Is the treatment of hepatocellular carcinoma on the waiting list necessary?

Among therapeutic procedures, transplantation is notable because the demand exceeds availability and because the therapy cannot be given immediately. One of the consequences of this shortage is that access to transplantation is usually restricted by rules that take into account both distributive justice and utility. One of the consequences of waiting for transplantation is that during this time, the disease may change, and effects on the outcome of transplantation are possible. Orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) well illustrates (1) the acceptance of restrictive access and the consensus to select only patients with early-stage tumors with a low risk of recurrence after transplantation [the most common selection criteria are the Milan criteria (MC), which are incorporated into the tumor-node-metastasis staging system as follows: T1, 1 nodule < 2 cm in diameter, and T2, 3 nodules up to 3 cm in diameter or 1 nodule up to 5 cm with no vascular invasion or extrahepatic spread (VI/ES)] and (2) the importance of the waiting time as a period in which the disease can evolve and strategies can be implemented to influence its course. Furthermore, since the publication of the seminal article of the Barcelona Clinic Liver Cancer (BCLC) study group,1 which compared the intention-to-treat (ITT) outcomes of resection and transplantation for HCC, the concept of dropout on the waiting list has been identified as crucial, and it has become the equivalent of the risk of pretransplant mortality addressed by the Model for End-Stage Liver Disease (MELD) priority system for non-HCC patients. To summarize our knowledge of the history of HCC in patients on the waiting list. To summarize our knowledge of different management strategies that can be implemented. To submit some recommendations for the standard of care and for the construction of studies that could improve our understanding in the short term. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CRT, conformal radiotherapy; HCC, hepatocellular carcinoma; ITT, intention to treat; LDLT, living donor liver transplantation; LRT, locoregional treatment; MC, Milan criteria; MELD, Model for End-Stage Liver Disease; NA, not available; OLT, orthotopic liver transplantation; OPTN, Organ Procurement and Transplantation Network; PEI, percutaneous ethanol injection; RFTA, radiofrequency thermal ablation; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; UCSF, University of California San Francisco; VI/ES, vascular invasion or extrahepatic spread. Some terms should be used consistently in discussions of the management of HCC in patients on the waiting list. Neoadjuvant treatments are given before a procedure to improve its outcome; they generally accomplish this by making more patients eligible for the procedure or by improving the procedure's results. In the context of OLT for HCC, neoadjuvant treatments [typically locoregional treatments (LRTs) such as transarterial chemoembolization (TACE) and radiofrequency thermal ablation (RFTA)] can be used for bridging or down-staging. We reserve the term bridging for strategies that are implemented in patients who already qualify for transplantation according to the accepted selection criteria so that they can wait until a graft is available. A bridging strategy can be effective because (1) it allows candidates to wait for a longer time or more candidates to wait for the same time (or both) or (2) it improves the results of transplantation by excluding patients whose disease will recur or by stopping the progression of a tumor before extrahepatic spread has occurred. Although the word down-staging refers to the reduction of the clinical stage of a disease from any initial stage (eg, from T2 to T1), down-staging in the context of transplantation for HCC is used for strategies allowing the transplantation of patients who at first do not qualify for OLT because their tumors are outside the accepted criteria (T3 or higher). Down-staging strategies may use the same neoadjuvant treatments that are used in bridging strategies, but the confusion between the 2 terms has produced a literature that is difficult to interpret. In the following paragraphs, we do not discuss down-staging further because this is the subject of another review. Instead, we focus on bridging for T1 and T2 patients. The term dropout refers to withdrawal from the transplant waiting list due to death (from an adverse event during the waiting time), tumor progression beyond what is accepted in the transplant program, or other reasons (eg, the resumption of drinking or “too sick to transplant”). When different studies and wait-list policies are reported, the causes of dropout should be specified, but this is rarely the case in the literature. Furthermore, although there are some indisputable contraindications to transplantation such as distant metastases and vascular invasion, other contraindications, although they are reasonable, are the result of regional policies and need to be validated. For instance, disease progression beyond stage T2 in listed patients appears to be a contraindication in the United States and requires a review by a regional board for exceptions, but this is not true in many European and Asian centers. Also, we should distinguish dropout due to distant metastases appearing a short time after listing (in some ways a desirable finding that allows the prevention of recurrence) from dropout due to less stringent causes (eg, size progression) that may be prevented by an effective bridging strategy. Although this kind of distinction is now clear among experts, it is not apparent in the literature. A further source of bias in the comparison of dropout rates is the timing of the surveillance protocol: the progression to a contraindication may not be detected because imaging procedures are scheduled too far apart. Access to transplantation (ie, no dropout from the waiting list) is not a goal per se; each management strategy also has to be evaluated in terms of the outcome of transplantation, and both endpoints should be merged as ITT results. In the literature, information on the prevalence of recurrence after transplantation and the duration of follow-up necessary to conclude that a bridging strategy does not transform dropout patients into patients with disease recurrence is either omitted or insufficient. For patients to remain good candidates until a graft is available. For the transplant program and society to exclude poor candidates even though on entry they fulfilled restrictive selection criteria. To improve the results after transplantation. To be compatible with a treatment other than transplantation in the case of dropout. To have an optimal cost and complication/effectiveness ratio. It is clear that the relevance of the different aims changes with the waiting time: for minimal waiting times, only the points of excluding poor candidates and improving posttransplant results apply, whereas for long waiting times, it is important for patients to remain on the waiting list (without dropout patients being transformed into patients with disease recurrence) and for the strategy to be compatible with fallback options in the case of dropout. The following discussion assumes median waiting times of 3 to 18 months (as is the case in several European and American programs). On the basis of the previously discussed definitions, these points can be addressed with a review of the literature; the main studies1-17 are summarized in Table 1. Ideally, studies should include a large number of cases, clearly separate treated and untreated patients, and specify details (treatment, surveillance, dropout, recurrence, and causes of death). Although no study satisfies all these requirements, some relevant information can be extracted by the examination of each publication and particularly its strong points. The history of HCC in patients on the waiting list can be studied with series using a consistent policy of surveillance only. The first study introducing the subject of dropout is the original BCLC publication.1 Among the 50 patients who waited for a mean of 2 months, there were no dropouts, but 8 of the 37 patients who waited for a mean of 5.3 months dropped out: 2 for hepatological reasons and 6 for tumor progression (the study did not specify whether the patients were outside the MC or had absolute contraindications such as vascular invasion or metastases). According to the number of dropouts, the total dropout rate was 22%, and this allows the extrapolation of a total monthly dropout rate of 4% and a monthly tumor-related dropout rate of 3%. The factors associated with dropout in this study were increased alpha-fetoprotein (AFP) concentrations and the time on the waiting list. The recurrence rate after OLT was very low (there were 3 patients, but the authors did not specify whether these patients belonged to the total population of 87 patients or to the group of 37 patients with the longer waiting time), and the follow-up was reasonable (median = 23 months, range = 3-26 months); the study did not specify the criteria for tumor dropout. A smaller retrospective study reported 23 untreated patients with a total dropout rate of 3% and a mean waiting time of 10.5 ± 6.5 months (range = 1 day to 57.4 months).13 In this study, however, the mean tumor size for the untreated patients was small (2.4 ± 1.8 cm), and because the study was designed for posttransplant outcomes, the dropout criteria were not specified. A few studies have addressed the issue of HCC progression on the waiting list in patients treated consistently with adjuvant therapies. The dropout rates for T2 patients managed with LRT can be extracted from the reliable cohort studies detailed in Table 1,3, 8, 9, 12 and they range from 0% to 10% at 12 months (the population sizes and the waiting times are listed in the table). The factors associated with tumor progression were investigated in single-center series; a consistent surveillance policy can be assumed, although the criteria for dropout were not specified. One study from Taiwan focused on 94 T1 patients and 296 T2 patients.18 The rate of disease progression [which was defined as exceeding a previous stage (T1 or T2) on imaging] at 3 months was 2.1% for T1 patients and 3.0% for T2 patients. At 6 months, the progression rate was 5.3% for T1 patients and 6.8% for T2 patients. The factors positively associated with progression were the AFP level and the tumor size, and RFTA was associated with the absence of tumor progression. Unfortunately, the actual rate of dropout from the waiting list is not a BCLC that the HCC population could be into 2 patients with and disease and patients with disease at risk of The factors associated with progression were to an AFP level and tumor progression in the previous 6 In a study from the University of California San with a more of treated and untreated patients, the dropout rate for HCC patients the MC was 0% at 3 months, at 6 months, at 12 months, and at 18 The total dropout rate was with a median waiting time of The initial tumor size and were the only factors of dropout. are for of the dropout rates of treated and untreated patients. In the of patients of had adjuvant or ablation was associated with a risk of dropout = but the population was with to the disease and the criteria for treatment were from A study of patients identified a in tumor-related dropout that apparent only after studies a treatment on the waiting time and the of The first study (from the BCLC compared percutaneous ethanol and no treatment in a in which the dropout rate treatment was 10% at 6 months, at 12 months, at 18 months, and at 2 In that study, resection increased the transplantation rate and in of to months with an cost per for waiting times than 1 however, it was not per for with waiting times or dropout PEI, which was used as an of a and effective increased by to months with a cost of per in all cases, and it for all waiting The study (from no treatment in T2 patients and a rate of and a tumor progression rate of per The treatment had a at the wait-list time of and months < When the wait-list times were less than months, the dropout rates were not different = When the wait-list times months, the wait-list dropout rates were = was used to a of as an adjuvant treatment is in some studies and not in with either too short or too long waiting the that to these studies to the of most and could be used as a reasonable basis for further The dropout rate for T2 patients to be the same for treated patients of the and untreated patients with ablation and with no ablation 1 after and it is than even we the short median wait-list for tumor progression can be that the dropout The of this to be by a of the causes of dropout, the results of transplantation, and the use of neoadjuvant strategies are from the For T2 patients, the dropout rate on the AFP level at for AFP < and for AFP after and less so on the and the tumor ITT and graft rates are for treated patients untreated patients. finding has to be with because the of treated and untreated patients is not the study by allows the of To the of our no program has a policy of surveillance even though there are reasons for from there is an level of for the of the adjuvant A examination of the BCLC study, however, the low recurrence rate 2 of 87 patients of it is that a poor ITT may be the selection strategy for HCC patients the MC the is to graft use in the wait-list population of HCC and non-HCC patients. may be by a study in which a to waiting time can be For longer waiting times, the for tumor progression after 6 months should a at for T2 patients with tumors to the because of the in ITT results the ITT results of OLT after 12 In surveillance treatment may be the optimal bridging strategy for waiting times than 6 months, and this should be in a The of transplantation for HCC patients before tumors have the time to to dropout criteria is the to points to HCC patients on the basis of the dropout rate to this only to the of HCC and non-HCC of patients with HCC be is not in any program to the of our and the of whether a short waiting time is associated with more recurrence after transplantation. patients with HCC may be a because time on the waiting list can be a period for the tumor and for excluding patients with that will to the contraindication stage they are to this can be from the literature. are results from University the recurrence rate for patients either by United for Organ rules or by the use of living donor liver transplantation was than the rate for patients from a previous period with longer waiting times (T1 and T2, and A was in a study from the Liver Transplantation which compared patients donor to The waiting time was for the group but were more A study from which results for in patients the MC, cannot be used to the absence of more with the waiting times associated with because it is for patients to be treated with TACE, PEI, or resection before A study a for patients waiting for a short and so does the study from Barcelona we the first group of 50 patients who waited for of these however, the time from the of HCC to transplantation, and only the time from listing to transplantation is it is that some time before the patients were The wait-list from the United for Organ do not to the of whether is associated with a recurrence rate because the information is to the waiting list and does not take into The poor ITT results that have been reported, however, a On the a discussion the reasons for excluding patients with an tumor by treatment and the of time and wait can be in a review article by the the results of patients, the authors or RFTA and a waiting period of 6 months for patients with tumors exceeding 3 cm whose reserve is to In it appears that a short waiting time does not the recurrence rate in patients with T1 or T2 tumors at the of the MC, but it that tumors to the may recur more than by the of may be with AFP as a of vascular it that even it were the of HCC patients for a waiting time than 3 to 6 months is The for before transplantation is from an extrapolation of studies the of this treatment in patients with HCC who are not candidates for transplantation. before 2 a for a study less tumor progression and these are relevant for a wait-list and the procedure was as the standard of care in many The of several in which is standard has that does not transplantation more this was by is in of treated nodules as summarized in a The issue of for the dropout rate and outcomes is more cohort studies from and have that allows long waiting times = (range = in the median = (range = in the with low total dropout rates and were in both studies and were not than what be for T2 patients A study compared patients with and The rates 5 after OLT were although this was not because of a there were in the group but more patients Also, the waiting times were short and the median number of procedures was only 1 = this prevented the of any for A retrospective study investigated the effects of on the outcomes of was no in at 5 with with no but were less after The mean waiting time was short and the study did not the dropout other studies with patients to a of as a bridging strategy in terms of outcomes after but were in of the studies Furthermore, the waiting times were so it is that a could not A was reported in a study from which an increased rate of have not been by other and need to be but the of of the vascular reasonable to In according to the reported is not in a population to the MC, may patients to wait longer than be and is not associated with more may in be less the of is it should be until the on tumor is RFTA was not at first an treatment in pretransplant patients because of the risk of and there were of RFTA in which was with the and a cohort study have that and recurrence are patients and contraindications are (ie, tumors and nodule studies have that the can be used in pretransplant patients and that the percutaneous is as as the and less In the results for RFTA to be to for and RFTA appears to be associated with less tumor The prevalence of can be in In the study by a tumor was in of the and this to for tumors 3 In the of finding a tumor increased with the waiting time and after 12 In another study, only of the a In RFTA appears to be and can be used as a bridging strategy this is to dropout rates and its effects on posttransplant results need to be in a The of resection before transplantation and the use of resection and transplantation as a strategy have been studied and discussed as summarized in a The to on the liver and the size and of the The with resection in patients with is also very and the availability of liver resection to improve the outcomes of the procedure and transplantation. A of the is an important The study that follow-up allows transplantation in up to of patients with Although resection appears to be before transplantation (in terms of results and and to have a in the waiting time is longer than 1 resection is very rarely used at the as a bridging strategy. The use of resection as a selection for patients with adverse tumor for transplantation can be (ie, before recurrence but after is but and requires further in patients cannot transplantation after resection because the tumor has been this the of the should be because this is not the case with RFTA even the tumor has been any In in our resection is as a bridging strategy (ie, from the issue of and policies such as the of priority after tumor should be with to 10% of bridging LRT procedures in the but on its are In a study that reported the between and in patients with HCC who with before transplantation, all some of and 23 of A study transarterial and in patients and patients and patients were at stage T2 were not Although there was no for TARE, the time to disease progression and the AFP were more with TARE, and this that this treatment could be a before In are too to the use of before OLT, but this may be an to use and should be the of further is as a and therapeutic for HCC patients who are for a treatment (ie, resection or only 2 the use of as a bridging for patients on the waiting list. A retrospective series from reported the use of in patients with HCC who were listed for OLT and for previous had or were not because of poor liver or tumors were beyond the the treatment was well and there were no or tumor was for all treated patients OLT with no to of the tumor and with of the untreated transplant patients treated with were at the time of the publication of the In may be a and bridging therapy for patients with HCC who are on the waiting list for studies are to the of and other therapeutic options in this with has been to be effective in the treatment of Although there is a for its use in patients waiting for transplantation, as by a its because of and has to be by Furthermore, the study a monthly dropout rate of which is than the rate in most The of the waiting time was by the study and appears relevant to all bridging It is apparent from this review that further are in of a we need that bridging strategies are because they improve the ITT outcomes of transplantation by the dropout rate and by posttransplant in patients waiting 3 to 12 months is the case for the of patients in The consensus of in the United States bridging and this is by Although this reasonable in patients waiting longer than 6 months with AFP and tumors cm), the that treatment does not transform dropout patients into patients with recurrence from only 5 cohort 12 2 of these studies had follow-up 12 and we are further we cannot a strong Furthermore, on are and are on a or whose cannot be Ideally, with a should be The first to such is that they be because of (1) the of LRT in terms of disease progression before transplantation and (2) the in treatments of a in the surveillance has to be LRT do that bridging with LRT does not result in more and outcomes after transplantation is not (the studies and particularly may have a strong selection bias in the of patients to treatment and and the short in treatments in dropout patients in the surveillance may not be Furthermore, the of dropout is for the the of recurrence is more important for with the shortage of do not the of transplantation (the graft is used for but recurrence The minimal for such include of (eg, 3 and dropout criteria (eg, progression beyond a tumor size and a AFP level as well as vascular invasion and distant as well as follow-up after transplantation for to become (eg, 3 with by The first could include T1 patients in these patients points. The could include T2 patients in the United the of patients transplantation 3 to 12 The of whether an in comparison with surveillance only and in our the construction of such be strategies using LRT with the of tumor are not and may be for T2 patients waiting longer than 6 months because of the low dropout rates and good posttransplant outcomes in a few cohort studies and in a of large level is more relevant for patients with tumors to the or a AFP level (or who are more to contraindications they are is no that bridging strategies should be used for T1 patients, and the has to be with the of and the waiting studies that RFTA may have a in terms of ablation level strategies and RFTA or using and may be and need to be is a bridging treatment before transplantation, and its as a selection due to the study of the requires further level as a bridging treatment is by the that a who has resection no longer for transplantation, and this to be that LRT is because it improves ITT by the dropout rate and the recurrence rate and information on can be only from studies are desirable and should include a the waiting time is less than 6