Hepatocellular Carcinoma

Key clinical point: In addition to being safe, perioperative administration of nivolumab with or without ipilimumab may elicit a major response with longer recurrence-free survival in patients with resectable hepatocellular carcinoma (HCC).

Main finding: Grade 3/4 treatment-related adverse events were observed in 43% and 23% of patients with nivolumab+ipilimumab and nivolumab alone, respectively (P = .69). Of the patients who underwent surgery, nivolumab alone and nivolumab+ipilimumab caused a major pathology-related response in 33% (95% CI 7.5%-70.1%) and 27% (95% CI 6%-61%), respectively, who showed improved recurrence-free survival vs. those with no pathological response (log-rank P = .049).

Study details: This was a single-center, phase 2 trial including 27 adult patients with resectable HCC who were randomly assigned to receive nivolumab alone (n = 13) or nivolumab plus ipilimumab (n = 14) before and after partial hepatectomy.

Disclosures: The study was sponsored by Bristol Myers Squibb (BMS) and the US National Institutes of Health. A few authors, including the lead author, served as a consultants/advisors or were stock owners of and received research funding/honoraria from numerous organizations including BMS.

Source: Kaseb AO et al. Lancet Gastroenterol Hepatol. 2022;7(3):P208-18 (Jan 19). Doi: 10.1016/S2468-1253(21)00427-1.

Key clinical point: In addition to being safe, perioperative administration of nivolumab with or without ipilimumab may elicit a major response with longer recurrence-free survival in patients with resectable hepatocellular carcinoma (HCC).

Main finding: Grade 3/4 treatment-related adverse events were observed in 43% and 23% of patients with nivolumab+ipilimumab and nivolumab alone, respectively (P = .69). Of the patients who underwent surgery, nivolumab alone and nivolumab+ipilimumab caused a major pathology-related response in 33% (95% CI 7.5%-70.1%) and 27% (95% CI 6%-61%), respectively, who showed improved recurrence-free survival vs. those with no pathological response (log-rank P = .049).

Study details: This was a single-center, phase 2 trial including 27 adult patients with resectable HCC who were randomly assigned to receive nivolumab alone (n = 13) or nivolumab plus ipilimumab (n = 14) before and after partial hepatectomy.

Disclosures: The study was sponsored by Bristol Myers Squibb (BMS) and the US National Institutes of Health. A few authors, including the lead author, served as a consultants/advisors or were stock owners of and received research funding/honoraria from numerous organizations including BMS.

Source: Kaseb AO et al. Lancet Gastroenterol Hepatol. 2022;7(3):P208-18 (Jan 19). Doi: 10.1016/S2468-1253(21)00427-1.

Key clinical point: In addition to being safe, perioperative administration of nivolumab with or without ipilimumab may elicit a major response with longer recurrence-free survival in patients with resectable hepatocellular carcinoma (HCC).

Main finding: Grade 3/4 treatment-related adverse events were observed in 43% and 23% of patients with nivolumab+ipilimumab and nivolumab alone, respectively (P = .69). Of the patients who underwent surgery, nivolumab alone and nivolumab+ipilimumab caused a major pathology-related response in 33% (95% CI 7.5%-70.1%) and 27% (95% CI 6%-61%), respectively, who showed improved recurrence-free survival vs. those with no pathological response (log-rank P = .049).

Study details: This was a single-center, phase 2 trial including 27 adult patients with resectable HCC who were randomly assigned to receive nivolumab alone (n = 13) or nivolumab plus ipilimumab (n = 14) before and after partial hepatectomy.

Disclosures: The study was sponsored by Bristol Myers Squibb (BMS) and the US National Institutes of Health. A few authors, including the lead author, served as a consultants/advisors or were stock owners of and received research funding/honoraria from numerous organizations including BMS.

Source: Kaseb AO et al. Lancet Gastroenterol Hepatol. 2022;7(3):P208-18 (Jan 19). Doi: 10.1016/S2468-1253(21)00427-1.

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.

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.

Key clinical point: Among patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT), a treatment regimen consisting of sirolimus- or everolimus-based immunosuppression prolonged survival compared with mammalian target of rapamycin inhibitor (mTORi)-free immunosuppression.

Major finding: Improvement in overall survival was observed with mTORi-based vs mTORi-free immunosuppression in both randomized controlled trials (RCTs; 1 year: relative risk [RR], 1.04; 95% CI, 1.00-1.08; 5 years: RR, 1.13; 95% CI, 1.02-1.26) and cohort studies (1 year: RR, 1.13; 95% CI, 1.06-1.20; 5 years: RR, 1.17; 95% CI, 1.10-1.24).

Study details: Findings are from a meta-analysis of 17 studies (RCTs, 3; cohort studies, 14) including adult patients undergoing LT for HCC who received mTORi-based or mTORi-free immunosuppression.

Disclosures: The study was supported by the National Natural Science Foundation of China. No conflict of interests was reported.

Source: Yan X et al. Liver Transpl. 2021 Dec 16. doi: 10.1002/lt.26387.

Key clinical point: Among patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT), a treatment regimen consisting of sirolimus- or everolimus-based immunosuppression prolonged survival compared with mammalian target of rapamycin inhibitor (mTORi)-free immunosuppression.

Major finding: Improvement in overall survival was observed with mTORi-based vs mTORi-free immunosuppression in both randomized controlled trials (RCTs; 1 year: relative risk [RR], 1.04; 95% CI, 1.00-1.08; 5 years: RR, 1.13; 95% CI, 1.02-1.26) and cohort studies (1 year: RR, 1.13; 95% CI, 1.06-1.20; 5 years: RR, 1.17; 95% CI, 1.10-1.24).

Study details: Findings are from a meta-analysis of 17 studies (RCTs, 3; cohort studies, 14) including adult patients undergoing LT for HCC who received mTORi-based or mTORi-free immunosuppression.

Disclosures: The study was supported by the National Natural Science Foundation of China. No conflict of interests was reported.

Source: Yan X et al. Liver Transpl. 2021 Dec 16. doi: 10.1002/lt.26387.

Key clinical point: Among patients with hepatocellular carcinoma (HCC) who underwent liver transplantation (LT), a treatment regimen consisting of sirolimus- or everolimus-based immunosuppression prolonged survival compared with mammalian target of rapamycin inhibitor (mTORi)-free immunosuppression.

Major finding: Improvement in overall survival was observed with mTORi-based vs mTORi-free immunosuppression in both randomized controlled trials (RCTs; 1 year: relative risk [RR], 1.04; 95% CI, 1.00-1.08; 5 years: RR, 1.13; 95% CI, 1.02-1.26) and cohort studies (1 year: RR, 1.13; 95% CI, 1.06-1.20; 5 years: RR, 1.17; 95% CI, 1.10-1.24).

Study details: Findings are from a meta-analysis of 17 studies (RCTs, 3; cohort studies, 14) including adult patients undergoing LT for HCC who received mTORi-based or mTORi-free immunosuppression.

Disclosures: The study was supported by the National Natural Science Foundation of China. No conflict of interests was reported.

Source: Yan X et al. Liver Transpl. 2021 Dec 16. doi: 10.1002/lt.26387.

Key clinical point: The presence of nonalcoholic fatty liver disease (NAFLD) or metabolic syndrome (MS) did not affect the long-term oncological outcomes in patients with hepatocellular carcinoma (HCC) treated with multibipolar percutaneous radiofrequency ablation (RFA).

Major finding: Neither NAFLD-HCC nor MS was associated with overall tumor recurrence (hazard ratio [HR], 1.12; P = .536 and HR, 0.99; P = .965, respectively) or overall survival (HR, 1.19; P = .45 and HR, 0.99; P = .980, respectively).

Study details: This multicenter retrospective study included 520 adult patients with HCC who underwent first-line multibipolar percutaneous RFA treatment.

Disclosures: The study did not receive any specific funding. T Dao, N Ganne-Carrié, and JC Nault reported receiving grants, speaker’s fees, personal fees, or invitations for medical meetings from various pharmaceutical companies.

Source: Nguyen N et al. Liver Int. 2021 Dec 11. doi: 10.1111/liv.15129.

Key clinical point: The presence of nonalcoholic fatty liver disease (NAFLD) or metabolic syndrome (MS) did not affect the long-term oncological outcomes in patients with hepatocellular carcinoma (HCC) treated with multibipolar percutaneous radiofrequency ablation (RFA).

Major finding: Neither NAFLD-HCC nor MS was associated with overall tumor recurrence (hazard ratio [HR], 1.12; P = .536 and HR, 0.99; P = .965, respectively) or overall survival (HR, 1.19; P = .45 and HR, 0.99; P = .980, respectively).

Study details: This multicenter retrospective study included 520 adult patients with HCC who underwent first-line multibipolar percutaneous RFA treatment.

Disclosures: The study did not receive any specific funding. T Dao, N Ganne-Carrié, and JC Nault reported receiving grants, speaker’s fees, personal fees, or invitations for medical meetings from various pharmaceutical companies.

Source: Nguyen N et al. Liver Int. 2021 Dec 11. doi: 10.1111/liv.15129.

Key clinical point: The presence of nonalcoholic fatty liver disease (NAFLD) or metabolic syndrome (MS) did not affect the long-term oncological outcomes in patients with hepatocellular carcinoma (HCC) treated with multibipolar percutaneous radiofrequency ablation (RFA).

Major finding: Neither NAFLD-HCC nor MS was associated with overall tumor recurrence (hazard ratio [HR], 1.12; P = .536 and HR, 0.99; P = .965, respectively) or overall survival (HR, 1.19; P = .45 and HR, 0.99; P = .980, respectively).

Study details: This multicenter retrospective study included 520 adult patients with HCC who underwent first-line multibipolar percutaneous RFA treatment.

Disclosures: The study did not receive any specific funding. T Dao, N Ganne-Carrié, and JC Nault reported receiving grants, speaker’s fees, personal fees, or invitations for medical meetings from various pharmaceutical companies.

Source: Nguyen N et al. Liver Int. 2021 Dec 11. doi: 10.1111/liv.15129.

Key clinical point: Treatment with immune checkpoint inhibitors (ICIs) was associated with prolonged survival and better safety compared with standard care in patients with unresectable hepatocellular carcinoma (HCC).

Major finding: ICIs vs standard care were associated with superior overall survival (hazard ratio [HR], 0.75; P = .006), progression-free survival (HR, 0.74; P = .03), and overall response rate (odds ratio [OR], 2.82; P < .001) and lower odds of grade 3 or 4 treatment-related adverse events (OR, 0.44; P = .04).

Study details: Findings are from a meta-analysis of 3 randomized controlled trials (KEYNOTE-240, CheckMate-459, and IMbrave150), including 1,657 patients with unresectable HCC treated with either ICIs (n=985) or standard care (n=672).

Disclosures: No source of funding was identified. The lead author and JPS Vasconcelos received grants and/or personal fees from various pharmaceutical companies.

Source: Jácome AA et al. JAMA Netw Open. 2021 Dec 6. doi: 10.1001/jamanetworkopen.2021.36128.

Key clinical point: Treatment with immune checkpoint inhibitors (ICIs) was associated with prolonged survival and better safety compared with standard care in patients with unresectable hepatocellular carcinoma (HCC).

Major finding: ICIs vs standard care were associated with superior overall survival (hazard ratio [HR], 0.75; P = .006), progression-free survival (HR, 0.74; P = .03), and overall response rate (odds ratio [OR], 2.82; P < .001) and lower odds of grade 3 or 4 treatment-related adverse events (OR, 0.44; P = .04).

Study details: Findings are from a meta-analysis of 3 randomized controlled trials (KEYNOTE-240, CheckMate-459, and IMbrave150), including 1,657 patients with unresectable HCC treated with either ICIs (n=985) or standard care (n=672).

Disclosures: No source of funding was identified. The lead author and JPS Vasconcelos received grants and/or personal fees from various pharmaceutical companies.

Source: Jácome AA et al. JAMA Netw Open. 2021 Dec 6. doi: 10.1001/jamanetworkopen.2021.36128.

Key clinical point: Treatment with immune checkpoint inhibitors (ICIs) was associated with prolonged survival and better safety compared with standard care in patients with unresectable hepatocellular carcinoma (HCC).

Major finding: ICIs vs standard care were associated with superior overall survival (hazard ratio [HR], 0.75; P = .006), progression-free survival (HR, 0.74; P = .03), and overall response rate (odds ratio [OR], 2.82; P < .001) and lower odds of grade 3 or 4 treatment-related adverse events (OR, 0.44; P = .04).

Study details: Findings are from a meta-analysis of 3 randomized controlled trials (KEYNOTE-240, CheckMate-459, and IMbrave150), including 1,657 patients with unresectable HCC treated with either ICIs (n=985) or standard care (n=672).

Disclosures: No source of funding was identified. The lead author and JPS Vasconcelos received grants and/or personal fees from various pharmaceutical companies.

Source: Jácome AA et al. JAMA Netw Open. 2021 Dec 6. doi: 10.1001/jamanetworkopen.2021.36128.

Key clinical point: The better safety profile of transarterial radioembolization (TARE) together with comparable efficacy makes it a potential therapeutic alternative to surgical resection for large single nodular hepatocellular carcinoma (HCC).

Main finding: After inverse probability weighting, TARE vs surgical resection achieved similar overall survival (hazard ratio [HR], 0.98; P = .97), time to progression (HR, 1.10; P = .80), and time to intrahepatic progression (HR, 1.45; P = .30), along with a shorter hospital stay (3 days vs 12 days; P < .001) and lower patient proportion experiencing adverse events requiring intervention (0.0% vs 3.2%; P = .39).

Study details: Findings are from a retrospective cohort study including 557 adult patients with single nodular HCC measuring ≥5 cm who underwent either surgical resection (n=500) or TARE (n=57) shortly after diagnosis.

Disclosures: The authors reported no source of funding. Some of the authors received lecture fees or research grants from various sources.

Source: Kim J et al. J Nucl Med. 2021 Dec 9. doi: 10.2967/jnumed.121.263147.

Key clinical point: The better safety profile of transarterial radioembolization (TARE) together with comparable efficacy makes it a potential therapeutic alternative to surgical resection for large single nodular hepatocellular carcinoma (HCC).

Main finding: After inverse probability weighting, TARE vs surgical resection achieved similar overall survival (hazard ratio [HR], 0.98; P = .97), time to progression (HR, 1.10; P = .80), and time to intrahepatic progression (HR, 1.45; P = .30), along with a shorter hospital stay (3 days vs 12 days; P < .001) and lower patient proportion experiencing adverse events requiring intervention (0.0% vs 3.2%; P = .39).

Study details: Findings are from a retrospective cohort study including 557 adult patients with single nodular HCC measuring ≥5 cm who underwent either surgical resection (n=500) or TARE (n=57) shortly after diagnosis.

Disclosures: The authors reported no source of funding. Some of the authors received lecture fees or research grants from various sources.

Source: Kim J et al. J Nucl Med. 2021 Dec 9. doi: 10.2967/jnumed.121.263147.

Key clinical point: The better safety profile of transarterial radioembolization (TARE) together with comparable efficacy makes it a potential therapeutic alternative to surgical resection for large single nodular hepatocellular carcinoma (HCC).

Main finding: After inverse probability weighting, TARE vs surgical resection achieved similar overall survival (hazard ratio [HR], 0.98; P = .97), time to progression (HR, 1.10; P = .80), and time to intrahepatic progression (HR, 1.45; P = .30), along with a shorter hospital stay (3 days vs 12 days; P < .001) and lower patient proportion experiencing adverse events requiring intervention (0.0% vs 3.2%; P = .39).

Study details: Findings are from a retrospective cohort study including 557 adult patients with single nodular HCC measuring ≥5 cm who underwent either surgical resection (n=500) or TARE (n=57) shortly after diagnosis.

Disclosures: The authors reported no source of funding. Some of the authors received lecture fees or research grants from various sources.

Source: Kim J et al. J Nucl Med. 2021 Dec 9. doi: 10.2967/jnumed.121.263147.

Key clinical point: Alpha-fetoprotein (AFP) levels during liver transplantation (LT) and their modulation while on the waitlist are predictors of hepatocellular carcinoma (HCC) recurrence after LT in patients meeting the Milan criteria.

Main finding: An AFP value >25.5 ng/mL (area under the receiver operating characteristic curve, 0.69) could strongly predict HCC recurrence after LT (subdistribution hazard ratio, 2.5; P = .01), which also showed a significant association with an increase in AFP levels by >20.8% while on the waitlist (P = .034).

Study details: The data are derived from a retrospective single-center study that analyzed 207 patients with HCC fulfilling the Milan criteria who were put on the waitlist for LT and had AFP levels >400 ng/mL at transplant.

Disclosures: Financial support for the study was provided by the association Friends of transplantation. The authors reported no conflict of interests.

Source: Magro B et al. Cancers. 2021 Nov 27. doi: 10.3390/cancers13235976.

Key clinical point: Alpha-fetoprotein (AFP) levels during liver transplantation (LT) and their modulation while on the waitlist are predictors of hepatocellular carcinoma (HCC) recurrence after LT in patients meeting the Milan criteria.

Main finding: An AFP value >25.5 ng/mL (area under the receiver operating characteristic curve, 0.69) could strongly predict HCC recurrence after LT (subdistribution hazard ratio, 2.5; P = .01), which also showed a significant association with an increase in AFP levels by >20.8% while on the waitlist (P = .034).

Study details: The data are derived from a retrospective single-center study that analyzed 207 patients with HCC fulfilling the Milan criteria who were put on the waitlist for LT and had AFP levels >400 ng/mL at transplant.

Disclosures: Financial support for the study was provided by the association Friends of transplantation. The authors reported no conflict of interests.

Source: Magro B et al. Cancers. 2021 Nov 27. doi: 10.3390/cancers13235976.

Key clinical point: Alpha-fetoprotein (AFP) levels during liver transplantation (LT) and their modulation while on the waitlist are predictors of hepatocellular carcinoma (HCC) recurrence after LT in patients meeting the Milan criteria.

Main finding: An AFP value >25.5 ng/mL (area under the receiver operating characteristic curve, 0.69) could strongly predict HCC recurrence after LT (subdistribution hazard ratio, 2.5; P = .01), which also showed a significant association with an increase in AFP levels by >20.8% while on the waitlist (P = .034).

Study details: The data are derived from a retrospective single-center study that analyzed 207 patients with HCC fulfilling the Milan criteria who were put on the waitlist for LT and had AFP levels >400 ng/mL at transplant.

Disclosures: Financial support for the study was provided by the association Friends of transplantation. The authors reported no conflict of interests.

Source: Magro B et al. Cancers. 2021 Nov 27. doi: 10.3390/cancers13235976.

Key clinical point: High diastolic whole blood viscosity (WBV) may serve as a new independent factor associated with extrahepatic metastasis and poor survival in patients with hepatocellular carcinoma (HCC).

Main finding: After adjusting for confounding variables, high diastolic WBV was independently associated with extrahepatic metastasis (adjusted odds ratio, 23.41; P < .001) and poor survival (adjusted hazard ratio, 3.81; P < .001) and significantly predicted extrahepatic metastasis at an optimal cutoff of 16 cP (area under the receiver operating characteristic curve, 0.768; P < .001).

Study details: Findings are from a pilot retrospective study including 181 patients with HCC, of which 148 were treatment-naïve having preserved liver function and 33 received nivolumab.

Disclosures: The study was sponsored by Young Medical Scientist Research Grant through the Daewoong Foundation and the Research Fund of Seoul St. Mary’s Hospital, The Catholic University of Korea. The authors did not declare any conflict of interests.

Source: Han JW et al. PLoS ONE. 2021 Dec 2. doi: 10.1371/journal.pone.0260311.

Key clinical point: High diastolic whole blood viscosity (WBV) may serve as a new independent factor associated with extrahepatic metastasis and poor survival in patients with hepatocellular carcinoma (HCC).

Main finding: After adjusting for confounding variables, high diastolic WBV was independently associated with extrahepatic metastasis (adjusted odds ratio, 23.41; P < .001) and poor survival (adjusted hazard ratio, 3.81; P < .001) and significantly predicted extrahepatic metastasis at an optimal cutoff of 16 cP (area under the receiver operating characteristic curve, 0.768; P < .001).

Study details: Findings are from a pilot retrospective study including 181 patients with HCC, of which 148 were treatment-naïve having preserved liver function and 33 received nivolumab.

Disclosures: The study was sponsored by Young Medical Scientist Research Grant through the Daewoong Foundation and the Research Fund of Seoul St. Mary’s Hospital, The Catholic University of Korea. The authors did not declare any conflict of interests.

Source: Han JW et al. PLoS ONE. 2021 Dec 2. doi: 10.1371/journal.pone.0260311.

Key clinical point: High diastolic whole blood viscosity (WBV) may serve as a new independent factor associated with extrahepatic metastasis and poor survival in patients with hepatocellular carcinoma (HCC).

Main finding: After adjusting for confounding variables, high diastolic WBV was independently associated with extrahepatic metastasis (adjusted odds ratio, 23.41; P < .001) and poor survival (adjusted hazard ratio, 3.81; P < .001) and significantly predicted extrahepatic metastasis at an optimal cutoff of 16 cP (area under the receiver operating characteristic curve, 0.768; P < .001).

Study details: Findings are from a pilot retrospective study including 181 patients with HCC, of which 148 were treatment-naïve having preserved liver function and 33 received nivolumab.

Disclosures: The study was sponsored by Young Medical Scientist Research Grant through the Daewoong Foundation and the Research Fund of Seoul St. Mary’s Hospital, The Catholic University of Korea. The authors did not declare any conflict of interests.

Source: Han JW et al. PLoS ONE. 2021 Dec 2. doi: 10.1371/journal.pone.0260311.