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Treatment - Liver Cancer
It is likely that <50% of patients with HCC undergo definitive treatment because of age, liver function, general medical condition, and patient refusal. The treatment modalities outlined here are based on a literature review. They do not represent official guidelines for the treatment of hepatocellular carcinoma in the VA health care system. For more information on treatment modalities, please visit www.cancer.gov/cancertopics/types/liver. Of the available treatments for HCC, only surgical resection and transplantation are potentially curative treatments. Other treatments are palliative, although they may be used in combination with resection or liver transplantation.
Learn about Sorafenib as a treatment for advanced hepatocellular carcinoma.
Surgical resection may be curative if HCC is detected at an early stage. Patients who are <65 years of age, have Child-Pugh Class A cirrhosis, and have only 1 or 2 tumors are the best candidates for hepatic resection. However, the rate of recurrence of HCC after resection is very high, approaching 25% per year. Once a liver has formed HCC, it can be considered a premalignant organ, at risk for forming additional tumors. Although early detection undoubtedly increases the likelihood of a tumor being resected, and early outcomes with resection are superior to those in patients whose tumors are first detected clinically, the 5-year recurrence-free survival rate after surgical resection is only 20%. Moreover, less than 20% of HCC patients are good candidates for surgical resection. That is, only 1 of 5 patients has HCC small enough and liver function good enough to perform a safe, curative resection that leaves no residual tumor and sufficient hepatic reserve. An anatomical resection can be performed safely only in noncirrhotic patients or in cirrhotic patients with fully compensated liver function. In such patients who undergo resection, the 3-year survival rate is 80% and the 3-year recurrence-free survival rate is 40%. Resection will not limit the development of new primary cancers in the diseased liver. Tumor size plays an important role in the likelihood of recurrence after resection. Contraindications to resection include:
- decompensated liver disease
- anatomically unresectable disease
- extrahepatic and vascular spread
- comorbid conditions precluding major abdominal surgery
Liver transplantation likely affords the best long-term survival to patients with localized HCC. It is an option for patients who are good transplant candidates and have small hepatocellular carcinomas. Limits on tumor size traditionally have been a solitary, encapsulated tumor <5 cm in diameter or no more than 3 lesions, each <3 cm in diameter. In one study, patients who met these selection criteria and underwent liver transplantation had a survival rate of 75% at 4 years posttransplant. Transplantation of patients with hepatocellular cancer slightly beyond these dimensions also has been successful, although it remains controversial. Many patients also undergo therapy for HCC prior to transplantation. In a recent nonrandomized study, such pretransplant therapy has even been found to confer some benefit to posttransplant clinical course.
Transcatheter Arterial Chemoembolization
Transcatheter arterial chemoembolization (TACE) is a combination of targeted chemotherapy and arterial embolization that has both selective ischemia and chemotherapeutic effects on HCC. This technique, or similar techniques involving ischemia without the use of chemotherapy, tend to be used in patients with several small tumors who cannot undergo resection or in patients immediately pretransplant to achieve a "tumor kill" before replacement of the organ. TACE causes minimal damage to normal liver parenchyma because of the dual blood supply to the liver. The hepatic artery supplies 80-100% of blood flow to liver tumors. In contrast, this artery supplies only 20-30% of blood flow to normal liver tissue. The portal vein supplies the liver with the remaining 70-80% of its blood flow.
For the TACE procedure, a cytotoxic agent such as doxorubicin or cisplatin can be mixed with iodized oil (Lipiodol) to form a suspension, which is then injected into the artery supplying the tumor. Access is obtained via the femoral artery, and angiography is utilized throughout the procedure. The iodized oil serves as a vehicle to carry the cytotoxic agent to the tumor and is also the embolizing agent that blocks the tumor's vessels. Major complications from TACE include portal vein thrombosis, hepatic abscess, hepatic artery dissection or thrombosis, and liver failure. One retrospective study found a morbidity rate of 5.1% and a treatment-related mortality rate of 4.1%. Contraindications for the TACE procedure include advanced (Child-Pugh Class C) cirrhosis, portal vein thrombosis, hepatic encephalopathy, and biliary obstruction.
The most important prognostic factor in evaluating the efficacy of TACE for HCC is the size of the main tumor. One study found a 100% survival at 3 years after TACE for tumors <2 cm in diameter, whereas, for tumors >5 cm in diameter, the 3-year survival rate was <1%. Other studies of TACE showed significant prolongation of survival in patients with tumor volumes <200 mL and an iodized oil retention ≥75%. In another study, a comparison was made between 69 patients treated with TACE vs 64 untreated patients. The 1-year and 3-year survival rates for patients treated with TACE were 64% and 28%, respectively. In comparison, the 1-year and 3-year survival rates for untreated patients were 16% and 3%, respectively.
TACE should not be recommended as the sole therapy to patients with operable HCC who are surgical or transplant candidates.
Percutaneous Ethanol Injection
Percutaneous injection of high-concentration ethanol directly into HCCs is another localized form of therapy. It is most effective for smaller HCCs, and is performed under direct tumor visualization, generally with ultrasound, either percutaneously or intraoperatively. The therapeutic response to percutaneous ethanol injection (PEI) can be evaluated by CT examination before the procedure, 1 month after the procedure, and then every 4-6 months. Necrosis is deemed to be complete when the CT shows no areas of enhancement remaining within the tumor. Contraindications to PEI include advanced cirrhosis, severe bleeding diathesis, portal vein thrombosis, and diffuse HCC. Major complications (intraperitoneal hemorrhage, right pleural effusion, cholangitis, liver abscess, hemobilia, arterioportal shunt, shock) are rare, ranging from 1.3% to 2.4%, and usually are treated conservatively. Compared with surgery, PEI causes minimal loss of normal liver tissue. Also, PEI can be repeated easily when new lesions appear, as they do in the majority of patients. The overall 5-year survival in 628 patients with lesions <5 cm in diameter and compensated cirrhosis was 48%, comparable to a 49% 5-year survival rate in a similar population of 1,272 patients who underwent surgical resection. To achieve more complete necrosis of large (>3 cm in diameter) HCC tumors, PEI has been combined with TACE. The 1-year and 3-year survival rates of PEI in combination with TACE were 100% and 85%, respectively. The partial response rate significantly increased from 10% with TACE alone to 45% with the combination of TACE and PEI. Also, the combination of TACE and PEI was significantly better than TACE alone in terms of the rate of primary tumor recurrence during follow-up.
Radiofrequency ablation (RFA) is another localized form of HCC therapy, usually performed under sonographic guidance. With RFA, an alternating electric current causes thermal injury around a needle electrode that is inserted into the tumor. The goal of each procedure is to ablate the tumor and a small margin of normal tissue around the tumor. One study of RFA was performed in 39 patients with 1 or more HCC tumor nodules <3 cm in diameter that were treated with intent to cure. Approximately 50% of the patients had tumor recurrence during follow-up. The 1-year and 3-year survival rates for patients treated with RFA were 95% and 67%, respectively. No complications were observed in any of the patients. The effectiveness of RFA also has been compared with that of PEI. In one study of 86 patients with HCCs <3 cm in diameter, the patients were treated with either RFA (42 patients) or PEI (44 patients). Complete tumor necrosis was achieved in 90% of tumors with RFA and in 80% of tumors with PEI. In contrast with other RFA series, 1 major complication and 4 minor complications were reported with RFA. In the patients treated with PEI, no complications were reported.
Hepatic Artery Chemotherapy
Chemotherapeutic agents can be delivered via hepatic arterial infusion through an implantable pump directly to HCCs. This increases local drug concentrations while minimizing adverse systemic effects. This approach is not widely used at present, but has been shown to be of some efficacy. The chemotherapeutics most commonly used alone or in combination with this technique include 5-fluorouracil (5-FU) and 5-fluorouracil deoxyribonucleoside (FUDR). The complications of hepatic artery chemotherapy include impaired liver function, biliary sclerosis, liver abscess, and dislodged catheter tip. In one study, 14 patients were treated with intrahepatic etoposide, 5-FU, and cisplatin (EFP) and another 14 patients were treated with etoposide, Adriamycin, and cisplatin (EAP). The partial response rate was 46% in the EFP group and 53% in the EAP group. In another study, 29 patients with nonresectable HCC confined to the liver were treated with intrahepatic FUDR, leucovorin, Adriamycin, and cisplatin (FLAP). The partial response rate was 41%, and the median time to disease progression was 13 months, with median survival of 15 months. Of note, patients in the latter study with hepatitis B or C experienced increased myelotoxicity from chemotherapy compared with patients with other forms of liver disease.
No systemic chemotherapeutic strategy has been shown to lead to improved outcomes in HCC compared with localized therapies. The first chemotherapeutic agent to be used in the treatment of HCC was 5-FU. As a single agent, the overall response rate of 5-FU is around 10% and the median survival time is 3-5 months. Adriamycin seems to be the most active single agent, with a response rate of 25%, as documented in one of the few randomized trials comparing therapy with supportive care. Finally, a combination of cisplatin, interferon-alfa-2b, Adriamycin, and 5-FU showed a partial response in 26% of the 50 patients studied. Disease previously considered unresectable became resectable in 9 patients (18%), and no evidence of tumor was seen with short-term follow-up in 4 patients (9%). Patients with advanced cirrhosis cannot tolerate cisplatin because associated portal hypertension and hypoalbuminemia precludes the necessary intravascular volume expansion necessary to prevent renal toxicity.