How should patients with hepatocellular carcinoma recurrence after liver transplantation be treated?

Abstract

Orthotopic liver transplantation (OLT) is performed in patients with hepatocellular carcinoma (HCC) for the purpose of curing their cancer; recurrence of HCC is generally equated with failure [[1]Schwartz M. Liver transplantation for hepatocellular carcinoma.Gastroenterology 2004;127(Suppl.). 2004; 1: S268-S276Google Scholar]. Based on currently available clinical parameters of tumor size and number, the risk of post-transplant tumor recurrence is a continuum [[1]Schwartz M. Liver transplantation for hepatocellular carcinoma.Gastroenterology 2004;127(Suppl.). 2004; 1: S268-S276Google Scholar]. Recurrence rates approach zero with solitary, well-differentiated tumors<2 cm, which are often discovered incidentally by the pathologist; about 10% recurrence is seen when the Milan criteria (single nodule ≤5 cm, 2–3 nodules all≤3 cm) are employed for candidate selection [2Mazzaferro V. Regalia E. Doci R. 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 (5561) Google Scholar, 3Llovet 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 (1468) Google Scholar]; and rates as high as 50% have been reported when patients with tumors>5 cm with portal vein invasion are included [4Iwatsuki S. Starzl T.E. Sheahan D.G. et al.Hepatic Resection Versus Transplantation for Hepatocellular Carcinoma.Ann Surg. 1991; 214: 221-228Crossref PubMed Scopus (569) Google Scholar, 5Ringe B. Pichlmayr R. Wittekind C. Tusch G. Surgical Treatment of Hepatocellular Carcinoma: Experience with Liver Resection and Transplantation in 198 Patients.World J Surg. 1991; 15: 270-285Crossref PubMed Scopus (534) Google Scholar]. Based on conventional criteria, it is impossible to avoid HCC recurrence entirely except by not transplanting patients for this indication. There is no evidence that the timing or severity of recurrence of HCC is different after living donor liver transplantation (LDLT) than after deceased donor OLT. The worse actuarial recurrence rates reported with LDLT in all likelihood reflect the selection of patients with more advanced HCC stages rather than a hypothetical risk related to stimulation of neoplastic cells by growth factors linked to hepatic regeneration [6Todo S. Furukawa H. Japanese Study Group on Organ Transplantation.Living Donor Liver Transplantation for Adult Patients with Hepatocellular Carcinoma: Experience in Japan Ann Surg. 2004; 240: 451-459Google Scholar, 7Gondolesi G.E. Roayaie S. Munoz L. et al.Adult Living Donor Liver Transplantation for Patients with Hepatocellular Carcinoma: Extending UNOS Priority Criteria.Ann Surg. 2004; 239: 142-149Crossref PubMed Scopus (188) Google Scholar]. In order to make the best use of the scarce donor organs, which can yield 75% 5-year survival in patients without HCC, the criteria used to select patients for OLT are typically designed to equal these survival rates and minimize recurrence. While current clinical practice bases candidate selection on size and number of tumors, these are but crude indices of the likelihood of recurrence. Genomic markers are urgently needed to refine candidate selection criteria in order to minimize dropout and recurrence rates. These gene signatures will enable both the exclusion of patients with apparently early HCC but with aggressive biologic behavior, and the identification of patients with tumors exceeding conventional criteria that nevertheless are unlikely to recur. This review will attempt to summarize what is known about the natural history of recurrent HCC after OLT and how best to manage it, acknowledging at the outset that there is a lack of randomized studies in this setting, and thus evidence of efficacy of treatments is derived from small cohort studies. Recurrence of HCC after OLT clearly has a major impact on outcome (Fig. 1). There is, however, a wide range in the time from OLT to recurrence and in survival post-recurrence. The median time to recurrence in various series ranges from 8–14 months [8Marsh J.W. Dvorchik I. Subotin M. et al.The Prediction of Risk of Recurrence and Time to Recurrence of Hepatocellular Carcinoma After Orthotopic Liver Transplantation: A Pilot Study.Hepatology. 1997; 26: 444-450Crossref PubMed Scopus (188) Google Scholar, 9Schlitt H.J. Neipp M. Weimann A. et al.Recurrence Patterns of Hepatocellular and Fibrolamellar Carcinoma After Liver Transplantation.J Clin Oncol. 1999; 17: 324-331PubMed Google Scholar, 10Regalia E. Fassati L.R. Valente U. et al.Pattern and Management of Recurrent Hepatocellular Carcinoma After Liver Transplantation.J Hepatobiliary Pancreat. 1998; 5: 29-34Crossref PubMed Scopus (136) Google Scholar, 11Roayaie S. Schwartz J.D. Sung M.W. et al.Recurrence of Hepatocellular Carcinoma After Liver Transplant: Patterns and Prognosis.Liver Transpl. 2004; 10: 534-540Crossref PubMed Scopus (363) Google Scholar]. Most recurrences occur within 2 years after OLT [[8]Marsh J.W. Dvorchik I. Subotin M. et al.The Prediction of Risk of Recurrence and Time to Recurrence of Hepatocellular Carcinoma After Orthotopic Liver Transplantation: A Pilot Study.Hepatology. 1997; 26: 444-450Crossref PubMed Scopus (188) Google Scholar], although around 20% of cases first present tumor relapse beyond 3 years post-OLT [9Schlitt H.J. Neipp M. Weimann A. et al.Recurrence Patterns of Hepatocellular and Fibrolamellar Carcinoma After Liver Transplantation.J Clin Oncol. 1999; 17: 324-331PubMed Google Scholar, 11Roayaie S. Schwartz J.D. Sung M.W. et al.Recurrence of Hepatocellular Carcinoma After Liver Transplant: Patterns and Prognosis.Liver Transpl. 2004; 10: 534-540Crossref PubMed Scopus (363) Google Scholar], indicating the need for prolonged surveillance (Table 1, Fig. 2). Time to recurrence is shorter in patients with tumors that are large (>5 cm) or poorly-differentiated. The median survival after the diagnosis of recurrence is around 9 months, with shorter time to recurrence and the presence of bone metastases the main factors significantly associated with poorer prognosis once recurrence is manifest [[11]Roayaie S. Schwartz J.D. Sung M.W. et al.Recurrence of Hepatocellular Carcinoma After Liver Transplant: Patterns and Prognosis.Liver Transpl. 2004; 10: 534-540Crossref PubMed Scopus (363) Google Scholar] (Fig. 3). It is important to bear in mind, however, that the median survival after recurrence of patients with solitary sites of disease amenable to surgery/ablation is 24 months [10Regalia E. Fassati L.R. Valente U. et al.Pattern and Management of Recurrent Hepatocellular Carcinoma After Liver Transplantation.J Hepatobiliary Pancreat. 1998; 5: 29-34Crossref PubMed Scopus (136) Google Scholar, 11Roayaie S. Schwartz J.D. Sung M.W. et al.Recurrence of Hepatocellular Carcinoma After Liver Transplant: Patterns and Prognosis.Liver Transpl. 2004; 10: 534-540Crossref PubMed Scopus (363) Google Scholar].Table 1Survival and time to recurrenceStudyStudy periodTransplants w/HCC (n)Recurrences (n)5 yr survival w/recurrence (%)Time to recurrenceMedian (mo)Range (mo)Roayaie, 20041988–200231157 (18%)2212.31.5–60Schlitt, 19991972–199411439 (34%)1814.51.4–105Regalia, 19981987–199613221 (16%)297.81–25 Open table in a new tab Fig. 2Time from transplant to recurrence of HCC. (modified from Roayaie S, Schwartz JD, Sung MW, et al. Recurrence of Hepatocellular Carcinoma After Liver Transplant: Patterns and Prognosis. Liver Transpl. 2004; 10(4):534–540).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 3Survival from time of recurrence based on characteristics found to be significant on multivariate analysis. Best candidates vs. overall vs. worst.View Large Image Figure ViewerDownload Hi-res image Download (PPT) While recurrence of HCC may present in the transplanted liver, the majority of recurrences are extrahepatic: 53% of patients present with extrahepatic sites only, 31% with both extra- and intrahepatic tumor, and only 16% with the liver as the sole site. Extrahepatic tumor presents most commonly in the lungs (43%) and bones (33%) (Table 2) [9Schlitt H.J. Neipp M. Weimann A. et al.Recurrence Patterns of Hepatocellular and Fibrolamellar Carcinoma After Liver Transplantation.J Clin Oncol. 1999; 17: 324-331PubMed Google Scholar, 10Regalia E. Fassati L.R. Valente U. et al.Pattern and Management of Recurrent Hepatocellular Carcinoma After Liver Transplantation.J Hepatobiliary Pancreat. 1998; 5: 29-34Crossref PubMed Scopus (136) Google Scholar, 11Roayaie S. Schwartz J.D. Sung M.W. et al.Recurrence of Hepatocellular Carcinoma After Liver Transplant: Patterns and Prognosis.Liver Transpl. 2004; 10: 534-540Crossref PubMed Scopus (363) Google Scholar].Table 2Patterns of recurrenceStudySites of recurrenceIntra vs. extrahepaticLiver (%)Lung (%)Bone (%)Other (%)Intrahepatic (%)Extrahepatic (%)Both (%)Roayaie, 200447433325163151Schlitt, 1999625618132338.538.5Regalia, 1998193348 Open table in a new tab There is no well-established schedule for follow-up of HCC patients after transplantation. For the purpose of surveillance for recurrence, it is our practice at Mount Sinai to stratify these patients into low- and high-risk groups based on findings at pathology. Low-risk patients, defined as having tumors found to be within the Milan criteria, to be well- or moderately differentiated, and to lack vascular invasion, are followed according to a protocol wherein a baseline CT scan of the chest and abdomen is obtained at 3 months, followed by yearly scans for 5 years. High-risk patients (those with tumors that exceed Milan criteria, are poorly-differentiated, or exhibit vascular invasion) are followed more closely, with scans every 3 months for the first year, every 6 months for the second and third year, then yearly until 5 years. In addition, alpha-fetoprotein is measured each time blood tests are obtained. The diagnosis of HCC recurrence can usually be made based on non-invasive criteria. The incidence of skin and virally-mediated cancers (e.g., Epstein–Barr Virus-related lymphoma) is clearly increased in transplant patients [12Herrero J.I. Lorenzo M. Quiroga J. et al.De Novo Neoplasia After Liver Transplantation: An Analysis of Risk Factors and Influence on Survival.Liver Transpl. 2004; 11: 89-97Crossref Scopus (131) Google Scholar, 13Haagsma E.B. Hagens V.E. Schaapveld M. et al.Increased Cancer Risk After Liver Transplantation: A Population-Based Study.J Hepatol. 2001; 34: 84-91Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar]. There is, however, no clear evidence that the incidence or the clinical course of common solid tumors like breast, colon, or lung cancer is affected by immune suppression [[14]Woodle E.S. Buell J. Hanaway M. First M.R. Trofe J. Israel Penn Intrnational Transplant Tumor Registry.Biologic Behavior of Carcinoid Tumors in Solid Organ Transplant Recipients: The Israel Penn International Transplant Tumor Registry Experience. Transplant Proc. 2001; 33: 3656-3657Google Scholar]. While HCC most commonly develops in the setting of cirrhosis due to viral hepatitis, the tumor is not driven by viral replication. Early reports suggested that the course of recurrent HCC after transplant was more aggressive than that of similar recurrence after hepatic resection, presumably due to immune suppression [[15]Yokoyama I. Carr B. Saitsu H. Iwatsuki S. Starzl T.E. Accelerated Growth Rates of Recurrent Hepatocellular Carcinoma After Liver Transplantation.Cancer. 1991; 68: 2095-2100Crossref PubMed Scopus (219) Google Scholar]. This has not been borne out in subsequent studies, however [[16]Steininger R. Herbst F. Fugger R. Muhlbacher F. Fritsch A. Immunosuppression does Not Enhance Tumor Growth After Orthotopic Liver Transplantation for Hepatoma.Transplant Proc. 1992; 24: 2690-2692PubMed Google Scholar]. Nevertheless, the drugs used to prevent transplant rejection have a variety of effects that go beyond immune suppression. The article by Majno et al., also included in this forum, discusses the effects of immunosuppression on HCC in detail. Poor results in historical series of transplantation for HCC through the 1980s led to the widespread abandonment of HCC as an indication for transplant [4Iwatsuki S. Starzl T.E. Sheahan D.G. et al.Hepatic Resection Versus Transplantation for Hepatocellular Carcinoma.Ann Surg. 1991; 214: 221-228Crossref PubMed Scopus (569) Google Scholar, 5Ringe B. Pichlmayr R. Wittekind C. Tusch G. Surgical Treatment of Hepatocellular Carcinoma: Experience with Liver Resection and Transplantation in 198 Patients.World J Surg. 1991; 15: 270-285Crossref PubMed Scopus (534) Google Scholar]. In the early 1990s a number of centers, including our own, began to readdress the issue by developing multimodality protocols for transplantation of patients with HCC, variably including pre-, intra-, and post-operative chemotherapy [17Schwartz M.E. Sung M. Mor E. et al.A Multidisciplinary Approach to Hepatocellular Carcinoma in Patients with Cirrhosis.J Am Coll Surg. 1995; 180: 596-603PubMed Google Scholar, 18Stone M.J. Klintmalm G.B. Polter D. et al.Neoadjuvant Chemotherapy and Liver Transplantation for Hepatocellular Carcinoma: A Pilot Study in 20 Patients.Gastroenterology. 1993; 104: 196-202Abstract PubMed Google Scholar, 19Olthoff K.M. Rosove M.H. Shackleton C.R. et al.Adjuvant Chemotherapy Improves Survival After Liver Transplantation for Hepatocellular Carcinoma.Ann Surg. 1995; 221: 734-741Crossref PubMed Scopus (151) Google Scholar]. Doxorubicin was the most widely used drug in these protocols, with cisplatin, 5-fluorouracil, and mitomycin-C also finding application. Early reports showed results better than those of historic controls, although no unquestionable benefit was ultimately proven. In retrospect, improving results of transplantation for HCC through the 1990s related primarily to advances in imaging and understanding of risk factors that led to improved case selection [[2]Mazzaferro V. Regalia E. Doci R. 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 (5561) Google Scholar]. Furthermore, the rationale of using drugs in an adjuvant setting that have minimal activity in the presence of measurable disease is highly questionable. Thus, apart from pre-transplant chemoembolization and local ablation employed in an effort to forestall tumor progression while awaiting transplant [20Maddala Y.K. Stadheim L. Andrews J.C. et al.Drop-Out Rates of Patients with Hepatocellular Cancer Listed for Liver Transplantation: Outcome with Chemoembolization.Liver Transpl. 2004; 10: 449-455Crossref PubMed Scopus (195) Google Scholar, 21Majno P.E. Adam R. Bismuth H. et al.Influence of Preoperative Transarterial Lipiodol Chemoembolization on Resection and Transplantation for Hepatocellular Carcinoma in Patients with Cirrhosis.Ann Surg. 1997; 226: 688-701Crossref PubMed Scopus (468) Google Scholar], these multimodality protocols have fallen out of favor, with the emphasis instead on preventing recurrence by imposing strict selection criteria. The majority of patients with post-transplant recurrence of HCC present with multifocal disease that is not amenable to local therapy. In that minority of cases where localized recurrence is detected, however, direct treatment by surgery or ablation warrants consideration (Table 3). In a series of 57 patients with recurrent HCC reported from our institution [[11]Roayaie S. Schwartz J.D. Sung M.W. et al.Recurrence of Hepatocellular Carcinoma After Liver Transplant: Patterns and Prognosis.Liver Transpl. 2004; 10: 534-540Crossref PubMed Scopus (363) Google Scholar], 18 (32%) underwent potentially curative treatment, including resection of the transplanted liver (n=5), lung resection (n=7), radiofrequency ablation of hepatic lesions (n=3), adrenalectomy (n=2), and resection of a chest wall recurrence at a pre-transplant tumor biopsy site (n=1). Five-year post-transplant survival among these patients was 47%. Surgical treatment was identified as an independent predictor of survival, and both overall post-transplant survival and survival post-recurrence were significantly longer in surgically treated patients (Fig. 4). As anecdotal cases, three patients- two after lung resection and one after excision of a biopsy site recurrence- survived more than 5 years after resection free of disease.Table 3Radical treatments of recurrent HCC after transplantStudyTreated radicallyLiver resectionLung resectionOther5 yr survival (%)Roayaie, 200418 (32%)57647Schlitt, 199915 (38%)38447Regalia, 19987 (33%)22357a4 yr survival.a 4 yr survival. Open table in a new tab The findings in our study are echoed in other series reported from Milan and Hamburg [9Schlitt H.J. Neipp M. Weimann A. et al.Recurrence Patterns of Hepatocellular and Fibrolamellar Carcinoma After Liver Transplantation.J Clin Oncol. 1999; 17: 324-331PubMed Google Scholar, 10Regalia E. Fassati L.R. Valente U. et al.Pattern and Management of Recurrent Hepatocellular Carcinoma After Liver Transplantation.J Hepatobiliary Pancreat. 1998; 5: 29-34Crossref PubMed Scopus (136) Google Scholar] that demonstrated better outcomes in patients with surgically treated post-transplant HCC recurrence. While it is clear that patients selected for surgical treatment are a subgroup with the best pre-operative variables, and the numbers of patients in these studies is too small to allow firm conclusions, it appears reasonable to consider surgical/ablative treatment of recurrent HCC when the tumor is confined to a single anatomic site that is readily amenable to treatment with low expected morbidity. Our approach has been to wait for a minimum of 3 months after initial detection of recurrence, restudying the patient with abdominal/chest CT scan and bone scintography to rule out other sites of disease prior to proceeding with surgical/ablative treatment. Retransplantation for recurrent HCC, though anecdotally reported [[9]Schlitt H.J. Neipp M. Weimann A. et al.Recurrence Patterns of Hepatocellular and Fibrolamellar Carcinoma After Liver Transplantation.J Clin Oncol. 1999; 17: 324-331PubMed Google Scholar], is not indicated except possibly in cases of late post-transplant ‘recurrences’ that in actuality represent de novo HCC in the transplanted liver, a phenomenon that has been observed as early as 5 years post-operatively [[22]Saxena R. Ye M.Q. Emre S. Klion F. Nalesnik M.A. Thung S.N. De Novo Hepatocellular Carcinoma in a Hepatic Allograft with Recurrent Hepatitis C Cirrhosis.Liver Transpl Surg. 1999; 5: 81-82Crossref PubMed Scopus (49) Google Scholar]. The same modalities (percutaneous ethanol injection, radiofrequency ablation, and chemoembolization) that are commonly employed to treat unresectable primary HCC can be used to treat recurrent HCC in the liver, but the rationale for doing so cannot necessarily be inferred from the non-transplant literature. Both ethanol injection and radiofrequency ablation rely on the physical characteristics of the tumor and the surrounding liver (soft, encapsulated tumor contained within a firm, cirrhotic liver) for their efficacy [[23]Livraghi T. Goldberg S.N. Lazzaroni S. Meloni F. Solbiati L. Gazelle G.S. Small Hepatocellular Carcinoma: Treatment with Radio-Frequency Ablation Versus Ethanol Injection.Radiology. 1999; 210: 655-661Crossref PubMed Scopus (1185) Google Scholar], and thus post-transplant intrahepatic recurrences, which are unencapsulated and not on a background of cirrhosis, may be less amenable to treatment by these means than are primary HCCs. Chemoembolization may be performed, though the lack of natural collateral arteries in the transplanted liver is thought by some to raise the risk of the procedure. While chemoembolization has been documented to prolong survival in HCC, this benefit was shown in a carefully selected population with primary HCC in the absence of extrahepatic spread [[24]Llovet J.M. Real M.I. Montana X. et al.Arterial Embolisation Or Chemoembolisation Versus Symptomatic Treatment in Patients with Unresectable Hepatocellular Carcinoma: A Randomised Controlled Trial.Lancet. 2002; 359: 1734-1739Abstract Full Text Full Text PDF PubMed Scopus (2822) Google Scholar]. These methods are commonly applied when liver-only recurrence is found after transplant, but there is no evidence that survival is thereby prolonged. There is no systemic treatment that has been shown to prolong survival in patients with locally advanced or metastatic HCC [[25]Llovet J.M. Bruix J. Systematic Review of Randomized Trials for Unresectable Hepatocellular Carcinoma: Chemoembolization Improves Survival.Hepatology. 2003; 37: 429-442Crossref PubMed Scopus (2508) Google Scholar]. Response rates with conventional chemotherapy, generally based on doxorubicin, are around 10%. More aggressive combination regimens, such as the so-called PIAF (cisplatin, interferon α-2b, doxorubicin and fluorouracil)regimen, may achieve a somewhat higher response rate, but at the expense of significant toxicity [[26]Leung T.W. Tang A.M. Zee B. et al.Factors Predicting Response and Survival in 149 Patients with Unresectable Hepatocellular Carcinoma Treated by Combination Cisplatin.Interferon-Alpha, Doxorubicin and 5-Fluorouracil Chemotherapy. Cancer. 2002; 94: 421-427Google Scholar]. Administration of chemotherapy to transplant patients, while possible, may be complicated by the coadministration of immunosuppressive medications. Given the absence of treatment that is of proven benefit, entry of these patients into clinical trials investigating new approaches would seem reasonable, but in many cases the fact that they have undergone liver transplantation renders them ineligible. The presence of bone metastases, irrespective of other sites of metastasis, has been shown to be an independent predictor of poor outcome in patients with post-transplant HCC recurrence [[11]Roayaie S. Schwartz J.D. Sung M.W. et al.Recurrence of Hepatocellular Carcinoma After Liver Transplant: Patterns and Prognosis.Liver Transpl. 2004; 10: 534-540Crossref PubMed Scopus (363) Google Scholar]. Treatment of bone metastases is aimed at palliating symptoms, and has the same modest role in the post-transplant setting as in non-transplant patients. Local radiotherapy provides effective palliation of painful skeletal lesions [27Koom W.S. Seong J.S. Lee M.J. et al.Radiation Therapy for Bone Metastasis from Hepatocellular Carcinoma.Taehan Kan Hakhoe Chi. 2002; 8: 304-311PubMed Google Scholar, 28van der Linden Y.M. Lok J.J. Steenland E. et al.Single Fraction Radiotherapy is Efficacious: A further Analysis of the Dutch Bone Metastasis Study Controlling for the Influence of Retreatment.Int J Radiat Oncol Biol Phys. 2004; 59: 528-537Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar]. Radiofrequency ablation of painful bone metastases has recently been reported as an effective alternative [[29]Goetz M.P. Callstrom M.R. Charboneau J.W. et al.Percutaneous Image-Guided Radiofrequency Ablation of Painful Metastases Involving Bone: A Multicenter Study.J Clin Oncol. 2004; 22: 300-306Crossref PubMed Scopus (480) Google Scholar]. Osteoclast inhibition by bisphosphonates, in particular with zoledronic acid (administered intravenously at a dose of 4 mg every 3 weeks) has been shown to significantly reduce the incidence of fractures [30Conte P. Coleman R. Bisphosphonates in the Treatment of Skeletal Metastases.Semin Oncol 2004;31(Suppl.). 2004; 10: 59-63Google Scholar, 31Rosen L.S. Gordon D. Tchekmedyian N.S. et al.Long-Term Efficacy and Safety of Zoledronic Acid in the Treatment of Skeletal Metastases in Patients with Nonsmall Cell Lung Carcinoma and Other Solid Tumors: A Randomized.Phase III, Double-Blind, Placebo-Controlled Trial. Cancer. 2004; 100: 2613-2621Google Scholar]. Unstable spinal metastases and pathologic fractures may require surgical treatment [[32]Bohm P. Huber J. The Surgical Treatment of Bony Metastases of the Spine and Limbs.J Bone Joint Surg Br. 2002; 84: 521-529Crossref PubMed Scopus (170) Google Scholar]. In conclusion, HCC recurrence after LT can be minimized/prevented by employing strict selection criteria. Adjuvant therapies prior to and after transplantation have not been proven to reduce recurrence. Tumor recurrence generally carries a poor prognosis; however, that subset of patients with recurrence that is amenable to curative treatment has a materially better outlook. Clearly, selection bias confounds comparison between surgically and non-surgically treated patients. Nevertheless, complete elimination of single-site recurrences by surgical/ablative treatment, when feasible, seems reasonable. Apart from surgery, there is no evidence to support any currently available treatment for recurrent HCC. There is theoretical rationale for the use of sirolimus in addition to or instead of calcineurin inhibitors in patients transplanted for HCC that warrants study in randomized, controlled trials. Studies aimed at the prevention and treatment of recurrent HCC will, because of the numbers of patients required to enable robust conclusions, require multiinstitutional efforts. The incorporation of molecular data into clinical practice has the potential both to prevent recurrence through improved case selection, and to guide treatment by identifying patterns of gene expression that predict response to targeted therapies. Myron Schwartz is supported by NIH grant K24 DK 60498-01 entitled, ‘Systematic Integration of Patient-Oriented Research into the Clinical Pathway for Hepatocellular Carcinoma’. Josep M Llovet is supported by a grant from AGAUR (2003BEAI00138 and 2004BE00226, Generalitat de Catalunya,Spain), Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias 2002-2005, PI02/0596) and Programa ‘Ramon y Cajal’ (IDIBAPS, Ministerio de Ciencia y Tecnología, Spain).