Update on perioperative management of patients undergoing surgery for liver cancer

Abstract Hepatocellular carcinoma is often accompanied by chronic hepatitis or cirrhosis. Preoperative evaluation of liver function and postoperative nutritional management are critical in patients with hepatocellular carcinoma who undergo liver surgery. Although the incidence of postoperative complications and death has declined in Japan over the last 10 years, postoperative complications have not been fully overcome. Therefore, surgical procedures and perioperative management must be improved. Accurate preoperative evaluations of liver function, nutrition, inflammation, and body skeletal muscle are required. Determination of the optimal surgical procedure should consider not only tumor characteristics but also the physical reserve of the patient. Nutritional management of chronic liver disorders, especially maintaining protein synthesis for postoperative protein/energy, is important. Prophylactic antibiotics are recommended for short‐term use within 24 hours after surgery. Abdominal drainage is recommended for patients with cirrhosis who may develop large amounts of ascites, who are at risk of postoperative bleeding, or who may have bile leakage due to a large resection area. Postoperative exercise therapy may improve insulin resistance in patients with chronic liver damage. Implementation of an early/enhanced recovery after surgery program is recommended to reduce biological invasive responses and achieve early independence of physical activity and nutrition intake. We review the latest information on the perioperative management of patients undergoing liver resection for hepatocellular carcinoma.

resection has been reported to range from 20% to 70%, with mortality rates of 5%-21%. [5][6][7][8][9][10] Mortality rates at high-volume centers in Japan are usually much lower, <2%, [11][12][13] although morbidity rates remain relatively high. The postoperative course of these patients does not always proceed as expected, owing to various types of intraoperative stress, including blood loss and ischemia. These findings emphasize the importance of improving both surgical techniques and perioperative care in reducing the mortality and morbidity of patients with HCC undergoing liver resection. In this review, we outline the current status of and topics regarding the perioperative management of patients undergoing surgery for liver cancer based on recent evidence.

| ALG ORITHM FOR THE TRE ATMENT OF H CC AND APPROPRIATE E VALUATI ON OF LIVER FUN C TI ON B EFORE HEPATEC TOMY
With regard to the therapeutic strategy for HCC, the Barcelona Clinic Liver Cancer (BCLC) staging system recommended by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver is used worldwide. 14 In Japan, the "treatment algorithm" described in the Clinical Guidelines for HCC is widely used to select the optimum treatment based on liver function and tumor status (Figure 1). 15 The Japanese treatment algorithm differs markedly from the BCLC system with regard to HCC with concomitant portal hypertension. 16 In the BCLC system, liver resection is not indicated if portal hypertension is present, and liver transplantation and radiofrequency ablation (RFA) are recommended. In contrast, liver resection is recommended based on the indocyanine green (ICG) retention rate at the 15-min (ICGR15) level in the Japanese treatment algorithm, and favorable outcomes have been reported. 17 Liver resection for HCC is chosen based on the balance between tumor status and liver function. Resection exceeding the hepatic functional reserve with the goal of cancer cure may lead to liver failure, whereas insufficient resection due to excessive safety concerns may have a high risk of early recurrence. Therefore, it is important to select the optimum surgical procedure based on the extent of the tumor and the acceptable liver resection range. As the liver reserve classification for preoperative liver function evaluation, the Child classification and its modified Child-Pugh classification have been widely used worldwide. In particular, the presence or absence of ascites is used as an index of the degree of portal hypertension, and poor control of ascites is not indicated for surgery. In Europe and the United States, it has been common that B and C cases of the Child-Pugh classification are not indicated for surgery, and even in cases of Child-Pugh classification A, if portal hypertension coexists, hepatectomy is not indicated.
This standard is adopted in the liver cancer treatment guidelines in Europe and the United States. 14 In contrast, reports from Europe and the United States have stated that portal hypertension is not a contraindication for hepatectomy with more than two sections. 18 It has been reported in Japan that reduced hepatectomy with portal hypertension is not contraindicated, because no increase in postoperative complications was observed. 17 The ICG loading test and technetium-99m-garactosyl human serum albumin ( 99m Tc-GSA) liver scintigraphy are the main quantitative preoperative evaluations of liver function for hepatectomy. Many studies of ICG load have found that it is a useful predictor of postoperative mortality. 5,19 The ICG retention rate at 15 minutes (ICGR15) has been adopted as a factor in the evaluation of liver damage by the Japan Liver Cancer Study Group 20 and has become a standard evaluation of preoperative liver function.
Yamanaka et al reported that the prediction score for the occurrence of postoperative liver failure as a surgical indication criterion, which consists of the ICGR15, amount of resection, and age, could accurately predict postoperative mortality. 21,22 Takasaki et al proposed a standard that set a different permissible amount of hepatectomy for each value of the ICG loading test. 23 Postoperative liver failure and death within the permissible hepatectomy criteria were 2% and 0%, respectively, whereas for non-permissible hepatectomy, they were 23% and 1%, respectively. 24 The Makuuchi standard, 25 which is widely used in Japan, clearly indicates whether hepatectomy is indicated and the allowable range of resection based on ascites, total serum bilirubin level, and ICGR15 ( Figure 2). It has been reported that 0% of surgical deaths occurred in 1056 patients who underwent hepatectomy in compliance with this standard. 26 Kokudo et al reported that the Albumin-Indocyanine Green Evaluation (ALICE) grade using the serum albumin level and ICGR15 is useful for predicting the occurrence of postoperative liver failure and survival. 27 The ALICE grade is superior to the Child-Pugh classification in predicting outcomes after hepatectomy and may be a more useful liver function evaluation classification when combined with the presence or absence of portal hypertension. 28,29 It has been reported that 99m Tc-GSA liver scintigraphy was superior to the ICGR15 in the histologic evaluation of liver damage. 30 Evaluation of functional residual liver volume calculated from 99m Tc-GSA liver scintigraphy was more informative than residual liver volume evaluation from computed tomography (CT) for predicting postoperative complications and death in patients with HCC and liver damage. 31 However, 99m Tc-GSA liver scintigraphy has facility restrictions due to the use of nuclides. In the evaluation of preoperative liver function to decide the surgical indication, in addition to information such as the Child-Pugh classification obtained in daily clinical practice, including blood tests, many reports recommend the ICG load test as a quantitative test. 15 For hepatectomy, it is considered appropriate to determine the indication based on the balance between the degree of liver damage estimated from the ICGR15 and the range of hepatectomy (the amount of resection required).

| Evaluation by biochemical and physical factors
Recent studies have proposed markers based on several nutritional or inflammation-based prognostic indicators of HCC. Nutritionalor inflammation-based markers include the prognostic nutritional index, 32-34 controlling nutritional status (CONUT) score, [35][36][37] Glasgow prognostic score, 38 C-reactive protein (CRP)-to-albumin ratio (CAR), 39 neutrophil-to-lymphocyte ratio (NLR), 40 plateletto-lymphocyte ratio (PLR), 41,42 lymphocyte-to-monocyte ratio (LMR), 43,44 and CRP-albumin-lymphocyte index. 45 Table 1 shows combined indices that can reportedly be used to estimate the nutritional or inflammatory status relevant to short-and long-term outcomes after hepatectomy for HCC. While some of the algorithms are complicated, CRP and serum albumin measurements are used more often as components of combined indices. 39 The use of sarcopenia to predict outcomes in patients with cancer has attracted more attention, including those with HCC 46-48 or colorectal liver metastases (CRLM) 49,50 undergoing hepatic resection. Previous studies also demonstrated that sarcopenia increased the risk of postoperative morbidity and longer hospital stay, as well as readmission rates, after partial liver resection for CRLM. 51,52 Those studies focused only on skeletal muscle mass, as assessed by CT of skeletal muscle area. In contrast, a few reports have described the deterioration of muscle quality associated with muscle fat deposition. The usefulness of intramuscular adipose tissue content in hepatectomy for HCC 53,54 and CRLM 55 has been reported. Preoperative sarcopenia and/or intramuscular adipose tissue content might be considered a new selection criterion for hepatectomy in patients with liver cancer.

| Nutrition therapy
Because many cases of hepatectomy for HCC coexist with chronic hepatitis and cirrhosis, these patients often have energy/substrate metabolic disorders. Specifically, it has been reported that nutritional disorders occur frequently in patients with liver cirrhosis; 84% and 95% of patients with Child-Pugh classifications B and C, respectively, are undernourished, and 45% of patients with Child-Pugh classification A are also undernourished. 56 The main characteristic of nutritional disorders in patients with liver cirrhosis is malnutrition of protein and energy, and a decrease in the burning ratio of glucose as an energy-burning source and an increase in the burning ratio of fat are observed. 57 These nutritional disorders in patients with cirrhosis are closely related to the incidence of complications after hepatectomy, and the importance of perioperative nutrition therapy has been noted. 58 In principle, oral and enteral nutrition should be

| PROPHYL AC TIC AB DOMINAL DR AINAG E
Routine prophylactic abdominal drainage was unnecessary or contraindicated for patients who underwent elective hepatectomy in RCTs, because drain placement increased the frequency of drainrelated complications, wound complications, sepsis and infectious

PNI Albumin, lymphocyte
PNI <44 was associated with higher transfusion rates and surgical outcomes, 32 PNI <45 was the most powerful predictor of complications after hepatic resection. 33 Patients with PNI <37 were at high risk for early recurrence and poor survival. 34 CONUT Albumin, lymphocyte, total cholesterol Early postoperative CONUT score >8 was identified as a risk factor for postoperative complication III-V. 35 Preoperative CONUT scores >4 was predictive of worse OS and RFS. 36 High CONUT score was an independent predictor of in-hospital mortality after hepatectomy 37  We speculate that the spread of ERAS programs in hepatectomy in Japan will be as follows. There are 15 ERAS items essential for liver surgery: "Pre-admission counseling," "No bowel preparation," "Fluid and CHO-loading/no fasting," "No pre-anesthetic medication," "No routine nasogastric tubes postoperatively," "Epidural analgesia," "Short-acting anesthetic agent," "Avoidance of sodium/ fluid overload," "Short incision," "Warm air body heating in theatre," "Early mobilization (routine mobilization care pathway)," "Non-opiate oral analgesics/NSAIDs," "Early feeding (stimulation of gut motility and perioperative oral nutrition)," and "Early removal of catheters." However, "No surgical drains," "Prevention of nausea and vomiting," and "Audit of compliance/outcome" are not yet widespread components of ERAS programs in Japan ( Figure 4).

| CON CLUS IONS
This review summarizes a series of unique approaches to the perioperative management of patients with HCC undergoing liver resection based on the available evidence, with the goal of achieving "no F I G U R E 3 Exercise therapy. (A) Cardiopulmonary exercise test. The anaerobic threshold (AT) was set at the break point between carbon dioxide production and Vo 2 , or the point at which the ventilatory equivalent for oxygen and end-tidal oxygen partial pressure curves reached their respective nadirs before beginning to increase again. Thus, the AT was set at a maximum point of fat combustion. • heart rate; ▲ glucose combustion; ■ fat combustion. (B) Effect of exercise on insulin resistance in patients with HCC with hepatic impairment. HOMA-IR in the diet group (□) and the exercise group (■). HOMA-IR, homeostasis model for assessment of insulin resistance; POD, postoperative day; POM, postoperative month. (C) Estimating the mechanism of hepatocellular carcinoma development due to exacerbation of insulin resistance. There is a vicious cycle among obesity, muscle steatosis, and the development of insulin resistance in patients with liver diseases. Exercise and/or BCAA therapy is considered to suppress the deterioration of the condition. Akt; protein kinase B; BCAA; branched-chain amino acid mortality" and "minimal postoperative complications." We believe that general perioperative management of patients undergoing surgery for liver cancer is basically the same, even when there is a wide variety of patient and surgical factors. Whether the associated liver disease is normal vs severe cirrhosis, and whether the surgery is laparoscopic vs open hepatectomy, we perform the perioperative management described above in the same way. New methods for the improvement of preoperative liver function and perioperative management are likely to facilitate expansion of the indication for liver resection.

ACK N OWLED G EM ENTS
We are indebted to the following surgeons for their excellent collection and management of the manuscripts: Satoru Imura (Department of Surgery, Tokushima University) and Shogo Tanaka (Department of Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine).

D I SCLOS U R E
Funding: All authors hereby declare that there is no potential or actual personal, financial, or political interest related to this study.
Conflict of Interest: None.

R E FE R E N C E S F I G U R E 4
Enhanced recovery after surgery (ERAS) program items performed in patients undergoing hepatectomy in Japan. ERAS program items that have already been implemented at many facilities in Japan are marked with a check mark, and items that have not yet been implemented sufficiently are marked as question marks