Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P15

9 Liver Resection for Hepatocellular Carcinoma 125 Several different parenchymal dissectiontechniques have been developed tomin-imize blood loss and expedite hepatic resection. Advances in instrumentation, such as development of the ultrasonic aspirator, the jet cutter, the argon beam coagulator, and saline-linked cautery, have all been purported to improve surgical technique. The ultrasonic dissector is a handheld device that destroys hepatocytes by cavita-tion based on water content and aspirates the liquefied tissue. Vessels and biliary ducts, which contain less water, are preserved allowing for a clear delineation of these structures within the transection plane. Saline-linked cautery (SLC) uses a metal probe to deliver radiofrequency energy conducted through a slow infusion of saline. At our institution, we recently combined saline-linked cautery with ultra-sonic dissection in a standardized fashion (Fig. 9.11). This combination allows a clear delineation of the vascular and biliary anatomy within the transection plane, resulting in a significant decrease in total operative time, blood loss, and need for suture control of intraparenchymal vessels. The primary surgeon dissects the hepatic parenchyma from the patient’s left side utilizing the ultrasonic dissector while the second surgeon operates the SLC from the patient’s right side. Vessels of 3 mm or smaller are coagulated and divided using the SLC device, while those of 3–5 mm in diameter are controlled with titanium clips and divided sharply. Larger vessels and portal triads are sutured with 3-0 silk ties in continuity and divided sharply. This two-surgeon technique resulted in a significant decrease in blood loss and total operative time [66]. The combined technique using the ultrasonic dissec-tor and the SLC has recently been validated by two different groups. Takatsuki Fig. 9.11 Two-surgeon technique for hepatic parenchymal transection. Using the ultrasonic dissection device, the primary surgeon directs the dissection from the patient’s left side. Simultaneously, the secondary surgeon operates the saline-linked cautery device from the patient’s right side. Traction on 4-0 polypropylene stay sutures is used to expose the deepening transection plane (From [66], used with permission) 126 D. Zorzi et al. et al. [67] analyzed outcomes in living donor hepatectomy. The authors found a statistically significant lower level of blood loss and donors complications when the two-surgeon technique was used. In a randomized controlled trial, El Moghazy et al. [68] demonstrated a lower blood loss and a faster parenchymal transection time in the group randomized to ultrasonic dissector and saline-linked cautery com-pared to ultrasonic dissector and bipolar cautery in living donor hepatectomy. This is of utmost importance since a faster parenchymal phase may reduce the time of the Pringle maneuver and of ischemic injury of the liver. In addition a recent study reported the level of intraoperative blood loss during resection of HCC to be an independent predictor of overall survival, disease-specific survival, and disease-free survival [69], hence a decreased intraoperative blood loss during HCC resection using the two-surgeon technique may improve oncologic outcome. Drainage Drains have not been shown to be beneficial after hepatic resection for HCC. In a meta-analysis of three randomized controlled trials, the incidence of postoperative biloma was approximately 5% and either equal or even higher in drained patients compared with not drained patients [70]. In one of these trials, which only included patients with chronic liver disease, drainage after resection was an independent pre-dictor of postoperative complications [71]. Drains also failed to detect significant postoperative complications such as bile leak and hemorrhage that needed surgical or radiologic interventions. Outcome After Resection Morbidity and Mortality Improvements in patient selection and surgical technique have resulted in a remark-able decrease in perioperative mortality rates. A large, multicenter review from the 1970s by Foster and Berman reported a perioperative mortality of 21% for major hepatectomy and 58% for patients with cirrhosis [72]. Currently, the mortality rate is approximately 5% with some centers approaching close to zero mortality [22, 29, 73]. Refinements are multifactorial and include surgical technique, anesthesia management, perioperative care, and the establishment of high-volume referral centers specializing in hepatobiliary surgery. Morbidity rates range from 25 to 50% in recent large series [4, 5, 9–11]. In addi-tion to complications associated with all major surgery, posthepatectomy specific complications include right pleural effusion, subphrenic abscess, bleeding, biliary leak/fistula, ascites, and hepatic insufficiency. Blood loss and the need for trans-fusion have clearly been shown to increase morbidity and mortality [74, 75]. In a review of extended hepatectomies for HCC, multivariate analysis identified the Pringle maneuver and blood transfusion as risk factors for morbidity with comorbid 9 Liver Resection for Hepatocellular Carcinoma 127 illness and blood transfusion as independent risk factors for death [11]. The risk of morbidity with Pringle maneuver was primarily for minor complications such as ascites/effusion and mainly in those patients with clamping time exceeding 80 min. Long-Term Outcome During the past two to three decades, survival after hepatic resection has markedly improved over earlier results, likely due to early diagnosis in high-risk patients screened with AFP and ultrasound, improved patient selection, and surgical man-agement. Large series have reported 30–50% 5-year overall survival rates following curative resection [69, 76–78]. The main cause of treatment failure is tumor recurrence. Indeed, cumulative 5-year recurrence rates of 70–100% have been reported after hepatic resection. Recurrence occurs in the liver remnant in about 80–90% [78, 79] of cases, as a result of vascular invasion leading to microsatellite tumors within the liver, i.e., intrahepatic metastases (early recurrence), or second primaries in the remnant liver associated with field effect from hepatitis and cirrhosis (late recurrence). Thoughsurgicalresectionofintrahepatictumorrecurrenceisademandingproce-dure because of reduced hepatic parenchyma and a more hostile environment, repeat hepatectomy has been proven to be safe and worthwhile [80–85]. About 10–31% of the patients with intrahepatic recurrence can be treated with a second hepatectomy. Utilizing the same selection criteria as for primary resection, three clinicopatho-logic variables were found to be independent prognostic factors: absence of portal invasion at the second resection, single HCC at the primary hepatectomy, and a disease-free interval of at least 1 year after the primary hepatectomy [86]. In a series of 67 patients, the overall 5-year survival after a repeat hepatectomy was 56% – a rate comparable to those reported in many series of initial resection [85]. Aggressive nonsurgical treatment with ethanol injection, radiofrequency ablation, and transar-terial chemoembolization may yield favorable results in patients not suitable for repeat resection. The prognosis after potentially curative therapy depends on tumor-related factors and underlying liver disease. Thus, clinical and pathologic predictors of survival have been extensively investigated. For example, in a stepwise analysis approach on 5,800 patients, the Liver Cancer Study Group of Japan established portal involvement as the predominant prognostic factor, followed by number of tumor nodules, AFP level, tumor size, cirrhosis, age, and surgical curability (as defined by resection margin, stage, and absence of remaining macroscopic tumor) [87]. Resection Prior to Liver Transplantation For those patients whose poor underlying liver function and tumor number or loca-tion preclude traditional hepatic resection, total hepatectomy with orthotopic liver 128 D. Zorzi et al. transplantation (OLT) has been advocated. Initial series of OLT for HCC reported poor results, with tumor recurrence in up to 75% of patients. Bismuth et al. were the first to show that in the early era of liver transplantation, the surgical strategy for the treatment of hepatocellular carcinoma in cirrhosis had followed a misconception in selecting patients suffering from advanced, unresectable cancers as transplant candi-dates [88]. Currently, those patients suffering from HCC and cirrhosis with three or less tumor nodules up to 3 cm in maximum diameter or a single tumor not exceeding 5 cm and no signs of vascular invasion are considered for transplantation (Milano criteria) [6]. OLT based on these Milan criteria have been shown to provide very good disease-free survival, so that it is considered to be the optimal treatment of small HCC, especially in patients with underlying chronic liver disease [7, 89]. The evidence that OLT should be the preferred treatment choice for these patients has increased the demand resultinginlonger waitinglistintheface ofarelative shortage of available donors. During long waiting times, some patients suffer progression of disease such that they can never benefit from OLT. Bridge treatments to halt or delay tumor progression during the waiting period for OLT include also liver resection [90–94]. Poon et al. noted that 80% of patients who recur after primary resection for HCC remain eligible for OLT [90]. Thus a new strategy was proposed for patients with preserved liver function and HCC: hepatic resection prior to “salvage” or sec-ondary OLT. The major drawbacks of this concept of primary liver resection prior to transplantation could be the increase technical difficulty during OLT procedure and the risk of impaired posttransplant survival. Belghiti et al. showed that in selected patients with cirrhosis and resectable HCC perioperative and postoperative course of OLT following liver resection did not differ in terms of operative time, blood loss, morbidity and mortality compared to upfront OLT. Also, long-term survival after liver resection prior to OLT was not different compared to upfront OLT [95]. Fibrolamellar Variant of HCC Fibrolamellar carcinoma (FLHCC) is a distinct clinical variant of HCC. This hepatic tumor usually occurs in young patients, most commonly within the second and third decades of life with no gender predominance. There seems to be a preponderance of FLHCC in American Caucasians, with few cases reported in Asian populations. The incidence of FLHCC has been reported at 6–23% of western patients with HCC. Pathologically, FLHCC typically consists of well-circumscribed, large soli-tary lesions with a central scar. Unlike classic HCC, cirrhosis is not a common component of the hepatic disease in patients with FLHCC. In addition, hepatitis infection isuncommon and serumalpha-fetoprotein levels areusually withinnormal limits. Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) often demonstrate a heterogeneous mass with a central scar that is similar to those seen in cases of focal nodular hyperplasia (FNH). Central calcifications within the mass have been used to distinguish FLHCC from FNH, but this is not specific. Conflicting data exist regarding whether patients with fibrolamellar carcinoma have a better survival when compared to patients with classic HCC. In a series 9 Liver Resection for Hepatocellular Carcinoma 129 published from Memorial Sloan-Kettering Cancer Center, resected patients with FLHCC did not have an improved long-term survival compared to classic HCC, although there were too few patients with FLHCC to make meaningful conclu-sions [96]. These survival data were similar to those published by Nagorney et al. [97] who found no survival advantage for FLHCC over classic HCC without cir-rhosis. They noted, however, a higher resection rate for patients with FLHCC. In contrast, Soreide et al. reported a 56% 5-year survival and a 58% resectability rate for patients with FLHCC [98]. In a large review of the literature, Okuda noted a 95% resectability rate and improved survival for patients with FLHCC as compared to HCC patients [99]. Tumor stage has a profound influence on survival as demon-strated by Hemming et al., with stage II FLHCC patients experiencing extended survival times as compared to patients with stage III disease [100]. Ringe et al. observed the number of hepatic lesions and the presence of nodal disease to be significant variables in predicting survival in resected patients [101]. Survival times are longer in patients with recurrences of FLHCC following resection when com-pared to recurrences of classic HCC. In addition, patients with recurrent FLHCC following resection have been reported to have prolonged survival following re-excision of a local recurrence. Unlike HCC, patients with FLHCC are more likely to have solitary tumors, thus potentially increasing the resection rate. The rate of metastases, both nodal and distant, has been reported up to 30% at the time of diag-nosis. Indeed, the rate of lymph node positivity is quite high in FLHCC, raising the question of en bloc lymphadenectomy at the time of the primary surgery. To date, no one has reported data to adequately answer this question. Patients with unresectable metastatic FLHCC have been reported to have a median survival of 14 months, double that for matched-for-stage HCC patients. Controversy exists as to whether resection or transplantation for FLHCC pro-vides superior survival. One study from the UK noted a 3-year survival of 100% for patients treated with major liver resection versus 76% 3-year survival follow-ing hepatic transplantation for FLHCC (P < 0.025) [102]. These data are similar to data published from Pittsburgh. Pinna et al. [103] documented superior survival for FLHCC patients treated with resection as compared to transplanted patients. Additionally, the survival gap at 5 years was 44%, with 75% of resected patients alive versus 36% of transplant recipients. Further evidence of the apparent superior-ity of hepatic resection compared to transplantation in patients with FLHCC came from Germany, where resected patients had a median survival of 44.5 months versus 28.5 months for transplantation. In a review of the literature on transplantation for HCC, Neuhaus et al. concluded that transplantation is not appropriate for FLHCC without cirrhosis [104]. The potential neoadjuvant role for continuous infusion fluorouracil and subcuta-neous interferon alpha-2b has been suggested based on a phase II trial conducted at the M.D. Anderson Cancer Center [105]. There was a 62.5% response rate follow-ing chemotherapy seen in patients with FLHCC as compared to a 14% response rate in patients with HCC. This suggests that in patients with advanced stage FLHCC, downstaging with chemotherapy should be considered to increase the resectability rate, although further trials are necessary. ... - tailieumienphi.vn