Systematic review with meta‐analysis: the critical role of dermatological events in patients with hepatocellular carcinoma treated with sorafenib

Abstract

Background: The positive results of the REFLECT trial in terms of survival (sorafenib vs lenvatinib) offer a new first-line option for hepatocellular carcinoma. Additionally, the expected results of immunotherapy could change the first-line treatment in hepatocellular carcinoma or the clinical trial design in first and second-line. Aims: To evaluate the impact of dermatologic adverse events under sorafenib in hepatocellular carcinoma patients as a clinical marker to predict prognosis and critically evaluate outcomes within trials. Methods: A systematic search of original articles published until October 2018 was performed using PubMed/MEDLINE and a meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.Results: A total of 393 studies were identified and 13 articles with 2035 patients (79.5% Child-Pugh-A, 73.2% BCLC-C) were selected for qualitative and quantitative analysis. The main type of dermatologic adverse events was hand-foot skin reaction (47.7%) but other dermatologic adverse events were reported in 31.7% of the cases.Presence of dermatologic adverse events was associated with a lower mortality when compared with those patients without them (pooled Hazard Ratio for the univariate analysis 0.45 (95% CI: 0.38-0.53) and there was no heterogeneity for the analysis (P = 0.511; I 2 = 0.0%). Refuting this association would require the future report of 1370 negative studies. Conclusions:This meta-analysis shows a clinically meaningful association between dermatologic adverse events and a higher probability of longer survival. These data support the use of dermatologic adverse events in the clinical decision-making when informing the prognosis and when systemic treatment is decided.

Evolving role of regorafenib for the treatment of advanced cancers

“…Post hoc exploratory analyses of CORRECT and RESORCE indicate that patients with treatment-related HFSR had greater regorafenib benefit than those without; notably, a significant OS benefit was observed when HFSR occurred during the first treatment cycle, supporting continued treatment with dose adjustment [104,105]. Similar outcomes have been reported for regorafenib in the real-world REBECCA study [20], in the Japanese mCRC post-marketing surveillance study [23], and for the TKIs sorafenib and sunitinib in HCC and renal cell carcinoma [99][100][101]. Recently, early HFSR following sorafenib treatment in HCC has been associated with improved treatment response [106].…”

“…One of the most common toxicities associated with TKIs, including regorafenib, is HFSR [96][97][98][99][100][101]. A published meta-analysis of regorafenib trials observed a clinically significant variation in all-grade regorafenib-related HFSR incidence across studied tumor types, with higher rates in patients with GIST (60%) versus HCC (50%) and mCRC (47%) [102].…”

Sequencing of systemic treatment for hepatocellular carcinoma: Second line competitors

“…However, radiological tumor progression can be distinguished in four different patterns with a different impact on OS [39,40] . The key clinical question is when to move to second line treatment under tumor progression in a patient tolerating treatment or even more strikingly, if during treatment the patient has shown clinical benefit hallmarks such as dermatological events [41] . A new intrahepatic lesion has a better prognosis than a new extrahepatic lesion or a new vascular invasion [39,40] .…”

Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients

“…Methods. We analysed the prospectively collected data of consecutive patients who started sorafenib [5,6]. Thus, avoiding a definitive suspension of sorafenib in these patients would be extremely beneficial.…”