Hepatocellular Carcinoma Treatment & Management

Updated: Sep 29, 2017
  • Author: Luca Cicalese, MD, FACS; Chief Editor: John Geibel, MD, DSc, MSc, AGAF  more...
  • Print
Treatment

Approach Considerations

Management of hepatocellular carcinoma (HCC) 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. [2]

Overall, transplantation remains the best option for patients with HCC. Unfortunately, there is a limited supply of good-quality deceased donor organs. Thus, other treatments, including resection, radiofrequency ablation (RFA), and, potentially, systemic therapy with sorafenib (or, if sorafenib fails, with regorafenib or nivolumab), 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. [32]

Next:

Medical Therapy

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.

Transcatheter arterial chemoembolization

The most commonly offered therapy is transcatheter arterial chemoembolization (TACE). [33, 34] 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 HCCs 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. [35] Some studies suggested no benefit, but others 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. [36] One meta-analysis of 7 randomized controlled trials with 516 patients suggested a survival advantage of chemoembolization (odds ratio for death, 0.53) 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. [37] 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.

Brachytherapy

Another treatment option involves the local delivery of low-dose brachytherapy to the tumor. One such treatment, TheraSphere (BTG, Ottawa, Ontario, Canada), uses 20- to 40-μm 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 Gy. The maximum distance affected is 1 cm. [38]

Early reports suggested that a small number of patients can be successfully downstaged and subsequently transplanted by using this approach. Risks include radiation damage to nearby organs (eg, the gastrointestinal tract).

Chemotherapy

The use of systemic or regional chemotherapy has also been attempted in patients with HCC. Unfortunately, HCC 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 RFA. [37]  In an effort to provide care in this difficult population, various hormonal and biologic agents have been tried with minimal success, including tamoxifen, antiandrogens (eg, cyproterone, ketoconazole), interferon, interleukin (IL)-2, and octreotide. [39] Currently, liver-directed therapies (eg, resection, transplantation, RFA) offer the only genuine hope for extended survival in patients with advanced HCC.

The combination of gemcitabine and oxaliplatin (GEMOX) helped to shrink large hepatomas to the point where some could be resected, according to a retrospective, multicenter study in France. [41]

Sorafenib is an oral agent that has antiangiogenic, proapoptotic, and raf-kinase inhibitory properties. [42, 43, 44] ​ In 2007, it was approved by the US Food and Drug Administration (FDA) for use in patients with unresectable HCC. Sorafenib is regarded as a standard medical treatment for advanced HCC. [45, 46]

Two additional systemic drug options now exist for patients with HCC who have stopped responding to initial treatment with sorafenib.

In April 2017, regorafenib was approved by the FDA for use in patients with HCC who have been previously treated with sorafenib. Approval was based on the RESORCE trial results (N=573) in patients with progressive HCC who had undergone treatment with sorafenib. [47] In this trial, regorafenib improved overall survival compared with placebo (10.6 months vs 7.8 months). Median progression-free survival was also significantly better with regorafenib than with placebo (3.1 months vs 1.5 months), as were the disease control rate (65.2% vs 36.1%) and the complete or partial response rate (10.6% vs 4.1%).

In September 2017, nivolumab was approved by the FDA for patients with HCC who have been previously treated with sorafenib. Accelerated approval was based on the CheckMate-040 trial, a phase 1/2, open-label, multicenter trial evaluating nivolumab in patients with advanced HCC who progressed on or were intolerant to sorafenib. [77]  Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In the CheckMate-040 trial, 154 patients received nivolumab 3 mg/kg IV every 2 weeks. Of the 154 patients, 22 (14.3%) responded to nivolumab, with complete response seen in 3 (1.9%). [77] The duration of response ranged from 3.2 months to greater than 38.2 months. In those who responded, 91% had responses lasting at least 6 months, and 55% had responses lasting at least 12 months.

Other nonsurgical measures

For most patients, treatment options other than palliative care are limited. For patients with Child class C cirrhosis and contraindications for 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, in that 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 fewer than two or three bowel movements daily.

Aspirin and aspirinlike 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/day), replaced by amiloride (10-20 mg/day) in case of painful gynecomastia, and furosemide (40-160 mg/day). Excessive diuresis leading to a weight loss of more than 1-2 lb 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 every effort should be made to preserve and enhance quality of life. Early referral to palliative care practitioners should be considered.

Previous
Next:

Surgical Therapy

In view of the absence of effective chemotherapy and the insensitivity of HCC to radiotherapy, complete tumor extirpation represents the only opportunity for a long-term cure. Resection of the tumor by partial hepatectomy (see the videos below) can be accomplished in a limited number of patients (generally <15-30%) in most Western series due to the degree of underlying cirrhosis.

Right hepatectomy. Part 1: Dissection of portal vein. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)
Right hepatectomy. Part 2: Devascularization of right liver. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)
Right hepatectomy. Part 3: Suturing and dividing. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)

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, TACE, and transarterial brachytherapy, can be considered in patients who are not candidates for curative procedures.

Surgical resection

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 smaller 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 of less than 2% can be expected in experienced centers. [29, 2]

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 in excess of 10), esophageal varices, or splenomegaly with a platelet count lower than 100,000/μL predicts poor outcome with significant resection. In general, resection of more than two 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 as high as 74% in patients without significant decompensation.

After liver resection, as many as 75% of patients will develop intrahepatic recurrence within 5 years. [48, 49] This recurrence can be either de-novo HCC or local spread. Pathologic characteristics associated with a higher rate of recurrence include the following:

  • Tumor at the resection margin
  • Presence of cirrhosis
  • Vascular invasion
  • Advanced tumor grade
  • Number of tumor nodules
  • Microvascular portal vein thrombosis

Other clinical factors associated with a higher rate of HCC recurrence include the following:

  • Preresection serum alpha-fetoprotein (AFP) level higher than 10,000 ng/mL
  • Large intraoperative transfusion requirements
  • Preoperative aspartate aminotransferase (AST) level greater than twice normal
  • Diagnosis of hepatitis C

In patients with recurrence and preserved liver function, repeat resection may be indicated. In one single-center series, operative resection was associated with prolonged survival (44 months vs 10.6 months) in comparison with medical management. [50]

Resection of HCCs that are 2 cm or smaller has been shown to be safe and effective in both Asian and Western populations, though recurrence is common. The presence of satellites and platelet count are associated with survival in these patients, and the presence of satellites, cirrhosis and non-anatomic resection are associated with recurrence. [51]

Liver transplantation

Compared with resection for HCC, 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 HCC was unrewarding with high rates of recurrence in the allograft (transplanted liver) and extrahepatically. [52] Reports from the national transplant tumor registry in 1991 revealed a 5-year survival rate of only 18%. [53] In the survivors, only 9% remained tumor-free at 2 years.

These dismal survival data led to a moratorium on transplantation for HCC in the early 1990s. However, further investigations 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 subsequent reassessment of HCC as an indication for OLT.

The approach to patients with HCC was dramatically altered by the 1996 publication of the results from Mazzaferro et al in Milan, [54] who demonstrated that patients with limited HCC 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 the experience of the Milan investigators, patients with established cirrhosis and either a single HCC no larger than 5 cm in diameter or as many as three HCCs no larger than 3 cm had 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%. After this report, OLT was established as the therapy of choice for patients with significant cirrhosis and limited tumor burden. [54, 55, 56, 57]

These results were subsequently duplicated by several other transplant centers (see Table 3 below). [54]

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 after transplantation has also been correlated with a variety of anatomic and pathologic features. Poor prognosis has been associated with the following [33, 58, 59] :

  • Bilobar distribution of tumor
  • Vascular invasion (particularly macroscopic tumor invasion)
  • Higher histologic grade
  • Pretreatment AFP level higher than 300 ng/mL

In these patients, tumor recurrence is highly likely. Whereas 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 virus (HBV) or hepatitis C virus (HCV) 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. [60]

The application of OLT to HCC 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 et al reported that as a result of tumor progression, as many as 37.8% of waitlist patients were no longer eligible at 12 months. [61]

Beginning in February 2002, liver allografts have been allocated according to 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 international normalized ratio (INR), which accurately predicts mortality from complications of cirrhosis (see the MELD Score calculator). 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 HCC are more likely to die from their malignancy than they are from their liver disease, surgeons feared that patients with HCC would be disadvantaged under the MELD system. To ensure access to deceased donor organs, patients with HCC 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.

The priority accorded to patients with HCC has been challenged, and a number 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. [62]

Additional strategies to provide OLT to patients with HCC have included the use of living-donor liver 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.

On the basis of this experience, several centers have advocated expanding the maximum tumor burden that can be considered for MELD upgrades to include patients with one tumor no larger than 6.5 cm or three or fewer tumors no larger than 4.5 cm with a total tumor diameter no larger than 8 cm. Transplantation in this population resulted in a survival rate of 90% at 1 year and 72.5% at 5 years. [63] Further refinement in both listing criteria and degree of MELD upgrade accorded to patients with HCC is likely in the future.

Ablative therapies

Curative treatment of patients with HCC 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, RFA, and cryotherapy, can be performed percutaneously, laparoscopically, or via an open surgical approach.

Percutaneous ethanol injection (PEI) was the first ablative technique used for HCC. 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. It 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. [64] PEI has not been compared with surgery in a randomized fashion; however, in retrospective reviews, the 3-year survival rates with PEI and surgery were 71% and 79%, respectively, 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, PEI has largely been supplanted by 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. [65] 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 trend did not achieve statistical significance. [64] However, significant differences in recurrence-free survival rates clearly favor RFA at 24 months (64% vs 43%). Complication rates are low, with a 0.3% 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 et al. [63]

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. [66] 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 newer 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. [33]

Previous
Next:

Prevention

Strategies to limit the epidemic of HCC are likely to pay off in the long term. The vaccination campaign against hepatitis B has already resulted in a reduced incidence of HCC in Taiwan. [67, 68] Moreover, failure to complete HBV vaccination continues to lead to HCC in patients.

Other strategies to reduce the incidence of HCC include the treatment of HBV and HCV [69] 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, [70] 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 HCC. [71]

Other preventive approaches include programs to reduce obesity and type 2 diabetes. [72] 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.

Previous
Next:

Long-Term Monitoring

Despite optimal treatment, HCC continues to have a high recurrence rate. It recurs in 50-80% of patients following resection, with the majority of recurrences developing within 2 years. [73] 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%. [73] Factors that increase the likelihood of recurrence include the presence of multiple foci of HCC, liver capsule invasion, and tumor size greater than 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 dependent upon the characteristics of the tumor in the explanted liver. [74] Overall recurrence in patients transplanted within the Milan criteria is 4-10%. [54] The majority of these recurrences occur early (8-14 months); however, as many as 30% of recurrences may occur late. [75] 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, central nervous system, 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. [76]

Unfortunately, no established guidelines exist regarding the frequency of imaging procedures in the postoperative period. In general, CT should be performed at 1 month post resection to ensure complete tumor clearance. After this initial scan, serum AFP measurements and repeat imaging studies (eg, ultrasonography, 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.

Previous