Introduction

The prognosis of patients with hepatocellular carcinoma (HCC) is very variable, and the relative contribution of tumour burden and liver dysfunction to survival is uncertain. Median overall survival (OS) of patients managed with best supportive care is around 3-6 months, although longer values may be observed in clinical practice. Aim of this study was to identify the factors linked to tumour or liver dysfunction associated with survival in patients with HCC treated with BSC.

Aims & Methods

We retrospectively evaluated the clinical characteristics of 1414 patients who had an indication for BSC recorded in the Ita.Li.Ca database between 2000 and 2020. We analysed both patient and tumour characteristics to identify predictors of OS.

Results

Median age was 69y and 76% of patients were male. Aetiology included chronic viral infection (68.3%), alcohol use disorder (30.9%) and non-alcoholic steatohepatitis (8.3%). 67.4% of patients had a performance status 0-1 and 41.4% were in Child-Pugh B class. Median MELD was 13.60% of patients had a multifocal HCC with a median number of 3 lesions and a median size of 33mm. 533 patients had vascular invasion. Median alpha-fetoprotein was 49.25 ng/ml. 111 patients were classified as BCLC-A, 148 as BCLC-B, 791 as BCLC-C and 325 as BCLC-D (12 unknown). No differences in terms of OS were observed considering the aetiology of liver disease or the presence of cirrhosis. Obesity ( p<0.001), hypercholesterolemia (p=0.036) and hypertriglyceridemia (p=0.034) were associated with lower OS. Absence of symptoms (6 vs 10 months, p<0.001), lack of vascular invasion (9.1 vs 5.03, p<0.001), and absence of metastasis (8.167 vs 4.733, p<0.001) were associated with a better OS. Survival in BCLC-A patients was longer than in stages B or C. Survival progressively declined according to severity of liver function using three different scores (CPS, ALBI, pALBI, p<0.001). Women tended to survive longer (23 vs 19 months, p= 0.053). Comparing patients surviving more or less than 12 months ( 398 vs 1016), age, size of lesions, albumin, bilirubin, alpha-fetoprotein, and MELD were significantly different. At Cox univariate analysis presence of cirrhosis, number and size of lesions, vascular invasion, metastasis, ALBI and pALBI grades, MELD and CPS were significantly associated with OS. Using different models to avoid collinearity ALBI, pALBI and CPS maintained an independent prognostic role on OS.

Conclusion

In a large series of patients with HCC in BSC, parameters of liver function are strongly associated with survival.

Introduction

There is a well-established association between inflammation and malignant tumors. Furthermore, in hepatocellular carcinoma (HCC), liver functional is a critical determinant of prognosis. Accordingly, the C-reactive protein-to-albumin ratio (CAR), which integrates C-reactive protein—a biomarker of systemic inflammation—and albumin—an indicator of liver functional—has been proposed as a potentially valuable prognostic marker in HCC.

Aims & Methods

This study aims to assess the prognostic value of CAR in predicting outcomes in patients with unresectable HCC treated with Atezolizumab/Bevacizumab (Atezo/Bev) combination therapy.A total of 289 patients who received Atezo /Bev across multiple centers between September 2020 and December 2024 were included in this analysis.The baseline characteristics of the cohort were as follows: median age 74.0 years ( IQR, 67.0–79.0), male/female gender distribution 224/65, performance status (PS 0/1/≥2）185/95/9, etiology (hepatitis B/hepatitis C/alcoholic/non-B, non-C) 58/92/37/102, CRP 0.27 mg/dL (0.10–0.91), albumin 3.8 g/dL (3.4–4.2), CAR 0.068 (0.026–0.239), Child-Pugh score (5/6/≥7 points) 165/82/42, Barcelona Clinic Liver Cancer (BCLC) stage (≤A/B/≥C) 24/84/181, alpha-fetoprotein (AFP) level 27.5 ng/mL (5.2–606.6), and median observation period 14.8 months (6.9–26.4). The distribution of patients according to the line of Atezo/Bev was 233/56 for primary/secondary or later systemic therapy lines, respectively.

Results

The median cumulative progression-free survival (PFS) was 6.8 months (95% confidence interval [CI], 5.4–9.8), and the median cumulative overall survival (OS) was 26.5 months (95% CI, 21.4–29.9). Time-dependent receiver operating characteristic (ROC) analysis identified an optimal cutoff for predicting median OS at 0.0056. The radiological responses, according to RECIST version 1.1, were as follows: partial response 5.7%, stable disease 24.7%, progressive disease 45.9%, respectively. The objective response rate (ORR) and disease control rate were 30.5% and 76.3%. Notably, significant differences in radiological responses (p=0.002) and ORR (p = 0.011) were observed based on CAR values. Multivariate analysis, incorporating age, gender, PS, etiology, BCLC stage, Child-Pugh classification, systemic therapy line, AFP, neutrophil-to-lymphocyte ratio (NLR), and CAR, revealed that age (≥75 years) (hazard ratio [HR], 1.361; 95% confidence interval [CI], 1.028–1.802; p=0.031), BCLC stage (≥C) (HR, 1.439; 95% CI, 1.017–2.037; p=0.040), and CAR (≥0.056) (HR, 1.471; 95% CI, 1.105–1.957; p=0.008) were independently associated with PFS. Additionally, in multivariate analysis adjusted for the same covariates, age (≥75 years) (HR, 1.458; 95% CI, 1.004–2.117; p=0.048), Child-Pugh classification (≥7) (HR, 2.329; 95% CI, 1.445–3.754; p<0.001), AFP (≥100ng/ml) (HR, 1.587; 95% CI, 1.087–2.319; p=0.017), and CAR (≥0.056) (HR, 2.042; 95% CI, 1.386–3.008; p<0.001) were independently associated with OS. In the time-dependent ROC analysis, the area under the ROC curve (AUROC) at 6, 12, 18, 24, 30, and 36 months for NLR was 0.690, 0.683, 0.651, 0.573, 0.493, and 0.474, respectively, and 0.757, 0.687, 0.699, 0.695, 0.663, and 0.597 for CAR, with CAR showing a significantly better AUROC after 24 months.

Conclusion

CAR serves as a valuable predictive biomarker for survival in patients undergoing Atezo/Bev for unresectable HCC.

References

Toshifumi Tada, Takashi Kumada , Atsushi Hiraoka et al. C‑reactive protein to albumin ratio predicts survival in patients with unresectable hepatocellular carcinoma treated with Lenvatinib. Scientific Reports. 2022 May 19;12(1):8421.

Introduction

The prognosis for patients with hepatocellular carcinoma (HCC) remains extremely poor, with a 5-year survival rate of 20% without curative treatment. A recent studyⁱ demonstrated that the use of a computed CT score including muscle density and muscle area could identify frailty in cirrhotic patients and predict 6-month mortality. The objective of the study was to evaluate predictors of 6-month mortality in patients with HCC and to establish the impact of sarcopenia in this context.

Aims & Methods

We performed a retrospective analysis of 86 patients with HCC treated at the Hôtel Dieu de France in Beirut between 2016 and 2024. The collection included clinical and biological data, prognostic indices (Child Pugh scores, MELD) as well as CT parameters for measuring sarcopenia and myosteatosis, including skeletal muscle index, muscle densities, and muscle surfaces at L3 level. The coreslicer® software was used to calculate muscle and fat surfaces on CT. The measurements evaluated included the surfaces at L3 of the psoas and paravertebral and parietal muscles, as well as the density of the psoas. Among these, the “L3 skeletal muscle area adjusted to height and density ratio (L3- SMHDR)” which is calculated by the total muscle area at the L3 level * Average size / density of the psoas muscles at the L3 level. This measurement helps include myosteatosis in the assessment of sarcopenia.

Results

• Our population included 86 patients with HCC, 74 men, 12 women, with a mean age of 66.1 ± 10.7 years. MELD-Na score was 16.1 ± 8.2, and Child-Pugh score was A, B, and C in 39%, 27%, and 34%, respectively. Twelve patients (14%) were eligible for curative treatment, in accordance with BCLC guidelines.
• Decreased survival is significantly associated with increasing L3-SMHDR. An AUROC analysis for L3-SMHDR as a predictor of mortality at 1 month found the same cutoff values as a previously published study with cutoffs of 5.4 and 4.7 in men and women, respectively. Populations with low L3-SMHDR vs. high L3-SMHDR had a survival time of 31.2 months vs. 11.09 months (P=0.035).
• In order to determine the different factors linked to a decrease in survival at 6 months, we conducted a univariate analysis which identified the following parameters: muscle density at scan (p=0.016), L3-SMHDR (p=0.004), L3-DRMI (p=0.034) and the MELD-Na score (P=0.077). A value of L3-SMHDR > threshold had a risk of mortality OR= 7.8 [1.8-34, P=0.003] and 5.64 [1.3-23.8, P=0.013] at 6 and 12 months respectively.
• In multivariate analysis, the two independent prognostic factors were the MELD-Na score and L3-SMHDR, which allowed us to arrive at the following equation:
• Probability = 0.112* MELDNa + 2.518* L3-SMHDR – 3.11.
• This analysis allowed us to classify patients according to the above function categories, and to estimate the risk of mortality at 6 and 12 months at respectively OR = 10 [2-50, P=0.003] and 11.4 [2.2-58.6, P=0.002].

Conclusion

The 6-month prognosis of patients with HCC depends primarily on liver function and the severity of sarcopenia and myosteatosis, not tumor stage. This should provide additional prioritization for patients eligible for liver transplantation. Confirmation of these results should be considered in a larger-scale study.

References

i. El Khoueiry C, Slim R, Rida M, Khoury B, Honein K, Smayra T, Yaghi C. New Scanographic Index for the Detection of Frailty in Patients with Cirrhosis with a Prognostic Impact. Middle East J Dig Dis. 2024 Apr;16(2):102-108. doi: 10.34172/mejdd.2024.376. Epub 2024 Apr 30. PMID: 39131107; PMCID: PMC11316193.

Introduction

Recently, a Japanese expert consensus introduced oncological resectability criteria for hepatocellular carcinoma (HCC) [1]. Notably, these criteria do not incorporate the concept of unresectable tumors, but rather classify borderline resectability into two distinct subgroups, defined from the therapeutic perspective of hepatic resection. Based on these classifications, resectability is categorized into three groups: resectable (R), borderline resectable 1 (BR1), and borderline resectable 2 (BR2).

Aims & Methods

In this study, we aimed to assess the clinical outcomes of patients with HCC who were treated with atezolizumab plus bevacizumab (Atezo/Bev) in a real-world context, categorized by oncological resectability criteria. Between May 2018 and May 2024, a total of 1,055 patients with unresectable HCC were treated with Atezo/Bev across 26 institutions in Japan. Of these, 467 met the following inclusion criteria: (1) Child–Pugh class A, (2) Atezo/Bev administered as the first-line systemic therapy, (3) Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1, (4) BR1 or BR2 classification, (5) treatment conducted within a clinical trial setting, and (6) availability of complete clinical data.

Results

Of 467 patients, 102 (21.8%) were women, and 365 (78.2%) were men. The median age was 74.0 (69.0–79.0) years. Patients were categorized into BR1 (n=153 [32.8%]) and BR2 (n=314 [67.2%]) groups. The median follow-up period was 14.3 (7.5–24.0) months. The median progression-free survival (PFS) was 9.0 months in the BR1 group and 6.8 months in the BR2 group (p = 0.014). Multivariable analysis identified the following independent prognostic factors for PFS: age ≥75 years (hazard ratio [HR], 1.309; 95% confidence interval [CI], 1.057–1.622; p=0.014), albumin–bilirubin (ALBI) grade 2 or 3 (HR, 1.494; 95%CI, 1.201–1.859; p<0.001), neutrophil-to-lymphocyte ratio (NLR) ≥3 (HR, 1.289; 95%CI, 1.030–1.613; p=027), α-fetoprotein (AFP) ≥100 ng/mL (HR, 1.523; 95%CI, 1.214–1.912; p<0.001), and BR2 classification (HR, 1.360; 95%CI, 1.076–1.718; p=0.010). The median overall survival (OS) was 25.3 months in the BR1 group and 22.3 months in the BR2 group (p = 0.048). Similarly, multivariable analysis identified the following independent prognostic factors for OS: age ≥75 years (HR, 1.522; 95%CI, 1.155–2.007; p=0.033), ALBI grade 2 or 3 (HR, 2.411; 95%CI, 1.802–3.224; p<0.011), NLR ≥3 (HR, 1.635; 95%CI, 1.233–2.169; p<0.011), AFP ≥100 ng/mL (HR, 1.530; 95%CI, 1.152–2.032; p=0.003), and BR2 classification (HR, 1.421; 95%CI, 1.048–1.927; p=0.024). When oncological resectability factors (tumor number and size, vascular invasion, and extrahepatic spread) were incorporated into the multivariable analysis, major vascular invasion emerged as a significant predictor of both PFS (HR, 3.188; 95%CI, 2.051–4.953; p<0.011) and OS (HR, 2.650; 95%CI, 1.541–4.556; p<0.001). No significant differences were observed between the BR1 and BR2 groups regarding concomitant or subsequent treatments following Atezo/Bev therapy, as indicated by the Sankey diagram (p = 0.391).

Conclusion

Among HCC patients with a low probability of surgical resection (i.e., those classified as BR1 or BR2) undergoing Atezo/Bev treatment, vascular invasion serves as a critical prognostic factor for tumor progression. Moreover, beyond tumor progression, preserved liver function also plays a pivotal role in determining the prognosis of patients treated with Atezo/Bev.

References

1. Akahoshi K, Shindoh J, Tanabe M, Ariizumi S, Eguchi S, Okamura Y, et al. Oncological Resectability Criteria for Hepatocellular Carcinoma in the Era of Novel Systemic Therapies: The Japan Liver Cancer Association and Japanese Society of Hepato-Biliary-Pancreatic Surgery Expert Consensus Statement 2023. Liver Cancer 2024; 13: 1–11.

Disclosure

Toshifumi Tada: lecture fees from AbbVie, AstraZeneca, Eisai, and Chugai
Atsushi Hiraoka: lecture fees from Eisai, Bayer, Eli Lilly, and Otsuka
Hidenori Toyoda: lecture fees from AbbVie, Eisai, Gilead, Terumo, and Bayer

Introduction

The literature regarding the risk of progression to extrahepatic disease and clinical factors associated with the development of metastases in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) is sparse.

Aims & Methods

We aimed to assess the incidence of extrahepatic recurrence and to identify clinically relevant risk factors for the development of metastases in patients with HCC treated with TACE as first-line treatment.
From the Italian Liver Cancer (ITA.LI.CA) database, data of 981 HCC patients undergoing TACE as first-line treatment were retrieved and retrospectively analyzed. Incidence of extrahepatic recurrence was compared between two groups according to the diameter of the largest liver lesion at the time of TACE (HCC ≤ 3 cm vs. HCC > 3 cm). Multivariate Cox regression was used to identify predictor of extrahepatic recurrence.

Results

During a median follow-up of 27.0 months (IQR, 13.2-49.0) the overall recurrence rate was 75.4%. Only 78/981 patients (8.0%) had an extrahepatic tumor localization at first recurrence (5.4% in the ≤3 cm group and 10.7% in the >3 group; p=0.002), while the overall extrahepatic recurrence rate was 26.0% (21.2% and 31.0% patients in the ≤3 cm and >3 cm groups, respectively; p=0.0006) (Figure 1). Compared to those with larger tumors, patients with HCC ≤ 3 cm had a significantly longer recurrence-free survival (12.0 [95% CI 10.7-13.3] vs. 9.7 [95% CI 8.2-11.2] months; p=0.02) and overall survival (52.5 [95% CI 45.5-59.4] vs. 34.7 [95% CI 30.7-38.7] months; p<0.0001). HCC size ≥ 3 cm, multifocality and AFP levels were independent predictors of extrahepatic recurrence.

Conclusion

Although the majority of patients treated with TACE do not develop metastases during their lifespan, knowledge of risk factors for extrahepatic recurrence (HCC size, multifocality, AFP levels) may help to assess patient prognosis and to identify patients deserving closer follow-up in order to start early systemic therapy.