Primary Hepatic Carcinoma Treatment & Management

Updated: Feb 21, 2018
  • Author: Keith E Stuart, MD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Treatment

Approach Considerations

Treatment options for hepatocellular carcinoma depend on the following [22, 23, 24] :

  • Size, number, and location of tumors
  • Presence or absence of cirrhosis
  • Operative risk based on extent of cirrhosis and comorbid diseases
  • Overall performance status
  • Portal vein patency
  • Presence or absence of metastatic disease

Before instituting definitive therapy, it is best to treat the complications of cirrhosis, as follows:

  • Sodium restriciton, diuretics, and paracentesis for ascites
  • Lactulose for encephalopathy
  • Ursodiol for pruritus
  • Sclerosis or banding for variceal bleeding

Surgical resection and liver transplantation provide the only chances of cure but have limited applicability. The main prognostic factors for resectability are tumor size and liver function. Only about 5% of hepatocellular carcinoma patients are suitable for transplantation; these patients may have a 5-year survival of greater than 75% with tumor recurrence rates as low as 15% at 5 years. [25]  

Other local therapies are chemoembolization, ethanol ablation, radiofrequency ablation, cryoablation, and radiotherapy. Patients whose disease is downstaged following chemoembolization may be eligible for transplantation. Systemic treatment with chemotherapy may be used for advanced disease.

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Medical Care

Systemic chemotherapy

Systemic chemotherapy remains the mainstay of therapy for patients with advanced hepatocellular carcinoma who are not candidates for surgical resection, liver transplantation, or localized tumor ablation. Unfortunately, hepatocellular carcinoma is a relatively chemotherapy-resistant tumor; therefore, outcomes using this mode of treatment are unsatisfactory. Resistance to chemotherapy may be caused by the universal expression of the multidrug resistance gene protein on the surface of the malignant cells, leading to active efflux of chemotherapeutic agents.

Chemotherapy is usually not well tolerated and seems to be less efficacious in patients with hepatocellular carcinoma with underlying hepatic dysfunction. Younger patients with well-compensated cirrhosis due to chronic hepatitis B or C infections have better outcomes with chemotherapy than older patients with alcoholic cirrhosis and other comorbid diseases.

The most active single agent drugs tested have been doxorubicin, cisplatin, and fluorouracil. Response rates are about 10%, and treatment shows no clear impact on overall survival. [26, 23] More recently, gemcitabine and capecitabine have been evaluated in clinical trials; response rates have been low and short term.

Various combination chemotherapy regimens have also been studied. Cisplatin-based combination regimens, such as gemcitabine and oxaliplatin, have shown improved response rates around 20%, but to date, no survival advantage as compared with supportive care alone has been shown. No difference seems to exist in response rates between 2- or 3-drug regimens. Moreover, some of these combination regimens cause considerable toxicity.

Chemoimmunotherapy uses a combination of chemotherapy and immunomodulatory agents, such as interferon-alpha, to try to achieve better tumor response rates. Immunotherapy has had encouraging results in patients with certain types of cancers such as renal cell carcinoma and melanoma.

PIAF is a combination of cisplatin, interferon-alpha, doxorubicin, and infusional 5-fluorouracil that is associated with a response rate of 26%, which is higher than the response rates with single chemotherapy agents. Although overall median survival is longer with PIAF than single-agent doxorubicin, treatment-related toxicity is significant. The best candidates for this therapy are young patients without liver cirrhosis and normal bilirubin levels. [27]

Antiangiogenic therapy 

Antiangiogenesis agents (ie, bevacizumab), which work by disrupting the formation of blood vessels that feed tumors, are a new class of drugs that may prove to be of benefit in the treatment of hepatocellular carcinoma. The highly vascular nature of hepatocellular carcinoma tumors suggested that therapy with an antiangiogenesis agent might be effective. Bevacizumab by itself, however, is of limited clinical use.  However, the combination of bevacizumab with gemcitabine and oxaliplatin produced a 20% response rate, and stable disease in an additional 27% of patients. [28]  

Sorafenib, a multitargeted oral kinase inhibitor, has been shown in a phase III trial to prolong survival in patients with hepatocellular carcinoma. [29] This agent, which targets various pathways, including those encoded by VEGFR, PDGFR, KIT, FLT-3, and RET, was compared with placebo in a trial of 602 patients. Median survival was prolonged significantly to 10.7 from 7.9 months, and time to progression was 5.5 months, compared with 2.8 months in the placebo group. Currently, this is the only FDA-approved antineoplastic for hepatocellular carcinoma. The revised National Comprehensive Cancer Network (NCCN) guidelines for hepatocellular carcinoma recommend sorafenib as a treatment option at several points in the treatment algorithm. [22]

The benefit of sorafenib was also demonstrated in a study by Abou-Alfa et al, which showed a longer overall and progression-free survival with the addition of sorafenib to doxorubicin. The same study underlines the lack of efficacy of doxorubicin alone. [30] Still unanswered is the question of whether doxorubicin adds any benefit to treatment with sorafenib by itself.

Sunitinib is another multitargeted tyrosine kinase inhibitor with reported activity in hepatocellular carcinoma. [31] Erlotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has also shown some activity against hepatocellular carcinoma when used alone or in combination with bevacizumab. [32, 33] One report has suggested that the mTOR inhibitor sirolimus may have benefit in the treatment of both cholangiocellular carcinoma and hepatocellular carcinoma. [33]

Immunotherapy

Immune checkpoint inhibitors have been proven to lead to durable tumor shrinkage in a subset of patients that has translated into significant overall survival advantages over standard therapy in several cancer types. Interference with the CTLA-4-CD80/86 and PD-1/PD-L1 axis has shown promise in patients with hepatocellular carcinoma and many clinical trials using this approach have been reported or are currently under way. [34]

On September 22, 2017, the US Food and Drug Administration granted accelerated approval to the anti–programmed death 1 monoclonal antibody nivolumab (Opdivo) for the treatment of hepatocellular carcinoma in patients who have been previously treated with sorafenib.  Approval was based on a 154-patient subgroup of CHECKMATE-040, a multicenter, open-label trial conducted in patients with hepatocellular carcinoma and Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib. Patients received nivolumab 3 mg/kg by intravenous infusion every 2 weeks. The confirmed overall response rate was 14.3% (95% CI: 9.2, 20.8), with 3 complete responses and 19 partial responses. Response duration ranged from 3.2 to 38.2+ months; 91% of responders had responses lasting 6 months or longer and 55% had responses lasting 12 months or longer. [35]

Common adverse reactions occurring in greater than 20% of patients in nivolumab clinical trials include fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia. [35]

 

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Surgical Care

Partial hepatectomy

The videos below demonstrate a right hepatectomy.

Right hepatectomy. Part 1: Dissection of right 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 the United States, resection is possible in only 5% of patients. In general, solitary hepatocellular carcinoma lesions confined to the liver without vascular invasion with well-preserved hepatic function have the best outcomes. Although there are no strict criteria in terms of tumor size, many surgeons use less than 5 cm as their cutoff.

Five-year survival rates for resectable lesions vary widely from 30% to as high as 90% for very early stage hepatocellular carcinoma lesions. [36, 37] Fibrolamellar hepatocellular carcinoma may have a better prognosis for survival after surgical resection because of a more favorable size, predominantly left lobe location, and the absence of cirrhosis in the unaffected portion of the liver.

Appropriate evaluation of patients prior to resection is crucial since intraoperative mortality is doubled in cirrhotic versus noncirrhotic patients. Preoperative laparoscopic inspection aids in diagnosing both the tumor and extent of cirrhosis.

Local liver factors rather than tumor-associated characteristics may be instrumental in tumor recurrences following surgical resection. For instance, one study found that the level of HBV-DNA in the liver tissue surrounding the tumor was a strong determinant of recurrence, rather than the amount of HBV-DNA in the resected tumor itself. [38]

Transplantation

Many patients are not candidates for partial hepatectomy due to extent of underlying liver disease. Some of these patients are good candidates for liver transplantation since it has the potential for eliminating the cancer as well as curing the underlying liver disease.

Orthotopic liver transplantation can be considered for patients who meet the Milan criteria—one tumor less than 5 cm or up to 3 tumors all less than 3 cm. These highly selected patients have excellent survival rates, similar to those of patients who undergo liver transplantation for end-stage liver disease without hepatocellular carcinoma. [39, 40, 41, 42]

Although availability of donor organs is still limited, the Organ Procurement and Transplantation Network (OPTN) and the United Network for Organ Sharing (UNOS) have recognized the urgency of proceeding to transplantation in patients with limited stage hepatocellular carcinoma. Over the past 5 years, revision of the UNOS policy has established medical criteria by which a patient with early/small hepatocellular carcinoma can be assigned additional priority for liver allocation so as to increase the likelihood of a favorable transplant outcome. This has resulted in shorter wait times to transplantation and better overall outcomes. Bridging therapy with local therapies, such as chemoembolization or radiofrequency ablation (RFA), is sometimes considered for patients on the transplant waiting list.

Locally ablative therapy

Intratumoral injections of ethanol or acetic acid, heat (via radiofrequency, microwave, or laser ablation), or cold (cryoablation with liquid nitrogen) may be used to locally control tumors smaller than 4-5 cm. These techniques are frequently performed percutaneously as outpatient procedures. In general, these procedures are reserved for patients who do not meet criteria for surgical resection yet are candidates for a liver-directed procedure based on the presence of limited liver-only disease. This has generally been supplanted by other local modalities.

Radiofrequency ablation (RFA) is the delivery of radiofrequency thermal energy to the hepatocellular carcinoma lesion causing necrosis of the tumor. During RFA, a high frequency alternating current is delivered from the tip of an electrode into the surrounding tissue. The ions within the tissue attempt to follow the direction of the alternating current, resulting in friction and eventual heating of the tissue. As tissue temperature elevates above 60°C, tumor cells begin to die, resulting in an area of tumor necrosis.

The needle electrode is advanced into the hepatocellular carcinoma lesion usually via a percutaneous route with the guidance of ultrasonography. The procedure can also be performed surgically via laparoscopy or laparotomy.

RFA is usually used for treatment of tumors less than 4 cm in size. For small tumors, studies show good initial local tumor control with an average local recurrence rate of 5-6% within the first 20 months. The treatment of larger tumors results in much higher rates of local recurrence. Unfortunately, a significant proportion of patients eventually develop clinically detectable hepatic or extrahepatic disease from their preexisting micrometastatic lesions. RFA is usually well-tolerated, but complications including fever, pain, bleeding, pleural effusion, hematoma, and intermittent transaminitis among others have been reported. [43, 44]

Multimodel management by combining RFA with different techniques, including percutaneous ethanol injection, transarterial chemo-embolization, targeted molecular therapy, nanoparticle-mediated therapy, and immunotherapy have been investigated. The combination strategy  has improved outcomes in comparison to RFA alone. [45]

Cryoablation, using a liquid nitrogen–filled probe, can achieve similar results to RFA and is also used for tumors smaller than approximately 5 cm. The degree of collateral damage to uninvolved liver tissue or other organs may be more easily appreciated, so this technique is more useful for lesions near the surface of the liver, the gallbladder, or large blood vessels.

Percutaneous ethanol or acetic acid ablation is reserved for patients with small tumors; however, in many areas, the ease and efficacy of RFA has now replaced these older techniques. Radiation therapy is limited by dose-related radiation hepatitis, which precludes the administration of external beam radiation in doses effective for tumor eradication. Doses of 2500 cGy may be used for palliative measures.

CyberKnife system is a new technology that uses a combination of robotics and image guidance to deliver concentrated and highly focused beams of radiation to the tumor while minimizing radiation exposure to the surrounding healthy liver tissue. CyberKnife stereotactic radiosurgery is a promising new treatment tool for localized hepatocellular carcinoma lesions. Currently, its availability is limited to a few medical centers, and long-term efficacy for hepatocellular carcinoma lesions is yet to be determined.

Chemoembolization is the delivery of high concentrations of chemotherapeutic agents directly to the hepatocellular carcinoma tumor via the hepatic artery, which provides the tumor with most of its blood supply. The remainder of the liver may be spared because it can rely on the portal vein for its blood supply. [46]

Some centers are adding RFA to chemoembolization in the hope that the combined treatments would improve outcome by adding thermal ablation to arterial ischemia. A randomized controlled trial by Morimoto et al demonstrated an improved local control without a definite improvement in overall survival. [47] However, the study did not include a chemoembolization-alone arm, so it remains unclear whether both procedures together are necessary for local control.

Embolizing agents such as cellulose, microspheres, [48] lipoidal, and gelatin foam particles are used to deliver intra-arterial chemotherapy (mitomycin, doxorubicin, cisplatin) to the tumor via the hepatic artery. A relatively new technology using drug-eluting beads may offer similar efficacy with less toxicity.

Morbidity from this procedure is greatly dependent on the extent of cirrhosis. In general, patients with portal vein thrombosis, significant encephalopathy, or biliary obstruction are not candidates for chemoembolization. [49]

Response rates of 60-80% are seen. In addition, 2 clinical trials from Spain and Hong Kong showed a modest survival benefit with the use of doxorubicin (Adriamycin) or cisplatin with embolization as compared to supportive care only in patients with unresectable tumors. [50, 51, 52]

Radioembolization (or selective internal radiotherapy) uses 32-μm glass microspheres to carry yttrium-90 intra-arterially into the capillary beds of the tumor. This technique can cause excellent necrosis and tumor responses. Unlike chemoembolization, which uses larger particles, arterial embolization and ischemia are not necessary for the therapeutic effect, meaning this procedure may be performed for patients with portal vein thrombosis. [53, 54]

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Consultations

Consultation with the following specialists is recommended:

  • Hepatobiliary surgeon

  • Oncologist

  • Interventional radiologist

  • Interventional gastroenterologist

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Diet

Patients should avoid alcohol and other hepatic toxins because prognosis is related to worsening cirrhosis and tumor stage. The consumption of fish and fish-associated fatty acids is associated in a dose-dependent fashion with a lower risk of the development of HCC, regardless of hepatitis status. [55]

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Prevention

Although it is currently one of the most common worldwide causes of cancer death, a major impact on the incidence of hepatocellular carcinoma should be achieved through current vaccination strategies for hepatitis B virus (HBV) infection. Assuming that present HBV vaccination trends continue, between 2020 and 2050, the number of new HBV infections is estimated to drop by 70%. [56]  

Other primary prevention approaches include decreasing harmful use of alcohol, implementation of safe injection and transfusion practices, improved diagnoses of chronic infections, and increased treatment for HBV and HCV including increased accessibility and affordability of the highly effective HCV antiviral medication. [56, 57]

The Centers for Disease Control and Prevention (CDC) recommends one-time HCV testing for everyone born from 1945 to 1965 because this cohort  accounts for about three-fourths of HCV-infected individuals in the US. Preventive measures for HBV and HCV infection recommended by the CDC include screening of donated blood, organs, and tissues; adherence to infection control practices during medical and dental procedures; needle-exchange programs for injection drug users; and practicing safe sex.  [58]

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Long-Term Monitoring

Monitor the progression of disease or adequacy of treatment with imaging studies every 2-3 months and LFTs and AFP monthly or as appropriate for the stage of disease and patient's performance status. These interventions, however, have little or no impact on prognosis for survival and therefore should be performed in accordance with the patient's functional status.

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