Efficacy of iron chelator deferoxamine for hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma patients refractory to current treatments

The prognosis of advanced hepatocellular carcinoma (HCC) remains poor. For patients with advanced HCC, the multikinase inhibitor sorafenib is recommended as the current standard of care. In contrast, hepatic arterial infusion chemotherapy (HAIC) is one of the recommended treatments in Japan. However, in Japan, the use of sorafenib versus hepatic arterial infusion chemotherapy for first-line treatment remains unclear, because there have been no randomized controlled trials comparing HAIC with sorafenib. HAIC can substantially prolong survival in patients with complete and partial response, while non-responders may be suitable candidates for sorafenib therapy. Nonetheless, HAIC non-responders with deteriorated liver function currently have no treatment options. We have shown the efficacy of an alternative therapy, the iron chelator deferoxamine, for advanced HCC patients with deteriorated liver function. Iron chelators may have future therapeutic possibilities in this patient population.     

Treatment strategies for advanced hepatocellular carcinoma: Sorafenib vs hepatic arterial infusion chemotherapy

Sorafenib is used worldwide as a first-line standardsystemic agent for advanced hepatocellular carcinoma(HCC) on the basis of the results of two large-scale Phase Ⅲ trials. Conversely,hepatic arterial infusion chemotherapy(HAIC) is one of the most recommended treatments in Japan. Although there have been no randomized controlled trials comparing sorafenib with HAIC,several retrospective analyses have shown no significant differences in survival between the two therapies. Outcomes are favorable for HCC patients exhibiting macroscopic vascular invasion when treated with HAIC rather than sorafenib,whereas in HCC patients exhibiting extrahepatic spread or resistance to transcatheter arterial chemoembolization,good outcomes are achieved by treatment with sorafenib rather than HAIC. Additionally,sorafenib is generally used to treat patients with Child-Pugh A,while HAIC is indicated for those with either Child-Pugh A or B. Based on these findings,we reviewed treatment strategies for advanced HCC. We propose that sorafenib might be used as a first-line treatment for advanced HCC patients without macroscopic vascular invasion or Child-Pugh A,while HAIC is recommended for those with macroscopic vascular invasion or Child-Pugh A or B. Additional research is required to determine the best second-line treatment for HAIC non-responders with Child-Pugh B through future clinical trials.     

Efficacy of hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma

AIM: To investigate the efficacy of hepatic arterial infusion chemotherapy (HAIC) using floxuridine (FUDR) in patients with advanced hepatocellular carcinoma (HCC) confined to the liver.METHODS: Thirty-four patients who had advanced HCC with unresectability or unsuccessful previous therapy in the absence of extrahepatic metastasis were treated with intra-arterial FUDR chemotherapy at our hospital between March 2005 and May 2008. Among the 34 patients, 9 patients were classified as Child class C, and 18 patients had portal vein tumor thrombus (PVTT). One course of chemotherapy consisted of continuous infusion of FUDR (0.3 mg/kg during day 1-14) and dexamethasone (10 mg on day 1, 4, 7 and 11), and this treatment was repeated every 28 d.RESULTS: Two patients (5.9%) displayed a complete response, and 12 patients (35.3%) had a partial response. The tumor control rate was 61.8%. The median overall survival times were 15.3 mo, 12.4 mo and 4.3 mo for the patients who were classified as Child class A, Child class B and Child class C, respectively (P = 0.0392). The progression-free survival was 12.9 mo, 7.7 mo and 2.6 mo for the patients who were classified as Child class A, Child class B and Child class C, respectively (P = 0.0443). The cumulative survival differed significantly according to the Child-Pugh classification and the presence of PVTT. In addition to hepatic reserve capacity and PVTT, the extent of HCC was an independent factor in determining a poor prognosis. The most common adverse reactions to HAIC were mucositis, diarrhea and peptic ulcer disease, but most of these complications were improved by medical treatment and/or a delay of HAIC.CONCLUSION: The present study demonstrates that intra-arterial FUDR chemotherapy is a safe and effective treatment for advanced HCC that is recalcitrant to other therapeutic modalities, even in patients with advanced cirrhosis.     

Diagnosis and treatment of hepatocellular carcinoma

The diagnosis and treatment of hepatocellular carcinoma (HCC) have witnessed major changes over the past decade. Until the early 1990s, HCC was a relatively rare malignancy, typically diagnosed at an advanced stage in a symptomatic patient, and there were no known effective palliative or therapeutic options. However, the rising incidence of HCC in several regions around the world coupled with emerging evidence for efficacy of screening in high-risk patients, liver transplantation as a curative option in select patients, ability to make definitive diagnosis using high-resolution imaging of the liver, less dependency on obtaining tissue diagnosis, and proven efficacy of transarterial chemoembolization and sorafenib as palliative therapy have improved the outlook for HCC patients. In this article, we present a summary of the most recent information on screening, diagnosis, staging, and different treatment modalities of HCC, as well as our recommended management approach.     

Long-term clinical outcomes of hepatic arterial infusion chemotherapy with cisplatin with or without 5-fluorouracil in locally advanced hepatocellular carcinoma

Purpose  

Hepatic arterial infusion chemotherapy (HAIC) has often been used as a therapeutic option for patients with advanced hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy and safety of HAIC using cisplatin with or without 5-fluorouracil in patients with advanced HCC.     

Current management of patients with hepatocellular carcinoma

The current management therapies for hepatocellular carcinoma(HCC) patients are discussed in this review. Despite the development of new therapies, HCC remains a "difficult to treat" cancer because HCC typically occurs in advanced liver disease or hepatic cirrhosis. The progression of multistep and multicentric HCC hampers the prevention of the recurrence of HCC. Many HCC patients are treated with surgical resection and radiofrequency ablation(RFA), although these modalities should be considered in only selected cases with a certain HCC number and size. Although there is a shortage of grafts, liver transplantation has the highest survival rates for HCC. Several modalities are salvage treatments; however, intensive care in combination with other modalities or in combination with surgical resection or RFA might offer a better prognosis. Sorafenib is useful for patients with advanced HCC. In the near future, HCC treatment will include stronger molecular targeted drugs, which will have greater potency and fewer adverse events. Further studies will be ongoing.     

Effect of a late evening snack using branched‐chain amino acid‐enriched nutrients in patients undergoing hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma

Aim: A late evening snack (LES) is recommended for protein‐energy malnutrition in patients with liver cirrhosis. This study investigated energy metabolism in cirrhotic patients with hepatocellular carcinoma (HCC) and the effects of LES using a branched‐chain amino acid (BCAA)‐enriched nutrient in cirrhotic patients with advanced HCC undergoing hepatic arterial infusion chemotherapy (HAIC). Methods: Energy metabolism was measured using indirect calorimetry for 10 cirrhotic patients without HCC and 36 patients with various stages of HCC. Next, in 23 cirrhotic patients with advanced HCC undergoing HAIC, 13 patients received LES (LES group), and 10 patients received ordinary food (control group). Changes in energy metabolism and glucose tolerance were examined using indirect calorimetry and 75‐g oral glucose tolerance test (OGTT) before and after 1 cycle of treatment. Results: Non‐protein respiratory quotient (npRQ) was significantly lower in patients with advanced HCC than in cirrhotic patients without HCC, or in patients with early‐stage HCC. In cirrhotic patients with advanced HCC undergoing HAIC, npRQ, BCAA/tyrosine ratio (BTR), and prealbumin and ALT levels were significantly improved in the LES group, but not in controls. In addition, area under the concentration curve for glucose (AUC glucose) tended to be improved in the LES group. Conclusions: LES using BCAA‐enriched nutrients appears to improve energy metabolism and glucose tolerance in cirrhotic patients with advanced HCC undergoing HAIC.     

Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma and future treatments for the poor responders

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The most common problem associated with HCC is a high risk of intrahepatic recurrence despite radical treatment, and in many patients, this recurrence has fatal consequences. For patients with advanced-stage HCC according to the Barcelona Clinic Liver Cancer staging system, the multikinase inhibitor sorafenib is the current standard of care. In contrast, hepatic arterial infusion chemotherapy (HAIC) is the recommended treatment in Japan for patients with intermediate-stage or advanced-stage HCC. In this review, we describe the use of HAIC for advanced HCC. Furthermore, we demonstrate an alternative therapy for HCC, the iron chelator deferoxamine, and discuss future therapeutic possibilities.     

Potentiality of immunotherapy against hepatocellular carcinoma

Hepatocellular carcinoma(HCC),the predominant form of primary liver cancer,is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence,treatment options remain limited for advanced HCC,and as a result prognosis continues to be poor. Current therapeutic options,surgery,chemotherapy and radiotherapy,have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising,novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here,we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies,such as tumor-associated antigen therapy,immune checkpoint inhibitors and cell transfer immunotherapy,have demonstrated safety and feasibility in HCC patients. Unfortunately,immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this chal lenge will place immunotherapy at the forefront of HCC treatment,possibly in the near future.     

Pathological Complete Remission of Advanced Hepatocellular Carcinoma with Main Portal Vein Tumor Thrombosis by Hepatic Arterial Infusion Chemotherapy

Cures for advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) are rare and difficult. We report a case of pathologically confirmed complete remission of HCC induced by hepatic arterial infusion chemotherapy (HAIC). A 45-year-old male patient had a massive HCC in the right lobe of the liver and tumor thrombus in the right and main portal veins. He achieved a partial response after two cycles of HAIC with 5-fluorouracil (750 mg/m²) and cisplatin (25 mg/m²). After the completion of six cycles he received a curative partial hepatectomy, and histopathology revealed complete necrosis without any viable tumor cell. He was in good health at a 4-month follow-up. These results suggest that this regimen is a promising therapeutic modality for the treatment of advanced HCC with PVTT.     

Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out

As the leading cause of disease-related deaths, cancer is a major public health threat worldwide. Surgical resection is still the first-line therapy for patients with early-stage cancers. However, postoperative relapse and metastasis remain the cause of 90% of deaths of patients with solid organ malignancies, including hepatocellular carcinoma (HCC). With the rapid development of molecular biology techniques in recent years, molecularly targeted therapies using monoclonal antibodies, small molecules, and vaccines have become a milestone in cancer therapeutic by significantly improving the survival of cancer patients, and have opened a window of hope for patients with advanced cancer. Hypervascularization is a major characteristic of HCC. It has been reported that anti-angiogenic treatments, which inhibit blood vessel formation, are highly effective for treating HCC. However, the efficacy and safety of anti-angiogenesis therapies remain controversial. Sorafenib is an oral multikinase inhibitor with anti-proliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC. While sorafenib has shown promising therapeutic effects, substantial evidence of primary and acquired resistance to sorafenib has been reported. Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC, but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib. Therefore, understanding the mechanism(s) underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC. This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies.     

Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma

Hepatocellular carcinoma （HCC） is one of the most common malignancies worldwide, including Japan. Although the development of imaging modalities has made the early diagnosis of HCC possible, surgically resectable cases are relatively uncommon because of hepatic function reserve and/or an advanced stage at presentation. Several modalities, such as transcatheter arterial chemoembolization, percutaneous ethanol injection, microwave coagulation therapy and radiofrequency ablation are reportedly useful in treating patients with non-resectable disease. However, unfortunately, many HCC patients have tumor recurrence. The overall prognosis of patients with HCC is very poor, and treatment of the advanced form is still problematic. In this article, we review the clinical efficacy and toxicity of enteric-coated tegafur/uracil in the treatment of patients with advanced non-resectable HCC.     

Evaluation of the “assessment for continuous treatment with hepatic arterial infusion chemotherapy” scoring system in patients with advanced hepatocellular carcinoma

Aim

Sorafenib is the recommended standard of care for advanced hepatocellular carcinoma (HCC) patients. However, hepatic arterial infusion chemotherapy (HAIC) is a treatment option in Asia. We recently developed the assessment for continuous treatment with HAIC (ACTH) score to guide decision‐making for continuous HAIC treatment. The purpose of this study was to validate the utility of the ACTH score in a dedicated cohort.

Methods

One hundred and thirty‐one patients with advanced HCC were enrolled in this study (90 in the training group and 41 in the validation group). The point score (range, 0–3) was calculated as follows: Child–Pugh score before HAIC (A = 0, B = 1), α‐fetoprotein (AFP) response (yes = 0, no = 1), and des‐γ‐carboxy prothrombin (DCP) response (yes = 0, no = 1). The AFP and DCP responses were assessed 2 weeks after HAIC induction; a positive response was defined as a reduction of ≥20% from the baseline.

Results

The DCP response in the validation group was significantly associated with treatment response, and the median survival time (MST) was longer in patients with an ACTH score ≤1 (15.9 months) than in those with a score ≥2 (7.0 months; P = 0.002). Survival in all patients showed significant stratification according to the ACTH score; the MSTs associated with scores of 0, 1, 2, and 3 points were 21.7, 14.4, 9.5, and 3.8 months, respectively.

Conclusion

The ACTH score can aid in the therapeutic assessment and continued treatment planning of HCC patients receiving HAIC.     

Immunobiology and gene-based immunotherapy of hepatocellular carcinoma

PURPOSE: Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide. For most patients with advanced or multifocal HCC treatment options are limited resulting in a poor prognosis. Several local ablation methods have been developed as minimally invasive strategies for HCC treatment. It is unclear, until now, whether these therapies will significantly improve the poor prognosis of patients with unresectable HCC. Novel therapeutic strategies and a better understanding of HCC imunobiology are, therefore, urgently required. DESIGN: The scientific literature since 1970 in all languages cited in Medline was systematically reviewed. RESULTS: Until now, a variety of specific and non-specific immunostimulatory strategies against HCC has been applied in preclinical experimental models with some promising results. The molecular characterization of HCC associated tumour antigens such as alpha-fetoprotein (AFP) and the increased understanding of the immunological pathways involved in liver and tumor immunology have paved the way for the design of promising gene-based cancer vaccines. The first phase I and II immunotherapeutic clinical trials based on dendritic cell immunotherapy and peptide vaccines are ongoing in HCC-patients. Clinical trials have, in general, demonstrated the safety of such strategies. Recently, exciting new immunological techniques and tools have been developed which allow to characterize antigen specific T cells at a single-cell level. In future, HCC specific tumor rejection antigens which can be used therapeutically have to be identified using microarray-based analysis. The different therapeutic modalities need to be compared directly resulting in optimised therapeutic approaches and the identification of sub-groups of HCC-patients responding favourably to treatment.     

根治性肝切除联合索拉非尼治疗肝细胞癌的研究进展

根治性肝切除仍然是肝细胞癌(hepatocellularcarcinoma,HCC)的主要治疗手段,但术后转移复发导致肝切除的疗效进入瓶颈期.探索术后复发的治疗措施是有效延长患者生存时间的重要课题.目前,以经皮肝动脉化疗栓塞为代表的多种治疗措施已在临床广泛开展,但尚缺乏大规模、多中心随机对照临床试验的循证医学证据.分子靶向药物索拉非尼的出现为改善HCC预后开辟了新局面,对于已接受过根治性肝切除治疗的HCC患者,索拉非尼可能是一种有效的辅助治疗方法,值得深入探索.     

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.     

Treatment for hepatocellular carcinoma in Japan over the last three decades: Our experience and published work review

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer‐related mortality worldwide. In the last few decades, there has been a marked increase in therapeutic options for HCC and epidemiological characteristics at HCC diagnosis have also significantly changed. With these changes and advances in medical technology and surveillance program for detecting earlier stage HCC, survival in patients with HCC has significantly improved. Especially, patients with liver cirrhosis are at high risk of HCC development, and regular surveillance could enable early detection of HCC and curative therapy, with potentially improved clinical outcome. However, unfortunately, only 20% of HCC patients are amenable to curative therapy (liver transplantation, surgical resection or ablative therapies). Locoregional therapies such as radiofrequency ablation, percutaneous ethanol injection, microwave coagulation therapy and transcatheter arterial chemoembolization play a key role in the management of unresectable HCC. Currently, molecular‐targeted agents such as sorafenib have emerged as a promising therapy for advanced HCC. The choice of the treatment modality depends on the size of the tumor, tumor location, anatomical considerations, number of tumors present and liver function. Furthermore, new promising therapies such as gene therapy and immunotherapy for HCC have emerged. Approaches to the HCC diagnosis and adequate management for patients with HCC are improving survival. Herein, we review changes of epidemiological characteristics, prognosis and therapies for HCC and refer to current knowledge for this malignancy based on our experience of approximately 4000 HCC cases over the last three decades.     

Effective treatment strategies other than sorafenib for the patients with advanced hepatocellular carcinoma invading portal vein

Patients with hepatocellular carcinoma(HCC) accompanying portal vein tumor thrombosis(PVTT) have relatively few therapeutic options and an extremely poor prognosis. These patients are classified into barcelonaclinic liver cancer stage C and sorafenib is suggested as the standard therapy of care. However, overall survival(OS) gain from sorafenib is unsatisfactory and better treatment modalities are urgently required. Therefore, we critically appraised recent data for the various treatment strategies for patients with HCC accompanying PVTT. In suitable patients, even surgical resection can be considered a potentially curative strategy. Transarterial chemoembolization(TACE) can be performed effectively and safely in a carefully chosen population of patients with reserved liver function and sufficient collateral blood flow nearby the blocked portal vein. A recent metaanalysis demonstrated that TACE achieved a substantial improvement of OS in HCC patients accompanying PVTT compared with best supportive care. In addition, transarterial radioembolization(TARE) using yttrium-90 microspheres achieves quality-of-life advantages and is as effective as TACE. A large proportion of HCC patients accompanying PVTT are considered to be proper for TARE. Moreover, TACE or TARE achieved comparable outcomes to sorafenib in recent studies and it was also reported that the combination of radiotherapy with TACE achieved a survival gain compared to sorafenib in HCC patients accompanying PVTT. Surgical resectionbased multimodal treatments, transarterial approaches including TACE and TARE, and TACE-based appropriate combination strategies may improve OS of HCC patients accompanying PVTT.     

Chemotherapy for advanced hepatocellular carcinoma in the sorafenib age

The kinase inhibitor sorafenib is the only systemic therapy proven to have a positive effect on survival of patients with advanced hepatocellular carcinoma(HCC).After development of sorafenib and its introduction as a therapeutic agent used in the clinic,several critical questions have been raised.Clinical parameters and biomarkers predicting sorafenib efficacy are the most important issues that need to be elucidated.Although it is difficult to know the responders in advance using conventional characteristics of patients,there are specific serum cytokines and/or gene amplification in tumor tissues that have been reported to predict efficacy of sorafenib.Risk and benefits of continuation of sorafenib beyond radiological progression is another issue to consider because no other standard therapy for advanced HCC as yet exists.In addition,effectiveness of the expanded application of sorafenib is still controversial,although a few studies have shed some light on combinational treatment with sorafenib for intermediate-stage HCC.Recently,over 50 relevant drugs have been developed and are currently under investigation.The efficacy of some of these drugs has been extensively examined,but none have demonstrated any superiority over sorafenib,so far.However,there are several drugs that have shown efficacy for treatment after sorafenib failure,and these are proceeding to further studies.To address these issues and questions,we have done extensive literature review and summarize the most current status of therapeutic application of sorafenib.     

Role of radiotherapy in the management of hepatocellular carcinoma:A systematic review

Many patients with hepatocellular carcinoma(HCC) present with advanced disease,not amenable to curative therapies such as surgery,transplantation or radiofrequency ablation. Treatment options for this group of patients include transarterial chemoembolization(TACE) and radiation therapy. Especially TACE,delivering a highly concentrated dose of chemotherapy to tumor cells while minimizing systemic toxicity of chemotherapy,has given favorable results on local control and survival. Radiotherapy,as a therapeutic modality of internal radiation therapy with radioisotopes,has also achieved efficacious tumor control in advanced disease. On the contrary,the role of external beam radiotherapy for HCC has been limited in the past,due to the low tolerance of surrounding normal liver parenchyma. However,technological innovations in the field of radiotherapy treatment planning and delivery,have provided the means of delivering radical doses to the tumor,while sparing normal tissues. Advanced and highly conformal radiotherapy approaches such as stereotactic body radiotherapy and proton therapy,evaluated for efficacy and safety for HCC,report encouraging results. In this review,we present the role of radiotherapy in hepatocellular carcinoma patients not suitable for radical treatment.