Current pharmacological treatment of hepatocellular carcinoma.

The landscape of hepatocellular carcinoma (HCC) has changed since the incorporation of sorafenib in 2007 as the first pharmacological treatment for HCC. The combination of atezolizumab plus bevacizumab is currently the first-line treatment for HCC patients, and there are several second-line options approved for patients who had received sorafenib as the first-line treatment. The advantage of having multiple options of pharmacological treatment for HCC patients is associated to the need to redefine the clinical decision-making approach and considering new endpoints for the clinical trials design. The aim of this review was to share the Barcelona Clinic Liver Cancer approach and to summarize the ongoing clinical trials, which are testing pharmacological treatments.

Early diarrhoea under sorafenib as a marker to consider the early migration to second-line drugs.

BACKGROUND: Despite atezolizumab and bevacizumab (A + B) is currently the first-line treatment for hepatocellular carcinoma (HCC) patients, some patients will not be adequate for this combination. In the setting of sorafenib some adverse events have been proposed as prognostic factors. OBJECTIVE: To characterize the early diarrhoea development as prognostic factor in 344 HCC patients. METHODS: The development of early diarrhoea in sorafenib treatment defined as patients who developed diarrhoea and needed dose modification within the first 60 days of treatment (e-diarrhoea) and 3-grouping variables were analysed: Patients with e-diarrhoea, patients who developed diarrhoea after the first 60 days of treatment (L-diarrhoea) and patients that never developed diarrhoea (never diarrhoea). RESULTS: The median overall survival in sorafenib treated patients was significantly different across groups (6.8 months for e-diarrhoea, 26.7 months for L-diarrhoea and 13.3 months for never-diarrhoea). The emergence of e-diarrhoea was associated with poor outcomes (hazard ratio [HR] 1.84 [95%CI 1.15-2.95]), while there was no increased/decreased risk of dismal evolution in patients with L-diarrhoea (HR 0.66 [95%CI 0.42-1.03]). CONCLUSION: The emergence of e-diarrhoea in HCC patients treated with sorafenib is an early predictor of dismal evolution under this therapy. Thus, prompt identification of these non-responders may be useful for an early switch to second-line therapies.

Pancreatic Insufficiency in Patients Under Sorafenib Treatment for Hepatocellular Carcinoma.

GOALS: To describe the occurrence of malabsorption (MA) in hepatocellular carcinoma (HCC) patients under sorafenib, the potential relationship with pancreatic insufficiency (PI), and the role of pancreatic enzymes supplementation. BACKGROUND: With the increasing options of second-line systemic therapies for HCC, the recognition of drug intolerance using practical tools is crucial. It has been proposed that a MA syndrome could be due to sorafenib-induced pancreatic dysfunction. STUDY: All sorafenib-treated patients with suspicion of MA (defined as decreased stool consistency lasting >4 wk or presenting ≥10% body weight loss without HCC progression) were prospectively evaluated by serum markers, endoscopy, and imaging techniques. RESULTS: We evaluated 81 sorafenib-treated patients and 21 developed MA suspicion (85.7% male, 81.5% Child-Pugh A, 52.4% BCLC-B, and 47.6% BCLC-C) within a median 5.9 months after starting sorafenib. The median treatment duration, follow-up, and overall survival after MA suspicion were 5.9, 20.3, and 20.3 months, respectively. Nine of them (42.9%) presented hyperparathyroidism secondary to vitamin D deficiency and 8 with PI. A gradual decrease in pancreatic volume of up to 19% was observed among patients with PI. Six of the 8 patients with PI received pancreatic enzymes, with complete recovery from MA symptoms and stabilization of pancreatic volume. CONCLUSIONS: We validated the association between MA and PI in 10% of sorafenib-treated patients. Pancreatic enzymes supplementation successfully led to symptomatic recovery. Awareness of this adverse event can help in the management of sorafenib irrespective of cancer type and likely, of other tyrosine kinase inhibitors for HCC patients.

Postprogression survival of patients with advanced hepatocellular carcinoma: rationale for second-line trial design.

UNLABELLED: Sorafenib improves overall survival (OS) of patients with hepatocellular carcinoma (HCC) in the absence of objective response. Thus, time to tumor progression (TTP) is used to capture benefits of novel molecular agents, but proof of its surrogacy with survival is lacking. Furthermore, survival predictors upon progression are not established and there is a need to characterize postprogression survival (PPS) and assess with time-dependent covariates analysis if it is influenced by progression pattern, and not solely by simultaneous impairment of liver function and performance status. We prospectively followed HCC patients treated with sorafenib. Clinical and biochemical evaluation were done every 4 weeks. Radiologic assessment of progression was done at week 4 and then every 8 weeks using RECIST 1.1. The progression pattern was divided into: intrahepatic/extrahepatic increase in tumor size, new intrahepatic lesion, and new extrahepatic lesion (NEH). We included 147 patients (hepatitis C virus [HCV] 57.1%, performance status [PS] 0 83.6%, Child-Pugh A 82.3%, and BCLC-C 47.3%). The median OS was 12.7 months and its independent predictors (hazard ratio [HR], 95% confidence interval [CI]) were: baseline BCLC 2.49 [1.66-3.73], PS 1.86 [1.12-3.10], registration during follow-up of Child-Pugh B or Child-Pugh C scores (2.36 [1.51-3.69] and 2.89 [1.62-5.15], respectively), definitive sorafenib interruption 2.48 [1.54-4.01], and TTP 3.39 [1.89-6.1]. The presence of NEH 2.42 [1.32-4.44] is also an independent predictor of OS and PPS in patients with radiologic progression. CONCLUSION: Tumor progression is a surrogate of survival but its impact varies according to progression pattern. Thus, PPS is influenced by progression pattern and this is key in prognostic prediction and second-line trial design and analysis.