ALBI grade predicts suitability for further systemic therapy following sorafenib in patients with advanced hepatocellular carcinoma

Preserved performance status (PS) and liver function are required for systemic therapy in patients with advanced hepatocellular carcinoma (aHCC). We investigated the frequency of suitability for further systemic therapies following sorafenib in aHCC.


| INTRODUC TI ON
Primary liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related death globally, and hepatocellular carcinoma (HCC) accounts for over 80%. 1 The incidence of liver cancer globally has increased by 25% from 2007 to 2017. 2 In countries with a high sociodemographic index, the increase in incidence is thought to be related to an increase in HCC in the context of fatty liver disease and higher rates of hepatitis C. 1 For example, the incidence and mortality of HCC in the United Kingdom (UK), has tripled in the last 20 years, with 5.5 cases and 4.0 deaths per 100 000 in 2017. 3 The poor outcomes of patients with HCC may be a reflec- Factor antibodies atezolizumab and bevacizumab. 10 For patients to qualify for these promising new therapy options however, they must meet eligibility criteria set in these phase 3 clinical trials. Universally, this includes CP class A (CP-A) liver disease, and PS 0-1. These criteria often extend to the funding for the use of these treatments by governing bodies, such as the National Institute for Health and Clinical Excellence in the UK. Therefore, the promising benefit of sequential therapy following sorafenib is reliant on patients maintaining PS and liver function, as determined by the CP score, during initial treatment.
As an alternative to the CP score in categorising liver dysfunction in aHCC, the ALBI grading system was developed and validated using patients treated with sorafenib in clinical trials recruiting predominantly CP-A patients. 11 In a real-world context, similar to patients who are CP-B, patients with an ALBI grade of >2 are less likely to benefit from sorafenib treatment. 12 This system was determined to have better discriminative value as a prognostic indicator in HCC when compared to CP scoring, as well as performing better as an assessment tool for hepatic dysfunction. [13][14][15] However, the ALBI grading system does not feature in licensing criteria for the available systemic therapy options in aHCC.
Real-world data are required regarding what proportion of patients with aHCC will potentially be eligible for the additional systemic therapy options now available following sorafenib treatment. To address this need, a retrospective analysis of patients with aHCC treated with sorafenib was undertaken, aiming to define the proportion of patients eligible by contemporary, trial-based, criteria of CP score and PS to receive further agents after disease progression or intolerance to sorafenib, and to identify baseline patient and tumour-related factors at commencement of sorafenib that may predict future eligibility for systemic therapies. To validate these findings, a retrospective analysis was then performed in an independent cohort of patients in a tertiary European centre.

| Study design
Sequential patients with a histologically confirmed diagnosis of HCC referred to The Christie NHS Foundation Trust, Manchester, UK from June 2008 to December 2018 were identified retrospectively using electronic hospital records, and those who were treated with sorafenib for aHCC were eligible for inclusion in the training cohort. Patients treated in the context of a clinical trial were eligible if treatment with sorafenib could be confirmed. Data were collected retrospectively from hospital medical records using a study-specific database, including patient demographics, tumour stage, prior therapy for HCC, PS and CP score at commencement and discontinuation of sorafenib, duration and dose intensity of sorafenib, and receipt of any subsequent systemic therapies. ALBI grade was calculated using albumin and bilirubin prior to sorafenib commencement, as described by Johnson et al. 11 Presence/absence of portal invasion or extrahepatic disease was captured from the most recent imaging performed prior to starting sorafenib.
Patients were defined as eligible for further systemic therapy if they met the criteria of PS of ≤1 and CP-A at discontinuation of sorafenib. If patients initially failed to meet these criteria, but were subsequently re-assessed for further therapy and did meet criteria, then they were defined as eligible at best assessment. Findings in the training cohort with regard to eligibility for further systemic therapy

Key points
Most patients with advanced liver cancer who receive chemotherapy with sorafenib do not qualify for further available therapies due to a deterioration in their liver function during sorafenib treatment. However, patients with better liver function prior to starting sorafenib, as determined by the ALBI grade, are more likely to maintain adequate liver function to receive additional treatments.
The ALBI grade may help guide clinicians in choosing between sorafenib, or other alternatives, as the first line of treatment in patients with advanced liver cancer.
were then validated by a retrospective analysis of an independent validation cohort of patients with histologically confirmed aHCC treated with sorafenib at the Centre Eugène Marquis, Rennes, France.

| Ethics statement
The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. No ethical approval was required as all data collected were sourced retrospectively from medical records of routine investigation and treatment. All data presented have been anonymised and no individual patient's results have been included in this manuscript.

| Study objectives
The primary objective was to determine the proportion of patients that would be considered eligible for consideration of second-line therapy after failure of first-line therapy, using standard PS ≤1 and CP-A score criteria. Secondary objectives included assessing whether patient and tumour-related factors at commencement of sorafenib were predictive for eligibility for further therapy; and comparing the clinical outcomes of patients who were suitable for further therapy with those who were not.

| Statistical analysis
Summary statistics were provided for patient characteristics.
Ranges, interquartile ranges, medians and means were listed for continuous variables; frequencies and percentages for categorical variables. Chi-squared Test or Fisher's Exact Test (when expected frequencies are small) were applied when comparing patients who were eligible at best assessment following sorafenib treatment vs those who were not, across various baseline variables of interest in both the training and validation cohort (univariate analysis). A multivariable logistic regression was applied subsequently including variables found significant in the univariate analysis. The Kaplan-Meier method was used to estimate the median survival times from commencement of sorafenib and corresponding 95% confidence intervals. Comparisons between groups of interest were performed using log-rank tests. Univariable Cox Proportional Hazards regression was applied to assess the association between OS and various baseline variables of interest. Two-sided P-values <.05 were considered statistically significant. All analyses were performed using R 3.6.2. 16

| RE SULTS
Eligibility criteria were met by 182 patients in the training cohort, and baseline characteristics are presented in Table 1. The majority of patients were male (88%), and the mean age at diagnosis was 67 years (range 29-88). Documented cirrhosis was identified in 75% of patients, in the context of alcohol excess (47%), diabetic steatohepatitis (36%) and viral hepatitis (30%). Multiple cirrhosis aetiologies were identified in 38% of patients. Prior to receiving sorafenib, the majority of patients were PS ≤1 (87%), and nearly all patients had CP-A liver disease (98%), with the majority being CP-A5 (74% overall). In addition, 55% of patients were ALBI grade 1 prior to treatment, with the remainder being nearly all ALBI grade 2 (43%). At first assessment after discontinuation of sorafenib, 93 patients were CP-A (51%), and 60 patients were PS 0 or 1 (33%) (

| CON CLUS IONS
In this study, we sought to define the proportion of patients with aHCC receiving sorafenib in a real-world context that would qualify for further systemic therapy on sorafenib discontinuation. We demonstrate that in a Western population, only a minority of patients  In comparison to our study, Ogasawara et al. reported a considerably higher eligibility rate (70%) for further systemic therapy after sorafenib discontinuation in a similarly sized (n = 185) singlecentre retrospective study of aHCC patients treated in Japan. 17 This difference may be due to differing baseline patient characteristics, for example a higher number of patients with PS 0 (61%) and liver cirrhosis secondary to Hepatitis C (46%), and a lower proportion due to alcohol-related cirrhosis (9%). In our analysis, these baseline factors were not found to significantly influence eligibility for further systemic therapy although this could be due to low statistical power to demonstrate such an effect, and in addition, the known positive influence of Hepatitis C cirrhosis aetiology on outcomes with sorafenib may also favourably preserve PS and liver function at sorafenib discontinuation. 18  In our study, lower ALBI grade had a significant influence on suitability for post-sorafenib therapy, whereas the influence of CP score was not statistically significant, and this finding was validated in an independent cohort. Furthermore, the more even distribution of patients across ALBI grades 1 and 2 prior to sorafenib treatment, com- prior treatment or those who received prior curative therapy. The expanding options for systemic therapy may therefore also have a role in patients traditionally treated with loco-regional therapies such as TACE.
Of further interest is the recent demonstration that combination atezolizumab and bevacizumab results in improved OS, PFS and ORR, similar rates of high-grade toxicities, and improved symptom con- Our study is limited by its retrospective design, and modest sample size, however to our knowledge, it is the first in press to report on eligibility for further systemic therapy following treatment with sorafenib in a real-world Western population. Although the training cohort came from a single-centre study, we were able to externally validate our findings in an independent population of patients treated at another European centre. We acknowledge that Atezolizumab-Bevacizumab has emerged as a preferred first-line option in aHCC, however a significant proportion of patients will remain ineligible for this and other emerging therapies (such as those with PS >1, or auto-immune disease), or will not have these treatments available to them based on locality. Finally, we feel that is likely that the same predictors will apply to other treatments, as progression of hepatic dysfunction is linked to underlying disease progression, rather than as a consequence of treatment.
To conclude, we demonstrate that in a Western population of patients with aHCC treated with sorafenib, there is a significant de-

ACK N OWLED G EM ENTS
All patients included, and their families.

FU N D I N G I N FO R M ATI O N
Dr Angela Lamarca's salary was part-funded by The Christie Charity.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.