Introduction

An aging population is a major issue worldwide especially in developed countries [1, 2]. Singapore has the third longest life expectancy in the world with an average life expectancy of 83 years according to the 2017 World Health Organization report [3]. Hepatocellular carcinoma (HCC) is a common malignancy in the region due to the prevalence of hepatitis B, and it is not surprising that an increasing incidence of HCC is observed in elderly patients.

Elderly patients frequently present with more comorbidities especially cardiovascular and pulmonary disease which places them at an increased risk of postoperative complications than for young patients [2, 4]. This coupled with the increased risk of bleeding and liver decompensation after liver resection especially for HCC patients with cirrhosis [5] leaves many surgeons more reluctant to propose liver surgery for these specific groups of patients. Nonetheless, advances in surgical techniques and perioperative care have greatly improved the outcomes of hepatic surgery, allowing increasing numbers of patients even in those with comorbidities to undergo safe hepatectomy [5, 6]. Today, open hepatectomy is a well-accepted treatment modality for HCC even in elderly patients due to the reported safety and its excellent oncological outcomes [4,5,6,7].

In recent times, there has been a vast amount of interest in laparoscopic hepatectomy (LH) [8] and numerous studies have demonstrated that LH results in superior perioperative outcomes without compromising oncological outcomes in patients with malignancies including HCC [9,10,11]. This is despite HCC being frequently associated with liver cirrhosis which increases the risk of bleeding and technical difficulty of liver resection [9,10,11]. The role and benefits of LH in elderly patients remain less clear today although several recent studies [1, 2, 12, 13] have reported that the safety and advantages of LH can be translated to elderly patients. However, none of these studies have focused specifically on elderly patients with HCC, and most of these were small series with an even smaller number of HCC patients [1, 2, 12, 13]. The aim of this study was to evaluate the feasibility, safety and outcome of laparoscopic minor hepatectomy (LMH) in elderly patients with HCC. To our knowledge, this is the first study to date to focus specifically on the issue of LMH in elderly patients with HCC.

Methods

Between 2007 and 2016, 278 consecutive patients who underwent LH at Singapore General Hospital were retrospectively reviewed from a prospective database. The study was approved by our institution review board. Of these, 134 consecutive patients who underwent LMH for HCC were identified. A total of 40 consecutive elderly (≥ 70 years) patients who underwent LMH were the focus of this study. This patient cohort was compared with 94 young patients (< 70 years) who underwent LMH for HCC during the same period.

From 2005 to 2015, 105 consecutive elderly patients underwent conventional open hepatectomy for HCC at our institution. Of these, patients who underwent major hepatectomy had tumors larger than 90 mm, who underwent concomitant radiofrequency ablation had more than 2 nodules or who had locally advanced HCC requiring adjacent organ resection were excluded. Finally, 85 consecutive elderly patients who underwent OMH were selected as the open control group.

The patients’ clinical, radiological and pathological data were retrospectively reviewed and collected. Surgical data were collected from a prospective computerized database (OTM 10, IBM, Armonk, New York), whereas clinical data were collected from another prospective computerized clinical database (Sunrise Clinical Manager version 5.8, Eclipsys Corporation, Atlanta, Georgia).

Postoperative complications were classified according to the Clavien–Dindo grading system [14] and recorded up to 30 days or during the same hospitalization of surgery. Ninety-day mortality was defined as any death within 90 days from surgery. There was no specific protocol for the preoperative evaluation of elderly patients compared to young patients. Laboratory tests such as complete blood count, electrolyte panel, liver function tests and coagulation profile were routinely performed. Electrocardiogram, chest X-ray and preoperative evaluation by an anesthetist were also routinely performed. Specific tests such as echocardiography, myocardial perfusion scan or pulmonary function tests were only performed in individual cases if deemed necessary but in general were performed more liberally in elderly than in younger patients.

Definitions

The definitions used in this study were reported in our previous studies [15,16,17]. In this study, LMH was defined according to the traditional Brisbane 2000 classification [18] which included only resections 0 < 3 contiguous segments. Laparoscopic resection included all patients who underwent an attempted pure laparoscopic, robotic-assisted, hand-assisted laparoscopy or laparoscopic-assisted resections. Tumors involving segments 2, 3, 4b, 5 and 6 were defined as located in the anterolateral segments, whereas tumors involving segments 1, 7, 8 and 4a were defined as located in the difficult posterosuperior segments. An open conversion was defined as when a resection was attempted via the laparoscopic or hand-assisted approach but required an open incision to complete the resection. Conversion from pure laparoscopy to hand-assist was not considered an open conversion. Our operative technique has been previously described [15,16,17]. In general, this was not standardized and our technique including the type of laparoscopic instruments used evolved over time. This also varied according to individual surgeon preference and type of resection.

Statistical analyses were performed using the computer program Statistical Package for Social Sciences for Windows, version 21.0 (SPSS Inc, Chicago, IL, USA) and Stata (version 13, StataCorp). Univariate analyses were performed using Mann–Whitney U test, Chi-squared or Fisher’s exact tests as appropriate. All tests were two-sided, and p < 0.05 was considered statistically significant. Sensitivity analyses by way of propensity-score matching were conducted. The laparoscopic and open patients were paired 1:1 using a greedy algorithm without replacement and with a caliper of 0.2, and adequacy of matching was assessed using kernel density and histogram plots. After propensity-score matching, both groups were well balanced for all variables. The Wilcoxon signed-rank test and exact McNemar’s test (or the Cochran Q test when there are more than two levels) were, respectively, utilized to compare distributions and proportions, taking into account stratification by matched pairs.

Results

During the study period, 134 underwent LMH for HCC. Of these, 40 were elderly and 94 were young patients. The baseline characteristics and outcomes of these 134 patients are summarized in Tables 1 and 2.

Table 1 Comparison between the baseline demographic and perioperative data of elderly (≥ 70) and young patients who underwent LMH for HCC
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Table 2 Comparison between the perioperative and oncologic outcomes of elderly and young patients who underwent LMH for HCC
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Comparison between LMH for HCC in elderly and young patients (Tables 1 and 2)

Comparison between the baseline characteristics demonstrated that elderly patients were significantly more likely to have cardiac disease, diabetes, hypertension and hyperlipidemia than young patients. They were also significantly more likely to have 2 or more comorbidities, American Society of Anaesthesiologists (ASA) score ≥ 3, tumors of larger size and previous liver resection. Elderly patients were significantly less likely to have hepatitis B. Comparison between outcomes showed that elderly patients had significantly longer operation time, increased blood loss, increased need for blood transfusion, longer Pringles time (when applied) and longer postoperative stay.

Comparison between LMH and OMH for HCC in elderly patients before and after propensity-score matching (Tables 3 and 4)

Comparison between the baseline characteristics of LMH and OMH in elderly patients demonstrates no significant difference except an increased frequency in patients having more than 1 comorbidity, lower median AFP level and higher median platelet count in patients who underwent LMH. Comparison between LMH and OMH outcomes demonstrated a significantly longer operation time, increased blood loss, shorter hospital stay and decreased frequency of pulmonary complications with LMH. After 1:1 propensity-score matching, the baseline characteristics of both groups were well matched. Nonetheless, comparison between LMH and OMH in elderly patients demonstrated the same differences in outcomes. The type of pulmonary complications occurring in elderly patients after hepatectomy were pleural effusion (n = 7), pneumonia (n = 4), postoperative respiratory failure requiring intubation (n = 2) and pulmonary embolism (n = 1).

Table 3 Comparison between the baseline demographic and perioperative data of elderly (≥ 70 years) patients who underwent LMH versus OMH for HCC before and after 1:1 propensity-score matching
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Table 4 Comparison between the perioperative and oncologic outcomes of elderly patients who underwent LMH versus elderly patients who underwent OMH before and after 1:1 propensity-score matching
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Discussion

Presently, with improvement in surgical techniques and advancements in laparoscopic equipment, LH is increasingly adopted in numerous institutions worldwide [15,16,17]. The role of LH in elderly patients remains debatable, and to date, most studies have been carried out to analyze outcomes in patients with liver metastases [2, 13, 20] or various malignancies [1, 12, 19,20,21,22]. To our knowledge, there have been no studies specifically evaluating the outcomes of LH in elderly patients with HCC to date. The first study of LH for elderly patients was published in 2013 [22] which reported no difference in outcomes between 25 (≥ 70 years) elderly patients and 35 young patients who underwent LH for malignant liver tumors. Only 9 of the 25 elderly patients had HCC, and all were cirrhotic. Subsequently, Chan et al. [1] compared the outcomes of LH in 17 elderly patients with 34 elderly patients who underwent OH for malignant liver tumors in a matched case-controlled study. They demonstrated decreased blood loss and hospital stay in the LH cohort. Only 12 of the 17 patients had HCC, and 9 were cirrhotic. More recently, investigators from France demonstrated first in a single-center study [2] and subsequently in a multi-institution series [20] that laparoscopic major hepatectomy can be performed safely in elderly patients with similar outcomes to young patients and with the same advantages of decreased length of stay and morbidity over the open approach. The indications for resection were colorectal metastases in the single-center study [2], and only 10 of the 35 elderly patients in the multi-institution series had HCC [20]. The advantages of LH for colorectal liver metastases in the elderly were recently confirmed in a recent large European multi-institution study [13].

The results of our present study demonstrate that contrary to earlier reports, compared to young patients, LMH for HCC in elderly patients was associated with significantly longer operation time, increased blood loss, increased need for blood transfusion, longer Pringles time (when applied) and longer postoperative stay. In our opinion, this observation was not unexpected as elderly patients not surprisingly were more likely to have comorbidities such as cardiac disease, diabetes, hypertension and hyperlipidemia. They were also significantly more likely to have 2 or more comorbidities and have an ASA score ≥ 3. In our experience, it was more difficult for anesthetists to maintain a low central venous pressure in elderly patients during surgery which could be attributed to the higher incidence of comorbidities such as cardiac disease. This together with the frequent presence of liver cirrhosis likely accounted for the increased blood loss and blood transfusion observed with elderly patients undergoing LMH for HCC compared to young patients. Additionally, elderly patients had significantly larger tumors and were significantly more likely to undergo a repeat liver resection for recurrent HCC.

In our experience, comparison between LMH and OMH for elderly patients demonstrated mixed outcomes. LMH was associated with the significantly decreased frequency of pulmonary complications and shorter length of stay at the expense of an increase in blood loss and longer operation time. The increase in blood loss was contrary to previous studies on LMH and OMH for elderly patients which reported either a decrease or no difference in blood loss associated with LMH [1, 2, 13, 20,21,22]. However, none of these studies focused specifically on LMH for HCC. It is difficult to postulate the reason behind the difference in the results of our study although we postulate that the high complexity of many of the cases in the LMH in this series may have partly attributed to this observation. Forty percent of the 40 patients had resection of tumors in the difficult posterosuperior segments, 37.5% had liver cirrhosis, and 12.5% underwent laparoscopic repeat liver resection for recurrent HCC.

The main limitations of this study are its relatively small sample size and its retrospective nature. Hence, the results comparing LMH and OMH were likely to be affected by some degree of selection bias even after propensity-score matching. This bias can only be eliminated completely by the performance of a prospective randomized controlled trial. Nonetheless, this study represents the first experience in specifically studying the outcomes of LH for HCC in elderly patients to date.

Conclusion

The present study demonstrated that LMH is safe and feasible in elderly patients with HCC. In general, LMH in elderly patients was associated with poorer perioperative outcomes such as longer operation time, increased blood loss and increased length of stay compared to young patients. However, this was not unexpected as elderly patients were significantly more likely to have more comorbidities, larger tumors and repeat liver resections. Comparison between LMH and OMH in elderly patients demonstrated mixed outcomes whereby LMH was associated with decreased pulmonary complications and shorter length of stay at the expense of increased blood loss and longer operation time.