Argentinian clinical practice guideline for surveillance,diagnosis, staging and treatment of hepatocellular carcinoma

The A.A.E.E.H has developed this guideline for the best care of patients with hepatocellular carcinoma (HCC) from Argentina. It was done from May 2018 to March 2020. Specific clinical research questions were systematically searched. The quality of evidence and level of recommendations were organized according to GRADE. HCC surveillance is strongly recommended with abdominal ultrasound (US) every six months in the population at risk for HCC (cirrhosis, hepatitis B or hepatitis C); it is suggested to add alpha-feto protein (AFP) levels in case of inexeperienced sonographers. Imaging diagnosis in patients at risk for HCC has high specificity and tumor biopsy is not mandatory. The Barcelona Clinic Liver Cancer algorithm is strongly recommended for HCC staging and treatment-decision processes. Liver resection is strongly recommended for patients without portal hypertension and preserved liver function. Composite models are suggested for liver transplant selection criteria. Therapies for HCC with robust clinical evidence include transarterial chemoembolization (TACE) and first to second line systemic treatment options (sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab). Immunotherapy with nivolumab and pembrolizumab has failed to show statistical benefit but the novel combination of atezolizumab plus bevacizumab has recently shown survival benefit over sorafenib in frontline.     

Navigating the new landscape of second‐line treatment in advanced hepatocellular carcinoma

Sorafenib and lenvatinib are approved for first‐line treatment of patients with advanced hepatocellular carcinoma (HCC), and the efficacy of atezolizumab plus bevacizumab has been demonstrated versus sorafenib. Over time, first‐line treatment frequently fails, and regorafenib, cabozantinib, ramucirumab (for patients with alpha fetoprotein ≥400 ng/mL), nivolumab, pembrolizumab and ipilimumab plus nivolumab are approved for use after sorafenib (but not lenvatinib) treatment in advanced HCC. Given the considerable complexity in the therapeutic landscape, the objective of this review was to summarize the clinical evidence for second‐line agents and provide practical guidance for selecting the best sequential treatment approach. The timing and sequencing of treatment switches are key to optimizing patient outcomes in advanced HCC, and decisions should be informed by reasons for discontinuation of previous therapy and disease progression. It is important not to switch too soon, because sequential treatment benefit may then be lost, nor should switching be delayed too long. Effectiveness, safety and tolerability, patient quality of life, route of administration, dosing regimen, drug class, molecular target and individual patients’ characteristics, including comorbidities, inform the selection of second‐line systemic treatment, independently of the aetiology of HCC, tumour stage and the response to previous treatment. Biomarkers predictive of treatment effectiveness are of great value, but currently biomarker‐driven patient selection is possible only in the case of ramucirumab. The approval of new combination therapies for advanced HCC in the first‐line setting will further increase the complexity of decision‐making. However, the important factors will remain the individual patient’s characteristics and preferences.     

Recent advances in medical management of hepatocellular carcinoma

Transcatheter arterial therapies for hepatocellular carcinoma (HCC) have developed during the last decade. A fine powder formulation of cisplatin and the new platinum agent miriplatin became standard medicines in addition to anthracyclines in transcatheter arterial chemoembolization (TACE) in Japan. Recent prospective and retrospective studies supported the usefulness of platinum agents as a chemotherapeutic at the time of varied TACE therapy. Although balloon‐occluded TACE is an effective therapy for localized HCC and drug‐eluting microspheres seemed to show a higher response rate in certain HCCs, the definite advantages of those procedures still remain uncertain. Intermediate stage HCC, or Barcelona Clinic Liver Cancer stage B, is regarded as a heterogeneous category with a wide spectrum of tumors and patients, and several subclassifications of the stage have been proposed to show different prognoses; there are also different recommended therapies in each subgroup. Authors have subclassified patients based on combinations of tumor size, tumor number, and liver function, with or without performance status. Because of differences of available medical resources and techniques in treatment procedures between countries, the most ideal and useful subgrouping remains inconclusive at present. Recently, a few systemic chemotherapies proved to be effective for advanced stage HCC in phase III studies: lenvatinib as the first line of therapy, and regorafenib, cabozantinib, and ramucirumab as second‐line therapy. Other molecular‐targeted and immune‐oncological medicines are expected to follow in the near future. Some studies have suggested an advantage of early introduction of molecular‐targeted therapy for TACE‐resistant HCC in the intermediate stage.     

Sequencing of systemic treatment for hepatocellular carcinoma:Second line competitors

During the last decades, further knowledge of hepatocellular carcinoma(HCC)molecular mechanisms has led to development of effective systemic treatments including tyrosine kinase inhibitors(TKIs) and immunotherapy. In this review,we describe first and second line systemic treatment options for advanced HCC.Several trials have evaluated new drugs for the treatment of HCC patients: In first line, lenvatinib resulted non-inferior to sorafenib and it can be used as alternative, even in the lack of evidence for sequential treatment options in second line after lenvatinib. Recently, atezolizumab plus bevacizumab have shown superiority over sorafenib in first-line. Sorafenib-regorafenib sequential administration in selected patients has opened a new paradigm of treatment in advanced HCC with a life expectancy exceeding two years. Other TKIs for second line treatment include cabozantinib and ramucirumab(specifically for patients with Alpha-fetoprotein values ≥ 400 ng/mL). The combination of TKIs with immunotherapy may represent a big step forward for these patients in the near future.     

Comparative efficacy and safety for second-line treatment with ramucirumab,regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma progressed on sorafenib treatment: A network meta-analysis

Background:The present network meta-analysis was conducted to perform an indirect comparison among ramucirumab, regorafenib, and cabozantinib in patients with advanced hepatocellular carcinoma (HCC) progressed on sorafenib treatment.Methods:A systematic review through Medline, Embase, and Cochrane library was developed, with eligible randomized clinical trials been included. Hazard ratios (HRs) including progression-free survival (PFS), overall survival (OS), odds ratios of disease control rate (DCR), objective response rate (ORR), and adverse events were compared indirectly with network meta-analysis using random model in software STATA version 13.0.Results:A total of 4 randomized clinical trials including 2137 patients met the eligibility criteria and enrolled. Indirect comparisons showed that there was no statistical difference observed in the indirect comparison of PFS, OS, ORR, or DCR among agents of regorafenib, cabozantinib, and ramucirumab in advanced HCC patients with elevated α-fetoprotein (AFP) (400 ng/mL or higher). However, in patients with low-level AFP (lower than 400 ng/mL), regorafenib was the only agent associated with significant superiority in OS, compared with placebo (hazard ratio 0.67, 95% CI, 0.50–0.90).Conclusions:The present network meta-analysis revealed that there might be no statistical difference observed in the indirect comparison of PFS, OS, ORR, or DCR among regorafenib, cabozantinib, or ramucirumab in advanced HCC patients with elevated AFP (400 ng/mL or higher). However, in patients with low-level AFP (lower than 400 ng/mL), regorafenib might be associated with significant superiority in OS, compared to placebo, which need further investigation in clinical practice.     

Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other smallmolecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c- MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.     

Management of advanced hepatocellular carcinoma in the era of targeted therapy

Systemic chemotherapy has had a disappointing track record in the management of advanced hepatocellular carcinoma (HCC). Single‐agent doxorubicin produces a response rate of 10–15%, but without any survival benefit, and combination chemotherapy has also yielded unimpressive results. With recent advances in the knowledge of hepato‐carcinogenesis, there has been encouraging development in the systemic therapy of advanced HCC patients, and particularly in the targeted therapy of advanced HCC. Among the newly identified targets, exciting results have been shown in targeting the anti‐angiogenic pathway and the Raf/mitogen‐activated protein kinase pathways. Bevacizumab, both as a single agent and in combination with other agents, has shown initial encouraging activity in treating advanced HCC. More recently, single‐agent sorafenib, a putative multitargeted kinase inhibitor, has shown to prolong the overall survival of patients with advanced HCC in the pivotal phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) and Oriental study. Currently, sorafenib is the only approved targeted therapy for patients with advanced HCC. In addition, however, promising early results have been reported for other molecular‐targeted drugs including erlotinib and sunitinib. Future progress seems likely to depend on using controlled clinical trials to optimize synergistic combination treatments.     

MET inhibitors for treatment of advanced hepatocellular carcinoma: A review

The current standard treatment option for advanced hepatocellular carcinoma(HCC) is sorafenib, but its clinical benefit is modest. In spite of many attempts, few drugs can provide any significant improvement of survival as the first- or second-line therapy of choice in phase Ⅲ randomized controlled trials. Recently, the subgroup analysis of a phase Ⅱ randomized controlled trial has shown that tivantinib, a selective MET inhibitor, can significantly improve the overall survival in patients with MET-positive advanced HCC after the failure or intolerance of a prior systemic therapy. These findings enlighten the role of MET inhibitors in the treatment of advanced HCC. In this paper, we review all ongoing and completed clinical trials regarding this topic. As for the first-line therapy of advanced HCC, INC280 and foretinib are being evaluated in 2 phase Ⅱ single-arm trials; and MSC2156119 J and golvatinib plus sorafenib are being compared with sorafenib alone in 2 phase Ⅱ randomized controlled trials. As for the second-line therapy of advanced HCC, tivantinib and cabozantinib are being compared with placebo in 2 phase Ⅲrandomized controlled trials.     

Second-line treatment of advanced hepatocellular carcinoma: Time for more individualized treatment options?

Hepatocellular carcinoma (HCC) is the most frequently diagnosed primary tumor of the liver and is usually detected as advanced disease. It is an aggressive disease that often progresses rapidly when it fails to respond to treatment. As such, patients have limited opportunities to try different subsequent-line treatment regimens. In the last 5 years, the number of agents and/or regimens available for the treatment of advanced HCC has significantly increased, which has made treatment choices for this patient population increasingly complex. In the second-line setting, several phase III trials of regorafenib (RESORCE), ramucirumab (REACH/REACH-2), and cabozantinib (CELESTIAL) have demonstrated clinically meaningful survival benefits in patients with the disease. However, the median overall survival of patients with advanced HCC remains unchanged at approximately 12 mo from the start of systemic second-line therapy, with a limited duration of response. Evidence from the REACH/REACH-2 trials demonstrated for the first time that baseline alpha-fetoprotein (AFP) levels can be used as an identification factor to select those who are likely to benefit the most from ramucirumab treatment. Ramucirumab is both well tolerated and efficacious and has a clinically acceptable safety profile. Therefore, it should be considered an option for patients with AFP levels ≥ 400 ng/mL.     

Systemic treatment for unresectable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and,in rare cases,in a healthy liver.Its prevalence has risen in recent years,particularly in Western nations,due to the increasing frequency of nonalcoholic fatty liver disease.Advanced HCC has a poor prognosis.For many years,the only proven therapy for unresectable HCC (uHCC) was sorafenib,a tyrosine kinase inhibitor.Recently,the synergistic effect of an immune checkpoint inhibitor,atezolizumab,and bevacizu...     

Recent advances in multidisciplinary management of hepatocellular carcinoma

The incidence of hepatocellular carcinoma(HCC) is increasing, and it is currently the second leading cause of cancer-related death worldwide. Potentially curative treatment options for HCC include resection, transplantation, and percutaneous ablation, whereas palliative treatments include trans-arterial chemoembolization(TACE), radioembolization, and systemic treatments. Due to the diversity of available treatment options and patients’ presentations, a multidisciplinaryteam should decide clinical management of HCC, according to tumor characteristics and stage of liver disease. Potentially curative treatments are suitable for very-early- and early-stage HCC. However, the vast majority of HCC patients are diagnosed in later stages, where the tumor characteristics or progress of liver disease prevent curative interventions. For patients with intermediate-stage HCC, TACE and radioembolization improve survival and are being evaluated in addition to potentially curative therapies or with systemic targeted therapy. There is currently no effective systemic chemotherapy, immunologic, or hormonal therapy for HCC, and sorafenib is the only approved moleculartargeted treatment for advanced HCC. Other targeted agents are under investigation; trials comparing new agents in combination with sorafenib are ongoing. Combinations of systemic targeted therapies with local treatments are being evaluated for further improvements in HCC patient outcomes. This article provides an updated and comprehensive overview of the current standards and trends in the treatment of HCC.     

Management of hepatocellular carcinoma with transarterial chemoembolization in the era of systemic targeted therapy

The clinical management of hepatocellular carcinoma (HCC) is often complicated by poor liver function. Treatment options for intermediate- and advanced-stage disease are limited. Transcatheter arterial chemoembolization (TACE) is an effective first-line therapy for intermediate-stage HCC. By interrupting blood flow to the tumor and administering concentrated chemotherapy locoregionally, TACE induces necrosis at the tumor site, but may create conditions that permit or encourage angiogenesis and recurrence of the tumor. Combination of TACE with new targeted agents may be an effective way to treat intermediate-stage HCC, particularly in higher risk patients. Because of the efficacy and safety of sorafenib-the first systemic therapy to show significant clinical benefit in advanced HCC-there is great interest in its potential use in combination with existing treatment modalities. The synergistic combination of TACE plus sorafenib represents a promising opportunity for tumor control.     

Selection of first-line systemic therapies for advanced hepatocellular carcinoma: A network meta-analysis of randomized controlled trials

BACKGROUNDThe majority of clinical trials of first-line systemic treatments for hepatocellular carcinoma (HCC) used placebo or sorafenib as comparators, and there are limited data providing a cross comparison of treatments in this setting, especially for newly-approved immune checkpoint inhibitor and vascular endothelial growth factor inhibitor combination treatments.AIMTo systematically review and compare response rates, survival outcomes, and safety of first-line systemic therapies for advanced hepatocellular carcinoma.METHODSWe searched PubMed, Science Direct, the Cochrane Database, Excerpta Medica Database, and abstracts from the American Society of Clinical Oncology 2020 annual congress. Eligible studies were randomized controlled trials of systemic therapy enrolling adults with advanced/unresectable HCC. Risk of bias was assessed with the Cochrane risk of bias tool for randomized controlled trials. A network meta-analysis was used to synthesize data and perform direct and indirect comparisons between treatments. P value, a frequentist analog to the surface under the cumulative ranking curve, was used to rank treatments.RESULTSIn total, 1398 articles were screened and 27 included. Treatments compared were atezolizumab plus bevacizumab, brivanib, donafenib, dovitinib, FOLFOX4, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies, and three other combination therapies. For overall response rate, lenvatinib ranked 1/19, followed by atezolizumab plus bevacizumab and nivolumab. For progression-free survival (PFS), atezolizumab + bevacizumab was ranked 1/15, followed by lenvatinib. With the exception of atezolizumab + bevacizumab [hazard ratios (HR)_PFS = 0.90; 95% confidence interval (CI): 0.64-1.25], the estimated HRs for PFS for all included treatments vs lenvatinib were > 1; however, the associated 95%CI passed through unity for bevacizumab plus erlotinib, linifanib, and FOLFOX4. For overall survival, atezolizumab plus bevacizumab was ranked 1/25, followed by vandetanib 100 mg/d and donafinib, with lenvatinib ranked 6/25. Atezolizumab + bevacizumab was associated with a lower risk of death vs lenvatinib (HR_os = 0.63; 95%CI: 0.44-0.89), while the HR for overall survival for most other treatments vs lenvatinib had associated 95%CIs that passed through unity. Vandetanib 300 mg/d and 100 mg/d were ranked 1/13 and 2/13, respectively, for the lowest incidence of treatment terminations due to adverse events, followed by sorafenib (5/13), lenvatinib (10/13), and atezolizumab + bevacizumab (13/13).CONCLUSIONThere is not one single first-line treatment for advanced HCC associated with superior outcomes across all outcome measurements. Therefore, first-line systemic treatment should be selected based on individualized treatment goals.     

Molecularly targeted therapies for hepatocellular carcinoma: sorafenib as a stepping stone

Since sorafenib, a multikinase inhibitor targeting angiogenesis of hepatocellular carcinoma (HCC), demonstrated survival benefits in recent clinical trials, it has changed the treatment paradigm and become the standard first-line treatment for patients with advanced HCC. However, disease stabilization with sorafenib lasts a few months, possibly due to the development of resistance, and thus the survival advantage was modest, even in patients with preserved liver function. Furthermore, there is currently no biomarker for monitoring the response or resistance to sorafenib. Currently, various kinds of molecularly targeted agents have been developed and are being evaluated in clinical trials. There are several steps required to improve the outcome from sorafenib therapy. First, a reliable predictive and prognostic biomarker is urgently needed. Second, a compelling indication of sorafenib treatment for HCC needs more clinical studies and consensus. Third, the actual benefits of sorafenib to patients with advanced liver dysfunction should be clarified and a more effective strategy for targeted therapy needs to be developed, for example, using a combination of targeted agents acting on different pathways or different levels of a key pathway. Finally, sorafenib could be used with other treatment modalities, such as local ablation or transarterial chemoembolization, to synergize efficacy. Based on the successful introduction of sorafenib, future studies should focus on plans to further improve the outcome of HCC patients by overcoming resistance and maximizing the efficacy of molecularly targeted therapy.     

Targeted therapies for hepatocellular carcinoma

Unlike most solid tumors, the incidence and mortality of hepatocellular carcinoma (HCC) have increased in the United States and Europe in the past decade. Most patients are diagnosed at advanced stages, so there is an urgent need for new systemic therapies. Sorafenib, a tyrosine kinase inhibitor (TKI), has shown clinical efficacy in patients with HCC. Studies in patients with lung, breast, or colorectal cancers have indicated that the genetic heterogeneity of cancer cells within a tumor affect its response to therapeutics designed to target specific molecules. When tumor progression requires alterations in specific oncogenes (oncogene addiction), drugs that selectively block their products might slow tumor growth. However, no specific oncogene addictions are yet known to be implicated in HCC progression, so it is important to improve our understanding of its molecular pathogenesis. There are currently many clinical trials evaluating TKIs for HCC, including those tested in combination with (eg, erlotinib) or compared with (eg, linifanib) sorafenib as a first-line therapy. For patients who do not respond or are intolerant to sorafenib, TKIs such as brivanib, everolimus, and monoclonal antibodies (eg, ramucirumab) are being tested as second-line therapies. There are early stage trials investigating the efficacy for up to 60 reagents for HCC. Together, these studies might change the management strategy for HCC, and combination therapies might be developed for patients with advanced HCC. Identification of oncogenes that mediate tumor progression, and trials that monitor their products as biomarkers, might lead to personalized therapy; reagents that interfere with signaling pathways required for HCC progression might be used to treat selected populations, and thereby maximize the efficacy and cost benefit.     

舒尼替尼治疗肝细胞癌的临床研究现状

舒尼替尼是一种口服小分子多靶点酪氨酸激酶抑制剂,具有抗血管生成和抗肿瘤活性。然而Ⅱ期临床试验显示其治疗肝细胞癌(HCC)有较高的药物相关死亡事件发生率,且客观应答率较低。近年一项Ⅲ期临床试验提示,舒尼替尼治疗进展期HCC的中位总体生存期显著短于多激酶抑制剂索拉非尼,因此舒尼替尼单药不被推荐用于治疗进展期HCC。一项正在进行的Ⅲ期临床试验拟比较舒尼替尼联合经动脉化疗栓塞术(TACE)与单用TACE治疗HCC的疗效,其结果将证实舒尼替尼是否可作为TACE治疗HCC的辅助手段。     

Current status and future prospects of chemotherapy for advanced hepatocellular carcinoma

Sorafenib is the only drug that demonstrates a survival benefit for advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is limited, so development of a more effective treatment method and second-line treatments is needed. Since the advent of sorafenib, clinical studies have been conducted with a variety of drugs and treatment methods, mainly with molecular targeted therapy, but almost all trials have ended in failure. The reasons for the difficulty in the development of a novel drug or treatment method include the diversity of mechanisms in the carcinogenesis and development of HCC, as well as the presence of background liver diseases such as chronic hepatitis and cirrhosis. Trials with immune-checkpoint inhibitors, which have an entirely different anti-tumor mechanism from that of molecular targeted drugs or cytotoxic drugs, have recently begun. Based on the results to date, clinical trials are now being conducted with enriched target subjects. In the future, providing more individualized treatment approaches for patients with advanced HCC will be essential.     

Targeted therapy of hepatocellular carcinoma: present and future

Following the encouraging results of sorafenib in advanced hepatocellular carcinoma (HCC), targeted therapy has become a new direction of research in the treatment of HCC. Emerging data provide evidence that the pathogenesis and progression of HCC are mediated by a number of molecular defects and dysregulated pathways. Novel targeted therapies are designed to inhibit the aberrant pathways at a molecular level with an aim to improve the clinical outcome. For the past few years, an increasing number of targeted agents have been tested in HCC in the clinical setting. This review aims to summarize the current status of clinical development of targeted therapy in HCC, with focus on novel agents targeting angiogenesis, signal transduction and epigenetic dysregulation of tumors. The review also discusses the lessons learned from outcomes of completed clinical trials and provides perspectives on future clinical trials in HCC.     

Systemische Therapie des hepatozellul?ren Karzinoms

Sorafenib, a receptor tyrosine kinase inhibitor with anti-proliferative and anti-angiogenic activity is currently the only approved systemic treatment for patients with hepatocellular carcinoma (HCC). It inhibits VEGFR-2, PDGFR and c-KIT signaling pathways as well as BRAF. In the pivotal western study in patients with advanced HCC, sorafenib resulted in a 3 months improved overall survival compared to placebo. This trend was comparable in the pivotal Asian phase 3 study and has also been confirmed in large post-market registries. The main side effects of sorafenib are diarrhea, skin toxicity, fatigue and hypertension. Other systemic treatments are currently not approved but are being investigated in numerous randomized phase 2 and pivotal phase 3 studies either as alternative first line therapy (brivanib or linifanib), as a sorafenib add-on (erlotinib or doxorubicin) or after sorafenib failure (brivanib, everolimus, ramucirumab, tivantinib and others). Moreover, the use of sorafenib as adjuvant treatment after potential curative resection or ablation and the combination of sorafenib or brivanib together with transarterial chemoembolization are currently being investigated in randomized clinical trials.