 + 0.933a + 1.11b + 0.999c, where a is the resection fraction (%) calculated using computed tomography (CT) volumetry (19), b is the indocyanine green retention rate at 15 min (ICGR15), and c is the patient age. A PS of <40 was considered acceptable for performing surgery. In principle, we initially considered anatomical resection as the hepatectomy procedure, even in elderly patients. If the resection fraction exceeded the limit for anatomical resection, non-anatomical resection was selected. In some patients with multiple tumors, combined anatomical and non-anatomical resections were performed depending on the tumor distribution. Major hepatic resection was defined as the involvement of more than three segments. The terminology for liver anatomy and resections followed the guidelines of the Brisbane 2000 Terminology of the International Hepato-Pancreato-Biliary Association (20).
Adjuvant therapy. After hepatic resection, adjuvant therapy was administered to patients with microscopic vascular invasion in principle. Hepatic arterial infusion chemotherapy using 5-fruorouracil and cisplatin was performed once-a-week, for 8 weeks. In fact, the type of the adjuvant therapy was decided on a case-by-case basis, while considering the patient age and performance status after resection.
Perioperative factors analyzed. The incidence of concomitant pulmonary disease, cardiovascular disease, and diabetes mellitus was compared, and these factors were considered as preoperative co-morbidities. Pulmonary disease includes chronic obstructive pulmonary disease and bronchial asthma, whereas cardiovascular disease is defined as a history of ischemic heart disease, heart failure, or arrhythmia.
Postoperative complications were based on the Clavien-Dindo Classification (21), and postoperative liver failure was defined as described in ISGLS criteria (22). Liver-related morbidity was defined as liver failure, bile leakage, and postoperative ascites. Postoperative mortality was defined as the occurrence of in-hospital death after the surgery.
Patient follow-up. Patients underwent monthly evaluations at our outpatient clinic. The serum alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin were measured once a month, whereas computed tomography or ultrasonography was performed every 3-4 months. In cases with a good performance status where HCC recurrence was suspected based on tumor marker concentrations or radiographic findings, the recurrence limited to the remnant liver was treated by re-resection, ablation therapy such as percutaneous ethanol injection or radiofrequency therapy, transcatheter arterial chemoembolization (TACE), or lipiodolization. Some cases with distant metastases were treated by systemic chemotherapy. The principles underlying the selection criteria for the resection of recurrent HCC were the same as those for the initial hepatic resection.
Statistics. Continuous data are expressed as mean±standard deviation (SD). Data of different groups were compared using the Man-Whitney U-test. Categorical data were analyzed using the Chi-square test. Disease-free survival and overall survival rates were calculated according to the Kaplan-Meier methods, and the differences between the groups were tested for significance using the log-rank test. All statistical analyses were performed using the SPSS computer software package version 22.0 for Windows (SPSS, Inc., Chicago, IL, USA). p-Values <0.05 were considered significant.
Results
Preoperative characteristics, pathological findings, tumor staging and adjuvant therapy. The data on preoperative factors are described in Table I. The gender distribution in the elderly group (25 men and 9 women) was similar to that in the non-elderly group (144 men and 51 women). The PS was higher in the elderly group (p<0.01). Moreover, the elderly group had a significantly higher incidence of concomitant cardiovascular disease than the non-elderly group (p<0.01). In contrast, no significant differences were observed for both concomitant pulmonary disease and diabetes mellitus between the groups. Although the ICGR15 value was higher in the elderly group (p=0.044), the Child-Pugh class and presence of liver cirrhosis were comparable between the 2 groups.
With regard to the etiology of HCC, the proportion of patients with the hepatitis B antigen was significantly higher in the non-elderly group than in the elderly group (p=0.012). Data on cancer-related factors, including UICC staging, were similar between the groups. Adjuvant therapy was administered in 4 (12.1%) patients in the elderly group and in 41 (21.1%) patients in the non-elderly group (p=0.230).
Perioperative factors. There was no significant difference between the groups in terms of the proportion of patients who underwent major hepatectomy, operative time, intraoperative blood loss, and blood transfusion. Non-anatomical resection was performed more frequently and the weight of the resected specimen was significantly lower in the elderly group than in the non-elderly group (p=0.015 and p=0.019, respectively). Moreover, the length of postoperative hospital stay was shorter in the elderly group than in the non-elderly group (p<0.01, Table II).
Postoperative complications. The postoperative mortality rate did not differ between the groups (p=0.365). Moreover, although the total postoperative morbidity rates did not differ between the groups, postoperative arrhythmia was more frequently observed in the elderly group than in the non-elderly group (p=0.014). The liver-related, infection-related, and pulmonary complication rates did not differ between the groups. However, postoperative delirium tended to occur more frequently in the elderly group than in the non-elderly group, although the difference was not significant (p=0.067) (Table III).
Postoperative recurrence and treatment for recurrence. Recurrence occurred in 34 (50.0%) patients in the elderly group and 128 (65.6%) patients in the non-elderly group (p=0.081). Although no difference was observed in the recurrence rate, recurrence in the remnant liver was observed significantly more frequently in the non-elderly group than in the elderly group (p=0.012). No differences in the frequency of treatment and repeat resection for recurrence were observed between groups (p=0.182 and 0.937, respectively; Table IV).
Clinical characteristics and tumor-related factors.
Perioperative factors.
Postoperative morbidity and mortality.
Postoperative recurrence and treatment for recurrence.
Survival. There was no significant difference in disease-free survival between the elderly group (1-, 3-, and 5-year: 69.2%, 53.0%, and 38.9%, respectively) and the non-elderly group (1-, 3-, and 5-year: 67.8%, 43.9%, and 36.3%, respectively; p=0.546). Furthermore, there was no difference in overall survival between the elderly group (1-, 3-, and 5-year: 85.3%, 79.0%, and 75.2%, respectively) and the non-elderly group (1-, 3-, and 5-year: 92.3%, 77.0%, and 63.5%, respectively; p=0.780).
Discussion
The number of elderly patients undergoing hepatic resection for HCC is increasing (3, 10-14, 16, 23-26). Resection is an effective treatment for HCC in patients with well-preserved liver function (27), but it is associated with a high risk in older patients (9, 11, 23, 24, 26). Nevertheless, improvements in the operative technique (28-30), imaging methods, and perioperative management have reduced the age-related contraindications for liver surgery.
Certain studies indicated that elderly patients have a higher incidence of postoperative complications following hepatic resection (9, 11, 15), that may be possible due to the presence of degradation as a result of advanced age or comorbidities. In the present study, although liver-related complications did not significantly differ between the 2 groups, systemic complications such as cardiovascular complications were more common in the elderly group than in the non-elderly group, similar to that observed in a previous report (24). The higher incidence of preoperative concomitant cardiovascular disease in the elderly group may be a reason for the higher incidence of postoperative cardiovascular complications. Hence, careful postoperative management of the associated cardiovascular disease among elderly patients is essential (31). In our Institution, we routinely perform echocardiography in all elderly patients in order to estimate ventricular kinetics and ejection fraction. Moreover, we routinely recommend cardiology consultations in cases with a concomitant cardiovascular disease or in those with abnormalities in electrocardiography or echocardiography.
In the present study, postoperative delirium tended to occur more frequently in the elderly group than in the non-elderly group. According to a previous report, age and low cognitive function are important risk factors for postoperative delirium (32). We occasionally estimate the Hasegawa dementia score (33) in elderly patients prior to surgery; however this is not recorded in each case. Thus, routine cognitive function assessment may help predict the risk of postoperative delirium in elderly patients.
Some reports indicated that there is no difference in the type of hepatectomy procedures performed between non-elderly and elderly patients (13, 34-36), whereas another report (12) demonstrated that non-elderly patients tend to undergo more aggressive procedures than the elderly. In the present study, the resected weight and frequency of anatomical resection were higher in the non-elderly patients than in elderly patients (14). However, the rate of recurrence in the remnant liver is higher in non-elderly patients than in elderly patients. Cancer-related factors, such as TNM staging, were not different between the groups, and hence, the severely malignant behavior of HCC in non-elderly patients may have led to the high recurrence rate in this group (14). Kim et al. reported that HBV infection was a significant factor influencing the overall survival rate after curative hepatectomy in HCC patients (37). Even though non-elderly patients underwent anatomical resection more frequently, the high rate of HBV infection may result in higher liver recurrence in the non-elderly group (38). Lee et al. showed that postoperative HCC recurrence is the most important factor affecting survival among those underwent hepatectomy (15). According to our results, there was no difference in the frequency of treatment after HCC recurrence between the 2 groups, including the frequency of repeat hepatic resection. The more aggressive treatment for recurrent HCC in elderly patients may be one of the reason for the better acceptable long-term results in this group, compared to non-elderly patients. Huang et al. (14) indicated that if certain selected elderly patients with HCC would show a better curative effect than younger patients, the methods of procedure selection based on PS criteria can be considered to be validated. Furthermore, several studies (1, 39-42) reported that the HCC cases treated with anatomical resection did not show any superiority in terms of survival. Hence, non-anatomical resection could also be validated for elderly patients, and it also associated with fewer postoperative complications.
In conclusion, age alone may not be a contraindication for hepatic resection. After an exhaustive evaluation of the preoperative general condition and an assessment of hepatic reserve, the appropriate selection of the hepatectomy procedures, while considering patient age, can help decrease postoperative complications and mortality in the treatment of elderly HCC patients. Furthermore, the selection of non-anatomical resection, on the basis of the PS criteria will not affect survival in elderly HCC patients, if it is ensured that aggressive treatments are performed for patients with HCC recurrence and a good performance status.
- Received September 13, 2015.
- Revision received October 1, 2015.
- Accepted October 19, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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