Surgery offers the greatest potential for cure, albeit for a small number of patients with this diagnosis. Careful patient selection requires complete preoperative staging.
Only stage I or II tumors have a significant likelihood of being resectable for cure. Resectability is limited by the functioning liver tissue at the completion of a negative margin (R0) operation. Therefore, even a large tumor may still be potentially resectable for cure. Moreover, contiguous involvement of large vessels (including the portal vein and inferior vena cava) or bile ducts does not automatically mitigate against a resection. Resection is contraindicated in patients with metastatic disease to non-portal nodes and in extrahepatic locations. The use of the Child-Pugh score and volumetric evaluation aids in assessment of resectability. Other evaluations of liver functional and structural status, such as indocyanine green(Drug information on indocyanine green) excretion and portal wedge pressure, are used infrequently to predict post-resection liver failure. For cirrhotic patients in whom less than 30% to 35% of the liver remains at the completion of resection, operative treatment is contraindicated. Likewise, this is true for noncirrhotic patients in whom less than 25% to 30% of the liver remains.
Bilobar disease may be addressed with formal resection, tumor ablation techniques (eg, radiofrequency ablation [RFA], microwave ablation, cryotherapy, and ethanol injection ablation), or a combination of the modalities.
Contraindications to resection. These include factors related to the medical comorbidities rendering the patient a nonoperative (nonsurgical) candidate: uncorrectable clinical hepatic failure (jaundice in the absence of biliary obstruction), hypoalbuminemia, ascites, renal insufficiency, hypoglycemia, prolongation of the prothrombin and partial thromboplastin times. Main portal vein involvement, extrahepatic metastatic disease, or the requirement for an R0 resection and/or ablation that would leave inadequate hepatic reserve would preclude surgery of any kind. These parameters are for the most part included in the Childs-Pugh classification and augmented with the other elements described.
Noncirrhotic vs cirrhotic patients. For lesions 3 cm and smaller, RFA done either open or laparoscopic-assisted is considered to be the primary treatment for resectable hepatocellular carcinoma. Resection of hepatocellular carcinoma in the presence of cirrhosis is associated with increased morbidity. Cirrhosis had been a major deterrent to resection in Western nations. Historically, resectability rates varied from 0% to 43% for cirrhotic patients, whereas up to 60% of patients without cirrhosis had resection. This bias is being addressed with better preoperative functional evaluation and use of minimally invasive surgical techniques. Use of the modified Child-Pugh classification of liver reserve (Table 3) may guide the surgeon in preoperative assessment of liver function status and may aid in the selection of operable patients.
When resection is performed in the presence of cirrhosis, Child-Pugh class A patients fare better than do Child-Pugh class B or C patients. Survival rates at 5 years following resection range from 4% to 36%, with noncirrhotic patients living longer than cirrhotic patients. However, this survival is a combination of the morbidity of the chronic liver disease and higher risk of new primary hepatocellular cancer.
Transplant. Transplant has become an option for patients with hepatocellular cancer and cirrhosis. The transplant addresses the malignancy as well as the hepatic dysfunction. Therefore, it is a particularly excellent option when these two conditions occur synchronously. In addition, the distribution of grafts to this patient population fulfills both goals. A study of 181 patients with hepatocellular carcinoma (Iwatsuki et al: Ann Surg 1991) found similar overall 5-year survival rates in patients treated with transplant vs resection (36% vs 33%). Survival rates were similar in the two groups when tumors were compared for TNM stage. However, survival was significantly improved in patients with concomitant cirrhosis if they were treated with transplant. Tumor recurrence rates for stages II and III tumors were significantly lower after transplant than after resection, but no differences were seen for stage IV tumors. The cause of the cirrhosis may affect the transplant success. For patients with hepatitis B– or hepatitis C–associated hepatocellular carcinoma, the viral cause and status of the viral load are important considerations. Hepatitis C patients have a higher risk of hepatocellular carcinoma recurrence, lower graft survival, and increased mortality. Numerous additional studies have examined the relative value of transplant, ablation, and resection. There is much debate over their interpretation owing primarily to the selection of patients.
Given the high risk of recurrence after resection, the multifocal nature of hepatocellular carcinoma, and its association with chronic liver disease, therapies for nonresectable disease in patients who cannot withstand an operation or minimal resection can play an important role in management. A number of prognostic factors have been identified for patients with unresectable hepatocellular carcinoma. These factors, taken alone, can greatly affect survival rates, making cross-treatment comparisons more difficult because considerable selection bias may be present in any nonrandomized trial. In addition, direct comparisons are difficult, because there are few randomized trials among the large number of nonresectional, liver-directed therapies currently available. It is worth noting that a number of these treatments do not have overlapping toxicities and that research into combinations is potentially worthwhile.
Ablation techniques include RFA, microwave ablation, cryotherapy, and injection of chemicals (eg, ethanol) directly into the tumor. RFA can be performed via laparotomy, laparoscopic-assisted with ultrasound guidance, or percutaneously with CT or ultrasonographic guidance. It is best suited for lesions smaller than 3 cm. The overall recurrence rate after ablation is related to the intent—cure vs control, clinical status, and technique. Some recurrence represents undertreatment of lesions, microscopic satellites that were not included in the ablation site, poor imaging due to technical issues, inexperience of the ablator, and selection of large tumors. Ablation is safe and effective for patients who cannot undergo resection or who need a bridge to transplant.
Adverse effects of RFA may include pleural effusions and peritoneal bleeding. In 1,000 patients treated with RFA for hepatocellular carcinoma, neoplastic seeding from percutaneous RFA occurred at a rate of 3.2% per patient, or 1.8% per treatment. The patients underwent 1,845 RFA treatments for 3,837 nodules; 20% had nodules larger than 3 cm. The observation period was 5 to 64 months, and poor differentiation was the only risk factor for neoplastic seeding in multivariate analysis. Surrogate markers for poor differentiation were larger tumor size and elevated tumor marker levels. Other investigators have reported occurrences of "seeding" in as many as 12% and as few as 0.9% of patients undergoing RFA for hepatocellular carcinoma, with subcapsular tumor location being a risk factor. A Japanese study by Morimoto et al compared the efficacy of RFA combined with transarterial chemoembolization (TACE) vs RFA alone in patients with intermediate-sized hepatocellular carcinoma (3.1 to 5 cm) in a small, randomized, controlled trial. The rate of local tumor progression was 39% in the RFA-only group vs 6% in the TACE-RFA combination group at the end of 3 years. However, there was no statistical difference in the overall survival rates between the two groups. TACE before RFA may be beneficial because it enables better ablation and possibly facilitates the treatment of larger hepatocellular carcinomas.
• Intratumoral ethanol injection—The direct injection of 95% ethanol into a neoplastic lesion causes cellular dehydration and coagulation necrosis. This procedure has been largely replaced by RFA, which in several clinical trials has shown efficacy superior to that of ethanol injection.
These techniques require image guidance to ensure accurate device placement and assessment of extent of ablation during the active phase of treatment (tissue destruction). Cryotherapy (largely replaced by RFA) and RFA techniques are suitable for treating localized disease. Cryotherapy has been used intraoperatively to ablate small, solitary tumors outside a planned resection (ie, in patients with bilobar disease). Cryotherapy must be performed using laparotomy. In performing RFA and microwave ablation, the wires and antennae, respectively, are placed within the tumor. For RFA, the current creates ionic agitation and heat, which causes coagulative necrosis at the site of the tumor and to a margin in the periphery. Microwave ablation uses microwaves of specific intensity and duration to create heat for tissue destruction. Average temperatures generated are in the 100°C to 110°C range. RFA has efficacy superior to that of ethanol injections for lesions larger than 2 cm. Posttreatment imaging is performed 6 to 12 weeks postoperatively and should evaluate the extent of tumor destruction and local peripheral failures. The imaging report will paradoxically describe a larger lesion because of the destruction of both the primary hepatocellular carcinoma and a margin around it creating an R0 ablation.
Hepatic transcatheter embolization (TACE). Normal hepatocytes receive most of their blood supply from the portal vein, whereas tumors create new blood vessels from branches of the hepatic arterial system. This target is exploited by embolization of the hepatic artery with any number of substances, resulting in radiographic responses in about 50% of patients and evidence of tumor liquefaction in more than two-thirds of patients. At 2 years, the overall survival benefit from this procedure ranges from 20% to 60%. Embolization is accomplished by advancing a catheter within the tumor-feeding branch of the hepatic artery. Materials injected have included polyvinyl alcohol(Drug information on polyvinyl alcohol), iodized oil (Lipiodol), collagen(Drug information on collagen), and autologous blood clot. If chemotherapy is given, it usually is suspended in iodized oil, which is retained in the tumor. Common chemotherapeutic agents used have included cisplatin(Drug information on cisplatin) and doxorubicin(Drug information on doxorubicin), which may produce systemic adverse effects. Postembolization syndrome, with fever, abdominal pain, and, occasionally, ileus, occurs in 50% of patients when a large volume of liver is treated. Complications include infections and abscesses. Because few complete responses are achieved, treatments may be repeated on the same tumor for better results. Because of the risk of liver failure, TACE may be contraindicated in patients with portal vein thrombosis and for most individuals with Child-Pugh B status. Patients with Child-Pugh C liver disease cannot receive chemoembolization because of the risk of liver failure. One innovation in chemotherapy delivery during TACE is the use of drug-eluting beads (DEBs). These perforated beads allow for slow, localized release of chemotherapy after embolization. In a study by Varela et al, 27 patients with Child-Pugh A liver disease and unresectable hepatocellular carcinoma underwent DEB-TACE. Pharmacokinetic samples were analyzed for doxorubicin, demonstrating lower systemic drug exposure than expected with conventional TACE. Two patients had abcesses, but radiographic response rate was a promising 75%. Studies of this technology are ongoing.
Sidebar: A prospective, single-center, phase II study investigated combination therapy with sorafenib(Drug information on sorafenib) and DEB-TACE in patients with unresectable hepatocellular carcinoma Sorafenib was an attractive agent to use because of the elevations in vascular endothelial growth factor and platelet-derived growth factor levels that occur after TACE procedures. Thirty-five patients with advanced hepatocellular carcinoma and Childs-Pugh A or B liver dysfunction were entered into the study and sorafenib 400 mg twice daily was started one week before DEB-TACE and continuously thereafter. The study demonstrated a disease control rate of 95% based on RECIST criteria (9% partial response and 86% stable disease). Furthermore, the toxicity profile of sorafenib plus DEB-TACE appears to be similar to that of sorafenib alone. The most common adverse effects included fatigue (50%), hand-foot-skin reaction (30%), and right upper quadrant pain (18%), with most toxicities being grade 1 to 2 (Pawlik TM et al: J Clin Oncol 29:3960-3967, 2011). SPACE (Sorafenib or Placebo in Combination with TACE) was a large, randomized, phase II trial (307 patients) that randomized patients to sorafenib 400 mg twice daily or placebo with DEB-TACE. The primary endpoint was time to progression and overall survival was a secondary endpoint. For the sorafenib arm, the HR for time to progression was 0.797 (95% confidence interval [CI], 0.588–1.08; P = .072) and the HR for overall survival was 0.898 (95% CI, 0.606–1.330; P = .295). The authors concluded that the study met its primary endpoint of improving time to progression. However, the study was unusual in that a P value of .15 was considered significant on the basis of the trial’s design. Overall survival data were immature. These results do not suggest a large benefit of sorafenib in this setting, but do support the continuation of more definitive studies, such as the ongoing ECOG-1208 trial (TACE with sorafenib vs TACE alone; Lencioni R et al: J Clin Oncol 30[4s] abstract LBA154, 2012).
• Adjuvant treatment—There is no evidence that adjuvant radiation therapy can improve local or regional tumor control after adequate resection or ablation.
• Unresectable disease—Whole-liver radiation therapy can provide palliation in patients with unresectable tumors but is limited to a total dose of 30 Gy or less because of the risk of radiation-induced liver disease. Whole-liver irradiation has been combined with chemotherapy and TACE, with objective response rates of approximately 40% to 50% and median survival rates of about 18 months. Patients with tumor regrowth after chemoembolization may respond to radiation therapy. Radiation therapy has also been delivered using 90yttrium microspheres (radioembolization) infused via the hepatic artery to carefully selected patients; response rates as high as 89% have been reported. One study reported that 56% of treated T3 tumors were downstaged to T2, which allowed for subsequent liver-directed therapy or use as a bridge to transplant. Randomized trials of liver-directed therapy are uncommon. In a retrospective comparison of a single institution’s experience with chemoembolization compared with radioembolization, Salem et al found there was a benefit in time-to-progression (13.3 months vs 8.4 months; P = .046) for radioembolization in 245 patients, although there was no difference in overall survival. A report by Sangro et al of the results of treatment with radioembolization in 325 patients at eight European centers found an overall median survival of 13 months (24.4 months in Barcelona Clinic Liver Cancer stage A).
Three-dimensional conformal radiation therapy planning can allow patients with nondiffuse disease to be safely irradiated to doses well above the whole-liver tolerance dose, with doses up to 90 Gy given safely to select patients, resulting in a response rate of 40% and a median survival of 15 months. Conformal radiation therapy has been successfully combined with TACE in patients with portal vein tumor thrombosis, using the conformal radiation therapy to target the portal vein thrombus and TACE to treat the rest of the liver. In a study of more than 400 patients treated with this combination, the median survival was 10.6 months with a 2-year survival rate of 23%.
Multiple institutions have reported response rates as high as 90%, with acceptable toxicity when conformal radiation therapy was combined with TACE. Good response and local tumor control rates have also been reported for proton, carbon ion, and stereotactic radiation therapy. In select patients, Andolino et al found stereotactic radiation therapy to have an excellent local control rate (90% at 2 years for tumors measuring 6 cm or less) and a median time-to-progression of 4 years.
• Systemically administered chemotherapy—The low response rates to chemotherapy are related to the role of the hepatocyte in detoxification. Hepatocytes also have high multidrug resistance expression. Furthermore, many patients with hepatocellular carcinoma have cirrhosis or hepatic dysfunction, which complicates the administration of chemotherapeutic agents that undergo hepatic metabolism. Agents with partial response rates near or above 10% include doxorubicin, 5-fluorouracil (5-FU), and cisplatin. Table 4 describes the results of studies testing various chemotherapeutic agents in patients with hepatocellular carcinoma.
A double-blind phase II trial by Abou-Alfa et al was done in Child-Pugh A patients with advanced hepatocellular carcinoma. Doxorubicin combined with sorafenib was compared with doxorubicin alone. Median overall survival was 13.7 months in the combination-therapy arm vs 6.5 months in the doxorubicin-only arm. The progression-free survival was 6 months vs 2.7 months for these groups, respectively. The toxicity profile was similar to those of individual single agents. The combination of doxorubicin with sorafenib showed favorable results compared with doxorubicin alone. This is the basis for an ongoing phase III trial (CALGB 80802) of doxorubin with sorafenib compared with sorafenib alone.
Inhibiting angiogenesis in hepatocellular carcinoma is based on several factors. Hepatocellular carcinoma is a vascular tumor; increased levels of vascular endothelial growth factor are found in hepatomas compared with normal hepatic tissue, and increased endothelial growth factor levels before resection of tumor or TACE are associated with early relapse, aggressive behavior, and poor prognosis. Other targets include epidermal growth factor receptor (EGFR, which is frequently expressed in hepatoma cells), the mitogen-activated protein kinase (MAPK) pathway, and the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. Conventional markers of radiographic response are poorly related to tumor cell kill in hepatocellular carcinoma. More meaningful markers of therapeutic benefit may be time to disease progression, progression-free survival, and overall survival.
Erlotinib (Tarceva), an oral agent that inhibits the EGFR-related tyrosine kinase enzyme, was evaluated for efficacy in hepatocellular carcinoma. In a number of phase II trials, agents targeting EGFR have been tested in patients with hepatocellular carcinoma, and they appear to have only modest activity. In two phase II studies with erlotinib, "disease control" was greater than 50% (response rate > 10%), and median survival was 10 to 13 months. The combination of bevacizumab(Drug information on bevacizumab) (Avastin) and erlotinib in a phase II study of 40 patients with Child-Pugh A or B liver disease that was not amenable to surgery or regional therapy resulted in a progression-free survival of 9 months and a median survival of 15.6 months, which compares favorably with sorafenib. Use of this regimen in the cirrhotic patient may be associated with bleeding and thrombosis.
The SHARP (Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol) trial compared sorafenib (Nexavar, 400 mg PO bid) with placebo in 600 patients with Child-Pugh class A liver disease. About one-third of patients had undergone embolization, and the disease progressed. In all, 70% of patients had portal vein thrombosis and/or metastatic lesions. In spite of a low radiographic response rate, median survival for the 300 patients given sorafenib was significantly better than that for the placebo group (10.7 months vs 7.9 months; HR = 0.69). This is the first well-powered trial to convincingly demonstrate a survival benefit with the use of a systemic agent for this disease. Sorafenib is the standard of care for hepatocellular carcinoma not amenable to locoregional therapy and is the first FDA-approved agent for this indication. Studies using the drug with embolization are ongoing. In the Asia-Pacific Trial, 226 patients with Child-Pugh class A liver disease were randomized to receive sorafenib or placebo. These patients primarily had HBV infection; compared with the SHARP study patients, they had more local therapy before their entry into the trial and, as a whole, more advanced disease. Median survival was 6.5 months, compared with 4.2 months for sorafenib and placebo (HR, 0.68). More data are needed to establish the role of sorafenib in treating Child-Pugh class B liver disease.
The GIDEON registry (Marrero et al) is an ongoing, global, prospective study of patients with Child-Pugh A and Child-Pugh B hepatocellular carcinoma who are suitable for sorafenib therapy. The second interim analysis showed that treatment-related adverse effects were similar in both Child-Pugh A and Child-Pugh B patients but that treatment-related serious adverse events were more common in the Child-Pugh B patients. As a result, a greater percentage of the Child-Pugh B patients ultimately had to discontinue treatment (38% vs 23%). In the intent-to-treat population (1614 patients), preliminary median overall survival was 10.5 months in the Child-Pugh A group and 4.8 months in the Child-Pugh B group. This suggests that although it may be safe to use sorafenib in CP-B patients, close attention must be paid to the adverse effects and the benefit, if any, of sorafenib in this group.
Sidebar: The US data from the second interim analysis of the GIDEON study showed that the median sorafenib dosages in Child-Pugh A and Child-Pugh B patients were 580 mg/d and 577 mg/d, respectively. The median treatment duration was 14.4 weeks in Child-Pugh A patients and 10.1 weeks in Child-Pugh B patients. Grade 3/4 treatment-related adverse events were 22% and 23% in Child-Pugh A and Child-Pugh B patients, respectively. Despite a similar toxicity profile and similar sorafenib dosing in both groups, Child-Pugh B patients were more likely to discontinue sorafenib because of adverse effects, resulting in a shorter treatment duration (Piperdi B et al: J Clin Oncol 30[4s]:abstract 282, 2012).
Sidebar: Brivanib is oral selective dual inhibitor of vascular endothelial growth factor (VEGF) receptor and fibroblast growth factor (FGF) receptor. The FGF pathway may play a role in the development of resistance to anti-VEGF therapy. Brivanib demonstrated antitumor activity in a phase II first-line study for the treatment of advanced hepatocellular carcinoma (Park JW et al: Clin Cancer Res 17:1973-1983, 2011). Therefore, a second-line phase II trial was conducted in patients with hepatocellular carcinoma who had progressed or had been intolerant of prior antiangiogenic treatments, and it showed promising results (Finn RS et al: Clin Cancer Res 18:2090-2098, 2012). Results from the phase III study (BRISK-PS) were recently presented in abstract form. The BRISK-PS study randomized 395 patients in a 2:1 fashion between brivanib 800 mg PO daily and placebo. Patients who entered the study were required to have been treated with sorafenib for at least 14 days and then progressed on or were intolerant of sorafenib. The primary endpoint was overall survival and key secondary endpoints were time to progression and disease control rates. Median overall survival was 9.4 months vs 8.2 months (HR = 0.89; CI, 0.69–1.15) in the brivanib-treated group vs the placebo group, respectively. Therefore, the primary endpoint for improved overall survival was not met. Median time to progression was 4.2 months vs 2.7 months (HR = 0.56; CI, 0.42–0.76) in the brivanib-treated group vs the placebo group, respectively. In spite of the study not meeting its primary endpoint, the improvment in time to progression suggests that brivanib does have some activity in this population (Llovet JM: EASL International Liver Congress 2012, Barcelona, Spain).