Cost-effectiveness of Radiofrequency Ablation vs. Percutaneous Ethanol Injection for Early-stage HCC in a Resource-poor Setting - a Randomized Trial

Hepatocellular carcinoma (HCC) is the fifth most common neoplasm worldwide, with more than 500,000 cases diagnosed annually. Its incidence has been increasing around the world, having doubled in the last 25 years in the United States and England. American statistics indicate that mortality from HCC is increasing compared to mortality from the vast majority of other types of cancer and it is estimated that mortality will double in the next two decades. In Brazil, an increasing trend in mortality was also observed for both sexes. The average mortality coefficient for the country was 3.59 deaths per 100 thousand inhabitants, with an annual linear increase of 0.020 (R2=0.588; p<0.001), being 4.20 deaths per 100 thousand men for males, with a linear increase of 0.044 (R2=0.81; p<0.001) per year and, for females, 2.98 per 100 thousand women, with an increase of 0.0194 (R2=0.35; p=0.008) per year.

The main etiological agents in the pathogenesis of HCC are chronic liver disease from chronic infection with hepatitis B (HBV) and hepatitis C (HCV) viruses and other causal factors of lower incidence such as alcohol abuse, metabolic/autoimmune disorders or environmental agents. Regarding HBV-mediated HCC, despite the availability of a vaccine against this virus, the World Health Organization estimates that, globally, 400 million people are chronically infected with HBV. There is no vaccine for HCV to date.

Proper diagnosis and treatment of HCC involves a multidisciplinary team comprised of oncologists, hepatologists, surgeons, pathologists, radiologists, and interventional radiologists. Currently, there are well-defined radiological criteria for the diagnosis of HCC, with biopsy being restricted to cases of diagnostic doubt. Multiphase cross-sectional imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI), or even contrast-enhanced ultrasound, allows for the non-invasive definitive diagnosis of HCC in patients considered to be at high risk. The Liver Imaging Reporting and Data System (universally known by its acronym LI-RADS - Liver Imaging Reporting and Data System), created in 2008 to address the need to improve the consistency and clarity of communication between radiologists and healthcare physicians. reference, has high specificity (above 85%) for patients at risk of HCC. Based on hyperenhancement in the arterial phase (HRFA), in addition to main criteria such as non-peripheral "washout", "capsule" with enhancement or growth above the threshold, suspicious nodules are categorized as probably HCC (LR-4) or definitely HCC , (LR-5).

Historically, radio and chemotherapy were not very effective in curing HCC and it was considered that surgical resection and liver transplantation were the only curative therapies in terms of disease-free survival for patients with HCC, but locoregional therapies such as ablation have become more effective in curing HCC. become potentially curative. Patients with preserved liver function or with lesions that require removal of a small non-tumorous liver mass are the best candidates for surgery. Unfortunately, only a minority of these patients can be candidates for surgery with definitive curative purposes, either due to the advanced stage of the disease at diagnosis, limitations in liver function, the presence of large, multiple tumors and/or located in an unfavorable location for safe resection.

The number of candidates for liver transplantation in relation to the limited supply of organs is still the main limiting factor for carrying out this procedure in our country. In Brazil, in May 2006, Ordinance No. 1160 modified the liver distribution criteria for transplants, implementing the severity criterion of the patient's clinical status, or model for end-stage liver disease (MELD - (MELD - mModel fFor Eend -sStage Liver Disease (MELD)), a scoring system that comprises a scale of values from 6 to 40, being considered a well-established method (AUC=0.78-0.87) as a predictor of three-month mortality in patients who are still on the waiting list for an organ. As an indicator of the severity of the recipient's end-stage biochemical dysfunction, the MELD score uses a logarithmic calculation that involves serum creatinine, bilirubin and International Normalized Ratio (INR), which evaluates the blood clotting tendency according to the formula: [0.957 x natural logarithm (Ln) (creatinine mg/dLl) + 0.378 x Ln (bilirubin mg/dlL) + 1.120 x Ln (INR) + 0.643] x 104.(6 ) Patients with HCC are classified as a special situation on the transplant list, with an initial MELD value of 20, as they are at a higher risk of death due to tumor progression, as well as the development of metastases or clinical decompensation, which can reach the maximum value of 29 after six months of inclusion on the list, if he has not been transplanted. Starting in 2016 in the United States and recently in Brazil, with the purpose of making the patient classification criteria increasingly more effective, it was proposed to adopt the serum sodium level in the MELD calculation (MELD-Na or MELD-sodium) , for the allocation of liver grafts. MELD-Na is calculated using the formula "MELD-Na=MELD + 1.32 x (137 - Na) - [0.033 x MELD*(137 - Na)]", considering the correction of the serum sodium value for the range of 125-137 mEq/lL and increasing the effectiveness in predicting mortality on the wait list. Another important factor considered when selecting patients with HCC for liver transplantation is the estimation of the risk of tumor recurrence in the post-surgical period. In current clinical practice in our country, this estimate is based on the size and number of tumor nodules and the presence of macroscopic vascular invasion, as defined in preoperative imaging studies. The rule proposed by the Milan group for patient selection, universally called the Milan Criteria (one nodule less than or equal to 5.0 cm or 2 to 3 nodules all less than or equal to 3.0 cm, and without macroscopic vascular invasion) has been shown to provide survival rates above 70% at 5 years with about a 10% probability of recurrence. These criteria have been validated by several groups and are widely used to select candidates in the United States and Europe. Despite its proven usefulness, however, it is well known that some patients with tumors exceeding these criteria are also potentially curable by liver transplantation. More recently, with the development of cell and molecular biology techniques, many molecular markers related to invasion, metastasis, recurrence and survival have been explored. In hepatocellular carcinomaHCC, DNA ploidy, proliferative activity of tumor cells, tumor suppressor and promoter genes, cell cycle controllers, proteinases that degrade the extracellular matrix, adhesion molecules, angiogenic factors and metabolic genes were considered biomarkers for the malignant phenotype of hepatocellular carcinoma, and are related to prognosis and therapeutic results.