Salvage liver transplantation for recurrent hepatocellular carcinoma after radiofrequency ablation: A new strategy?
Authors: Robin K. Kelley, Francis Yao
Journal: Journal of Hepatology (2011)

Survival after radiofrequency ablation and salvage transplantation in patients with hepatocellular carcinoma and Child-Pugh A cirrhosisJournal of HepatologyVol. 56Issue 1PreviewIn patients with hepatocellular carcinoma (HCC) within the Milan criteria, liver transplantation (LT) may be the best therapeutic option. However, the shortage of grafts, leads to attempt liver resection (LR) or radiofrequency ablation (RFA) as a first-line treatment for patients with Child-Pugh A cirrhosis. Full-Text PDF In this issue of the Journal, Dr. Nkontchou et al. describe the recurrence and survival outcomes of a retrospective cohort of 67 patients diagnosed with hepatocellular carcinoma (HCC) within the Milan criteria between 2000 and 2007, who were treated at a single center in France with percutaneous radiofrequency ablation (RFA), followed by close surveillance and salvage transplant for liver failure or recurrence [[1]Nkontchou GAM, Laurent A, Nahon P, et al. Survival after radiofrequency ablation and salvage transplantation in patients with hepatocellular carcinoma and Child-Pugh A cirrhosis. J Hepatology, in press.Google Scholar]. Among the 64 patients who achieved complete response to RFA, 38 (59.4%) experienced recurrence within 5 years. Twenty-one patients with recurrence were treated by liver transplantation, 14 were ineligible due to recurrence outside of the Milan Criteria, and 3 declined transplant and were treated with repeat RFA. Three additional patients from the original cohort required transplantation for hepatic decompensation without recurrence. The 5-year overall and recurrence-free survival rates were 74% and 69%, respectively. The authors conclude that RFA as a first-line strategy reserving liver transplant as a salvage option achieves “survival figures that are as least as good as first line liver transplantation,” in patients with HCC within the Milan Criteria and Child Pugh A cirrhosis, and that this two-step strategy may help to conserve the scarce resource of liver allografts. Particularly when facing widespread organ shortages, there is great need for studies such as Nkontchou et al. which seek to identify those patients who will experience equivalent outcomes from loco-regional therapies as from transplantation, thereby safeguarding graft livers for patients most likely to benefit, including patients with other indications for transplantation for whom similar alternative treatment options may not be available [2Freeman R.B. Edwards E.B. Harper A.M. Waiting list removal rates among patients with chronic and malignant liver diseases.Am J Transplant. 2006; 6: 1416-1421Crossref PubMed Scopus (187) Google Scholar, 3Pomfret E.A. Washburn K. Wald C. Nalesnik M.A. Douglas D. Russo M. et al.Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States.Liver Transplant. 2010; 16: 262-278Crossref PubMed Scopus (332) Google Scholar]. It is clear that, although the Milan Criteria remain a worldwide standard for identifying appropriate candidates for liver transplantation, there are patients, whose tumors meet these radiographic criteria, who may have excellent survival outcomes from loco-regional therapy alone, while others with similar baseline imaging findings develop distant metastatic disease despite transplantation [4Cherqui D. Laurent A. Mocellin N. Tayar C. Luciani A. Van Nhieu J.T. et al.Liver resection for transplantable hepatocellular carcinoma: long-term survival and role of secondary liver transplantation.Ann Surg. 2009; 250: 738-746Crossref PubMed Scopus (202) Google Scholar, 5Kudo M. Radiofrequency ablation for hepatocellular carcinoma: updated review in 2010.Oncology. 2010; 78: 113-124Crossref PubMed Scopus (126) Google Scholar, 6Otto G. Herber S. Heise M. Lohse A.W. Monch C. Bittinger F. et al.Response to transarterial chemoembolization as a biological selection criterion for liver transplantation in hepatocellular carcinoma.Liver Transplant. 2006; 12: 1260-1267Crossref PubMed Scopus (359) Google Scholar, 7Takahashi S. Kudo M. Chung H. Inoue T. Nagashima M. Kitai S. et al.Outcomes of nontransplant potentially curative therapy for early-stage hepatocellular carcinoma in Child-Pugh stage A cirrhosis is comparable with liver transplantation.Dig Dis. 2007; 25: 303-309Crossref PubMed Scopus (28) Google Scholar, 8Ioannou G.N. Perkins J.D. Carithers Jr., R.L. Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival.Gastroenterology. 2008; 134: 1342-1351Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar]. In non-randomized, retrospective cohort analyses, however, careful examination of patient selection criteria is imperative to guide interpretation of results. In Nkontchou et al., 22 out of the 67 patients (33%) were classified as Barcelona Clinic Liver Cancer (BCLC) Stage 0 (very early stage disease) at baseline, and the remainder had BCLC1 disease [[1]Nkontchou GAM, Laurent A, Nahon P, et al. Survival after radiofrequency ablation and salvage transplantation in patients with hepatocellular carcinoma and Child-Pugh A cirrhosis. J Hepatology, in press.Google Scholar]. In the United States, patients with BCLC0 and BCLC1 HCC and evidence of minimal or no portal hypertension are generally recommended to undergo liver resection rather than transplantation given similar published survival rates in this subpopulation along with the need to preserve organ resources [3Pomfret E.A. Washburn K. Wald C. Nalesnik M.A. Douglas D. Russo M. et al.Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States.Liver Transplant. 2010; 16: 262-278Crossref PubMed Scopus (332) Google Scholar, 4Cherqui D. Laurent A. Mocellin N. Tayar C. Luciani A. Van Nhieu J.T. et al.Liver resection for transplantable hepatocellular carcinoma: long-term survival and role of secondary liver transplantation.Ann Surg. 2009; 250: 738-746Crossref PubMed Scopus (202) Google Scholar, 9Belghiti J. Cortes A. Abdalla E.K. Regimbeau J.M. Prakash K. Durand F. et al.Resection prior to liver transplantation for hepatocellular carcinoma.Ann Surg. 2003; 238 ([discussion 892–883]): 885-892Crossref PubMed Scopus (366) Google Scholar, 10Belghiti J. Cortes A. Abdalla E.K. Regimbeau J.M. Prakash K. Durand F. et al.Resection prior to liver transplantation for hepatocellular carcinoma.Ann Surg. 2003; 238: 885-892Crossref PubMed Google Scholar, 11Llovet J.M. Fuster J. Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation.Hepatology. 1999; 30: 1434-1440Crossref PubMed Scopus (1498) Google Scholar]. The authors state that most of the patients in this study were selected for RFA due to tumor anatomic location and/or portal hypertension as contraindications to liver resection, though the proportion of patients with adequate hepatic reserve for liver resection is not provided, and it is unclear how candidacy for resection was adjudicated in this cohort. It is noteworthy that 2 out of the 3 patients, who failed to demonstrate a complete response to first-line RFA, were treated thereafter with resection. Conflicting data regarding the efficacy of resection versus RFA for BCLC early and very early stage HCC confound interpretation of the findings in this study, noting in particular a body of evidence suggesting that RFA is associated with a higher local recurrence rate than resection as recently reviewed by Kudo [[5]Kudo M. Radiofrequency ablation for hepatocellular carcinoma: updated review in 2010.Oncology. 2010; 78: 113-124Crossref PubMed Scopus (126) Google Scholar]. Nkontchou et al. define “local recurrence” as recurrent tumor at the previously treated site(s), while “distant recurrence” is defined as the emergence of one or several tumors not adjacent to an ablation site. Among the 38 patients with recurrence post complete response to first-line RFA in this cohort, 2 patients had local recurrence, 33 patients had distant recurrence, and 3 patients had both. The anatomic proximity required to be considered adjacent is not defined. It is also not stated whether any of the patients with recurrence were candidates for resection. Cumulatively, these points raise the following important question: Would a proportion of the patients studied by Nkontchou et al. have been spared from intrahepatic recurrence requiring salvage transplantation had they been treated with first-line resection? This question cannot be rigorously answered by non-randomized data, however, and any inferences require careful identification of appropriate historical controls. A closely-related question emerges when examining the median time to recurrence in this cohort of patients treated with first-line RFA with curative intent. Although the authors report that all but 3 of the 67 patients had a complete response to RFA as defined by the absence of enhancing tissue at the tumor site(s) on imaging one month later, the remaining recurrences in this study occurred quite early, with median time to recurrence of 1.16 years (95% CI: 0.71; 2.58). For patients with recurrence, the median time to transplant was 1.38 years (95% CI: 0.58; 1.92) from the time of the initial RFA with a median waiting time of 5 months. The short interval between median times to recurrence and transplant suggests that the distribution of recurrences was skewed toward an even earlier mean, though this figure is not provided. Considering the rapidity of recurrences in this study along with the data cited above suggesting higher local recurrence rates with RFA by comparison to resection, it is possible that many of the recurrences in this study actually represent preexisting lesions that were occult on baseline and post-RFA imaging rather than de novo secondary lesions. It is unclear whether imaging practices were symmetric across patients; the authors state that “ultrasound, triphasic computerized tomography, or magnetic resonance imaging” was performed one month after RFA then every three months, but they do not specify whether all patients were mandated to undergo at least one of the multiphase contrast-enhanced options at each timepoint. Incomplete initial RFA could also explain the rapid time to recurrence but is not supported by the explant histology findings which showed complete necrosis at the site of RFA in most patients, though the histology and location of recurrent lesions is not described. Based upon this rapid time to recurrence, suggesting a high likelihood of residual disease post RFA, it may be more accurate to consider RFA as a bridge to transplant for the majority of patients in this cohort, rather than as a definitive therapy with transplant as a salvage measure. The rapid time to transplant in this series also calls into question whether the salvage strategy in this study can be generalized to sites with longer waiting list times. At first glance, the 5-year overall and recurrence-free survival rates in this cohort appear promising. Nkontchou et al. compare the survival outcomes in this study to historical control data from patients treated with “first-line” transplantation and conclude that first-line RFA in this patient population is associated with similar if not better results. Looking more closely, however, it is not surprising that the survival of patients in Nkontchou et al., all of whom were Child Pugh A with early stage disease, would compare favorably to the heterogeneous, often pre-treated populations in HCC transplantation studies, particularly if intent-to-treat analyses are employed which are heavily influenced by drop-out. The majority of studies of liver transplantation include patients with higher Model for End-Stage Liver Disease (MELD) scores, more advanced tumors, and prior loco-regional therapies, and many transplantation algorithms exclude early-stage patients eligible for resection [8Ioannou G.N. Perkins J.D. Carithers Jr., R.L. Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival.Gastroenterology. 2008; 134: 1342-1351Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 11Llovet J.M. Fuster J. Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation.Hepatology. 1999; 30: 1434-1440Crossref PubMed Scopus (1498) Google Scholar, 12Mazzaferro V. Regalia E. Doci R. Andreola S. Pulvirenti A. Bozzetti F. et al.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med. 1996; 334: 693-699Crossref PubMed Scopus (5785) Google Scholar, 13Pelletier S.J. Fu S. Thyagarajan V. Romero-Marrero C. Batheja M.J. Punch J.D. et al.An intention-to-treat analysis of liver transplantation for hepatocellular carcinoma using organ procurement transplant network data.Liver Transplant. 2009; 15: 859-868Crossref PubMed Scopus (119) Google Scholar]. In a retrospective cohort study of patients treated with liver transplantation for HCC before and after the adoption of MELD allocation system, 3595 patients with tumors ⩾2 cm underwent transplantation with MELD exception points between 2002 and 2007 in the United States [[8]Ioannou G.N. Perkins J.D. Carithers Jr., R.L. Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival.Gastroenterology. 2008; 134: 1342-1351Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar]. Subset analysis according to tumor size and number of nodules demonstrated 4-year overall survival rates ranging from 69.1% to 79.4%, with the highest rate for patients with solitary tumors less than 2 cm in size. The majority (65.1%) of the overall population had received prior treatment for HCC, and MELD scores were widely distributed. It is difficult and perhaps premature to draw any firm conclusions regarding the outcomes of patients in the Nkontchou et al. cohort compared to outcomes in liver transplantation studies due to this heterogeneity. In addition to a high degree of clinical heterogeneity, however, HCC is a tumor with exceptional biologic heterogeneity that is thought to arise from longstanding inflammation and hepatocyte regeneration from underlying liver injury [[14]Hoshida Y. Toffanin S. Lachenmayer A. Villanueva A. Minguez B. Llovet J.M. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements.Semin Liver Dis. 2010; 30: 35-51Crossref PubMed Scopus (268) Google Scholar]. Gene expression profiling in HCC suggests there may be common molecular and genetic subclasses in HCC, including several distinct subclasses with greater genetic instability, high grade histology, and poor clinical outcome [14Hoshida Y. Toffanin S. Lachenmayer A. Villanueva A. Minguez B. Llovet J.M. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements.Semin Liver Dis. 2010; 30: 35-51Crossref PubMed Scopus (268) Google Scholar, 15Hoshida Y. Nijman S.M. Kobayashi M. Chan J.A. Brunet J.P. Chiang D.Y. et al.Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma.Cancer Res. 2009; 69: 7385-7392Crossref PubMed Scopus (801) Google Scholar, 16Hoshida Y. Villanueva A. Kobayashi M. Peix J. Chiang D.Y. Camargo A. et al.Gene expression in fixed tissues and outcome in hepatocellular carcinoma.N Engl J Med. 2008; 359: 1995-2004Crossref PubMed Scopus (1048) Google Scholar, 17Katoh H. Ojima H. Kokubu A. Saito S. Kondo T. Kosuge T. et al.Genetically distinct and clinically relevant classification of hepatocellular carcinoma: putative therapeutic targets.Gastroenterology. 2007; 133: 1475-1486Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 18Villanueva A. Hoshida Y. Toffanin S. Lachenmayer A. Alsinet C. Savic R. et al.New strategies in hepatocellular carcinoma: genomic prognostic markers.Clin Cancer Res. 2010; 16: 4688-4694Crossref PubMed Scopus (103) Google Scholar]. Certain clinical features, such as high AFP and hepatitis B virus infection, are often associated with the most aggressive subclasses [[14]Hoshida Y. Toffanin S. Lachenmayer A. Villanueva A. Minguez B. Llovet J.M. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements.Semin Liver Dis. 2010; 30: 35-51Crossref PubMed Scopus (268) Google Scholar]. It is probable that intrinsic tumor biology, for which radiographic features are merely a crude surrogate marker, is a much stronger determinant of patient outcome than the type, technique, or timing of liver-directed interventions or transplantation. In small, non-randomized cohorts, the chance proportion of patients with aggressive molecular and genetic subtypes of tumor has great potential to drive results and confound interpretation. Although not yet a standard of care in risk assessment and treatment decision-making in HCC, molecular and genetic studies of HCC tumors at diagnosis and recurrence have great investigational promise to answer important clinical questions, such as whether the recurrences represent clonal intrahepatic metastases from a single primary tumor as opposed to de novo secondary tumors, and which patients are at highest risk of metastatic recurrence and unlikely to benefit from loco-regional strategies. Due to the validation of radiographic diagnoses without biopsy in HCC as well as the concerns of tumor seeding and bleeding in potential transplant candidates, there is a paucity of tissue available for research purposes in HCC, a deficiency which may contribute to the very dismal treatment options for patients with advanced HCC by comparison to nearly all other cancer types. Studies such as this offer an invaluable opportunity to obtain paired biopsy material for molecular and genetic analyses without conferring undue risk to patients who will already be undergoing RFA and, in many cases, subsequent transplantation. Nkontchou et al. hypothesize that a two-step strategy provides a necessary “test of time” to identify those patients with aggressive tumor biology most likely to recur post transplantation. This hypothesis is in keeping with results from our experience at the University of California, San Francisco (UCSF) using a downsizing approach prior to transplantation in patients with HCC tumors exceeding the Milan Criteria [19Roberts J.P. Venook A. Kerlan R. Yao F. Hepatocellular carcinoma: ablate and wait versus rapid transplantation.Liver Transplant. 2010; 16: 925-929Crossref PubMed Scopus (110) Google Scholar, 20Yao F.Y. Kerlan Jr., R.K. Hirose R. Davern 3rd, T.J. Bass N.M. Feng S. et al.Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis.Hepatology. 2008; 48: 819-827Crossref PubMed Scopus (424) Google Scholar]. In a cohort of 61 patients treated with RFA and/or chemoembolization to downsize tumors, approximately 30% of patients experienced radiographic progression during the waiting period and were excluded. The remaining patients underwent transplantation a median of 8.2 months after the initial downsizing procedure. Outcomes were excellent with intention-to-treat survival of 69.3% at 4 years [[20]Yao F.Y. Kerlan Jr., R.K. Hirose R. Davern 3rd, T.J. Bass N.M. Feng S. et al.Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis.Hepatology. 2008; 48: 819-827Crossref PubMed Scopus (424) Google Scholar]. The UCSF experience along with other studies suggest that an “Ablate and Wait” strategy will facilitate identification of those patients with unfavorable tumor biology who demonstrate progression despite downsizing techniques and who are, unfortunately, unlikely to benefit from transplantation. In summary, Nkontchou et al. have described a cohort of patients with preserved hepatic function and HCC within the Milan Criteria treated with first-line RFA and salvage transplant, with the important goal of improving the allocation of liver allografts to those patients most likely to benefit. Although the survival outcomes in this cohort appear promising, the results cannot be generalized to the broader population of patients with HCC within Milan Criteria due to the highly selected, early-stage patient population and the short waiting list times for patients with recurrence. Another major limitation of this study is the lack of clear definition of resectability, noting that the current literature suggests higher recurrence rates post RFA by comparison to liver resection. The early median time to recurrence in this study also raises the possibility of incomplete response to RFA versus occult residual disease in the majority of patients with recurrence, rather than de novo tumors. Although the authors conclude that this treatment strategy is associated with survival outcomes equivalent to if not better than first-line transplantation, the comparison is confounded by great clinical and biologic heterogeneity among HCC patients and their tumors. Importantly, this study corroborates other recent work suggesting that a two-step approach with a mandatory waiting period prior to transplantation may permit identification of those patients with biologically-unfavorable disease most likely to recur post transplant, thereby sparing these patients from a high risk procedure without benefit while conserving the scarce resource of liver allografts. A better understanding of tumor biology is critical to refine our assessment of which patients are most and least likely to benefit from loco-regional therapies and transplant, as well as to identify novel therapeutic targets in this complex and grim disease. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Dr. Kelley is supported in part by a Young Investigator Award from the American Society of Clinical Oncology (ASCO) to study markers of prognosis and response to therapy in hepatocellular carcinoma.