Is the treatment of hepatocellular carcinoma on the waiting list necessary?†‡
This review is an improved version of a previous work that served as a syllabus for the 2010 transplant course of the American Association for the Study of Liver Diseases. That work was written with Christian Toso and Gilles Mentha (the Geneva group), whose intellectual contributions are gratefully acknowledged.
Potential conflict of interest: Nothing to report.
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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.
The aims of this review are as follows:
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.
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.
AIMS OF MANAGEMENT STRATEGIES
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.
On the basis of the previously discussed definitions, we can define the goals of the ideal bridging strategy:
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.
Table 1. Main Series Providing Data on the Management of Patients Wait-Listed for Liver Transplantation for HCC
|Llovet et al.1||Prospective||T1/T2||50 (50)||62‡||None||VI/ES||0||0||0||?|| || ||No adjuvant treatment|
|T1/T2||37 (29)||162‡||None||VI/ES||6||2||22%||3?||23 (3-26)§||54 (2 years)||Predictors of dropout: AFP and waiting time|
|Herrero et al.2||Retrospective|| ||49 (47)||117‡||TACE (23), PEI (5), RFTA (3)||Progression||?||2||NA||4%||33∥||NA|| |
|Maddala et al.3||Retrospective||T1 (2), T2 (45), T3 (7)||54 (45)||211 (28-1099)§||TACE||Progression||6||2||15%||5||?||—/—/61|| |
|Hayashi et al.4||Retrospective||T2||20 (12)||343 ± 293¶||TACE||Progression||4||2||30%|| ||35‡||—/—/61||No recurrence in transplant patients|
|Yao et al.5||Retrospective||T2||70 (38)||OLT: 186∥||TACE (11), PEI (7), RFTA (11)||UCSF||18||2||29%||3||18∥||87/57/—||1 death after TACE|
|Dropout: 323∥|| |
|Yamashiki et al.6||Retrospective||T1 (9), T2 (73), T3 (11)||93||104 (1-897)§||None, microwave (22), TACE (8)||Stage 4||14||3 + 5||24%|| ||NA||66 (survival)||Dropout due to tumor: 5% with AFP < 100 ng/mL and 32% with AFP > 100 ng/mL|
|Fisher et al.7||Retrospective||T0/T1 (1/9), T2 (17), T3 (6)||33 (28)||278 ± 451¶||Multimodal||Stage 4||3||2||15%|| ||32‡||79 (survival)||Predictors of dropout: AFP > 400 ng/mL and T3|
|Mazzaferro et al.8||Prospective||T1/T2 (40)||50 (50)||289‡||Percutaneous RFTA (29), laparoscopic RFTA (21)||VI/ES||0||0||0||2||22‡ (after transplantation)||95/83/NA||Recurrence in partial responders > 5 cm|
|Lu et al.9||Prospective||T1/T2 (42)||52||387 (9-1326)#||RFTA||VI/ES||3||3||12%||0||9∥|| || |
|Martin et al.10||Prospective|| ||47||253 (29-794)#||RFTA||VI/ES||5||5||21%||1||16∥|| ||Short follow-up after OLT|
|Otto et al.11||Retrospective||T1/T2||34 (?)||250 (22-756)§||TACE|| ||6||1||?||Total 7||29∥|| ||Recurrence associated with progression|
|M-||62 (34)||268 (129-818)§||5||1||?||Total 7||29∥|| |
|Millonig et al.12||Prospective||T1/T2||68 (41)||274 (36-1037)§||TACE||Progression||2||0||2||5 (8%)|| || || |
|UCSF||33|| || ||Progression|| || || || || || || |
|Down-staging (>50% decrease in maximum tumor diameter) and no VI/ES||15 (10)||254∥|| ||Progression||3||1||4|| ||37.2‡||93/78/31||Down-staging in 42% and 3 non–cancer- related deaths|
|Porrett et al.13||Retrospective||T1/T2||31||320‡||None||Progression beyond T2?|| || || ||4|| ||88 (36 months)||Biased selection (treated/ not treated)|
|33||201‡||TACE, RFTA, or combination; TARE (1)||7||84 (36 months)|| |
|Decaens et al.14||CC||T1/T2||TACE: 100||128‡||TACE||?||?||?||?||13||49.7 ±35.8¶||59.3||Nontumor deaths more frequent with TACE (15 versus 7)|
|No TACE: 100||131‡||23||53.7 ±41.1¶||59.4|| |
|Pelletier et al.15||OPTN registry||T1/T2 (73%)||4482 (2898)||64∥||None (74%), RFTA or TACE (26%)||?||500||592||24%||—||29∥||81/65/51||294 patients (7%) removed from the list for unspecified causes|
|Freeman et al.16||OPTN registry||T2||2470||54∥||No treatment|| || || || || || ||—/75/—|| |
|1732||54∥||LRT|| || || || || || ||—/79/—|| |
|Washburn et al.17||OPTN registry||T2||2408||54?||No treatment||?|| || ||10% at 6 months, 11.8% at 12 months||—||—||—||Study period: 2005-2008|
|Median waiting time extrapolated from Freeman et al.16|
|T2||1783||54?||TACE (62%) RFTA (26.8%), combination (10.6%)||?|| ||8% at 6 months, 11.2% at 12 months||—||—||—|| |
NATURAL HISTORY OF HCC IN PATIENTS ON THE WAITING LIST AND DROPOUT RATES IN THE ABSENCE OF TREATMENT
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.
NEOADJUVANT THERAPY AND DROPOUT RATES ON THE WAITING LIST
Series With Neoadjuvant Treatments
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 reported.
Similarly, a BCLC study19 (179 patients) suggested that the HCC population could be divided into 2 groups: patients with limited and stable disease and patients with (rapidly) progressive disease at risk of dropping out. The factors associated with progression were resistance to treatment, an AFP level > 200 ng/mL, and tumor progression in the previous 6 months.
In a study from the University of California San Francisco (UCSF) with a more heterogeneous mix of treated and untreated patients, the dropout rate for HCC patients within the MC was 0% at 3 months, 11.0% at 6 months, 57.4% at 12 months, and 68.7% at 18 months.5 The total dropout rate was 22% with a median waiting time of 330 days. The initial tumor size and multifocality were the only factors predictive of dropout.
Studies Comparing the Dropout Rates of Treated and Untreated Patients
Limited data are available for direct comparisons of the dropout rates of treated and untreated patients. In the UCSF analysis of 70 patients (29 of whom had adjuvant treatments), preoperative TACE or ablation was associated with a significantly lower risk of dropout (hazard ratio = 0.40), but the population was heterogeneous with respect to the disease stage, and the criteria for treatment were biased from referral patterns.5 A preliminary Toronto study of 74 patients identified a difference in tumor-related dropout that became apparent only after 300 days.20
Two decision analysis studies found a treatment advantage based on the waiting time and the type of treatment.21, 22 The first study (from the BCLC group)21 compared resection, percutaneous ethanol injection (PEI), and no treatment in a scenario in which the dropout rate without treatment was 10% at 6 months, 20% at 12 months, 35% at 18 months, and 50% at 2 years. In that study, surgical resection increased the transplantation rate (>10%) and provided gains in life expectancy of 4.8 to 6.1 months with an acceptable cost ($40,000 per life year gained) for waiting times greater than 1 year; however, it was not cost-effective ($74,000 per life year gained) for scenarios with shorter waiting times or high dropout rates. PEI, which was used as an example of a cheap and relatively effective treatment, increased life expectancy by 5.2 to 6.7 months with a marginal cost of approximately $20,000 per life year gained in all cases, and it remained cost-effective for all waiting times. The second study (from Paul Brousse Hospital)22 analyzed TACE versus no treatment in T2 patients and assumed a TACE response rate of 30% and a tumor progression rate of 7% per month. The TACE treatment had a statistical benefit at the wait-list time breakpoints of 4 and 9 months (P < 0.05). When the wait-list times were less than 4 months, the dropout rates were not statistically different (20% versus 34%, P = 0.08). When the wait-list times exceeded 9 months, the wait-list dropout rates were re-equilibrated (33% versus 46%, P = 0.06). This benefit pattern was convincingly used to explain why a benefit of TACE as an adjuvant treatment is found in some studies and not in others with either too short or too long waiting times. Despite the limitations that apply to decision analyses, these studies appear to fit the experience of most centers and could be used as a reasonable basis for further investigations.
Dropout Rate and ITT Results: Studies of Organ Procurement and Transplantation Network (OPTN) Data
Useful information about the history of HCC in untreated and treated patients can be extracted from the large number of patients in the OPTN database. These studies, however, have to be interpreted with some caveats: the allocation of treated and untreated patients does not correspond to a consistent prospective policy; the causes of dropout are not specified (with the partial exception of Pelletier et al.15); data on recurrences are not available (NA); the ITT survival rates are low (55% at 5 years and 65% for transplant patients within the MC) despite the low number of dropouts17; and overall, patients undergo transplantation within a very short time (54 days), and this possibly masks the benefits of neoadjuvant treatments for dropout patients.16 These reservations notwithstanding, 4 points relevant to our discussion can be mentioned:
The dropout rate for T2 patients seems to be the same for treated patients (42.5% of the cohort) and untreated patients (11.2% with ablation and 11.8% with no ablation 1 year after listing),17 and it is lower than expected, even when we consider the short median wait-list time.
An equation for tumor progression can be constructed that accommodates the observed dropout rate.23 The utility of this projection needs to be validated by a finer analysis of the causes of dropout, the results of transplantation, and the use of neoadjuvant strategies (which are missing from the equation).
For T2 patients, the dropout rate depends markedly on the AFP level (dropout at 180 days: 7.4% for AFP < 500 ng/mL and 24.9% for AFP > 1000 ng/mL after listing) and less so on the intrinsic MELD score and the tumor size.16, 17
ITT patient and graft survival rates are better for treated patients versus untreated patients. This finding again has to be interpreted with caution because the allocation of treated and untreated patients is not randomized.16
DIFFERENT TREATMENT STRATEGIES
Observation/Surveillance Without Treatment
Only the study by Llovet et al.1 allows the extraction of direct data. To the best of our knowledge, no program has adopted a policy of surveillance only, even though there are theoretical reasons for abstaining from actions when there is an insufficient level of evidence for the supposed benefit of the adjuvant treatment.24 A close examination of the BCLC study, however, raises questions about the unusually low recurrence rate (only 2 of 87 patients died of recurrence). Therefore, it is possible that a surveillance-only policy, despite apparently poor ITT results, may be the ultimate selection strategy for HCC patients within the MC if the aim is to optimize graft use in the whole wait-list population of HCC and non-HCC patients. This point may be verified by a prospective study in which a 3- to 9-month waiting time can be maintained. For longer waiting times, the aforementioned data for tumor progression after 6 months should discourage a surveillance-only strategy, at least for T2 patients with tumors close to the 5-cm mark, because of the expected deterioration in ITT results versus the excellent ITT results of OLT after state-of-the-art LRT.8, 12
In conclusion, surveillance without treatment may be the optimal bridging strategy for waiting times shorter than 6 months, and this should be tested in prospective randomized trials including a no-treatment arm.
The idea of performing transplantation for HCC patients before tumors have the time to progress to dropout criteria is appealing. Indeed, the decision to grant MELD exception points to HCC patients on the basis of the estimated dropout rate corresponds to this intent (ideally only to balance the chances of HCC and non-HCC patients).17 Further prioritization of patients with HCC would probably be unacceptable, is not done in any program to the best of our knowledge, and would raise the question of whether a short waiting time is associated with more recurrence after transplantation. Indeed, fast-tracking patients with HCC may be a double-edged sword because time on the waiting list can be a privileged period for observing the biology tumor and for excluding patients with aggressive cancers that will progress to the contraindication stage while they are waiting. No conclusive answer to this question can be obtained from the literature. Standing against prioritization are preliminary results from Northwestern University (Chicago, IL): the recurrence rate for patients fast-tracked either by recent United Network for Organ Sharing/MELD rules or by the use of split living donor liver transplantation (LDLT) grafts was higher than the rate for patients from a previous period with longer waiting times (T1 and T2, 5/32 versus 0/25; T3 and T4, 4/9 versus 1/8).25 A similar concern was raised in a study from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study consortium, which compared 34 patients receiving deceased donor organs to 58 undergoing LDLT.26 The waiting time was shorter for the LDLT group (160 versus 469 days), but recurrences were more frequent (29% versus 0%). A multicenter study from Japan, which found excellent results for LDLT in patients within the MC, cannot be used to prove the absence of more frequent recurrences with the shorter waiting times associated with LDLT because it is customary for Japanese patients to be treated with TACE, PEI, or resection before LDLT.27 A UCSF study argues against a disadvantage for patients waiting for a short time,28 and so does the study from Barcelona if we consider the first group of 50 patients who waited for 2.3 months.1 None of these studies, however, provide the time from the diagnosis of HCC to transplantation, and only the time from listing to transplantation is known; it is possible that some observation time elapsed before the patients were listed.
The wait-list data from the United Network for Organ Sharing do not allow us to answer the question of whether prioritization is associated with a high recurrence rate because the available information is limited to the waiting list and does not take recurrences into account. The relatively poor ITT results that have been reported, however, require a closer analysis.15
On the contrary, a thoughtful discussion about the reasons for excluding patients with an unfavorable tumor biology by treatment and the test of time (an ablate and wait policy) can be found in a recent review article by the UCSF team.29 Extrapolating the results of down-staged patients, the authors suggested TACE or RFTA and a waiting period of 6 months for patients with tumors exceeding 3 cm whose hepatic functional reserve is sufficient to tolerate this.
In conclusion, it appears that a short waiting time does not increase the recurrence rate in patients with T1 or T2 tumors at the lower end of the MC, but it remains possible that tumors close to the 5-cm mark may recur more frequently than those selected by the test of time. Finer discrimination may be possible with AFP as a surrogate marker of vascular invasion. Overall, it seems that even if it were possible, the prioritization of HCC patients for a waiting time shorter than 3 to 6 months is neither practical nor desirable.
The rationale for TACE before transplantation is derived from an extrapolation of studies showing the efficacy of this treatment in patients with intermediate-stage HCC who are not candidates for transplantation. Even before 2 randomized controlled trials demonstrated a survival advantage for TACE patients,30, 31 a multicenter French study showed less tumor progression and fewer tumoral portal thromboses32; these are intuitively relevant goals for a wait-list population, and the procedure was adopted as the standard of care in many programs. The extensive experience of several units in which TACE is standard practice has demonstrated that TACE does not make transplantation more complicated; this was reviewed by Lesurtel et al.24 Tumor necrosis is observed in various percentages of treated nodules (27%-50%), as summarized in a recent review.33 The issue of specific advantages for the dropout rate and long-term outcomes is more complicated. Two well-documented cohort studies from Rochester (54 patients)3 and Innsbruck (116 patients)12 have confirmed that TACE allows long waiting times [median = 211 days (range = 28-1099 days) in the Rochester study; median = 274 days (range = 36-1037 days) in the Innsbruck study] with relatively low total dropout rates (9% and 14%, respectively). Recurrences were rare in both studies and were not higher than what would be expected for T2 patients (Table 1).
A multicenter case-control study compared matched patients with TACE (100) and without TACE (100).14 The survival rates 5 years after OLT were similar (59.3% versus 59.4%). However, although this was not significant (possibly because of a type II error), there were fewer recurrences in the TACE group (13 versus 23) but more non–tumor-related deaths (15 patients versus 7 patients). Also, the waiting times were short (128 versus 131 days), and the median number of TACE procedures was only 1 (mean = 1.8); this possibly prevented the detection of any advantage for TACE.
A retrospective case-control study investigated the effects of TACE on the outcomes of transplantation.13 There was no significant difference in survival at 5 years (69% with TACE versus 64% with no treatment), but recurrences were less frequent after TACE (13 versus 23). The mean waiting time was short (4.2 months), and the study did not consider the dropout rate. Two other studies with fewer patients failed to show a statistical advantage of TACE as a bridging strategy in terms of outcomes after transplantation,34, 35 but notably, recurrences were rarer in one of the studies [3/18 (17%) versus 8/28 (29%)]. Furthermore, the waiting times were short, so it is possible that a beneficial effect could not appear.
A caveat against incomplete TACE was reported in a study from Italy, which found an increased rate of recurrence.36 These findings have not been observed by other groups and need to be confirmed, but the aim of complete extinction of the tumor's vascular supply seems reasonable to pursue.
In conclusion, according to the reported series, TACE apparently is not harmful in a population close to the MC, may allow patients to wait longer than would otherwise be possible, and is not associated with more recurrences (which may in fact be less frequent). If the option of TACE is chosen, it should be pursued until the best possible effect on tumor necrosis is obtained.
RFTA was not at first sight an appealing treatment in pretransplant patients because of the risk of local spread, and there were early reports of RFTA in which seeding was frequent. Experience with the technique and a well-conducted cohort study have shown that seeding and recurrence are rare when patients and contraindications are selected carefully (ie, subcapsular tumors and direct nodule puncture).8 Other confirmatory studies have shown that the technique can be used safely in pretransplant patients and that the percutaneous route is as safe as the laparoscopic approach and less cumbersome.9, 10 In pathological studies, the results for RFTA appear to be superior to those for TACE,37, 38 and RFTA appears to be associated with less tumor progression.18 The prevalence of viable cells can be easily assessed in explant specimens.8 In the study by Mazzaferro et al.,8 a viable tumor was present in 37% of the explants, and this rose to 71% for tumors > 3 cm. In addition, the probability of finding a viable tumor increased with the waiting time and reached 60% after 12 months. In another study, only 30% of the specimens included a viable tumor.9
In conclusion, RFTA appears to be safe and can be used as a bridging strategy if this is indicated. Its ability to reduce dropout rates and its effects on posttransplant results need to be proven in a prospective, comparative study.
The safety of resection before transplantation and the use of resection and salvage transplantation as a graft-sparing strategy have been studied and discussed extensively, as summarized in a recent article.39 The decision to resect depends on the liver function and the size and location of the tumor. The team's experience with partial resection in patients with cirrhosis is also very important, and the availability of laparoscopic liver resection seems to improve the early outcomes of the procedure and subsequent transplantation. A complete pathological assessment of the specimen is an important advantage. The study showed that close follow-up allows salvage transplantation in up to 60% of patients with recurrence.
Although resection appears to be safe before transplantation (in terms of operative results and long-term outcomes) and to have a place in decision analysis when the waiting time is longer than 1 year,21 resection is very rarely used at the moment as a bridging strategy. The use of resection as a selection tool [eg, for patients with adverse tumor characteristics for whom preemptive transplantation can be advised (ie, before recurrence but after sufficient observation)] is attractive but still anecdotal and requires further assessment.40, 41
Finally, in certain countries, patients cannot undergo transplantation after resection because the tumor has been removed; this limits the possibilities of the approach. This should be rediscussed because this is not the case with RFTA even if the tumor has been destroyed without any histological assessment.
In conclusion, in our opinion, resection is underused as a bridging strategy (ie, aside from the issue of salvage transplantation), and seemingly arbitrary policies such as the loss of priority after tumor removal should be rediscussed.
Currently, radioembolization with yttrium-90 represents 5% to 10% of bridging LRT procedures in the OPTN registry, but data on its impact are scanty. In a study that reported the correlation between radiological and pathological findings in patients with HCC who underwent radioembolization with yttrium-90 microspheres before transplantation, all target lesions demonstrated some degree of histological necrosis, and 23 of 38 (61%) showed complete pathological necrosis.38 A recent study retrospectively analyzed transarterial radioembolization (TARE) and TACE in similar patients (122 and 123, respectively); 44 TARE patients and 46 TACE patients were at stage T2 (they were not analyzed separately).42 Although there was no survival benefit for TARE, the time to disease progression and the AFP responses were significantly more favorable with TARE, and this suggests that this treatment could be a promising modality before OLT.
In conclusion, current data are too scanty to recommend the use of TARE before OLT, but this technique may be an appropriate one to use and should be the object of further investigation.
Conformal Radiotherapy (CRT)
CRT is known as a feasible and efficient therapeutic option for HCC patients who are ineligible for a curative treatment (ie, surgical resection or transplantation).43, 44 However, only 2 published reports describe the use of CRT as a bridging option for patients on the waiting list.
A retrospective series from Toronto, Canada, reported the use of hypofractionated CRT in 10 patients with HCC who were listed for OLT and for whom previous local therapies had failed or were not possible because of poor liver function or anatomic issues.45 Eight tumors were beyond the MC.
Overall, the treatment was well tolerated, and there were no significant or severe complications. Local tumor control was achieved for all treated tumors. Five patients underwent OLT with no complications attributable to CRT. Histopathological examinations of the explant livers showed tumor necrosis and fibrosis with sparing of the untreated parenchyma. All transplant patients treated with CRT were cancer-free at the time of the publication of the article.
In conclusion, CRT may be a safe and potent local bridging therapy for patients with advanced HCC who are on the waiting list for OLT. Further studies are warranted to compare the effectiveness of CRT and other local therapeutic options in this setting.
Treatment with sorafenib has been proven to be effective in the treatment of advanced HCC. Although there is a rationale for its use in patients waiting for transplantation, as suggested by a decision analysis study,46 its value remains hypothetical because of possible complications and has to be proven by prospective trials. Furthermore, the study assumed a monthly dropout rate of 5%, which is higher than the rate observed in most studies. The central role of the expected waiting time was highlighted by the study and appears relevant to all bridging strategies.47
NEED FOR FURTHER RESEARCH
It is apparent from this review that further data are needed; in particular, instead of a likelihood, we need proof that bridging strategies are useful because they improve the ITT outcomes of transplantation by decreasing the dropout rate and by increasing posttransplant survival in patients waiting 3 to 12 months (which is currently the case for the majority of patients in Western centers). The recent consensus conference of centers in the United States recommended bridging LRT,48 and this is supported by compelling evidence.16 Although this recommendation seems reasonable in patients waiting longer than 6 months with high AFP levels and larger tumors (4-5 cm), the data showing that treatment does not transform dropout patients into patients with recurrence originate from only 5 moderately sized cohort studies.3, 8-10, 12 Only 2 of these studies had sufficient follow-up periods,8, 12 and while we are awaiting further studies, we cannot make a strong recommendation. Furthermore, data on cost-effectiveness are scanty and are based on a decision analysis21, 22 or local realities whose financial conditions cannot be generalized.49
Ideally, randomized controlled trials with a no-treatment arm should be constructed. The first objection to such trials is that they would be unethical because of (1) the perceived advantages of LRT in terms of disease progression before transplantation and (2) the delay in palliative treatments of proven benefit if a patient in the surveillance arm drops out. This view has to be tempered: LRT complications do occur, proof that bridging with LRT does not result in more recurrences and worse outcomes after transplantation is not yet available (the aforementioned studies and particularly OPTN data may have a strong selection bias in the allocation of patients to treatment and no-treatment arms), and the short delay in starting palliative treatments in dropout patients in the surveillance arm may not be relevant. Furthermore, if the avoidance of dropout is paramount for the individual patient, the avoidance of recurrence is more important for society; with the current shortage of grafts, dropouts do not affect the utility of transplantation (the graft is used for somebody else), but recurrence does. The minimal requirements for such trials would include strict definitions of monitoring practices (eg, quadruple-phase spiral computed tomography every 3 months) and dropout criteria (eg, progression beyond a certain tumor size and a certain AFP level as well as vascular invasion and distant metastases) as well as enough follow-up after transplantation for recurrences to become visible (eg, 3 years with regular monitoring by computed tomography).
The first trial could include T1 patients in Europe, where these patients receive MELD exception points. The second trial could include T2 patients in the United States, where the majority of patients undergo transplantation within 3 to 12 months. The determination of whether LRTs confer an advantage in comparison with surveillance only would come relatively quickly, and in our opinion, the construction of such trials would be worthwhile.
CONCLUSIONS AND RECOMMENDATIONS
Bridging strategies using LRT with the aim of complete tumor destruction are not harmful and may be beneficial for T2 patients waiting longer than 6 months because of the low dropout rates and good posttransplant outcomes observed in a few well-conducted cohort studies and in a preliminary analysis of large registry data (recommendation level 4). This recommendation is probably more relevant for patients with tumors close to the 5-cm limit or a high AFP level (or both), who are more likely to develop contraindications while they are waiting.
There is no evidence that bridging strategies should be used for T1 patients, and the decision has to be balanced with the risks of complications and the likely waiting time.
Pathological studies suggest that RFTA may have a marginal advantage over TACE in terms of local ablation (recommendation level 4-5). Newer strategies combining TACE and RFTA or using radiotherapy, yttrium-90, and targeted therapies may be promising and need to be investigated.
Resection is a safe bridging treatment before transplantation, and its potential as a useful selection tool due to the pathological study of the specimen requires further investigation (recommendation level 4). Resection as a bridging treatment is disfavored by the rule that a patient who has undergone resection no longer qualifies for transplantation, and this rule needs to be modified.
Proof that LRT is useful because it improves ITT survival by decreasing the dropout rate and reducing the recurrence rate and information on cost-effectiveness can be obtained only from prospective investigations. Such studies are desirable and ideally should include a no-treatment arm if the waiting time is less than 6 months.