Summary of Recommended practice for the treatment and diagnosis of hepatocellular carcinoma.docx

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**Summary of: Recommended practice for the treatment and diagnosis of hepatocellular carcinoma** **Introduction** The introduction discusses the significance of hepatocellular carcinoma (HCC) of the liver, a common type of cancer globally. HCC is the fifth most prevalent cancer worldwide, and it o...

**Summary of: Recommended practice for the treatment and diagnosis of hepatocellular carcinoma** **Introduction** The introduction discusses the significance of hepatocellular carcinoma (HCC) of the liver, a common type of cancer globally. HCC is the fifth most prevalent cancer worldwide, and it often arises as a consequence of the high prevalence of chronic hepatitis B infection in developing countries. However, in the authors\' region, the Czech Republic, HCC is a relatively rare cancer, occurring in approximately 500 people per year and almost exclusively in patients with underlying liver cirrhosis. Despite the relatively low incidence of HCC in the Czech Republic, the introduction highlights the importance of this disease in the local context. The key point is that the significance of HCC is not necessarily based on its frequency, but rather on the potential for screening, early diagnosis, and effective treatment. Early detection of HCC is crucial, as it can enable more effective interventions and potentially improve patient outcomes. The introduction suggests that although HCC may not be as common in the authors\' setting compared to other parts of the world, it remains an important public health concern due to the possibility of implementing screening programs and providing timely diagnosis and treatment. This could have significant implications for improving the management and outcomes of HCC patients in the Czech Republic. Overall, the introduction frames HCC as a significant health issue, even in regions where its incidence may be lower, due to the potential benefits of early detection and intervention. The authors emphasize the importance of addressing HCC in their local context, despite its relatively low frequency, in order to optimize patient care and outcomes. **Screening** The provided text discusses the screening and early detection of hepatocellular carcinoma (HCC). It is noted that patients with symptomatic HCC have a very poor prognosis, with 5-year survival rates ranging from 0-10%. In contrast, patients with asymptomatic HCC detected through screening have significantly better outcomes, with more than 50% surviving the 5-year period due to the ability to undergo radical treatment. The purpose of screening is to enable the early detection of HCC and thereby prolong the survival of patients in the target population. The summary highlights a randomized controlled trial that evaluated the efficacy of screening using alpha-fetoprotein (AFP) testing and ultrasonography at 6-month intervals in patients with chronic hepatitis B virus (HBV) infection. This study demonstrated a 37% reduction in HCC mortality in the group of patients enrolled in the screening program compared to those who were not routinely screened. However, the study is criticized for low patient compliance, suggesting that the observed positive outcome may represent the minimum that can be expected from screening. The text also notes that there are many uncontrolled studies that have shown that screening can indeed lead to the diagnosis of HCC at an earlier stage, thus achieving longer patient survival. However, the shortcoming of these uncontrolled studies is the presence of bias due to the fact that HCC is detected before it becomes symptomatic, which automatically increases the observed survival time. In summary, the provided text highlights the importance of screening for the early detection of HCC, which can significantly improve patient prognosis and survival. While the randomized controlled trial provides evidence of the efficacy of screening, the text also acknowledges the limitations of both controlled and uncontrolled studies in this area. **Target group** The research paper discusses the target group for screening for hepatocellular carcinoma (HCC). HCC screening is expected to yield significant prolongation of survival in patient groups with an annual incidence of HCC of at least 1.5%. The annual incidence of HCC is 3-8% in patients with cirrhosis due to hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, 3-4% in hereditary hemochromatosis, and is probably similar to that of HCV cirrhosis in primary biliary cirrhosis. For alcoholic cirrhosis or non-alcoholic fatty liver disease (NAFLD), the exact rate is not known, but it is assumed that the risk of HCC is sufficiently established and screening is necessary. The classification of patients with chronic HCV infection without cirrhosis is ambiguous, as the 5-year risk of HCC in this group is known to be less than 5%. The specifics of HCC risk in Asian or black populations are not mentioned for practical reasons. The research paper recommends that the following groups of patients must be included in the HCC screening program in the Czech Republic: 1\. Patients with liver cirrhosis of any etiology. 2\. Patients with chronic HBV infection (HBsAg positive individuals). 3\. Patients with chronic HCV infection and significant fibrosis (stage 3) or patients with fibrosis in non-alcoholic steatohepatitis. The reason for including the third group is that the exact point of transition to liver cirrhosis and thus the increased risk of HCC cannot be determined. The recommendation is that all patients with liver cirrhosis and chronic HBV infection who can receive some treatment (level I) if HCC is detected should be included in the HCC screening program. **Screening method** The screening method section of the research paper discusses the use of alpha-fetoprotein (AFP) testing and liver ultrasound for screening for hepatocellular carcinoma (HCC). The paper notes that a combination of these two methods has been used for many years, but in 2010, a panel of experts from the American Association for the Study of Liver Diseases (AASLD) recommended that AFP testing be excluded from screening and that only ultrasound be used. The main reason for this recommendation is the low chance of detecting small HCC foci with AFP testing. The paper cites a study, the HALT-C study, which showed a low yield of AFP for HCC screening. The paper states that the interval between screening ultrasound examinations is 6 months, and that according to the available data, there is no point in shortening this interval. The procedure for detecting a lesion during the screening examination is outlined in a figure. The paper concludes with a recommendation that the method of screening for HCC should be ultrasound examination performed at 6-month intervals, which is classified as a level II recommendation. In summary, the key points of the screening method section are: \- AFP testing is no longer recommended for HCC screening, and only liver ultrasound should be used \- The reason for excluding AFP is its low chance of detecting small HCC foci \- The recommended interval for ultrasound screening is 6 months, and this interval does not need to be shortened \- The procedure for detecting lesions during the screening ultrasound is described in a figure \- The recommended screening method is liver ultrasound every 6 months, which is a level II recommendation. **Diagnosis** The diagnosis of hepatocellular carcinoma (HCC) can be made through either histological analysis or non-invasive investigations. Over the past decade, the criteria for the histological diagnosis of HCC have evolved. In cirrhotic patients, for nodules smaller than 2 cm with atypical imaging characteristics, biopsy is a method to determine the biological nature of the lesion. The primary challenge in the histopathological diagnosis of early HCC is the structure of the liver tissue itself. Hepatocytes naturally lack a basement membrane, which in other organs would be considered a criterion for invasive growth. This has made the assessment of small foci equivalent to carcinoma in situ very complex and heavily reliant on expert interpretation. Additionally, there have been differences in the interpretation of early HCC morphology between pathologists from Europe and North America versus those from Asia. Meetings of the International Working Group on Hepatocellular Neoplasms from both regions led to the formulation of histological diagnostic criteria for dysplastic nodules and early HCC. This classification refined definitions of certain features and incorporated immunohistochemical markers into the diagnostic procedures, significantly reducing the number of problematic cases evaluated in biopsy services. The basic features that improve the histopathological diagnosis of HCC include clearer definitions and the incorporation of immunohistochemical markers. These advancements have helped to standardize the diagnosis of HCC, particularly in the early stages, and reduce the reliance on expert interpretation. **Diagnosis by non-invasive investigations** The diagnosis of hepatocellular carcinoma (HCC) has traditionally relied on the alpha-fetoprotein (AFP) value in conjunction with typical imaging findings from computed tomography (CT), magnetic resonance imaging (MRI), or contrast-enhanced ultrasound (CEUS). However, a reassessment of the available data led the AASLD expert panel to recommend in 2010 that the AFP value be excluded from the diagnostic criteria for HCC. This recommendation was supported by evidence of the non-specificity of AFP, as it may be elevated in patients with cholangiogenic carcinoma and liver metastases from colorectal cancer. The current understanding is that a clear finding on only one imaging modality is adequate to diagnose HCC in the cirrhotic liver, contrary to the previous requirement of a combination of one imaging modality and AFP or two imaging modalities. The determination of AFP levels is now considered important for monitoring the treatment\'s effects rather than for diagnostic purposes. The identification of a hypervascular nodule larger than 1 cm in the cirrhotic liver, with typical washout in the venous or late phase, as observed on CT or MRI, is considered a clear indication of HCC. It is important to perform CT in four phases (native, arterial, venous, late) and to conduct dynamic MRI using contrast for accurate diagnosis. Contrast-enhanced ultrasound (CEUS) has been excluded from the diagnostic algorithm due to its lower specificity. These non-invasive diagnostic criteria do not apply to patients without liver cirrhosis. In summary, the use of AFP value as part of the diagnostic criteria for HCC has been reconsidered and excluded based on its non-specificity, leading to a shift towards relying on imaging modalities alone for diagnosis. Additionally, specific criteria for identifying hypervascular nodules larger than 1 cm in the cirrhotic liver, using CT and MRI with contrast, have been outlined, while CEUS has been deemed less specific and excluded from the diagnostic process. It is important to note that these non-invasive criteria are applicable only to patients with liver cirrhosis. **Staging** The research paper discusses the importance of staging in the treatment of hepatocellular carcinoma (HCC). HCC is one of the few cancers where staging systems other than the TNM classification are used in routine practice. This is primarily due to the presence of liver cirrhosis, which affects the prognosis and treatment of HCC patients. The progression of liver cirrhosis is evaluated using the Child-Pugh classification or the MELD score. Of the various classification systems available, the one developed by the Barcelona Group, known as the BCLC criteria, is considered the most comprehensive. This system divides HCC patients with liver cirrhosis into five groups based on factors such as the extent of the primary tumor, liver disease progression, and the patient\'s general condition. The BCLC classification is favored because it not only provides a simple and straightforward approach but also clearly defines the appropriate therapeutic approach for each patient group. This is important as most studies evaluating new treatments for HCC use the BCLC system as a reference. The research paper recommends the use of the \"Barcelona\" classification of HCC (level II) to determine the appropriate treatment for HCC patients. This staging system is preferred because it takes into account both the extent of the primary tumor and the severity of the underlying liver disease, which are crucial factors in the management of HCC. In summary, the research paper emphasizes the importance of using a comprehensive staging system, such as the BCLC criteria, to stratify HCC patients and guide their treatment. This approach ensures that patients receive the most appropriate therapy based on the specific characteristics of their disease. **Surgical treatment of HCC** The provided section discusses the surgical treatment options for hepatocellular carcinoma (HCC), which is considered the only potentially curative treatment known to date. The two main surgical treatment modalities are liver resection (LR) and liver transplantation (Tx). Liver resection can be performed either through open surgery or laparoscopic procedures. Radiofrequency ablation (RFA) is also mentioned as a potentially curative method, which can be done either non-operatively under imaging guidance or through open surgery. However, surgical treatments are associated with some morbidity and mortality, mainly due to the underlying liver cirrhosis, which is present in 95% of HCC patients. The indication for the use of LR or Tx is based on several factors, including the number and size of the tumor deposits. The goal of the surgical treatment is to provide the patient with a chance of cure or a significant prolongation of the symptom-free period, while balancing the risks of the surgery. The section emphasizes that the selection of the appropriate surgical treatment modality is guided by the knowledge of prognostic criteria that can provide the patient with the best chance of cure or prolonged survival. This decision-making process is crucial in ensuring that the benefits of the surgical treatment outweigh the risks associated with the underlying liver disease and the extent of the surgical intervention. In summary, the surgical treatment of HCC, including LR and Tx, is the only potentially curative option known to date. However, the selection of the appropriate surgical approach requires careful evaluation of the prognostic factors and a balanced assessment of the risks and benefits for each individual patient. **Indication criteria for liver transplantation for HCC** The research paper discusses the criteria used for determining the suitability of patients with hepatocellular carcinoma (HCC) for liver transplantation. The most widely accepted and studied criteria are the Milan Criteria (MC), which state that a patient with liver cirrhosis can be indicated for transplantation if they have a single tumor lesion up to 5 cm or a maximum of three lesions up to 3 cm, and no evidence of vascular invasion. Patients meeting these criteria have a 5-year survival rate similar to those transplanted for non-tumor causes. The introduction of the MC led to a significant improvement in transplant outcomes. However, it was observed that some patients outside the MC criteria also benefited from transplantation, leading to the expansion of the criteria. The University of California San Francisco (UCSF) criteria were proposed, which allow for a single node up to 6.5 cm or a maximum of three nodes, the largest of which is less than 4.5 cm and the sum of which is less than 8 cm, without vascular invasion. Mazzaferro, the pioneer of the MC, subsequently developed the \"metroticket concept\", which provides a model to calculate the likely survival based on the extent to which the MC are exceeded. This concept suggests that any expansion beyond the MC is associated with higher recurrence rates and lower 5-year survival rates. Mazzaferro has recently introduced the \"up-to-seven criteria\", which allow for any combination of tumor size and number of lesions, up to a total of seven, without vascular invasion, and have been shown to have a 5-year survival probability of 70%, similar to the MC. The research paper highlights the importance of carefully selecting patients for liver transplantation in the context of HCC, and the ongoing efforts to refine the criteria to optimize outcomes. **Efficacy of the method:** In the treatment of small hepatocellular carcinoma (HCC), radiofrequency (RF) ablation has been found to provide satisfactory local tumor control. Imaging studies have indicated a frequency of complete ablation of approximately 90% in tumors smaller than 3 cm. Histological data from liver samples of patients who underwent RF ablation demonstrated that tumor size and the presence of large vessels (3 mm or more) pressing on the tumor significantly affect the local effect of treatment. The data revealed that complete tumor necrosis at autopsy was found in 83% of tumors smaller than 3 cm and 88% of tumors outside the perivascular localization. Additionally, compared to percutaneous ethanol injection (PEI), RF ablation was found to have a greater local antitumor effect, leading to improved disease control. As a result, the use of PEI currently has no place in the treatment of HCC if RF ablation can be performed. When it comes to survival rates, studies comparing RF ablation with PEI showed mixed results. Two European studies found no statistically significant difference in overall survival between patients who underwent RF ablation and PEI, while three studies from Asia reported better survival rates among those who received RF ablation. This led to the conclusion that RF ablation is preferred as a percutaneous treatment modality for patients with early HCC due to the higher frequency of successful local tumor treatment and improved median survival. Furthermore, long-term survival outcomes of patients treated with RF ablation have been investigated. The findings revealed that in patients with liver cirrhosis in Child-Pugh A classification and early-stage HCC, the 5-year survival rate ranged from 61% to 77%. Moreover, in patients with a single tumor less than or equal to 2 cm, the 5-year survival rate was 68%. In conclusion, the research supports the efficacy of RF ablation in providing satisfactory local tumor control for small HCC, demonstrating its superiority over PEI and its favorable effect on the survival of patients. Furthermore, long-term survival outcomes indicate that RF ablation is associated with positive 5-year survival rates in specific patient groups. **Tumor staging:** The research paper discusses the considerations for imaging examination and tumor staging before treatment using radiofrequency (RF) ablation. The key points are: Lesions located on the surface of the liver may be suitable for RF ablation, but require sufficient expertise and experience, and are associated with a higher risk of complications. Thermal ablation of superficial lesions adjacent to the gastrointestinal tract should not be performed due to the increased risk of thermal injury to the stomach, intestine, or colon wall, which can lead to perforation. Special methods like intraperitoneal injection of dextrose may be considered in such cases. Treatment of lesions adjacent to the hepatic hilum increases the risk of thermal injury to the bile ducts and gallbladder, making it a relative contraindication for RF ablation. Thermal ablation of tumors close to the gallbladder is feasible but should be reserved for sites with sufficient experience, as it is often associated with iatrogenic cholecystitis that resolves spontaneously. Thermal ablation of lesions adjacent to hepatic vessels is possible, as the blood flow usually protects the vessel wall from thermal injury. However, the risk of incomplete treatment of neoplastic tissue near the vessel may increase due to heat loss. The paper emphasizes the importance of thoroughly defining the location of each lesion in relation to surrounding structures through imaging examination before treatment, as the proximity to critical anatomical structures can significantly impact the feasibility and safety of RF ablation. Appropriate patient selection and expertise of the treatment team are crucial factors in minimizing the risk of complications. **Examination and follow-up of patients after treatment** Summary: This section of the research paper discusses the procedures for examining and following up with patients after they have undergone treatment. The standard methods for assessing patient outcomes are CT or MRI scans with contrast agent administration. These imaging techniques are typically performed 4-6 weeks after the treatment. On the CT and MR images, successful ablation sites can be identified as areas with no contrast saturation or with peripheral saturation. The edge of saturation around the ablation zone appears as a relatively concentric, symmetrical, and uniform formation with smooth inner edges. This is a temporary phenomenon resulting from a normal physiological response to the thermal injury, involving initial reactive hyperemia followed by fibrosis and giant cell reaction. It is important to distinguish this benign saturation around the ablation site from irregular peripheral saturation due to residual tumor. Unlike the benign saturation, residual tumor will have a different character on post-contrast images. After the procedure, an ultrasound scan with intravenous contrast can be performed to provide an initial assessment of the treatment\'s effect. Subsequent follow-up examinations should focus on detecting local tumor progression, new hepatic lesions, or the discovery of extrahepatic disease. The recommended follow-up protocol includes CT or MRI scans at 3, 6, 9, and 12 months after treatment, and then at six-month intervals for the following 3 years. The research paper also provides recommendations stating that local ablation is a safe and effective treatment for patients who cannot undergo surgical treatment for hepatocellular carcinoma (HCC), and that the effect of radiofrequency ablation (RFA) is more predictable and clearly better for lesions larger than 2 cm compared to ethanol injection. **Chemoembolization** The research paper discusses the use of transarterial chemoembolization (TACE) as a treatment method for hepatocellular carcinoma (HCC). It is noted that during growth, HCC becomes reliant on the vascular supply from the artery, making non-invasive diagnosis by CT/MR possible and explaining the efficacy of arterial occlusion in HCC treatment. TACE involves the angiographic occlusion of the artery supplying the tumor, along with the administration of a cytostatic agent into the hepatic artery just before the embolization itself. The cytostatic agent is typically dissolved in Lipiodol, which is selectively taken up in the tumor tissue. Cisplatin or adriamycin are commonly used cytostatic agents in TACE. This treatment is used in patients with surgically or percutaneously unresectable HCC who have no evidence of extrahepatic spread. However, TACE has some contraindications, such as inadequate portal vein flow (e.g., v. portae thrombosis, significant collaterals, or reversed (hepatofugal) blood flow in the v. portae). Patients with advanced hepatic insufficiency (Child-Pugh B and C) and/or clinical symptoms should not be indicated for TACE due to increased risk of liver failure and death after the procedure. In such cases, sorafenib at a dose of 800 mg/day is recommended for the treatment of advanced inoperable hepatocellular carcinoma in patients in good overall condition (PS 0-1). Sorafenib is considered the first-line treatment for systemic hepatocellular carcinoma. The paper also mentions historically used chemotherapy regimens with little actual efficacy. In conclusion, the paper highlights the efficacy and considerations of transarterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma, along with its contraindications and alternative treatments, such as sorafenib. It emphasizes the importance of patient condition and tumor characteristics in determining the appropriate treatment approach. **Selected information on biologic therapy Sorafenib in the treatment of hepatocellular carcinoma** The selected information on biologic therapy Sorafenib in the treatment of hepatocellular carcinoma section provides detailed information on the use of Sorafenib for the treatment of inoperable or metastatic hepatocellular carcinoma. Sorafenib is indicated as the first-line therapy for the treatment of inoperable or metastatic hepatocellular carcinoma, but is limited to patients with Child-Pugh class A and B liver function. The drug is contraindicated in patients with hypersensitivity to the drug substance or any of the excipients contained in the preparation. In terms of drug interactions, Sorafenib should not be administered with acidity reducing agents or metabolic enzyme inducers. Adverse reactions associated with Sorafenib include dermatological toxicity, hypertension, bleeding, cardiac ischemia or infarction, impaired wound healing, and impaired liver function. Temporary discontinuation of Sorafenib is recommended as a precaution in patients undergoing major surgery. The recommended dosage of Sorafenib is 2 tablets of 200 mg twice daily, taken at the same time each day, with or without a low-fat meal. Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs. In conclusion, the selected information emphasizes that Sorafenib (level I) is the first-line treatment of choice for inoperable or metastatic hepatocellular carcinoma limited to Child-Pugh stage A and B in indicated patients. **If indicated** The provided section discusses the management of patients with liver cirrhosis and hepatocellular carcinoma (HCC) who undergo invasive procedures, specifically in the case of variceal bleeding or gastropathy unresponsive to standard treatment. The summary indicates that the presence of HCC may not be a major contraindication to the use of Transjugular Intrahepatic Portosystemic Shunt (TIPS) in these patients. However, it emphasizes that each patient should be treated individually, particularly with regard to their future prognosis. The section also highlights the lack of sufficient data in the literature regarding the necessity and modality of prolonged coagulation management in patients with liver cirrhosis. Most current recommendations are based on clinical observations and personal experience, rather than evidence-based medicine. There are differing opinions on whether adjusting coagulation parameters before invasive procedures is necessary or if it should only be initiated when true bleeding complications occur. Additionally, it is unclear whether the frequent administration of vitamin K improves the prognosis of patients with liver cirrhosis or prevents bleeding complications. Consequently, no clear recommendation can be made regarding the adjustment of coagulation parameters before invasive procedures in these patients. Finally, the section notes that the treatment of ascites or other complications of liver cirrhosis in patients with HCC is not substantially different from the management of patients without HCC. In summary, the provided section discusses the complex management considerations for patients with liver cirrhosis and HCC who require invasive procedures, highlighting the need for individualized treatment approaches and the lack of clear evidence-based guidelines in this area. **Summary of the treatment process** The summary outlines the treatment process for patients with hepatocellular carcinoma (HCC). It emphasizes the importance of staging each patient\'s condition and making treatment decisions based on the Barcelona classification. Patients with early-stage HCC are candidates for resection, transplantation, or percutaneous ablation. Resection is considered for patients with a single lesion, no clinically significant portal hypertension, and no jaundice. Transplantation is the appropriate method for patients with a maximum of 3 lesions smaller than 3 cm or a single lesion up to 5 cm. Percutaneous ablation is suitable for small HCCs that are unresectable by resection or transplantation. Transarterial chemoembolization (TACE) is indicated for asymptomatic patients with multiple foci, no evidence of vascular invasion or extrahepatic spread. Patients who respond positively to TACE treatment have prolonged survival. Patients with more advanced HCC or those who do not respond to TACE but have preserved liver function are candidates for systemic cancer therapy. In contrast, patients with manifestations of hepatic insufficiency, poor overall condition (performance status \>2), or massive tumor spread outside the liver have no proven effect of any treatment modality and should be treated symptomatically. The summary emphasizes the importance of a comprehensive staging process and the selection of appropriate treatment approaches based on the individual patient\'s condition and disease stage. It highlights the different treatment options, including resection, transplantation, percutaneous ablation, TACE, and systemic cancer therapy, and the specific criteria for each treatment modality.

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