Hepatic resection for hepatocellular carcinoma in the octogenarian: is it justified?

Patient demographics

A total of 3,386 HCC patients treated with curative hepatectomy were included in the study. Among them, 77 patients were ≥ 80 years old and were classified as the octogenarian group (O-HCC, 2.3%). The remaining patients were younger than 80 years old and were designated as the younger patient group (Y-HCC, n=3,309, 97.7%). The mean age at diagnosis in the two groups was 83 and 57 years, respectively. The median follow-up time was 39.3 months in the O-HCC group and 45.8 months for the Y-HCC group. Their respective clinical characteristics are summarized in Table 1. As shown, the O-HCC group had significantly more co-morbidities, less hepatitis B virus (HBV) infection, and lower hemoglobin and albumin levels than the Y-HCC group (all P < 0.05). While HBV infection accounted for more than 66% of HCC in the Y-HCC group, hepatitis C virus (HCV) infection was the most common etiology in the O-HCC group (n=28; 43.1%). Interestingly, 27 patients (37.5%) in the O-HCC group had neither HBV nor HCV infection, which was significantly higher than in the Y-HCC group (10.6%, P <0.001). Furthermore, not listed in the table was our finding that 73.1% of non-viral O-HCC patients had diabetes mellitus (DM), as compared to only 21.6% of viral O-HCC had DM (P < 0.001).

There were no significant differences between the two groups with respect to tumor size, encapsulation, capsular invasion, tumor rupture, vascular invasion, daughter nodules, resection margin, or Edmondson-Steiner grade (all P>0.05) (Table 2). In the O-HCC group, however, there was significantly less liver cirrhosis than in the Y-HCC group (38.2% vs. 53.9%, P=0.007).

Comparison of surgical and oncological outcomes

The outcomes after hepatectomy for HCC are summarized in Table 3. The total complication rate was 42.4% for the entire cohort. There were no significant differences in the complication rate, 30-day mortality rate, in-hospital mortality rate, or mean hospital stay between the O-HCC and Y-HCC groups (all P >0.05). To further investigate the differences between younger and older patients, a subgroup of 278 HCC patients operated on by a single surgeon between 2011 and 2015 was analyzed. Among this group, 11 patients (4%) were ≥ 80 years old. After statistical analysis, the most common surgical complication within both groups was ascites requiring diuretics. Post-operative bleeding, surgical site infection, jaundice, and bile leakage rarely occurred in the O-HCC group. However, one patient in the O-HCC group underwent endotracheal intubation and mechanical ventilation due to respiratory failure.

The median disease-free survival (DFS) for the entire cohort was 25.1 months (95% CI, 22.7-27.4). There was no significant difference in median DFS between the O-HCC and Y-HCC groups (27.9 vs. 24.9 months, P=0.888) (Figure 1). The overall survival (OS) for the entire cohort was 76.5 months (95% CI, 69.8-83.2), and the median OS for the two groups were comparable (57.4 vs. 77.1 months, P=0.371) (Figure 1). The 5-year DFS rate was 29.3% in the O-HCC group and 34.3% in the Y-HCC group (P =0.671), while the 5-year OS rate was 45.8% in the O-HCC group and 54.4% in the Y-HCC group (P =0.379). To reduce bias related to the prolonged study duration, a subgroup analysis of patients operated on after year 2001 was conducted. The results were comparable to those for the entire cohort, and there was no significant difference in DFS or OS between the two groups (P=0.735 and 0.123, respectively). To strengthen the result further, a propensity score matched analysis derived from the entire cohort was performed. Clinical variables including gender, co-morbidity, hepatitis viral status, preoperative hemoglobin, albumin, and cirrhosis were matched between the two groups. Again, the DFS and OS for the two groups were comparable (P=0.287 and 0.433, respectively).

Figure 1. Kaplan–Meier disease-free survival (DFS) and overall survival (OS) curves for hepatocellular carcinoma treated by hepatectomy in the O-HCC and Y-HCC groups. (A) Disease-free survival curves. The median DFS was 27.9 months in the O-HCC group and 24.9 months in the Y-HCC group (P=0.888). The 5-year DFS rate was 29.3% in the O-HCC group and 34.3% in the Y-HCC group (P =0.671). (B) Overall survival curves. The median OS was comparable between the two groups. The median OS was 57.4 months in the O-HCC group and 77.1 months in the Y-HCC group (P=0.371). The 5 year-OS rate was 45.8% in the O-HCC group and 54.4% in the Y-HCC group (P =0.379).

Risks factors for in-hospital mortality in the octogenarians

Five patients (6.5%) in the O-HCC group died in hospital after hepatectomy for HCC. The risk factors for in-hospital mortality were analyzed, and the results are summarized in Table 4. INR >1.4, serum α-fetoprotein >200 ng/mL, major procedure, and major surgical complications were all potential risk factors for in-hospital mortality after hepatectomy for HCC in the octogenarian group (all P <0.05). All other clinical variables tested were unrelated to in-hospital mortality.

Prognostic factors for the octogenarians

Cox regression multivariate analysis revealed that only HCV infection and tumor rupture are independently associated with a significantly poorer DFS in the O-HCC group. As shown in Table 5, HCV infection and tumor rupture were respectively associated with a 4.26-fold and 7.36-fold increase in risk of HCC recurrence after hepatectomy in the octogenarians (all P < 0.001). Although its impact was not yet statistically significant, O-HCC patients with α-fetoprotein ≥400 ng/mL were also prone to recurrence. On the other hand, serum α-fetoprotein ≥400 ng/mL, tumor size ≥10 cm, tumor rupture, and vascular invasion were all found to be associated with a poorer OS (Table 6, all P <0.05). Cox regression multivariate analysis revealed serum α-fetoprotein ≥400 ng/mL, tumor size ≥10 cm, and vascular invasion to be independent poor prognostic factors for poorer OS in the octogenarians (all P <0.05).

Study population

We retrospectively reviewed HCC patients treated with curative hepatectomy by our surgical team at Chang Gung Memorial Hospital (CGMH) between 1986 and 2015. The patients were divided into a younger patient group (Y-HCC group; age < 80 years old) and an octogenarian group (O-HCC group; ≥ 80 years old) according to their age at first diagnosis. Patients with distant metastases, patients who underwent non-curative intent hepatectomy, or those whose detailed medical records were unavailable were excluded from the study. A total of 3,386 patients were ultimately enrolled. The demographics, perioperative and survival data were reviewed. Our primary study endpoints were surgical complications and in-hospital mortality. Secondary endpoints were disease relapse and long-term survival. The study end date was December 31, 2015. Tumor staging was based on the American Joint Committee on Cancer (AJCC) TNM staging system for HCC [30].

Diagnosis and preoperative evaluation

Diagnoses of HCC were established based on definitive pathological examination; typical image features on dynamic computed tomography (CT), magnetic resonance imaging (MRI), arterial angiography; and/or a serum α-fetoprotein level >200 ng/ml. Resection criteria included appropriate liver function, adequate future liver remnant, no distant metastasis to other organs, and an absence of tumor thrombi in the main portal vein. Liver function was routinely evaluated using the Child-Pugh classification and indocyanine green retention test at 15 minutes (ICG-15). In our institute, an ICG-15 ≤ 10% was necessary for major liver resection (three or more liver segments) [22,23]. In addition, an ECOG score of 0 to 1 was a prerequisite at the time the operation was to be performed [31]. For octogenarians, echocardiography and pulmonary function tests were routinely performed before the operation. High risk patients were routinely assessed by cardiologists and anesthesiologists to determine the operative risk. For diabetic patients, blood sugar was maintained below 200 mg/dl during the perioperative period. Blood pressure was controlled at an appropriate level and anticoagulant/antiplatelet medications were adjusted or held as indicated before the operation.

Surgery, postoperative management, and follow-up

All operations were conducted by the same surgical team in the Department of General Surgery. The liver texture, tumor location and extent, and vascular patency were routinely evaluated by manual palpation and intraoperative ultrasonography. Hilar lymph node dissection was performed if enlarged lymph nodes were detected [32]. Liver parenchyma transection was performed using either the clamp crush technique, cavitron ultrasonic surgical aspirator (CUSA) and/or other energy devices. Inflow control was applied based on the individual patient's condition and the surgeon's preference. Bleeding and bile leakage were checked meticulously at the end of the surgery.

Patients were sent to either intensive care units or ordinary wards for postoperative care. Enteral nutrition was resumed as early as possible. Blood products and albumin were transfused whenever necessary to maintain adequate serum albumin levels (usually > 3.0 g/dL), urine output, and ascites control. Prophylactic antibiotics were discontinued 24 hours after surgery if there were no signs of infection. Hemograms and biochemical data were checked routinely on postoperative days 2 and 7. All patients were followed-up with triphasic CT and measurement of serum α-fetoprotein levels every 3 to 6 months after hospital discharge.

Definitions

Major liver resection was defined as resection of three or more liver segments including tri-segmentectomy, right/left lobectomy, and extended right/left lobectomy [33]. Complications after hepatectomy included wound infections, bile leakage, bleeding requiring re-intervention, ascites requiring diuretics, jaundice, pleural effusion, respiratory failure requiring intubation, and mortality. Patients who tested positive for bacteria in the wound discharge were considered to have a wound infection. Bile leakage was defined as one or more of the following: 1) drainage of bile from the abdominal wound or drain; 2) intraabdominal collection of bile confirmed at the time of reoperation or percutaneous drainage; and 3) cholangiographic evidence of biliary leakage or stricture [34]. Ascites was defined as daily ascites fluid drainage exceeding 500 ml and/or more than grade 2 ascites on ultrasonography or clinical assessment showing a moderately symmetrical distension of the abdomen [35,36]. Diuretics, starting with an aldosterone antagonist (spironolactone) and then a loop diuretic (furosemide), were administered in a stepwise manner in these circumstances. Clinically symptomatic fluid collection in the pleural space that was confirmed by either X-ray or ultrasound was considered to be postoperative pleural effusion. As for jaundice, a persistently abnormal serum bilirubin level on postoperative day 7 and/or no significant improvement compared to day 2 was classified as postoperative jaundice.

Recurrence was defined as the appearance of characteristic image findings during regular postoperative radiologic examinations. Early recurrence was defined as recurrence within two years of the initial curative operation. DFS was calculated from the date of surgery to the date of the first documented clinical disease recurrence. OS was defined as the time elapsing from the date of diagnosis to either the date of death or the date of last contact. Cases with surgical mortality, defined as death within one month of surgery, were excluded from the survival analyses.

Statistical analysis

Statistical analysis was performed using IBM SPSS Statistics 21 (IBM Corporation, Software Group, Somers, NY, USA). Student’s t test or Mann-Whitney U test was used to analyze continuous variables. Fisher’s exact test or Pearson’s χ² test was used to analyze categorical data. Kaplan-Meier analysis was used to determine the OS and DFS. The log-rank test and Cox proportional hazard regression multivariate analysis were adopted to determine prognostic significance of clinicopathological variables in the octogenarian group. Values of P < 0.05 in two-sided tests were considered significant.

Ethics approval and consent to participate

This study was approved by the Institutional Review Boards (CGMH IRB No: 201600359B0) of Chang Gung Memorial Hospital (CGMH).

Availability of data and materials

All data generated or analyzed during the study are included in this published article. Raw data may be requested from the authors with the permission of the institution.