Hepatocellular Carcinoma Treatment & Management
- Author: David A Axelrod, MD, MBA; Chief Editor: John Geibel, MD, DSc, MA more...
Medical Therapy
Nonsurgical therapies
In patients who are not candidates for liver transplantation or resection, tumor ablation can be offered to extend life and to potentially downstage the tumor to permit transplantation or resection. Alternatively, patients who have advanced disease may benefit from palliative care interventions rather than be subjected to often ineffective therapies.
The most commonly offered therapy is transcatheter arterial chemoembolization (TACE).[32, 33] TACE is performed by an interventional radiologist who selectively cannulates the feeding artery to the tumor and delivers high local doses of chemotherapy, including doxorubicin, cisplatin, or mitomycin C. To prevent systemic toxicity, the feeding artery is occluded with gel foam or coils to prevent flow. Because most hepatocellular carcinomas derive 80-85% of their blood flow from the hepatic artery, the therapy can be well targeted, leaving the normal parenchyma, which is primarily supplied by portal blood, minimally affected. A reduction in tumor burden can be achieved in 16-61% of treated patients.
The impact of TACE on the clinical outcome remains unclear, with some studies suggesting no benefit. However, other investigators have reported a marked improvement in survival, including an increase in the 2-year survival rate from 27% to 63% in a group of 112 patients.[34] A recent meta-analysis of 7 randomized controlled trials with 516 patients suggested a survival advantage of chemoembolization (Odds Ratio for death 0.53 p=.017) compared with medical therapy. Because the treatment is reasonably well tolerated and has minimal morbidity, it can be offered to well-compensated patients with cirrhosis as a method to reduce their disease burden and to potentially extend their life.
The most common complication is postembolization syndrome, which is characterized by fever, elevated alanine aminotransferase, and abdominal pain; it occurs in 32-80% of treated patients.[35] However, in patients with advanced cirrhosis and hepatic decompensation, TACE is contraindicated because the ischemic damage associated with embolization can lead to a rapid decline in liver function with worsening encephalopathy, increased ascites, and, potentially, death.
One newly developed local treatment, TheraSphere, delivers low-dose brachytherapy to the tumor. TheraSphere uses 20-40 micrometer glass beads that are loaded with radioactive yttrium and delivered angiographically. The radiotherapy is then delivered over 10-12 days with a total dose of about 150 Gray. The maximum distance affected is 1 cm.[36] Early reports suggest that a small number of patients can be successfully downstaged and subsequently transplanted using this approach. Risks include radiation damage to nearby organs, such as the gastrointestinal tract.
The use of systemic or regional chemotherapy has also been attempted in patients with hepatocellular carcinoma. Unfortunately, hepatocellular carcinoma is minimally responsive to systemic chemotherapy. Among the agents tried, doxorubicin-based regimens appear to have the greatest efficacy with response rates of 20-30% and a minimal impact on survival. There is also no apparent benefit to chemotherapy in the adjuvant setting following resection or radiofrequency ablation (RFA).[35] In an effort to provide care in this difficult population, a variety of hormonal and biologic agents have been tried with minimal success, including tamoxifen, antiandrogens (eg, cyproterone, ketoconazole), interferon, interleukin 2 (IL-2), and octreotide.[37] Currently, liver-directed therapies (eg, resection, transplantation, RFA) offer the only genuine hope for extended survival in patients with advanced hepatocellular carcinoma.
Recently, the novel agent, sorafenib (Nexavar), was evaluated in patients with hepatocellular carcinoma in phase II and phase III clinical trials.[38] Sorafenib is an oral agent that has antiangiogenic, pro-apoptotic, and raf-kinase inhibitory properties. Preclinical trials have implicated the Raf/MAPK-ERK (MED)/extracellular signal regulated kinase (ERK) in hepatocellular carcinoma carcinogenesis.[39]
Additionally, Raf-1 activity was found to be up-regulated in HCV infected hepatocytes, which increases the risk of neoplastic transformation. Hepatocellular carcinoma development has been tied to pro-angiogenic factors, including vascular endothelial growth factor (VEGF), given its highly vascular nature. Sorafenib is unique in its ability to target multiple pathways by blacking RAF/MEK/ERK signaling at the level of raf-kinase as well as by inhibiting vascular endothelial growth factor receptor (VEGFER) and platelet-derived growth factor receptor beta (PDGFR-beta).
Initial phase II clinical trials reported in 2004 demonstrated safety and clinical efficacy in 137 patients with Child Class A or B cirrhosis.[38] Patients were treated with oral sorafenib 400 mg twice daily for 4-week cycles. Tumor response was variable; 2.2% of patients had a partial response, 5.8% of patients had a minimal response, and 33% of patients had stable disease for more than 16 weeks. Overall toxicity was limited; grade 3 toxicities included fatigue (9.5%), diarrhea (8%), and hand-foot syndrome (5.1%).
The efficacy of sorafenib has been recently investigated in a phase III trial, reported in abstract form at the 2007 American Society of Clinical Oncology meeting. LLovet and colleagues randomized 602 patients with Child Class A cirrhosis and hepatocellular carcinoma to sorafenib versus placebo.[40] The overall results were encouraging. Treatment with sorafenib significantly improved survival (hazard ratio for all cause mortality: 0.69, p=0.0006). Treatment was also associated with an increased time to disease progression (5.5 mo vs 2.8 mo) and disease control rate (43% vs 32%). Overall toxicity did not differ between treatment and placebo arm (52% vs 54%). Based on this trial, sorafenib has become the most promising chemotherapeutic agent in the treatment of hepatocellular carcinoma in patients with preserved liver function. Various somewhat similar agents are under investigation.
For most patients, treatment options other than palliative care are limited. For patients with Child Class C cirrhosis and contraindications to transplantation, any intervention has the potential to result in progressive hepatic decompensation. In these patients, treatment focuses on pain control, ascites, edema, and portosystemic encephalopathy management.
Pain control may provoke worsening of portosystemic encephalopathy, as some patients are sensitive to narcotics and sometimes benzodiazepines. Insomnia may be the consequence of depression and fear, but it can also be a reflection of portosystemic encephalopathy. The latter can be worsened by (narcotic-induced) constipation that should be prevented. Lactulose can be helpful, and the ideal dosage should lead to not more than and not less than 2-3 bowel movements daily.
Aspirin and aspirin-like products, as a rule, are contraindicated in the patient with fluid retention because prostaglandin inhibition can strongly enhance retention of water and salt. In addition, consequences of platelet dysfunction may occur.
Fluid overload is best managed with a combination of spironolactone (50-400 mg daily), replaced by amiloride (10-20 mg daily) in case of painful gynecomastia, and furosemide (40-160 mg daily). Excessive diuresis leading to a weight loss of more than 1-2 lbs daily usually causes worsening renal and electrolyte problems. Large-volume paracentesis in excess of 5-7 L, even accompanied by intravenous albumin, can result in renal decompensation and worsening of portosystemic encephalopathy.
In terminal patients, hypoglycemia can be confused with hepatic coma and can be managed with glucose infusions. Patients with large tumors have a short life expectancy, and care should be designed to preserve and enhance quality of life. Early referral to palliative care practitioners should be considered.
Surgical Therapy
Given the absence of effective chemotherapy and the insensitivity of hepatocellular carcinoma to radiotherapy, complete tumor extirpation represents the only opportunity for a long-term cure. Resection of the tumor by partial hepatectomy can be accomplished in a limited number of patients (generally < 15-30%) in most Western series due to the degree of underlying cirrhosis. In patients with decompensated liver disease, liver transplantation offers the potential for a long-term cure in patients with limited tumor burden. Alternative treatments, including local ablative therapy, transarterial chemoembolization, and transarterial brachytherapy, can be considered in patients who are not candidates for curative procedures.
Surgical resection of hepatocellular carcinoma
Advances in the technique of liver resection, better patient selection, improved postoperative care, and expert anesthetic management have resulted in a dramatic reduction in perioperative morbidity and mortality. Liver resection is the operation of choice for patients with tumors less than 5 cm in the absence of cirrhosis. These patients can often tolerate resection of up to 50% of the total liver volume. In these patients, an operative mortality rate of less than 2% can be expected in experienced centers.[29, 13]
In patients with cirrhosis, the extent of liver resection that can be tolerated is significantly more limited. Clinically evident portal hypertension defined as a hepatic vein to right atrial pressure gradient of greater than 10, esophageal varices, or splenomegaly with a platelet count of less than 100,000/mm3 predict poor outcome with significant resection. In general, resection of more than 2 segments is contraindicated in patients with Child Class B or C cirrhosis. However, among patients who do undergo successful resection, long-term survival is possible, with 5-year survival rates of up to 74% in patients without significant decompensation.
Following liver resection, up to 75% of patients will develop intrahepatic recurrence within 5 years.[41, 42] This recurrence can be either de novo hepatocellular carcinoma or local spread. Pathologic characteristics associated with a higher rate of recurrence include tumor at the resection margin, presence of cirrhosis, vascular invasion, advanced tumor grade, number of tumor nodules, and microvascular portal vein thrombosis. Other clinical factors associated with a higher rate of hepatocellular carcinoma recurrence include a preresection serum AFP level of greater than 10,000 ng/mL, large intraoperative transfusion requirements, preoperative AST greater than twice normal, and diagnosis of hepatitis C. In patients with recurrence and preserved liver function, re-resection may be indicated. In one single center series, operative resection was associated with prolonged survival (44 mo vs 10.6 mo) when compared to patients managed medically.[43]
Liver transplantation
Compared with resection for hepatocellular carcinoma, orthotopic liver transplantation (OLT) offers several potential advantages. Complete hepatectomy eliminates the possibility of local recurrence at the resection margin and, moreover, removes the cirrhotic liver, which is clearly predisposed to tumor formation. Liver transplantation also eliminates concerns about the capacity of the postresection liver remnant to provide adequate liver volume.
The initial experience with liver transplantation for patients with hepatocellular carcinoma was unrewarding with high rates of recurrence in the allograft (transplanted liver) and extrahepatically.[44] Reports from the national transplant tumor registry in 1991 revealed a 5-year survival rate of only 18%.[45] In the survivors, only 9% remained tumor free at 2 years. These dismal survival data led to a moratorium on transplantation for hepatocellular carcinoma in the early 1990s. However, further investigations have suggested that these results were likely the result of poor patient selection and transplantation in the face of extensive tumor burden. In patients with incidentally discovered small tumors, the results were actually quite good, leading to the recent reassessment of the hepatocellular carcinoma as an indication for OLT.
The approach to patients with hepatocellular carcinoma has been dramatically altered following the 1996 publication of the results from Mazzaferro and colleagues in Milan.[46] They demonstrated that patients with limited hepatocellular carcinoma tumor burden could achieve posttransplant patient survival rates equivalent to patients without malignancies. Mazzaferro defined the Milan criteria, which have been used to determine candidacy for OLT. In their experience, patients with established cirrhosis and a single hepatocellular carcinoma (≤5 cm in diameter) or up to 3 hepatocellular carcinomas (all ≤3 cm in diameter) have a 4-year overall survival rate of 85% and a tumor-free survival rate of 92%. By comparison, patients with a large tumor burden had a 4-year survival rate of 50%. Following this report, OLT was established as the therapy of choice for patients with significant cirrhosis and limited tumor burden.[46, 47, 48, 49]
These results have also now been duplicated by several other transplant centers.[46] See Table 3.
Table 3. Patient Survival Rates Following Liver Transplantation for Hepatocellular Carcinoma (Open Table in a new window)
| Author (Year) | N | Survival Rate | |
| 1 year | 5 years | ||
| Mazzefero (1996) | 48 | 84% | 74% |
| Bismuth (1999) | 45 | 82% | 74% |
| Llovet (1999) | 79 | 86% | 75% |
| Jonas (2001) | 120 | 90% | 71% |
In addition to tumor burden, survival following transplantation has also been correlated with a variety of anatomic and pathologic features. Poor prognosis has been associated with bilobar distribution of tumor, vascular invasion (particularly macroscopic tumor invasion), higher histologic grade, and pretreatment AFP level of greater than 300 ng/mL.[50, 51, 32] In these patients, tumor recurrence is highly likely. While fibrolamellar histology has been associated with improved prognosis following resection, posttransplant survival appears to be equivalent to hepatocellular carcinoma in general. Finally, clinically evident reinfection with hepatitis B or C virus has been correlated with tumor recurrence. In patients with hepatitis C, active viral recurrence is associated with a 40% risk of tumor development in the transplanted organ.[52]
The application of OLT to hepatocellular carcinoma has also been limited by access to deceased donor organs. Until 2002, patient waiting time was the primary driver of liver allocation, leading to high dropout rates among patients listed for transplant. In their report in 2002, Yao and colleagues reported that as a result of tumor progression, up to 37.8% of waitlist patients were no longer eligible at 12 months.[53]
Beginning in February 2002, liver allografts have been allocated based upon the patients’ likelihood of dying from their liver disease. In general, liver allografts are allocated to patients according to their Model for End Stage Liver Disease (MELD) score. MELD is a complex equation, including creatinine, bilirubin, and INR, which accurately predicts mortality from complications of cirrhosis. Under the MELD system, the patient with the highest MELD score and, therefore, the highest risk of dying without a liver transplant, is transplanted first.
Because patients with hepatocellular carcinoma are more likely to die from their malignancy than they are from their liver disease, surgeons feared that patients with hepatocellular carcinoma would be disadvantaged under the MELD system. To ensure access to deceased donor organs, patients with hepatocellular carcinoma with stage 1 or 2 tumors were assigned higher MELD scores based on tumor stage rather than tumor function. Patients with stage 3 or greater were precluded from transplantation. This change in allocation systems led to a dramatic reduction in waiting time and near elimination of patients dropping out from tumor progression. Early reports suggested that the waitlist dropout rates were less than 5% at 8 months.
Currently, the priority accorded to patients with hepatocellular carcinoma has been challenged, and a variety of authors have suggested that these patients have been disproportionately advantaged compared to the rest of the waiting list. This has led to a reduction in the MELD point upgrade.[54]
Additional strategies to provide OLT to patients with hepatocellular carcinoma have included the use of living donor living transplantation and split liver transplant. These techniques expand the organ pool and appear to offer equivalent survival to whole organ transplant. They have also been used in patients undergoing transplantation whose tumor burden exceeds the Milan criteria. Based on this experience, several centers have advocated expanding the maximum tumor burden that can be considered for MELD upgrades to include patients with 1 tumor up to 6.5 cm or 3 or fewer tumors less than or equal to 4.5 cm with a total tumor diameter of less than or equal to 8 cm. Transplantation in this population resulted in a survival rate of 90% at 1 year and 72.5% at 5 years.[55] Further refinement in both listing criteria and degree of MELD upgrade accorded to patients with hepatocellular carcinoma islikely in the future.
Ablative therapies
Curative treatment of patients with hepatocellular carcinoma who are not candidates for resection or OLT is limited. However, local ablative therapies can be used either as a bridge to transplant by reducing the risk of tumor progression or as a palliative procedure to extend disease-free survival. Ablative procedures, including ethanol injection, radiofrequency ablation, and cryotherapy, can be performed percutaneously, laparoscopically, or using an open surgical approach.
Percutaneous ethanol injection (PEI) was the first ablative technique used for hepatocellular carcinoma. PEI involves the injection of alcohol directly into the tumor leading to complete ablation of up to 70% of lesions, which are less than or equal to 3 cm. The alcohol is generally performed with ultrasound guidance and requires 4-6 sessions to complete the ablation. In patients with Child Class A cirrhosis, 40-55% survival can be achieved at 3 years.[56] PEI has not been compared with surgery in a randomized fashion; however, in retrospective reviews, the 3-year survival rate with PEI and surgery were 71% and 79% in patients with Child Class A cirrhosis and 40% and 41% in those with Child Class B disease.
Although generally well tolerated, PEI can result in death and rare instances of tumor seeding. Unfortunately, PEI treated lesions have a high rate of local recurrence (ie, 33% for tumors ≤3 cm, 43% for larger tumors).
In the United States, the use of PEI has been largely replaced with RFA, in which a conducting needle is placed within the tumor and current travels to a large dispersive electrode (grounding pad). The electric current leads to agitation of the ions in the tissue, heat generation, and desiccation of the tissues surrounding the probe. The coverage of the electric field can be extended with water cooling, multiple deployable tines within the needle, and other modified electrodes.[57] Treatment is generally performed at one session (compared with multiple sessions using PEI). Guidance with ultrasound, CT, or laparoscopy can be used depending upon the patient’s health, tumor location, and center expertise.
When compared with PEI in a prospective trial, RFA was associated with a trend toward improved 24-month patient survival rates (98% vs 88%), but this did not achieve statistical significance.[56] However, significant differences in recurrence-free survival rates clearly favor RFA at 24 months (64% vs 43%, p=.012). Complication rates are low with a 0.3% risk of mortality and a 2.2% incidence of major complications. Tumor seeding occurred in 0.5% of 1610 lesions treated in a large study reported by Llovet and colleagues.[55]
RFA success may also be limited by the presence of large blood portal or hepatic vein branches adjacent to the tumor. Flowing blood can act as a heat sink and limit the ability to heat the tissue to a sufficient temperature. The temporary use of selective arterial/venous occlusion can be used to reduce the amount of heat sink.
RFA can also be used as an adjunctive therapy for patients waiting for transplantation. In these patients, tumor progression can be delayed without the increased morbidity associated with liver transplantation following open resection. Preliminary data are available in a variety of new technologies, including microwave ablation, laser ablation, and focal external beam radiation. Unfortunately, no randomized trial data are available for this population. Cryoablation of tumors using a liquid nitrogen filled probe had been used historically for ablation. However, as a result of higher complication rates and lower efficacy rates, it has largely fallen out of the clinical armamentarium.[32]
Follow-up
Despite optimal treatment, hepatocellular carcinoma continues to have a high recurrence rate. Hepatocellular carcinoma recurs in 50-80% of patients following resection, the majority of which occur within 2 years.[58] Careful follow-up in the postoperative period is mandatory. Early recurrence after resection is associated with a dismal prognosis, reducing 5-year survival rates from 70% to 30%.[58] Factors that increase the likelihood of recurrence include the presence of multiple foci of hepatocellular carcinoma, liver capsule invasion, and tumor size (>5 cm). Vascular invasion, both microscopic and macroscopic, also correlates with a higher risk of recurrence.
Among patients undergoing liver transplantation, the rate of recurrence is dependant upon the characteristics of the tumor in the explanted liver. Overall recurrence in patients transplanted within the Milan criteria is 4-10%.[46] The majority of these recurrences occur early (8-14 mo); however, up to 30% of recurrences may occur late.[59] In these patients, 23% develop intrahepatic-only recurrence, 39% develop both intrahepatic and extrahepatic recurrence, and 39% develop extrahepatic–only recurrence. Common extrahepatic sites of metastatic disease include lung, bone, CNS, and adrenal glands. Resection in the posttransplant population can be accomplished in up to one third of patients. In those patients who undergo successful resection, 4-year survival rates increase from 14% to 57%, justifying an aggressive approach.[60]
Unfortunately, no established guidelines exist regarding the frequency of imaging procedures in the postoperative period. In general, a CT scan at 1 month postresection should be obtained to ensure complete tumor clearance. Following this initial scan, serum alpha-fetoprotein measurements and repeat imaging studies (eg, ultrasound, CT, MRI) should be obtained every 3-6 months depending on the likelihood of recurrence. After 2-3 years, it appears safe to increase the follow-up interval.
Complications
See Medical therapy and Surgical therapy.
Outcome and Prognosis
See Medical therapy and Surgical therapy.
Future and Controversies
The threat of hepatocellular carcinoma is expected to continue to grow in the coming years.[13] The peak of the hepatocellular carcinoma associated with HCV infection has not yet occurred. There is also a growing problem with cirrhosis, which develops in the setting of nonalcoholic steatohepatitis (NASH). NASH typically develops in the setting of obesity, type 2 diabetes, dyslipidemia, and hypertension, and it will undoubtedly remain a significant problem, given the obesity epidemic occurring in the United States.[4] Thus, developing effective and efficient care for patients with end-stage liver disease and hepatocellular carcinoma must become a significant focus.
Management of hepatocellular carcinoma is best performed in a multidisciplinary setting. Patients should be cooperatively managed by hepatologists, transplant and hepatobiliary surgeons, medical oncologists, interventional radiologists, and palliative care specialists. Specifically, this is crucial to ensure that patients who are candidates for liver transplantation are referred in a timely manner, while their tumors are within the Milan criteria.[13]
Overall, transplantation remains the best option for patients with hepatocellular carcinoma. Unfortunately, there is a limited supply of good quality deceased donor organs. Thus, alternative treatments, including resection, RFA, and, potentially, systemic therapy with sorafenib, should be used to bridge patients to transplant or to delay recurrence if possible. In patients who experience a recurrence following resection or transplantation, aggressive surgical treatment appears to be associated with the best possible outcome.[61]
Other strategies to limit this epidemic will pay off in the long term. The vaccination campaign against hepatitis B has already resulted in a reduced incidence of hepatocellular carcinoma in Taiwan.[62] Moreover, failure to complete HBV vaccination continues to lead to hepatocellular carcinoma in patients.
Other strategies to reduce the incidence of hepatocellular carcinoma include the treatment of HBV and HCV infection to eradicate the virus with rapidly effective therapies, including pegylated interferons, nucleoside analogues (HBV), and ribavirin (HCV). Promising protease inhibitors are in ongoing clinical trials,[63] and adequate screening of high-risk patients is needed to treat small lesions early. Analysis of patients from The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial found that, in patients with chronic hepatitis C who did not have a sustained virologic response to therapy, long-term pegylated interferon therapy does not reduce the incidence of hepatocellular carcinoma.[64]
Other preventative approaches include programs to reduce obesity and type 2 diabetes. Major efforts are also needed to specifically warn patients with chronic liver disease to discontinue alcohol abuse. Hemochromatosis should be recognized in a timely manner.
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| Europe and United States | Japan | Africa and Asia | ||||
| Estimate | Range | Estimate | Range | Estimate | Range | |
| HBV | 22 | 4-58 | 20 | 18-44 | 60 | 40-90 |
| HCV | 60 | 12-72 | 63 | 48-94 | 20 | 9-56 |
| Alcohol | 45 | 8-57 | 20 | 15-33 | - | 11-41 |
| Tobacco | 12 | 0-14 | 40 | 9-51 | 22 | - |
| OCPs | - | 10-50 | - | - | 8 | - |
| Aflatoxin | Limited exposure | Limited exposure | Limited exposure | |||
| Other | < 5 | - | - | - | < 5 | - |
| Alpha-fetoprotein (ng/mL) | Interpretation |
| >400-500 | - HCC likely if accompanied by space-occupying solid lesion(s) in cirrhotic liver or levels are rapidly increasing. - Diffusely growing HCC, may be difficult to detect on imaging. - Occasionally in patients with active liver disease (particularly HBV or HCV infection) reflecting inflammation, regeneration, or seroconversion |
| Normal value to < 400 | - Frequent: Regeneration/inflammation (usually in patients with elevated transaminases and HCV) - Regeneration after partial hepatectomy - If a space-occupying lesion and transaminases are normal, suspicious for HCC |
| Normal value | Does not exclude HCC (cirrhotic and noncirrhotic liver) |
| Author (Year) | N | Survival Rate | |
| 1 year | 5 years | ||
| Mazzefero (1996) | 48 | 84% | 74% |
| Bismuth (1999) | 45 | 82% | 74% |
| Llovet (1999) | 79 | 86% | 75% |
| Jonas (2001) | 120 | 90% | 71% |
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