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  1. AASLD guidelines for the treatment of hepatocellular ...

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    This document presents official recommendations of the American Association for the Study of Liver Diseases (AASLD) on the surveillance, diagnosis, and treatment of hepatocellular carcinoma (HCC) occurring in the setting of adults with cirrhosis. Unlike previous AASLD practice guidelines, the current guideline was developed in compliance with the Institute of Medicine standards for trustworthy practice guidelines and uses the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach.1 Multiple systematic reviews of the literature were conducted to support the recommendations in this practice guideline. An enhanced understanding of the guideline can be obtained by reading the applicable portions of the systematic reviews. In addition, more detailed information may be found in the associated guidance document related to clinically important aspects of HCC that lacked sufficient evidence to warrant a systematic review. The guideline focuses on a broad spectrum of clinical practice, including surveillance of patients with cirrhosis for HCC, establishing the diagnosis of HCC, and various therapeutic options for the treatment of HCC. To address other issues on HCC such as epidemiology, staging, and additional aspects of diagnosis and treatment, the authors have created a new guidance document that will be published soon and is based upon the previous HCC AASLD guidelines by Bruix and Sherman.2

    The guideline developers from the AASLD identified key questions that health care providers are faced with frequently in the evaluation and management of patients with HCC. These questions were:

    This guideline is intended primarily for health care providers who care for patients with cirrhosis. Additionally, the guideline may inform policy decisions regarding patients with HCC.

    According to the World Health Organization, HCC is the fifth most common tumor worldwide and the second most common cause of cancerrelated death (http://globocan.iarc.fr/old/FactSheets/cancers/liver-new.asp). Maletofemale predominance is greater than 2:1 with liver cancer, and approximately 83% of the estimated 782,000 new HCC cases in 2012 occurred in less developed regions of the world, with East and South Asia plus subSaharan Africa being the regions of highest incidence, Southern Europe and North America being the regions of intermediate incidence, and Northern Europe and South Central Asia being the regions of lowest incidence.3 The incidence of HCC has been rising rapidly in the United States over the last 20 years.4 According to estimates from the Surveillance Epidemiology End Results (SEER) program of the National Cancer Institute, the United States will have witnessed an estimated 39,230 cases of HCC and 27,170 HCC deaths in 2016 (https://seer.cancer.gov). In addition, a recent study using the SEER registry projects that the incidence of HCC will continue to rise until 2030,5 with the highest increase in Hispanics, followed by African Americans and then Caucasians, with a decrease noted among Asian Americans. The increase in incidence of HCC in the United States is attributed primarily to the hepatitis C virus (HCV) epidemic, prompting Petrick et al.4 to suggest that preventive efforts should target the birth cohort with the highest prevalence of HCV infection (19451965). Recent data have also shown that metabolic disordersdefined as nonalcoholic fatty liver disease (NAFLD) and the metabolic syndromecontribute numerically more to the burden of HCC than any other risk factor including HCV infection,6 which is due primarily to the high prevalence of NAFLD in the population overall. The presence of cirrhosis represents a key risk factor for the development of HCC. The prevalence of cirrhosis among patients with HCC has been estimated to be 85%95%,7, 8 and the HCC incidence rate among patients with cirrhosis has been shown to be 2%4% per year.9 Therefore, patients with cirrhosis constitute a highrisk group for efforts at prevention and early detection. The fact that patients with HCC have underlying liver disease impacts the management and therapeutic options substantially.

    The evidence profile of surveillance for HCC is included in Supporting Table 1, which uses the data from a recent systematic review on surveillance.13 There were no randomized controlled trials (RCTs) of surveillance in patients with cirrhosis. There were 38 observational cohort studies that evaluated surveillance in patients with cirrhosis, making the overall quality of the evidence moderate (Supporting Table 1). The majority of the data was reported with 3year survival. The pooled 3year survival rate was 50.8% among the 4735 patients who underwent HCC surveillance, compared with only 27.9% among the 6115 patients without previous surveillance, with an odds ratio (OR) of 1.90 (95% confidence interval [CI], 1.672.17; P < 0.001). There were six studies that controlled for leadtime bias, and the improvement in survival persisted (3year survival rates of 39.7% for surveillance versus 29.1% without surveillance; P < 0.001). Of the 23 studies evaluated, 10 were considered highquality studies in which the 3year survival with surveillance was greater than no surveillance (45.6% versus 28.8%; P < 0.001.)

    In addition to improved survival, surveillance also led to an increase in the detection of earlystage HCC, with an OR of 2.11 (95% CI, 1.882.33) compared with no surveillance. In terms of anticipated absolute effects, surveillance led to 163 per 1000 more patients detected at early stages compared with no surveillance. In addition, surveillance led to more curative treatments compared with no surveillance (61.8% versus 38.2%; P < 0.001). Thus, improvement in survival seen with surveillance appears to be due to higher earlystage detection and higher curative treatment rates. Forner et al.17 in 2008 reported outcomes for 2 cm hepatic nodules detected during surveillance ultrasound in patients with cirrhosis. The authors performed percutaneous biopsy of 2 cm nodules in addition to MRI and contrastenhanced US. They found a sensitivity and specificity of MRI to be 61.7% and 96.6%, whereas contrastenhanced US was 51.7% and 93.1% compared with the standard, which was biopsy. When both tests were in concordance, the sensitivity was only 33%, with 100% specificity. Biopsy had a false negative rate of 30%, as patients with suspicious imaging findings or growth were rebiopsied up to three times. In 2011, Khalili et al. 28 reported that in patients with cirrhosis, only 14%23% of 1 to 2cm indeterminate nodules initially detected at surveillance ultrasound are malignant. Given the low likelihood of malignancy, they argued that biopsy for all indeterminate hepatic nodules may be impractical and suggested an alternative strategy of close followup imaging with sequential contrast imaging using an alternate technique for most indeterminate 2 cm nodules, with biopsy reserved for 12 cm nodules with arterial phase hyperenhancement or in the presence of a synchronous HCC. Numerous other studies also reported low likelihoods of malignancy among 2 cm indeterminate nodules, as characterized by CT or MRI.19, 23, 29-37 Importantly, there were three RCTs that compared RFA with resection, including a total of 578 patients.42-44 Two of these three trials had a low risk of bias and moderate evidence quality,42, 43 and one trial had a high risk of bias.44 The results of the two lowriskofbias trials demonstrate that hepatic resection is more effective than RFA regarding overall survival (hazard ratio [HR], 0.56; 95% CI, 0.400.78) as well as 2year survival (HR, 0.38; 95% CI, 0.170.84). When a third trial with a high risk of bias is added to the analysis, the difference in survival between resection and RFA became insignificant (overall survival: HR, 0.71; 95% CI, 0.441.15). The reason for an increased risk of bias in the third study is related to an unusually high number of patients (n = 19) who switched from the RFA arm to the resection arm yet were still counted within the RFA group because of intention to treat, thus potentially overstating the benefit of RFA. The additional endpoints of 2year eventfree survival and local progression favored resection regardless of inclusion of the potentially biased trial. Not unexpectedly, the complication rate was higher for resection compared with RFA (OR, 8.3). In addition to the trials included in the systematic review by Weis et al.41 comparing resection with RFA, two recently published RCTs confirm the findings of improved survival for patients after resection.45, 46 One singlecenter RCT compared resection with RFA combined with TACE (TACE was performed first, followed by RFA within 4 weeks) and demonstrated improved survival at 1, 3, and 5 years for the resection group (P = 0.007).45 Another RCT trial compared resection with TACE alone for lesions up to and exceeding Milan criteria (up to five tumors, with the largest being <5 cm) and found resection to be superior in 1 and 3 years of followup (HR, 0.4; P < 0.001).46 The study by Huo et al.59 reported on outcomes for 390 patients in Taiwan with T1 (n = 94) and T2 (n = 296) HCC who were eligible for transplantation but who were treated instead with LRT. Patients were treated with a number of different methods including RFA, percutaneous ethanol injection (PEI) or acetic acid injection, and TACE. Patients treated with RFA had the lowest rate of waitlist dropout. Overall, patients with T1 HCC had a 6month waitlist dropout rate of 5.3% for tumor progression beyond T2 criteria, though this represented only 2% of patients treated with RFA. Notably, a majority of patients in the study had HBV and were of slightly older age than the typical transplantation patient, which may limit the generalizability of the findings. In addition, the primary aim of the study by Huo et al. was to validate a potential allocation score proposal called the HCCMELD score rather than to observe the impact of LRT on waitlisted patients with T1 or T2 HCC. The majority of the remaining studies that examined downstaging were noncomparative studies. Among the 21 noncomparative studies, 14 reported recurrence rates posttransplantation that averaged 20.4% (CI 0.1527.7), with the lowest recurrence rate noted to be in studies that employed multitherapies. Overall, the 5year post LT OS was 77.6%. These outcomes are comparable to what has been reported posttransplantataion among patients with HCC within Milan criteria. The number of studies that examined various individual modalities (including Y90, drugeluting beads TACE [DEBTACE], PEI, RFA, TACE, transarterial chemoinfusion [TACI], and TAE) were small, with a range of 14 for each modality. The highest 5year OS was reported in those treated with multitherapies (84.4%), and the lowest 5year OS was seen in those that were treated with TACI (54.1%). A lack of a comparative group beyond historical controls severely limits interpretation. Noncomparative studies examining the success of downstaging may include patients who are not deemed liver transplant candidates for other reasons (e.g., advanced age or significant comorbidities), and thus the results of these studies may be affected by the inclusion of nontransplant candidates in whom LRT is palliative in its intent.

    The studies were also evaluated to determine whether US alone or US plus AFP improved survival. US plus AFP had a pooled risk ratio of 1.86 (95% CI, 1.761.97) for improving survival, whereas US alone had a slightly lower pooled risk ratio of 1.75 (95% CI, 1.561.98) for improving survival. There was no statistical difference between the two strategies. However, there are serious issues when comparing these surveillance tests for their impact on survival, which include: (1) no description of the trigger to perform a diagnostic test, (2) some studies appear to evaluate AFP or US rather than the combination, (3) no mention of the performance characteristics of these tests, and (4) most importantly, the studies were not powered to determine an improvement in survival.

    Given the current burden of HCC and the projected continued increase in incidence of this tumor, better studies including appropriate study design comparing US with US plus AFP as surveillance strategies are needed. Such studies should evaluate the characteristics of US, including its operator dependency and reliability as a surveillance test in specific patient populations. In addition, it would be important to determine whether other serum biomarkers in addition to AFP complement US, such as desgamma carboxy prothrombin, AFP L3, and other novel serum tests.14

    In patients with cirrhosis and suspected HCC, diagnostic imaging is used to noninvasively verify the presence of HCC (diagnosis) and determine its extent (radiological staging). The goals are to measure tumor burden, guide management, and help prioritize patients for possible liver transplantation. Unlike most other malignancies, the diagnosis of HCC can be established noninvasively, and treatment may be initiated based on imaging alone, without confirmatory biopsy. The rationale is that in patients with cirrhosis, the pretest probability of HCC is sufficiently high, and the pretest probability of lesions that may mimic HCC at imaging is sufficiently low such that a lesion meeting HCC imaging criteria can be assumed reliably and confidently to be HCC. Although there is strong consensus that the imaging diagnosis of HCC requires multiphasic imaging, there is not agreement about which diagnostic imaging test to use. Commonly used methods in clinical practice include multiphasic CT with extracellular agents, multiphasic MRI with extracellular agents (gadoliniumbased compounds that stay in the extracellular space and permit characterization of blood flow), and multiphasic MRI with gadoxetate disodium (a specific gadoliniumbased compound that accumulates in hepatocytes and permits characterization of hepatocellular function in addition to blood flow). The evidence profile of diagnostic accuracy for HCC is included in Supporting Table 2, which uses the data from a de novo systematic review on imaging in HCC performed to address this question. There were no randomized comparative studies of CT versus MRI, no studies identified that compared multiphasic MRI with an extracellular agent versus multiphasic MRI with gadoxetate disodium, and no data on patient preference. There were 19 observational studies in patients with cirrhosis and suspected HCC that compared the perlesion diagnostic accuracy of CT and MRI, reporting true positive, false positive, false negative, and true negative values. An additional 14 studies reported only detection rate (sensitivity), but these are not further discussed, as sensitivity cannot be interpreted in the absence of data on specificity and/or positive predictive value. Quality of evidence was low and was downgraded because of the methodological limitations of the included studies, inconsistency across studies, and possible publication bias. The performance characteristics of these imaging modalities overall and for lesions of different sizes are reviewed below. Because many if not most indeterminate small hepatic nodules are nonmalignant, strategies for risk stratification are needed. Tanabe et al.38 evaluated the natural history of indeterminate lesions detected at CT or MRI. The indeterminate lesions were categorized as probably benign, intermediate probability of HCC, and probably HCC based only on imaging features.25 No lesions initially categorized as probably benign progressed to definite HCC during followup, whereas 7% of lesions initially categorized as intermediate probability progressed to HCC, and 38% of lesions initially categorized as probably HCC progressed to definite HCC. Similarly, Darnell et al.39 in 2015 showed that the various LIRADS categories are associated with different likelihood of HCC in patients with cirrhosis, using contemporaneous biopsy as the reference standard. Taken together, these studies suggest that a substantial proportion of 1 to 2cm indeterminate nodules are nonmalignant histologically and unlikely to progress to HCC during imaging followup. Thus, a strategy of obtaining a biopsy of all indeterminate nodules would result in a considerable number of unnecessary biopsies. However, indeterminate nodules do require further evaluation. Other diagnostic options include followup imaging, imaging with an alternative modality or contrast agent, and referral to a specialty center. A study by Sersté et al.40 performed CT, MRI, and biopsy for a series of 74 patients with nodules identified by surveillance ultrasound. The authors concluded that sensitivity and specificity of the combination of the two diagnostic tests was 98% and 81%, respectively, and that biopsy could be reserved for those without definitive findings on either CT or MRI. An individualized diagnostic workup based on clinical context and imaging findings such as nodule characteristics, feasibility of biopsy, and institutional expertise may be the optimal approach. In selected circumstances, a multidisciplinary group may elect to treat a probable HCC without biopsy confirmation, though practitioners and patients need to be aware that such treatment may affect transplant priority.

    With regard to overall accuracy, eight studies compared multiphasic MRI using an extracellular agent versus multiphasic CT. MRI with an extracellular agent provided higher pooled sensitivity than CT (0.76 [95% CI, 0.720.81] versus 0.63 [95% CI, 0.570.69]; P < 0.001) with similar specificity (0.78 [95% CI, 0.630.88] versus 0.82 [95% CI, 0.710.89]; P = 0.62). Eight studies compared multiphasic MRI with gadoxetate disodium versus multiphasic CT. MRI with gadoxetate disodium provided higher pooled sensitivity than CT (0.87 [95% CI, 0.790.93] versus 0.73 [95% CI, 0.640.81]; P < 0.02) with similar specificity (0.94 [95% CI, 0.900.97] versus 0.96 [95% CI, 0.900.98]; P = 0.47). When looking specifically at lesions larger than 2 cm, three studies compared multiphasic MRI with an extracellular agent versus multiphasic CT and showed a similar pooled sensitivity, with a higher pooled specificity of 0.87 versus 0.7 (P = 0.02). Examining accuracy in HCC between 1 and 2 cm, there were six studies that compared multiphasic MRI versus CT, and this also showed similar sensitivity and specificity. For HCC <1 cm, two studies compared multiphasic CT versus multiphasic MRI with an extracellular agent. The sensitivity of MRI for <1 cm was significantly higher compared with CT (0.69 versus 0.49; P = 0.049), whereas the specificity was, at a trend level, lower (0.46 versus 0.69; P = 0.08).

    Although multiphasic MRI may be marginally more sensitive than CT in a pooled analysis of comparative studies, the differences in pooled diagnostic performance are insufficient to recommend MRI over CT. Mitigating factors include the low quality of the evidence, concerns about generalizability to nonacademic settings, and recognition that multiple factors beyond diagnostic accuracy inform the selection of optimal imaging modalities in individual patients. Compared with multiphasic CT, multiphasic MRI has important advantages and disadvantages. Advantages include greater soft tissue contrast, more comprehensive assessment of nodule and background liver tissue properties, and absence of ionizing radiation. Disadvantages include greater technical complexity, longer scan times, lower throughput, increased susceptibility to artifact, less consistent image quality (largely because of patient factors such as breath holding, difficulty holding still, or highvolume ascites), larger number of potential contraindications, higher charges, andespecially outside the United Stateslower availability and longer scheduling backlogs. From a patient perspective, CT is faster, more spacious, and provokes less claustrophobia, but it exposes patients to radiation. Both modalities require IV access and contrast agents, the use of which may be problematic in patients with acute kidney injury or chronic renal failure.15, 16

    In its previous HCC clinical practice guidelines,2 the AASLD recommended biopsy for all indeterminate lesions initially detected by surveillance ultrasound, with the presumed rationale being that biopsy can establish a definitive diagnosis, thereby permitting earlier intervention. Because of its many limitations, however, biopsy may not be an optimal strategy in all cases. Biopsy is expensive, may cause anxiety or pain, and has a risk of complications, including tumor track seeding and bleeding.27 Sampling error, especially for very small lesions, is an additional drawback. A negative biopsy may not exclude malignancy, and repeated biopsies may be necessary to establish a diagnosis. Followup imaging may be especially relevant in patients awaiting liver transplantation with a single small, indeterminate nodule, given that biopsy confirmation of <20 mm HCC would not change management or contribute to liver transplantation priority. Because there is controversy regarding optimal workup for an indeterminate nodule, the aim of this question was to determine whether current data are able to elucidate an optimal strategy.

    Because cirrhosis is one of the primary risk factors for HCC, the selection of treatment modality depends as much on the underlying liver function and the degree of portal hypertension as on the oncologic stage of the tumor. Therefore, whereas therapeutic options are limited for patients who present with advanced liver disease and/or advanced tumor stages, multiple options exist for those presenting with wellcompensated cirrhosis and smaller, potentially resectable tumors. These include ablative strategies such as radiofrequency, microwave, chemical, and cryoablation, as well as surgical resection. Most studies define patients with resectable HCC as those (1) with one to three unilobar lesions, with an upper size limit of 5 cm for single lesions and 3 cm for more than one lesion (some trials accept two lesions up to 4 cm); (2) without radiographic evidence of extrahepatic disease or macrovascular invasion; and (3) occurring in the setting of minimal or no portal hypertension and in the absence of synthetic dysfunction (Barcelona Clinic Liver Cancer stage 0 or A). However, a number of clinical and laboratory variables and circumstances, including the availability of alternative therapies, can influence the individual clinician's decision to proceed with resection. The absence of a standard definition of resectability constitutes a limitation of the interpretation of data from analyses of studies comparing resection to ablation of resectable tumors and may lead to biased analyses and conclusions. Given the unique biology of HCC in which risk includes both recurrence of the primary tumor and the development of de novo tumors, the ideal adjuvant therapy would have an antineoplastic component aimed at the original tumor and a chemopreventive effect aimed at the development of a de novo tumor. The distinction of these two scenarios is difficult and often based on the time of the recurrence (e.g., early versus late, with the latter believed to be related to the development of a de novo tumor).49 Early studies with the adjuvant use of acyclic retinoids were promising,50 with a decrease in the development of secondary tumors, but larger studies did not confirm a benefit.51 The lack of proven active agents in advanced disease has hampered the development of agents targeting earlystage disease. To date, most of the adjuvant agents studied did not have clinical evidence that they improve survival in any stage of HCC. Of the agents evaluated in the adjuvant setting, only sorafenib has been shown to improve survival in advanced disease,52 yet it ultimately did not show any improvement in outcomes for the adjuvant treatment of HCC in randomized studies.53 Resection of HCC with curative intent or ablation is associated with rates of recurrence at 5 years as high as 75%.47 Therefore, there is a clear need for adjuvant systemic therapies.

    Lesion size was a risk factor for worse outcome in both arms of the systematic review. This is not surprising given that it is known that RFA is more effective in lesions <3 cm. However, the specific question of survival for patients with single HCC lesions <3 cm treated with resection versus RFA has not been addressed in an RCT. A recent multicenter retrospective report from Italy did examine this question.47 This report included 544 ChildPugh class A patients from 15 centers, and the authors observed similar complication rates (4.5% for resection, 2.0% for RFA; P = 0.101), recurrence rates (56% for resection, 57.1% for RFA; P = 0.765), and 4year survival rates (74.4% for resection, 66.2% for RFA; P = 0.353). A subgroup analysis for outcomes of smaller single lesions was not performed by Weis et al.,41 but examining the three individual RCT trials included in the systematic review, Huang et al.42 demonstrated that survival following resection remained favorable compared with RFA (P = 0.03) in patients with smaller tumors. This subgroup analysis was not performed in the other two RCTs.

    The evidence profile is included in Supporting Table 5, which uses the data from a recent systematic review performed by Wang et al.54 on adjuvant treatment for HCC after treatment. The systematic review by Wang et al. identified that adjuvant interferon therapy can improve both recurrencefree and overall survival in patients with virusassociated liver disease; however, the side effects of interferon are significant, limiting its use in clinical practice.55 RCTs of adjuvant chemotherapy, internal radiation, and heparanase inhibitor PI88 therapy were included in the systematic review and failed to improve recurrencefree or overall survival. The efficacy of several cytotoxic chemotherapy regimens has also been tested in RCTs and has never been shown to improve survival in advanced HCC,56 which limits their use in the adjuvant setting.

    There is a clear need for the development of new, effective chemotherapy agents for treatment of HCC in both the advanced setting and in the adjuvant setting. In addition, the impact of HCV eradication by directacting antiviral therapies on the future risk of HCC is uncertain and requires further study.57 Finally, the role of statin therapy in the adjuvant setting is unknown, though it may warrant investigation given the recent reports of an associated reduction in HCC risk for patients with HBV who are on statin therapy.58

    The decision to offer LRT consisting of either local ablation or transarterial treatment to patients with cirrhosis who have a single HCC nodule between 1 and 2 cm (T1) and are listed for liver transplantation is dependent in large part on an assessment of the patient's underlying liver function and ability to safely undergo LRT, the anticipated wait time, and organ allocation policy. In the United States, current liver allocation policy prioritizes patients with OPTN T2 stage HCC (either a single lesion between 25 cm, or 2 or 3 lesions each between 13 cm) but not for those with OPTN stage T1 (https://optn.transplant.hrsa.gov/governance/policies). Therefore, if a T1 lesion is treated with LRT, it may not reach stage T2, denying the patient increased priority for transplantation. LRT of a T1 HCC may be of significant benefit to patients who are well compensated and have no other indication for transplantation, as they may be able to avoid transplantation. Importantly, the patient will remain at risk for HCC recurrence and will require continued monitoring. This is the outcome assessed by the study by Huo et al.,59 which is discussed below.

    Additional longitudinal data from multicenter cohorts of patients with T1 HCC would be beneficial to gain a better understanding of its natural history. In addition, predictive markers of poor biologic behavior such as rapid progression would also better inform decisions about nontreatment of T1 HCC with regard to a risk/benefit analysis.

    Downstaging is defined as a reduction in tumor burden to predefined criteria, most commonly the Milan criteria, through the use of LRT. Although some may consider the Milan criteria to be too restrictive, the severe organ shortage and concerns about futility support limiting access to organs to patients within these criteria. Within the United States, patients who exceed these criteria who can be successfully downstaged to within the Milan criteria may become eligible for HCC MELD exception points after undergoing review by their respective regional review board. Reported success with downstaging is highly variable (24%90%).68 This variability is largely because of differences in tumor burden before LRT, type of LRT used, definition of successful downstaging, as well as differing methods to assess radiographic response (WHO, EASL, RECIST, mRECIST) and lack of a standardized time period at which response to therapy is gauged. Furthermore, some have proposed the incorporation of tumor markers in addition to tumor size and number to meet criteria for successful downstaging. This key question attempts to determine whether patients with HCC burden beyond Milan criteria should undergo liver transplantation after successful downstaging to within Milan criteria.

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