Hepatocellular carcinoma (HCC) is one of the few cancers whose incidence has been on the rise for decades. Therefore, given the unique complexity of treatment modalities for this patient population, research has often focused on aspects such as diagnostic accuracy and safety. Over the past decade, non-surgical treatment platforms have gained ground, and diagnostic and liver transplantation techniques have improved. The difficulty in meeting the challenge lies in 1) patient-related variability, such as the presence of multiple coexisting diseases that may affect the applicability of treatment options; 2) liver-related variability, with differences in cirrhotic patient scores such as the Child-Pugh score; and 3) tumor-related variability, such as size, volume, hepatic dissemination patterns, and whether vascular invasion is involved. The purpose of this review is to provide insights into the available treatment modalities for HCC to clarify the advantages and disadvantages of each treatment option and to gather evidence supporting the introduction of sorafenib in the multidisciplinary treatment of HCC. OVERVIEW Hepatocellular carcinoma (HCC) is the second most lethal cancer in the world and its incidence has been on the rise worldwide. Approximately 750,000 new cases of hepatocellular carcinoma are seen reported globally each year. Population-based studies have found that incidence rates continue to approach mortality rates, suggesting that the majority of patients die from HCC. 5-year survival rates in the United States have increased steadily to 26%, which is thought to be related to improvements in screening for high-risk populations (e.g., hepatitis B and C) and surgical interventions (resection or transplantation) for patients with early-stage cancer. The vast majority of patients with HCC have chronic liver disease caused by viral hepatitis, excessive alcohol consumption, and/or nonalcoholic steatohepatitis (NASH). Therefore, prevention efforts for HCC should be directed toward preventing the transmission of hepatitis B virus and hepatitis C virus, as well as the development of guidelines to reduce the prevalence of obesity. The agreed upon guidelines have been published by several institutions, including the American Association for the Study of Liver Diseases (AASLD), as well as the National Comprehensive Cancer Network (NCCN), and the European Association for the Study of the Liver (EASL), in order to promote the standardization of their diagnosis and treatment. For most of the disease process, early diagnosis is most beneficial in the treatment of HCC. The best chance for early diagnosis comes from monitoring patients who are known to be at high risk. This includes patients with cirrhosis due to a variety of factors, hepatitis B carriers, and others. The 2012 NCCN guidelines recommend serum alpha-fetoprotein (AFP) testing or ultrasound every 6 to 12 months for those at risk. Elevated AFP levels associated with hepatic nodules larger than 1 cm in diameter are associated with increased susceptibility to HCC and require tomography. The diagnostic criteria for HCC have evolved over the past decade. In an effort to minimize the use of percutaneous biopsy and to reduce the risks inherent in patients with major liver disease (perforation spread, bleeding, etc.), the AASLD, NCCN, and EASL working groups have developed imaging criteria of acceptable accuracy for the prediction of cancer. Using CT enhancement or magnetic resonance enhanced imaging (MRI), HCC has been found to be characterized on imaging by early arterial enhancement as well as venous phase washout, which may be associated with hepatic arterial branching vessel-rich lesions. For chronic liver disease, injuries greater than 1 cm in diameter confirmed by triple-phase CT and contrast-enhanced MRI-enhanced scans were used as a criterion for the classification of HCC. This is a change from previous guidelines, which considered injuries 1 cm to 2 cm in diameter to require confirmation of enhancement by both imaging modalities (CT and MRI) to be definitively HCC, and although the imaging criteria have changed, only injuries with enhancement greater than 2 cm in diameter that are excluded from the Model for End-Stage Liver Disease (MELD) score are suitable for liver transplantation. Some medical centers have adopted new contrast agents for MRI, such as gadoxetic acid, in an effort to better define injuries that do not meet traditional criteria or for venous phase imaging. Injuries suspected to be HCC appear to be darker than the liver background on T1-weighted imaging (hepatocyte phase). To this day, gadoxetic acid-enhanced MR has not changed the norms of diagnostic features used to define eligibility for treatment strategies, although improved imaging specificity has been reported. Some clinical staging systems include the scoring system defined by the Cancer of the Liver Italian Program and the Barcelona Clinical Liver Cancer Scoring System (BCLC) to accomplish prognostic prediction and stratification of treated patients. Their goals are the same: to more effectively predict the prognosis and clinical outcome of patients considered suitable for treatment or clinical trials.The CLIP system includes Child-Pugh score, tumor morphology (solitary, multinodular, extensive), AFP, and portal vein thrombosis or absence.The BCLC system includes Child-Pugh score, functional status, tumor stage (solitary, multinodular, extensive), AFP, and portal vein thrombosis or absence.The BCLC system includes Child-Pugh score, functional status, tumor stage (solitary, multinodular, extensive), AFP, and portal vein thrombosis or absence. The BCLC system includes Child-Pugh score, functional status, tumor stage (isolated, multinodular, vascular invasion, or extrahepatic spread) and classifies patients as having early stage HCC (BCLC stage A1-A4), including compensated (Child-Pugh class A) with good hepatic reserve and limited tumor load. Intermediate HCC (BCLC stage B) includes moderate hepatic reserve (Child-Pugh class A and B), good functional status, and multinodularity. Advanced HCC (BCLC stage C) includes moderate hepatic reserve function (Child-Pugh classes A and B), vascular invasion or extrahepatic spread, and fragile functional status (Eastern Cooperative Oncology Group [ECOG]). Patients with BCLC staging class A compared to patients with BCLC staging class C had a 3-year survival assessment of 50% vs 8% for both, respectively. The effect of any known treatment modality on more advanced patients is unknown. The addition of plasma-based tumor markers such as vascular epidermal growth factor or insulin-like growth factor to existing staging systems has been suggested to improve the prediction of the stratification of patients with advanced HCC and to more effectively select which patients are suitable for which treatment modality. Liver transplantation Liver transplantation is considered the most effective treatment for cancer and associated major liver disease (which develops into the majority of HCC cases), and suitability for transplantation depends on the size and number of tumor foci, and transplantation criteria have been defined to optimize cancer-specific outcomes. The Milan criteria, which are the most common transplantation criteria worldwide, state that patients with HCC are suitable for liver transplantation if they have up to three nodules less than 3 cm in diameter or one nodule less than 5 cm in diameter. The 5-year survival rate for these patients is 75%, which is similar to the survival rate of patients who are tumor-free at the time of liver transplantation. Other centers, such as the University of California, San Francisco (UCSF), have relaxed their criteria (1 nodule less than 6.5 cm in diameter or 2 to 3 tumor nodules all less than 4.5 cm in diameter and no more than 8 cm in total diameter) for suitability for liver transplantation, based on the evidence-based clinical outcomes that do not have sufficiently robust data to demonstrate an adverse effect on overall survival. As liver-targeted HCC regimens improved, Milan or UCSF explicitly downstaged patients. Patients whose disease continues to progress on liver-targeted therapy are at high risk for post-transplant recurrence. Treatment based on liver status prior to liver transplantation and monitoring of the patient prior to transplantation allow medical centers to choose the most appropriate individualized treatment for the patient. Surgical resection Liver resection remains the gold standard for the treatment of patients with resectable HCC that has developed from normal liver tissue. However, the majority of HCC patients with substantial diseased tissue undergoing concomitant resection are of concern for their potential complications. Thus, the question is how to preserve hepatic parenchymal reserve function, and treatment needs to balance the efficacy of surgical procedures lacking liver transplantation with the potential threat of a fragile high-risk remnant. Most published studies show that patients undergoing hepatic resection tend to have a single tumor focus or limited tumor load (tumor volume up to a specific criterion) and well-maintained liver function (Child-Pugh class A) . With the development of targeted liver therapeutic regimens, there has been a substantial reduction in the gap between the overall survival of their patient population and that of patients who have undergone liver resection for major liver disease. This is due in part to the high rate of recurrence or the presence of primary tumors remaining in the residual liver tissue. The 2-year and 5-year recurrence rates after resection in most populations are 50% and 75%, respectively. In some regions of the world where the hepatitis B virus is a major risk factor for cancer, the reasons why the use of surgical resection is becoming more common include the following: 1) the source of valid transplant organs is limited; 2) medical centers outside of the United States tend to rely more on valid surviving donor sources, with an increasing investment in human resources in this procedure; and 3) more patients with hepatitis B have preserved liver function, making resection safer. As a result, the use of resection is becoming more common in order to minimize donor risk and to select those patients who can maximize their benefit from liver transplantation, making transplantation a salvage option after cancer recurrence or after liver failure. The natural history of HCC in the NASH setting predicts an increasing proportion of non-cirrhotic patients and a decreasing rate of recurrence (primary tumor recurrence) compared with hepatitis B or C. The natural history of HCC in the NASH setting predicts an increasing proportion of non-cirrhotic patients and a decreasing rate of recurrence (primary tumor recurrence). For this reason, the rise of resective surgical treatment in this patient population is considered a reasonable option. Comparison of resection versus transplantation in the context of NASH must be based on prioritizing liver preservation only. Stereotactic radiation therapy Stereotactic radiation therapy (SBRT) is a form of targeted radiotherapy based on the premise that a computer model assists in outlining the treatment area. It uses an instrument to immobilize respiratory changes during treatment. SBRT is a non-invasive, outpatient, well-tolerated treatment. In studies of single injuries up to 6 cm in diameter or up to three tumors (all less than 3 cm), the outcome was found to be no tumor larger than 3 cm in diameter. there was at least 700 cc of liver volume outside of the treatment area. data from the phase 1 trial showed a gradual increase in dose up to 16 grays in 3 fractions. there was no mention of dose-limiting in the case of patients with Child-Pugh Class A. toxicity events. For Child-Pugh B patients, dose-limiting toxicity events occurred, so the protocol was modified to be administered in 5 lengthy fractions to achieve the same total dose. This will result in a reduction in toxicity events to the level of Child-Pugh Grade A patients. Phase 2 trial data from the same patient population found a 2-year tumor control rate of 90%. Response rates were consistently higher than 90% for patients with greater tumor loads who did not follow the regimen, although long-term control rates were somewhat lower for indicators of increased tumor volume (data not published). Ablation Ablation is a potentially curative treatment option for patients with early-stage disease. Ablation has the highest treatment success rate for lesions 2 cm to 3 cm in diameter and significantly lower success rates for lesions greater than 3 cm in diameter. For tumors that are larger or have fewer lesions, ablation combined with embolization may be indicated. For solid tumors larger than 7 cm in diameter, this combination therapy has a similar effect on 5-year survival as surgical resection. Ablative procedures (radiofrequency ablation, microwave, laser-induced mesenchymal hyperthermia) as well as chemoablation (alcohol and acetic acid) have been used in the treatment of patients with HCC, which is an ideal target for ablation because most cases are characterized by soft tumor tissue surrounded by fibrous liver tissue. This is known as the “furnace effect,” where heat reaches the tumor and is blocked by the harder liver tissue. Tumor soft tissue and hardened liver tissue are also beneficial for chemoablation because the alcohol or acetic acid can easily diffuse into the tumor soft tissue and not into the harder liver tissue. The appropriateness of ablation depends on the location and size of the targeted tumor tissue. For example, radiofrequency ablation is sensitive to the “heat sink” effect, in which heat is carried away by blood in large vessels close to the tumor tissue, and microwave ablation is a more appropriate choice because it is less susceptible to this effect. The long-term effects of both techniques will decrease substantially as the size and number of tumors increase. Ablation is often performed under general anesthesia and can also be applied percutaneously, laparoscopically, or intraoperatively. In contrast to the technique of intubation, the RECIST criteria cannot be applied to the assessment of imaging response. Following ablation, the ideal response is the presence of necrosis, with the treated tumor foci being at least 2 cm smaller in diameter than the untreated one (including 1-cm margin tissue). As a preparation for transplantation, ablation thus complicates the evaluation process because the ablated area is larger than the primary tumor, whereas transplantation criteria are based on the size of the tumor focus. Chemotherapy Sorafenib is approved by the FDA for the treatment of HCC. Since its approval, there has been a surge of HCC patients scrambling to take advantage of treatment with haemorrhagic sorafenib, regardless of their tumor stage. Based on Phase 2 and Phase 3 clinical data, sorafenib can be used to treat patients with advanced metastatic HCC, with a survival advantage of close to 3 months in the treated group compared to the non-treated group.The Phase 2 and Phase 3 trials highlighted a target response rate of approximately 2%, with disease stabilization rates ranging from 35% to 71%.More than 80% of patients in the Phase 3 trials were treated prior to enrollment with liver status-guided therapy ( chemoablation) prior to enrollment. Response rates to liver-guided therapy exceeded 70%, so sorafenib must be considered after all treatment options have been considered. Sorafenib has been associated with tolerable toxicity and improved efficacy in combination with liver state-guided therapy. The vast majority of patients require dose-delayed or reduced treatment. Recent results from phase 3 trials exploring the benefit of adjuvant therapy with sorafenib after ablation were found to be unconvincing. There is a dearth of small cohort studies using sorafenib for neoadjuvant chemotherapy prior to targeted liver therapy, resection, or transplantation. Experience from other anti-angiogenic complexes applied to neoadjuvant chemotherapy induces perioperative complications that diminish the benefit of successful treatment. As an example, using cannulation techniques, arterial modifications associated with anti-angiogenic factors may affect the bedding of drug particles at the tumor site. A number of reasons exist for avoiding preoperative sorafenib in liver transplantation: 1) transplant patients are often at higher baseline risk for wound healing complications due to nutritional deficiencies; 2) arterial syndromes can have catastrophic consequences, and liver transplantation can also affect patient longevity; and 3) the near 70% disease stabilization rate observed in phase 3 trials may mask the aggressive nature of the disease and make people not recognize the need for transplantation. The combination of antiangiogenic drugs and radiation therapy for the treatment of other tumor types is also well advanced. Thus, therapeutic studies of internal radiation (yttrium-90) in combination with sorafenib or stereotactic radiotherapy plus sorafenib are of great interest, and data on these combination regimens will be available in the years to come. Summary The challenges of treating patients with HCC are due in part to the patient-specific clinical presentation (complex co-morbidities), tumor specificity (volume, number, location), and liver-specific diversity all impacting treatment outcomes and patient safety. Risk strategy programs such as the CLIP score or the BCLC staging system are used for risk assessment as well as in the search for a more rational disease staging for patients. Hepatic oncology programs require multidisciplinary collaboration and need to establish parameters that clearly determine the appropriateness of a particular treatment for a patient. Harmonization of treatment regimens can help to establish a set of procedures to assess cancer-specific outcomes while minimizing heterogeneity to the greatest extent possible.