P- Reviewer: Hann HW, Sun XY S- Editor: Tian YL L- Editor: A E- Editor: Liu SQ
Published online Apr 8, 2015. doi: 10.4254/wjh.v7.i4.673
Peer-review started: August 28, 2014
First decision: November 27, 2014
Revised: December 17, 2014
Accepted: January 15, 2015
Article in press: January 19, 2015
Published online: April 8, 2015
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 multidisciplinary team 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 molecular-targeted 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.
Core tip: This article reviews the available treatment options for hepatocellular carcinoma. The recent clinical trials of molecular-targeted therapies, as single agents or in combination with other treatments, are reviewed, and some future study directions are addressed. The importance of a multidisciplinary approach to management is highlighted.
Citation: Gomaa AI, Waked I. Recent advances in multidisciplinary management of hepatocellular carcinoma. World J Hepatol 2015; 7(4): 673-687
The incidence of hepatocellular carcinoma (HCC) is increasing, and is currently is the second leading cause of cancer-related death worldwide, accounting for approximately 800000 deaths every year. Clinical management of HCC is tailored according to tumor characteristics, stage of liver disease, and condition of the patients (age, performance status, and presence or absence of comorbidities). The American Association for the Study of Liver Diseases and the European Association for the Study of the Liver (EASL) endorse the use of Barcelona clinic liver cancer (BCLC) staging for the classification and management of patients with HCC. Therapeutic options are stage dependent and can be classified into three categories: curative, palliative, and symptomatic. However, curative treatment options, including resection and percutaneous ablation, are only suitable for early-stage tumors, and are associated with five-year survival rates of up to 75%.
Recently, treatment indications have been refined; patients who are not candidates for the first-line therapy for their stage can be shifted to the treatment option for the next BCLC stage (treatment stage migration concept)[3,5]. Trans-arterial chemoembolization (TACE) can be performed at an early stage in patients for whom radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI) cannot be performed because of tumor location (proximity to a gallbladder, biliary tree, or blood vessel), unresectability of the tumor, failed prior curative treatments, or medical comorbidities.
The presentations of HCC are variable within each patient. Although the management guidelines for HCC recommend monotherapies as a treatment option, combined or sequential treatment modalities are effective in improving the outcome of patients with HCC. In practice, a multi-modal approach combining various treatments is used, and a multidisciplinary team, where the roles are intertwined and complimentary, should be involved in the management of every case[7,8].
Surgical resection is the recommended treatment for patients with a single nodule, preserved liver function, and good performance status. It is associated with five-year survival rates up to 70% and a 2%-3% perioperative mortality in cirrhotic patients. Some centers report five-year survival rates above 50% in patients undergoing resection for multiple tumors fulfilling Milan criteria (up to three nodules, each ≤ 3 cm), who are not suitable for transplantation, and resection in patients with more advanced stages of HCC has been reported with acceptable outcomes.
The minimal critical remnant liver volume for safe resection is approximately 25% (15%-40%) for patients without cirrhosis and 50% (25%-90%) for patients with cirrhotic livers. Preoperative portal vein embolization is occasionally performed when the estimated remnant liver volume is less than the minimal requirement, aimed at diverting portal flow, with its content of growth factors, to the non-tumorous lobe to sufficiently increase its size to permit resection. However, the effectiveness of portal vein embolization in cases of HCC with a cirrhotic liver has not been sufficiently tested in large controlled studies.
Portal hypertension in cirrhotic patients is considered a relative contraindication for surgical resection, and a hepatic venous pressure gradient > 10 mmHg is reportedly the best predictor of postoperative liver decompensation and poor long-term outcome in compensated cirrhotic patients undergoing resection[2,13]. In practice, resection for patients with significant portal hypertension is still a subject of debate. Similarly, the presence of splenomegaly (major diameter > 12 cm) or esophageal varices with a platelet count of < 100000/mm3 was correlated with hepatic venous pressure gradient, postoperative decompensation, and poor survival. However, Cucchetti et al reported that patients with the same model for end-stage liver disease (MELD) score and extent of hepatectomy had similar outcomes regardless of portal hypertension.
Resection has been refined with the use of the RFA-based resection device, the Habib 4X sealer (a new bipolar RF device designed specifically for liver resection). It releases controlled RF energy between two pairs of electrodes, producing a plane of coagulative necrosis along the intended line of parenchymal resection, avoiding over-coagulation of liver parenchyma. The heat produced seals biliary and blood vessels, resulting in minimal blood loss. With this device, morbidity and mortality rates are superior to other methods of liver resection.
Laparoscopic resection, though a more sophisticated surgical procedure, is associated with reduced operative and postoperative morbidities. A recent meta-analysis showed that laparoscopic hepatectomy decreases blood loss, transfusion requirement, postoperative morbidity, recovery time, and hospital stay compared to open hepatectomy, with no difference in recurrence or survival. However, no randomized controlled trials (RCTs) were reported in this meta-analysis.
An important postoperative concern is the high risk of HCC recurrence. Five-year recurrence rates of 68% have been reported after liver resection of very-early-stage HCC. The presence of satellite nodules, cirrhosis, the use of non-anatomic resection, and elevated α-fetoprotein (AFP) levels are independently associated with tumor recurrence[14,19]. Late recurrence can be predicted using molecular biomarkers and gene signatures that are used for the selection of patients amenable to hepatic resection. The 5-gene score, based on combined expression levels of HN1, RAN, RAMP3, KRT19 and TAF9, was associated with disease-specific survival.
Liver transplantation (LTx) is the best treatment option for patients with decompensated cirrhosis. HCC is the only solid tumor where transplantation plays an important role in management, due to the fact that it allows removal of the primary tumor and treats hepatic insufficiency. The main obstacles for HCC patients amenable to LTx are the organ shortage and the long waiting time for transplantation. Increasing the donor pool by live donation, using bridging therapy, and applying prioritization policies can help overcome this problem. A MELD exception was developed to assign extra points to HCC patients due to their high dropout rate and mortality while on the waiting list. However, no extra points are assigned to patients with compensated cirrhosis and small HCC tumors (< 2 cm) because of the improved survival with local ablation. In practice, LTx is recommended for patients with tumors within the Milan criteria (a single lesion ≤ 5 cm, or up to three lesions ≤ 3 cm each). Restriction of LTx to patients within the Milan criteria results in a five-year overall survival rate of 75%, with a risk of recurrence < 15%. The perioperative mortality and one-year mortality are approximately 3 and ≤ 10%, respectively. For patients with early-stage HCC, LTx offers the best chance of survival (106 mo), compared with surgical resection (52 mo), RFA (62 mo), PEI (44 mo), and TACE (34 mo).
A systematic review of 90 studies over 15 years, including 17780 patients, identified the Milan criteria as an independent prognostic factor for outcome after LTx, with five-year survival rates comparable to non-HCC patients (65%-78%). An expansion of the Milan criteria to “up-to-seven” criteria (the sum of the size of the largest tumor and the number of tumors in patients without microvascular invasion) was proposed and externally validated in an independent series, but requires larger prospective validation studies. Although listing criteria for LTx currently depend on tumor number and size, the use of molecular markers and gene signatures for determining tumor behavior are under development.
The presence of vascular invasion, high AFP level, and transplant waiting time of more than 6 mo, are considered accurate predictive factors for poor survival and recurrence risk. Increased AFP was associated with higher risk of progression and dropout while waiting for a transplant[28,29], and a steady increase of AFP > 15 ng/mL per month was considered the most significant prognostic determinant. In a large French multicenter study, incorporation of AFP in a prognostic score model for post-LTx outcome significantly improved the predictive performance of the Milan criteria in prioritization for LTx. Moreover, adding AFP > 400 to a total tumor volume of 115 cm as a cutoff improved prognosis prediction in an analysis of data of 6478 patients from the Scientific Registry of Transplant Recipients, and performed better than tumor size and number characteristics for predicting post-LTx prognosis.
Tumor ablation can be obtained using either chemical (alcohol and acetic acid) or physical (heating or cooling) methods. The first technique used to locally treat HCC was PEI, which involves the intra-lesional injection of absolute alcohol. Temperature ablative techniques have advanced, including heating techniques such as RFA, microwave ablation (MWA), laser ablation, and cryoablation.
PEI is indicated for the treatment of nodular HCC ≤ 5 cm in diameter, and achieves complete necrosis in 90% of tumors < 2 cm, 70% in those 2- < 3 cm, and 50% in those between 3 and 5 cm. Patient outcome was improved with the use of a specific needle with three retractable prongs, achieving an 80%-90% rate of sustained complete response in tumors < 4 cm. The major limitation of PEI is the high incidence of local recurrence (33%-43%).
RFA is superior to other local ablative therapies, and is currently the most commonly used ablative method, replacing PEI as the locoregional therapy of choice for early HCC. RFA is considered the standard of care for patients with very early- and early-stage tumors, as well as those not suitable for or that refuse surgery. RFA is recommended as the main ablative therapy for tumors < 5 cm, whereas PEI is recommended in cases where RFA is not technically feasible.
In a cohort study, complete ablation was achieved in more than 90% of cases, with a local recurrence rate of < 1% and five-year survival rate ranging from 40% to 70% for lesions < 2 cm in diameter. Three independent meta-analyses, including five RCTs, showed better results regarding local tumor control and survival benefits in patients treated with RFA, compared to ablation with PEI. In addition, patients with tumors 2-5 cm had better survivals if treated by RFA rather than by PEI[40-42].
Some groups have suggested that RFA should be considered as a first-line therapy, even when resection is possible, because it is associated with fewer side effects. The main advantages compared to surgical intervention are that it is less invasive and provides an increased possibility for parenchymal sparing[39,43]. Whether surgical resection for very early HCC is superior to RFA remains controversial. Whereas a Markov model analysis indicated that surgical resection was preferable to RFA in terms of overall survival, Peng et al reported that RFA was better. A survey in Japan including 1235 patients with very early HCC (≤ 2 cm) who underwent resection and 1315 patients who received RFA showed no significant difference in overall survival between the two groups (one-year, 98% vs 99%; two-year, 94% vs 95%), over a median follow-up of 37 mo. However, the disease-free survival rate was significantly better after resection than after RFA (one-year, 91% vs 84%; two-year, 70% vs 58%; P < 0.001). Similarly, Wang et al suggested that surgical resection was equivalent to RFA in terms of overall survival, and was associated with better disease-free survival.
The size limitation of RFA has been overcome with the use of expandable tipped or cool-tip electrodes, allowing effective ablation of areas ≥ 5 cm in diameter. However, RCTs with a large sample size are needed before ablation therapy can be confirmed as an alternative to surgery for potentially resectable HCC.
MWA is an alternative to RFA for thermal ablation of HCC. Only one RCT compared the effectiveness of MWA to RFA, which revealed a tendency to favor RFA with respect to rates of local recurrence and complications, likely due to the small volume of coagulation obtained with a single probe insertion. However, newer devices may have overcome this limitation. One advantage of MWA over RFA is that treatment outcome is not affected by the heat-sink effect of vessels in proximity to the tumor.
Laser ablation refers to thermal tissue destruction by conversion of absorbed light into heat. The only randomized prospective study comparing laser ablation with RFA reported no significant difference in overall survival rates, with cumulative rates of 91.8%, 59.0% and 28.4% at one, three and five years respectively, without significant complications. However, a significantly better survival rate was reported for RFA in patients with Child-Pugh A stage disease.
Cryoablation uses the extreme cold of liquid nitrogen or argon gas to destroy abnormal tissue. Cryoablation showed better local control than RFA or MWA for tumors > 2 cm. A multicenter RCT in China that included 360 patients with one or two tumors < 4 cm in diameter found that cryoablation is safe and as effective as RFA, with a similar five-year survival.
HCC receives 90% of its blood supply from the hepatic artery and only 10% from the portal vein. Thus, the purpose of trans-arterial therapy is to block the blood supply and induce tumor necrosis, without significantly affecting hepatic blood supply. Trans-arterial therapies include TACE, trans-arterial embolization, trans-arterial chemotherapy, and trans-arterial radioembolization[57,58].
TACE is currently the standard of care for patients with compensated liver function and large multifocal lesions without evidence of vascular invasion or extra-hepatic spread. In Japan, TACE is recommended even for HCC patients with vascular invasion if radiologic portal invasion is distal to, or in the second-order branches of, the portal vein. The main contraindications to TACE are extended portal vein thrombosis, diffuse tumor, extra-hepatic spread, and decompensated liver cirrhosis[22,60]. TACE improves survival compared to supportive care or suboptimal therapies, observed as an increase in the median survival of patients with intermediate-stage HCC to 20 mo. However, a meta-analysis that included nine trials (six trials assessing TACE and three trials assessing trans-arterial embolization) has shown that trans-arterial therapy does not significantly increase survival in patients with unresectable HCC compared to controls.
Proper patient selection is crucial to prevent post-TACE-induced liver failure. Patients with total bilirubin > 3 mg/dL were excluded from TACE in several studies[64,65], and an AFP > 200 ng/mL and a MELD score > 10 were associated with greater risk of mortality. Bolondi et al proposed a substaging of intermediate-stage HCC (BCLC-B) patients from B1 to B4, taking into account the tumor burden and Child-Pugh score (A5 to B9). BCLC-B includes disease ranging from variable tumor burden, which can be a multifocal HCC affecting both lobes, extending up to near replacement of the liver, and includes patients with a wide range of liver function impairment (Child-Pugh score from 5 to 9). Substaging revealed decreasing survival for higher B substages, and thus TACE was recommended for early subgroups only.
Drug-eluting beads (DEB)-TACE involves the use of embolic microspheres with the ability to sequester and release chemotherapeutic agents in a controlled manner over a one-week period, which subsequently increases the local concentration of the drug with minimal systemic toxicity. A randomized phase II study (the PRECISIONV trial) reported that DEB-TACE is a valuable alternative and may be preferred over conventional TACE.
The use of locoregional options to induce tumor necrosis necessitated a refinement of the conventional criteria to evaluate treatment response. Extent of tumor necrosis has been correlated with outcome after ablation, TACE and systemic therapy. A modification of the response evaluation criteria in solid tumors (modified RECIST) takes into account the degree of tumor necrosis, evaluated by dynamic computed tomography or magnetic resonance imaging and has been adopted by the latest EASL guidelines for evaluating locoregional therapies for HCC.
There is no established definition for TACE refractoriness, nor is there a consensus for when to consider TACE failure and refer the patient to an alternative therapy. Despite the absence of solid evidence, however, panels of experts have proposed treatment migration to sorafenib (downward treatment stage migration) for intermediate-stage patients if they demonstrate disease progression or poor tolerance after first or second TACE[71,72]. The current EASL guidelines recommend switching to sorafenib if intermediate-stage patients are non-responsive to at least two cycles of TACE.
Repetition of TACE should be considered based on evidence using mRECIST and the risk of adverse events. The response to the first TACE and its effect on the underlying liver disease help in identifying patients at risk of adverse outcome with repeated TACE. Sieghart et al conducted a multivariate analysis to investigate TACE repeated for a second or third session and identified three prognostic factors: increase in aspartate aminotransferase by > 25%, increase in Child-Pugh score, and absence of tumor response. These factors were incorporated into an “ART” score, and patients with an ART score of 0-1.5 points benefitted from a second TACE, whereas those with a score ≥ 2.5 did not.
Radioembolization, or selective internal radiation therapy (SIRT), has recently emerged as a therapeutic option for intermediate-stage HCC. Unlike TACE, SIRT delivers local radiation to the tumor or liver tissue without causing ischemia. β radiation from radioactive yttrium-loaded glass or resin microspheres is applied to the tumor through the arteries that feed it, so that tumor nodules are treated irrespective of their number, size, or location. The procedure is well tolerated with survival rates similar to TACE. Moreover, it is as safe and effective as sorafenib in patients with more advanced-stage HCC, including patients with portal vein thrombosis and large tumor burden[76-79].
In a study comparing radioembolization to TACE, radioembolization was associated with fewer side effects, better response rate, and longer time to progression (13.3 mo vs 8.4 mo), without difference in median survival time (20.5 mo vs 17.5 mo). Another study reported similar safety profile and response rates. However, the cost associated with radioembolization may limit the applicability of this technique.
Stereotactic radiotherapy (SRT) allows the delivery of a high dose of radiation in a single (radio-surgery) or limited number (hypo-fractionation) of sessions, while sparing surrounding structures and healthy tissue. Blomgren et al first introduced SRT for liver tumors in 1995, with treatment doses ranging from 15 to 45 Gy, in one to five fractions. In a phase I/II study using a single dose ranging from 14 to 26 Gy, the treatment was well tolerated in all patients, with no major side effects, and the tumor control rate at 6 wk was 98%.
The CyberKnife Radio-surgery System is able to deliver very high doses of radiation to both primary and metastatic liver tumors with extreme accuracy, and treatments can be completed in one to five sessions. Louis et al treated 25 patients with CyberKnife stereotactic radiotherapy using respiratory motion tracking, which enables the radiation beam to track tumor movement in real time and allows patients to breathe normally during their treatment sessions. The actuarial one- and two-year local control rates were 95%, and the one- and two-year survival rates were 79% and 52% respectively, with good clinical tolerance. CyberKnife and SRT (though currently still very expensive) offer a local therapy for HCC patients who are not eligible for surgery, embolization, chemotherapy or radiofrequency ablation, without significant complications.
HCC is among the most chemoresistant tumors, and until 2007, no systemic chemotherapy was recommended for patients with advanced tumors. Systemic chemotherapy with cytotoxic agents, such as doxorubicin, gemcitabine, cisplatin, 5-fluorouracil or combined regimens for palliative care, was associated with low response rates (< 10%) with only marginal improvements in survival. Moreover, these drugs are poorly tolerated in patients with underlying liver cirrhosis[85-87].
Interferon (IFN) therapy, anti-androgens, or tamoxifen used in the treatment of advanced HCC show contradictory results without obvious benefit. A meta-analysis of seven RCTs, including 898 patients, evaluated tamoxifen vs conservative management and showed neither anti-tumor effects nor survival benefits for tamoxifen. Subsequent large RCTs reported negative results in terms of survival[90,91].
Cisplatin, IFN, doxorubicin, and fluorouracil (PIAF) used in combination showed promising activity in a phase II study. A randomized phase III study including 188 patients with HCC was conducted to investigate the effect of PIAF combination compared to doxorubicin alone. The median survival rate of the PIAF group did not significantly differ from the doxorubicin group (8.67 mo vs 6.83 mo), and patients treated with the PIAF regimen experienced a significantly higher rate of myelotoxicity.
Hepatocarcinogenesis is associated with epigenetic and genetic alterations that eventually lead to uncontrolled growth of hepatocytes. Signal transduction pathways, oncogenes, and growth factors and their receptors are considered new potential therapeutic targets for systemic targeted therapies, limiting widespread systemic toxicity. Several targeted agents are currently in clinical development.
Sorafenib is an orally administered multikinase inhibitor with antiproliferative and antiangiogenic activity. Sorafenib mediates downregulation of anti-apoptotic proteins, leading to enhanced cytotoxicity of HCC cells to tumor necrosis factor-related apoptosis inducing ligand. Two phase III randomized placebo-controlled trials, the SHARP multicenter trial and the Asia-Pacific trial, reported improved overall survival and better outcome for patients who received sorafenib, which was generally well tolerated with mild toxicity. The two most common grade 3 adverse reactions with sorafenib were the hand-foot-skin reaction (8%) and diarrhea (8%). The overall incidence of serious adverse events in the sorafenib and placebo groups was comparable (52% and 54%, respectively).
Based on these findings, sorafenib was approved for treatment of advanced HCC, including patients with unresectable Child-Pugh A or B HCC with performance status 0-2 and vascular invasion or distant metastasis, as well as for patients intolerant to TACE or in whom the procedure is technically difficult[98,99]. However, the prognosis for patients with this stage of HCC is still poor, with a median overall survival rate of 6.5-10.7 mo. In addition, Cammà et al recently concluded that sorafenib at full dose was not a cost-effective treatment compared to best supportive care in intermediate- and advanced-stage HCC.
Sorafenib is currently being tested as an adjuvant after resection, with local ablation for early-stage HCC, in combination with chemoembolization for intermediate stages, in combination with erlotinib or systemic doxorubicin in advanced stages. Additionally, sorafenib was effective as a first-line treatment in Child-Pugh B patients with lower survival. In a large retrospective study, the median survival with sorafenib was 5.5 mo compared to 11.3 mo for Child-Pugh A patients. The prospective GIDEON trial confirmed that the median overall survival was shorter in Child-Pugh class B patients (5.2 mo vs 13.6 mo in Child A), although the time to progression was similar across subgroups. Serious adverse events were more common in Child-Pugh class B patients[103,104].
The antiangiogenic tyrosine kinase inhibitors, sunitinib, linifanib, brivanib[107,108], or the combination of sorafenib with erlotinib are not superior to sorafenib in sorafenib-naïve advanced HCC patients, or as a second-line therapy (Table 1). This may be due to the fact that inhibition of a single signaling pathway can induce feedback activation of other pathways. Therefore, combination therapies may demonstrate beneficial synergistic activity.
|Ref.||Study design||Patients, n||Overall survival, mo|
|Zhu et al (SEARCH trial)||Sorafenib vs sorafenib + erlotinib||358 vs 362||Sorafenib: 8.5 Sorafenib + erlotinib: 9.5|
|Cheng et al (SUN1170 trial)||Sorafenib vs sunitinib||544 vs 530||Sorafenib: 10.2 Sunitinib: 7.9|
|Cainap et al (LIGHT trial)||Sorafenib vs linifanib||517 vs 518||Sorafenib: 9.8 Linifanib: 9.1|
|Johnson et al (BRISK-FL trial)||Sorafenib vs brivanib||578 vs 577||Sorafenib: 9.9 Brivanib: 9.5|
|Llovet et al (BRISK-PS trial)||Brivanib vs placebo||263 vs 132||Brivanib: 9.4 Placebo: 8.3|
Many molecular-targeted agents other than sorafenib, used in combination or with sorafenib, are in different stages of clinical development, with encouraging results from phase I-II studies[112-115]. The first phase III study of combination therapy in advanced HCC was SEARCH, a randomized trial testing sorafenib with the epithelial growth factor tyrosine kinase inhibitor erlotinib, which found no survival benefit over sorafenib alone.
Persistence of chronic viral hepatitis in patients treated for HCC is associated with increased rates of recurrence and poor survival, thus control of hepatitis C virus (HCV) replication is an important factor for infected patients. IFN therapy following successful ablation of HCC was shown to be safe and lead to a reduction in recurrence, and patients who continued IFN therapy after tumor ablation had better survival. Long-term, intermittent standard IFN therapy successfully delayed recurrence of HCC after RFA, PEI, and surgical resection. A meta-analysis evaluating the effect of adjuvant standard IFN treatment following resections showed significant improvement in three-year recurrence-free survival (54% vs 30%), and other studies have shown similar results[3,119,120]. The use of pegylated-IFN was more effective, and postoperative administration in combination with ribavirin for ≥ 16 wk was associated with reduced recurrence of HCC in patients with HCV infection. Further improvement in prognosis may be expected with the higher efficacy of direct antiviral therapy.
Patients with hepatitis B virus (HBV)-related HCC, even after successful treatment of the initial tumor, usually have multiple recurrences or metastases. High viral load is one of the most important risk factors for HCC development and recurrence following surgical resection. Similar to HCV, antiviral therapy for HBV following curative HCC ablation improved patient survival and decreased HCC recurrence. In their study, Hann et al followed patients for 12 years who underwent local tumor ablation with or without concomitant antiviral therapy with lamivudine. Although initially there was no difference between the treatment groups with respect to tumor size (all ≤ 7 cm), levels of AFP and albumin, antiviral therapy was significantly associated with increased median survival (36 mo vs 16 mo).
No other modality has demonstrated equivalent effectiveness for decreasing recurrence after curative treatment of HCC as antiviral therapy has for viral hepatitis-related tumors. Chemoembolization, internal radiation[125,126], immune therapies, retinoids, and the heparanase inhibitor PI-88 have been investigated as methods of reducing postoperative recurrence; however, none can be recommended as a preoperative/postoperative adjuvant/neo-adjuvant therapy for improving prognosis and diminishing the incidence of recurrence following curative therapy.
HCC has diverse presentations that are compounded by the status of liver disease, and the multiple treatment options available make choosing the first line of treatment for a given patient a difficult task. Treatment of HCC patients should be undertaken by a multidisciplinary team that includes all the specialties involved in delivering the different therapies. In addition, simultaneous or sequential multi-modal therapies for patients with HCC show promise for improving patient outcome, further emphasizing the importance of a multidisciplinary approach to HCC management.
The multidisciplinary team should include hepatologists, medical and surgical oncologists, transplant surgeons, diagnostic and interventional radiologists, radiation oncologists, and pathologists. All members should play an active role, as their expertise is required to provide optimal care for patients with HCC. The hepatologist should assess underlying liver disease, identify patients at risk for HCC, and monitor for early detection. Hepatologists are essential for managing liver disease and its complications, arranging for and monitoring treatment, and referring eligible patients for LTx. Oncologists are responsible for assigning systemic or targeted therapy as initial treatment or adjuvant therapy, and for managing associated side effects. The diagnostic radiologist makes and confirms the diagnosis, stages the tumor, its spread and vascular invasion, and assesses the radiologic response to treatment. The interventional radiologist delivers ablative therapy in early stages, and palliative therapy for intermediate-stage tumors. The hepatobiliary surgeon evaluates for and performs resection or transplantation. The pathologist assesses the grade of tumor differentiation, stage of progression, and evaluates tissue markers. This multidisciplinary team also involves nurses, supportive care specialists, and palliative physicians.
With the multidisciplinary approach, various treatments are being delivered simultaneously or sequentially, as first- or second-line therapies, to improve patient outcome.
Patients whose tumors exceed the Milan criteria can undergo locoregional treatment (TACE or RFA) to down-stage the tumor to within the Milan criteria to allow LTx. Two prospective studies showed similar survival after LTx for patients with successfully down-staged HCC compared with those who initially met the Milan criteria[131,132].
Neo-adjuvant therapies for patients while on the waiting list are used in most centers. Systemic and interventional treatments are used to bridge patients in order to control disease and prevent tumor progression when the waiting time exceeds 6 mo[133,134]. Percutaneous treatments are more cost-effective than surgical resection. Moreover, a poor response to TACE before transplantation is an indicator of post-transplantation recurrence.
Sorafenib following curative surgery in a phase II trial including 30 patients resulted in a lower tumor recurrence rate compared to surgery alone (33.3% vs 73.6%).
Combining PEI with TACE has been shown to be effective for unresectable HCC. The three-year survival rate was longer in patients with large and unresectable HCC treated with a combination of TACE and PEI than with TACE alone (22% vs 4%, respectively).
Combining RFA with TACE was evaluated in a RCT for patients with tumors between 3 and 5 cm. The local tumor progression rate was significantly lower with combined treatment compared to RFA only (6% vs 39%).
There are more than 20 clinical trials in progress evaluating locoregional treatments combined with molecular-targeted agents, and some have demonstrated promising results[140-142]. A large phase III, randomized, placebo-controlled trial (the STORM trial) evaluating sorafenib as an adjuvant therapy after curative treatment (resection or local ablation) is ongoing.
Following TACE, the tumor microenvironment becomes unbalanced due to increased hypoxia, leading to upregulation of hypoxia inducible factor-1, which in turn upregulates vascular endothelial and platelet-derived growth factors, thus increasing tumor angiogenesis[144,145]. Studies have shown a significant association between poor prognosis after TACE and risk of extrahepatic metastasis with upregulation of vascular endothelial growth factor[146,147]. Efforts to improve the outcome of TACE include the use of adjuvant or concurrent antiangiogenic agents to block the neovascularization.
Sorafenib can be used a few days to weeks after the first TACE (sequential introduction) or started prior to the planned TACE and only interrupted for a few days around the time of the procedure (interrupted scheduling). Studies that evaluated the effects of sequential sorafenib treatment after TACE revealed inconsistent results. In phase II studies, sorafenib concomitant with TACE or DEB-TACE was well tolerated and effective in unresectable HCC[148-151]. Synchronous therapy with sorafenib and TACE has also been retrospectively analyzed: the median overall survival for the combined sorafenib and TACE was 27 mo compared to 17 mo for TACE alone.
Several prospective controlled studies have evaluated the efficacy of combination treatment[153-158] (Table 2). However, there is a diversity of study designs, including various primary endpoints, patient populations, TACE procedures, timing of randomization and drug administration, which may account for the observed conflicting results. Overall, the results of combined TACE and sorafenib in intermediate- and advanced-stage HCC appear promising. The results of ongoing trials will define the role of this combination in clinical practice, whether it can overcome TACE refractoriness in intermediate-stage HCC patients, and whether it will have an additive role for advanced-stage HCC treatment.
|Ref.||Study design||Timing of sorafenib||Patients, n||BCLC stage||Child-Pugh class||Primary endpoint results|
|Kudo et al||Sorafenib + TACE vs TACE||Sequential||229 vs 229||B||A||TTP (5.4 mo vs 3.7 mo)|
|Lencioni et al (SPACE trial)||Sorafenib + DEB-TACE vs DEB-TACE + placebo||Continuous||154 vs 153||B||A||TTP (169 d vs 166 d; P = 0.072)|
|Martin et al||Sorafenib + DEB-TACE vs DEB-TACE||NR||30 vs 120||B, C||B||OS (12 mo vs 10 mo)|
|Sansonno et al||Sorafenib + TACE vs TACE||Sequential||40 vs 40||B||A||TTP (9.2 mo vs 4.9 mo)|
|Han et al (subgroup analysis of START)||Sorafenib + TACE||Sequential||63||A, B, C||A||TTP (10.6 mo) OS (16.5 mo)|
|Chung et al (subgroup analysis of START)||Sorafenib + TACE||Sequential||63||A, B, C||A||DCR (52%)|
|Park et al (COTSUN Korea)||Sorafenib + TACE||Interrupted||50||B, C||A, B||TTP (7.1 mo) PFS (52% at 6 mo)|
|Pawlik et al||Sorafenib + DEB-TACE||Continuous||35||B, C||A, B||DCR (95%) OR (58%)|
|Cabrera et al||Sorafenib + DEB-TACE or Y-90||Continuous||47||B, C||A, B||At 6 mo DCR (68%) OS (8.5 mo)|
Several ongoing clinical trials are evaluating the combination of radioembolization and sorafenib in patients with HCC. A retrospective analysis of Child-Pugh class A and B HCC patients who received sorafenib first, followed by yttrium-90, then resumed sorafenib post-treatment, showed that the overall survival was higher than has been previously reported for sorafenib alone. Further prospective studies are being conducted to evaluate this combination.
Several combinations of sorafenib with systemic chemotherapeutic agents have been evaluated, including sorafenib with doxorubicin, octreotide, oxaliplatin, 5-fluorouracil, S-1 fluoropyrimidines, PR-104, tegafur/uracil, cisplatin and gemcitabine, and AVE 1642 (a human monoclonal antibody inhibiting the insulin-like growth factor-1 receptor) (Table 3). Other ongoing phase II trials include the combination of sorafenib with gemcitabine/oxaliplatin, modified FOLFOX, or capecitabine/oxaliplatin.
|Ref.||Chemotherapeutic agent||Type of study||Patients, n||Median OS, mo||DCR, %||Median PFS, mo|
|Abou-Alfa et al||Doxorubicin||Multicenter randomized prospective phase II||47 vs 49||13.7 vs 6.5||62||6.0 vs 2.7|
|Hsu et al||Tegafur/uracil||Prospective phase II||53||7.4||57||3.7|
|Prete et al||Long-acting octreotide||Prospective phase II||50||12||76||7|
|Abou-Alfa et al||PR-104||Prospective phase I||14||NR||50||NR|
|Lee et al||S-1 fluoropyrimidines||Prospective phase I||20||10.4||52.9||3.9|
|Petrini et al||5-Fluorouracil||Prospective phase II||39||13.7||48.7||7.5|
A randomized, double-blind phase II trial in advanced HCC that compared the efficacy of sorafenib and doxorubicin vs doxorubicin plus placebo showed encouraging results (median overall survival 13.7 mo vs 6.5 mo; median time to progression 6.4 mo vs 2.8 mo; and progression-free survival 6.0 mo vs 2.7 mo). A phase III randomized study of sorafenib plus doxorubicin compared with sorafenib alone (CALGB 80802) is ongoing in patients with advanced HCC.
In a systematic review of eight studies with sorafenib combined with other anti-cancer agents for therapy of advanced HCC, the disease control rate was 50%-70%, median progression-free survival was 3.7-7.5 mo, and median overall survival was 7.4-40.1 mo. Xie et al performed a systematic review of 21 prospective studies with sorafenib treatment alone (seven studies) or combined with other treatment (14 studies) and found that sorafenib increased overall survival by 2.3-2.8 mo, prolonged the time to tumor progression by 1.4-2.7 mo, and increased disease control rate by 11%-19%. Advanced cirrhosis and combined treatment of sorafenib with 5-fluorouracil drugs were the major risk factors for developing adverse events.
These results are promising, and suggest that sorafenib in combination with some agents (particularly mammalian target of rapamycin inhibitors) is an effective and tolerable treatment option for advanced HCC. However, these trials included small numbers of patients, and although some reported survival advantage over sorafenib alone, combination therapy cannot be recommended for routine practice outside the setting of clinical trials. Large RCTs are needed to establish the efficacy and safety of these combination regimens.
Treatment of patients with HCC represents a major challenge in clinical practice. HCC patients require multidisciplinary clinical management and selection of tailored treatments according to disease stage, patient age, and comorbidities. Earlier diagnosis will allow therapies to be more effective, leading to a better prognosis. Several areas in management of HCC still need further evaluation, including the use of neoadjuvant/adjuvant therapies to decrease recurrence after resection or ablation, combinations of local and systemic therapies, combinations of systemic targeted therapies, and second-line therapies. Analysis of the cost-effectiveness of the treatments under investigation should also be an important consideration in future trials.
|1.||World Health Organization (WHO). Global battle against cancer won’t be won with treatment alone Effective prevention measures urgently needed to prevent cancer crisis. Lyon, London: International Agency for Research on Cancer; 2014;.|
|2.||Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020-1022. [PubMed] [DOI]|
|3.||European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908-943. [PubMed] [DOI]|
|4.||Roskams T. Anatomic pathology of hepatocellular carcinoma: impact on prognosis and response to therapy. Clin Liver Dis. 2011;15:245-259, vii-x. [PubMed] [DOI]|
|5.||Bruix J, Gores GJ, Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives. Gut. 2014;63:844-855. [PubMed] [DOI]|
|6.||Cabibbo G, Enea M, Attanasio M, Bruix J, Craxì A, Cammà C. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma. Hepatology. 2010;51:1274-1283. [PubMed] [DOI]|
|7.||Guy J, Kelley RK, Roberts J, Kerlan R, Yao F, Terrault N. Multidisciplinary management of hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2012;10:354-362. [PubMed] [DOI]|
|8.||Kaseb AO, Abaza YM, Roses RE. Multidisciplinary management of hepatocellular carcinoma. Recent Results Cancer Res. 2013;190:247-259. [PubMed] [DOI]|
|9.||Lee KK, Kim DG, Moon IS, Lee MD, Park JH. Liver transplantation versus liver resection for the treatment of hepatocellular carcinoma. J Surg Oncol. 2010;101:47-53. [PubMed] [DOI]|
|10.||Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, Bhoori S, Capussotti L, Calise F, Pellicci R, Belli G. Prevention of hepatocellular carcinoma recurrence with alpha-interferon after liver resection in HCV cirrhosis. Hepatology. 2006;44:1543-1554. [PubMed] [DOI]|
|11.||Yang T, Lin C, Zhai J, Shi S, Zhu M, Zhu N, Lu JH, Yang GS, Wu MC. Surgical resection for advanced hepatocellular carcinoma according to Barcelona Clinic Liver Cancer (BCLC) staging. J Cancer Res Clin Oncol. 2012;138:1121-1129. [PubMed] [DOI]|
|12.||Kinoshita H, Sakai K, Hirohashi K, Igawa S, Yamasaki O, Kubo S. Preoperative portal vein embolization for hepatocellular carcinoma. World J Surg. 1986;10:803-808. [PubMed] [DOI]|
|13.||Bruix J, Castells A, Bosch J, Feu F, Fuster J, Garcia-Pagan JC, Visa J, Bru C, Rodés J. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology. 1996;111:1018-1022. [PubMed] [DOI]|
|14.||Roayaie S, Obeidat K, Sposito C, Mariani L, Bhoori S, Pellegrinelli A, Labow D, Llovet JM, Schwartz M, Mazzaferro V. Resection of hepatocellular cancer ≤2 cm: results from two Western centers. Hepatology. 2013;57:1426-1435. [PubMed] [DOI]|
|15.||Cucchetti A, Ercolani G, Vivarelli M, Cescon M, Ravaioli M, Ramacciato G, Grazi GL, Pinna AD. Is portal hypertension a contraindication to hepatic resection? Ann Surg. 2009;250:922-928. [PubMed] [DOI]|
|16.||Pai M, Jiao LR, Khorsandi S, Canelo R, Spalding DR, Habib NA. Liver resection with bipolar radiofrequency device: Habib 4X. HPB (Oxford). 2008;10:256-260. [PubMed] [DOI]|
|17.||Gagner M, Rogula T, Selzer D. Laparoscopic liver resection: benefits and controversies. Surg Clin North Am. 2004;84:451-462. [PubMed] [DOI]|
|18.||Li N, Wu YR, Wu B, Lu MQ. Surgical and oncologic outcomes following laparoscopic versus open liver resection for hepatocellular carcinoma: A meta-analysis. Hepatol Res. 2012;42:51-59. [PubMed] [DOI]|
|19.||Kim BW, Kim YB, Wang HJ, Kim MW. Risk factors for immediate post-operative fatal recurrence after curative resection of hepatocellular carcinoma. World J Gastroenterol. 2006;12:99-104. [PubMed]|
|20.||Nault JC, De Reyniès A, Villanueva A, Calderaro J, Rebouissou S, Couchy G, Decaens T, Franco D, Imbeaud S, Rousseau F. A hepatocellular carcinoma 5-gene score associated with survival of patients after liver resection. Gastroenterology. 2013;145:176-187. [PubMed] [DOI]|
|21.||Mazzaferro V, Chun YS, Poon RT, Schwartz ME, Yao FY, Marsh JW, Bhoori S, Lee SG. Liver transplantation for hepatocellular carcinoma. Ann Surg Oncol. 2008;15:1001-1007. [PubMed] [DOI]|
|22.||de Lope CR, Tremosini S, Forner A, Reig M, Bruix J. Management of HCC. J Hepatol. 2012;56 Suppl 1:S75-S87. [PubMed] [DOI]|
|23.||Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, Camerini T, Roayaie S, Schwartz ME, Grazi GL. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009;10:35-43. [PubMed] [DOI]|
|24.||Mazzaferro V, Bhoori S, Sposito C, Bongini M, Langer M, Miceli R, Mariani L. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl. 2011;17 Suppl 2:S44-S57. [PubMed] [DOI]|
|25.||Farinati F, Sergio A, Baldan A, Giacomin A, Di Nolfo MA, Del Poggio P, Benvegnu L, Rapaccini G, Zoli M, Borzio F. Early and very early hepatocellular carcinoma: when and how much do staging and choice of treatment really matter? A multi-center study. BMC Cancer. 2009;9:33. [PubMed] [DOI]|
|26.||Raj A, McCall J, Gane E. Validation of the “Metroticket” predictor in a cohort of patients transplanted for predominantly HBV-related hepatocellular carcinoma. J Hepatol. 2011;55:1063-1068. [PubMed] [DOI]|
|27.||Schwartz M, Dvorchik I, Roayaie S, Fiel MI, Finkelstein S, Marsh JW, Martignetti JA, Llovet JM. Liver transplantation for hepatocellular carcinoma: extension of indications based on molecular markers. J Hepatol. 2008;49:581-588. [PubMed] [DOI]|
|28.||Toso C, Mentha G, Majno P. Selection of patients with hepatocellular carcinoma before liver transplantation: need to combine alpha-fetoprotein with morphology? Hepatobiliary Pancreat Dis Int. 2010;9:460-461. [PubMed]|
|29.||Duvoux C, Roudot-Thoraval F, Decaens T, Pessione F, Badran H, Piardi T, Francoz C, Compagnon P, Vanlemmens C, Dumortier J. Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria. Gastroenterology. 2012;143:986-984.e3; quiz e14-15. [PubMed] [DOI]|
|30.||Vibert E, Azoulay D, Hoti E, Iacopinelli S, Samuel D, Salloum C, Lemoine A, Bismuth H, Castaing D, Adam R. Progression of alphafetoprotein before liver transplantation for hepatocellular carcinoma in cirrhotic patients: a critical factor. Am J Transplant. 2010;10:129-137. [PubMed] [DOI]|
|31.||Toso C, Asthana S, Bigam DL, Shapiro AM, Kneteman NM. Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the Scientific Registry of Transplant Recipients database. Hepatology. 2009;49:832-838. [PubMed] [DOI]|
|32.||Livraghi T, Festi D, Monti F, Salmi A, Vettori C. US-guided percutaneous alcohol injection of small hepatic and abdominal tumors. Radiology. 1986;161:309-312. [PubMed] [DOI]|
|33.||Rossi S, Di Stasi M, Buscarini E, Quaretti P, Garbagnati F, Squassante L, Paties CT, Silverman DE, Buscarini L. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR Am J Roentgenol. 1996;167:759-768. [PubMed] [DOI]|
|34.||Seki T, Wakabayashi M, Nakagawa T, Itho T, Shiro T, Kunieda K, Sato M, Uchiyama S, Inoue K. Ultrasonically guided percutaneous microwave coagulation therapy for small hepatocellular carcinoma. Cancer. 1994;74:817-825. [PubMed]|
|35.||Pacella CM, Bizzarri G, Magnolfi F, Cecconi P, Caspani B, Anelli V, Bianchini A, Valle D, Pacella S, Manenti G. Laser thermal ablation in the treatment of small hepatocellular carcinoma: results in 74 patients. Radiology. 2001;221:712-720. [PubMed] [DOI]|
|36.||Ross WB, Horton M, Bertolino P, Morris DL. Cryotherapy of liver tumours--a practical guide. HPB Surg. 1995;8:167-173. [PubMed]|
|37.||Lencioni R. Loco-regional treatment of hepatocellular carcinoma. Hepatology. 2010;52:762-773. [PubMed] [DOI]|
|38.||Kuang M, Lu MD, Xie XY, Xu HX, Xu ZF, Liu GJ, Yin XY, Huang JF, Lencioni R. Ethanol ablation of hepatocellular carcinoma Up to 5.0 cm by using a multipronged injection needle with high-dose strategy. Radiology. 2009;253:552-561. [PubMed] [DOI]|
|39.||Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C, Rossi S. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology. 2008;47:82-89. [PubMed] [DOI]|
|40.||Orlando A, Leandro G, Olivo M, Andriulli A, Cottone M. Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials. Am J Gastroenterol. 2009;104:514-524. [PubMed] [DOI]|
|41.||Cho YK, Kim JK, Kim MY, Rhim H, Han JK. Systematic review of randomized trials for hepatocellular carcinoma treated with percutaneous ablation therapies. Hepatology. 2009;49:453-459. [PubMed] [DOI]|
|42.||Shen A, Zhang H, Tang C, Chen Y, Wang Y, Zhang C, Wu Z. Systematic review of radiofrequency ablation versus percutaneous ethanol injection for small hepatocellular carcinoma up to 3 cm. J Gastroenterol Hepatol. 2013;28:793-800. [PubMed] [DOI]|
|43.||Chen MS, Li JQ, Zheng Y, Guo RP, Liang HH, Zhang YQ, Lin XJ, Lau WY. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg. 2006;243:321-328. [PubMed]|
|44.||Cho YK, Kim JK, Kim WT, Chung JW. Hepatic resection versus radiofrequency ablation for very early stage hepatocellular carcinoma: a Markov model analysis. Hepatology. 2010;51:1284-1290. [PubMed] [DOI]|
|45.||Peng ZW, Lin XJ, Zhang YJ, Liang HH, Guo RP, Shi M, Chen MS. Radiofrequency ablation versus hepatic resection for the treatment of hepatocellular carcinomas 2 cm or smaller: a retrospective comparative study. Radiology. 2012;262:1022-1033. [PubMed] [DOI]|
|46.||Takayama T, Makuuchi M, Kojiro M, Lauwers GY, Adams RB, Wilson SR, Jang HJ, Charnsangavej C, Taouli B. Early hepatocellular carcinoma: pathology, imaging, and therapy. Ann Surg Oncol. 2008;15:972-978. [PubMed] [DOI]|
|47.||Wang JH, Wang CC, Hung CH, Chen CL, Lu SN. Survival comparison between surgical resection and radiofrequency ablation for patients in BCLC very early/early stage hepatocellular carcinoma. J Hepatol. 2012;56:412-418. [PubMed] [DOI]|
|48.||Cucchetti A, Piscaglia F, Cescon M, Colecchia A, Ercolani G, Bolondi L, Pinna AD. Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma. J Hepatol. 2013;59:300-307. [PubMed] [DOI]|
|49.||Shibata T, Iimuro Y, Yamamoto Y, Maetani Y, Ametani F, Itoh K, Konishi J. Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave coagulation therapy. Radiology. 2002;223:331-337. [PubMed]|
|50.||Ellestad LE, Carre W, Muchow M, Jenkins SA, Wang X, Cogburn LA, Porter TE. Gene expression profiling during cellular differentiation in the embryonic pituitary gland using cDNA microarrays. Physiol Genomics. 2006;25:414-425. [PubMed]|
|51.||Goldberg SN, Grassi CJ, Cardella JF, Charboneau JW, Dodd GD, Dupuy DE, Gervais D, Gillams AR, Kane RA, Lee FT. Image-guided tumor ablation: standardization of terminology and reporting criteria. Radiology. 2005;235:728-739. [PubMed] [DOI]|
|52.||Ferrari FS, Megliola A, Scorzelli A, Stella A, Vigni F, Drudi FM, Venezia D. Treatment of small HCC through radiofrequency ablation and laser ablation. Comparison of techniques and long-term results. Radiol Med. 2007;112:377-393. [PubMed] [DOI]|
|53.||Orlacchio A, Bazzocchi G, Pastorelli D, Bolacchi F, Angelico M, Almerighi C, Masala S, Simonetti G. Percutaneous cryoablation of small hepatocellular carcinoma with US guidance and CT monitoring: initial experience. Cardiovasc Intervent Radiol. 2008;31:587-594. [PubMed] [DOI]|
|54.||Ei S, Hibi T, Tanabe M, Itano O, Shinoda M, Kitago M, Abe Y, Yagi H, Okabayashi K, Sugiyama D. Cryoablation Provides Superior Local Control of Primary Hepatocellular Carcinomas of & gt; 2 cm Compared with Radiofrequency Ablation and Microwave Coagulation Therapy: An Underestimated Tool in the Toolbox. Ann Surg Oncol. 2015;22:1294-1300. [PubMed] [DOI]|
|55.||Wang C, Wang H, Yang W, Hu K, Xie H, Hu KQ, Bai W, Dong Z, Lu Y, Zeng Z. Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma. Hepatology. 2014;Epub ahead of print. [PubMed] [DOI]|
|56.||Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, Wong J. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35:1164-1171. [PubMed] [DOI]|
|57.||Tsochatzis EA, Germani G, Burroughs AK. Transarterial chemoembolization, transarterial chemotherapy, and intra-arterial chemotherapy for hepatocellular carcinoma treatment. Semin Oncol. 2010;37:89-93. [PubMed] [DOI]|
|58.||Lin S, Hoffmann K, Schemmer P. Treatment of hepatocellular carcinoma: a systematic review. Liver Cancer. 2012;1:144-158. [PubMed] [DOI]|
|59.||Kudo M, Han KH, Kokudo N, Cheng AL, Choi BI, Furuse J, Izumi N, Park JW, Poon RT, Sakamoto M. Liver Cancer Working Group report. Jpn J Clin Oncol. 2010;40 Suppl 1:i19-i27. [PubMed] [DOI]|
|60.||Zhang ZM, Guo JX, Zhang ZC, Jiang N, Zhang ZY, Pan LJ. Therapeutic options for intermediate-advanced hepatocellular carcinoma. World J Gastroenterol. 2011;17:1685-1689. [PubMed] [DOI]|
|61.||Forner A, Llovet JM, Bruix J. Chemoembolization for intermediate HCC: is there proof of survival benefit? J Hepatol. 2012;56:984-986. [PubMed] [DOI]|
|62.||Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236. [PubMed] [DOI]|
|63.||Oliveri RS, Wetterslev J, Gluud C. Transarterial (chemo)embolisation for unresectable hepatocellular carcinoma. Cochrane Database Syst Rev. 2011;16:CD004787. [PubMed] [DOI]|
|64.||Cabibbo G, Genco C, Di Marco V, Barbara M, Enea M, Parisi P, Brancatelli G, Romano P, Craxì A, Cammà C. Predicting survival in patients with hepatocellular carcinoma treated by transarterial chemoembolisation. Aliment Pharmacol Ther. 2011;34:196-204. [PubMed] [DOI]|
|65.||Dhanasekaran R, Kooby DA, Staley CA, Kauh JS, Khanna V, Kim HS. Prognostic factors for survival in patients with unresectable hepatocellular carcinoma undergoing chemoembolization with doxorubicin drug-eluting beads: a preliminary study. HPB (Oxford). 2010;12:174-180. [PubMed] [DOI]|
|66.||Sawhney S, Montano-Loza AJ, Salat P, McCarthy M, Kneteman N, Meza-Junco J, Owen R. Transarterial chemoembolization in patients with hepatocellular carcinoma: predictors of survival. Can J Gastroenterol. 2011;25:426-432. [PubMed]|
|67.||Bolondi L, Burroughs A, Dufour JF, Galle PR, Mazzaferro V, Piscaglia F, Raoul JL, Sangro B. Heterogeneity of patients with intermediate (BCLC B) Hepatocellular Carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis. 2012;32:348-359. [PubMed] [DOI]|
|68.||Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, Ayuso C, Castells L, Montañá X, Llovet JM. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol. 2007;46:474-481. [PubMed] [DOI]|
|69.||Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, Pitton M, Sergent G, Pfammatter T, Terraz S. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33:41-52. [PubMed] [DOI]|
|70.||Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52-60. [PubMed] [DOI]|
|71.||Raoul JL, Sangro B, Forner A, Mazzaferro V, Piscaglia F, Bolondi L, Lencioni R. Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat Rev. 2011;37:212-220. [PubMed] [DOI]|
|72.||Piscaglia F, Bolondi L. The intermediate hepatocellular carcinoma stage: Should treatment be expanded? Dig Liver Dis. 2010;42 Suppl 3:S258-S263. [PubMed] [DOI]|
|73.||Sieghart W, Hucke F, Pinter M, Graziadei I, Vogel W, Müller C, Heinzl H, Trauner M, Peck-Radosavljevic M. The ART of decision making: retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma. Hepatology. 2013;57:2261-2273. [PubMed] [DOI]|
|74.||Hucke F, Sieghart W, Pinter M, Graziadei I, Vogel W, Müller C, Heinzl H, Waneck F, Trauner M, Peck-Radosavljevic M. The ART-strategy: sequential assessment of the ART score predicts outcome of patients with hepatocellular carcinoma re-treated with TACE. J Hepatol. 2014;60:118-126. [PubMed] [DOI]|
|75.||Salem R, Mazzaferro V, Sangro B. Yttrium 90 radioembolization for the treatment of hepatocellular carcinoma: biological lessons, current challenges, and clinical perspectives. Hepatology. 2013;58:2188-2197. [PubMed] [DOI]|
|76.||Sangro B, Iñarrairaegui M, Bilbao JI. Radioembolization for hepatocellular carcinoma. J Hepatol. 2012;56:464-473. [PubMed] [DOI]|
|77.||Kim YH, Kim do Y. Yttrium-90 radioembolization for hepatocellular carcinoma: what we know and what we need to know. Oncology. 2013;84 Suppl 1:34-39. [PubMed] [DOI]|
|78.||Salem R, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu RK, Ibrahim S, Atassi B, Baker T, Gates V, Miller FH. Radioembolization for hepatocellular carcinoma using Yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology. 2010;138:52-64. [PubMed] [DOI]|
|79.||Sangro B, Carpanese L, Cianni R, Golfieri R, Gasparini D, Ezziddin S, Paprottka PM, Fiore F, Van Buskirk M, Bilbao JI. Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology. 2011;54:868-878. [PubMed] [DOI]|
|80.||Salem R, Lewandowski RJ, Kulik L, Wang E, Riaz A, Ryu RK, Sato KT, Gupta R, Nikolaidis P, Miller FH. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2011;140:497-507.e2. [PubMed] [DOI]|
|81.||Louis C, Dewas S, Mirabel X, Lacornerie T, Adenis A, Bonodeau F, Lartigau E. Stereotactic radiotherapy of hepatocellular carcinoma: preliminary results. Technol Cancer Res Treat. 2010;9:479-487. [PubMed] [DOI]|
|82.||Blomgren H, Lax I, Näslund I, Svanström R. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients. Acta Oncol. 1995;34:861-870. [PubMed] [DOI]|
|83.||Herfarth KK, Debus J, Lohr F, Bahner ML, Rhein B, Fritz P, Höss A, Schlegel W, Wannenmacher MF. Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol. 2001;19:164-170. [PubMed]|
|84.||Wulf J, Guckenberger M, Haedinger U, Oppitz U, Mueller G, Baier K, Flentje M. Stereotactic radiotherapy of primary liver cancer and hepatic metastases. Acta Oncol. 2006;45:838-847. [PubMed] [DOI]|
|85.||Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer. 1988;62:479-483. [PubMed]|
|86.||Fuchs CS, Clark JW, Ryan DP, Kulke MH, Kim H, Earle CC, Vincitore M, Mayer RJ, Stuart KE. A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer. 2002;94:3186-3191. [PubMed] [DOI]|
|87.||Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY, Koh J, Mo FK, Yu SC, Chan AT. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 2005;97:1532-1538. [PubMed] [DOI]|
|88.||Nowak AK, Stockler MR, Chow PK, Findlay M. Use of tamoxifen in advanced-stage hepatocellular carcinoma. A systematic review. Cancer. 2005;103:1408-1414. [PubMed] [DOI]|
|89.||Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology. 2003;37:429-442. [PubMed] [DOI]|
|90.||Barbare JC, Bouché O, Bonnetain F, Raoul JL, Rougier P, Abergel A, Boige V, Denis B, Blanchi A, Pariente A. Randomized controlled trial of tamoxifen in advanced hepatocellular carcinoma. J Clin Oncol. 2005;23:4338-4346. [PubMed] [DOI]|
|91.||Chow PK, Tai BC, Tan CK, Machin D, Win KM, Johnson PJ, Soo KC. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial. Hepatology. 2002;36:1221-1226. [PubMed] [DOI]|
|92.||Leung TW, Patt YZ, Lau WY, Ho SK, Yu SC, Chan AT, Mok TS, Yeo W, Liew CT, Leung NW. Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res. 1999;5:1676-1681. [PubMed]|
|93.||Cervello M, McCubrey JA, Cusimano A, Lampiasi N, Azzolina A, Montalto G. Targeted therapy for hepatocellular carcinoma: novel agents on the horizon. Oncotarget. 2012;3:236-260. [PubMed]|
|94.||Chang YS, Adnane J, Trail PA, Levy J, Henderson A, Xue D, Bortolon E, Ichetovkin M, Chen C, McNabola A. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol. 2007;59:561-574. [PubMed] [DOI]|
|95.||Nojiri K, Sugimoto K, Shiraki K, Tameda M, Inagaki Y, Ogura S, Kasai C, Kusagawa S, Yoneda M, Yamamoto N. Sorafenib and TRAIL have synergistic effect on hepatocellular carcinoma. Int J Oncol. 2013;42:101-108. [PubMed] [DOI]|
|96.||Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. [PubMed] [DOI]|
|97.||Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25-34. [PubMed] [DOI]|
|98.||Kudo M, Tateishi R, Yamashita T, Ikeda M, Furuse J, Ikeda K, Kokudo N, Izumi N, Matsui O. Current status of hepatocellular carcinoma treatment in Japan: case study and discussion-voting system. Clin Drug Investig. 2012;32 Suppl 2:37-51. [PubMed] [DOI]|
|99.||Kudo M, Ueshima K, Arizumi T. Real-life clinical practice with sorafenib in advanced hepatocellular carcinoma: a single-center experience. Dig Dis. 2012;30:609-616. [PubMed] [DOI]|
|100.||Cammà C, Cabibbo G, Petta S, Enea M, Iavarone M, Grieco A, Gasbarrini A, Villa E, Zavaglia C, Bruno R. Cost-effectiveness of sorafenib treatment in field practice for patients with hepatocellular carcinoma. Hepatology. 2013;57:1046-1054. [PubMed] [DOI]|
|101.||Dufour JF, Hoppe H, Heim MH, Helbling B, Maurhofer O, Szucs-Farkas Z, Kickuth R, Borner M, Candinas D, Saar B. Continuous administration of sorafenib in combination with transarterial chemoembolization in patients with hepatocellular carcinoma: results of a phase I study. Oncologist. 2010;15:1198-1204. [PubMed] [DOI]|
|102.||Pinter M, Sieghart W, Graziadei I, Vogel W, Maieron A, Königsberg R, Weissmann A, Kornek G, Plank C, Peck-Radosavljevic M. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist. 2009;14:70-76. [PubMed] [DOI]|
|103.||Lencioni R, Kudo M, Ye SL, Bronowicki JP, Chen XP, Dagher L, Furuse J, Geschwind JF, Ladrón de Guevara L, Papandreou C. First interim analysis of the GIDEON (Global Investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafeNib) non-interventional study. Int J Clin Pract. 2012;66:675-683. [PubMed] [DOI]|
|104.||Lencioni R, Kudo M, Ye SL, Bronowicki JP, Chen XP, Dagher L, Furuse J, Geschwind JF, de Guevara LL, Papandreou C. GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis. Int J Clin Pract. 2014;68:609-617. [PubMed] [DOI]|
|105.||Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, Chung HC, Song X, Xu J, Poggi G. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31:4067-4075. [PubMed] [DOI]|
|106.||Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, Kudo M, Kang YK, Chen PJ, Toh HC. Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2013;31 Suppl 4:abstr 249.|
|107.||Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31:3517-3524. [PubMed] [DOI]|
|108.||Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study. J Clin Oncol. 2013;31:3509-3516. [PubMed] [DOI]|
|109.||Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ, Bruix J, Qin S, Thuluvath PJ, Llovet JM. SEARCH: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Sorafenib Plus Erlotinib in Patients With Advanced Hepatocellular Carcinoma. J Clin Oncol. 2015;33:559-566. [PubMed] [DOI]|
|110.||Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, Poon RT, Blanc JF, Vogel A, Chen CL. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014;312:57-67. [PubMed] [DOI]|
|111.||O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66:1500-1508. [PubMed] [DOI]|
|112.||Lim HY, Yen CJ, Tak WY, Heo J, Choi HJ, Lin CY, Yoon JH, Hsu C, Rau KM, Poon RTP. A phase II trial of MEK inhibitor BAY 86-9766 in combination with sorafenib as first-line systemic treatment for patients with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2012;30 Suppl 15:abstr4103.|
|113.||Choo SP, Ng QS, Chen WJJ, CK , Yong WP, Wang LZ, Koh TS, Goh BC, Thng CH, Huynh HT. A phase I/II study of AZD6244 in combination with sorafenib in advanced hepatocellular carcinoma. J Clin Oncol. 2012;30 Suppl 15:abstr4100.|
|114.||Finn RS, Poon RT, Yau T, Klümpen HJ, Chen LT, Kang YK, Kim TY, Gomez-Martin C, Rodriguez-Lope C, Kunz T. Phase I study investigating everolimus combined with sorafenib in patients with advanced hepatocellular carcinoma. J Hepatol. 2013;59:1271-1277. [PubMed] [DOI]|
|115.||Faivre SJ, Fartoux L, Bouattour M, Bumsel F, Dreyer C, Raymond E, Rosmorduc O. A phase I study of AVE1642, a human monoclonal antibody-blocking insulin-like growth factor-1 receptor (IGF-1R), given as a single agent and in combination with sorafenib as first-line therapy in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2011;29 Suppl 4:abstr270.|
|116.||Ishikawa T. Secondary prevention of recurrence by interferon therapy after ablation therapy for hepatocellular carcinoma in chronic hepatitis C patients. World J Gastroenterol. 2008;14:6140-6144. [PubMed] [DOI]|
|117.||Sakaguchi Y, Kudo M, Fukunaga T, Minami Y, Chung H, Kawasaki T. Low-dose, long-term, intermittent interferon-alpha-2b therapy after radical treatment by radiofrequency ablation delays clinical recurrence in patients with hepatitis C virus-related hepatocellular carcinoma. Intervirology. 2005;48:64-70. [PubMed] [DOI]|
|118.||Shen YC, Hsu C, Chen LT, Cheng CC, Hu FC, Cheng AL. Adjuvant interferon therapy after curative therapy for hepatocellular carcinoma (HCC): a meta-regression approach. J Hepatol. 2010;52:889-894. [PubMed] [DOI]|
|119.||Miyake Y, Takaki A, Iwasaki Y, Yamamoto K. Meta-analysis: interferon-alpha prevents the recurrence after curative treatment of hepatitis C virus-related hepatocellular carcinoma. J Viral Hepat. 2010;17:287-292. [PubMed] [DOI]|
|120.||Singal AG, Waljee AK, Shiffman M, Bacon BR, Schoenfeld PS. Meta-analysis: re-treatment of genotype I hepatitis C nonresponders and relapsers after failing interferon and ribavirin combination therapy. Aliment Pharmacol Ther. 2010;32:969-983. [PubMed] [DOI]|
|121.||Hsu YC, Ho HJ, Wu MS, Lin JT, Wu CY. Postoperative peg-interferon plus ribavirin is associated with reduced recurrence of hepatitis C virus-related hepatocellular carcinoma. Hepatology. 2013;58:150-157. [PubMed] [DOI]|
|122.||Tan YJ. Hepatitis B virus infection and the risk of hepatocellular carcinoma. World J Gastroenterol. 2011;17:4853-4857. [PubMed] [DOI]|
|123.||Hann HW, Coben R, Brown D, Needleman L, Rosato E, Min A, Hann RS, Park KB, Dunn S, DiMarino AJ. A long-term study of the effects of antiviral therapy on survival of patients with HBV-associated hepatocellular carcinoma (HCC) following local tumor ablation. Cancer Med. 2014;3:390-396. [PubMed] [DOI]|
|124.||Yamasaki S, Hasegawa H, Kinoshita H, Furukawa M, Imaoka S, Takasaki K, Kakumoto Y, Saitsu H, Yamada R, Oosaki Y. A prospective randomized trial of the preventive effect of pre-operative transcatheter arterial embolization against recurrence of hepatocellular carcinoma. Jpn J Cancer Res. 1996;87:206-211. [PubMed] [DOI]|
|125.||Lau WY, Leung TW, Ho SK, Chan M, Machin D, Lau J, Chan AT, Yeo W, Mok TS, Yu SC. Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet. 1999;353:797-801. [PubMed] [DOI]|
|126.||Boucher E, Corbinais S, Rolland Y, Bourguet P, Guyader D, Boudjema K, Meunier B, Raoul JL. Adjuvant intra-arterial injection of iodine-131-labeled lipiodol after resection of hepatocellular carcinoma. Hepatology. 2003;38:1237-1241. [PubMed] [DOI]|
|127.||Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000;356:802-807. [PubMed] [DOI]|
|128.||Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, Takasaki KT, Tanaka T, Tsurumi K, Okuno M, Tomita E. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med. 1996;334:1561-1567. [PubMed]|
|129.||Liu CJ, Lee PH, Lin DY, Wu CC, Jeng LB, Lin PW, Mok KT, Lee WC, Yeh HZ, Ho MC. Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage. J Hepatol. 2009;50:958-968. [PubMed] [DOI]|
|130.||Barone C, Koeberle D, Metselaar H, Parisi G, Sansonno D, Spinzi G. Multidisciplinary approach for HCC patients: hepatology for the oncologists. Ann Oncol. 2013;24 Suppl 2:ii15-ii23. [PubMed] [DOI]|
|131.||Cucchetti A, Cescon M, Bigonzi E, Piscaglia F, Golfieri R, Ercolani G, Cristina Morelli M, Ravaioli M, Daniele Pinna A. Priority of candidates with hepatocellular carcinoma awaiting liver transplantation can be reduced after successful bridge therapy. Liver Transpl. 2011;17:1344-1354. [PubMed] [DOI]|
|132.||Yao FY, Kerlan RK, Hirose R, Davern TJ, Bass NM, Feng S, Peters M, Terrault N, Freise CE, Ascher NL. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis. Hepatology. 2008;48:819-827. [PubMed] [DOI]|
|133.||Belghiti J, Carr BI, Greig PD, Lencioni R, Poon RT. Treatment before liver transplantation for HCC. Ann Surg Oncol. 2008;15:993-1000. [PubMed] [DOI]|
|134.||Schwartz M, Roayaie S, Uva P. Treatment of HCC in patients awaiting liver transplantation. Am J Transplant. 2007;7:1875-1881. [PubMed]|
|135.||Llovet JM, Mas X, Aponte JJ, Fuster J, Navasa M, Christensen E, Rodés J, Bruix J. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut. 2002;50:123-128. [PubMed]|
|136.||Bouchard-Fortier A, Lapointe R, Perreault P, Bouchard L, Pomier-Layrargues G. Transcatheter arterial chemoembolization of hepatocellular carcinoma as a bridge to liver transplantation: a retrospective study. Int J Hepatol. 2011;2011:974514. [PubMed] [DOI]|
|137.||Lee KT, Wang SR. The impact of sorafenib on early recurrence of HCC after hepatic surgery. ILCA 2012: The International Liver Cancer Association’s 6th Annual Conference; 2012 Sep 14-16; Berlin, Germany. 2012;abstr 197.|
|138.||Lubienski A, Bitsch RG, Schemmer P, Grenacher L, Düx M, Kauffmann GW. [Long-term results of interventional treatment of large unresectable hepatocellular carcinoma (HCC): significant survival benefit from combined transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) compared to TACE monotherapy]. Rofo. 2004;176:1794-1802. [PubMed]|
|139.||Morimoto M, Numata K, Kondou M, Nozaki A, Morita S, Tanaka K. Midterm outcomes in patients with intermediate-sized hepatocellular carcinoma: a randomized controlled trial for determining the efficacy of radiofrequency ablation combined with transcatheter arterial chemoembolization. Cancer. 2010;116:5452-5460. [PubMed]|
|140.||Liapi E, Geschwind JF. Combination of local transcatheter arterial chemoembolization and systemic anti-angiogenic therapy for unresectable hepatocellular carcinoma. Liver Cancer. 2012;1:201-215. [PubMed] [DOI]|
|141.||Weintraub JL, Salem R. Treatment of hepatocellular carcinoma combining sorafenib and transarterial locoregional therapy: state of the science. J Vasc Interv Radiol. 2013;24:1123-1134. [PubMed] [DOI]|
|142.||Kim HY, Park JW. Clinical trials of combined molecular targeted therapy and locoregional therapy in hepatocellular carcinoma: past, present, and future. Liver Cancer. 2014;3:9-17. [PubMed] [DOI]|
|143.||Printz C. Clinical trials of note. Sorafenib as adjuvant treatment in the prevention of disease recurrence in patients with hepatocellular carcinoma (HCC) (STORM). Cancer. 2009;115:4646. [PubMed] [DOI]|
|144.||Li X, Feng GS, Zheng CS, Zhuo CK, Liu X. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol. 2004;10:2878-2882. [PubMed]|
|145.||Wang B, Xu H, Gao ZQ, Ning HF, Sun YQ, Cao GW. Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol. 2008;49:523-529. [PubMed] [DOI]|
|146.||Shim JH, Park JW, Kim JH, An M, Kong SY, Nam BH, Choi JI, Kim HB, Lee WJ, Kim CM. Association between increment of serum VEGF level and prognosis after transcatheter arterial chemoembolization in hepatocellular carcinoma patients. Cancer Sci. 2008;99:2037-2044. [PubMed] [DOI]|
|147.||Sergio A, Cristofori C, Cardin R, Pivetta G, Ragazzi R, Baldan A, Girardi L, Cillo U, Burra P, Giacomin A. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol. 2008;103:914-921. [PubMed] [DOI]|
|148.||Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF. Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma. J Clin Oncol. 2011;29:3960-3967. [PubMed] [DOI]|
|149.||Park JW, Koh YH, Kim HB, Kim HY, An S, Choi JI, Woo SM, Nam BH. Phase II study of concurrent transarterial chemoembolization and sorafenib in patients with unresectable hepatocellular carcinoma. J Hepatol. 2012;56:1336-1342. [PubMed] [DOI]|
|150.||Chung YH, Han G, Yoon JH, Yang J, Wang J, Shao GL, Kim BI, Lee TY, Chao Y. Interim analysis of START: Study in Asia of the combination of TACE (transcatheter arterial chemoembolization) with sorafenib in patients with hepatocellular carcinoma trial. Int J Cancer. 2013;132:2448-2458. [PubMed] [DOI]|
|151.||Lencioni R, Llovet JM, Han G, Tak WY, Yang J, Leberre M, Niu W, Nicholson K, Meinhardt G, Bruix J. Sorafenib or placebo in combination with transarterial chemoembolization (TACE) with doxorubicin-eluting beads (DEBDOX) for intermediate stage hepatocellular carcinoma (HCC): phase II, randomized, double-blind SPACE trial. J Clin Oncol. 2012;30 Suppl 4:LBA154.|
|152.||Qu XD, Chen CS, Wang JH, Yan ZP, Chen JM, Gong GQ, Liu QX, Luo JJ, Liu LX, Liu R. The efficacy of TACE combined sorafenib in advanced stages hepatocellullar carcinoma. BMC Cancer. 2012;12:263. [PubMed] [DOI]|
|153.||Cabrera R, Pannu DS, Caridi J, Firpi RJ, Soldevila-Pico C, Morelli G, Clark V, Suman A, George TJ, Nelson DR. The combination of sorafenib with transarterial chemoembolisation for hepatocellular carcinoma. Aliment Pharmacol Ther. 2011;34:205-213. [PubMed] [DOI]|
|154.||Sansonno D, Lauletta G, Russi S, Conteduca V, Sansonno L, Dammacco F. Transarterial chemoembolization plus sorafenib: a sequential therapeutic scheme for HCV-related intermediate-stage hepatocellular carcinoma: a randomized clinical trial. Oncologist. 2012;17:359-366. [PubMed] [DOI]|
|155.||Kudo M, Imanaka K, Chida N, Nakachi K, Tak WY, Takayama T, Yoon JH, Hori T, Kumada H, Hayashi N. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer. 2011;47:2117-2127. [PubMed] [DOI]|
|156.||Han G, Yang J, Shao G, Teng G, Wang M, Yang J, Liu Z, Feng G, Yang R, Lu L. Sorafenib in combination with transarterial chemoembolization in Chinese patients with hepatocellular carcinoma: a subgroup interim analysis of the START trial. Future Oncol. 2013;9:403-410. [PubMed] [DOI]|
|157.||Hsu C, Po-Ching-Liang S, Hu FC, Cheng AL. Perspectives on the design of clinical trials combining transarterial chemoembolization and molecular targeted therapy. Liver Cancer. 2012;1:168-176. [PubMed] [DOI]|
|158.||Martin RC, Keck G, Robbins K, Strnad B, Dubel G, Longares J, Padr R, Narayanan G. Evaluation of sorafenib in combination with doxorubicin-loaded DC bead as a combination treatment option for HCC. 2010;abstr 216.|
|159.||Gadani S, Mahvash A, Avritscher R, Chasen B, Kaseb A, Murthy R. Yttirum-90 resin microspheres as an adjunct to sorafenib in patients with unresectable HCC: A retrospective study for evaluation of survival benefit and adverse events. J Vasc Interv Radiol. 2013;24:S35. [DOI]|
|160.||Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, Gansukh B, Saltz LB. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010;304:2154-2160. [PubMed] [DOI]|
|161.||Prete SD, Montella L, Caraglia M, Maiorino L, Cennamo G, Montesarchio V, Piai G, Febbraro A, Tarantino L, Capasso E. Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR. study. Cancer Chemother Pharmacol. 2010;66:837-844. [PubMed] [DOI]|
|162.||Yau T, Chan P, Cheung FY, Lee AS, Yau TK, Choo SP, Lau J, Wong JS, Fan ST, Poon RT. Phase II trial of sorafenib with capecitabine and oxaliplatin (SECOX) in patients with locally advanced or metastatic hepatocellular carcinoma. European Journal of Cancer Supplements. 2009;7:20-21. [DOI]|
|163.||Petrini I, Lencioni M, Ricasoli M, Iannopollo M, Orlandini C, Oliveri F, Bartolozzi C, Ricci S. Phase II trial of sorafenib in combination with 5-fluorouracil infusion in advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2012;69:773-780. [PubMed] [DOI]|
|164.||Lee SJ, Lee J, Park SH, Park JO, Park YS, Kang WK, Lee J, Yim DS, Lim HY. Phase 1 trial of S-1 in combination with sorafenib for patients with advanced hepatocellular carcinoma. Invest New Drugs. 2012;30:1540-1547. [PubMed] [DOI]|
|165.||Abou-Alfa GK, Chan SL, Lin CC, Chiorean EG, Holcombe RF, Mulcahy MF, Carter WD, Patel K, Wilson WR, Melink TJ. PR-104 plus sorafenib in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2011;68:539-545. [PubMed] [DOI]|
|166.||Hsu CH, Shen YC, Lin ZZ, Chen PJ, Shao YY, Ding YH, Hsu C, Cheng AL. Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma. J Hepatol. 2010;53:126-131. [PubMed] [DOI]|
|167.||Giuliana FAR, Addeo R, Febbraio A, Rizzi D, Macello E, del Prete S, Pisconti S, Fico M, Colucci G. Sorafenib plus cisplatin and gemcitabine in the treatment of advanced hepatocellular carcinoma: a phase II study by the Grupo Oncologico Dell’Italia Meridonale (PROT. GOIM 2705). Cancer Treat Rev. 2010;36 Suppl 4:S96.|
|168.||Abstracts of the American Association for the Study of Liver Diseases 61st Annual Meeting and Postgraduate Course. October 29-November 2, 2010. Boston, Massachusetts, USA. Hepatology. 2010;52 Suppl:320A-1291A. [PubMed]|
|169.||ClinicalTrials ; National Cancer Institute (NCI). Sorafenib Tosylate With or Without Gemcitabine Hydrochloride and Oxaliplatin in Treating Patients With Locally Advanced, Unresectable, or Metastatic Liver Cancer. 2009. gov [Internet]. Bethesda (MD): National Library of Medicine (US). [Cited; 2014;October] Available from: http: //clinicaltrials.gov/ct2/show/NCT00941967 NLM Identifier: NCT00941967.|
|170.||Zhu AX. Sorafenib mFOLFOX for Hepatocellular Carcinoma. gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2013. [Cited; 2014;October] Available from: http: //clinicaltrials.gov/ct2/show/NCT01775501 NLM Identifier: NCT01775501.|
|171.||ClinicalTrials ; The University of Hong Kong. Sorafenib With Capecitabine and Oxaliplatin for Advanced or Metastatic Hepatocellular Carcinoma (SECOX). gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2008. [Cited; 2014;October] Available from: http: //clinicaltrials.gov/ct2/show/NCT00752063 NLM Identifier: NCT00752063..|
|172.||Dollinger M. Sorafenib Plus Doxorubicin Versus Sorafenib Alone for the Treatment of Advanced Hepatocellular Carcinoma: a Randomized Phase II Trial (SoraDox). gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2011. [Cited; 2014;October] Available from: http: //clinicaltrials.gov/ct2/show/NCT01272557 NLM Identifier: NCT01272557.|
|173.||Abdel-Rahman O, Fouad M. Sorafenib-based combination as a first line treatment for advanced hepatocellular carcinoma: a systematic review of the literature. Crit Rev Oncol Hematol. 2014;91:1-8. [PubMed] [DOI]|