Abstract Background & Aims Various grades of adverse events are associated with sorafenib and have recently been considered as a surrogate of response in patients with advanced hepatocellular carcinoma. The aim of this prospective study was to measure the efficacy of a sorafenib dose reduction regimen, adjusted on patient's tolerability, and aimed at increasing the exposure to the drug. Methods A total of 73/140 patients with advanced hepatocellular carcinoma receiving sorafenib developed relevant adverse events (grade ≥2) and were managed with a tolerable‐adverse‐event‐protocol consisting of a drug stepwise dose reduction adjusted on patient's tolerability. The remaining 67 patients with toxicity grade 0–1 (minor adverse event group) were managed conventionally with just symptomatic treatment. Results Median follow‐up was 7 months. By adopting the tolerable‐adverse‐event‐protocol, 48% of patients meant to transiently or definitively interrupt the drug were kept on treatment. Macrovascular invasion with/out extra‐hepatic spread ( HR = 1.9, 95% CI : 1.3–2.8; P = 0.001) and sorafenib exposure <2 months ( HR = 4, 95% CI : 2.5–6.4; P < 0.0001) were independently related to a worse survival. Overall disease control rate, time to progression and survival were: 63.5%, 6 and 9.1 months respectively. The tolerable‐adverse‐event‐protocol group experienced a more favourable outcome with respect to the minor adverse event group as for disease control rate (78% vs. 48%: P < 0.0001), time to progression (9.5 vs. 3 months; HR = 0.3, 95% CI : 0.2–0.5, P < 0.0001) and survival (12.5 vs. 5.7 months; HR = 0.4, 95% CI : 0.3–0.6; P < 0.0001). Conclusions In patients with advanced hepatocellular carcinoma, sorafenib dose adjustments based on inducing tolerability of relevant adverse events prolong drug exposure and maximize survival.
Fibroblast growth factor receptor 2 (FGFR2) might have an important role in the pathogenesis and biology of cholangiocarcinoma (CCA). We examined FGFR expression in CCA tumor specimens obtained from patients and CCA cell lines, and then determined the effects of the novel FGFR inhibitor, derazantinib (DZB; formally, ARQ 087), which is currently in clinical phase 2 trials for intrahepatic CCA. DZB inhibited the growth of CCA cell lines in a dose-dependent manner, and extracellular signal-regulated kinase 1/2 and AKT. It also activated apoptotic and cell growth arrest signaling. DZB reduced the in vitro invasiveness and the expression of key epithelial-mesenchymal transition genes. The in vitro data correlated with the expression of FGFRs in human CCA specimens by immunohistochemistry (FGFR1, 30% positive; and FGFR2, 65% positive) and the CCA cell lines assayed by Western blot analysis. These correlated in vitro studies suggest that FGFR may play an important role in the pathogenesis and biology of CCA. Our findings support the notion that FGFR inhibitors, like DZB, should be further evaluated at the clinical stage as targeted therapy for CCA treatment.
Liver resection is the treatment of choice for hepatocellular carcinoma (HCC) in well-compensated liver cirrhosis. Postoperative liver decompensation (LD) is the most representative and least predictable cause of morbidity and mortality.
Objectives
To determine the hierarchy and interaction of factors associated with the risk for LD and to define applicable risk classes among surgical candidates.
Design, Setting, and Participants
This retrospective review collected data from 543 patients with chronic liver disease who underwent hepatic resection for HCC from January 1, 2000, through December 31, 2013, in a tertiary comprehensive cancer center. Final follow-up was completed on January 31, 2015, and data were assessed from February 1 to 28, 2015.
Major Outcomes and Measures
Preoperative prognostic factors and risk stratification for postoperative LD. Multivariate logistic regression was performed, and the independent risk factors for LD were included in a recursive partitioning analysis model. Results were validated by means of 10-fold cross-validation.
Results
The analysis included 543 patients, of whom 411 (75.7%) were male, 132 (24.3%) were female, and the median age was 68 (interquartile range, 62-73) years. An independent association with LD was found for major hepatectomy (odds ratio [OR], 2.41; 95% CI, 1.17-4.30;P = .01), portal hypertension (OR, 2.20; 95% CI, 1.13-4.30;P = .01), and Model for End-Stage Liver Disease (MELD) score greater than 9 (OR, 2.26; 95% CI, 1.10-4.58;P = .02). Recursive partitioning analysis confirmed portal hypertension as the most important factor (OR, 2.99; 95% CI, 1.93-4.62;P < .001), followed by extension of hepatectomy with (OR, 2.76; 95% CI, 1.85-4.77;P = .03) and without (OR, 2.98; 95% CI, 1.97-4.52;P < .001) portal hypertension, and MELD score (OR, 1.79; 95% CI, 1.23-2.13;P < .001). Low-risk patients (LD rate, 4.9% [11 of 226]) without portal hypertension underwent minor resection with a MELD score of 9 or less; intermediate-risk patients (LD rate, 28.6% [85 of 297]) had no portal hypertension and underwent major resections or, in case of minor resections, had portal hypertension or a MELD score greater than 9; and high-risk patients (LD rate, 60.0% [12 of 20]) underwent major resection with portal hypertension. Risk-class progression paralleled median length of stay (7, 8, and 11 days, respectively;P < .001) and liver-related mortality (4.4% [10 of 226], 9.0% [27 of 297], and 25.0% [5 of 20], respectively;P = .001). A 10-fold cross-validation of the model resulted in a C index of 0.78 (95% CI, 0.74-0.82) and an overall error rate of 0.06.
Conclusions and Relevance
The risk for postoperative LD after resection for HCC in chronic liver disease is associated with preoperative hierarchic interaction of portal hypertension, planned extension of hepatectomy, and the MELD score.
Although liver transplantation (LT) is the best treatment for patients with localized hepatocellular carcinoma (HCC), recurrence occurs in 6%-18% of patients. Several factors, particularly morphological criteria combined with dynamic parameters, known before LT modify this risk and combined in prediction models may be used to stratify patients at need of variable surveillance strategies. Additional variables though likely explain differences in recurrence rates in patients with the same pre-LT HCC status. One of these variables is possibly immunosuppression (IS). Once recurrence takes place, management is highly heterogenous. Within the International Liver Transplantation Society Consensus Conference on Liver Transplant Oncology, working group 4 aim was to analyze the data regarding posttransplant management of recipients undergoing LT for HCC. Three areas of research were considered: (1) cancer prediction models and surveillance strategies; (2) tailored IS for cancer recipients; and (3) new adjuvant therapies for HCC recurrence. Following formulation of several questions, a literature search was undertaken with abstract review followed by article retrieval and full-data extraction. The grading of recommendations assessment, development and evaluation (GRADE) system was used for evidence rating incorporating strength of recommendation and quality of evidence.
Regorafenib is one option for second-line treatment of hepatocellular carcinoma (HCC), improving overall survival (OS) of sorafenib-tolerant patients who develop progression. We aim to evaluate the safety and outcomes of regorafenib as second-line treatment for HCC recurrence after liver transplantation (LT). This is a retrospective, multicenter, international study including regorafenib-treated LT patients (2015-2018), with analysis of baseline characteristics and evolutionary events during sorafenib/regorafenib treatment. Twenty-eight LT patients (57 years, 7% cirrhotics, 54% performance status 1) were included. Median time from LT to regorafenib initiation was 3.9 (1.1-18.5) years; median time on sorafenib was 11.3 (0.7-76.4) months and 14 (1-591) days from sorafenib discontinuation to regorafenib. During regorafenib (6.3 months), all patients had at least one adverse event (AE), the most common grade 3/4 AEs were fatigue (n = 7) and dermatological reaction (n = 5). While no liver rejection was observed, plasma levels of immunosuppressive drugs increased in five. Twenty-four patients developed progression (38% extrahepatic growth, 33% new extrahepatic lesions/vascular invasion). Median OS from regorafenib initiation was 12.9 (95% CI, 6.7-19.1) and 38.4 months (95% CI, 18.5-58.4) for the sorafenib initiation. This is the first study showing safety of regorafenib after LT, thus providing the rational of considering regorafenib in the clinical decision-making in sorafenib-tolerant patients with HCC recurrence after LT.
