Chemotherapy is one of the important methods for the treatment of colorectal cancer with liver metastases (CLM). In the era of 5-fluorouracil-based chemotherapy, the tumor response rate and mean survival time for patients without surgical resection were about 20% and 11 months, respectively. Modern regimens combining 5-fluorouracil with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI regimen) have a tumor response rate of more than 50%, with a 5-year survival rate of 25-40% after hepatectomy in even mildly treated patients [1], extending survival to 22-24 months in patients without surgical resection, and the combination of hepatectomy and modern chemotherapy has resulted in a 5-year Survival rates approach 60%. A recent prospective randomized controlled trial comparing the prognostic impact of the FOLFOX regimen (6 cycles) combined with surgery (N= 159) versus surgery alone (N = 170) for patients with perioperative CLM,. The combination treatment group increased 3-year progression-free survival (35.4 vs. 28.1%, P = 0.058) [2], however, with improved efficacy, chemotherapy also caused liver damage, including steatosis (fatty degeneration), steatohepatitis, and veno-occlusive disease called hepatic sinusoidal obstruction syndrome (SOS) [3]. Here, Luo Guifen, Department of Medical Oncology, Henan Provincial People’s Hospital, reviews the impact of these potential chemotherapy-related liver injuries on the surgical outcome of CLM. I, Classification of chemotherapy-related liver injury Fatty liver disease (steatosis) is a growing concern in Western societies, with autopsy reports indicating that 6-11% of the general population has fatty changes in the liver. The severity of steatosis is graded pathologically by the percentage of hepatocytes containing fatty inclusions compared to all hepatocytes (mild 30%, moderate, 30-60%, severe 60%) [4], with an increased prevalence of steatosis in individuals with previous alcohol abuse and non-alcoholic fatty liver disease (NAFLD). Obesity, type 2 diabetes, hypothyroidism, metabolic syndrome, various drugs and toxins are predisposing factors. Whereas the second strike involves an oxidative stress response leading to lipid peroxidation, endotoxin-mediated release of cytokines that contribute to the next stage of necrotizing inflammation, the main histological feature is steatosis producing a characteristic yellow appearance compared to normal liver tissue. The “second strike theory” of steatohepatitis liver disease suggests that steatosis constitutes degeneration, lobular inflammation, and vacuolar degeneration of hepatocytes. Steatohepatitis not associated with alcohol consumption is referred to as “non-alcoholic steatohepatitis (NASH), while steatohepatitis associated with chemotherapy is referred to as chemotherapy-associated steatohepatitis. Although the pathogenesis of the “second strike” is not fully understood, the mechanism of chemotherapy-induced liver injury is thought to be a product of secondary oxidative stress that induces apoptosis of tumor cells, and the steatotic liver appears to be most susceptible to impaired regenerative capacity and abnormal innate immune function. Hepatic sinusoidal obstruction syndrome (SOS) is another chemotherapy-associated outcome. Histopathologic features include central zone hepatocyte edema, anatomic cell lines, and fibrotic hepatic sinusoidal occlusion, leading to erythrocyte crowding conditions at the hepatic sinusoidal level. More severe vascular toxicity includes hemorrhagic lobular central necrosis and regenerative nodular hyperplasia [5].SOS is a semi-quantitative graded measure of blood sinusoidal involvement (mild: 1 / 3, moderate: 1 / 3 to 2 / 3, severe: (2 / 3), with macroscopic evidence characterized by blue liver discoloration. II. Chemotherapy-associated liver injury Not all chemotherapy patients develop liver injury, but few risk factors have been identified. Metabolic disorders such as obesity, diabetes and hyperlipidemia have been directly associated with steatosis and higher degrees of fatty liver, common comorbidities that may further increase the susceptibility to liver injury with chemotherapy.Brouquet et al. found that body mass index (BMI) greater than 27 kg/m2 and hyperglycemia were independent factors associated with steatosis [6].5 – Fluorouracil is the modern chemotherapy Keystone, who has been shown to be associated with the development of steatohepatitis, SOS. As early as 1990, Chase et al. developed steatosis in 40-47% of patients treated with 5-FU, although some of the changes may be reversible. The addition of oxaliplatin or irinotecan led to increased liver injury due to their specific toxicity. For the first time, Fernandez et al. demonstrated significantly increased steatohepatitis scores and degree of liver injury with irinotecan or oxaliplatin compared to 5-FU chemotherapy alone or without, and Vauthey et al. concluded that irinotecan was associated with steatohepatitis and oxaliplatin with the development of SOS by analyzing resection specimens from each patient to evaluate the pathological effects of each drug (p = 0.001). Specifically, it was found that 19% of patients had SOS after receiving oxaliplatin, while only 4% had it after the irinotecan group (P = 0.001) [7]. This confirms Rubbia’s initial report that more than 78% of patients found to have SOS had received oxaliplatin [8].Karoui et al. reported a higher rate of hepatic sinusoidal dilatation in patients receiving chemotherapy compared to controls (49% vs. 14%, P = 0.005) [9] The addition of the anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab, may have a protective effect against oxaliplatin-induced hepatic sinusoidal injury with a protective effect. Ribero et al. reported a significantly lower incidence of hepatic sinusoidal dilatation in the group receiving oxaliplatin plus bevacizumab. The incidence of any grade of hepatic sinusoidal dilatation in this combination regimen was reduced to half (27% vs. 54%), and those with severe to less than a severe (grade 2-3) hepatic sinusoidal dilatation were reduced to one-third (8% vs. 28%) [10]. Third, the perioperative impact of liver injury Behrns et al. first reported the perioperative impact of lobectomy of large portions of the liver for CLM after hepatic steatosis, showing increased morbidity and mortality related to the severity of steatosis. belghiti et al. reported increased complication rates after CLM resection in patients with steatosis (n=37) versus normal liver (n= 710) (22 VS 8%, P= 0.001) [11]. Similarly McCormack et al. found a significantly higher incidence of major complications (27%) after major hepatic resection in patients with steatosis (n= 58) compared with that of controls (5%, P = 0.001) 0.39 No study demonstrated a difference in perioperative mortality [12]. One of the largest studies of 485 patients showed 325 patients with steatosis versus 160 controls, and multifactorial analysis found that steatosis was an independent predictor of postoperative complications (P = 0.01). The incidence of all complications and infections was 62% and 43%, respectively, 35% in the steatosis group (N= 102) versus 14% in the control group (P = 0.01), and there was an increasing trend in mortality, but it was not significant [13]. Gomez et al. demonstrated that lobectomy of large portions of the liver for CLM increased infection rates, intensive care unit (ICU) utilization, and worsened biochemical markers in patients with steatosis .40 Multifactorial analysis analysis showed that the severity of steatosis could be an independent factor in predicting the incidence of postoperative complications (p = 0.001) [14]. In conclusion, the current data suggest that moderate to severe steatosis presenting for hepatectomy is associated with an increased incidence of postoperative complications, mainly infection, but has no significant impact on mortality. Fourth, the effect of steatohepatitis steatohepatitis on hepatic resection is less reported. The first description of body mass index by Fernandez et al. Patients with greater than 35 kg/m2 with steatohepatitis, preoperative 5-FU combined with oxaliplatin treatment may increase the incidence of steatohepatitis. multicenter clinical study by Vauthey et al. suggested that steatohepatitis induced by irinotecan-based chemotherapy increased mortality 90 days after major CLM rod resection (14.7% vs. 1.4%, p = 0.001). The incidence of postoperative liver failure was higher in patients with steatohepatitis than in controls (6% vs. 1%, P = 0.01) [15]. The researchers found that the development of steatohepatitis was consistent with the two strikes theory, with patients with a body mass index greater than 25 kg/m2 being more likely to develop steatohepatitis. Therefore, it appears that steatohepatitis has detrimental postoperative liver function effects and patient survival after hepatectomy, and major hepatic resection should be approached with caution in cases of diagnosed or suspected significant steatohepatitis. Fifth, hepatic sinusoidal obstruction syndrome (SOS) platinum is the most common drug associated with the development of SOS, but how it affects postoperative recovery remains unclear. Karoui et al. reported that oxaliplatin-based chemotherapy significantly increased the incidence of postoperative complications in patients compared with controls (38% vs. 14%, P = 0.03). This was mainly attributed to the higher incidence of transient liver failure in the chemotherapy group (11% vs 0%) [16]. Aloia et al. found that patients were more likely to have increased perioperative transfusion rates after oxaliplatin administration (mean 1.9% – 0.5 units, P = 0.03) and longer hospital stays (15 days vs 11 days, P = 0.02), presumably due to hepatic sinusoidal remodeling and bleeding lobules in the remnant liver higher incidence of central necrosis [17]. Patients receiving more than one unit of blood transfusion have a tendency to have increased mortality. Strasburg reported a higher morbidity (P = 0.03) and longer hospital stay (P = 0.006) for CLM compared to normal liver tissue in patients with impaired liver reserve function as measured by preoperative indocyanine green excretion assay in patients with SOS [18]. Recent studies have divided SOS into two components namely hepatic sinusoidal fibrosis and dilatation, with fibrosis being associated with increased intraoperative transfusion requirements and the development of liver failure after hepatectomy [19] The current data illustrate the clinical importance of hepatic sinusoidal obstruction syndrome in liver metastases from colorectal cancer, and the pathological changes in the nature of this venous obstruction predispose one to an increased incidence of blood transfusion and complications after hepatectomy. Sixth, the impact of time to liver damage on surgery Although some studies have demonstrated the impact of chemotherapy-related liver injury on perioperative morbidity, there are also many studies directly comparing hepatic resection for CLM without preoperative chemotherapy with hepatic resection with preoperative chemotherapy that found significant differences [20]. One possible explanation for this difference is that it is related to the duration and course of chemotherapy. There is evidence that hepatectomy performed shortly after chemotherapy cessation may impair residual liver function and, theoretically, a longer time interval may provide time for the liver to recover from any reversible hepatotoxicity of chemotherapy. Wales et al. compared 252 patients who underwent hepatectomy after chemotherapy with 245 who underwent surgical resection without preoperative chemotherapy. , complication rates were overall sepsis (2.4%) and respiration (10.3%) in the chemotherapy group and controls (0 and 5.3%, P.003). However, the complication rate was 11% for those operated within 5 weeks after chemotherapy and fell when surgery after chemotherapy was delayed to 5-9 weeks . to 5%, and surgery after 9-12 weeks was then 2.5% or less (P = 0.009) [21]. Seven, regarding preoperative chemotherapy cycles Karoui et al. reported a higher rate of hepatic sinusoidal dilatation (49% vs. 13.6%, P = 0.005) and postoperative complications (38% vs. 13.5%, P = 0.03) in patients receiving systemic chemotherapy (mainly oxaliplatin) compared to those without chemotherapy, and postoperative complications were considerably higher in those receiving >6 cycles of chemotherapy compared to <6 cycles (54% vs. 19 percent, P = 0.047). In addition five cases of postoperative liver failure were observed in those with greater than 10 cycles of chemotherapy [22]. Although the ideal regimen, timing, and duration of chemotherapy are still under investigation, close collaboration between surgical specialists and medical oncologists is available to maximize the benefit-toxicity ratio and optimize patient selection prior to chemotherapy. Eight, preoperative biopsy and pathology for detection of liver injury remain the best methods for assessing changes in hepatotoxicity. However, this approach has its inherent limitations. In addition to hemorrhage and tumor dissemination, fat deposition, liver fibrosis and inflammation can appear artifactual [23]. In addition, the classification of injuries remains unclear. Some investigators advocate laparoscopic visual inspection of the staging, liver tissue before hepatectomy samples . , however, this approach may be difficult to apply in daily clinical practice. Standardizing the classification of preexisting liver injury by performing cross-sectional imaging at regular intervals could be part of a potentially standard preoperative examination. Fatty liver detection can be performed with computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography.51 Specifically, magnetic resonance spectroscopy has been found to reproducibly measure hepatic triglyceride levels.Cho et al. systemic cross-sectional study, magnetic resonance imaging has high sensitivity (88%) but low specificity (63%) in the accurate analysis of fatty liver [24]. Estimation of the extent of fatty liver by contrast-free CT is the most reliable method with excellent sensitivity (100%), but still achieved low specificity (33%), especially in obese patients with steatosis Further differentiation between steatosis and steatohepatitis faces another challenge because of the lack of distinct imaging manifestations of intrahepatic inflammation. Conclusions Preoperative chemotherapy is increasingly being used to treat liver metastases from colorectal cancer, with consequent changes in liver injury in resected specimens ranging from mild steatosis to steatohepatitis and hepatic sinusoidal obstruction syndrome. Some studies have shown higher perioperative morbidity and mortality in damaged livers compared to patients with healthy livers. Veno-occlusive disease is frequently seen after platinum-based chemotherapy and may increase perioperative transfusion requirements and morbidity. The duration of preoperative chemotherapy and its cessation interval are associated with surgery that may result in increased perioperative complications. Evolving imaging techniques for the noninvasive detection of underlying liver disease, particularly advances in magnetic resonance imaging, offer new hope. Preoperative assessment of liver damage and identification of patients at high risk may help minimize the incidence of postoperative complications in patients undergoing resection. References: omitted