Introduction

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, review the HCC AASLD practice guidance, ASCO guidelines on Systemic Therapy for Advanced Hepatocellular Carcinoma and the National Oncology Clinical Pathways SharePoint (only available to internal VA Users). Of the available treatments for HCC, only surgical resection, liver transplantation, and ablative therapies are potentially curative. Other treatments are considered palliative, although they may prolong survival or be used in combination with resection or liver transplantation.

Multidisciplinary Liver Tumor Board (MLTB)

Treatment for liver cancer is a complicated decision-making process and involves an assessment of HCC stage and location, liver function, performance status and comorbidities as well as the patient’s priorities and wishes. It is important to note that in patients with poor underlying liver function and performance status, the best treatment might be supportive care regardless of tumor stage.

Therefore, multidisciplinary conversation in a multidisciplinary liver tumor board (MLTB) with key stakeholders, including hepatology, radiology, interventional radiology, surgery and oncology is key in determining the most suitable treatment option for a patient with HCC.

Surgical Resection

Surgical resection may be curative if HCC is detected at an early stage. Patients who do not have cirrhosis or who have well compensated cirrhosis with a single tumor and sufficient liver reserve are the best candidates for resection. In these patients who undergo resection, the 5-year survival rate is >70%. However, the rate of recurrence of HCC after resection is very high, approximately 50-70% at 5 years. Although there is no limitation in size, the risk of recurrence increases with tumor size.

However, less than 20% of HCC patients are good candidates for surgical resection. That is, only 1 of 5 patients has acceptable HCC tumor burden and liver function to perform a safe, curative resection that leaves no residual tumor and sufficient hepatic reserve. In the presence of clinically significant portal hypertension (CPSH), defined as hepatic venous pressure gradient (HVPG) >10 mmHg, there is a high rate of postoperative complications as well as lower long-term survival.

Contraindications to resection include:

• Decompensated liver disease
• Anatomically unresectable disease
• Extrahepatic and vascular spread
• Comorbid conditions precluding major abdominal surgery

Liver Transplantation

Liver transplantation affords the best long-term survival to patients with localized HCC. It is an option for patients who are good transplant candidates and have hepatocellular carcinoma that falls within the number and size limits acceptable for transplantation. Limits on tumor size traditionally have been a solitary, encapsulated tumor 2-5 cm in diameter or no more than 3 lesions, none >3 cm in diameter. In one study, patients who met these selection criteria and underwent liver transplantation had 4-year overall survival of 85% and recurrence-free survival (RFS) rates of 92%. Transplantation of patients with hepatocellular cancer beyond these dimensions whose tumors are treated successfully (i.e., “downstaged”) with locoregional therapy (LRT) has also been successful. All patients generally undergo LRT for HCC prior to transplantation to prevent tumor extension while waiting for liver transplantation. Given organ limitation and current rules for HCC MELD exception points, this option should be considered when resection is not an option.

The United Network Organ Sharing (UNOS) liver transplant listing criteria include: unresectable HCC, AFP <1000 ng/mL, and radiologic evidence of a single lesion between 2 and 5 cm in diameter or 2-3 lesions between 1-3 cm with no evidence of macrovascular or extrahepatic involvement. For more information visit the Policies & Bylaws section at https://optn.transplant.hrsa.gov/

Ablative Therapies

Patients who are not candidates for or decline surgical resection should be considered for ablative procedures. These procedures, such as radiofrequency ablation (RFA) or microwave ablation (MWA) cause thermal tumor necrosis. These are performed by either percutaneous or laparoscopic approaches and have largely replaced percutaneous ethanol injection (PEI) due to better efficacy and lower recurrence rate. Comparative studies of RFA and surgical resection have not provided conclusive evidence and there are very few studies comparing MWA with surgical resection.

However, ablation can be considered as an alternative to surgical resection in patients with tumors <3 cm in size and in an appropriate location, namely away from major organs, bile ducts or vessels.

Transarterial Therapies

Chemoembolization

Transarterial 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, is recommended in patients with intermediate stage HCC (Barcelona Clinic Liver Cancer - BCLC - stage B) who cannot undergo resection or in patients immediately pretransplant as a bridge before replacement of the organ. TACE causes only mild 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 can be mixed with iodized oil (Lipiodol) to form a suspension or loaded into drug eluting beads, 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 or drug eluting beads serves as a vehicle to carry the cytotoxic agent to the tumor; the vessel feeding the tumor is occluded to provide an additional ischemic effect. Contraindications to TACE include advanced (Child-Pugh Class C) cirrhosis, portal vein thrombosis, and bilirubin elevation.

The most important prognostic factor in evaluating the efficacy of TACE for HCC is the size of the main tumor. TACE should not be recommended as the sole therapy to patients with operable HCC who are surgical or transplant candidates.

Y-90 Transarterial Radioembolization (TARE) (also known as Selective Internal Radiation Therapy - SIRT)

Y-90 transarterial radioembolization (TARE), also known as selective internal radiation therapy (SIRT) is another internal delivery of a toxic substance to the tumor’s capillary bed, this time radiation. A catheter inserted through the femoral or radial artery delivers microspheres that are embedded with Yttrium-90, a radioactive isotope. There is new evidence that this method can be considered curative for small <3 cm HCC. Although this method also can cause particle-induced vascular occlusion, the effect is more microvascular and related to radiation rather than ischemia, therefore this method can be considered for treatment of locally advanced HCC with lobar or segmental portal vein thrombosis.

Radiation segmentectomy is the administration of ablative doses of Y90 to a single hepatic segment or two adjacent hepatic segments. Radiation segmentectomy can be performed for tumors that are challenging for thermal ablation and may provide durable local tumor control.

External beam radiation therapy (EBRT)

In patients who are not candidates for thermal ablation, EBRT, including proton beam therapy (PBT) and stereotactic body radiation therapy (SBRT) delivered in several sessions, is another method of achieving durable control. In contrast to ablation, EBRT can be used for central tumors and for tumors adjacent to vascular structures. There is no size limit if there is sufficient uninvolved liver, although most data are for HCC <8 cm. Most data on the efficacy of SBRT are derived from studies of patients with Child-Pugh A cirrhosis. However, dose modification can be considered in those with Child-Pugh B cirrhosis.

There is recent evidence that SBRT may also be considered as a curative option in patients with smaller size tumors who are not candidates for ablation.

Systemic Therapy

Systemic therapy is currently reserved for patients with advanced, unresectable HCC who are not suitable for locoregional therapy (LRT), including patients with advanced-stage HCC (BCLC Stage C), some patients with intermediate-stage HCC (BCLC Stage B), and patients with disease progression despite LRT. It is generally reserved for patients with preserved liver function (Child-Pugh A or well-selected Child-Pugh B cirrhosis) and good performance status (ECOG PS 0-1). In clinical practice, systemic therapy can be administered by hepatologists or oncologists depending on available expertise locally. However, the use of systemic therapy is best performed in a multidisciplinary manner, since both severity of liver disease and HCC tumor burden are considerations.

Patients with advanced HCC with CTP-A cirrhosis should be offered atezolizumab plus bevacizumab OR durvalumab plus tremelimumab as preferred first-line treatments. Patients should undergo assessment of clinically significant portal hypertension by appropriate providers (including possible consideration of EGD) prior to atezolizumab plus bevacizumab.

Further details on systemic therapy can be found on the National Oncology Clinical Pathways SharePoint (only available to internal VA Users).

Advance Care Planning

Advance care planning should be offered to all patients receiving palliative-intent therapy or best supportive care for HCC, regardless of transplant eligibility. Advance care planning may be considered for patients with multifocal HCC or those in evaluation for liver transplantation. Both the diagnosis of liver cancer and the process of liver transplant evaluation and listing involve considerable uncertainty and may be accompanied by significant physical, psychological, and spiritual challenges that can be explored and addressed through advance care planning.