Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P14 potx

9 Liver Resection for Hepatocellular Carcinoma 115 Fig. 9.2 Japanese algorithm for resection in cirrhosis (Adapted from [22] used with permission) are safe; ICGR15 30–39%, only wedge resections are safe; ICGR15 ≥40%, only enucleations are safe). This algorithmic approach was prospectively validated in 107 patients; the 30-day mortality rate was zero, and there were no major complications [29]. Evaluation of Future Liver Remnant Volume Computed tomography (CT) can now provide an accurate, reproducible method for preoperatively measuring the volume of the future liver remnant (FLR). The FLR is measured directly by three-dimensional CT volumetry, and the total liver vol- ume is calculated using a mathematical formula that relies on the linear correlation between liver size and body surface area (BSA). The ratio of the CT measure FLR volume/calculated total liver volume (TLV) is defined as the standardized FLR and it provides the percent of TLV remaining after resection [30]. The formula used to estimate TLV based on BSA was recently evaluated in a meta-analysis and recom- mended as one of the least biased and most precise formulas for the estimation of the total liver volume in adults [31] (Fig. 9.3). Although there is a general consensus that the extent of resection that is safe is mainly limited by the function, attention has also focused on the FLR volume after major hepatectomy. In general, a FLR of 20% is considered the minimum safe volume needed following extended hepatic resection in patients with normal underlying liver, while an FLR of 40% is required in patients with chronic l iver disease (cirrhosis or hepatitis) [32, 33] (Fig. 9.4). Current suggested indications for PVE in normal, injured, and cirrhotic liver are presented in Fig. 9.5. 116 D.Zorzietal. Fig. 9.3 Method of systemic preoperative liver volume calculation using three-dimensional CT volumetry. CT outline of the segments included in the measurement of future liver remnant (FLR) volume for a planned extended right hepatectomy (white outline = FLR). (a) The FLR is measured directly by three-dimensional CT volumetry, and the total liver volume (TLV) is calculated using a mathematical formula that relies on the linear correlation between liver size and body surface area (BSA). The ratio of the CT measure FLR volume/calculated total liver volume (TLV) is defined as the standardized FLR (sFLR) and it provides the percent of TLV remaining after resection Preoperative Therapy Transarterial Chemoembolization (TACE) and Portal Vein Embolization (PVE) In patients who are otherwise candidates for hepatic resection, an inadequate FLR volume – ≤20 or <40% of the estimated TLV in patients with normal or cirrhotic liver, respectively – may be the only obstacle to curative resection. Three- dimensional CT volumetry and calculation of the FLR allows the planning of hepatic resection to be individualized for each patient. Portal vein embolization (PVE) can be performed to prime the growth of the anticipated FLR, thereby making a major or extended hepatectomy possible. PVE is safe with less than a 5% complication rate, causes little periportal reaction, and generates durable portal vein occlusion especially when used in com- bination with coils. PVE has been shown to increase both the size of the FLR as well as the percentage of indocyanine green (ICG) excretion and bile volume flow in the remnant liver. In addition, in patients with chronic liver disease PVE has also been reported to decrease the incidence of postoperative complications, intensive care unit stay, and the total hospital stay after major hepatic resection. Thus, the 9 Liver Resection for Hepatocellular Carcinoma 117 Fig. 9.4 Standardized calculation of future liver remnant (FLR) volume accurately predicts the likelihood of postoperative complications after hepatic resection in normal liver (a) and in chronic liver disease (b). (a) Complication rate stratified by standardized future liver remnant (% FLR) volume in relation to FLR in normal liver; 90% of patients with a % FLR of 20% or less had com- plications; 39% of patients with a % FLR of greater than 20% had complications (P = 0.003) [33]. (b) A comparison of FLR volume of patients who died of liver failure and those without liver fail- ure after surgery in chronic liver disease. Remnant liver volume in patients who died of liver failure was significantly smaller than that in patients who did not die of liver failure (P = 0.0008) and it was never more than 250 mL/m 2 (From [33], used with permission) Fig. 9.5 Indications for portal vein embolization (PVE). There is a consensus that in patients treated with aggressive preoperative chemotherapy, the remnant liver volume should be at least 30% of the total liver volume to avoid a high risk of complications following hepatic resection. BMI, body mass index (From [34], used with permission) selective use of PVE may enable safe and potentially curative extended hepatec- tomy in a subset of patients with advanced hepatobiliary malignancies who would otherwise have been marginal candidates for resection. Palavecino et al. [ 35] reported on 54 patients who underwent major hepatic resec- tion for HCC with or without PVE before resection. This study demonstrates that PVE before major hepatectomy for HCC is associated with decreased perioperative mortality. The overall and disease-free survival rates were similar between patients 118 D.Zorzietal. Fig. 9.6 Overall survival after major hepatectomy in patients with and without preoperative por- tal vein embolization (PVE), excluding postoperative deaths (P = 0.35) (From [35], used with permission) who underwent major hepatectomy with and without PVE (Fig. 9.6). Thus, PVE increases the safety of major hepatectomy in patients with HCC without compro- mising long-term oncologic outcomes. Because the main blood supply for HCC is the hepatic artery and PVE results in increased hepatic arterial flow, concerns have been raised about the potential for accelerated tumor growth after PVE [36, 37]. To avoid this possibility, TACE has been proposed as a complementary procedure to PVE in patients with HCC (Fig. 9.7). TACE eliminates the arterial blood supply to the tumor and embolizes potential arteriovenous shunts resulting from cirrhosis and/or HCC that attenuate the effects of PVE. In addition, 60–80% complete necrosis of tumor can be achieved by the combination of TACE and PVE [38, 39]. Our results support a study by Ogata et al. [38] in which patients who underwent TACE before PVE had improved disease-free survival and increased FLR hypertrophy than patients who underwent PVE alone [35] (Fig. 9.8). Our current recommendation for those patients with bilo- bar HCC and tumor nodules in the FLR is to perform TACE before PVE to avoid tumor growth in the FLR after PVE. Chemotherapy Sorafenib is an oral multikinase inhibitor, which exerts an antiangiogenic effect by targeting vascular endothelial growth factor receptors (VEGFRs) 9 Liver Resection for Hepatocellular Carcinoma 119 Fig. 9.7 Sequential transartherial chemoembolization (TACE) and portal vein embolization (PVE) in cirrhotic liver. A 74-year-old male patient HCV genotype 2b with a 12.5 hepatocellular car- cinoma involving the right liver with periportal fibrosis and focal bridging. (a, b) Future liver remnant (FLR) volume of segments 1, 2, 3, and 4 equal to 27%. Computed tomography following TACE and right PVE shows hypertrophy of the FLR (47%) (c). Right hepatectomy was performed. The specimen indicated complete pathologic response with no residual tumor. The patient had no evidence of disease 53 months postresection (d) and platelet-derived growth factor receptor (PDGFR). Recently, a randomized, placebo-controlled phase III trial of sorafenib reported an improvement in median overall survival along with increased time to progression and disease control rate in advanced HCC [40]. There is no evidence that sorafenib has a role as a neoadjuvant agent in downstaging patients to render them resectable because the response rate to sorafenib is only 3%. In contrast the PIAF treatment regimen (platinum, interferon, adriamycin, and 5 FU) allows a selected group of patients with normal liver and HCC confined to the liver to become eligible for aggressive surgical techniques [41, 42] (Fig. 9.9). Using the PIAF regimen in patients with preserved liver function Lau et al. found 18% major tumor response rate (more than 50% reduction in tumor size). Furthermore, 10% percent of the entire cohort, who presented with tumors that were considered unresectable, underwent subsequent complete resection after chemotherapy; 53% of the resected patients were alive 3 years after hepatic resection [43]. 120 D.Zorzietal. Fig. 9.8 Sequential arterial and portal vein embolization. Patients who underwent transartherial chemoembolization (TACE) before portal vein embolization (PVE) had increased future liver rem- nant (FLR) hypertrophy than patients who underwent PVE alone (P = 0.13) (From [36], used with permission) Surgical Technique In patients with HCC, the goal of the surgical approach is to optimize the oncologic resection (negative margin) while sparing the noncancerous hepatic parenchyma. Advances in anesthetic and surgical techniques, as well as a thorough understanding of the liver anatomy and tumor biology, have contributed dramatically to the safety and effectiveness of liver resection for HCC. Modern surgical principles include anatomic resection, the use of vascular inflow occlusion, and low central venous pressure anesthesia. New surgical approaches such as the anterior approach and liver hanging maneuver have been developed along with the use of more effective instruments for parenchymal transection. For a safe liver resection, both the bilateral subcostal incision, with or without superior/midline extension to the xiphoid (hockey-stick incision), and the J-type incision are valid options. At M.D. Anderson Cancer Center the modified Makuuchi J-incision where the vertical midline portion converges with the horizontal limb at the level of the umbilicus. Our modification aims to spare the nerves supplying the skin and the rectus muscle, thus reducing skin numbness, muscle atrophy, and post- operative pain [44]. After mobilization of the liver, intraoperative ultrasound (IOUS) is systematically performed to confirm the extent of disease, review the intrahep- atic portal and hepatic vein anatomy, and define the parenchymal transection plane. IOUS identifies new nodules in 15–30% of patients with HCC [45, 46], although only about 25% of these new nodules are malignant. The classic description of HCC by IOUS is a mosaic pattern with posterior enhancement and lateral shadowing. In nodules that lack specific findings of HCC, malignancy is found in 24–30% of 9 Liver Resection for Hepatocellular Carcinoma 121 Fig. 9.9 A 60-year-old male patient with a 15 cm hepatocellular carcinoma involving left lobe, right anterior sector and abutting the right hepatic vein. (a, b) Computed tomography following six cycles of chemotherapy with PIAF (platinum, i nterferon, adriamycin, and 5 FU), three cycles of capecitabine + interferon, and transarterial chemoembolization (TACE) revealed response of the tumor. (c, d) Extended left hepatectomy with caudate and vena cava resection was performed. The patient had no evidence of disease 4 years postresection (e, f) 122 D.Zorzietal. hypoechoic nodules and 0–18% of hyperechoic nodules [45, 46]. IOUS may there- fore decrease recurrence through the identification of unrecognized multifocal HCC. In addition, IOUS is considered an essential aid for guidance of resection [47] and has proven useful in obtaining a margin negative resection [48](seeChapter 10). Anatomic Resection HCC has a high propensity to invade the portal and hepatic veins; thus, the spread of HCC is essentially through the bloodstream – first via the portal vein to cause intrahepatic metastasis, a primary mechanism of intrahepatic recurrence, and later to extrahepatic organs such as the lungs, bone, and adrenal glands. These two forms of spread, vascular invasion and intrahepatic metastasis, are among the risk factors that most strongly influence the postoperative prognosis. On this basis, Makuuchi et al. introduced the concept of anatomic resection – segmentectomy and subseg- mentectomy – which involves systematic removal of a hepatic segment confined by tumor-bearing portal tributaries that might contain portal metastases or daughter micronodules. The theoretical advantage of anatomic over nonanatomic resection has been demonstrated in two large series in which anatomic resection was found to be an independent factor for both overall and disease-free survival [49, 50]. Therefore, segment-oriented anatomical resection should be proposed for any HCC, whenever technically and functionally possible. The width of a negative resection margin has also been investigated. A study predating the reports on anatomic resection showed that the rate of postoperative recurrence of HCC was not related to the width of the resection margin but rather to microvascular invasion or the presence of microsatel- lites [51], further supporting the superior value of the anatomic approach. As the margin size has not been found to be an independent predictor of recurrence across multiple studies, functional liver should not be sacrificed in an attempt to obtain a wide margin [51–54]. Resection of Large Right Liver Tumors Surgical resection of a large right lobe tumor represents one of the most challeng- ing situations. With the conventional technique for hepatectomy, mobilization of the right lobe from the retroperitoneum and anterior surface of the IVC may be chal- lenging because of the tumor volume and adhesion to the diaphragm and may result in injury to the right hepatic vein or the venous branches between the IVC and the posterior aspect of the right lobe. To overcome these problems, the anterior approach has been proposed [55]. With this approach, after hilar control of the vascular inflow is achieved, the parenchyma is transected from the anterior surface of the liver down to the anterior surface of the IVC, without prior mobilization of the right lobe. After control is achieved of all venous tributaries to the IVC, including the right hepatic vein, the right lobe is detached from the diaphragm. In a retrospective comparative analysis, Liu et al. demonstrated that the anterior approach for large right lobe HCCs resulted in less 9 Liver Resection for Hepatocellular Carcinoma 123 intraoperative blood loss, lower transfusion requirements, a lower in-hospital death rate, and significantly better overall and disease-free survival compared to the con- ventional approach to right or extended right hepatectomy [56]. More recently in a prospective randomized controlled study, Liu et al. confirmed findings of the previ- ous study, demonstrating improved operative and survival outcomes of the anterior approach technique compared to the conventional approach [57]. With the ante- rior approach, it may be difficult to control bleeding in the deeper parenchymal plane. Because of this, in 2001, Belghiti et al. proposed a new technique of hanging the liver after lifting it with a tape passed between the anterior surface of the IVC and the liver parenchyma (“liver-hanging maneuver”) [58]. To allow for passage of the tape, the space between the right and middle hepatic veins is initially dissected for 2 cm downward. The dissection of the anterior plane of the IVC begins with placement of a long vascular clamp posterior to the caudate lobe on the left side of the right inferior hepatic vein, if present (Fig. 9.10). Then the clamp is gently pushed cranially in the middle plane of the IVC to allow a blind dissection. When the clamp appears between the right and middle hepatic veins, the tape is seized and Fig. 9.10 Hanging Maneuver. Pediatric suction (grafting suction tube, 4-mm tip, 9.5 in. length; Cardinal Health/V Mueller Products) is used to explore the space of Couinaud and to perform the liver hanging maneuver (a). Avascular retrohepatic plane between right and middle hepatic veins (arrow)(b). Intraoperative view after removal of the specimen. Avascular retrohepatic plane is shown with a dot line (c). Right hepatic vein (RHV), middle hepatic vein (MHV), inferior right heparic veins (IHRVs), segment 1 vein (Sg1V) 124 D.Zorzietal. passed around the hepatic parenchyma. The parenchymal dissection is facilitated by upward traction on the tape, which allows the s urgeon to follow a direct plane and facilitates exposure and hemostasis of the posterior parenchymal plane in front of the IVC. Prevention and Control of Bleeding Many studies have shown that intraoperative blood loss and transfusion require- ments are independent predictors of major morbidity and death from surgery. Blood transfusion can add to the risk of coagulopathy as well as exert immunosuppres- sive effects. Given this, efforts to minimize blood loss become critical. Techniques of temporary vascular occlusion such as portal triad clamping and total vascular exclusion (TVE) have been used to reduce bleeding from the cut edge of the liver. In a prospective randomized study, portal triad clamping, otherwise known as the Pringle maneuver, has been shown to significantly reduce blood loss result- ing in improved postoperative liver function [59]. Further, the authors suggested that the reduction in blood loss offset the potential adverse effects of ischemia– reperfusion-induced hepatocellular injury. In a different randomized trial, Belghiti et al. demonstrated that intermittent Pringle maneuver – 15 min of inflow occlu- sion followed by 5 min of liver revascularization – is safer than continuous inflow occlusion in patients with chronic liver disease and should be considered, in this population, the technique of choice [60]. While Pringle maneuvers exceeding 4 h have been reported, Wei et al. found that inflow occlusion time exceeding 80 min was associated with a higher mortality rate [11]. Total vascular exclusion (TVE), a technique which involves the Pringle maneuver as well as clamping of the supra- and infra-hepatic vena cava, has not been shown to be more effective in decreas- ing blood loss when compared to portal triad clamping alone, while associated with increased morbidity [61]. Indications for TVE are limited to those cases with tumor involvement of the cavo-hepatic junction [62]. The drawback of hepatic pedicle clamping is that it does not prevent back bleed- ing from the hepatic veins. In fact, one of the most important factors related to intra- operative blood loss is pressure within the inferior vena cava (IVC). In a prospective study examining blood loss and IVC pressure, there was a direct linear correla- tion between mean caval pressure and blood loss [63]. As hepatic vein pressure directly reflects the caval pressure, the maintenance of a low central venous pres- sure is an effective technique to reduce back bleeding from the hepatic veins [64, 65]. At our institution, all patients who undergo hepatic resection have mainte- nance of a low central venous pressure (<5 cm H 2 O), with a minimal acceptable urine output of 0.5 mL/kg/h, until the parenchymal transection is completed. Infusions and transfusions are minimized, and transient hypotension that can occur with hepatic mobilization is treated with vasopressor support (usually phenyle- phrine). When the parenchymal transection is complete and hemostasis achieved, patients are rendered euvolemic with crystalloid and/or albumin infusions. . (TLV) is defined as the standardized FLR (sFLR) and it provides the percent of TLV remaining after resection Preoperative Therapy Transarterial Chemoembolization (TACE) and Portal Vein Embolization (PVE) In. parenchyma. Advances in anesthetic and surgical techniques, as well as a thorough understanding of the liver anatomy and tumor biology, have contributed dramatically to the safety and effectiveness of liver. mechanism of intrahepatic recurrence, and later to extrahepatic organs such as the lungs, bone, and adrenal glands. These two forms of spread, vascular invasion and intrahepatic metastasis, are among