Locoregional therapy: surgery and ablation

Potential curative therapies include surgery, either resection or orthotopic liver transplantation (OLT), and possibly ablation in selected patients. Locoregional interventions remain the cornerstone of treatment of early stage, localized HCC. Underlying chronic liver dysfunction in the form of viral or nonviral cirrhosis determines the appropriate surgical or locoregional treatment. Despite the absence of a prospective, randomized controlled trial comparing partial hepatectomy and OLT, surgical resection of early stage HCC remains the standard of care in well-compensated cirrhotic livers. A trial comparing resection with transplantation is difficult to perform, given the critical shortage of donor organs and the relatively small proportion of patients who are candidates for both treatments.

Historically, in patients with advanced cirrhosis undergoing hepatic resection for HCC closed suction drainage was used to evacuate perihepatic collections adjacent to the cut surface of the liver. One RCT showed no difference in overall survival and morbidity in patients who did not have a closed suction drain placed following partial hepatectomy. Most patients in this study had well-preserved hepatic function and the hepatectomies were done for reasons other than HCC. In a report by Liu and colleagues, 104 patients were randomized to either closed suction drainage or no drainage following hepatic resection. The two cohorts consisted predominantly of patients with HCC and underlying viral-induced cirrhosis. There was no difference in overall in-hospital mortality or subsequent need for additional postoperative drainage but there was a significantly higher overall perioperative morbidity and hospital length of stay in the closed suction drainage group. This difference was most likely the result of a significantly higher rate (62% versus 21%; P <.001) of wound complications in the drainage group. The data do not support the routine use of closed suction drains following partial hepatectomy in the absence of a biliary-enteric anastomosis.

The use of low central venous pressure during liver mobilization and parenchymal transection has been advocated to reduce intraoperative blood loss and perioperative morbidity. Until recently, no RCTs examined this practice during partial hepatectomy for HCC. Although this recent trial demonstrated the use of low central venous pressure reduced both intraoperative blood loss and the length of the hospital stay, the paucity of patients in each arm of the trial precluded finding differences in perioperative morbidity or mortality. Because low central venous pressure anesthetic technique has been adopted as the standard of care in most high-volume centers and has shown to reduce perioperative morbidity in retrospective studies, it is unlikely that further, larger RCTs are possible.

The goals of partial hepatectomy for HCC are to resect the tumor with an adequate margin to prevent tumor recurrence and to preserve enough functional hepatic parenchyma to prevent perioperative hepatic failure. A recent trial attempted to determine the optimal margin of resection by randomizing patients with a solitary HCC tumor to a partial hepatectomy with either 1- or 2-cm gross, intraoperative margins. Patients with an intended 2-cm operative margin had a significant recurrence-free and overall survival benefit compared with the 1-cm margin group. This study failed to comment on the number of positive margins in the 1-cm group and median period of follow-up. Because most recurrences in the narrow margin group occurred at the site of resection and the pathologic mean margin was only 0.7 cm in this group, it is conceivable that positive intraoperative margins could be a confounding factor.

Other technical aspects of partial hepatectomy for HCC have been evaluated through RCTs. The use of the anterior approach to right hepatectomy in large (>5 cm), solitary tumors, where initial vascular inflow and venous outflow and parenchymal dissection occurs before the right liver mobilization was compared with the more conventional approach, where the right liver is mobilized before vascular control and parenchymal dissection. The median disease-free survival was similar in both resection approaches but patients undergoing the anterior approach had a significantly increased overall survival. This difference seemed to be caused by more frequent recurrences that were either multifocal or extrahepatic, and not amenable to salvage resection or ablation techniques. The authors postulated that early and frequent tumor manipulation as seen in the conventional approach promoted hematogenous tumor spread outside the site of local resection. This study was well done and provocative, because it is one of the few to show an impact of surgical technique on oncologic outcome; however, its applicability to the field as a whole is limited because of the paucity of patients with solitary, large HCC tumors limited to the right liver that are candidates for surgical resection.

Two additional studies compared percutaneous local therapies with partial hepatectomy for small HCC in patients with preserved hepatic function. The first trial demonstrated that patients undergoing percutaneous ethanol injection (PEI) had similar recurrence-free and overall survival rates when compared with a cohort undergoing partial hepatectomy. The second trial also demonstrated similar rates of recurrence and overall survival when comparing percutaneous radiofrequency ablation (RFA) with partial hepatectomy for solitary, small (<5 cm) HCC tumors. Although both studies demonstrate equivalence when comparing local ablative with resection therapies they are a highly selected group of patients representing fewer than 5% of patients presenting to their respective institutions with HCC. Both studies also suffer from relatively short mean follow-up time (under 3 years in both studies) and small patient numbers (38 and 90, respectively) that may have masked potential differences in treatment. Unless medical comorbidities or hepatic dysfunction are present, hepatic resection should be considered the treatment of choice. Further larger trials with longer follow-up are needed to fully address the use of favoring percutaneous ablative techniques over partial hepatectomy.

Despite the increased efficacy of surveillance programs using alpha fetoprotein and abdominal ultrasonography only 25% to 30% of HCC tumors are amenable to curative surgical therapies because of underlying hepatic dysfunction or tumor multifocality. Percutaneous ablative therapies provide an additional approach to unresectable HCC tumors. The ideal local ablative therapy has been addressed in multiple trials comparing RFA with PEI in patients with unresectable HCC. Shiina and colleagues randomized 232 patients with HCC who had three or fewer lesions, each 3 cm or less in size with a Child-Pugh class of A or B, that either were deemed surgical unresectable or refused resection, to either ablation with RFA or PEI. The clinical characteristics of the two groups were similar with most patients having positive hepatitis C serology and tumors between 2 and 3 cm in size. Overall survival at 4 years in the RFA group (74%) was significantly higher than the PEI group (57%). Overall recurrence at 3 years was also significantly improved in the RFA (60%) group compared with the PEI (80%) group. Local tumor progression or recurrence was significantly increased (11% versus 2%) in the PEI group versus the RFA group. Both groups had similar rates of adverse events. This well done study by an experienced group demonstrates that RFA rather than PEI should be the choice for percutaneous local therapy in unresectable HCC.

Adjuvant or palliative therapy

Attempts to reduce the 75% to 100% recurrence rate of HCC after partial hepatectomy with adjuvant, cytotoxic chemotherapy regimens have historically been unsuccessful. Two recent trials readdressed this question by giving adjuvant chemotherapy following OLT or partial hepatectomy for HCC demonstrating a lack of improvement in either overall or disease-free survival.

The use of adjuvant interferon therapy in patients with HCC secondary to chronic viral hepatitis hypothetically may improve disease-free survival and reduce recurrence rates caused by tumoricidal effects or suppression of viral hepatitis within the remnant liver. Five recent trials have investigated this hypothesis with none showing conclusively that adjuvant interferon therapy following partial hepatectomy in viral hepatitis–linked HCC improves either disease-free or overall survival. All of the studies have demonstrated significant levels of adverse events associated with interferon use even in these highly selected noncirrhotic patient populations.

Two other trials demonstrated that the administration of menatetrenone, a vitamin K ₂ analog, reduced the rates of recurrence following partial hepatectomy or local ablative therapies for HCC. Unfortunately, none of these studies demonstrated a survival benefit, which may be explained by the low patient enrollment in both studies. Further, larger confirmatory studies are needed.

Sorafenib is a molecular targeted therapy that inhibits the serine-threonine kinases, Raf-1 and B-raf; the receptor tyrosine kinase activity of vascular endothelial growth factor receptors 1, 2, and 3; and platelet-derived growth factor β. Llovet and colleagues randomized 599 patients with advanced-stage HCC, most secondary to chronic viral hepatitis, and Child-Pugh class A status to either oral sorafenib or placebo. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group ( P <.001). Median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group ( P <.001). The sorafenib group demonstrated a similar treatment response to the placebo group with only 2% and 1% partial response rates, respectively. Neither group demonstrated any complete responses by radiologic criteria. This is consistent with other studies examining molecular targeted therapy in solid tumors and demonstrates the need for developing other less traditional biomarkers than axial imaging to assess treatment response. The adverse event profile of sorafenib was similar to the placebo group with a similar rate of discontinuation of therapy. This and other studies have shown that sorafenib is poorly tolerated in patients with other than Child-Pugh class A cirrhosis.

Estrogen receptors are expressed in low concentration in HCC tumors and the administration of exogenous estrogens, in the form of birth control pills, promotes hepatocyte proliferation and is associated with an increased incidence of hepatic adenomas. Anecdotal case reports and small retrospective studies demonstrated the use of the antiestrogen receptor, tamoxifen, is associated with regression of HCC tumor burden. Two recent trials failed to demonstrate an improvement in overall survival or response rate with tamoxifen in patients with advanced-stage, unresectable HCC.

Multiple trials addressed the use of octreotide alone or in conjunction with other chemotherapy regimens to induce tumor regression or provide symptomatic relief in HCC patients without any measurable success.

Because most patients with HCC present with advanced disease not amenable to curative therapies and the benefits of systemic chemotherapy regimens are unclear, alternative locoregional treatment approaches using transarterial embolization and chemoembolization techniques have been examined in RCTs. Llovet and colleagues randomized 112 patients with unresectable HCC, most secondary to hepatitis C cirrhosis, preserved liver function, and no evidence of extrahepatic disease to either chemoembolization with Gelfoam and doxorubicin, embolization with Gelfoam, or best symptomatic therapy. Median overall survival was 28.7 months in the chemoembolization group and 17.9 months in the best symptomatic control group ( P = .009). The trial was stopped because sequential inspection showed superiority in the chemoembolization group precluding a comparison between bland embolization and chemoembolization. In a similar trial, Lo and colleagues randomized 79 patients with unresectable HCC, most with hepatitis B cirrhosis, preserved liver function, and no evidence of extrahepatic disease to either chemoembolization with cisplatin and Lipiodol or best symptomatic control. The 2-year overall survival was 31% in the chemoembolization group and 11% in the control group. The rate of objective tumor response in the measurable patients was significantly higher in the chemoembolization group than in the control group (39% versus 6%; P = .014). These two studies demonstrate in a carefully selected group of patients with preserved liver function and no evidence of extrahepatic spread, locoregional arterial embolization remains the preferred treatment method. Until RCTs currently underway are completed, however, the question of whether bland embolization or chemoembolization is the superior technique remains unanswered.

In one recent RCT, the combination of percutaneous ablative therapy with transarterial chemoembolization in patients with unresectable HCC demonstrated improved overall survival and response rates. Performing transarterial chemoembolization before RFA increases the area of coagulation necrosis negating the heat sink effect mediated by the tissue perfusion of larger HCC tumors allowing the combination approach to provide a more effective treatment than RFA alone.

Adjuvant or palliative therapy

Attempts to reduce the 75% to 100% recurrence rate of HCC after partial hepatectomy with adjuvant, cytotoxic chemotherapy regimens have historically been unsuccessful. Two recent trials readdressed this question by giving adjuvant chemotherapy following OLT or partial hepatectomy for HCC demonstrating a lack of improvement in either overall or disease-free survival.

The use of adjuvant interferon therapy in patients with HCC secondary to chronic viral hepatitis hypothetically may improve disease-free survival and reduce recurrence rates caused by tumoricidal effects or suppression of viral hepatitis within the remnant liver. Five recent trials have investigated this hypothesis with none showing conclusively that adjuvant interferon therapy following partial hepatectomy in viral hepatitis–linked HCC improves either disease-free or overall survival. All of the studies have demonstrated significant levels of adverse events associated with interferon use even in these highly selected noncirrhotic patient populations.

Two other trials demonstrated that the administration of menatetrenone, a vitamin K ₂ analog, reduced the rates of recurrence following partial hepatectomy or local ablative therapies for HCC. Unfortunately, none of these studies demonstrated a survival benefit, which may be explained by the low patient enrollment in both studies. Further, larger confirmatory studies are needed.

Sorafenib is a molecular targeted therapy that inhibits the serine-threonine kinases, Raf-1 and B-raf; the receptor tyrosine kinase activity of vascular endothelial growth factor receptors 1, 2, and 3; and platelet-derived growth factor β. Llovet and colleagues randomized 599 patients with advanced-stage HCC, most secondary to chronic viral hepatitis, and Child-Pugh class A status to either oral sorafenib or placebo. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group ( P <.001). Median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group ( P <.001). The sorafenib group demonstrated a similar treatment response to the placebo group with only 2% and 1% partial response rates, respectively. Neither group demonstrated any complete responses by radiologic criteria. This is consistent with other studies examining molecular targeted therapy in solid tumors and demonstrates the need for developing other less traditional biomarkers than axial imaging to assess treatment response. The adverse event profile of sorafenib was similar to the placebo group with a similar rate of discontinuation of therapy. This and other studies have shown that sorafenib is poorly tolerated in patients with other than Child-Pugh class A cirrhosis.

Estrogen receptors are expressed in low concentration in HCC tumors and the administration of exogenous estrogens, in the form of birth control pills, promotes hepatocyte proliferation and is associated with an increased incidence of hepatic adenomas. Anecdotal case reports and small retrospective studies demonstrated the use of the antiestrogen receptor, tamoxifen, is associated with regression of HCC tumor burden. Two recent trials failed to demonstrate an improvement in overall survival or response rate with tamoxifen in patients with advanced-stage, unresectable HCC.

Multiple trials addressed the use of octreotide alone or in conjunction with other chemotherapy regimens to induce tumor regression or provide symptomatic relief in HCC patients without any measurable success.

Because most patients with HCC present with advanced disease not amenable to curative therapies and the benefits of systemic chemotherapy regimens are unclear, alternative locoregional treatment approaches using transarterial embolization and chemoembolization techniques have been examined in RCTs. Llovet and colleagues randomized 112 patients with unresectable HCC, most secondary to hepatitis C cirrhosis, preserved liver function, and no evidence of extrahepatic disease to either chemoembolization with Gelfoam and doxorubicin, embolization with Gelfoam, or best symptomatic therapy. Median overall survival was 28.7 months in the chemoembolization group and 17.9 months in the best symptomatic control group ( P = .009). The trial was stopped because sequential inspection showed superiority in the chemoembolization group precluding a comparison between bland embolization and chemoembolization. In a similar trial, Lo and colleagues randomized 79 patients with unresectable HCC, most with hepatitis B cirrhosis, preserved liver function, and no evidence of extrahepatic disease to either chemoembolization with cisplatin and Lipiodol or best symptomatic control. The 2-year overall survival was 31% in the chemoembolization group and 11% in the control group. The rate of objective tumor response in the measurable patients was significantly higher in the chemoembolization group than in the control group (39% versus 6%; P = .014). These two studies demonstrate in a carefully selected group of patients with preserved liver function and no evidence of extrahepatic spread, locoregional arterial embolization remains the preferred treatment method. Until RCTs currently underway are completed, however, the question of whether bland embolization or chemoembolization is the superior technique remains unanswered.

In one recent RCT, the combination of percutaneous ablative therapy with transarterial chemoembolization in patients with unresectable HCC demonstrated improved overall survival and response rates. Performing transarterial chemoembolization before RFA increases the area of coagulation necrosis negating the heat sink effect mediated by the tissue perfusion of larger HCC tumors allowing the combination approach to provide a more effective treatment than RFA alone.