Tools for monitoring patients with hepatocellular carcinoma on the waiting list and after liver transplantation

For patients who are initially being listed for liver transplantation and for patients who are seeking to retain their active status on the wait list, the first step in the diagnostic consideration of hepatocellular carcinoma (HCC) is the accurate identification and staging of the tumors. Advances in imaging and biomarkers have improved our ability to diagnose HCC and in parallel have reduced the incidence of incidental HCC after liver transplantation. For the initial diagnosis, high sensitivity and high specificity are paramount considerations. The requirements change, however, when we are considering listing for transplantation: then, the prediction of the risk for posttransplant tumor recurrence and patient survival assume primacy. We must understand with confidence not only that the patient has a tumor but also that the tumor will affect the 5-year patient survival rate through the risk of tumor recurrence. Our first task in making the decision to list a patient with HCC for liver transplantation is to rule out factors representing absolute contraindications: extrahepatic disease and macrovascular tumor invasion. Beyond these variables, an understanding of the risk of posttransplant HCC recurrence is dominated by 2 major variables: tumor mass and tumor biology. Three major types of information can inform the decision to list a patient with HCC for liver transplantation. The first and usually dominant factors are the imaging characteristics, which include the size and number of the malignant lesions. The second type consists of biomarkers, which are most commonly abnormal proteins in the circulation that signify the presence of more dedifferentiated malignant cells with a higher propensity to invade and metastasize. The third type consists of factors from histological evaluations of tumor tissue obtained by biopsy or excision; these include factors such as the tumor grade, the presence of microvascular invasion, and protein, messenger RNA (mRNA), or DNA markers that have been correlated with more aggressive tumor behavior. Our team was tasked with generating recommendations for the best protocol for monitoring HCC patients on the wait list and for screening them for tumor recurrence after transplantation. The role of pretransplant histological factors in decision making is controversial even for listing. Does histological information add significantly to the prognostic power of the Milan criteria, the University of California San Francisco (UCSF) criteria, the rule of 7, or the total tumor volume (TTV)/alpha-fetoprotein (AFP) criteria as they are used at various centers? Do the risk of biopsy and a patient's aversion to biopsy trump the information gained? When we focus on the specific question being addressed here, however, we find no published evidence or guidelines from experts or center protocols that advocate the use of routine biopsy for evaluating possible alterations in the tumor characteristics of patients on the wait list. Therefore, we leave this question for discussions of the initial listing criteria. We focus our attention on the use of imaging modalities and tumor biomarkers for monitoring patients on the wait list and after transplantation. Wait-list screening addresses the question of what impact a change in imaging or biomarkers has on the risk of HCC recurrence and on patient survival. We must recognize that the impact of such changes may vary in the presence or absence of interventions such as ablation or angiographic chemotherapy or radiotherapy aimed at the control or elimination of tumors in the liver. Modifications in posttransplant immunosuppression or the use of adjuvant chemotherapy may also have an influence. Our task is also more than establishing the simple presence of an impact on the risk of posttransplant recurrence and survival; we must determine whether the risk is great enough to justify withholding or withdrawing liver transplantation as a suitable therapeutic modality from a patient with specific characteristics. In practice, these recommendations may require a flexibility that recognizes the dynamic balance between the limitations in access to liver transplantation in various countries and the transplant benefits accrued by both patients with HCC and patients without tumors. Changing the stringency of the listing or maintenance characteristics that are required for tumor patients will alter the posttransplant outcomes, change the number of patients who qualify for transplantation, and thus affect others on the waiting list. 3D, 3-dimensional; AFP, alpha-fetoprotein; CI, confidence interval; CT, computed tomography; DC-MRI, dual-contrast magnetic resonance imaging; DCP, des-gamma carboxyprothrombin; FAT SAT, fat saturation; [18F]-FDG, fludeoxyglucose F 18; HCC, hepatocellular carcinoma; HR, hazard ratio; MDCT, multidetector computed tomography; MRI, magnetic resonance imaging; mRNA, messenger RNA; PET, positron emission tomography; RFA, radio frequency ablation; S-MRI, superparamagnetic iron oxide–enhanced magnetic resonance imaging; TACE, transarterial chemoembolization; TTV, total tumor volume; UCSF, University of California San Francisco. The keywords used in the searches varied with each question. For electronic searches, we concentrated on MEDLINE, but we also reviewed the Cochrane database. Reference articles were ranked according to the University of Oxford Centre for Evidence-Based Medicine classification. For imaging strategies, we performed a search of the MEDLINE database for January 2002 to March 2010 with the medical subject headings hepatocellular carcinoma, primary liver cancer, liver cell carcinoma, and liver cancer as free text words in combination with liver transplantation, waiting list, and imaging. All titles and abstracts were reviewed, and appropriate studies were further assessed. We further reviewed the reference sections of all these publications to identify studies that may have been missed during the primary search. The main analysis concentrated on randomized controlled trials, controlled studies, and meta-analysis reviews. A second analysis concentrated on case-control analytical studies. Different concordant clinical studies and studies reporting the opinions of respected experts were also considered for inclusion. For biomarkers, the same medical subject headings were combined for the same period with liver transplantation, waiting list, waitlist progression, biomarkers, alpha-fetoprotein, and prothrombin produced by vitamin K absence or antagonism II. The same progressive search strategy was then employed. What imaging strategy is optimal for monitoring patients with HCC on the liver transplant waiting list? What biomarker monitoring is best for patients with HCC on the liver transplant waiting list? What is the most effective and efficient method for monitoring patients for recurrence after transplantation? The recommendations generated by our group may require modifications to mesh appropriately with those of the group on imaging criteria for transplant candidacy because wait-list monitoring is in practical terms a direct extension of the initial evaluation of the patient for transplant eligibility. We found that evidence-based studies of the best imaging approaches for patients before liver transplantation, on the waiting list, and after liver transplantation were extremely limited. We propose in general to accept the conclusions established by the experts on imaging at the National Conference on Liver Allocation in the United States.1 We agree with these experts that the current United Network for Organ Sharing criteria are inadequate, and we support the consensus position on the need for minimal hardware requirements and image acquisition protocols, which are outlined here in Tables 1 and 2. These experts also proposed a new classification system for local liver lesions. These precautions are justified by the unacceptable inaccuracy of staging reported by some centers.2 We support contrast-enhanced magnetic resonance imaging (MRI) and computed tomography (CT) as the gold-standard imaging examinations, as reported previously,3-7 with appropriate specifications of their minimal requirements. Three additional considerations merit consideration. First, an increase in quality can be obtained with dual-contrast magnetic resonance imaging (DC-MRI), which has been shown to be significantly better at detecting small HCCs than CT or superparamagnetic iron oxide–enhanced magnetic resonance imaging (S-MRI).8 DC-MRI consists of baseline magnetic resonance images, superparamagnetic iron oxide–enhanced images, and gadobenate dimeglumine–enhanced dynamic images. DC-MRI provides not only the T1 and T2 signal character of hepatic nodules and superparamagnetic iron oxide–enhanced T2 or vT2* signal information but also the dynamic enhancement character of the nodules. In Lee et al.'s study,8 the mean sensitivities for detecting small HCCs (<2 cm) were 37.3%, 39.1%, and 55.5% for CT, S-MRI, and DC-MRI, respectively (P < 0.001). Second, outcomes equivalent to those obtained with contrast-enhanced CT and MRI have been reported by several centers with contrast-enhanced ultrasound, which we believe fulfils some of the requirements for a third diagnostic option when the appropriate hardware and expertise exist. The lack of protocolized/regimented image capture with contrast-enhanced ultrasound remains its main drawback and prevents a recommendation for equivalence with CT and MRI. Routine sonography (ie, not contrast-enhanced), however, is not recommended as the sole imaging modality for lesion detection before transplantation. Despite this, many institutions worldwide still use sonography as the study of choice for surveillance because of its relatively low cost, its lack of ionizing radiation, and its availability.9 Although their research was not performed in a transplant setting, Thompson Coon et al.10 reported that a combination of AFP testing and an ultrasound examination every 6 months was an effective surveillance strategy. The model estimated that in comparison with no surveillance, this strategy may triple the number of people with operable tumors at diagnosis and almost halve the number of people who die from HCC. Third, consideration is also required for a potentially important role for positron emission tomography (PET).11-14 The preoperative AFP level and vascular invasion in poorly differentiated HCCs were found to be significantly associated with positive fludeoxyglucose F 18 ([18F]-FDG) PET findings,11, 13, 14 and its uptake during PET was specifically predictive of microvascular invasion and tumor recurrence after liver transplantation for HCC.13 Furthermore, [11C]-choline PET requires further study as a potential tracer that could complement [18F]-FDG because it is better at detecting moderately differentiated HCC.12 Despite the advances in PET/CT and its clinical applications, [18F]-FDG PET/CT was recently reported to be unsuitable as a screening tool for recurrence after liver transplantation because of its limitations for small lesions, intrahepatic lesions, and brain lesions. Nevertheless, [18F]-FDG PET/CT could provide additional information for the diagnosis of suspected recurrence beyond that provided by conventional modalities, and it could contribute to the clinical management of HCC recurrence after liver transplantation, especially in patients with extrahepatic recurrence.15 We found no publications addressing the specific points of timing or optimal imaging modalities for screening liver transplant candidates on the wait list. Our recommendations are based on the evidence for the accuracy of imaging modalities in the diagnosis and staging of HCC as well as our understanding of the biology of HCC (eg, tumor doubling times) and program practices in the area of tumor surveillance for liver transplant patients on the wait list. Wait-list monitoring should be performed every 3 months with contrast-enhanced CT or MRI. The quality of the imaging studies during the evaluation for listing and the radiation exposure for each patient should be given due consideration during the selection of the follow-up imaging modality DC-MRI and PET/CT require further study for the evaluation and monitoring of patients with HCC on the liver transplant wait list. who have beyond the criteria for listing for liver transplantation should be on and consideration should be given to therapeutic no transarterial radio frequency ablation or transarterial is to be appropriate or the tumors be controlled by the the patients should be from the wait list for monitoring HCC patients on the liver transplant waiting list. hardware should should the frequency of monitoring to every to 6 in with the disease is for 3 or 6 months in with the The liver transplant listing criteria for patients with HCC have been the subject of the of et in and especially clinical have on the impact of in the criteria, because the initial by et not find the AFP level to be associated with for the of candidacy from the Milan criteria to guidelines such as the or the rule of by of the predictive has to focus on The of microvascular invasion, the tumor grade, and the presence of tumors to HCC recurrence and survival is from several and this the consideration of aggressive tumor or biology to information the size and this information is obtained from the study of and be used for listing a for such biopsy from a triple the risk of tumor and with patient biomarkers that are by relatively well with microvascular invasion, the tumor grade, and and they should provide a method for considering the of HCC as well as information and thus for the predictive In et found AFP and to be and of posttransplant patient survival; this is a for both and factors to be when the patient criteria for listing for liver transplantation are being AFP is a produced in that is during and but it can in such as is produced by of and its in the diagnosis of liver tumors is by this lack of AFP has major it is relatively and AFP has been in a of for its ability to posttransplant predictive power has been reported at from to Despite an of AFP has not been as a selection et reviewed patients in the of database who transplantation for HCC between 2002 and and they reported that only the confidence < and the AFP level < patient survival. The combination of a < and an AFP level < posttransplant survival < 0.001). not these criteria a survival rate than at 3 The that a patient selection the and the AFP level was the most effective of all the criteria for patient survival. criteria that they the tumor the number of the Milan criteria, and the criteria. The criteria have been by the University of and the University of for patients for liver transplantation and for monitoring patients on the wait list. published information on the use of AFP for patients on the wait list is articles are from and have reported the of AFP changes as a dominant of HCC recurrence after transplantation, and they have proposed and as optimal for the of these A analysis of patients who transplantation for HCC in a positive between the preoperative AFP and vascular invasion (P the total tumor in the (P the of the Liver (P and survival (P In a a preoperative AFP and a total tumor to a risk were as of tumor recurrence. a the sensitivity was the specificity was the positive predictive was and the predictive was for the ability to recurrence. The survival rate was for patients with a preoperative AFP and for those with a < (P < 0.001). The in the AFP before transplantation with recurrence 18 without was not (P because of a lack of power in the All patients the Milan criteria in this all patients beyond the Milan criteria a of 3 patient who not transplantation 2 months a et reviewed database for with AFP at listing. an aggressive tumor control that routine initial for all A and patients at listing and follow-up or for those patients or in their AFP were from the wait list only because of the of extrahepatic or macrovascular invasion by may the low in their a to even a in the AFP level important in the of aggressive the AFP to after or in outcomes to those for patients initial were in the low of AFP was a of outcomes in this the 5-year survival were with AFP than and with AFP than The lack of predictive power in survival of to at may be associated with the number of patients in this The study was in an for its positive and predictive and and in a it an area the of only The of an increase of may also mean a the baseline is or and the use of the may more Although the were even the group with this low rate of a 5-year survival rate of the of on the waiting list and the in tumor to qualify patients for liver transplantation who are the current guidelines at such as changes in AFP and the of characteristics in patients on the waiting list may increase in We recently published an analysis of patients in the of in which we the of for the transplantation of patients with HCC with AFP We the and impact of absolute of AFP and changes in patients on the waiting list with to and survival and we whether AFP could be a pretransplant A local HCC RFA, or before transplantation was used in of the patients on the waiting list. with AFP at the of listing were to before transplantation a better survival rate than patients AFP were not reduced to at 3 and their survival rate was to the rate for patients with AFP AFP were to and patients with also of from the list in both and posttransplant survival at 3 AFP was associated with survival the AFP level was it was the pretransplant AFP level survival in a analysis the AFP level at listing or AFP The for the pretransplant AFP level was the posttransplant survival was < 0.001). HCC patients with high AFP is and to and posttransplant survival to those of patients with AFP Wait-list beyond the initial listing criteria for or (AFP) that a patient is no as a for liver transplantation. may be most appropriate to the patient's candidacy interventions are to tumor control this to the from consideration for transplantation. Therefore, a high initial AFP level or a AFP level the patient is on the wait list should not be as an to the from consideration for transplantation but should be considered an for a need for an a more effective to control the tumors. survival outcomes according to an analysis can be as as AFP than can be and at the of transplantation. In to these outcomes with AFP in patients on the waiting list, the impact of the of the tumor size and number on the posttransplant recurrence risk has also been et and et reported survival with a protocol that required tumor or a period after the proposed the consideration of transplantation for most patients and for all patients with tumors after for they that the potential for tumor after an the biology of the tumor the risk of recurrence after transplantation. AFP can be 3 and according to the for to the is the major of AFP in the of HCC patients and can be in of patients with small HCCs A high of is to and malignant characteristics of HCC, and HCC patients who are positive for have liver tumor and tumor is also significantly in the presence of is significantly to invasion and patient outcomes and to be a prognostic for as prothrombin produced by vitamin K absence or antagonism is an prothrombin from an of the prothrombin in HCC cell is in to of all HCC patients but in only to of HCC prothrombin not well with AFP AFP and not in patients with HCC, it to determine the of both markers to the accuracy of an HCC A study of has been reported in the of liver transplantation for HCC. et found that in 6 of patients with posttransplant the level was beyond this the sensitivity was and the specificity was et found a combination of AFP AFP, and to be to of HCC in the outcomes of patients with HCC. such study has been performed for monitoring patients for HCC recurrence after liver transplantation. AFP factors have been associated with HCC invasion and have potential prognostic markers for the malignant cell include changes in cell markers cell and the and cell and and their and and factors to and markers in invasion and include cell and and in have also been considered as biomarkers for the malignant of HCC and have been to and For the first group of are in a transplant and are for wait-list For the second only in a diagnostic or for a transplant All the limitations of a for analysis by the great of liver transplant at AFP should be every 3 months for all patients on the liver transplant wait list increase in the AFP level for patients on the wait list the consideration of an to tumor control before transplantation in patients with HCC or a further diagnostic imaging evaluation for patients without a diagnosis of HCC AFP level beyond should be on the of for the AFP level to this the AFP level at a rate for a patient on the wait list, the patient on the outcomes of interventions are should be requires further evaluation in AFP be controlled interventions or for interventions are not considered appropriate should be from the wait list and AFP merit further study in the of HCC after transplantation and in the of monitoring patients on the wait list. The is with to studies addressing the question of screening protocols for monitoring patients for HCC recurrence after liver transplantation. The sole specifically addressing this is a of from The the of published information on this and provided an by for the that only of patients liver transplantation for HCC to have a and at of such the first 2 after transplantation. imaging studies and monitoring for tumor biomarkers are performed by most for at 2 to 3 after liver transplantation for HCC. In to published a from at the 2010 reported on the ability to provide potentially to more than of patients with HCC after transplantation a program of imaging and AFP In a recently published study an of of the sensitivity and specificity of AFP as a of recurrence were and with the sensitivity and specificity were and are on the diagnostic ability of the of biomarkers for HCC recurrence. The high of imaging studies appropriate for the diagnosis of HCC recurrence the liver CT and or should their to for the first 3 to after transplantation in patients who have of risk for recurrence beyond the Milan criteria, AFP level before transplantation or markers such as microvascular invasion, a high tumor grade, and according to or for are by abnormal biomarker studies or for clinical ultrasound is accurate but is also and may add when it is at especially in AFP monitoring is and may be appropriate at more are to the use of of the question of whether of patients can be for the risk of HCC recurrence is low that routine monitoring after liver transplantation is not The risk of recurrence in patients the Milan criteria has been reported to be to The of additional criteria such as pretransplant AFP or a risk analysis based on should be of this In the University of 2 of of patients who were the Milan criteria, AFP and more than 6 months after liver transplantation HCC only 2 of patients who were the Milan criteria and AFP < recurrence. The absence of risk factors such as microvascular invasion according to almost further the the risk of recurrence being than and with being possible for no more than of these the and benefits of imaging studies for monitoring these patients their of the and the high of and risk factors in HCC patients thus the additional risk of tumor posttransplant monitoring for AFP who have an risk of HCC recurrence by staging beyond the Milan criteria at listing or at by AFP at or by criteria such as microvascular invasion, a high tumor grade, or by should contrast-enhanced CT or MRI every 6 months for 3 to with no of risk the Milan criteria, AFP < before transplantation, and no criteria according to not merit imaging for follow-up AFP should be every 3 months for 2 and every 6 months in all patients with HCC that was before transplantation or during the examination in AFP beyond imaging CT or and imaging for the diagnosis of potentially interventions or or ablation or should be considered for posttransplant patients with HCC recurrence the liver and the are monitoring of HCC

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