Late-onset benefit in progressive advanced hepatocellular carcinoma with continued sorafenib therapy: a case report

<p>Abstract</p> <p>Introduction</p> <p>In the past, no effective systemic therapy has existed for patients with advanced hepatocellular carcinoma. Sorafenib, an oral multikinase inhibitor, has recently been shown to improve overall survival in patients with advanced hepatocellular carcinoma in two randomized, double-blinded, placebo-controlled trials. This drug has been approved as the first-line therapy for advanced hepatocellular carcinoma patients. We report an intriguing case of advanced hepatocellular carcinoma in which the patient achieved late- onset partial response by prolonged administration of sorafenib in spite of progressive disease.</p> <p>Case presentation</p> <p>A 54-year-old Japanese man was treated with sorafenib for multiple lung metastases after surgical resection for advanced hepatocellular carcinoma accompanied by vascular invasion of the left branch of the portal vein. Although the effective diagnosis was progressive disease, almost all sites began to reduce or disappear eight months after the diagnosis of progressive disease. A dramatic reduction in alpha-fetoprotein and des-gamma-carboxy prothrombin levels was observed. The patient finally achieved partial response and his status remains unchanged.</p> <p>Conclusions</p> <p>If tolerated, prolonged sorafenib treatment may be beneficial.</p

Tyrosine kinase Inhibitors in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma is the third leading cause of cancer-related mortality in the world. Locoregional therapy is used for early stage hepatocellular carcinoma. Tyrosine kinase inhibitors have been the mainstay of treatment for advanced hepatocellular carcinoma. Sorafenib was the first drug approved based on data from two pivotal phase III trials. Although sorafenib provided a survival benefit, development of adverse events limits its use in some patients. These adverse events, such as hand–foot syndrome and diarrhea, have a significant impact on the quality of life and, in some circumstances, are severe enough to prompt cessation of the drug. In recent times, a range of new therapeutic options have come on the scene including lenvatinib, regorafenib, and cabozantinib. Lenvatinibis now approved as an alternative first-line agent for hepatocellular carcinoma. Regorafenib and cabozantinib are both second-line agents. These medications provide a promising range of treatment options for patients who progress on sorafenib or are intolerant to it. This chapter provides an insight into the range of tyrosine kinase inhibitors available for the treatment of hepatocellular carcinoma

A unique bleeding-related complication of sorafenib, a tyrosine kinase inhibitor, in advanced hepatocellular carcinoma: a case report

INTRODUCTION: Sorafenib, a multikinase inhibitor as a standard of care for advanced hepatocellular carcinoma, may lead endothelial cells to an unstable state by blocking the signaling pathway of vascular endothelial growth factor receptor, which may result in the disruption of the architecture and integrity of the microvasculature, and eventually increase the risk of hemorrhage. Hemobilia is a relatively uncommon condition as a consequence of hepatocellular carcinoma and its risk factors remain uncertain. CASE PRESENTATION: Here we report a unique case of hemobilia occurring in a 55-year-old Korean man with hepatitis B virus-related hepatocellular carcinoma on Barcelona Clinic Liver Cancer advanced stage after seven days of treatment with sorafenib. He had received prior radiation therapy. Endoscopy revealed bleeding from the major duodenal papilla and endoscopic retrograde cholangiography revealed an amorphous filling defect throughout the common bile duct. Blood clots were removed by balloon sweeping and a nasobiliary drainage tube was placed. No further bleeding has been detected as of eight months after discontinuation of sorafenib. CONCLUSION: Sorafenib may increase the risk of biliary bleeding in hepatocellular carcinoma patients who were primed with irradiation, by blocking the signaling pathway of the vascular endothelial growth factor receptor. Therefore, sorafenib should be used with caution in patients with advanced hepatocellular carcinoma, especially when combined with radiation therapy

Liver Resection after Downstaging Hepatocellular Carcinoma with Sorafenib

Background. Sorafenib is a molecular-targeted therapy used in palliative treatment of advanced hepatocellular carcinoma in Child A patients. Aims. To address the question of sorafenib as neoadjuvant treatment. Methods. We describe the cases of 2 patients who had surgery after sorafenib. Results. The patients had a large hepatocellular carcinoma in the right liver with venous neoplastic thrombi (1 in the right portal branch, 1 in the right hepatic vein). After 9 months of sorafenib, reassessment showed that tumours had decreased in size with a necrotic component. A right hepatectomy with thrombectomy was performed, and histopathology showed 35% to 60% necrosis. One patient had a recurrence after 6 months and had another liver resection; they are both recurrence-free since then. Conclusion. Sorafenib can downstage hepatocellular carcinoma and thus could represent a bridge to surgery. It may be possible to select patients in good general condition with partial regression of the tumour with sorafenib for a treatment in a curative intent

Old disease, new targets--part-I, solid malignancies

Targeted agents are now an integral part of treatment regimens for some cancers. Trastuzumab is established in treatment of human epidermal receptor 2 (Her2) positive breast cancers, with improvements in both, the disease free and over all survival. Monoclonal antibody (MoAB) against vascular growth factor receptor (VEGF), bevacizumab and cetuximab a MoAB against epidermal growth factor receptor (EGFR) are establishing their role in a many cancers after making their mark in colorectal cancer. Sorafenib and sunitinib have success stories in renal carcinoma. The Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) trial has established sorafenib role in advanced hepatocellular carcinoma, while in gastrointestinal tumors; imatinib and sunitinib have proven role. At this point in time side effect profile of all these agents appears relatively safe however cost for developing countries remains an issue

Hepatocellular carcinoma and multidrug resistance: Past, present and new challenges for therapy improvement

Hepatocellular carcinoma (HCC) is the most common malignancy of the liver and the third cause of cancer death worldwide. Chronic hepatitis due to HBV and HCV infection are two major risk factors for HCC worldwide. Advances in early detection and treatment have improved life expectancy of patients with HCC. However, this disorder remains as a disease with poor prognosis. In fact, epidemiological studies have shown that the median survival of patients is 8 months and approximately 20% of them survive one year, while only 5% remain alive after three years. Additionally, HCC is particularly difficult to treat because of its high recurrence rate, and its resistance to conventional chemotherapy due to, among other mechanisms, the over-expression of several members of the ATP-Binding Cassette (ABC) protein family involved in drugs transport. Fortunately, there is evidence that these patients may benefit from alternative molecular-targeted therapies. This manuscript reviews the current knowledges on the etiology, molecular mechanisms involved in HCC development and the current therapy strategies for the management of this malignancy. The challenges in the development of drug delivery systems for the targeting of antitumoral drugs to the liver parenchyma are also discussed. Finally, perspectives in the design of a more efficient pharmacotherapy to overcome multidrug resistance are reviewed.Fil: Cuestas, María Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Oubiña, Jose Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Mathet, Veronica Lidia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentin

A Surgical Perspective on Targeted Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide, is difficult to treat and highly lethal. Since HCC is predominantly diagnosed in patients with cirrhosis, treatment planning must consider both the severity of liver disease and tumor burden. To minimize the impact to the patient while treating the tumor, techniques have been developed to target HCC. Anatomical targeting by surgical resection or locoregional therapies is generally reserved for patients with preserved liver function and minimal to moderate tumor burden. Patients with decompensated cirrhosis and small tumors are optimal candidates for liver transplantation, which offers the best chance of long-term survival. Yet, only 20%-30% of patients have disease amenable to anatomical targeting. For the majority of patients with advanced HCC, chemotherapy is used to target the tumor biology. Despite these treatment options, the five-year survival of patients in the United States with HCC is only 16%. In this review we provide a comprehensive overview of current approaches to target HCC. We also discuss emerging diagnostic and prognostic biomarkers, novel therapeutic targets identified by recent genomic profiling studies, and potential applications of immunotherapy in the treatment of HCC

Yttrium-90 Selective Internal Radiation Therapy with Glass Microspheres for Hepatocellular Carcinoma: Current and Updated Literature Review.

Hepatocellular carcinoma is the most common primary liver cancer and it represents the majority of cancer-related deaths in the world. More than 70% of patients present at an advanced stage, beyond potentially curative options. Ytrrium-90 selective internal radiation therapy (Y90-SIRT) with glass microspheres is rapidly gaining acceptance as a potential therapy for intermediate and advanced stage primary hepatocellular carcinoma and liver metastases. The technique involves delivery of Y90 infused glass microspheres via the hepatic arterial blood flow to the appropriate tumor. The liver tumor receives a highly concentrated radiation dose while sparing the healthy liver parenchyma due to its preferential blood supply from portal venous blood. There are two commercially available devices: TheraSphere® and SIR-Spheres®. Although, Y90-SIRT with glass microspheres improves median survival in patients with intermediate and advanced hepatocellular carcinoma and has the potential to downstage hepatocellular carcinoma so that the selected candidates meet the transplantable criteria, it has not gained widespread acceptance due to the lack of large randomized controlled trials. Currently, there are various clinical trials investigating the use of Y90-SIRT with glass microspheres for treatment of hepatocellular carcinoma and the outcomes of these trials may result in the incorporation of Y90-SIRT with glass microspheres into the treatment guidelines as a standard therapy option for patients with intermediate and advanced stage hepatocellular carcinoma

Multidisciplinary Management of Patients with Unresectable Hepatocellular Carcinoma: A Critical Appraisal of Current Evidence

Hepatocellular carcinoma (HCC) is a leading cause of new cancer diagnoses in the United States, with an incidence that is expected to rise. The etiology of HCC is varied and can lead to differences between patients in terms of presentation and natural history. Subsequently, physicians treating these patients need to consider a variety of disease and patient characteristics when they select from the many different treatment options that are available for these patients. At the same time, the treatment landscape for patients with HCC, particularly those with unresectable HCC, has been rapidly evolving as new, evidence-based options become available. The treatment plan for patients with HCC can include surgery, transplant, ablation, transarterial chemoembolization, transarterial radioembolization, radiation therapy, and/or systemic therapies. Implementing these different modalities, where the optimal sequence and/or combination has not been defined, requires coordination between physicians with different specialties, including interventional radiologists, hepatologists, and surgical and medical oncologists. As such, the implementation of a multidisciplinary team is necessary to develop a comprehensive care plan for patients, especially those with unresectable HCC

Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer histotype, characterized by high biological aggressiveness and scarce treatment options. Recently, we have established a clinically relevant murine HCC model by co-expressing activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and oncogene c-mesenchymal-epithelial transition (c-Met) proto-oncogenes in the mouse liver via hydrodynamic tail vein injection (AKT/c-MET mice). Tumor cells from these mice demonstrated high activity of the AKT/ mammalian target of rapamycin (mTOR) and Ras/ Mitogen-activated protein kinase (MAPK) signaling cascades, two pathways frequently co-induced in human HCC. Methods: Here, we investigated the therapeutic efficacy of sorafenib, regorafenib, the MEK inhibitor PD901 as well as the pan-mTOR inhibitor MLN0128 in the AKT/c-Met preclinical HCC model. Results: In these mice, neither sorafenib nor regorafenib demonstrated any efficacy. In contrast, administration of PD901 inhibited cell cycle progression of HCC cells in vitro. Combined PD901 and MLN0128 administration resulted in a pronounced growth constraint of HCC cell lines. In vivo, treatment with PD901 or MLN0128 alone moderately slowed HCC growth in AKT/c-MET mice. Importantly, the simultaneous administration of the two drugs led to a stable disease with limited tumor progression in mice. Mechanistically, combined mitogen-activated extracellular signal-regulated kinase (MEK) and mTOR inhibition resulted in a stronger cell cycle inhibition and growth arrest both in vitro and in vivo. Conclusions: Our study indicates that combination of MEK and mTOR inhibitors might represent an effective therapeutic approach against human HCC