Abstract
Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5-11.6) vs 5.0 (4.2-5.7)months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8-12.9) vs. 5.8 (4.8-6.8)months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5-24.1) vs. 7.8 (5.2-10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.
Highlights
The oral multi-tyrosine kinase inhibitor sorafenib currently represents the only evidence-based treatment for advanced hepatocellular carcinoma (HCC) in patients with preserved liver function
Male sex accounted for about 80% of cases in both groups, whereas Metronomic capecitabine (MC) patients were slightly younger than best supportive care (BSC) patients
The two groups differed for the following features: MC patients showed a more frequently preserved PS (PS 0: 62.9 vs 49.1%, respectively, p = 0.007), smaller HCCs (4.7 vs 6.4 cm, p < 0.001), a lower prevalence of neoplastic thrombosis (23.1 vs 35.7%, p = 0.036) than BSC patients
Summary
The oral multi-tyrosine kinase inhibitor sorafenib currently represents the only evidence-based treatment for advanced hepatocellular carcinoma (HCC) in patients with preserved liver function. Several different anticancer agents, such as brivanib, ramucirumab and everolimus have failed to improve survival as second-line treatments in phase 3 randomized controlled trials (RCTs) (Llovet et al 2013; Finn et al 2012; Zhu et al 2014, 2015) The reasons of these failures may be either an inadequate stratification of patients or the intrinsic toxicity of some of these drugs that cause severe AEs, the occurrence of which is facilitated by the co-presence of cirrhosis (Llovet et al 2015). This dismal scenario has been partially modified by regorafenib, a potent multikinase inhibitor, that succeeded in improving the survival of patients tolerant to sorafenib but with cancer progression, compared with placebo (Bruix et al 2017). Even this new cornerstone of systemic therapy for HCC does not accomplish the need of patients who do not tolerate sorafenib
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