Second-line Treatment Of Hepatocellular Carcinoma Research Articles

Regorafenib with immunotherapy versus regorafenib alone as second-line treatment for hepatocellular carcinoma: A multicenter real-world study.

Regorafenib remains the standard and widely used second-line strategy for advanced hepatocellular carcinoma (HCC). There is still a lack of large-scale multicenter real-world evidence concerning the concurrent use of regorafenib with immune checkpoint inhibitors (ICI). This study aims to evaluate whether combining regorafenib with ICI provides greater clinical benefit than regorafenib monotherapy as second-line therapy for advanced HCC under real-world circumstances. The study included 208 patients from five medical facilities. One hundred forty-three patients received regorafenib plus ICI combination therapy, while 65 patients received regorafenib monotherapy. Propensity score matching (PSM) analysis was employed. The regorafenib plus ICI group demonstrated significantly higher objective response rate (24.3% vs. 10.3%, after PSM, p = 0.030) and disease control rate (79.4% vs. 50.0%, after PSM, p < 0.001) compared to the regorafenib monotherapy group based on mRECIST criteria. Median progression-free survival (7.9 vs. 3.2 months, after PSM, p < 0.001) and overall survival (25.6 vs. 16.4 months, p = 0.010, after PSM) were also considerably longer in the regorafenib plus ICI group. The incidence of Grades 3-4 treatment-related adverse events (TRAEs) was marginally greater in the regorafenib plus ICI group than in the regorafenib group (23.8% vs. 20.0%, p = 0.546). Notably, there were no instances of treatment-related mortality or emergence of new TRAEs in any treatment group. The combination of regorafenib and ICI shows potential as a viable second-line treatment for advanced HCC, exhibiting favorable efficacy while maintaining a tolerable safety profile in contrast to regorafenib monotherapy.

The second-line treatment of hepatocellular carcinoma with CalliSpheres drug-eluting bead transarterial chemoembolization combined with regorafenib: A safety and efficacy analysis.

This study aimed to investigate the efficacy and safety of CalliSpheres drug-eluting beads transarterial chemoembolization (DEB-TACE) combined with regorafenib in the second-line treatment of unresectable hepatocellular carcinoma. A retrospective analysis was made of 34 patients with unresectable hepatocellular carcinoma (HCC) that had progressed after first-line treatment in Linyi Tumor Hospital from October 2019 to June 2021. These patients were divided into observation group (n = 15) and control group (n = 19) based on their treatment plans, who were respectively treated with regorafenib alone and regorafenib combined with DEB-TACE. The objective response rate (ORR) and the disease control rate (DCR) were evaluated by the modified Response Evaluation Criteria in Solid Tumors (mRECIST), and the progression-free survival (PFS) and the overall survival (OS) were calculated; the factors influencing PFS and OS of patients were analyzed by the Cox proportional hazards model; and the adverse reactions to the treatments were observed and recorded. After 2months of treatment, the ORR and the DCR of the observation group were 73.3% (11/15) and 86.7% (13/15) respectively, both higher than 10.5% (2/19) and 47.4% (9/19) of the control group. Their differences are statistically significant (P < 0.05). There were no statistically significant differences in the incidences of regorafenib-related adverse reactions including hand-foot skin reactions, fatigue, hypertension, diarrhea, and proteinuria between the two groups (P > 0.05). In the observation group, the main adverse reactions to DEB-TACE such as fever, pain, nausea, and vomiting were relieved after symptomatic treatment, and no serious complications such as ectopic embolization of CalliSpheres drug-eluting beads occurred. As of July 31, 2022, the median follow-up time was 12.5months, and the average was (14.00 ± 5.69) months. The median PFS was 9months in the observation group, and 6months in the control group, presenting a statistically significant difference (P < 0.05), and the median OS was 18months in the observation group, and 12months in the control group, also presenting a statistically significant difference (P < 0.05). The results of monofactor prognostic analysis showed that Child grade, AFP level, and treatment method had an influence on the PFS and the OS of liver cancer patients receiving regorafenib second-line treatment (P < 0.05), and the results of multifactor prognostic analysis showed that child grade and treatment method independently influenced the PFS of patients, while treatment method independently influenced the OS of patients (P < 0.05). DEB-TACE combined with regorafenib is safe and feasible in the treatment of unresectable HCC, with good efficacy and mild adverse reactions.

Bevacizumab combined with atezolizumab or sintilimab as second-line treatment in patients with advanced hepatocellular carcinoma: A retrospective study.

544 Background: The combination of bevacizumab and immune checkpoint inhibitors (ICI) has demonstrated promising efficacy and safety in the first-line treatment of advanced hepatocellular carcinoma (HCC). However, this combination has not been examined in patients with previous first-line treatment of ICI and tyrosine kinase inhibitor. This study aimed to investigate the effectiveness and safety of bevacizumab combined with atezolizumab or sintilimab as second-line treatment in patients with advanced HCC. Methods: The retrospective study included patients with advanced HCC who received combined therapy of bevacizumab and atezolizumab or sintilimab after failure of lenvatinib plus ICI between July 28, 2020 and March 7, 2022. Baseline patient characteristics were collected. Treatment response, overall response rate (ORR) and disease control rate (DCR) were evaluated according to response evaluation criteria in solid tumors (RECIST) version 1.1. Overall survival (OS) and progression-free survival (PFS) were analyzed by the Kaplan-Meier method. Treatment-related adverse events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Results: A total of 20 patients with advanced HCC were included, with a median follow-up time of 11.05 (5.03-20.63) months. Eleven patients died by the last follow-up on August 12, 2022. There were 18 males (90%) and two females (10%). The average age was 59.9±12.08 years. Seven patients (35%) had distant metastasis, and nine (45%) had vascular invasion. Liver function was classified as Child-Pugh grade A in 17 patients (85%) and grade B in three (15%). Patients with Barcelona Clinic Liver Cancer (BCLC) stages B, C and D were 1 (5%), 16 (80%) and 3 (15%), respectively. Eighteen patients (90%) had previous topical therapy. Of all patients previously administered lenvatinib plus ICI as first-line treatment, 14 (70%) had PFS longer than three months. ORR and DCR were 15% (95% confidence interval [CI], 3.2-37.9) and 55% (95% CI, 31.5-76.9), respectively. Median OS was 8.00 months (95% CI, 0.00-16.66), while median PFS was 3.80 months (95% CI, 2.41-5.19). Adverse events were observed in 14 patients (70%). Adverse events of grade 3 or worse occurred in six patients (30%). Conclusions: The combination of bevacizumab with atezolizumab or sintilimab had tolerable safety profile but poor response in the second-line treatment of HCC. Despite the satisfying efficacy as first-line therapy, this combination is not a cost-effective recommendation for advanced HCC cases who failed the first-line treatment of lenvatinib plus ICI. [Table: see text]

Efficacy and Prognostic Factors of Regorafenib in the Treatment of BCLC Stage C Hepatocellular Carcinoma After Failure of the First-Line Therapy.

Regorafenib is a standard second-line treatment for hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy and safety of regorafenib in the treatment of patients with Barcelona clinic liver cancer (BCLC) stage C HCC after failure of the first-line therapy and to analyze factors affecting the efficacy of regorafenib as the second-line treatment. A retrospective analysis was conducted on 103 BCLC stage C HCC patients who received regorafenib as the second-line treatment. Among them, 51 patients received regorafenib plus transarterial chemoembolization (TACE) and 52 patients received regorafenib alone. Progression-free survival (PFS), overall survival (OS), and adverse events were compared between the two groups, and factors influencing the efficacy of regorafenib were analyzed. In patients with BCLC stage C HCC after failure of the first-line therapy, there was no statistically significant difference in median PFS between regorafenib plus TACE group and regorafenib group (5.3 vs 4.0 months, P=0.432). The median OS was significantly longer in the regorafenib plus TACE group than that in the regorafenib group (11.3 vs 8.2 months, P=0.034). Patients in both groups experienced adverse events at rates of 78.43% and 75%, respectively. Rates of grade III-IV serious adverse events were 19.61% and 13.46%, respectively. Hand-foot skin reactions, fatigue, abdominal pain, and hypertension were common side effects of regorafenib. The number of tumors was noted as an independent prognostic factor for PFS in the univariate and multivariate Cox regression analyses, while Eastern Cooperative Oncology Group (ECOG) performance status (ECOG-PS) score, tumor size, the number of tumors, and combined local therapy were independent prognostic factors for OS. Regorafenib combined with TACE treatment improved OS for patients with ECOG-PS scores of 0-1, tumor size < 5 cm, and the number of tumors ≥ 3 compared with regorafenib alone. Regorafenib exhibited to be a safe and effective sequential therapy for patients with BCLC stage C HCC after failure of the first-line treatment, and its combination with TACE could achieve a higher efficacy. ECOG-PS score, tumor size, the number of tumors, and combined local therapy were noted as prognostic factors affecting patients with BCLC stage C HCC who were treated with regorafenib.

Abstract IA19: Impact of single checkpoint inhibitors and biomarkers of response

Abstract Single agent anti PD-1 antibodies have shown consistent safety and efficacy for the treatment of advanced hepatocellular carcinoma (HCC). Response rates range between 15 and 20% and the rate of grade 3 and 4 adverse events is generally below 25%. Recently, the HIMALAYA trial showed that durvalumab was non-inferior to sorafenib for first-line treatment of HCC. Further, Keynote-394 showed that pembrolizumab improved survival compared to placebo in second line treatment of HCC. Nivolumab was evaluated in a dedicated cohort of Checkmate 040 in patients with child pugh B cirrhosis and determined to have a manageable safety profile, similar to that in child pugh A. Given the fact that immunotherapy-based combinations are the current standard of care for advanced HCC, and given the absence of biomarkers for patient selection, the use of single agent anti PD-1 or PD-L1 antibodies in advanced first line HCC treatment is limited to patients who are not candidates for combination therapy or patients with compromised liver function. Single agent anti PD-1/PD-L1 antibodies are being evaluated in the adjuvant setting and in combination with liver directed therapy. Emerging biomarker data suggest an association between T cell inflammation signature and outcome with single agent anti PD-1 and PD-L1 agents. Further research is needed to validate the early biomarker data. Citation Format: Anthony El-Khoueiry. Impact of single checkpoint inhibitors and biomarkers of response [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA19.

Cost-effectiveness of Pembrolizumab as a Second-Line Therapy for Hepatocellular Carcinoma

Immune checkpoint inhibitors have been approved for use as a second-line therapy for hepatocellular carcinoma (HCC) in patients who previously received sorafenib. Pembrolizumab has shown substantial antitumor activity and a favorable toxicity profile as a second-line treatment of HCC. However, considering the high cost of pembrolizumab, there is a need to assess its value by considering both the clinical efficacy and cost. To evaluate the cost-effectiveness of pembrolizumab vs placebo as second-line therapy in patients with HCC from the US payer perspective. A Markov model was developed to compare the lifetime cost and efficacy of pembrolizumab as a second-line treatment of HCC with those of placebo using outcome data from the KEYNOTE-240 randomized placebo-controlled trial, which included 413 patients with advanced HCC previously treated with sorafenib and randomized patients to receive pembrolizumab plus best supportive care or placebo plus best supportive care in a 2:1 ratio. Life-years, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER) were estimated at a willingness-to-pay threshold of $150 000 per QALY. One-way and probabilistic sensitivity analyses were performed to account for the parameter of uncertainty. A cost-threshold analysis was also performed. The study was conducted from January 31 to July 29, 2020. The base-case model found that treatment with pembrolizumab was associated with increased overall cost by $47 057 and improved effectiveness by 0.138 QALYs compared with placebo, leading to an ICER of $340 409 per QALY. The model was most sensitive to the hazard ratio of overall survival (range, 0.61-1.00), health utility of placebo (range, 0.59-0.93), price of pembrolizumab (range, $5531-$8297), and price of postprogression therapies (range, $5596-$7944 for pembrolizumab and $4770-$7156 for placebo). The ICER of pembrolizumab was larger than $150 000 per QALY in most of the sensitivity and subgroup analyses. The price of pembrolizumab needed to be reduced by 57.7% to $2925 per cycle to achieve cost-effectiveness. The findings of this cost-effectiveness analysis suggest that, at its current price, pembrolizumab is not a cost-effective second-line therapy for HCC in the US, with a willingness-to-pay threshold of $150 000 per QALY.

A MEA is a MEA is a MEA? Sequential decision making and the impact of different managed entry agreements at the manufacturer and payer level, using a case study for an oncology drug in England.

In a typical single-payer setting that uses an explicit cost-effectiveness (CE) threshold in its decision-making, the payer aims to maximize the net-monetary-benefit (NMB) given the CE threshold, whilst the manufacturer aims to maximize the expected discounted-cash-flow (DCF) resulting from the sales of that technology. Managed entry agreements (MEAs) are tools that are used to improve access to expensive technologies that would otherwise not be deemed to be cost-effective to payers. While simple discount on the list price is the most commonly applied MEA type, there are different forms, each having a different impact on the cost-effectiveness of the technology, on the lifetime DCF-per-patient and on the decision uncertainty. We aim to analyze the sequential decision-making (SDM) of different MEAs (i.e. simple discount, free treatment initiation, lifetime treatment acquisition cost-capping [LTTACC], performance-based money-back guarantee [MBG]) at the manufacturer and at the payer level, respectively. We first model the SDM of the manufacturer and the payer as a sequential game and explain the challenges to find an equilibrium analytically. Then we propose a heuristic computational method to follow for each of the MEA types, based on practice. To demonstrate this SDM on a case study, a UK-based cost-utility analysis using a three-state, partitioned-survival-model was constructed to determine the cost-effectiveness of regorafenib versus best-supportive-care for the second-line treatment of hepatocellular carcinoma. The optimal agreement terms that would maximise the lifetime DCF-per-patient for each MEA, whilst remaining below the CE-threshold (£50,000/QALY gained) were obtained in the deterministic base-case. Robustness for each optimized MEA was then assessed using probabilistic sensitivity and scenario analyses, the value of information (VoI), and HTA-risk analyses. As expected, the introduction of all MEAs improved the probabilistic ICER and NMB values to (almost) acceptable levels, compared to the "no-MEA" case (ICER ~ £78,000/QALY-gained). The expected DCFs across the explored MEAs were all similar, whilst the payer strategy & uncertainty burden (PSUB) for regorafenib decreased in all MEAs explored. VoI analyses revealed that regorafenib mean-dose-intensity and time-on-treatment (ToT) parameters attributed most to the decision uncertainty. LTTACC provided the smallest PSUB and the most robust NMB estimates under parametric uncertainty. For scenarios assuming increased regorafenib ToT or mean-dose-intensity, LTACC again provided acceptable cost-effectiveness outcomes, whereas for scenarios assuming decreased regorafenib progression-free/overall survival effectiveness, only MBG resulted in plausible ICER values. In scenarios, where the source of uncertainty was not targeted by MEA parameters (e.g. the scenario assuming higher progressed disease resource utilization), all investigated MEA types resulted in unacceptable cost-effectiveness outcomes. Each MEA type has a different implication. The impact of different MEAs on the NMB is more noteworthy than on the DCF, in relative terms, hence payers will benefit from the early participation of the MEA design rather than leaving this up to the prerogative of the manufacturer. While simple discount might be practical for implementation purposes, other MEAs can provide additional benefits to the payer in terms of increased NMB, reduced decision risk and reduced uncertainty. MEA performance should be investigated not only under parametric uncertainty, but also under-identified structural uncertainty, and the barriers of implementation should be considered thoroughly before choosing the most appropriate MEA type.

P-259 Pembrolizumab as second-line therapy of hepatocellular carcinoma: A cost-effectiveness analysis

Recently, checkpoint inhibitors have been approved for the second-line therapy of hepatocellular carcinoma (HCC) in patients who previously received sorafenib. Pembrolizumab has demonstrated substantial anti-tumor activity and favorable toxicity profile as second-line treatment of HCC. However, considering the high cost of pembrolizumab, there is a need to assess its value by considering both efficacy and cost. We aimed to evaluate the cost-effectiveness of pembrolizumab vs. placebo as second-line therapy in hepatocellular carcinoma (HCC) patients from the US payer perspective.

The Synergistic Anti-Cancer Effects of NVP-BEZ235 and Regorafenib in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Regorafenib is a multi-kinase inhibitor and the second-line treatment for HCC. Since the PI3K/Akt/mTOR signaling pathway is dysregulated in HCC, we evaluated the therapeutic effects of regorafenib combined with a dual PI3K/mTOR inhibitor BEZ235 in the human HCC cell lines (n = 3). The combined treatment with BEZ235 and regorafenib enhanced the inhibition of cell proliferation and increased the expression of cleaved caspase-3 and cleaved PARP in HCC cells. Moreover, the combined treatment suppressed HCC cell migration and invasion in the transwell assay. Further, the Western blot analyses confirmed the involvement of epithelial-mesenchymal transition (EMT)-related genes such as slug, vimentin, and matrix metalloproteinase (MMP)-9/-2. Additionally, the proteinase activity of MMP-9/-2 was analyzed using gelatin zymography. Furthermore, the inhibition of phosphorylation of the Akt, mTOR, p70S6K, and 4EBP1 after combined treatment was validated using Western blot analysis. Therefore, these results suggest that the combined treatment with BEZ235 and regorafenib benefits patients with HCC.

Regorafenib Alteration of the BCL-xL/MCL-1 Ratio Provides a Therapeutic Opportunity for BH3-Mimetics in Hepatocellular Carcinoma Models.

Background: The multikinase inhibitor regorafenib, approved as second-line treatment for hepatocellular carcinoma (HCC) after sorafenib failure, may induce mitochondrial damage. BH3-mimetics, inhibitors of specific BCL-2 proteins, are valuable drugs in cancer therapy to amplify mitochondrial-dependent cell death. Methods: In in vitro and in vivo HCC models, we tested regorafenib’s effect on the BCL-2 network and the efficacy of BH3-mimetics on HCC treatment. Results: In hepatoma cell lines and Hep3B liver spheroids, regorafenib cytotoxicity was potentiated by BCL-xL siRNA transfection or pharmacological inhibition (A-1331852), while BCL-2 antagonism had no effect. Mitochondrial outer membrane permeabilization, cytochrome c release, and caspase-3 activation mediated A-1331852/regorafenib-induced cell death. In a patient-derived xenograft (PDX) HCC model, BCL-xL inhibition stimulated regorafenib activity, drastically decreasing tumor growth. Moreover, regorafenib-resistant HepG2 cells displayed increased BCL-xL and reduced MCL-1 expression, while A-1331852 reinstated regorafenib efficacy in vitro and in a xenograft mouse model. Interestingly, BCL-xL levels, associated with poor prognosis in liver and colorectal cancer, and the BCL-xL/MCL-1 ratio were detected as being increased in HCC patients. Conclusion: Regorafenib primes tumor cells to BH3-mimetic-induced cell death, allowing BCL-xL inhibition with A-1331852 or other strategies based on BCL-xL degradation to enhance regorafenib efficacy, offering a novel approach for HCC treatment, particularly for tumors with an elevated BCL-xL/MCL-1 ratio.

Second-line treatment of hepatocellular carcinoma: from theory to practical issues

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with unmet needs of effective medications. Lenvatinib – a new oral multikinase inhibitor (MKI) proved to be as effective as sorafenib in terms of survival has been added recently to standard first-line treatment of advanced HCC. Regorafenib, another MKI in the RESORCE trial, a phase 3 study evaluating regorafenib in HCC patients who experience disease progression after first-line treatment with sorafenib, have shown a 2.8-month median survival benefit over placebo (10.6 versus 7.8 months). Cabozantinib and ramucirumab have all been shown to extend overall patient survival in sorafenib-refractory HCC patients and appear to have a reasonable safety profile. Immune checkpoint inhibitors therapy with nivolumab or pembrolizumab – monoclonal antibody to PD1-receptor are effective in about 15–18% of HСС patients presenting with long-lasting objective responses. Immunotherapy was safe in terms of viral hepatitis activation, but in comparative trials in first and second-line settings failed to achieve statistical difference in overall survival other sorafenib and placebo, respectively. Due to less toxic profile HCC immunotherapy seems to be a reasonable option to Child-Pugh B patients. Multiple ongoing trials are studying immune checkpoint inhibition alone or in combination with TKIs. The results of these trials will help determine the optimal choice, timing, and sequence of agents. This article reviews current situation in the field of new therapies of HCC from the point of common medical practice in searching for optimal second-line treatment decision in different clinical situations.

Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation.

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 (57years, 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 (6.3months), 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 38.4months (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.

Second-line Treatments of Advanced Hepatocellular Carcinoma: Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Advanced hepatocellular carcinoma (HCC) constitutes the second leading cause of cancer-related deaths. First-line therapy is either sorafenib or lenvatinib. Several treatment options have been recently added to the second-line treatment of advanced HCC. The aim of this network meta-analysis of randomized controlled trials was to compare the second-line treatments of advanced HCC. Network meta-analyses were computed for overall survival (OS), progression-free survival, rates of grade 3 to 5 adverse events, and for treatment discontinuation due to adverse events. OS was considered to be the primary outcome of this study, and everolimus was chosen to be the common comparator for efficacy analyses and placebo for safety analyses. Subgroup analyses were computed for OS in patients with hepatitis B, patients with hepatitis C, Asian patients, patients with macrovascular invasion, and patients with extrahepatic metastases. Thirteen randomized controlled trials including 5076 patients and evaluating 11 agents were found to be eligible. Regorafenib [hazard ratio (HR)=0.60, 95% confidence interval (CI)=0.44-0.81] and cabozantinib (HR=0.72, 95% CI=0.55-0.95) were found to significantly prolong OS compared with everolimus. The effect of regorafenib on OS tended to be conserved across patient subgroups. Regorafenib was also found to significantly prolong progression-free survival (HR=0.46, 95% CI=0.35-0.62) and significantly increase the rates of grade 3 to 5 adverse events (odds ratios=3.18, 95% CI=2.22-4.54) and treatment discontinuation due to adverse events (odds ratios=2.67, 95% CI=1.21-5.87). This network meta-analysis concludes that, based on current evidence, regorafenib could be the agent of choice in the second-line treatment of HCC, with cabozantinib as a possible alternative for sorafenib-intolerant patients.

ASCO update 2018: upper gastrointestinal cancer

Results from studies in upper gastrointestinal cancer presented at the 2018 American Society of Clinical Oncology (ASCO) meeting are promising. Prophylactic treatment of Barrett’s esophagus with high proton pump inhibitor therapy plus aspirin showed positive results on death, esophageal adenocarcinoma and dysplasia. Current studies on the treatment of gastric cancer included the following: S‑1 plus docetaxel as postoperative adjuvant chemotherapy in Asian patients, triplet therapy (cisplatin, S1, and docetaxel) in Asian patients, paclitaxel vs. pembrolizumab, and a biomarker study for trastuzumab continuation. Advances in the treatment of pancreatic cancer are likely to be practice changing: combined chemotherapy mFOLFIRINOX clearly improved disease-free survival in patients with resected pancreatic ductal adenocarcinomas. In the palliative setting, the introduction of FOLFIRINOX and gemcitabine/nab-paclitaxel may allow treatment with lower toxicity and allow broader patient selection. In the treatment of cholagiocellular cancer, gemcitabine plus S‑1 was non-inferior to gemcitabine plus cisplatin. Preliminary data in the treatment of neoendocrine tumors with temozolomide plus capecitabine are promising. Finally, the second-line treatment of hepatocellular carcinoma with ramucirumab showed a significant survival benefit.

Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation.

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.

Molecular targeted agents as second-line treatment for hepatocellular carcinoma: a meta-analysis and review.

It is unclear whether targeted agents can produce survival advantage in patients with advanced HCC previously treated with sorafenib. We performed this meta-analysis of randomized trials and reviewed clinical outcomes of molecular targeted agents in the second-line treatment for advanced HCC. A systematic computerized search of the electronic databases PubMed, Embase, Google Scholar, and Cochrane Library (up to May 2017) was carried out. From six studies, 2,388 patients were included in the meta-analysis. Almost all patients were treated with sorafenib as first-line therapy. Compared with placebo, targeted agents significantly improved time-to-progression (hazard ratio = 0.62, 95% confidence interval: 0.49–0.78, P < 0.0001). In terms of overall survival, targeted therapy tended to improve prognosis (hazard ratio = 0.86, 95% confidence interval: 0.74–1.01, P = 0.06). In conclusion, this meta-analysis indicates that molecular targeted agents have a potential to improve prognosis after failure of first-line treatment with sorafenib in patients with advanced HCC.

Systemic therapy for advanced hepatocellular carcinoma: an update.

Advanced hepatocellular carcinoma (HCC) is a deadly disease with few systemic therapeutic options. Sorafenib is the only agent to be FDA approved for the first-line treatment of patients with HCC. This drug increases overall survival (OS) by 3 months compared with placebo (10.7 months with sorafenib vs. 7.7 months with placebo). More recently, the RESORCE trial demonstrated efficacy of regorafenib in the second-line treatment of HCC: OS was increased from 7.8 months with placebo to 10.6 months with regorafenib after patients experienced disease progression on sorafenib. However, there is still an unmet need for effective systemic therapy of patients with advanced HCC. Numerous genetic pathways have been studied along with drugs to target these pathways but, thus far, drugs targeting cell proliferation, metastasis, angiogenesis, and metabolite use have been studied with minimal success. HCC can be divided into two subclasses: proliferative and non-proliferative, each dependent on separate pathways. HCC can be caused by alcoholic cirrhosis, hepatitis C virus (HCV), and hepatitis B virus (HBV); however no etiology-specific therapies have been demonstrated. Immunotherapy is currently being assessed in clinical trials and is demonstrating some efficacy. More research is needed to determine the most essential pathways to target in the war against this deadly cancer.

Transarterial Chemoembolization With Cisplatin as Second-Line Treatment for Hepatocellular Carcinoma Unresponsive to Chemoembolization With Epirubicin-Lipiodol Emulsion

The purpose of this retrospective study was to investigate the efficacy of transarterial chemoembolization (TACE) using cisplatin as a second-line treatment for advanced hepatocellular carcinoma (HCC) unresponsive to TACE using epirubicin-Lipiodol emulsion at our institution. Between January 2006 and March 2009, 51 patients with unresectable HCC underwent TACE using cisplatin. All patients had shown persistent viable tumor or tumor progression after at least 2 sessions of TACE using epirubicin-Lipiodol emulsion. TACE procedures consisted of arterial injection of a mixture of Lipiodol and cisplatin (30-100mg [mean 57±21]) (n=29) or arterial infusion of cisplatin (30-100mg [mean 87±19]) solution (n=22) followed by injection of 1-mm porous gelatin particles. Early tumor response was assessed by contrast-enhanced computed tomography (CT) according to Response Evaluation Criteria in Solid Tumors (RECIST) and European Association for the Study of the Liver (EASL) criteria. Overall survival and progression-free survival was calculated using the Kaplan-Meier method. Toxicity was assessed according to NCI-CTCAE version 3 criteria. Response rates were 11.8 and 27.5% by RECIST and EASL criteria, respectively. Overall survival rates were 61.9, 48.2, and 28.9% at 1, 2, and 3years, respectively, and the median survival time was 15.4months. Progression-free survival rate was 35.2% at 1year, and median progression-free survival time was 3.1months. No major complications were observed, and the occurrence of postembolization syndrome was minimal. Grade 3 to 4 toxicities included thrombocytopenia (5.8%), increased aspartate aminotransferase (AST) level (35.3%), and increased alanine aminotransferase (ALT) level (23.5%). Switching the TACE anticancer drug from epirubicin to cisplatin might be the feasible option for advanced HCC, even when considered resistant to the initial form of TACE.