To develop clinical predictive nomograms generating per-patient numerical probabilities of postoperative recurrence-free and overall survival at specific times.
The prognosis after surgical resection ...is diverse in patients with early-stage hepatocellular carcinoma (HCC).
In a retrospective review, we evaluated data from 1085 mostly early-stage patients newly diagnosed with HCC who were subsequently treated by curative resection. We randomly divided the subjects into derivation (n = 760) and validation (n = 325) samples. Multivariate Cox proportional hazards models were developed and separately validated on the basis of pre- and postoperative clinical and pathological covariates assessed for association with 2-year recurrence and 5-year HCC-specific death. The discriminatory accuracy of the models was compared with traditional tools by analyzing receiver operating characteristic curves.
The statistical nomograms built on the basis of sex, serum albumin, platelet count, microvascular invasion, and calculated tumor volume had good calibration and discriminatory abilities, with c-indices of 0.69 (2-year recurrence) and 0.66 (5-year survival), respectively. These models showed satisfactory goodness-of-fit and discrimination abilities in the independent validation cohort (c-index, 0.66 for 2-year recurrence; and 0.67 for 5-year survival). The areas under the receiver operating characteristic curve using our methods were greater than those of conventional staging systems in the validation patients, indicating better discriminatory capability (corresponding c-indices, 0.55-0.56; and 0.55-0.61, respectively).
Our simple user-friendly calculators, which present graphically postsurgical prognostic models for recurrence and survival outcomes in patients with curatively resectable HCC, offer useful guidance to clinicians and patients for individually planning recurrence surveillance and adjuvant therapy.
Summary Background There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo ...as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation. Methods We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov , number NCT00692770. Findings We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12·5 months (IQR 2·6–35·8) and 577 mg per day (SD 212·8) for sorafenib, compared with 22·2 months (8·1–38·8) and 778·0 mg per day (79·8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8·5 months (IQR 2·9–19·5) in the sorafenib group and 8·4 months (2·9–19·8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33·3 months in the sorafenib group vs 33·7 months in the placebo group; hazard ratio HR 0·940; 95% CI 0·780–1·134; one-sided p=0·26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 28% of 559 patients in the sorafenib group vs four <1% of 548 patients in the placebo group) and diarrhoea (36 6% vs five <1% in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten 2%), abnormal hepatic function (four <1%), and fatigue (three <1%). There were four (<1%) drug-related deaths in the sorafenib group and two (<1%) in the placebo group. Interpretation Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation. Funding Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals.
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•NAFLD was associated with HCC development.•NAFLD was associated with colorectal cancer development in males.•NAFLD was associated with breast cancer development in females.•High NFS ...and high FIB-4 score were associated with developing all cancers and HCC.
Little is known about the association between non-alcoholic fatty liver disease (NAFLD) and cancer development. This study investigated the cancer incidence rates in NAFLD and analysed the association between NAFLD and cancer development.
This historical cohort study included subjects who were followed up for >1 year after having a heath checkup at a tertiary hospital in Korea from September 1, 2004 to December 31, 2005. NAFLD was diagnosed by ultrasonographic detection of hepatic steatosis in the absence of other known liver disease, including alcoholic or viral hepatitis. Cox proportional hazards regression model was conducted to assess the association between NAFLD and cancer development.
Of 25,947 subjects, 8,721 (33.6%) had NAFLD. During the total follow-up of 164,671 person-years (median 7.5 years), the cancer incidence rate of the NAFLD group was higher than that of the non-NAFLD group (782.9 vs. 592.8 per 100,000 person-years; hazard ratio HR 1.32; 95% confidence interval CI 1.17–1.49; p <0.001). When demographic and metabolic factors were adjusted for, NAFLD showed a strong association with three cancers: hepatocellular carcinoma (HCC; HR 16.73; 95% CI 2.09–133.85; p = 0.008), colorectal cancer in males (HR 2.01; 95% CI 1.10–3.68; p = 0.02), and breast cancer in females (HR 1.92; 95% CI 1.15–3.20; p = 0.01). A high NAFLD fibrosis score (NFS) and a high fibrosis-4 (FIB-4) score were associated with the development of all cancers and HCC.
NAFLD was associated with the development of HCC, colorectal cancer in males, and breast cancer in females. A high NFS and a high FIB-4 score showed a strong association with the development of all cancers and HCC.
Non-alcoholic fatty liver disease (NAFLD) is associated with developing hepatocellular carcinoma (HCC). There have been limited data on the association between NAFLD and extrahepatic cancers. This study demonstrated that patients with NAFLD showed a higher association with the development of HCC, colorectal cancer in males, and breast cancer in females. A high NAFLD fibrosis score and a high fibrosis-4 score showed a strong association with the development of all cancers and HCC.
We have evaluated the clinical outcomes of patients after transarterial chemoembolization (TACE) and 3-dimensional conformal radiotherapy for hepatocellular carcinoma (HCC) with portal vein tumor ...thrombosis (PVTT).
A registry database of 412 patients treated with TACE and three-dimensional conformal radiotherapy for HCC with PVTT between August 2002 and August 2008 were analyzed retrospectively. The radiotherapy volume included the PVTT, with a 2- to 3-cm margin to cover adjacent HCC. Intrahepatic primary HCC was managed by TACE before or after radiotherapy.
Median patient age was 52 years old, and 88.1% of patients were male. Main or bilateral PVTT was observed in 200 (48.5%) patients. Median radiation dose was 40 Gy (range, 21-60 Gy) delivered in 2- to 5-Gy fractions. We found that 3.6% of patients achieved a complete response and that 24.3% of patients achieved a partial response. The response and progression-free rates of PVTT were 39.6% and 85.6%, respectively. Median patient survival was 10.6 months, and the 1- and 2-year survival rates were 42.5% and 22.8%, respectively. Significant independent variables associated with overall survival included advanced tumor stage, alpha-fetoprotein level, degree of PVTT, and response to radiotherapy. Forty-one patients (10.0%) showed grade 3-4 hepatic toxicity during or 3 months after completion of radiotherapy. Grades 2-3 gastroduodenal complications were observed in 15 patients (3.6%).
Radiotherapy is a safe and effective treatment for PVTT in patients with HCC. These results suggested that the combination of TACE and radiotherapy is a treatment option for relieving and/or stabilizing PVTT in patients with advanced HCC.
Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The ...phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence.
Tumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test.
BIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These
were significantly enriched in CD4
T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors.
In BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation.
NCT00692770.
No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of ...adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma.
In the global, open-label, phase 3 IMbrave050 study, adult patients with high-risk surgically resected or ablated hepatocellular carcinoma were recruited from 134 hospitals and medical centres in 26 countries in four WHO regions (European region, region of the Americas, South-East Asia region, and Western Pacific region). Patients were randomly assigned in a 1:1 ratio via an interactive voice–web response system using permuted blocks, using a block size of 4, to receive intravenous 1200 mg atezolizumab plus 15 mg/kg bevacizumab every 3 weeks for 17 cycles (12 months) or to active surveillance. The primary endpoint was recurrence-free survival by independent review facility assessment in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04102098.
The intention-to-treat population included 668 patients randomly assigned between Dec 31, 2019, and Nov 25, 2021, to either atezolizumab plus bevacizumab (n=334) or to active surveillance (n=334). At the prespecified interim analysis (Oct 21, 2022), median duration of follow-up was 17·4 months (IQR 13·9–22·1). Adjuvant atezolizumab plus bevacizumab was associated with significantly improved recurrence-free survival (median, not evaluable NE; 95% CI 22·1–NE) compared with active surveillance (median, NE 21·4–NE; hazard ratio, 0·72 adjusted 95% CI 0·53–0·98; p=0·012). Grade 3 or 4 adverse events occurred in 136 (41%) of 332 patients who received atezolizumab plus bevacizumab and 44 (13%) of 330 patients in the active surveillance group. Grade 5 adverse events occurred in six patients (2%, two of which were treatment related) in the atezolizumab plus bevacizumab group, and one patient (<1%) in the active surveillance group. Both atezolizumab and bevacizumab were discontinued because of adverse events in 29 patients (9%) who received atezolizumab plus bevacizumab.
Among patients at high risk of hepatocellular carcinoma recurrence following curative-intent resection or ablation, recurrence-free survival was improved in those who received atezolizumab plus bevacizumab versus active surveillance. To our knowledge, IMbrave050 is the first phase 3 study of adjuvant treatment for hepatocellular carcinoma to report positive results. However, longer follow-up for both recurrence-free and overall survival is needed to assess the benefit–risk profile more fully.
F Hoffmann-La Roche/Genentech.
Hepatocellular carcinoma recurs in 70-80% of cases following potentially curative resection or ablation and the immune component of the liver microenvironment plays a key role in recurrence. Many ...immunosuppressive mechanisms implicated in HCC recurrence are modulated by VEGF and/or immune checkpoints such as PD-L1. Atezolizumab (PD-L1 inhibitor) plus bevacizumab (VEGF inhibitor) has been shown to significantly improve overall survival, progression-free survival and overall response rate in unresectable HCC. Dual PD-L1/VEGF blockade may be effective in reducing HCC recurrence by creating a more immune-favorable microenvironment. We describe the rationale and design of IMbrave 050 (NCT04102098), a randomized, open-label, Phase III study comparing atezolizumab plus bevacizumab versus active surveillance in HCC patients at high-risk of recurrence following curative resection or ablation. The primary end point is recurrence-free survival.
NCT04102098.
Background
The prognosis of metabolic dysfunction‐associated steatotic liver disease (MASLD) is associated with liver fibrosis. We investigated the associations between changes in liver stiffness ...measurement (LSM) over 3‐year period and the development of cirrhosis or hepatocellular carcinoma (HCC) in patients with MASLD.
Methods
This study involved patients with MASLD who underwent transient elastography at baseline and 3 years after baseline from 2012 to 2020. Low (L), indeterminate (I) and high (H) LSM values were classified as <8 kPa, 8–12 kPa and >12 kPa respectively.
Results
Among 1738 patients, 150 (8.6%) were diagnosed with cirrhosis or HCC. The proportions of patients with L, I and H risk were 69.7%, 19.9% and 10.5% at baseline, and 78.8%, 12.8% and 8.4% at 3 years after baseline, respectively. The incidence rates of cirrhosis or HCC per 1000 person‐years were 3.7 (95% confidence interval CI, 2.4–5.5) in the L → L + I group, 23.9 (95% CI, 17.1–32.6) in the I → L + I group, 38.3 (95% CI, 22.3–61.3) in the H → L + I group, 62.5 (95% CI, 32.3–109.2) in the I → H group, 67.8 (95% CI, 18.5–173.6) in the L → H group and 93.9 (95% CI 70.1–123.1) in the H → H group. Two risk factors for the development of cirrhosis or HCC were LSM changes and low platelet counts.
Conclusion
LSM changes could predict clinical outcomes in patients with MASLD. Thus, it is important to monitor changes in the fibrotic burden by regular assessment of LSM values.
Abstract
Considering the lower risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients receiving long‐term potent antiviral therapy, models predicting HCC after 5 years of ...therapy are needed. We conducted a multicenter retrospective cohort study to construct and validate a model predicting HCC after 5 years of entecavir (ETV) or tenofovir (TFV) therapy for CHB. The endpoint was HCC after 5 years of ETV/TFV therapy. Information on age, sex, liver cirrhosis (assessed by diagnosis code and confirmed by clinical findings) and type of antiviral agent was obtained at baseline (initiation of ETV/TFV). Laboratory values were collected at baseline and 5 years. Risk factors for HCC were identified in the training set and the final prediction model was validated using the test set. Among 7542 patients, 345 (4.6%) developed HCC after 5 years of ETV/TFV therapy. HCC risk after 5 years of ETV/TFV therapy was increased by 4‐fold in patients with liver cirrhosis than in those without cirrhosis at baseline. Furthermore,
P
latelet counts and
P
rothrombin time at 5 years,
A
ge at baseline and
S
ex were associated with risk of HCC and were incorporated into a prediction model, PPACS. PPACS showed a good performance with a time‐dependent area under the curve of 0.80 (95% confidence interval, 0.75‐0.85) at 8‐year of ETV/TFV therapy, a Brier score of 0.031 and an integrated Brier score of 0.006 in the test set. In conclusion, the PPACS model provides a reliable assessment of HCC risk after 5 years of ETV/TFV therapy (
https://ppacs.shinyapps.io/shiny_app_up/
).
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•NAFLD was associated with an increased risk of cardiovascular events.•Non-calcified plaque is a vulnerable plaque with potential cardiac risks.•NAFLD was an independent risk factor ...for non-calcified plaque.•Appropriate therapy for NAFLD was required to reduce the future cardiac events.
There are limited data on the association between non-alcoholic fatty liver disease (NAFLD) and subclinical coronary atherosclerosis. This study investigated the influence of NAFLD on subclinical coronary atherosclerosis as detected by coronary computed tomography angiography (CCTA) in an asymptomatic population.
A total of 5,121 consecutive asymptomatic individuals with no prior history of coronary artery disease or significant alcohol intake voluntarily underwent abdominal ultrasonography and CCTA as part of a general health examination. Fatty liver was assessed by ultrasonography examination. The fatty liver index and NAFLD fibrosis score were also calculated. Coronary atherosclerotic plaques on CCTA were evaluated. The association between NAFLD and subclinical coronary atherosclerosis was determined by logistic regression analysis.
Of the study participants, 1,979 (38.6%) had ultrasonography-diagnosed NAFLD. After adjustment for cardiovascular risk factors, there were no statistically significant differences in the adjusted odds ratios of NAFLD for calcified plaque (1.03; 95% CI 0.89–1.20; p = 0.673) and mixed plaque (1.15; 95% CI 0.93–1.42; p = 0.214). However, adjusted odds ratios for any atherosclerotic plaque (1.18; 95% CI 1.03–1.35; p = 0.016) and non-calcified plaque (1.27; 95% CI 1.08–1.48; p = 0.003) were significantly higher in NAFLD. In addition, there was a significant association of fatty liver index ≥30 with non-calcified plaque (1.37; 95% CI 1.14–1.65; p = 0.001) and NAFLD fibrosis score ≥−1.455 with non-calcified plaque (1.20; 95% CI 1.08–1.42; p = 0.030).
In this large cross-sectional study of asymptomatic individuals undergoing CCTA, NAFLD was consistently associated with non-calcified plaque, suggesting an increased cardiovascular risk.
In asymptomatic individuals, non-alcoholic fatty liver disease (NAFLD) was an independent risk factor for non-calcified plaque, which has been known as a vulnerable plaque associated with sudden and unexpected cardiac events. Therefore, appropriate medical therapy for NAFLD was required to reduce future cardiac events.
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