The treatment of liver cancer remains a worldwide challenge, and the American Association for the Study of Liver Diseases (AASLD) released new guidelines for the treatment of hepatocellular carcinoma in 2018.
So what new insights does the guideline offer on the diagnosis and treatment of hepatocellular carcinoma? How do they compare to our Guidelines for the Management of Primary Liver Cancer (2017 Edition)?
Surveillance in people at risk for hepatocellular carcinoma
The study found that patients who were monitored for hepatocellular carcinoma were more likely to have their liver cancer detected early, had better 3-year survival rates, and ultimately had better outcomes than those who were not monitored at follow-up.
Patients with cirrhosis are at high risk for hepatocellular carcinoma, and the AASLD guidelines recommend that patients with cirrhosis be monitored for hepatocellular carcinoma. However, in patients with cirrhosis with Child-Pugh grade C liver function, monitoring is not necessary because of their low expected survival, such as in patients not awaiting transplantation.
The current AASLD guidelines recommend that patients with cirrhosis be monitored with ultrasound every 6 months and that the diagnostic process for hepatocellular carcinoma be initiated if the nodule is no less than 1 cm in diameter on ultrasound or if the AFP is greater than 20 ng/ml on ultrasound combined with methemoglobin.
Diagnosis of hepatocellular carcinoma
In terms of diagnosis, the AASLD guidelines give separate recommendations for patients with and without cirrhosis.
Patients with cirrhosis
Hepatocellular carcinoma differs from other malignancies in that it can be diagnosed based on imaging alone, without the need for biopsy.
- Enhanced CT or enhanced MRI is recommended for imaging, and its diagnosis is based on different vascular temporal features, emphasizing marked enhancement in the late arterial phase and fading in the portal or delayed phase.
- Hepatic biopsy should be considered if hepatocellular carcinoma or other malignant tumors are considered highly probable but lacking typical imaging manifestations.
Patients with cirrhosis presenting with liver nodules of a nature to be determined have a variety of testing options, including tissue biopsy, follow-up imaging, and other contrast agents.
- Tissue biopsy has important advantages, but it also carries risks of false negatives, bleeding, and tumor implantation. Therefore, the AASLD guidelines do not recommend routine tissue biopsy for liver nodules of undetermined nature.
- For patients with liver nodules of indeterminate nature, imaging follow-up is recommended for most nodules less than 2 cm in diameter, and tissue biopsy is recommended only for patients with nodules 1 to 2 cm in diameter with arterial enhancement.
Patients without cirrhosis
Hepatocellular carcinoma without a background of cirrhosis is less likely to show the typical imaging features of hepatocellular carcinoma and still requires a liver biopsy.
If the diagnosis of hepatocellular carcinoma is not confirmed by conventional pathologic histology, the histologic markers phosphatidylinositol glycan 3, heat shock protein 70, and glutamine synthetase can be evaluated to differentiate severe atypical hyperplasia from hepatocellular carcinoma.
Staging of hepatocellular carcinoma
Hepatocellular carcinoma differs from most solid tumors in the presence of both tumors and cirrhosis, two life-threatening diseases.
Curative treatment of hepatocellular carcinoma
The choice of the appropriate treatment option depends not only on the stage of the tumor but also on the reserve function of the liver and the degree of portal hypertension. In addition to surgical resection, treatment options such as radiofrequency ablation (RFA), microwave and cryoablation are also available.
Surgical treatment
Hepatectomy has a greater overall survival benefit than radiofrequency ablation, and 2-year event-free survival and local progression survival rates are both more favorable to surgical resection. Based on the current evidence, the AASLD guidelines consider surgical resection to be superior to radiofrequency ablation.
Hepatectomy is indicated for:
Limited hepatocellular carcinoma in the absence of cirrhosis;
No imaging evidence of extrahepatic disease or large vessel invasion;
Resectable hepatocellular carcinoma with cirrhosis, normal liver function, and no clinically significant portal hypertension.
Local therapy
Local therapy can be curative when applied to early-stage tumors. Thermal ablation is superior to anhydrous ethanol injection in ablative therapy, and is most effective for hepatocellular carcinoma with a maximum tumor diameter of less than 3 cm. Microwave ablation may have a higher tumor response rate than radiofrequency ablation.
The risk of recurrence of hepatocellular carcinoma after ablation therapy is high, and enhanced CT or MRI is recommended every 3 to 6 months to monitor for recurrence.
Stereotactic body radiation therapy is an alternative to thermal ablation but still needs to be validated in randomized controlled studies.
Stereotactic body radiation therapy (SBRT) in liver cancer treatment
Liver transplantation
Liver transplantation is indicated for early-stage hepatocellular carcinoma with clinically significant portal hypertension and/or decompensated cirrhosis, and is also limited by the extreme scarcity of liver donors.
Monitoring of recurrent hepatocellular carcinoma after liver transplantation should include thoracic and abdominal CT to more fully assess soft tissue. However, the optimal timing, interval, and effectiveness of surveillance remain uncertain.
For patients awaiting liver transplantation, the availability of treatment during the waiting period is closely related to tumor stage:
- Patients with stage T1 hepatocellular carcinoma combined with cirrhosis: observation only while awaiting liver transplantation is acceptable, but patients with methemoglobin no less than 500 ng/ml or rapid tumor growth will require local therapy.
- Patients with stage T2 hepatocellular carcinoma combined with cirrhosis: may receive transitional therapy to slow disease progression and avoid a wait for a liver transplant due to progression. Treatment options may include various local treatment modalities such as hepatic artery chemoembolization, yttrium 90 (Y-90) radiation therapy, ablative therapy, or a combination of different types of local therapies.
- Patients with stage T3 hepatocellular carcinoma beyond the Milan criteria combined with cirrhosis: downstaging therapy may allow patients with successful downstaging to obtain a liver transplant.
Adjuvant therapy for hepatocellular carcinoma
The risk of recurrence after surgical resection or ablation is related to the characteristics of the tumor, such as size, degree of differentiation, and the presence or absence of lymphovascular invasion. So, should patients with cirrhosis combined with hepatocellular carcinoma who have been successfully resected or ablated receive adjuvant therapy?
Studies have shown that adjuvant therapy does not improve survival in patients with advanced hepatocellular carcinoma. Current guidelines do not recommend adjuvant therapy routinely.
Systemic treatment of hepatocellular carcinoma
So far, the prognosis for advanced hepatocellular carcinoma remains poor, regardless of the treatment strategy used. Its prognosis and choice of treatment modality usually depends on vascular infiltration, tumor metastasis, the degree of underlying cirrhosis, and the general condition of the patient.
For patients with metastatic tumors, especially those with established extrahepatic metastases, concomitant large vessel infiltration usually leads to rapid tumor progression and disease-related symptoms, and there is no evidence to support local therapy as the first choice for this group of patients, and studies related to whether local therapy combined with sorafenib is superior to sorafenib alone are ongoing in phase III clinical trials.
Sorafenib is the standard of care for patients with advanced hepatocellular carcinoma, and patients with stage B and C hepatocellular carcinoma in BCLC staging who experience tumor progression after TACE should be considered for sorafenib or lenvatinib as a first-line treatment option.
If imaging suggests tumor progression after sorafenib treatment in patients with hepatocellular carcinoma, regorafenib and nabumab should be considered as second-line treatment options.
When tumor progression occurs in patients with hepatocellular carcinoma treated with lenvatinib, there are no data clearly supporting a switch to regorafenib or nabumab, but sequential applications of tyrosine kinase inhibitors with similar mechanisms of action may be considered.
Palliative care for hepatocellular carcinoma
For patients with intermediate-stage hepatocellular carcinoma with BCLC staged at stage B who are not candidates for curative treatment, local therapy should be considered, and TACE and hepatic artery embolization are widely used.
In recent years, external radiation therapy and transcatheter arterial radiotherapy embolization (TARE) have also been used in the treatment of hepatocellular carcinoma.
Systemic therapy should be considered for patients with BCLC stage B hepatocellular carcinoma who are not candidates for TACE/TARE or who experience tumor progression after treatment with TACE/TARE.
For patients with stage C BCLC, sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma. There is no evidence that TARE is superior to sorafenib for treating patients with advanced hepatocellular carcinoma.
Patients with end-stage hepatocellular carcinoma have a poor prognosis, so patients with end-stage disease are given only symptomatic management without antitumor therapy, and treatment to relieve symptoms has a positive impact on functional status, mood status, and quality of life. These patients should receive palliative supportive care.
Summary
The AASLD guidelines are more focused on exploring treatment options based on different clinical stages than the Chinese guidelines for hepatocellular carcinoma, whereas the Chinese guidelines are more focused on providing a standardized guidance and discussing the indications and contraindications for different treatments. The two have their respective strengths and should complement each other.
Both the AASLD guidelines and the Chinese guidelines for the treatment of liver cancer emphasize that surgery is the preferred treatment for liver cancer, including hepatectomy and liver transplantation. In addition, local ablation, transcatheter arterial chemoembolization, radiation therapy, and systemic therapy may also benefit patients with hepatocellular carcinoma.
The AASLD guidelines indicate that adjuvant therapy is not required after curative therapy compared with national guidelines, which may reduce the overtreatment of cancer patients after curative therapy and reduce the resulting adverse effects and financial burden.