The Role of Laparoscopic Surgery in the Management of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the 6th most common cause of cancer and 4th most common cause of cancer-related mortality globally (2018 WHO statistics). Worldwide, the highest incidence of HCC is found in low- and middle-resource countries such as those in Eastern and Southeastern Asia and Africa [1‐3]. Globally, etiologies for HCC are similarly broad, with chronic hepatitis B virus (HBV) and aflatoxin B1 accounting for much of the disease in developing regions such as China and India, while hepatitis C virus (HCV) and metabolic dysfunction–associated steatotic liver disease (MASLD) and metabolic dysfunction–associated steatohepatitis (MASH) account for the majority of cases in Western countries [4‐7].

Multiple staging systems have been developed for HCC. The most commonly used Barcelona Clinic Liver Cancer (BCLC) system is based upon tumor burden, patient performance status, and liver dysfunction and has the ability to predict prognosis to guide therapeutic decision-making for patients with HCC [8]. Surgical options, such as hepatic resection (HR) or liver transplant (LT), yield the best outcomes for patients with HCC with 5-year survival rates of 50–70%; however, only 10–23% of patients present with disease amenable to HR or LT [9‐11]. Most patients present with advanced HCC and face 1-year survival of 15–39% with limited treatment options [12, 13]. Nevertheless, marked advances in targeted and systemic therapies for HCC have been made over the last decade and have been reviewed elsewhere [14, 15]. Herein, we will primarily discuss surgical intervention, with a specific focus on the role of laparoscopic and minimally invasive surgery (MIS), for the treatment of HCC.

Surgical therapy for HCC comprises hepatic resection or liver transplantation. LT shows excellent outcomes, with 5-year survival rates of 60–70% [16]. LT, however, is limited to patients within Milan criteria, defined as up to three lesions, each < 3 cm in diameter, or a single lesion < 5 cm in diameter, and no extrahepatic manifestations or vascular invasion [17, 18]. Patients with HCC who undergo LT within Milan criteria have similar 5-year survival as those with non-HCC etiologies of liver disease [19]. Despite this excellent overall survival, approximately 10–20% of patients will develop tumor recurrence with a median recurrence free survival (RFS) of 12–16 months and increased mortality risk of death [20‐22]. Patients who do not meet Milan criteria have undergone LT using expanded criteria, such as the University of California-San Francisco (UCSF) criteria described in Yao et al. in 2001, the “Seven-Up” criteria by Mazzaferro and colleagues, or the “5–5 Rule” from the University of Tokyo [23‐25]. Together, they have reported 5-year survivals of 71.2% and higher. Nevertheless, current guidelines in the United States for awarding exception points to patients on the LT waitlist continue to follow Milan criteria.

Given the strict guidelines for LT waitlisting in the US, and the known increased risk of recurrence for patients with disease burden outside of Milan criteria, HR remains a viable option for patients with preserved liver function. HR in patients who fall within Milan criteria shows a similar 5-year survival of 60–70% [26]. According to both American Association for Study of Liver Disease (AASLD) and European Association for the Study of Liver (EASL) guidelines, hepatic resection should be reserved for patients with tumors confined to the liver and Child–Pugh-Turcotte class A liver function, with society-specific considerations for tumor number and size [27]. Historically, patients with portal hypertension were not considered for HR due to increased morbidity and mortality [28‐30]. However, recent advances in surgical technique and post-operative care have been associated with non-inferior outcomes [31‐33], making the presence of portal hypertension a point of controversy rather than contraindication in hepatic resection. Nevertheless, underlying liver dysfunction, such as that identified by the model for end-stage liver disease (MELD) score, remains a predictor of perioperative mortality for patients and may be used to guide patient selection [32].

In concert with the presence of underlying liver dysfunction, the extent of resection is a major determinant in the decision to proceed with surgical resection. Patients without any underlying liver dysfunction can typically tolerate partial hepatectomies as long as at least a 20–30% functional liver remnant (FLR) is preserved. Those with cirrhosis within, and almost always not beyond, BCLC stage A require at least 40% FLR to avoid post-operative liver failure [34]. Between these two extremes of liver disease, patients with steatosis, cholestasis, or chemotherapy-associated liver injury (particularly with oxaliplatin and irinotecan) may require 35–40% FLR to reduce risk of post-operative complications [35‐37]. As such, the extent of safe HR is closely associated with liver function and the presence of portal hypertension. While there remains ongoing debate between anatomic and non-anatomic approaches, resections of large tumors or those with macrovascular invasion may be undertaken if these safe principles are met [38‐40].

Surgical therapy with HR remains a first-line therapy for patients with HCC and compensated liver function [41]. The first laparoscopic liver resection was reported in 1991 [42]. Despite passage of more than two decades, however, widespread adoption of minimally invasive techniques in liver surgery has been slow, partly due to technical complexities, risk of bleeding, and oncologic concerns. These were issues brought up during two international consensus conferences that have occurred to provide summaries of the status and perspective of laparoscopic liver surgery—Louisville, KY, USA, in 2008 and Morioka, Japan, in 2014 [43, 44]. Fortunately, advances in technique, instrumentation, increased experience, and accumulation of data have contributed to increased utilization of minimally invasive techniques in liver surgery. The following sections will focus on laparoscopic techniques in liver surgery and describe both oncologic outcomes and patient-centered metrics.

The technical advantages of robotic liver resection for hepatocellular malignancy underscore the benefits of robotic surgery at large: improved three-dimensional (3D) visualization, increased degrees of freedom of movement with articulating instruments, ease of performance of intracorporeal suturing, and overall better instrumentation including the Vessel Sealer, SynchroSeal, various staplers, suction irrigator, and Firefly™ technology, to name a few [118, 119]. The improvements resulting from the ability to see tissue through highly magnified 3D high-definition vision, coupled with the ability to use IOUS simultaneously with picture-in-picture software, cannot be overstated. Traditionally, difficult areas of liver to reach laparoscopically, such as posterior segments and lesions near the diaphragm, can be approached more readily with the robotic platform. Difficult mobilization of the liver (e.g., right lobe) can be performed easier robotically than laparoscopically. Prior operations are less of a challenge thanks to the more versatile ability of the robotic techniques in lysis of adhesions and dealing with difficult dissections. Re-operations to investigate concerns for bleeding, bile leak, bowel injury, or other complications can be done (and often completed) robotically. Current “missing” robotic tools in liver surgery can, for now, be augmented by use of available laparoscopic instruments through appropriately placed assistant ports [120]. Finally, robotic approaches to liver resection in HCC may offer future additional advantages such as better tumor localization through 3D pairing of pre-operative imaging with computer-guided resection, better instrumentation, and more versatile “live” patient positionings through pairing of robotic platform with the surgical bed. One current limitation in robotic liver resection remains the lack of haptic feedback, while a highly mobile, 3D, high-definition robotic camera can compensate for this to a great extent. Eventually, it is very likely that haptic feedback will be added to the platform through technological advances that are current under investigation.

The learning curve of robotic liver resection appears to be similar to laparoscopic liver resection, but ultimately depends on underlying surgeon familiarity with the robotic platform. One series described initial competency following 15 robotic liver resections accompanied by decreasing operative duration and hospital stay, intermediate improvement after 25 additional resections resulting in decreased intraoperative blood loss, and mastery of increasingly complex robotic liver resections by 92 cases [121].

Robotic liver resection has demonstrated comparable patient outcomes to both open and laparoscopic liver resection. In a propensity score-matched comparison of patients undergoing robotic and open liver resection for HCC (n = 106 per group) between high volume centers in the United States and Europe, robotic liver resection patients had a longer operative time (295 vs 200 min; p < 0.001) but shorter post-operative inpatient hospital stay (4 vs 10 days; p = 0.002) [119]. Comparison of oncologic outcomes demonstrated equivalent 90-day survival (99.1% vs 97.1%, p = 0.33) and cumulative incidence of death related to tumor recurrence (8.8% vs 10.2%; p = 0.64) [119]. Another series comparing robotic (n = 71), laparoscopic (n = 141), and open (n = 157) liver resection for BCLC stage 0-A HCC demonstrated no difference in 5-year DFS, OS, or post-operative complications [122]. Finally, a meta-analysis comparing robotic liver resection to open and laparoscopic approaches found similar patient survival and complication rates between the approaches, but importantly emphasized the need for randomized controlled trials conducted independent of industry sponsorship [123].

Still, perhaps the greatest limitation in robotic surgery is the availability of the resource due to high costs of acquisition and maintenance. It is to be noted that for the last several years, our practice has transitioned to primarily robotic approaches for surgical treatment of hepato-pancreato-biliary issues, including surgical management of HCC. We strongly believe that robotic surgery offers significant advantages over laparoscopic surgery and represents our preferred technique.

Hepatic resection for HCC, and many other indications, is a technically demanding operation, often performed in patients with multiple pre-existing conditions. Successful completion of this operation requires appropriate patient selection and operative planning. Minimally invasive surgery, both laparoscopic and robotic platforms, offers safe and effective approaches for diagnostic biopsies, ablative therapies, and multi-segmental hepatic resections. Furthermore, there may be significant benefits to patients in post-operative recovery without sacrificing oncologic outcomes.