Nevena Damjanov, MD

Liver transplantation cures both HCC and the underlying cirrhosis; however, tumor progression while the patient is on the waiting list is an ongoing concern. Couillard and colleagues reported a retrospective study of 88 patients with HCC who underwent percutaneous microwave ablation for 141 tumors while on the liver transplant list. The median follow-up was 61 months. Seventy-one patients (80.7%) underwent liver transplantation after a median wait time of 8.5 months. No tumor seeding was identified. Seventeen patients (19.3%) were removed from the waitlist, four (4.5%) of whom because of tumor progression outside of the Milan criteria. A total of five of 71 (7.0%) patients had posttransplant recurrence of HCC and all died during this time. The 5-year overall survival (OS) following liver transplantation was 76.7% and the disease-specific survival after transplantation was 89.6%. The authors concluded that microwave ablation is a safe and effective treatment that bridges patients to successful transplantation.

Radiation segmentectomy is performed by the administration of radioactive yttrium (⁹⁰Y)-bound microspheres transarterially to the segment of liver containing an unresected tumor. Kim and colleagues described the results of a prospective trial that evaluated the efficacy of radiation segmentectomy with curative intent in patients with Child-Pugh score A–B7 and small (< 3 cm), unresectable HCC, where the tumors were in a location unsuitable for ablation. Of the 44 individuals assessed for eligibility, 29 patients were included in the study. A complete response was observed in 24 (83%) patients, and a partial response was observed in 5 (17%) patients. All patients had an initial objective tumor response, and 26 (90%) had a sustained complete response during 24 months of clinical follow-up. The treatment was well tolerated, with four (14%) patients having grade 3 leukopenia and two (7%) having grade 3 thrombocytopenia. The authors concluded that radiation segmentectomy should be investigated further as a potentially curative option for patients with HCC.

Portal vein thrombosis (PVT) has been considered a contraindication to transarterial chemoembolization (TACE) due to the concern for inadvertent liver ischemia if the hepatic artery becomes obstructed. Several studies have demonstrated that this risk is low. Stereotactic body radiation therapy (SBRT) is used to effectively target HCC (especially when there is a portal vein tumor) while minimizing collateral damage to the liver. Zhang and colleagues performed a meta-analysis of nine studies totaling 938 patients who had HCC with tumor PVT. Of those, 483 received either SBRT or TACE, and 455 were treated with both TACE and SBRT. There were 255 events reported in the monotherapy groups and 174 events in the combination groups. Following statistical analyses of all available data, the authors concluded that SBRT plus TACE yielded significantly higher 1-year OS (RR [relative risk] 1.52; 95% CI 1.33-1.74), 2-year OS (RR 2.00; 95% CI 1.48-2.70), and a lower progressive disease rate (RR 0.45; 95% CI 0.26-0.79) than monotherapy. The combination treatment was both safe and effective.

Liver transplantation cures both HCC and the underlying cirrhosis; however, tumor progression while the patient is on the waiting list is an ongoing concern. Couillard and colleagues reported a retrospective study of 88 patients with HCC who underwent percutaneous microwave ablation for 141 tumors while on the liver transplant list. The median follow-up was 61 months. Seventy-one patients (80.7%) underwent liver transplantation after a median wait time of 8.5 months. No tumor seeding was identified. Seventeen patients (19.3%) were removed from the waitlist, four (4.5%) of whom because of tumor progression outside of the Milan criteria. A total of five of 71 (7.0%) patients had posttransplant recurrence of HCC and all died during this time. The 5-year overall survival (OS) following liver transplantation was 76.7% and the disease-specific survival after transplantation was 89.6%. The authors concluded that microwave ablation is a safe and effective treatment that bridges patients to successful transplantation.

Radiation segmentectomy is performed by the administration of radioactive yttrium (⁹⁰Y)-bound microspheres transarterially to the segment of liver containing an unresected tumor. Kim and colleagues described the results of a prospective trial that evaluated the efficacy of radiation segmentectomy with curative intent in patients with Child-Pugh score A–B7 and small (< 3 cm), unresectable HCC, where the tumors were in a location unsuitable for ablation. Of the 44 individuals assessed for eligibility, 29 patients were included in the study. A complete response was observed in 24 (83%) patients, and a partial response was observed in 5 (17%) patients. All patients had an initial objective tumor response, and 26 (90%) had a sustained complete response during 24 months of clinical follow-up. The treatment was well tolerated, with four (14%) patients having grade 3 leukopenia and two (7%) having grade 3 thrombocytopenia. The authors concluded that radiation segmentectomy should be investigated further as a potentially curative option for patients with HCC.

Portal vein thrombosis (PVT) has been considered a contraindication to transarterial chemoembolization (TACE) due to the concern for inadvertent liver ischemia if the hepatic artery becomes obstructed. Several studies have demonstrated that this risk is low. Stereotactic body radiation therapy (SBRT) is used to effectively target HCC (especially when there is a portal vein tumor) while minimizing collateral damage to the liver. Zhang and colleagues performed a meta-analysis of nine studies totaling 938 patients who had HCC with tumor PVT. Of those, 483 received either SBRT or TACE, and 455 were treated with both TACE and SBRT. There were 255 events reported in the monotherapy groups and 174 events in the combination groups. Following statistical analyses of all available data, the authors concluded that SBRT plus TACE yielded significantly higher 1-year OS (RR [relative risk] 1.52; 95% CI 1.33-1.74), 2-year OS (RR 2.00; 95% CI 1.48-2.70), and a lower progressive disease rate (RR 0.45; 95% CI 0.26-0.79) than monotherapy. The combination treatment was both safe and effective.

Liver transplantation cures both HCC and the underlying cirrhosis; however, tumor progression while the patient is on the waiting list is an ongoing concern. Couillard and colleagues reported a retrospective study of 88 patients with HCC who underwent percutaneous microwave ablation for 141 tumors while on the liver transplant list. The median follow-up was 61 months. Seventy-one patients (80.7%) underwent liver transplantation after a median wait time of 8.5 months. No tumor seeding was identified. Seventeen patients (19.3%) were removed from the waitlist, four (4.5%) of whom because of tumor progression outside of the Milan criteria. A total of five of 71 (7.0%) patients had posttransplant recurrence of HCC and all died during this time. The 5-year overall survival (OS) following liver transplantation was 76.7% and the disease-specific survival after transplantation was 89.6%. The authors concluded that microwave ablation is a safe and effective treatment that bridges patients to successful transplantation.

Radiation segmentectomy is performed by the administration of radioactive yttrium (⁹⁰Y)-bound microspheres transarterially to the segment of liver containing an unresected tumor. Kim and colleagues described the results of a prospective trial that evaluated the efficacy of radiation segmentectomy with curative intent in patients with Child-Pugh score A–B7 and small (< 3 cm), unresectable HCC, where the tumors were in a location unsuitable for ablation. Of the 44 individuals assessed for eligibility, 29 patients were included in the study. A complete response was observed in 24 (83%) patients, and a partial response was observed in 5 (17%) patients. All patients had an initial objective tumor response, and 26 (90%) had a sustained complete response during 24 months of clinical follow-up. The treatment was well tolerated, with four (14%) patients having grade 3 leukopenia and two (7%) having grade 3 thrombocytopenia. The authors concluded that radiation segmentectomy should be investigated further as a potentially curative option for patients with HCC.

Portal vein thrombosis (PVT) has been considered a contraindication to transarterial chemoembolization (TACE) due to the concern for inadvertent liver ischemia if the hepatic artery becomes obstructed. Several studies have demonstrated that this risk is low. Stereotactic body radiation therapy (SBRT) is used to effectively target HCC (especially when there is a portal vein tumor) while minimizing collateral damage to the liver. Zhang and colleagues performed a meta-analysis of nine studies totaling 938 patients who had HCC with tumor PVT. Of those, 483 received either SBRT or TACE, and 455 were treated with both TACE and SBRT. There were 255 events reported in the monotherapy groups and 174 events in the combination groups. Following statistical analyses of all available data, the authors concluded that SBRT plus TACE yielded significantly higher 1-year OS (RR [relative risk] 1.52; 95% CI 1.33-1.74), 2-year OS (RR 2.00; 95% CI 1.48-2.70), and a lower progressive disease rate (RR 0.45; 95% CI 0.26-0.79) than monotherapy. The combination treatment was both safe and effective.

Verset and colleagues reported results from cohort 2 of the phase 2 KEYNOTE-224 trial, which investigated first-line pembrolizumab in patients with unresectable HCC. Fifty-one patients were included in cohort 2. The overall response rate (ORR) was 16% [95% CI 7-29] and was similar across key subgroups. Median duration of response was 16 months (range 3-24+), and disease control rate was 57%. The median progression-free survival (PFS) was 4 months (95% CI 2-8), and median time to progression was 4 months (95% CI 3-9). Median overall survival (OS) was 17 months (95% CI 8-23). Grade ≥ 3 treatment-related adverse events occurred in 16% of patients. The authors concluded that pembrolizumab is an effective treatment for patients with unresectable HCC and should be studied further in this setting.

Immunotherapy combinations are frequently used in the first-line setting for patients with unresectable HCC. In the past, many patients received immunotherapy in the second- or third-line settings. Sharma and coworkers reported patient outcomes following immunotherapy (immune checkpoint inhibitors, ICI). This retrospective, multicenter study examined anticancer treatment received after ICI treatment and assessed the impact of systemic treatment on post-ICI survival. A total of 420 patients with HCC were included. Most patients (n = 371; 88.3%) had received at least one prior treatment for HCC before ICI, including at least one line of systemic therapy (n = 289; 68.8%), with most receiving sorafenib (n = 237; 56.4%). Following immunotherapy, 31 (8.8%) died, 152 (36.2%) received best supportive care, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKI; n = 132; 80.9%), mostly sorafenib (n = 49; 30.0%), were the most common post-ICI therapy, followed by external beam radiotherapy (n = 28; 17.2%), further immunotherapy (n = 21; 12.9%), locoregional therapy (n = 23; 14.1%), chemotherapy (n = 9; 5.5%), and surgery (n = 6; 3.6%). Post-ICI therapy was associated with longer median OS compared with best supportive care (12.1 vs 3.3 months; hazard ratio [HR] 0.4; 95% CI 2.7-5.0). No difference in OS was noted if TKI were administered before or after ICI. The authors concluded that post-ICI therapy is associated with OS greater than 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICI.

Finally, Ahn and colleagues looked at racial disparities in patients with HCC. In this report, 3248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR 0.76; 95% CI 0.65-0.88). There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted odds ratio [aOR] 0.63; 95% CI 0.46-0.83) and Black (aOR 0.71; 95% CI 0.54-0.89) patients less likely to receive immunotherapy compared with White patients.

Verset and colleagues reported results from cohort 2 of the phase 2 KEYNOTE-224 trial, which investigated first-line pembrolizumab in patients with unresectable HCC. Fifty-one patients were included in cohort 2. The overall response rate (ORR) was 16% [95% CI 7-29] and was similar across key subgroups. Median duration of response was 16 months (range 3-24+), and disease control rate was 57%. The median progression-free survival (PFS) was 4 months (95% CI 2-8), and median time to progression was 4 months (95% CI 3-9). Median overall survival (OS) was 17 months (95% CI 8-23). Grade ≥ 3 treatment-related adverse events occurred in 16% of patients. The authors concluded that pembrolizumab is an effective treatment for patients with unresectable HCC and should be studied further in this setting.

Immunotherapy combinations are frequently used in the first-line setting for patients with unresectable HCC. In the past, many patients received immunotherapy in the second- or third-line settings. Sharma and coworkers reported patient outcomes following immunotherapy (immune checkpoint inhibitors, ICI). This retrospective, multicenter study examined anticancer treatment received after ICI treatment and assessed the impact of systemic treatment on post-ICI survival. A total of 420 patients with HCC were included. Most patients (n = 371; 88.3%) had received at least one prior treatment for HCC before ICI, including at least one line of systemic therapy (n = 289; 68.8%), with most receiving sorafenib (n = 237; 56.4%). Following immunotherapy, 31 (8.8%) died, 152 (36.2%) received best supportive care, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKI; n = 132; 80.9%), mostly sorafenib (n = 49; 30.0%), were the most common post-ICI therapy, followed by external beam radiotherapy (n = 28; 17.2%), further immunotherapy (n = 21; 12.9%), locoregional therapy (n = 23; 14.1%), chemotherapy (n = 9; 5.5%), and surgery (n = 6; 3.6%). Post-ICI therapy was associated with longer median OS compared with best supportive care (12.1 vs 3.3 months; hazard ratio [HR] 0.4; 95% CI 2.7-5.0). No difference in OS was noted if TKI were administered before or after ICI. The authors concluded that post-ICI therapy is associated with OS greater than 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICI.

Finally, Ahn and colleagues looked at racial disparities in patients with HCC. In this report, 3248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR 0.76; 95% CI 0.65-0.88). There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted odds ratio [aOR] 0.63; 95% CI 0.46-0.83) and Black (aOR 0.71; 95% CI 0.54-0.89) patients less likely to receive immunotherapy compared with White patients.

Verset and colleagues reported results from cohort 2 of the phase 2 KEYNOTE-224 trial, which investigated first-line pembrolizumab in patients with unresectable HCC. Fifty-one patients were included in cohort 2. The overall response rate (ORR) was 16% [95% CI 7-29] and was similar across key subgroups. Median duration of response was 16 months (range 3-24+), and disease control rate was 57%. The median progression-free survival (PFS) was 4 months (95% CI 2-8), and median time to progression was 4 months (95% CI 3-9). Median overall survival (OS) was 17 months (95% CI 8-23). Grade ≥ 3 treatment-related adverse events occurred in 16% of patients. The authors concluded that pembrolizumab is an effective treatment for patients with unresectable HCC and should be studied further in this setting.

Immunotherapy combinations are frequently used in the first-line setting for patients with unresectable HCC. In the past, many patients received immunotherapy in the second- or third-line settings. Sharma and coworkers reported patient outcomes following immunotherapy (immune checkpoint inhibitors, ICI). This retrospective, multicenter study examined anticancer treatment received after ICI treatment and assessed the impact of systemic treatment on post-ICI survival. A total of 420 patients with HCC were included. Most patients (n = 371; 88.3%) had received at least one prior treatment for HCC before ICI, including at least one line of systemic therapy (n = 289; 68.8%), with most receiving sorafenib (n = 237; 56.4%). Following immunotherapy, 31 (8.8%) died, 152 (36.2%) received best supportive care, and 163 patients (38.8%) received subsequent anticancer therapy. Tyrosine kinase inhibitors (TKI; n = 132; 80.9%), mostly sorafenib (n = 49; 30.0%), were the most common post-ICI therapy, followed by external beam radiotherapy (n = 28; 17.2%), further immunotherapy (n = 21; 12.9%), locoregional therapy (n = 23; 14.1%), chemotherapy (n = 9; 5.5%), and surgery (n = 6; 3.6%). Post-ICI therapy was associated with longer median OS compared with best supportive care (12.1 vs 3.3 months; hazard ratio [HR] 0.4; 95% CI 2.7-5.0). No difference in OS was noted if TKI were administered before or after ICI. The authors concluded that post-ICI therapy is associated with OS greater than 12 months, suggesting a role for therapeutic sequencing. OS from TKI therapy was similar to that reported in registration studies, suggesting preserved efficacy following ICI.

Finally, Ahn and colleagues looked at racial disparities in patients with HCC. In this report, 3248 (81.4%) patients received chemotherapy and 742 (18.6%) patients received immunotherapy as a first-line treatment. Immunotherapy was associated with improved OS compared with chemotherapy (adjusted HR 0.76; 95% CI 0.65-0.88). There were racial and ethnic disparities in access to immunotherapy, with Hispanic (adjusted odds ratio [aOR] 0.63; 95% CI 0.46-0.83) and Black (aOR 0.71; 95% CI 0.54-0.89) patients less likely to receive immunotherapy compared with White patients.

Clinical trials for unresectable HCC (uHCC) have mandated excellent underlying liver function. Patients with Child-Pugh (CP) A cirrhosis do not have cirrhosis as their most life-limiting disease. In clinical practice, there are many patients with uHCC who are functionally well yet have CP-B cirrhosis. D'Alessio and colleagues undertook a retrospective evaluation of 202 patients with either CP-A or CP-B cirrhosis who received atezolizumab and bevacizumab as first-line treatment of uHCC. The majority, 154 patients (76%), had CP-A cirrhosis, whereas 48 (24%) had CP-B, including 21 B7, 21 B8, and 6 B9. The authors found that in the overall population, median overall survival (mOS) was 14.9 months (95% CI 13.6-16.3), with patients with CP-A mOS of 16.8 months (95% CI 14.1-23.9), and CP-B mOS of 6.7 months (95% CI 4.3-15.6; P = .0003). Overall response rates (ORR) were comparable, with an ORR of 26% in CP-A and 21% in CP-B, not influenced by Barcelona Clinic Liver Cancer (BCLC) stage, performance status, etiology (viral vs nonviral), portal vein thrombosis (PVT), or extrahepatic spread (P > .05 for all associations). The investigators concluded that atezolizumab and bevacizumab in patients with CP-B was well tolerated, with no relevant difference in terms of clinically significant treatment-related adverse events compared with patients with CP-A.

Shi and colleagues reported a randomized controlled trial of patients with HCC and microvascular invasion (MVI) who underwent suboptimal resection (distance from tumor edge to the cut surface < 1 mm), followed by either stereotactic body radiotherapy (SBRT) or observation. From August 2015 to December 2016, 76 patients with BCLC stage 0/A liver disease, MVI, and no macroscopic vascular invasion were randomized after partial hepatectomy to either observation or SBRT (35 Gy delivered in a week). The 1-, 3-, and 5-year disease free survival (DFS) rates were 92.1%, 65.8%, and 56.1% in the SBRT group vs 76.3%, 36.8%, and 26.3% in the surgery alone group, respectively (P = .005). The 1-, 3-, and 5-year overall survival (OS) rates were 100%, 89.5%, and 75.0% in SBRT group vs 100.0%, 68.4%, and 53.7% in the surgery alone group, respectively (P = .053). The authors concluded that SBRT eradicates residual tumor cells present at the margin and improves surgical outcomes.

Roth and colleagues evaluated the safety and efficacy of transarterial chemoembolization (TACE) in older (> 70 years) patients with intermediate HCC. Out of 271 patients evaluated, 88 were older patients. 20.5% of older patients experienced serious adverse events vs 21.3% of younger patients (P = .87). The predictive factors of serious adverse events were CP stage ≥ B7 (P < .0001), Eastern Cooperative Oncology Group (ECOG) scale ≥ 1 (P = .0019), and Model for End-stage Liver Disease (MELD) score ≥ 9 (P = .0415). The serious adverse event rate was not increased with age (P = .87). The authors concluded that age should not be an exclusionary factor when considering TACE.

Clinical trials for unresectable HCC (uHCC) have mandated excellent underlying liver function. Patients with Child-Pugh (CP) A cirrhosis do not have cirrhosis as their most life-limiting disease. In clinical practice, there are many patients with uHCC who are functionally well yet have CP-B cirrhosis. D'Alessio and colleagues undertook a retrospective evaluation of 202 patients with either CP-A or CP-B cirrhosis who received atezolizumab and bevacizumab as first-line treatment of uHCC. The majority, 154 patients (76%), had CP-A cirrhosis, whereas 48 (24%) had CP-B, including 21 B7, 21 B8, and 6 B9. The authors found that in the overall population, median overall survival (mOS) was 14.9 months (95% CI 13.6-16.3), with patients with CP-A mOS of 16.8 months (95% CI 14.1-23.9), and CP-B mOS of 6.7 months (95% CI 4.3-15.6; P = .0003). Overall response rates (ORR) were comparable, with an ORR of 26% in CP-A and 21% in CP-B, not influenced by Barcelona Clinic Liver Cancer (BCLC) stage, performance status, etiology (viral vs nonviral), portal vein thrombosis (PVT), or extrahepatic spread (P > .05 for all associations). The investigators concluded that atezolizumab and bevacizumab in patients with CP-B was well tolerated, with no relevant difference in terms of clinically significant treatment-related adverse events compared with patients with CP-A.

Shi and colleagues reported a randomized controlled trial of patients with HCC and microvascular invasion (MVI) who underwent suboptimal resection (distance from tumor edge to the cut surface < 1 mm), followed by either stereotactic body radiotherapy (SBRT) or observation. From August 2015 to December 2016, 76 patients with BCLC stage 0/A liver disease, MVI, and no macroscopic vascular invasion were randomized after partial hepatectomy to either observation or SBRT (35 Gy delivered in a week). The 1-, 3-, and 5-year disease free survival (DFS) rates were 92.1%, 65.8%, and 56.1% in the SBRT group vs 76.3%, 36.8%, and 26.3% in the surgery alone group, respectively (P = .005). The 1-, 3-, and 5-year overall survival (OS) rates were 100%, 89.5%, and 75.0% in SBRT group vs 100.0%, 68.4%, and 53.7% in the surgery alone group, respectively (P = .053). The authors concluded that SBRT eradicates residual tumor cells present at the margin and improves surgical outcomes.

Roth and colleagues evaluated the safety and efficacy of transarterial chemoembolization (TACE) in older (> 70 years) patients with intermediate HCC. Out of 271 patients evaluated, 88 were older patients. 20.5% of older patients experienced serious adverse events vs 21.3% of younger patients (P = .87). The predictive factors of serious adverse events were CP stage ≥ B7 (P < .0001), Eastern Cooperative Oncology Group (ECOG) scale ≥ 1 (P = .0019), and Model for End-stage Liver Disease (MELD) score ≥ 9 (P = .0415). The serious adverse event rate was not increased with age (P = .87). The authors concluded that age should not be an exclusionary factor when considering TACE.

Clinical trials for unresectable HCC (uHCC) have mandated excellent underlying liver function. Patients with Child-Pugh (CP) A cirrhosis do not have cirrhosis as their most life-limiting disease. In clinical practice, there are many patients with uHCC who are functionally well yet have CP-B cirrhosis. D'Alessio and colleagues undertook a retrospective evaluation of 202 patients with either CP-A or CP-B cirrhosis who received atezolizumab and bevacizumab as first-line treatment of uHCC. The majority, 154 patients (76%), had CP-A cirrhosis, whereas 48 (24%) had CP-B, including 21 B7, 21 B8, and 6 B9. The authors found that in the overall population, median overall survival (mOS) was 14.9 months (95% CI 13.6-16.3), with patients with CP-A mOS of 16.8 months (95% CI 14.1-23.9), and CP-B mOS of 6.7 months (95% CI 4.3-15.6; P = .0003). Overall response rates (ORR) were comparable, with an ORR of 26% in CP-A and 21% in CP-B, not influenced by Barcelona Clinic Liver Cancer (BCLC) stage, performance status, etiology (viral vs nonviral), portal vein thrombosis (PVT), or extrahepatic spread (P > .05 for all associations). The investigators concluded that atezolizumab and bevacizumab in patients with CP-B was well tolerated, with no relevant difference in terms of clinically significant treatment-related adverse events compared with patients with CP-A.

Shi and colleagues reported a randomized controlled trial of patients with HCC and microvascular invasion (MVI) who underwent suboptimal resection (distance from tumor edge to the cut surface < 1 mm), followed by either stereotactic body radiotherapy (SBRT) or observation. From August 2015 to December 2016, 76 patients with BCLC stage 0/A liver disease, MVI, and no macroscopic vascular invasion were randomized after partial hepatectomy to either observation or SBRT (35 Gy delivered in a week). The 1-, 3-, and 5-year disease free survival (DFS) rates were 92.1%, 65.8%, and 56.1% in the SBRT group vs 76.3%, 36.8%, and 26.3% in the surgery alone group, respectively (P = .005). The 1-, 3-, and 5-year overall survival (OS) rates were 100%, 89.5%, and 75.0% in SBRT group vs 100.0%, 68.4%, and 53.7% in the surgery alone group, respectively (P = .053). The authors concluded that SBRT eradicates residual tumor cells present at the margin and improves surgical outcomes.

Roth and colleagues evaluated the safety and efficacy of transarterial chemoembolization (TACE) in older (> 70 years) patients with intermediate HCC. Out of 271 patients evaluated, 88 were older patients. 20.5% of older patients experienced serious adverse events vs 21.3% of younger patients (P = .87). The predictive factors of serious adverse events were CP stage ≥ B7 (P < .0001), Eastern Cooperative Oncology Group (ECOG) scale ≥ 1 (P = .0019), and Model for End-stage Liver Disease (MELD) score ≥ 9 (P = .0415). The serious adverse event rate was not increased with age (P = .87). The authors concluded that age should not be an exclusionary factor when considering TACE.

Yao and colleagues confirmed that there are well-known risk factors for recurrence of HCC after surgical resection. They retrospectively analyzed 1424 patients who underwent resection with curative intent for Barcelona Clinical Liver Cancer (BCLC) stage 0/A HCC in several centers in China. Of those patients, 679 (47.7%) developed recurrence at a median follow-up of 54.8 months, including 408 (60.1%) with an early recurrence (≤ 2 years after surgery) and 271 (39.9%) with a late recurrence (> 2 years). Cirrhosis (adjusted hazard ratio [aHR] 1.49; P < .001), preoperative alpha-fetoprotein (AFP) level > 400 µg/L (aHR 1.28; P = .004), tumor size > 5 cm (aHR 1.74; P < .001), the presence of satellite nodules (aHR 1.35; P = .040), multiple tumors (aHR 1.63; P = .015), microvascular invasion (aHR 1.51; P < .001), and intraoperative blood transfusion (aHR 1.50; P = .013) were identified as independent risk factors associated with postoperative HCC recurrence. The authors concluded that those patients with risk factors for recurrence would benefit from more intensive surveillance and potentially additional liver-directed therapy with curative intent.

Not all patients with hepatitis C virus (HCV) infection and HCC are offered antiviral therapy. Takaura and colleagues confirmed that active HCV infection worsens the prognosis of patients with very early-stage HCC who undergo treatment with radiofrequency ablation (RFA). In this single-center retrospective study, 302 patients with BCLC stage 0 HCC who underwent RFA were analyzed. Of those patients, 195 had evidence of HCV, and 132 had an active infection. The authors concluded that active HCV infection was a significant risk factor for shorter overall survival (aHR 2.17; P = .003) and early recurrence of HCC (aHR 1.47; P = .022). Patients with active HCV infection had a shorter median overall survival (66 months vs 145 months) and recurrence-free survival (20 months vs 31 months) (both P < .001). Therefore, treatment of active HCV should be offered to patients even after the development of HCC.

Kuroda and colleagues retrospectively analyzed a multicenter cohort of 247 patients with unresectable HCC treated with lenvatinib between 2018 and 2020. Out of those, 63 patients who received lenvatinib and transarterial chemoembolization (TACE) sequential therapy were propensity-score matched to those receiving lenvatinib monotherapy. The overall survival and progression-free survival in the sequential group were significantly higher than those in the lenvatinib monotherapy group, 31.2 (26.4-34.3) vs 15.7 (13.1-19.4) months and 12.2 (8.5-17.3) vs 6.7 (5.3-10.2) months (P = .002 and P = .037), respectively. Multivariate analysis showed that the deep response was independently associated with the initial response to levatinib; the partial response showed an odds ratio of 13.75 (95% CI 0.41-1.32; P < .001). The authors concluded that sequential therapy might provide more clinical benefits than lenvatinib monotherapy in patients who responded to initial lenvatinib treatment, with objective response to initial lenvatinib being an independent factor predicting sequential therapy deep response.

Yao and colleagues confirmed that there are well-known risk factors for recurrence of HCC after surgical resection. They retrospectively analyzed 1424 patients who underwent resection with curative intent for Barcelona Clinical Liver Cancer (BCLC) stage 0/A HCC in several centers in China. Of those patients, 679 (47.7%) developed recurrence at a median follow-up of 54.8 months, including 408 (60.1%) with an early recurrence (≤ 2 years after surgery) and 271 (39.9%) with a late recurrence (> 2 years). Cirrhosis (adjusted hazard ratio [aHR] 1.49; P < .001), preoperative alpha-fetoprotein (AFP) level > 400 µg/L (aHR 1.28; P = .004), tumor size > 5 cm (aHR 1.74; P < .001), the presence of satellite nodules (aHR 1.35; P = .040), multiple tumors (aHR 1.63; P = .015), microvascular invasion (aHR 1.51; P < .001), and intraoperative blood transfusion (aHR 1.50; P = .013) were identified as independent risk factors associated with postoperative HCC recurrence. The authors concluded that those patients with risk factors for recurrence would benefit from more intensive surveillance and potentially additional liver-directed therapy with curative intent.

Not all patients with hepatitis C virus (HCV) infection and HCC are offered antiviral therapy. Takaura and colleagues confirmed that active HCV infection worsens the prognosis of patients with very early-stage HCC who undergo treatment with radiofrequency ablation (RFA). In this single-center retrospective study, 302 patients with BCLC stage 0 HCC who underwent RFA were analyzed. Of those patients, 195 had evidence of HCV, and 132 had an active infection. The authors concluded that active HCV infection was a significant risk factor for shorter overall survival (aHR 2.17; P = .003) and early recurrence of HCC (aHR 1.47; P = .022). Patients with active HCV infection had a shorter median overall survival (66 months vs 145 months) and recurrence-free survival (20 months vs 31 months) (both P < .001). Therefore, treatment of active HCV should be offered to patients even after the development of HCC.

Kuroda and colleagues retrospectively analyzed a multicenter cohort of 247 patients with unresectable HCC treated with lenvatinib between 2018 and 2020. Out of those, 63 patients who received lenvatinib and transarterial chemoembolization (TACE) sequential therapy were propensity-score matched to those receiving lenvatinib monotherapy. The overall survival and progression-free survival in the sequential group were significantly higher than those in the lenvatinib monotherapy group, 31.2 (26.4-34.3) vs 15.7 (13.1-19.4) months and 12.2 (8.5-17.3) vs 6.7 (5.3-10.2) months (P = .002 and P = .037), respectively. Multivariate analysis showed that the deep response was independently associated with the initial response to levatinib; the partial response showed an odds ratio of 13.75 (95% CI 0.41-1.32; P < .001). The authors concluded that sequential therapy might provide more clinical benefits than lenvatinib monotherapy in patients who responded to initial lenvatinib treatment, with objective response to initial lenvatinib being an independent factor predicting sequential therapy deep response.

Yao and colleagues confirmed that there are well-known risk factors for recurrence of HCC after surgical resection. They retrospectively analyzed 1424 patients who underwent resection with curative intent for Barcelona Clinical Liver Cancer (BCLC) stage 0/A HCC in several centers in China. Of those patients, 679 (47.7%) developed recurrence at a median follow-up of 54.8 months, including 408 (60.1%) with an early recurrence (≤ 2 years after surgery) and 271 (39.9%) with a late recurrence (> 2 years). Cirrhosis (adjusted hazard ratio [aHR] 1.49; P < .001), preoperative alpha-fetoprotein (AFP) level > 400 µg/L (aHR 1.28; P = .004), tumor size > 5 cm (aHR 1.74; P < .001), the presence of satellite nodules (aHR 1.35; P = .040), multiple tumors (aHR 1.63; P = .015), microvascular invasion (aHR 1.51; P < .001), and intraoperative blood transfusion (aHR 1.50; P = .013) were identified as independent risk factors associated with postoperative HCC recurrence. The authors concluded that those patients with risk factors for recurrence would benefit from more intensive surveillance and potentially additional liver-directed therapy with curative intent.

Not all patients with hepatitis C virus (HCV) infection and HCC are offered antiviral therapy. Takaura and colleagues confirmed that active HCV infection worsens the prognosis of patients with very early-stage HCC who undergo treatment with radiofrequency ablation (RFA). In this single-center retrospective study, 302 patients with BCLC stage 0 HCC who underwent RFA were analyzed. Of those patients, 195 had evidence of HCV, and 132 had an active infection. The authors concluded that active HCV infection was a significant risk factor for shorter overall survival (aHR 2.17; P = .003) and early recurrence of HCC (aHR 1.47; P = .022). Patients with active HCV infection had a shorter median overall survival (66 months vs 145 months) and recurrence-free survival (20 months vs 31 months) (both P < .001). Therefore, treatment of active HCV should be offered to patients even after the development of HCC.

Kuroda and colleagues retrospectively analyzed a multicenter cohort of 247 patients with unresectable HCC treated with lenvatinib between 2018 and 2020. Out of those, 63 patients who received lenvatinib and transarterial chemoembolization (TACE) sequential therapy were propensity-score matched to those receiving lenvatinib monotherapy. The overall survival and progression-free survival in the sequential group were significantly higher than those in the lenvatinib monotherapy group, 31.2 (26.4-34.3) vs 15.7 (13.1-19.4) months and 12.2 (8.5-17.3) vs 6.7 (5.3-10.2) months (P = .002 and P = .037), respectively. Multivariate analysis showed that the deep response was independently associated with the initial response to levatinib; the partial response showed an odds ratio of 13.75 (95% CI 0.41-1.32; P < .001). The authors concluded that sequential therapy might provide more clinical benefits than lenvatinib monotherapy in patients who responded to initial lenvatinib treatment, with objective response to initial lenvatinib being an independent factor predicting sequential therapy deep response.

Kaseb et al report the results of a Phase 2 study where 27 patients with resectable HCC were randomized to receive either nivolumab alone or the combination of nivolumab and ipilimumab for 6 weeks before surgery, and then for up to 2 years after resection. Estimated median progression-free survival (PFS) was 9.4 months with nivolumab and 19.53 months with nivolumab plus ipilimumab (hazard ratio [HR] 0.99, 95% CI 0.31–2.54); median time to progression was 9.4 months in the nivolumab group and 19.53 months in the nivolumab plus ipilimumab group (HR 0.89, 95% CI 0.31–2.54). Three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumor area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. Grade 3–4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The authors concluded that immunotherapy is safe and feasible in patients with resectable hepatocellular carcinoma.

Marron et al. evaluated the clinical activity of cemiplimab (an anti-PD-1) in 21 patients with resectable hepatocellular carcinoma. Cemiplimab was administered twice every 3 weeks before and 8 times after surgery. Of the 20 patients with resected tumors, four (20%) had significant (>70%) tumor necrosis with 15% showing complete (100%) tumor necrosis. Three (15%) of 20 patients had a radiologic partial response, and all other patients maintained stable disease. Seven (33%) patients had grade 3 adverse events. No grade 4 or 5 events were observed. The investigators concluded that perioperative cemiplimab should be studied further in patients with resectable HCC.

Finally, Guan et al. compared outcomes of 498 patients with resected HCC who also had hepatitis B virus infection (defined as HBsAg-positivity for >90 days). Of those, 367 patients (73.69%) received at least 3 months of postoperative anti-viral treatment (AVT), while 131 (27.31%) did not (non-AVT group). Propensity score matching (PSM) analysis was performed on 206 patients. AVT was associated with better recurrence-free survival (RFS) and overall survival (OS) either before or after PSM.  After PSM, the 1-, 3-, and 5-year RFS rates were 85.3%, 65.7%, and 19.1% vs. 76.7%, 46.6%, and 5.8% in the AVT and non-AVT groups, respectively (P = .001). The corresponding 1-, 3-, and 5-year OS rates were 99.0%, 89.8%, and 64.0% vs. 96.1%, 70.5%, and 43.2% in the AVT and non-AVT groups (P < .001). Risk factors that were independently associated with a poor RFS included HBV DNA positivity (P = .002), preoperative alpha fetoprotein (AFP) level of ≥20 ng/mL (P < .001), poor differentiation (P = .022), multiple tumors (P = .037), and microvascular invasion (P < .001). The conclusion was that AVT improves outcomes in patients with HBV and resectable HCC.

Kaseb et al report the results of a Phase 2 study where 27 patients with resectable HCC were randomized to receive either nivolumab alone or the combination of nivolumab and ipilimumab for 6 weeks before surgery, and then for up to 2 years after resection. Estimated median progression-free survival (PFS) was 9.4 months with nivolumab and 19.53 months with nivolumab plus ipilimumab (hazard ratio [HR] 0.99, 95% CI 0.31–2.54); median time to progression was 9.4 months in the nivolumab group and 19.53 months in the nivolumab plus ipilimumab group (HR 0.89, 95% CI 0.31–2.54). Three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumor area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. Grade 3–4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The authors concluded that immunotherapy is safe and feasible in patients with resectable hepatocellular carcinoma.

Marron et al. evaluated the clinical activity of cemiplimab (an anti-PD-1) in 21 patients with resectable hepatocellular carcinoma. Cemiplimab was administered twice every 3 weeks before and 8 times after surgery. Of the 20 patients with resected tumors, four (20%) had significant (>70%) tumor necrosis with 15% showing complete (100%) tumor necrosis. Three (15%) of 20 patients had a radiologic partial response, and all other patients maintained stable disease. Seven (33%) patients had grade 3 adverse events. No grade 4 or 5 events were observed. The investigators concluded that perioperative cemiplimab should be studied further in patients with resectable HCC.

Finally, Guan et al. compared outcomes of 498 patients with resected HCC who also had hepatitis B virus infection (defined as HBsAg-positivity for >90 days). Of those, 367 patients (73.69%) received at least 3 months of postoperative anti-viral treatment (AVT), while 131 (27.31%) did not (non-AVT group). Propensity score matching (PSM) analysis was performed on 206 patients. AVT was associated with better recurrence-free survival (RFS) and overall survival (OS) either before or after PSM.  After PSM, the 1-, 3-, and 5-year RFS rates were 85.3%, 65.7%, and 19.1% vs. 76.7%, 46.6%, and 5.8% in the AVT and non-AVT groups, respectively (P = .001). The corresponding 1-, 3-, and 5-year OS rates were 99.0%, 89.8%, and 64.0% vs. 96.1%, 70.5%, and 43.2% in the AVT and non-AVT groups (P < .001). Risk factors that were independently associated with a poor RFS included HBV DNA positivity (P = .002), preoperative alpha fetoprotein (AFP) level of ≥20 ng/mL (P < .001), poor differentiation (P = .022), multiple tumors (P = .037), and microvascular invasion (P < .001). The conclusion was that AVT improves outcomes in patients with HBV and resectable HCC.

Kaseb et al report the results of a Phase 2 study where 27 patients with resectable HCC were randomized to receive either nivolumab alone or the combination of nivolumab and ipilimumab for 6 weeks before surgery, and then for up to 2 years after resection. Estimated median progression-free survival (PFS) was 9.4 months with nivolumab and 19.53 months with nivolumab plus ipilimumab (hazard ratio [HR] 0.99, 95% CI 0.31–2.54); median time to progression was 9.4 months in the nivolumab group and 19.53 months in the nivolumab plus ipilimumab group (HR 0.89, 95% CI 0.31–2.54). Three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumor area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. Grade 3–4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The authors concluded that immunotherapy is safe and feasible in patients with resectable hepatocellular carcinoma.

Marron et al. evaluated the clinical activity of cemiplimab (an anti-PD-1) in 21 patients with resectable hepatocellular carcinoma. Cemiplimab was administered twice every 3 weeks before and 8 times after surgery. Of the 20 patients with resected tumors, four (20%) had significant (>70%) tumor necrosis with 15% showing complete (100%) tumor necrosis. Three (15%) of 20 patients had a radiologic partial response, and all other patients maintained stable disease. Seven (33%) patients had grade 3 adverse events. No grade 4 or 5 events were observed. The investigators concluded that perioperative cemiplimab should be studied further in patients with resectable HCC.

Finally, Guan et al. compared outcomes of 498 patients with resected HCC who also had hepatitis B virus infection (defined as HBsAg-positivity for >90 days). Of those, 367 patients (73.69%) received at least 3 months of postoperative anti-viral treatment (AVT), while 131 (27.31%) did not (non-AVT group). Propensity score matching (PSM) analysis was performed on 206 patients. AVT was associated with better recurrence-free survival (RFS) and overall survival (OS) either before or after PSM.  After PSM, the 1-, 3-, and 5-year RFS rates were 85.3%, 65.7%, and 19.1% vs. 76.7%, 46.6%, and 5.8% in the AVT and non-AVT groups, respectively (P = .001). The corresponding 1-, 3-, and 5-year OS rates were 99.0%, 89.8%, and 64.0% vs. 96.1%, 70.5%, and 43.2% in the AVT and non-AVT groups (P < .001). Risk factors that were independently associated with a poor RFS included HBV DNA positivity (P = .002), preoperative alpha fetoprotein (AFP) level of ≥20 ng/mL (P < .001), poor differentiation (P = .022), multiple tumors (P = .037), and microvascular invasion (P < .001). The conclusion was that AVT improves outcomes in patients with HBV and resectable HCC.

Takayama et al evaluated 301 Japanese HCC patients who had a Child-Pugh score ≤ 7, no more than 3 HCC nodules (none more than 3 cm in greatest diameter), who were then randomly assigned to undergo either surgery (n=150) or RFA (n=151). The authors reported that though the median procedure duration was longer in the surgery group than in the RFA group (274 versus 40 minutes, P < 0.01) as was the median duration of hospital stay (17 days versus 10 days, P < 0.01), recurrence free survival (RFS) did not differ significantly between the groups. The median RFS was 3.5 years (95% confidence interval [CI], 2.6–5.1) in the surgery group and 3.0 years (95% CI, 2.4–5.6) in the RFA group (hazard ratio, 0.92; 95% CI, 0.67–1.25; P = 0.58). The overall survival (OS) data for this study are not yet mature.

Cao et al looked at outcomes of patients with periportal HCCs who were treated with RFA. They evaluated 233 patients who had a single nodular HCC that was ≤ 5 cm in greatest diameter who underwent RFA with or without transarterial chemoembolization (TACE) as first-line therapy. In that group, 56 patients had a periportal HCC. The authors reported that patients with periportal HCCs had worse outcomes. Local recurrence rates at 1, 3, and 5 years were significantly higher with periportal HCCs than with nonperiportal HCCs (15.7, 33.7, and 46.9% vs 6.0, 15.7, and 28.7%, respectively, P = 0.0067). The 1-, 3- and 5-year OS rates with periportal HCCs were significantly worse than with nonperiportal HCCs (81.3, 65.1 and 42.9% vs 99.3, 90.4 and 78.1%, respectively, P < 0.0001). In the subgroup of HCC ≤ 3 cm, patients with periportal HCCs showed significantly higher local recurrence rates (P = 0.0006) and OS (P < 0.0001) after RFA than patients with single nonperiportal HCCs. Subgroup analyses revealed that tumor size, periportal HCC and AFP ≥ 400ug/ml were independent prognostic factors for tumor progression after RFA. The authors concluded that periportal HCCs have a worse prognosis, and need better treatment options than are currently available.

Lee at al report a retrospective evaluation of Korean patients with HCC who were either treated with RFA or microwave ablation (MWA). Of 150 HCC patients (100 in the RFA group and 50 in the MWA group), the complete response rate, two-year survival rate, and complication rate were similar between the two groups. However, the MWA group had better one- and two-year disease-free survival than the RFA group (P = 0.035 and P = 0.032, respectively). In addition, there were fewer major complications in the MWA group (P = 0.043). In a subgroup analysis, patients with perivascular tumors, high risk of recurrence, and small tumor size (≤3 cm) were more suitable for MWA than RFA. The authors concluded that in patients with HCC, initial treatment with microwave ablation leads to better 1- and 2-year disease-free survival and a lower risk of major complications than RFA.

Takayama et al evaluated 301 Japanese HCC patients who had a Child-Pugh score ≤ 7, no more than 3 HCC nodules (none more than 3 cm in greatest diameter), who were then randomly assigned to undergo either surgery (n=150) or RFA (n=151). The authors reported that though the median procedure duration was longer in the surgery group than in the RFA group (274 versus 40 minutes, P < 0.01) as was the median duration of hospital stay (17 days versus 10 days, P < 0.01), recurrence free survival (RFS) did not differ significantly between the groups. The median RFS was 3.5 years (95% confidence interval [CI], 2.6–5.1) in the surgery group and 3.0 years (95% CI, 2.4–5.6) in the RFA group (hazard ratio, 0.92; 95% CI, 0.67–1.25; P = 0.58). The overall survival (OS) data for this study are not yet mature.

Cao et al looked at outcomes of patients with periportal HCCs who were treated with RFA. They evaluated 233 patients who had a single nodular HCC that was ≤ 5 cm in greatest diameter who underwent RFA with or without transarterial chemoembolization (TACE) as first-line therapy. In that group, 56 patients had a periportal HCC. The authors reported that patients with periportal HCCs had worse outcomes. Local recurrence rates at 1, 3, and 5 years were significantly higher with periportal HCCs than with nonperiportal HCCs (15.7, 33.7, and 46.9% vs 6.0, 15.7, and 28.7%, respectively, P = 0.0067). The 1-, 3- and 5-year OS rates with periportal HCCs were significantly worse than with nonperiportal HCCs (81.3, 65.1 and 42.9% vs 99.3, 90.4 and 78.1%, respectively, P < 0.0001). In the subgroup of HCC ≤ 3 cm, patients with periportal HCCs showed significantly higher local recurrence rates (P = 0.0006) and OS (P < 0.0001) after RFA than patients with single nonperiportal HCCs. Subgroup analyses revealed that tumor size, periportal HCC and AFP ≥ 400ug/ml were independent prognostic factors for tumor progression after RFA. The authors concluded that periportal HCCs have a worse prognosis, and need better treatment options than are currently available.

Lee at al report a retrospective evaluation of Korean patients with HCC who were either treated with RFA or microwave ablation (MWA). Of 150 HCC patients (100 in the RFA group and 50 in the MWA group), the complete response rate, two-year survival rate, and complication rate were similar between the two groups. However, the MWA group had better one- and two-year disease-free survival than the RFA group (P = 0.035 and P = 0.032, respectively). In addition, there were fewer major complications in the MWA group (P = 0.043). In a subgroup analysis, patients with perivascular tumors, high risk of recurrence, and small tumor size (≤3 cm) were more suitable for MWA than RFA. The authors concluded that in patients with HCC, initial treatment with microwave ablation leads to better 1- and 2-year disease-free survival and a lower risk of major complications than RFA.

Takayama et al evaluated 301 Japanese HCC patients who had a Child-Pugh score ≤ 7, no more than 3 HCC nodules (none more than 3 cm in greatest diameter), who were then randomly assigned to undergo either surgery (n=150) or RFA (n=151). The authors reported that though the median procedure duration was longer in the surgery group than in the RFA group (274 versus 40 minutes, P < 0.01) as was the median duration of hospital stay (17 days versus 10 days, P < 0.01), recurrence free survival (RFS) did not differ significantly between the groups. The median RFS was 3.5 years (95% confidence interval [CI], 2.6–5.1) in the surgery group and 3.0 years (95% CI, 2.4–5.6) in the RFA group (hazard ratio, 0.92; 95% CI, 0.67–1.25; P = 0.58). The overall survival (OS) data for this study are not yet mature.

Cao et al looked at outcomes of patients with periportal HCCs who were treated with RFA. They evaluated 233 patients who had a single nodular HCC that was ≤ 5 cm in greatest diameter who underwent RFA with or without transarterial chemoembolization (TACE) as first-line therapy. In that group, 56 patients had a periportal HCC. The authors reported that patients with periportal HCCs had worse outcomes. Local recurrence rates at 1, 3, and 5 years were significantly higher with periportal HCCs than with nonperiportal HCCs (15.7, 33.7, and 46.9% vs 6.0, 15.7, and 28.7%, respectively, P = 0.0067). The 1-, 3- and 5-year OS rates with periportal HCCs were significantly worse than with nonperiportal HCCs (81.3, 65.1 and 42.9% vs 99.3, 90.4 and 78.1%, respectively, P < 0.0001). In the subgroup of HCC ≤ 3 cm, patients with periportal HCCs showed significantly higher local recurrence rates (P = 0.0006) and OS (P < 0.0001) after RFA than patients with single nonperiportal HCCs. Subgroup analyses revealed that tumor size, periportal HCC and AFP ≥ 400ug/ml were independent prognostic factors for tumor progression after RFA. The authors concluded that periportal HCCs have a worse prognosis, and need better treatment options than are currently available.

Lee at al report a retrospective evaluation of Korean patients with HCC who were either treated with RFA or microwave ablation (MWA). Of 150 HCC patients (100 in the RFA group and 50 in the MWA group), the complete response rate, two-year survival rate, and complication rate were similar between the two groups. However, the MWA group had better one- and two-year disease-free survival than the RFA group (P = 0.035 and P = 0.032, respectively). In addition, there were fewer major complications in the MWA group (P = 0.043). In a subgroup analysis, patients with perivascular tumors, high risk of recurrence, and small tumor size (≤3 cm) were more suitable for MWA than RFA. The authors concluded that in patients with HCC, initial treatment with microwave ablation leads to better 1- and 2-year disease-free survival and a lower risk of major complications than RFA.

For many years, sorafenib was the only FDA-approved systemic treatment for patients with uHCC. Initial case reports of remarkable responses of tumors to immunotherapy, and results of the Phase I/II CheckMate-040 clinical trial, led to the September 2017 FDA approval of nivolumab for the treatment of patients with uHCC after progression on sorafenib. Thereafter, several randomized clinical trials comparing sorafenib to immunotherapy and immunotherapy combinations were initiated, including the comparison of nivolumab to sorafenib. In June 2019 it was announced that this trial did not reach its prespecified endpoint, and the FDA approval for the uHCC indication was voluntarily withdrawn. In December 2021, Yau et al published the final results of the CheckMate-459 randomized trial that included 743 adult patients with advanced HCC randomly assigned to receive either nivolumab (n=371) or sorafenib (n=372) in the first line setting.  The primary endpoint was overall survival (OS) assessed in the intention-to-treat population. The median OS was 16.4 months (95% CI 13.9–18.4) with nivolumab and 14.7 months (11.9–17.2) with sorafenib (hazard ratio 0.85 [95% CI 0.72–1.02]; P = 0.075; minimum follow-up 22.8 months). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. The authors concluded that though first-line nivolumab treatment did not significantly improve OS compared with sorafenib, single-agent nivolumab might be considered a treatment option for patients in whom tyrosine kinase inhibitors or antiangiogenic drugs are not safe.

Cheng et al reported an update on the outcomes of the IMbrave150 study, 12 months after the primary analysis. This study established atezolizumab and bevacizumab as the current standard of care for the initial systemic treatment of patients with uHCC. The median OS was 19.2 months (95% CI 17.0-23.7) with atezolizumab/bevacizumab and 13.4 months (95% CI 11.4-16.9) with sorafenib (hazard ratio [HR], 0.66; 95% CI 0.52-0.85; descriptive P < 0.001). The overall response rate (ORR) was 30% with atezolizumab/bevacizumab, while treatment-related grade 3/4 adverse events occurred in 143 (43%) of 329 receiving atezolizumab/bevacizumab and 72 (46%) of 156 receiving sorafenib. Treatment-related grade 5 events occurred in 6 (2%) and 1 (<1%) patients. Therefore, atezolizumab/bevacizumab remains the first-line standard of care for patients with uHCC.

Finally, Jácome et al undertook a combined analysis of 3 randomized controlled trials (KEYNOTE-240, CheckMate-459, and IMbrave150), with 1,657 patients with uHCC and who were treated with either immunotherapy (n=985) or sorafenib (in the first-line setting) or placebo (in the sorafenib-refractory setting) (n=672). The conclusion of the meta-analysis was that checkpoint inhibitors were associated with superior OS (HR, 0.75; P = .006), progression-free survival (HR, 0.74; P = .03), and ORR (odds ratio [OR], 2.82; P < .001) and lower odds of grade 3 or 4 treatment-related adverse events (OR, 0.44; P = .04) than the comparators, confirming that immunotherapy remains an integral part of the treatment of patients with uHCC.

For many years, sorafenib was the only FDA-approved systemic treatment for patients with uHCC. Initial case reports of remarkable responses of tumors to immunotherapy, and results of the Phase I/II CheckMate-040 clinical trial, led to the September 2017 FDA approval of nivolumab for the treatment of patients with uHCC after progression on sorafenib. Thereafter, several randomized clinical trials comparing sorafenib to immunotherapy and immunotherapy combinations were initiated, including the comparison of nivolumab to sorafenib. In June 2019 it was announced that this trial did not reach its prespecified endpoint, and the FDA approval for the uHCC indication was voluntarily withdrawn. In December 2021, Yau et al published the final results of the CheckMate-459 randomized trial that included 743 adult patients with advanced HCC randomly assigned to receive either nivolumab (n=371) or sorafenib (n=372) in the first line setting.  The primary endpoint was overall survival (OS) assessed in the intention-to-treat population. The median OS was 16.4 months (95% CI 13.9–18.4) with nivolumab and 14.7 months (11.9–17.2) with sorafenib (hazard ratio 0.85 [95% CI 0.72–1.02]; P = 0.075; minimum follow-up 22.8 months). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. The authors concluded that though first-line nivolumab treatment did not significantly improve OS compared with sorafenib, single-agent nivolumab might be considered a treatment option for patients in whom tyrosine kinase inhibitors or antiangiogenic drugs are not safe.

Cheng et al reported an update on the outcomes of the IMbrave150 study, 12 months after the primary analysis. This study established atezolizumab and bevacizumab as the current standard of care for the initial systemic treatment of patients with uHCC. The median OS was 19.2 months (95% CI 17.0-23.7) with atezolizumab/bevacizumab and 13.4 months (95% CI 11.4-16.9) with sorafenib (hazard ratio [HR], 0.66; 95% CI 0.52-0.85; descriptive P < 0.001). The overall response rate (ORR) was 30% with atezolizumab/bevacizumab, while treatment-related grade 3/4 adverse events occurred in 143 (43%) of 329 receiving atezolizumab/bevacizumab and 72 (46%) of 156 receiving sorafenib. Treatment-related grade 5 events occurred in 6 (2%) and 1 (<1%) patients. Therefore, atezolizumab/bevacizumab remains the first-line standard of care for patients with uHCC.

Finally, Jácome et al undertook a combined analysis of 3 randomized controlled trials (KEYNOTE-240, CheckMate-459, and IMbrave150), with 1,657 patients with uHCC and who were treated with either immunotherapy (n=985) or sorafenib (in the first-line setting) or placebo (in the sorafenib-refractory setting) (n=672). The conclusion of the meta-analysis was that checkpoint inhibitors were associated with superior OS (HR, 0.75; P = .006), progression-free survival (HR, 0.74; P = .03), and ORR (odds ratio [OR], 2.82; P < .001) and lower odds of grade 3 or 4 treatment-related adverse events (OR, 0.44; P = .04) than the comparators, confirming that immunotherapy remains an integral part of the treatment of patients with uHCC.

For many years, sorafenib was the only FDA-approved systemic treatment for patients with uHCC. Initial case reports of remarkable responses of tumors to immunotherapy, and results of the Phase I/II CheckMate-040 clinical trial, led to the September 2017 FDA approval of nivolumab for the treatment of patients with uHCC after progression on sorafenib. Thereafter, several randomized clinical trials comparing sorafenib to immunotherapy and immunotherapy combinations were initiated, including the comparison of nivolumab to sorafenib. In June 2019 it was announced that this trial did not reach its prespecified endpoint, and the FDA approval for the uHCC indication was voluntarily withdrawn. In December 2021, Yau et al published the final results of the CheckMate-459 randomized trial that included 743 adult patients with advanced HCC randomly assigned to receive either nivolumab (n=371) or sorafenib (n=372) in the first line setting.  The primary endpoint was overall survival (OS) assessed in the intention-to-treat population. The median OS was 16.4 months (95% CI 13.9–18.4) with nivolumab and 14.7 months (11.9–17.2) with sorafenib (hazard ratio 0.85 [95% CI 0.72–1.02]; P = 0.075; minimum follow-up 22.8 months). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. The authors concluded that though first-line nivolumab treatment did not significantly improve OS compared with sorafenib, single-agent nivolumab might be considered a treatment option for patients in whom tyrosine kinase inhibitors or antiangiogenic drugs are not safe.

Cheng et al reported an update on the outcomes of the IMbrave150 study, 12 months after the primary analysis. This study established atezolizumab and bevacizumab as the current standard of care for the initial systemic treatment of patients with uHCC. The median OS was 19.2 months (95% CI 17.0-23.7) with atezolizumab/bevacizumab and 13.4 months (95% CI 11.4-16.9) with sorafenib (hazard ratio [HR], 0.66; 95% CI 0.52-0.85; descriptive P < 0.001). The overall response rate (ORR) was 30% with atezolizumab/bevacizumab, while treatment-related grade 3/4 adverse events occurred in 143 (43%) of 329 receiving atezolizumab/bevacizumab and 72 (46%) of 156 receiving sorafenib. Treatment-related grade 5 events occurred in 6 (2%) and 1 (<1%) patients. Therefore, atezolizumab/bevacizumab remains the first-line standard of care for patients with uHCC.

Finally, Jácome et al undertook a combined analysis of 3 randomized controlled trials (KEYNOTE-240, CheckMate-459, and IMbrave150), with 1,657 patients with uHCC and who were treated with either immunotherapy (n=985) or sorafenib (in the first-line setting) or placebo (in the sorafenib-refractory setting) (n=672). The conclusion of the meta-analysis was that checkpoint inhibitors were associated with superior OS (HR, 0.75; P = .006), progression-free survival (HR, 0.74; P = .03), and ORR (odds ratio [OR], 2.82; P < .001) and lower odds of grade 3 or 4 treatment-related adverse events (OR, 0.44; P = .04) than the comparators, confirming that immunotherapy remains an integral part of the treatment of patients with uHCC.

Laparoscopic HCC resections are increasing worldwide. Ivanics et al. report on a retrospective single-institution experience in North America that involves 149 patients who were matched by propensity score. Laparoscopic liver resection was performed in 57, and open liver resection was completed in 92. The laparoscopic liver resection group experienced a lower number of serious complications (14% vs 29%; P = .01). The 1-year overall survival (OS) rate was 90.9% vs 91.3% in the laparoscopic liver resection versus open liver resection group, while 3-year OS was 79.3% vs 88.5%, and 5-year OS was 70.5% vs 83.1% (P = .26). The cumulative incidence of recurrence at 1 year was 31.1% vs 18.9% in the laparoscopic liver resection versus open liver resection group, at 3 years was 59.7% vs 40.6%, and at 5 years was 62.9% vs 49.2% (P = .06). The authors concluded that laparoscopic HCC resection had fewer short-term complications, and statistically equivalent tumor control, compared to open liver resection, and should be considered as an option for treatment of patients with resectable liver cancer.

Radioembolization is a common treatment for liver-dominant HCC. Selective internal radiation therapy (SIRT) has a high objective response rate, but has yet to demonstrate a OS benefit. This could be due to incidental damage to the healthy liver, resulting in scarring, liver decompensation and a shorter survival. Van Doom et al. retrospectively analyzed 69 patients with advanced HCC who underwent SIRT. The primary outcome was the percentage of patients who developed Child-Pugh (CP) ≥ B7 liver disease after SIRT. The secondary outcomes were OS and response. After a median follow-up of 30 months, 38/69 patients (55%) developed CP ≥ B7. A lower ALBI score at baseline was significantly associated with a better outcome. The median OS in the SIRT-treated patients was 18 months (95% CI 14–22) compared to a case-matched cohort of 300 patients treated with sorafenib between 2007 and 2016 where the median OS was 8 months (95% CI 6–12; p = 0.0027). The authors concluded that patients with intermediate- or advanced-stage HCC treated with SIRT have a substantial risk of developing liver decompensation, but improved patient selection using the ALBI score may mitigate this risk. Note is made that the sorafenib patients were treated at a time when limited systemic options were available.

Finally, Peng et al. analyzed 699 adults with newly diagnosed HCC who were initially treated with transarterial chemoembolization (TACE) between 2010 and 2013. Initial treatment with TACE resulted in a complete response (CR) in 22.3% of the patients. The patients with a CR had a better OS than those who did not achieve CR (35.8 vs 24.0 months, P < 0.001). Predictors of lower likelihood of CR included CP B cirrhosis, higher tumor load, bilobar tumor, alpha-fetoprotein (AFP) level ≥20, and platelet counts >150,000. The authors concluded that TACE is an excellent treatment for selected patients with localized HCC.

Laparoscopic HCC resections are increasing worldwide. Ivanics et al. report on a retrospective single-institution experience in North America that involves 149 patients who were matched by propensity score. Laparoscopic liver resection was performed in 57, and open liver resection was completed in 92. The laparoscopic liver resection group experienced a lower number of serious complications (14% vs 29%; P = .01). The 1-year overall survival (OS) rate was 90.9% vs 91.3% in the laparoscopic liver resection versus open liver resection group, while 3-year OS was 79.3% vs 88.5%, and 5-year OS was 70.5% vs 83.1% (P = .26). The cumulative incidence of recurrence at 1 year was 31.1% vs 18.9% in the laparoscopic liver resection versus open liver resection group, at 3 years was 59.7% vs 40.6%, and at 5 years was 62.9% vs 49.2% (P = .06). The authors concluded that laparoscopic HCC resection had fewer short-term complications, and statistically equivalent tumor control, compared to open liver resection, and should be considered as an option for treatment of patients with resectable liver cancer.

Radioembolization is a common treatment for liver-dominant HCC. Selective internal radiation therapy (SIRT) has a high objective response rate, but has yet to demonstrate a OS benefit. This could be due to incidental damage to the healthy liver, resulting in scarring, liver decompensation and a shorter survival. Van Doom et al. retrospectively analyzed 69 patients with advanced HCC who underwent SIRT. The primary outcome was the percentage of patients who developed Child-Pugh (CP) ≥ B7 liver disease after SIRT. The secondary outcomes were OS and response. After a median follow-up of 30 months, 38/69 patients (55%) developed CP ≥ B7. A lower ALBI score at baseline was significantly associated with a better outcome. The median OS in the SIRT-treated patients was 18 months (95% CI 14–22) compared to a case-matched cohort of 300 patients treated with sorafenib between 2007 and 2016 where the median OS was 8 months (95% CI 6–12; p = 0.0027). The authors concluded that patients with intermediate- or advanced-stage HCC treated with SIRT have a substantial risk of developing liver decompensation, but improved patient selection using the ALBI score may mitigate this risk. Note is made that the sorafenib patients were treated at a time when limited systemic options were available.

Finally, Peng et al. analyzed 699 adults with newly diagnosed HCC who were initially treated with transarterial chemoembolization (TACE) between 2010 and 2013. Initial treatment with TACE resulted in a complete response (CR) in 22.3% of the patients. The patients with a CR had a better OS than those who did not achieve CR (35.8 vs 24.0 months, P < 0.001). Predictors of lower likelihood of CR included CP B cirrhosis, higher tumor load, bilobar tumor, alpha-fetoprotein (AFP) level ≥20, and platelet counts >150,000. The authors concluded that TACE is an excellent treatment for selected patients with localized HCC.

Laparoscopic HCC resections are increasing worldwide. Ivanics et al. report on a retrospective single-institution experience in North America that involves 149 patients who were matched by propensity score. Laparoscopic liver resection was performed in 57, and open liver resection was completed in 92. The laparoscopic liver resection group experienced a lower number of serious complications (14% vs 29%; P = .01). The 1-year overall survival (OS) rate was 90.9% vs 91.3% in the laparoscopic liver resection versus open liver resection group, while 3-year OS was 79.3% vs 88.5%, and 5-year OS was 70.5% vs 83.1% (P = .26). The cumulative incidence of recurrence at 1 year was 31.1% vs 18.9% in the laparoscopic liver resection versus open liver resection group, at 3 years was 59.7% vs 40.6%, and at 5 years was 62.9% vs 49.2% (P = .06). The authors concluded that laparoscopic HCC resection had fewer short-term complications, and statistically equivalent tumor control, compared to open liver resection, and should be considered as an option for treatment of patients with resectable liver cancer.

Radioembolization is a common treatment for liver-dominant HCC. Selective internal radiation therapy (SIRT) has a high objective response rate, but has yet to demonstrate a OS benefit. This could be due to incidental damage to the healthy liver, resulting in scarring, liver decompensation and a shorter survival. Van Doom et al. retrospectively analyzed 69 patients with advanced HCC who underwent SIRT. The primary outcome was the percentage of patients who developed Child-Pugh (CP) ≥ B7 liver disease after SIRT. The secondary outcomes were OS and response. After a median follow-up of 30 months, 38/69 patients (55%) developed CP ≥ B7. A lower ALBI score at baseline was significantly associated with a better outcome. The median OS in the SIRT-treated patients was 18 months (95% CI 14–22) compared to a case-matched cohort of 300 patients treated with sorafenib between 2007 and 2016 where the median OS was 8 months (95% CI 6–12; p = 0.0027). The authors concluded that patients with intermediate- or advanced-stage HCC treated with SIRT have a substantial risk of developing liver decompensation, but improved patient selection using the ALBI score may mitigate this risk. Note is made that the sorafenib patients were treated at a time when limited systemic options were available.

Finally, Peng et al. analyzed 699 adults with newly diagnosed HCC who were initially treated with transarterial chemoembolization (TACE) between 2010 and 2013. Initial treatment with TACE resulted in a complete response (CR) in 22.3% of the patients. The patients with a CR had a better OS than those who did not achieve CR (35.8 vs 24.0 months, P < 0.001). Predictors of lower likelihood of CR included CP B cirrhosis, higher tumor load, bilobar tumor, alpha-fetoprotein (AFP) level ≥20, and platelet counts >150,000. The authors concluded that TACE is an excellent treatment for selected patients with localized HCC.

Tyrosine kinase inhibitors are the mainstay of systemic HCC therapy, however treatment at FDA-approved doses frequently leads to unacceptable toxicities, leading to reductions in the prescribed dose. Tokunaga et al. investigated whether lenvatinib dose intensity affects outcomes of patients with unresectable HCC. This was a retrospective analysis of 100 patients who received lenvatinib in the first- or later-line settings. Fifty-one patients started lenvatinib at the standard dose and 49 patients at a reduced dose. Dose reduction was carried out in 29 patients during cycle 1, and 62 patients during all cycles, with the cumulative dose reduction rate in all cycles of 79.9%.  Upon analysis, the authors confirmed that tumor responses and stable disease on lenvatinib correlated favorably with overall survival (OS) and time to progression (TTP). In addition, they found that higher dose intensity correlated with a higher response rate, though most (56%) patients were unable to maintain the recommended dose intensity due to unacceptable adverse events. In the final analysis, dose modification was not negatively associated with OS, TTP, or disease control with lenvatinib. Therefore, it remains reasonable to adjust the dose of lenvatinib to minimize toxicity that would affect adversely patient quality of life. Disease control remains the best predictor of longer survival, though it does not seem that highest doses of lenvatinib are needed to achieve that benefit.

Cabozantinib is approved for previously treated patients with unresectable HCC based on the phase III CELESTIAL trial that enrolled patients with Child Pugh A liver disease who had received up to two previous systemic treatments, one of which was sorafenib. This study demonstrated a statistically significant improvement in overall- and disease-free survival. Kelley et al analyzed the outcomes based on the albumin-bilirubin (ALBI) grade, an objective measure of liver function, of patients in the CELESTIAL trial. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin. The median OS was 17.5 months in the cabozantinib arm versus 11.4 months in the placebo arm for the ALBI grade 1 subgroup, and 8.0 months in the cabozantinib arm versus 6.4 months in the placebo arm for the ALBI grade 2 subgroup. The authors concluded that cabozantinib benefits patients with unresectable HCC irrespective of their ALBI grade, though liver dysfunction remains a poor prognostic indicator in patients with HCC.

Finally, Liu et al analyzed 27 patients with HCC (8 with extrahepatic spread) who received a combination of chemotherapy via hepatic artery infusion, anti-PD-1 immunotherapy, and tyrosine kinase inhibitor. Combination chemotherapy and immunotherapy resulted in a median progression-free survival of 10.6 months with a median 12.9 months’ follow up; the objective response rate was 63.0% and the disease control rate was 92.6%. The authors concluded that this combination of therapies was effective and well-tolerated, with a confirmatory phase 3 study planned.

Tyrosine kinase inhibitors are the mainstay of systemic HCC therapy, however treatment at FDA-approved doses frequently leads to unacceptable toxicities, leading to reductions in the prescribed dose. Tokunaga et al. investigated whether lenvatinib dose intensity affects outcomes of patients with unresectable HCC. This was a retrospective analysis of 100 patients who received lenvatinib in the first- or later-line settings. Fifty-one patients started lenvatinib at the standard dose and 49 patients at a reduced dose. Dose reduction was carried out in 29 patients during cycle 1, and 62 patients during all cycles, with the cumulative dose reduction rate in all cycles of 79.9%.  Upon analysis, the authors confirmed that tumor responses and stable disease on lenvatinib correlated favorably with overall survival (OS) and time to progression (TTP). In addition, they found that higher dose intensity correlated with a higher response rate, though most (56%) patients were unable to maintain the recommended dose intensity due to unacceptable adverse events. In the final analysis, dose modification was not negatively associated with OS, TTP, or disease control with lenvatinib. Therefore, it remains reasonable to adjust the dose of lenvatinib to minimize toxicity that would affect adversely patient quality of life. Disease control remains the best predictor of longer survival, though it does not seem that highest doses of lenvatinib are needed to achieve that benefit.

Cabozantinib is approved for previously treated patients with unresectable HCC based on the phase III CELESTIAL trial that enrolled patients with Child Pugh A liver disease who had received up to two previous systemic treatments, one of which was sorafenib. This study demonstrated a statistically significant improvement in overall- and disease-free survival. Kelley et al analyzed the outcomes based on the albumin-bilirubin (ALBI) grade, an objective measure of liver function, of patients in the CELESTIAL trial. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin. The median OS was 17.5 months in the cabozantinib arm versus 11.4 months in the placebo arm for the ALBI grade 1 subgroup, and 8.0 months in the cabozantinib arm versus 6.4 months in the placebo arm for the ALBI grade 2 subgroup. The authors concluded that cabozantinib benefits patients with unresectable HCC irrespective of their ALBI grade, though liver dysfunction remains a poor prognostic indicator in patients with HCC.

Finally, Liu et al analyzed 27 patients with HCC (8 with extrahepatic spread) who received a combination of chemotherapy via hepatic artery infusion, anti-PD-1 immunotherapy, and tyrosine kinase inhibitor. Combination chemotherapy and immunotherapy resulted in a median progression-free survival of 10.6 months with a median 12.9 months’ follow up; the objective response rate was 63.0% and the disease control rate was 92.6%. The authors concluded that this combination of therapies was effective and well-tolerated, with a confirmatory phase 3 study planned.

Tyrosine kinase inhibitors are the mainstay of systemic HCC therapy, however treatment at FDA-approved doses frequently leads to unacceptable toxicities, leading to reductions in the prescribed dose. Tokunaga et al. investigated whether lenvatinib dose intensity affects outcomes of patients with unresectable HCC. This was a retrospective analysis of 100 patients who received lenvatinib in the first- or later-line settings. Fifty-one patients started lenvatinib at the standard dose and 49 patients at a reduced dose. Dose reduction was carried out in 29 patients during cycle 1, and 62 patients during all cycles, with the cumulative dose reduction rate in all cycles of 79.9%.  Upon analysis, the authors confirmed that tumor responses and stable disease on lenvatinib correlated favorably with overall survival (OS) and time to progression (TTP). In addition, they found that higher dose intensity correlated with a higher response rate, though most (56%) patients were unable to maintain the recommended dose intensity due to unacceptable adverse events. In the final analysis, dose modification was not negatively associated with OS, TTP, or disease control with lenvatinib. Therefore, it remains reasonable to adjust the dose of lenvatinib to minimize toxicity that would affect adversely patient quality of life. Disease control remains the best predictor of longer survival, though it does not seem that highest doses of lenvatinib are needed to achieve that benefit.

Cabozantinib is approved for previously treated patients with unresectable HCC based on the phase III CELESTIAL trial that enrolled patients with Child Pugh A liver disease who had received up to two previous systemic treatments, one of which was sorafenib. This study demonstrated a statistically significant improvement in overall- and disease-free survival. Kelley et al analyzed the outcomes based on the albumin-bilirubin (ALBI) grade, an objective measure of liver function, of patients in the CELESTIAL trial. ALBI scores were retrospectively calculated based on baseline serum albumin and total bilirubin. The median OS was 17.5 months in the cabozantinib arm versus 11.4 months in the placebo arm for the ALBI grade 1 subgroup, and 8.0 months in the cabozantinib arm versus 6.4 months in the placebo arm for the ALBI grade 2 subgroup. The authors concluded that cabozantinib benefits patients with unresectable HCC irrespective of their ALBI grade, though liver dysfunction remains a poor prognostic indicator in patients with HCC.

Finally, Liu et al analyzed 27 patients with HCC (8 with extrahepatic spread) who received a combination of chemotherapy via hepatic artery infusion, anti-PD-1 immunotherapy, and tyrosine kinase inhibitor. Combination chemotherapy and immunotherapy resulted in a median progression-free survival of 10.6 months with a median 12.9 months’ follow up; the objective response rate was 63.0% and the disease control rate was 92.6%. The authors concluded that this combination of therapies was effective and well-tolerated, with a confirmatory phase 3 study planned.

Treatment of patients with hepatocellular carcinoma (HCC) requires a multidisciplinary approach. This month we will review articles that analyze outcomes after liver resection compared to percutaneous ablation, prediction of immunotherapy efficacy based on observed treatment-related side effects, and the risk of subsequent malignancies in patients with HCC.

Xie et al. reported their retrospective review of outcomes of 67 adults with resectable caudate HCC within Milan criteria. Out of these, 46 underwent hepatic resection and 21 underwent percutaneous ablation. Overall survival at 1, 3, and 5 years was 97.6%, 83.6%, and 71.5%, respectively, for the hepatic resection patients, vs 89.4%, 58.5%, and 48.8%, respectively, for the percutaneous ablation patients (P = 0.032). Recurrence-free survival at these time points was 77.6%, 47.9%, and 42.6%, respectively, for the hepatic resection group, and 40.5%, 23.2%, and 15.4%, respectively, for the percutaneous ablation group (P = 0.010). The investigators concluded that HCC patients who underwent hepatic resection had significantly higher rates of recurrence-free and overall survival compared to those who underwent percutaneous ablation.

For those patients with unresectable HCC, systemic immune checkpoint inhibitor therapy is now part of the standard of care. Treatment-associated adverse events occur in over half of patients treated with immunotherapy. Pinato et al. reviewed the outcomes of a cohort of 406 adults with unresectable or advanced HCC who were receiving immune checkpoint inhibitor therapy while enrolled in clinical trials that were submitted to the Food and Drug Administration. the development of adverse events was associated with longer overall survival and progression-free survival rates compared to patients who did not develop treatment-related adverse events (16.7 months vs 11.2 months; 5.5 months vs 2.2 months, respectively).  The authors concluded that the development of treatment-related adverse events was significantly correlated with improve overall and progression-free survival in HCC patients treated with ICI monotherapy in clinical trials.

Finally, Kong et al. retrospectively looked at a cohort of 40,314 adult patients diagnosed with HCC between 2000 and 2014 in the SEER database, identifying the incidence of second primary cancers. Overall, the patients were followed for a median of 19 months following their HCC diagnosis. A total of 1,593 HCC patients (3.95%) developed secondary primary malignancies starting at 2 months after their initial HCC diagnosis. The 3-, 5-, and 10-year cumulative incidence of developing second primary malignancies were 2.35%, 3.12%, and 4.51%. The top five sites of the second primary malignancies were lung and bronchus, prostate, non-Hodgkin lymphoma, colon, and breast. The patients with poorer tumor-related characteristics such as larger tumor size, vascular invasion, positive AFP level, poorer tumor grade, and distant extension were associated with a decreased risk of developing second primary cancers, most probably because of their higher risk of dying from HCC. The authors developed a competing-risk nomogram for the purpose of improving guideline surveillance and further management of HCC survivors, concluding that HCC survivors should be monitored for evidence of secondary primary cancers.

Treatment of patients with hepatocellular carcinoma (HCC) requires a multidisciplinary approach. This month we will review articles that analyze outcomes after liver resection compared to percutaneous ablation, prediction of immunotherapy efficacy based on observed treatment-related side effects, and the risk of subsequent malignancies in patients with HCC.

Xie et al. reported their retrospective review of outcomes of 67 adults with resectable caudate HCC within Milan criteria. Out of these, 46 underwent hepatic resection and 21 underwent percutaneous ablation. Overall survival at 1, 3, and 5 years was 97.6%, 83.6%, and 71.5%, respectively, for the hepatic resection patients, vs 89.4%, 58.5%, and 48.8%, respectively, for the percutaneous ablation patients (P = 0.032). Recurrence-free survival at these time points was 77.6%, 47.9%, and 42.6%, respectively, for the hepatic resection group, and 40.5%, 23.2%, and 15.4%, respectively, for the percutaneous ablation group (P = 0.010). The investigators concluded that HCC patients who underwent hepatic resection had significantly higher rates of recurrence-free and overall survival compared to those who underwent percutaneous ablation.

For those patients with unresectable HCC, systemic immune checkpoint inhibitor therapy is now part of the standard of care. Treatment-associated adverse events occur in over half of patients treated with immunotherapy. Pinato et al. reviewed the outcomes of a cohort of 406 adults with unresectable or advanced HCC who were receiving immune checkpoint inhibitor therapy while enrolled in clinical trials that were submitted to the Food and Drug Administration. the development of adverse events was associated with longer overall survival and progression-free survival rates compared to patients who did not develop treatment-related adverse events (16.7 months vs 11.2 months; 5.5 months vs 2.2 months, respectively).  The authors concluded that the development of treatment-related adverse events was significantly correlated with improve overall and progression-free survival in HCC patients treated with ICI monotherapy in clinical trials.

Finally, Kong et al. retrospectively looked at a cohort of 40,314 adult patients diagnosed with HCC between 2000 and 2014 in the SEER database, identifying the incidence of second primary cancers. Overall, the patients were followed for a median of 19 months following their HCC diagnosis. A total of 1,593 HCC patients (3.95%) developed secondary primary malignancies starting at 2 months after their initial HCC diagnosis. The 3-, 5-, and 10-year cumulative incidence of developing second primary malignancies were 2.35%, 3.12%, and 4.51%. The top five sites of the second primary malignancies were lung and bronchus, prostate, non-Hodgkin lymphoma, colon, and breast. The patients with poorer tumor-related characteristics such as larger tumor size, vascular invasion, positive AFP level, poorer tumor grade, and distant extension were associated with a decreased risk of developing second primary cancers, most probably because of their higher risk of dying from HCC. The authors developed a competing-risk nomogram for the purpose of improving guideline surveillance and further management of HCC survivors, concluding that HCC survivors should be monitored for evidence of secondary primary cancers.

Treatment of patients with hepatocellular carcinoma (HCC) requires a multidisciplinary approach. This month we will review articles that analyze outcomes after liver resection compared to percutaneous ablation, prediction of immunotherapy efficacy based on observed treatment-related side effects, and the risk of subsequent malignancies in patients with HCC.

Xie et al. reported their retrospective review of outcomes of 67 adults with resectable caudate HCC within Milan criteria. Out of these, 46 underwent hepatic resection and 21 underwent percutaneous ablation. Overall survival at 1, 3, and 5 years was 97.6%, 83.6%, and 71.5%, respectively, for the hepatic resection patients, vs 89.4%, 58.5%, and 48.8%, respectively, for the percutaneous ablation patients (P = 0.032). Recurrence-free survival at these time points was 77.6%, 47.9%, and 42.6%, respectively, for the hepatic resection group, and 40.5%, 23.2%, and 15.4%, respectively, for the percutaneous ablation group (P = 0.010). The investigators concluded that HCC patients who underwent hepatic resection had significantly higher rates of recurrence-free and overall survival compared to those who underwent percutaneous ablation.

For those patients with unresectable HCC, systemic immune checkpoint inhibitor therapy is now part of the standard of care. Treatment-associated adverse events occur in over half of patients treated with immunotherapy. Pinato et al. reviewed the outcomes of a cohort of 406 adults with unresectable or advanced HCC who were receiving immune checkpoint inhibitor therapy while enrolled in clinical trials that were submitted to the Food and Drug Administration. the development of adverse events was associated with longer overall survival and progression-free survival rates compared to patients who did not develop treatment-related adverse events (16.7 months vs 11.2 months; 5.5 months vs 2.2 months, respectively).  The authors concluded that the development of treatment-related adverse events was significantly correlated with improve overall and progression-free survival in HCC patients treated with ICI monotherapy in clinical trials.

Finally, Kong et al. retrospectively looked at a cohort of 40,314 adult patients diagnosed with HCC between 2000 and 2014 in the SEER database, identifying the incidence of second primary cancers. Overall, the patients were followed for a median of 19 months following their HCC diagnosis. A total of 1,593 HCC patients (3.95%) developed secondary primary malignancies starting at 2 months after their initial HCC diagnosis. The 3-, 5-, and 10-year cumulative incidence of developing second primary malignancies were 2.35%, 3.12%, and 4.51%. The top five sites of the second primary malignancies were lung and bronchus, prostate, non-Hodgkin lymphoma, colon, and breast. The patients with poorer tumor-related characteristics such as larger tumor size, vascular invasion, positive AFP level, poorer tumor grade, and distant extension were associated with a decreased risk of developing second primary cancers, most probably because of their higher risk of dying from HCC. The authors developed a competing-risk nomogram for the purpose of improving guideline surveillance and further management of HCC survivors, concluding that HCC survivors should be monitored for evidence of secondary primary cancers.