Conundrum of treatment for early-stage hepatocellular carcinoma: Radiofrequency ablation instead of liver transplantation as the first-line treatment?
2014; Lippincott Williams & Wilkins; Volume: 20; Issue: 3 Linguagem: Inglês
10.1002/lt.23848
ISSN1527-6473
Autores Tópico(s)Liver Disease and Transplantation
ResumoLiver transplantation (LT) has had an enormous impact on the treatment of early-stage hepatocellular carcinoma (HCC) for almost 2 decades,1, 2 to the point where we no longer question the value of this lifesaving procedure but instead grapple with how to use the scarce resource of donor organs to best serve both HCC patients and those with end-stage liver disease without HCC.3, 4 Since the Model for End-Stage Liver Disease (MELD) allocation scheme for HCC was implemented in the United States in 2002, the proportion of patients receiving priority listing with HCC MELD exceptions has almost doubled from 10.5% to 19.4%.5, 6 There is a growing body of evidence showing that patients with HCC are given an unfair advantage in organ allocation over non-HCC patients listed for LT on the basis of their calculated MELD scores.4, 5, 7, 8 While LT is the only lifesaving treatment possible for listed patients with liver failure, there are alternative treatments for HCC that provide effective initial control of tumor progression, although the long-term outcomes are less favorable in comparison with LT. According to 2 recently updated guidelines from the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver,9, 10 surgical resection is the first-line treatment for patients with a small, solitary HCC and either no cirrhosis or Child A cirrhosis with no portal hypertension, whereas LT should be reserved for patients who are not resection candidates because of the presence of portal hypertension, hepatic dysfunction, or technical factors. Radiofrequency ablation (RFA) has emerged as another potentially curative treatment for HCC.9, 10 Published data on percutaneous RFA have shown that patients with a solitary HCC and Child class A cirrhosis can achieve long-term survival comparable to that achieved with surgical resection,11-14 and 3 randomized trials comparing RFA with surgical resection have not provided unequivocal evidence for the superiority of one modality over the other.15-17 A major limitation of RFA is the high incidence of HCC recurrence (50%-80% at 5 years), which is mostly due to the emergence of new tumors rather than local tumor progression.11-17 A strategy that has recently been proposed is first to perform RFA for LT candidates with HCC and then to subject them to LT only if recurrence develops after RFA; this would reduce the burden of HCC patients on the LT waiting list.18, 19 Who should be considered for this strategy? Ideally, we would select patients with the highest probability for a long-term cure after RFA and the lowest risk for HCC recurrence. However, HCC recurrence occurs in up to 80% of patients within 5 years after RFA, and thus a more clinically relevant question is what proportion of patients will remain candidates for salvage LT determined by size and number of the recurrent tumors still within acceptable LT criteria. The study from Japan by Tsuchiya et al.20 in this issue of Liver Transplantation sheds some light on these questions. Their cohort included 323 patients receiving RFA (percutaneous RFA for 279 and laparoscopic RFA for 44) as a definitive treatment. The primary aim of this study was to evaluate the probability and predictors of recurrent HCC beyond the Milan criteria.2 Close to 80% had Child class A cirrhosis, and the other 20% had Child class B cirrhosis. The majority (77%) had a chronic hepatitis C infection. At the time of RFA, all patients had tumors meeting the Milan criteria, and 70% had a solitary tumor. The overall cumulative patient survival rate was 70% at 5 years, but this decreased to 41% at 10 years. They observed an HCC recurrence rate of 84%, and 71% of these patients had a tumor stage beyond the Milan criteria. Overall, 60% of the entire cohort of 323 patients developed recurrent HCC beyond the Milan criteria. The cumulative risk of recurrent HCC beyond the Milan criteria at 1, 3, and 5 years was 15%, 46%, and 61%, respectively. In the multivariate analysis, an alpha-fetoprotein (AFP) level > 100 ng/mL, a tumor size > 2 cm, and early HCC recurrence within 1 year of RFA were significant predictors of HCC recurrence beyond the Milan criteria, whereas Child class B cirrhosis, an AFP level > 100 ng/mL, and early HCC recurrence were factors associated with worse overall survival. The subgroup with both an AFP level > 100 ng/mL and early HCC recurrence within 1 year of RFA had the worst 5-year survival at 23%. This large series on RFA as a primary treatment for HCC was aimed at assessing the possibility of salvage LT for recurrent HCC after RFA, but presumably because of the extreme scarcity of deceased organ donors in Japan, none of the patients actually underwent salvage LT. Consequently, one can only extrapolate from their findings without an analysis of wait-list factors that might influence the probability of salvage LT and without knowledge of the actual post-LT outcomes. This study also does not provide details on the pattern and extent of recurrent HCC after RFA, and it is unclear if some of these patients with recurrent HCC beyond the Milan criteria were eligible for tumor down-staging for LT.21 The diagnosis of HCC in this study was based on what the authors described as typical radiographic characteristics on cross-sectional imaging studies or liver biopsy, but no specific details were provided with respect to how many patients underwent liver biopsy for diagnostic confirmation or what proportion of patients had atypical radiographic features. This is an important consideration because 36% of the members of this cohort had 1 or more lesions that were all less than 2 cm in their maximal diameter. It is known that small tumors (<2 cm) often do not exhibit the typical radiographic characteristics of HCC, including arterial phase enhancement and portal venous phase washout.3, 9, 10 A previous analysis of the United Network for Organ Sharing database by Freeman et al.22 found a particularly high rate of pretransplant misdiagnosis with no HCC in the explant in a subgroup with a single lesion < 2 cm (stage T1). Despite a very impressive cumulative survival rate of 70% at 5 years in the study by Tsuchiya et al.,20 fewer than 20% of the members of this cohort were tumor-free 5 years after RFA, and less than 30% of the patients with recurrent HCC were eligible for salvage LT. Yamashiki et al.23 (another group in Japan) performed a simulative analysis of dropout from the waiting list after regional ablative therapy (RFA, percutaneous ethanol injection, or microwave coagulation therapy) for a cohort of 288 patients, and they reported tumor recurrence exceeding the Milan criteria (dropout) at a rate of 9% at 1 year and at a rate of 33% at 3 years. High AFP levels and a tumor diameter > 3 cm were predictors of tumor progression beyond the Milan criteria. N'Kontchou et al.18 from a single center in France presented a more optimistic outlook on salvage LT after initial RFA in a much smaller cohort of 67 patients (83 tumors) with Child A cirrhosis. HCC recurrence developed in 38 patients (57%) within 5 years: 14 patients (37%) were outside the Milan criteria, and 21 (55%) underwent salvage LT for recurrent HCC. The overall 5-year patient survival and recurrence-free survival rates were 74% and 69%, respectively. The authors suggested that the approach of RFA followed by salvage LT would yield survival similar to that achieved with primary LT.18 As noted in the editorial accompanying the report by N'Kontchou et al.,19 the rapid time to HCC recurrence suggests a high likelihood of residual disease after RFA, and on the basis of the very short interval between RFA and LT (median = 1.38 years), it may be more accurate to consider RFA as a bridge to LT for the majority of their cohort rather than a definitive therapy with LT as a salvage procedure. Tsuchiya et al.20 identified a high AFP level (>100 ng/mL), a tumor size > 2 cm, and early HCC recurrence within 1 year of RFA to be significant predictors of recurrence beyond the Milan criteria. How do we interpret these findings? Early HCC recurrence after RFA is an important prognostic factor but does not help with treatment decisions because in most cases, it is already too late to consider LT by the time of HCC recurrence. Although patients with high AFP levels have a greater risk for recurrence beyond the Milan criteria after RFA, they may not necessarily do better after LT because a high AFP level has been increasingly reported to be a poor prognostic factor after LT.24 A tumor size > 2 cm is the most clinically relevant predictor of recurrence beyond the Milan criteria when we take into consideration other reports suggesting that percutaneous RFA yields the best long-term results for patients with a solitary lesion ≤ 2 cm.10, 11 Sala et al.12 from the Barcelona group found a strong correlation between tumor size and an initial complete tumor response after percutaneous ablation (RFA or ethanol injection). Patients with a single lesion ≤ 2 cm achieved an initial complete response at a rate of 96%, whereas the rates were 78% for those with lesions between 2.1 and 3 cm, 56% for those with lesions > 3 cm, and 46% for those with 2 to 3 nodules. Furthermore, those who achieved complete tumor necrosis had the best long-term survival. In a multicenter Italian study of 218 patients with a single lesion ≤ 2 cm by Livraghi et al.,11 a sustained complete response was observed in 97%, and the 5-year patient survival rate was 69%.11 These results prompted the authors to conclude that RFA should be considered the treatment of choice over surgical resection for patients with a solitary HCC ≤ 2 cm. On the basis of what we have learned from this latest study by Tsuchiya et al.20 and from other published data on RFA, we should consider the following scenarios for applying RFA as the first-line treatment and then performing salvage LT in the event of recurrent HCC. First, patients with T1 HCC (solitary tumor < 2 cm) are not eligible for HCC MELD exception listing for LT under the current system of organ allocation in the United States. Many transplant centers have taken the approach of deferring locoregional therapy until the tumor progresses to stage T2 (1 lesion of 2-5 cm or 2-3 lesions up to 3 cm) and the patient is eligible for an HCC MELD exception for LT listing. These patients should be considered for RFA instead, especially if they have Child A cirrhosis, because they represent the group that achieves the highest rate of complete initial responses with RFA and has the best long-term survival after RFA.11, 12 It should again be emphasized that the accurate diagnosis of HCC in this subgroup is crucial before treatment decisions are made. Second, according to a recent study by Mehta et al.25 from the University of California San Francisco, a subgroup of patients meeting certain criteria—a solitary lesion 2 to 3 cm in diameter, a low AFP level (<20 ng/mL), and a complete response to the first locoregional therapy—are at very low risk for dropout from the LT waiting list (1.6% at 2 years) and may not even need LT. These criteria are, at the same time, also factors associated with favorable long-term outcomes after RFA.11-14 These patients should be considered for RFA first, and this should be followed by LT only in the event of local tumor progression or tumor recurrence, but the long-term outcomes of this approach need to be further evaluated. In summary, the important findings in this study by Tsuchiya et al.20 call into question the strategy of RFA followed by salvage LT as an alternative to primary LT. Although RFA achieved excellent patient survival at 5 years, 60% of their cohort developed recurrent HCC beyond the Milan criteria, and there was a substantial drop-off in patient survival at 10 years. How do the results of salvage LT after RFA compare with the results after surgical resection? There is still no consensus about the feasibility of salvage LT after resection, with reported salvage LT rates ranging from 16% to 65% in highly heterogeneous and small patient cohorts.26 We have come to a point in time when potentially curative treatment options for HCC, including surgical resection, RFA, and LT, should be evaluated in terms of patient survival at 10 years rather than 5 years. It appears that the best candidates for primary treatment with RFA followed by salvage LT are those with Child A cirrhosis and a solitary tumor < 2 cm (T1 HCC), who have the best long-term outcomes after RFA according to several previous studies11, 12 and who are also predicted to have a lower risk of developing recurrent HCC beyond the Milan criteria in comparison with patients with single or multiple tumors > 2 cm according to the present study by Tsuchiya et al. There is still a need for future investigations with greater confidence in the diagnostic accuracy of very small HCCs (<2 cm) to confirm that these patients are in fact the best candidates for primary treatment with RFA followed by salvage LT for recurrent disease. As of now, we should not consider RFA followed by salvage LT to be a widely applicable strategy to choose instead of primary LT for early-stage HCC.
Referência(s)