Key Points
Treatment
Design and created by Guideline Central in participation with the American Gastroenterological Association.
Systemic Therapy for Hepatocellular Carcinoma
American Gastroenterological Association
Publication Date: June 14, 2022
Key Points
- Hepatocellular carcinoma (HCC), the most common primary liver cancer, remains a deadly cancer, with an incidence that has tripled in the United States since 1980, accompanied by a substantial mortality rate.
- HCC is unique because prognosis and treatment are intimately related to both the severity of the underlying chronic liver disease and tumor biology.
- In recent years, a multitude of new systemic options have arisen, including molecularly targeted therapies and immunotherapies, which have shown promise in HCC.
Treatment
1. First-line Treatment for HCC in Patients With Preserved Liver Function
In patients with HCC with preserved liver function not eligible for locoregional therapy (LRT) or resection or with metastatic disease, the AGA suggests atezolizumab + bevacizumab over sorafenib. ( Low, Conditional (weak) )
Comment: Gastrointestinal bleeding is a known adverse effect of bevacizumab, and individuals should undergo endoscopic evaluation and treatment for esophageal varices before treatment.
In patients with HCC with preserved liver function not eligible for LRT or resection or with metastatic disease who are not candidates for treatment with atezolizumab + bevacizumab, the AGA suggests either lenvatinib or sorafenib over no systemic therapy. ( Low, Conditional (weak) )
Comment: Patients who place a higher value on delayed radiologic disease progression and lower value on the increase in adverse events (both serious and leading to discontinuation of the drug) may reasonably choose lenvatinib over sorafenib.
Patients who place a higher value on blood pressure control and a lower value on the adverse skin reactions would reasonably select sorafenib over lenvatinib. It should be noted that lenvatinib has not been studied in patients with invasion of the main portal vein and thus may not be appropriate for this population. Patients who place a higher value on the adverse events associated with sorafenib or lenvatinib and lower value on the reduction in mortality (2.8 months for sorafenib, unknown for lenvatinib) may reasonably select no systemic therapy.
Patients who place a higher value on blood pressure control and a lower value on the adverse skin reactions would reasonably select sorafenib over lenvatinib. It should be noted that lenvatinib has not been studied in patients with invasion of the main portal vein and thus may not be appropriate for this population. Patients who place a higher value on the adverse events associated with sorafenib or lenvatinib and lower value on the reduction in mortality (2.8 months for sorafenib, unknown for lenvatinib) may reasonably select no systemic therapy.
2. Second-line Treatment for Individuals With Disease Progression or Intolerance to First-line Systemic Therapy
In patients with HCC with preserved liver function not eligible for LRT or resection or with metastatic disease, who had progression of disease on sorafenib, the AGA suggests cabozantinib over no systemic therapy. ( Very Low, Conditional (weak) )
Comment: Patients who place a higher value on adverse effects associated with cabozantinib and lower value on the reduction in mortality (2.2 mo) may reasonably decline cabozantinib.
In patients with HCC with preserved liver function not eligible for LRT or resection or with metastatic disease, and who had progression of disease on sorafenib, the AGA suggests using pembrolizumab over no systemic therapy. ( Low, Conditional (weak) )
Comment: Patients who place a higher value on adverse effects associated with pembrolizumab and lower value on the reduction in mortality (3.3 mo) may reasonably decline pembrolizumab. Patients with main portal vein invasion or inferior vena cava or cardiac involvement of HCC on the basis of imaging were not studied.
In patients with HCC with preserved liver function and α-fetoprotein (AFP) >400 ng/mL not eligible for LRT or resection or with metastatic disease who had progression of disease on sorafenib, the AGA suggests using ramucirumab over no systemic therapy. ( Low, Conditional (weak) )
Comment: Patients who place a higher value on adverse effects associated with ramucirumab and lower value on the reduction in mortality (1.2 mo) may reasonably decline ramucirumab. In patients with AFP <400 ng/mL, the AGA suggests against the use of ramucirumab.
In patients with HCC with preserved liver function not eligible for LRT or resection or with metastatic disease, who had progression of disease on sorafenib, the AGA suggests regorafenib over no systemic therapy. ( Low, Conditional (weak) )
Comment: Patients who place a higher value on adverse effects associated with regorafenib and lower value on the reduction in mortality (2.8 mo) may reasonably decline regorafenib. Regorafenib should not be used in patients who did not tolerate sorafenib due to toxicity.
3. Systemic Therapy for HCC in Patients With Poor Liver Function
In patients with HCC with poor liver function not eligible for LRT or resection or with metastatic disease, the AGA suggests against routine use of sorafenib. ( Very Low, Conditional (weak) )
Comment: Patients, particularly those who are not Child-Turcotte-Pugh (CTP) C, who place a higher value on the uncertain reduction in mortality and lower value on the harms, may reasonably select to use sorafenib.
4. Systemic Therapy for HCC as Adjuvant Therapy
In patients with HCC undergoing curative surgical resection, the AGA suggests against adjuvant sorafenib therapy. ( Low, Conditional (weak) )
In patients with HCC undergoing curative local ablation, the AGA suggests against adjuvant sorafenib therapy. ( Low, Conditional (weak) )
In patients with HCC undergoing transarterial chemoembolization (TACE) LRT, the AGA suggests against adjuvant sorafenib therapy. ( Very Low, Conditional (weak) )
In patients with HCC undergoing TACE LRT, the AGA suggests against adjuvant bevacizumab therapy. ( Very Low, Conditional (weak) )
Figure 1. Systemic Therapy for Hepatocellular Carcinoma Clinical Decision Support Tool
a Esophageal varices screening and treatment prior to starting treatment is recommended. Although no prior studies compared atezolizumab/bevacizumab versus lenvatinib, the results of the REFLECT trial suggest that sorafenib and lenvatinib are comparable.
b Patients who place a higher value on delayed radiologic disease progression and lower value on the increase in adverse events (both serious and leading to discontinuation of the drug) may reasonably choose lenvatinib. Patients who place a higher value on blood pressure control and a lower value on the adverse skin reactions would reasonably select sorafenib.
c Patients who place a higher value on adverse effects associated with any of the second-line therapies (regorafenib, cabozantinib, pembrolizumab, or ramucirumab) and lower value on the reduction in mortality (1.2 to 2.8 mo) may reasonably decline second-line therapies.
b Patients who place a higher value on delayed radiologic disease progression and lower value on the increase in adverse events (both serious and leading to discontinuation of the drug) may reasonably choose lenvatinib. Patients who place a higher value on blood pressure control and a lower value on the adverse skin reactions would reasonably select sorafenib.
c Patients who place a higher value on adverse effects associated with any of the second-line therapies (regorafenib, cabozantinib, pembrolizumab, or ramucirumab) and lower value on the reduction in mortality (1.2 to 2.8 mo) may reasonably decline second-line therapies.
Table 1. Implementation
| Drug and indication | Mechanism of action | Dose | Limitations of the evidence | Implementation considerations |
| First-line treatment for individuals with HCC | ||||
| Atezolizumab + bevacizumab First-line agent in individuals with preserved liver function. | Atezolizumab Checkpoint inhibitor, anti-programmed death ligand-1 (anti-PD-L1) antibody Bevacizumab Anti-angiogenic agent: anti-vascular endothelial growth factor (VEGF) antibody | Atezolizumab 1,200 mg IV every 3 weeks (wk) Bevacizumab 15 mg/ kg IV every 3 wk | There are no data on efficacy and adverse events in individuals with CTP B or C. There are no studies reporting efficacy of atezolizumab + bevacizumab as second-line therapy in individuals with disease progression on sorafenib or lenvatinib. | Gastrointestinal bleeding is a known adverse effect of bevacizumab, and individuals should undergo endoscopic evaluation and treatment for esophageal varices before treatment. Atezolizumab may not be appropriate in patients with prior autoimmune diseases, allogeneic stem cell or solid organ transplantation, idiopathic pulmonary fibrosis or pneumonitis, and co-infection with hepatitis B and hepatitis C viruses, since they were excluded from the IMBrave150 trial. |
| Sorafenib First-line agent in individuals who are precluded from receiving atezolizumab + bevacizumab and have preserved liver function. | Multi-tyrosine kinase inhibitor | 400 mg oral twice daily | There are limited data on efficacy and adverse events in individuals with CTP B or C. There are no studies reporting efficacy of sorafenib as second-line therapy in individuals with disease progression on lenvatinib or atezolizumab + bevacizumab. | |
| Lenvatinib First-line agent in individuals who are precluded from receiving atezolizumab + bevacizumab and have preserved liver function. | Multi-tyrosine kinase inhibitor | 12 mg oral once daily, if weight ≥60 kg 8 mg oral once daily, if weight <60 kg | There are limited data on efficacy and adverse events in individuals with CTP B or C. There are no studies reporting efficacy of lenvatinib as second-line therapy in individuals with disease progression on sorafenib or atezolizumab + bevacizumab. | Lenvatinib has not been studied in individuals with HCC and invasion of the main portal vein. |
| Second-line treatment for individuals with disease progression or intolerance to sorafenib (listed in alphabetical order) | ||||
| Cabozantinib | Multi-tyrosine kinase inhibitor | 60 mg orally once daily | There are limited data on efficacy and adverse events in individuals with CTP B or C. There are no studies reporting efficacy of cabozantinib as second-line therapy in individuals with disease progression on atezolizumab + bevacizumab or lenvatinib. There are no studies comparing the efficacy of different second-line treatments for HCC. | |
| Pembrolizumab | Checkpoint inhibitor, anti-PD-1 antibody | 200 mg IV every 3 wk | There are limited data on efficacy and adverse events in individuals with CTP B or C. Individuals who had received prior immunotherapy or systemic therapy other than sorafenib were excluded from the KEYNOTE-240 trial. There are no studies reporting efficacy of pembrolizumab as second-line therapy in individuals with disease progression on atezolizumab + bevacizumab or lenvatinib. There are no studies comparing the efficacy of different second-line treatments for HCC. | Pembrolizumab may not be appropriate for individuals with invasion of the main portal vein or vena cava, since it has not been studied in this patient population. Pembrolizumab may not be appropriate as a second-line treatment in patients who received treatment with a PD-targeted agent (e.g., atezolizumab or nivolumab) and had progressive disease or those who were intolerant to immunotherapy due to immune-related adverse events. |
| Ramucirumab | Vascular endothelial growth factor receptor 2 (VEGFR 2) antagonist | 8 mg/kg IV every 2 wk | There are limited data on efficacy and adverse events in individuals with CTP B or C. There are no studies reporting efficacy of ramucirumab as second-line therapy in individuals with disease progression on atezolizumab + bevacizumab or lenvatinib. There are no studies comparing the efficacy of different second-line treatments for HCC. | Improvement in overall survival was only seen in individuals with AFP >400 ng/mL. Individuals should undergo endoscopic evaluation and treatment for esophageal varices before treatment. |
| Regorafenib | Multi-tyrosine kinase inhibitor | 160 mg orally once daily on days 1–21 of each 28-day cycle | There are no studies reporting efficacy of regorafenib as second-line therapy in individuals with disease progression on atezolizumab + bevacizumab or lenvatinib. There are no studies comparing the efficacy of different second-line treatments for HCC. | Regorafinib may not be appropriate in individuals with prior intolerance to or toxicity with sorafenib since these patients were excluded from the RESORCE trial. However, preliminary data from the ongoing REFINE study showed that regorafenib may be tolerated in patients who did not tolerate sorafenib previously. |
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GRADE Strength of Recommendations and Implications
| Grade | Quality of Evidence |
|---|---|
| High | We are very confident that the true effect lies close to the estimate of the effect. |
| Moderate | We are moderately confident that the true effect lies close to that of the estimate of the effect. There is a possibility that it is substantially different. |
| Low | Our confidence that the true effect lies close to that of the estimate of the effect is low. The true effect may be substantially different from the estimate of the effect. |
| Very low | We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. |
| Evidence / Knowledge Gap | Available evidence insufficient to determine true effect. |
| Grade | Strength of Recommendation | ||
|---|---|---|---|
| Strong “AGA recommends...” | For the Patient | For the Clinician | For policy makers |
| Most individuals in this situation would want the recommended course and only a small proportion would not. | Most individuals should receive the intervention. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. | The recommendation can be adapted as policy or performance measure in most situations. | |
| Conditional (weak) “AGA suggests...” | The majority of individuals in this situation would want the suggested course, but many would not. | Different choices will be appropriate for individual patients consistent with his or her values and preferences. Use shared decision making. Decision aids may be useful in helping patients make decisions consistent with their individual risks, values, and preferences. | Policy making will require substantial debate and involvement of various stakeholders. Performance measures should assess whether decision making is appropriate. |
| No recommendation “AGA makes no recommendation...” | The confidence in the effect estimate is so low that any effect estimate is speculative at this time. | ||
Abbreviations
- AFP
- α-fetoprotein
- AGA
- American Gastroenterological Association
- CTP
- Child-Turcotte-Pugh score
- HCC
- hepatocellular carcinoma
- LRT
- locoregional therapy
- mo
- month(s)
- TACE
- transarterial chemoembolization
- VEGF
- vascular endothelial growth factor
- VEGFR 2
- vascular endothelial growth factor receptor 2
- wk
- week(s)
Source Citation
Grace L. Su, Osama Altayar, Robert O’Shea, Raj Shah, Bassam Estfan, Candice Wenzell, Shahnaz Sultan, Yngve Falck-Ytter, AGA Clinical Practice Guideline on Systemic Therapy for Hepatocellular Carcinoma, Gastroenterology, Volume 162, Issue 3, 2022, Pages 920-934, ISSN 0016-5085, https://doi.org/10.1053/j.gastro.2021.12.276.
Disclaimer
This resource is for informational purposes only, intended as a quick-reference tool based on the cited source guideline(s), and should not be used as a substitute for the independent professional judgment of healthcare providers. Practice guidelines are unable to account for every individual variation among patients or take the place of clinician judgment, and the ultimate decision concerning the propriety of any course of conduct must be made by healthcare providers after consideration of each individual patient situation. Guideline Central does not endorse any specific guideline(s) or guideline recommendations and has not independently verified the accuracy hereof. Any use of this resource or any other Guideline Central resources is strictly voluntary.
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