Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P18

11 Portal Vein Embolization Prior to Resection 155 Most information about the molecular and cellular events during liver regen-eration comes from studies of partial hepatectomy in animal models [22, 32]. In short, the events that occur in hepatocytes result from growth factor stimulation in response to injury. In regenerating liver, hepatocyte growth factor (HGF), trans-forming growth factor-α(TGF-α), and epidermal growth factor (EGF) are important stimuli for hepatocyte replication. HGF is the most potent mitogen for hepato-cyte replication, and in combination with other mitogenic growth factors, such as TGF-α and EGF, it can induce the production of cytokines, including tumor necro-sis factor-α and interleukin-6, and activate immediate response genes that ready the hepatocytes for cell cycle progression and regeneration. Insulin is synergistic with HGF, resulting in slower regeneration rates seen in patients with diabetes [33, 34]. The extrahepatic factors are transported primarily from the gut to the liver via the portal vein and not from the hepatic artery and are directed [9, 23, 35, 36]. Rate of Liver Regeneration Hepatocyte regeneration occurs soon after partial hepatectomy, PVE, or liver injury. Shortly after the stimulus, hepatocytes leave the dormant stage of the cell cycle and undergo mitosis, with an initial peak of DNA synthesis occurring in the parenchy-mal cells (e.g., hepatocytes and biliary epithelial cells) at 24 and 40 h after resection in rat and mouse models, respectively [37]. In both species, non-parenchymal cells exhibit a first peak of proliferation about 12 h after the parenchymal cells [38]. In large animal models of regeneration after partial hepatectomy, DNA synthesis peaks later, at 72–96 h in canines [39] and 7–10 days in primates [40]. Notably, the extent of hepatocyte proliferation is directly proportional to the extent of insult (i.e., a small liver injury will result in a mitotic reaction limited to only a small area, but any insult greater than 10% will lead to proliferation of cells all over the liver) [41]. When more than half of the liver is resected, a second, less distinct rise of hepato-cyte mitoses is observed. In rat and mouse models, this second rise is observed at 3–5 days; in larger-sized animals, this second rise occurs over the course of many days. Studies performed in other injury models have hinted that comparable time-lines for regeneration and cellular signaling are implicated in the regenerative response. For example, examination of the regenerative response after PVE in swine showed induction of hepatocyte proliferation at 2–7 days [42]. Replication peaked at 7 days, taking place in roughly 14% of hepatocytes, and then decreased to baseline levels by day 12, a process similar to what is observed with PVE clinically. When contrasted with replication after resection, the peak replication after PVE is delayed about 3–4 days, implying that the stimulus of removing hepatocytes is superior to the stimulus of apoptosis seen with PVE [26]. Also critical to the understanding of liver regeneration is the observation that diseased (i.e., cirrhotic) liver has a reduced regenerative capacity when compared to healthy liver [26]. This may be the result of the diminished capacity of hepatocytes to react to hepatotropic factors or due to parenchymal damage such as fibrosis that 156 D.C. Madoff and R. Avritscher leads to slower portal blood flow velocities [43]. Lee and colleagues [26] assessed ratswithnormalorchemicallyinducedcirrhoticliversandshowedthattheweightof normalliversincreasedafter24h,tripledafter7days,andreachedaplateaubetween 7 and 14 days, whereas the regeneration rate of the cirrhotic livers was delayed and of a lesser degree. Findings in clinical studies have been similar. Non-cirrhotic livers in humans regenerate quickest, at rates of 12–21 cm3/day at 2 weeks, 11 cm3/day at 4 weeks, and 6 cm3/day at 32 days after PVE [34, 44]. The regeneration rates are slower (9 cm3/day at 2 weeks) in patients with cirrhotic livers, with equivalent rates found in diabetics [34, 45]. Kawarada et al. [46] reported that dogs subjected to a 70% hepatectomy combined with a pancreatectomy had delayed recovery of hepatic function and more limited regenerative capacity than dogs that underwent hepatectomy alone. The reduction in hepatic regeneration was proportional to the extent of the pancreatectomy. Steatosis also appears to impair liver regeneration in animal models but regener-ation may still occur after PVE [47]. Currently, however, the severity of clinically significant steatosis is unknown. In laboratory animals, exposure to a high-fat diet impairs liver regeneration after partial hepatectomy and is also associated with increased hepatocellular injury (i.e., necrosis with severe steatosis [48] and apop-tosis with mild steatosis [49]). Thus, a high-fat diet not only may limit liver regeneration but may also increase the risk for hepatic injury and result in delayed functional recovery after major hepatectomy [50]. Pathophysiology of Preoperative PVE Makuuchiandcolleagues[10]publishedthefirstexperienceusingpreoperativePVE to induce left liver hypertrophy prior to right hepatectomy. Their rationale for per-forming PVE in this situation was to lessen the sudden increase in portal pressure at resection that can result in hepatocellular damage to the FLR, to dissociate por-tal pressure-induced hepatocellular injury from the direct trauma to the FLR during physical handling of the liver at the time of surgery, and to improve overall tolerance to major resection by increasing hepatic mass before resection in order to reduce the risk of postresection metabolic changes. The justification for using PVE has also been based on data showing that increases in FLR volume are associated with improved function as verified by increases in biliary excretion [51, 52] and in technetium-99m-galactosyl human serum albumin uptake [53] and by significant improvements in the postoperative liver function tests after PVE compared with no PVE [3]. After PVE, changes in liver function tests are generally small and short-lived. When transaminase levels rise, they typically reach their zenith at levels less than three times baseline 1–3 days after PVE and return to baseline within 10 days, regardless of the embolic agent used [10, 11, 34, 45, 54–56]. Minor alterations in total serum bilirubin concentration and white blood cell count may be seen after PVE, and prothrombin time is rarely affected. 11 Portal Vein Embolization Prior to Resection 157 Unlike arterial embolization, the postembolization syndrome is not associated with PVE [9]. This relative lack of symptomatology results from the histopatho-logical basis of PVE; it produces no distortion of the hepatic anatomy, leads to negligible inflammation except for immediately around the embolized vein, and lit-tle, if any, parenchymal or tumor necrosis [10, 57]. Animal studies demonstrated that hepatocytes undergo apoptosis and not necrosis after portal venous occlusion [42, 58], which accounts for the relative lack of systemic symptoms after PVE. Portal blood flow to the non-embolized hepatic segments measured by Doppler sonography increases significantly and then falls to near-baseline values after 11 days. The resultant hypertrophy rates correlate with the portal blood flow rates [9, 43]. FLR Volume Measurement and Predicting Function After PVE Computed tomography (CT) with volumetry is an important tool to predict liver function after resection of the tumor-bearing liver, and several methods have been offered [14, 59, 60]. However, CT volumetry must be employed within the context of the patient’s underlying liver function and should not be used as a “stand-alone” value upon which resection will be solely based. Three-dimensional CT volumetric measurements are obtained by demarcating the hepatic segmental contours and calculating the volumes from the surface mea-surements from each sequential image. Multiphasic contrast-enhanced CT must be performed to best delineate the vascular landmarks of the segments [60]. This tech-nique makes it possible to easily obtain an accurate and reproducible FLR volume that can be calculated within minutes of imaging and with a margin of error <5% [61, 62]. The FLR can then be standardized to the total liver volume (TLV) to determine the %TLV that will need to remain after resection. Although measurement of the TLV is possible with CT, direct TLV measure-ments may not be appropriate for surgical planning for many reasons. First, in patientswithconsiderabletumorburden,theTLVischanged,andattemptstodeduct tumor volume from the TLV require additional time to calculate, especially when multiple tumors are present, and this may lead to additive mathematical errors in volume calculation (TLV minus tumor volume) [7, 63]. Furthermore, this approach does not account for the actual functional liver mass when chronic liver disease, vascular obstruction, or biliary dilatation is present within the liver to be resected. Patients with cirrhosis frequently have enlarged or shrunken livers such that the measured TLV may not be useful as an index to which FLR volume is standardized, leading various researchers to advocate clinical algorithms in which functional tests (e.g., indocyanine green retention at 15 min (ICGR15) are evaluated in combination with the planned extent of resection [64]. A straightforward, precise, and reproducible technique (Fig. 11.1) standardizes liver remnant size to individual patient size to account for the fact that large patients 158 D.C. Madoff and R. Avritscher a b c Fig. 11.1 Hypertrophy of the future liver remnant after portal vein embolization as determined by three-dimensional reconstruction of computed tomography images. (a) Three-dimensional volumetric measurements are determined by outlining the hepatic segmental contours and then calculating the volumes from the surface measurements of each slice. (b) The formula for calculat-ing total liver volume is based on the patient’s body surface area. (Modified from [22], used with permission.) (c) Before embolization, the volume of segments 2 and 3 was 283 cm3 or 14% of the total liver volume (2,036 cm3). After embolization, the volume of segments 2 and 3 was 440 cm3 or 21% of the total liver volume (a degree of hypertrophy of 7%) (Modified from [3], used with permission) require larger liver remnants than do smaller patients. CT is used to directly quan-tify the FLR, which is by definition disease free. The total estimated liver volume (TELV) is calculated by the formula (TELV = –794.41 + 1,267.28 × BSA) derived from the close association between liver size and patient size based on body weight and body surface area (BSA) [3, 14, 65]. The FLR/TELV ratio is subsequently calculated to give a volumetric estimate of FLR function. From this method of calculation, termed “standardized FLR measurement,” a correlation between the anticipated liver remnant and the operative outcome has been recognized [3]. This formula was recently appraised in a meta-analysis evaluating 12 different formulas and was found to be one of the least biased and most accurate for TELV estimation [66]. At our institution, CT scans are routinely performed before PVE and approx-imately 3–4 weeks after PVE to assess the degree of FLR hypertrophy. We have recently found that in addition to the FLR/TELV measurement, the degree of hyper-trophy (DH) (i.e., [FLR/TELV after PVE] – [FLR/TELV before PVE]) is also a predictor of postoperative course. If a patient has a DH <5% after PVE, they are at increased risk for postoperative complications [67]. Shirabe and colleagues [2] also realized the significance of standardizing liver volume to BSA and showed that no patient with underlying liver disease who had 11 Portal Vein Embolization Prior to Resection 159 a standardized liver volume of more than 285 mL/m2 BSA died of liver failure after liver resection. Given analogous data from a different study, the guideline for utilizing PVE in patients with cirrhotic livers has been set at a standardized FLR volume <40% [7]. Developments in nuclear imaging technology are currently being designed to quantify both anatomical and functional differences in liver volume. Technetium-99m-labeled diethylenetriamine pentaacetic acid-galactosyl-human serum albumin binds specifically to asialoglycoprotein receptors on hepatocyte cell membranes. Agent distribution is monitored in real time with single-photon emission scintig-raphy and has been shown to correlate with ICGR15 [68]. Another technique, axial image reconstruction, can be used to estimate the differential functions of the right and left liver. However, neither technique is as of yet sufficiently accurate in assessing segmental or bisegmental function during the planning for extended hepatectomy. Indications and Contraindications for PVE General Indications To determine whether a particular patient will benefit from PVE, several factors must be considered [15]. The first is whether or not there is underlying liver dis-ease as this will have a profound impact on the liver remnant volume needed for adequate function. Patient size also must be considered as larger patients require larger liver remnants. Next, the extent and complexity of the planned resection and the likelihood that associated non-hepatic surgery will be performed at the time of liver resection must be considered. These three factors are considered in the setting of the patient’s age and comorbidities (e.g., diabetes) that may affect hypertrophy and perioperative outcome. Thus, after all of these factors have been evaluated and the patient remains a candidate for resection, appropriate liver CT volumetry is performed so that the standardized FLR volume expressed as a percentage of the estimated TLV can be used to determine the need for PVE. As mentioned above, a normal liver has a superior regenerative capacity than a cirrhotic liver, functions more efficiently, and tolerates injury better. Patients with normal underlying liver can survive resection of up to 90% of the liver, but in cir-rhotic patients, survival after resection beyond 60% of the functional parenchyma is unlikely [5]. Furthermore, complications of the poorly functioning remnant liver (e.g., ascites and wound breakdown from poor protein synthesis) and fatal postop-erative liver failure are more common after resection in patients with cirrhosis than in those without cirrhosis. With regard to liver volume, there is a limit to how small a liver can remain after resection. If too little liver remains after resection, imme-diate postresection hepatic failure leads to multisystem organ failure and death. If a marginal volume of liver remains, cirrhotic or not, the lack of reserve often leads to a cascade of complications, prolonged hospital and intensive care unit stays, and ... - tailieumienphi.vn