- Email: [email protected]
Treatment of early hepatocellular carcinoma: Towards personalized therapy
Digestive and Liver Disease 42S (2010) S242–S248
Treatment of early hepatocellular carcinoma: Towards personalized therapy Silvia Tremosini, María Reig, Carlos Rodríguez de Lope, Alejandro Forner, Jordi Bruix * BCLC Group, Liver Unit, CIBEREHD, IDIBAPS, Hospital Clínic, Barcelona, Spain
Abstract In recent years, the wide implementation of surveillance programs has led to diagnose HCC at earlier stages, when curative options can be applied. In order to obtain the best results, treatment indication should take into account the estimation of baseline life expectancy. Patients at an early stage are those with single HCC or up to three nodules <3 cm with preserved liver function (Child-Pugh A–B) and no cancer related symptoms. These patients should be evaluated for any of the therapies that can offer complete responses with potential long-term cure, as reflected by a 5 years survival superior to 50–70%. These include surgical resection, liver transplantation and ablation. We briefly reviewed therapeutic management for early HCC, taking into account that any recommendation should be delivered in the clinical setting and based on an individualised evaluation of each patient. © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Ablation; Hepatocellular carcinoma; Personalized therapy; Surgical resection; Transplantation
1. Introduction Major advances have taken place during the last 20 years in the field of treatment for hepatocellular carcinoma (HCC) [1]. Years ago, the sole option available was surgical resection, but today, patients diagnosed with HCC can benefit from effective therapy at any evolutionary stage and hence, their survival has been unequivocally expanded. As in any clinical process, the key for optimal application of any health intervention is based on an individualised evaluation of the patient that ultimately should guide the decision making process, while never forgetting that evidence based data should be prime over personal wishful thinking. When considering treatment, the critical question to answer is what therapeutic intervention can be applied to benefit the patient, while a feasibility approach should be secondary. Frequently, clinical controversies revolve around the second concept putting major emphasis on technical potential (i.e., is * Correspondence to: Jordi Bruix, MD, BCLC Group, Liver Unit, CIBEREHD, IDIBAPS, Hospital Clínic, c/ Villarroel, 170. Escala 11, 4a planta, 08036 Barcelona, Spain. Tel.: +34 932279803, fax: +34 932275792. E-mail address: [email protected] (J. Bruix).
resection feasible?) rather than on impact on life expectancy (will outcome be significantly improved without incurring in risks of impairing it?). Thus, treatment indication should be based on the estimation of the baseline life expectancy [2] and its comparison with that offered by any intervention [3]. There are several systems aimed at estimating the life expectancy of HCC patients [4] unfortunately some of them do not offer a complete assessment of the patient as symptoms are neglected [5] while in other instances the evaluation of tumour burden and/or liver function [6,7] is done in a very coarse manner. As a whole, the usefulness in the clinical arena is limited. Only the Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy (Fig. 1) has gained wide acceptance and endorsement because of its stratification capacity and its linkage of staging with treatment indication [3,4]. According to this system, patients diagnosed with HCC are divided into four stages (BCLC 0/A: very early/early, BCLC B: intermediate, BCLC C: advanced and BCLC D: end-stage) (Fig. 1). Patients at BCLC 0/A are those with single HCC or up to three nodules <3 cm with preserved liver function (Child-Pugh A–B) and no cancer related symptoms. These patients should be evaluated for any of the therapies that can offer complete responses
1590-8658/$ – see front matter © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
S. Tremosini et al. / Digestive and Liver Disease 42S (2010) S242–S248
S243
Fig. 1. BCLC staging and treatment strategy. The figure shows the clinical decision making process applied to stratify patients diagnosed with HCC into very early/early, intermediate, advanced and end-stage. It links staging with treatment selection according to evidence based data (adapted from Llovet et al. [3]).
with potential long-term cure, as reflected by disease free survival exceeding 5 years in a relevant proportion of cases [4]. These include surgical resection, liver transplantation and ablation [3,4]. Patients at BCLC B are those with a preserved liver function and large/multifocal HCC without extrahepatic spread and/or cancer symptoms. In these patients transarterial chemoembolization is the preferred option if the liver function fits into Child-Pugh A [3]. Patients at BCLC C are those with extrahepatic spread and/or symptoms and the sole approach that has shown a positive impact in survival is sorafenib administration [8,9]. Finally, patients fitting into BCLC D (heavily impaired liver function, major physical impairment) should receive only symptomatic care and avoid unnecessary suffering. It is important to note that these recommendations apply to patients evaluated for HCC diagnosis and that evaluation of decompensated liver disease with major functional impairment is a different clinical scenario in which transplantation is the sole option with potential impact on survival. In this setting, the detection of liver cancer may become a contraindication for transplantation if too advanced (beyond the Milano criteria) and if transplant is not feasible, no option will be able to curb the grim life expectancy associated with extensive tumour stage and associated severe liver function impairment [10]. In this chapter we will review and discuss the criteria for the optimal selection of treatment for an individual patient diagnosed with very early/early HCC, while also exposing the limitations and potential areas of research that are currently ongoing and may have an impact in the next few years.
2. Definition of very early/early HCC As in all cancer types, there is a transition from an initial stage, where dissemination and risk of distant metastases is negligible, to a more invasive stage with vascular invasion spread to regional lymph nodes and other organs. This evolution has a correlation with tumour size, with a large set of data showing that the risk of vascular involvement and spread appears from a diameter of around 2 cm onwards and becomes almost universal beyond 5 cm [11–13] Indeed, while years ago small HCC was defined as being less than 5 cm, the cut-off and definition terms have changed over time to less than 4 cm, less than 3 and finally, less than 2 cm in size. The terms used to define this entity have included minute, subclinical and very early. The term “very early” was proposed a few years ago on the basis of pathology characterization of minute distinct nodules within a cirrhotic nodular liver ultimately leading to a consensus definition of the criteria to apply for a proper distinction between regenerative, dysplastic and malignant nodules [11]. It is important to note that even nodules <2 cm in size can be divided into two categories: the ill-defined indistinctly nodular type and the distinctly nodular type [11]. The indistinctly nodular type is composed of well differentiated hepatocytes. It has ill defined tumour boundaries and lacks vascular invasion or satellites. Contrarily, around 80% of small HCCs of distinctly nodular type are already moderately differentiated and microscopic vascular invasion in portal vein radicles or minute intrahepatic metastases (satellites) in the vicinity of the tumour can be observed in 27% and 10%
S244
S. Tremosini et al. / Digestive and Liver Disease 42S (2010) S242–S248
Fig. 2. MR showing a small nodule within a cirrhotic liver. The dynamic pattern is characteristic of HCC (intense arterial uptake – left panel – followed by venous washout in the venous phase – right panel).
of the cases, respectively [11]. Unfortunately, the accurate distinction between the very early HCC (corresponding to the carcinoma in situ entity) is not feasible as per today, since imaging criteria are not defined (very early HCC usually lacks arterial uptake on dynamic imaging [Fig. 2], but this may also occur in some already progressed HCC), and biopsy may not capture its specific profile. Hence, for treatment decision, both very early and early HCC within the BCLC staging classification share the same strategy. Thus, in the following paragraphs we will summarise the outcome data available for each of the options that may provide long-term cure, as this should serve as the background to establish the optimal therapy for each individual. In that sense, it has to be acknowledged that there are no large randomised controlled trials comparing the various options or each option to no treatment. Hence, any recommendation to be delivered in the clinical setting should be based on an individualised evaluation of each patient with an expert and sound assessment of the potential best outcome to be achieved by each of the options and even the decision to avoid treatment or to consider interventions that are first line options for more advanced stages, such as TACE or sorafenib.
3. Surgical resection Years ago this was the sole option to be considered and all efforts were aimed at increasing the resectability as per surgical technique and at avoiding liver failure and early postoperative death because of treatment related side effects. It is well known that patients with a normal liver tolerate large hepatectomy without significant risk of liver failure. However, in patients with chronic liver disease the tolerance to liver resection and long-term outcome is reduced in parallel to the degree of liver function impairment and appearance of portal hypertension [14,15]. Hemodynamic studies have shown that the presence of a hepatic vein pressure gradient greater than 10 mmHG is associated with a higher risk of postoperative liver decompensation and of poor long-term outcome [14]. Clinically relevant portal hypertension can also be detected
by the existence of esophageal varices or splenomegaly associated with reduced platelet count. The application of these criteria and the outcome correlation has been validated in both the East [16] and the West [17]. Thus, assessment of portal hypertension is a relevant step in risk assessment and outcome prediction. While 5 year survival in patients without portal hypertension exceeds 70%, those patients with such adverse profile present a reduction to 50–60%. If liver disease is decompensated (ascites, jaundice), survival is even further decreased. Obviously, higher risk does not translate into a full contraindication for resection, but the predicted outcome with surgery has to be confronted with that of applying alternative options. The best results are obtained in patients with small solitary tumours, while multifocality may not impede resection as regards technical feasibility, but all data show that long-term survival even in the absence of portal hypertension falls to around 50% with a high rate of disease recurrence [15]. This is the major drawback of surgical resection (as well as of ablation) and is due to two mechanisms. The most frequent is cell dissemination prior to treatment. This gives rise to metastatic nests and its incidence is higher in tumours exhibiting microscopic vascular invasion and/or satellites [18]. More than 80% of the patients with this profile will suffer recurrence within the first two years of follow-up and their prognosis is negatively affected. The second mechanism for recurrence is related to the oncogenic capacity of the underlying liver that can give rise to metachronous tumours [18,19]. They are more prevalent after the two years of followup and their potential to be successfully treated is higher as compared with early recurrence that is usually multifocal. Since the prevalence of vascular invasion/satellites increases along with tumour size, it is clear that the larger the tumour, the higher the risk of these and of recurrence. However, there are some infrequent patients with large solitary HCC in whom the expansive tumour growth has not been associated with development of additional tumour sites. Hence, if after proper staging of a large HCC there is no proven dissemination, surgery should not be contraindicated, but physicians and patients should be aware of the statistics showing that
S. Tremosini et al. / Digestive and Liver Disease 42S (2010) S242–S248
the likelihood of microscopic vascular invasion (and hence, early recurrence after surgery) parallels tumour size. Indeed, intraoperative ultrasound may disclose additional tumour sites not detected preoperatively and abort the proposed resection. Careful evaluation of the non-tumoural liver parenchyma to be resected and of the expected remaining volume is mandatory prior to operation. Preoperative portal vein embolization of the lobe free of disease may induce compensatory liver growth, but robust proof of benefit and safety needs assessment [20,21]. There are no strategies to effectively diminish the risk of recurrence. Antiviral treatment for the hepatitis B and C viruses may translate in the prevention of liver disease progression but does not act on the already disseminated tumour clones that will result in early recurrence. To what extent antiviral therapy may reduce metachronous HCC is still a matter of debate. Interferon administration has provided suggestive data, but of limited scientific strength [3]. Chemotherapy and preoperative chemoembolization have no benefits and may even induce severe side effects and impair outcome [22]. Promising results reported years ago with retinoid administration [23], adaptive immunotherapy [24] and intrarterial radiation [25] need proper evaluation and validation. Hence, major research is needed in this aspect and the proven activity of sorafenib in patients with HCC offers the rationale to test this antiangiogenic and antiproliferative multikinase inhibitor as an adjuvant to resection and ablation.
4. Transplantation This treatment is now part of the conventional armamentarium for the treatment of HCC. In the initial years of solid organ transplantation it was usually offered to patients with advanced HCC in whom the grim short-term prognosis due to cancer balanced the high risk of an experimental intervention. Refined surgical techniques and effective immune suppression permitted adequate survival and the analysis of the patients transplanted with incidental HCC allowed the establishment of limits of the tumour burden that could be accepted as an optimal indication because of long-term survival as good as that achieved in non-malignant conditions (70% at 5 years follow-up and around 50% at 10 years). The seminal study by Mazzaferro et al. [26] confirmed the validity of the so-called Milano criteria – single tumour ≤5 cm or 3 nodules ≤3 cm, with no vascular invasion or extrahepatic spread – and this has been widely accepted as the limit for candidate selection. Undoubtedly this definition excludes some patients with a slightly larger tumour burden that could achieve acceptable survival but significantly below the life expectancy of patients within Milano criteria. Suggestions for expansion [27–29] have been mostly based on the analysis of the explanted livers rather than on the radiology findings at the time of enlistment, use ill defined criteria to establish tumour burden, frequently dilute few patients with expanded criteria within a large group of conventional candidates, and finally, do not consider the impact of expanding the number of enlisted patients while it
S245
is well known that the major limitation for transplantation is the huge shortage of donors. The shortage varies according to countries and hence, every program/health system has to critically determine how many donors are available, how many candidates can be effectively treated within a fair system and the length of time patients will have to wait to be transplanted. During this period the HCC may progress and contraindicate transplantation and this impairs results according to intention to treat [3]. Priority policies have been established to transplant the sickest and diminish the risk of death while waiting. At the same time, it is common to treat the tumour upon enlistment as this may delay progression and reduce risk of exclusion. However, whatever is done to retain patients in the waiting list for longer or to advance those at higher risk, it is obvious that the number of livers is limited and that the sole effective approach to accommodate the demand is to increase the rate of donation. In this regard, living donation programs have become a valid possibility, but their applicability and impact in the West are still limited [30] as compared with data coming from countries where cadaveric donation is almost non-existent. Data from Asia [31–34] indicate a similar outcome using living donors, but despite technical refinements there is a 0.3–0.5% risk of death for the donor and this is likely the major reason for the limited applicability. Interestingly, the risk of HCC recurrence after transplantation is less than after resection or ablation even if stratifying for the same pathology risk profile. Hence, with similar survival and less recurrence, it would appear reasonable to consider transplantation as the first option as it would solve HCC and the underlying oncogenic liver. This consideration has to be tempered by the fact that liver transplantation is not a simple procedure. Morbidity and death rate in the early and intermediate follow-up period are higher than after resection surgery in optimal candidates. Finally, while recurrence of hepatitis B and alcoholic liver disease may be prevented, the status in patients infected with hepatitis C virus is not so encouraging [35–37]. Effective viral eradication is not common in cirrhotics (the underlying disease in most HCC), treatment pre and post-transplantation may have severe side effects, and, if not effective, reinfection of the graft is the rule and the long-term outcome is significantly impaired as compared to the other populations. All these facts have maintained surgical resection as the first line surgical option in patients with optimal profile as defined by solitary HCC in a liver without clinically relevant portal hypertension [14]. Operative risk is very low and analysis of the resected tumour will allow the classification of the tumor as at low risk for recurrence (no vascular invasion or satellites) (Fig. 3) [38] or as at high risk because of adverse pathology profile. If this is the case recurrence will impair prognosis and if the patient had been transplanted the risk and survival would have been significantly better. Based on this, the recommendation in these patients is to propose transplantation because of high risk of recurrence and not delay the decision to the appearance of recurrence as at that time multifocality will be the rule
S246
S. Tremosini et al. / Digestive and Liver Disease 42S (2010) S242–S248
Fig. 3. Small HCC with well defined limits and encapsulation. There is no evidence of microscopic vascular invasion or satellites. Hence, the risk of recurrence due to dissemination is low. If such adverse predictors were observed, the risk of recurrence after resection would be high and the patients would have to be considered for liver transplantation because of the risk of recurrence.
and transplantation will be contraindicated. By contrast, if the resected tumour does not have an invasive phenotype, the patient can avoid liver transplantation and the associated risks, while being under strict surveillance [38]. Recurrence will likely correspond to a metachronous tumour and benefit again of the same decision making process for treatment allocation.
5. Ablation This is the third therapy that can provide complete tumour elimination and long-term cure. To achieve this aim the patients have to fit into an optimal profile in terms of tumour burden and location. Ablation is based on inducing cell necrosis by either injecting agents that will induce cell death or by increasing or decreasing temperature, this also leading to cell death. The two most widely used techniques are ethanol injection and radiofrequency (RF), while other techniques such as laser, microwave, high intensity ultrasound, cryother-
Fig. 4. Small HCC treated by ethanol injection while waiting for liver transplantation. The nodule exhibits complete necrosis.
apy or acetic acid injection are less common or validated in terms of efficacy and safety. Ethanol injection at separate days until achieving complete tumour embedding (Fig. 4) was the standard technique until recently, but it has been replaced by RF. The needles for RF are thicker, but its advantage relies on its higher predictable antitumoral effect and the potential to treat successfully in one or two treatment sessions. Several studies have shown this higher disease control rate in a shorter time with RF and this is the basis for an improved outcome when it is compared against ethanol. However, the difference is apparent in nodules >2 cm while in lesions below this limit the efficacy and long-term outcome is very similar. Indeed, for any ablation technique the major limitations for efficacy is tumour size and even for RF, the long-term local disease control is significantly impaired when tumour size exceeds 3 cm. The extent of tumour necrosis is assessed by dynamic imaging, where absence of contrast uptake reflects successful necrosis (Fig. 5). While complete tumour necrosis exceeds 95% in nodules less than 2 cm, the success rate decreases to around 80% in HCC between 2 and 3 cm and to 50% at long
Fig. 5. Small hepatic nodule diagnosed as HCC and treated by radiofrequency ablation. While intense arterial uptake is recognised prior to treatment, the nodule appears avascular without any contrast uptake. This reflects tumor necrosis and hence, treatment success.
S. Tremosini et al. / Digestive and Liver Disease 42S (2010) S242–S248
term in larger tumours [39–42]. Initial response measured by tumour necrosis may appear successful in large lesions, but disease activity within the treated area is frequently detected during follow-up and this has given the basis for a combined treatment approach using chemoembolization followed by ablation. Up to now, there is no proof of its efficacy and application in practice should await data from research trials. Initial treatment with RF with later injection of ethanol to treat minute residual tumour foci is common practice and the two techniques should be seen as complementary rather than exclusive. Long-term studies indicate that Child-Pugh A patients with successful tumour necrosis may achieve a 50% survival at 5 years [43–45]. This compares well with the outcome of resection in those candidates who do not fit the optimal surgical profile [43].
6. Individualised decision making All the data exposed above should frame the rationale for the current treatment selection in an individual patient. The process has to take into account tumour extent, degree of liver function impairment and as in any other condition, the general health of the patient as reflected by age and associated comorbidities. If the underlying liver disease exhibits a preserved liver function without portal hypertension the first option to be considered is surgical resection. This provides optimal survival if the HCC is solitary. If high risk of recurrence is identified after resection, the patient will benefit from transplantation. However, if tumour staging has evidenced a multifocal HCC (up to three nodules <3 cm) resection might be feasible but the best outcome will be offered by transplantation. If this is not feasible because of any extrahepatic comorbidity, resection could again become an option. However, outcome may be similar to that offered by ablation if all tumours could be effectively ablated. Indeed, in solitary HCC <2 cm, ablation should be considered the first choice over transplant because the recurrence risk would not make the latter feasible. Then, resection would be considered if ablation should fail. If the same early HCC had appeared in a cirrhotic liver with portal hypertension, the best outcome would have been offered by transplantation, while resection and ablation may provide a lower life expectancy outcome if technically viable. Central tumour location may imply the need of large hepatectomy and thus, become too risky. The limiting factors for effective ablation are size and location: proximity to a large vessel impedes effective RF; subcapsular HCC may require direct puncture without a protective rim of non-tumoral liver and this increases the risk of seeding. Hence, if a solitary HCC is larger or unable to be ablated, surgery may become an option even in the presence of portal hypertension. Operative risk is increased, long-term outcome is not optimal, but even so it may compare positively with no treatment or TACE. Finally, if liver disease is decompensated, the sole option to improve survival is transplantation. Indeed, patients with advanced Child-Pugh stage or MELD >15
S247
should be considered for transplantation even in the absence of HCC and in such setting cancer detection may just become an exclusion criterion if the Milano criteria are exceeded.
7. Future perspectives The briefly reviewed therapeutic management for early HCC is valid for 2010. New data gathered in the next few years will surely change our understanding of cancer and specifically of HCC. The better knowledge of the molecular abnormalities leading to cancer and the specific profile associated to a better or worse prognosis will allow a biology-based prediction of the outcome of patients. This will also affect the treatment selection and the prediction of its long-term success [46]. Current data show that this refinement of the clinical evaluation of cancer is almost available [47] and the demonstration of the therapeutic activity of sorafenib [8] assures that this change in clinical practice based on cell biology is becoming a reality. The clinical management of patients according to robust clinical evidence and homogeneous decision making will provide the necessary setting to test if any serum or tissue marker is of any use to detect, diagnose and select treatment for HCC. In that way, serum and tissue banks with accurately annotated clinical data become a key tool for the generous and fruitful collaboration between clinicians and basic researchers, and this is the ultimate basis for a better care of our patients.
Conflict of interest JB has received a fee from Bayer HealthCare for his contribution to this supplement. Bayer HealthCare played no role in the preparation, review, or approval of the manuscript. ST, MR, CR and AF have no conflict of interest.
Financial support The BCLC group is supported by the Spanish Biomedical Research Network (CIBERehd) for the area of hepatic and digestive disorders of Ministry of Science and Innovation. This work was in part supported by a grant of the Instituto de Salud Carlos III (PI 08/0146). Silvia Tremosini and Carlos Rodriguez de Lope are funded by a grant of the BBVA foundation.
References [1] Bruix J, Llovet JM. Major achievements in hepatocellular carcinoma. Lancet 2009;373:614–6. [2] D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44:217–31. [3] Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints
S248
[4]
[5]
[6]
[7]
[8] [9]
[10] [11]
[12] [13] [14]
[15]
[16] [17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
S. Tremosini et al. / Digestive and Liver Disease 42S (2010) S242–S248 of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698–711. Forner A, Reig M, Rodrigruez de Lope C, et al. Current Strategy for Staging and Treatment : the BCLC Update and Future Prospects Semin Liver Dis 2010;30:61–74. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998;28:751–5. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646– 9. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33:464– 70. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia–Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25–34. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–36. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 2009;49:658–64. Kojiro M, Roskams T. Early hepatocellular carcinoma and dysplastic nodules. Semin Liver Dis 2005;25:133–42. Nakashima T, Kojiro M, editors. Hepatocellular carcinoma. Tokyo: Springer-Verlag; 1987. Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:1018–22. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30:1434–40. Cucchetti A, Ercolani G, Vivarelli M, et al. Is portal hypertension a contraindication to hepatic resection? Ann Surg 2009;250:922–8. Ishizawa T, Hasegawa K, Aoki T, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 2008;134:1908–16. Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003;38:200–7. Chen YJ, Yeh SH, Chen JT, et al. Chromosomal changes and clonality relationship between primary and recurrent hepatocellular carcinoma. Gastroenterology 2000;119:431–40. Farges O, Belghiti J, Kianmanesh R, et al. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg 2003;237:208–17. Tanaka H, Hirohashi K, Kubo S, et al. Preoperative portal vein embolization improves prognosis after right hepatectomy for hepatocellular carcinoma in patients with impaired hepatic function. Br J Surg 2000;87:879–82. Yamasaki S, Hasegawa H, Kinoshita H, et al. A prospective randomized trial of the preventive effect of pre-operative transcatheter arterial embolization against recurrence of hepatocellular carcinoma. Jpn J Cancer Res 1996;87:206–11. Muto Y, Moriwaki H, Ninomiya M, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 1996;334:1561–7. Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000;356:802–7. Schwartz JD, Schwartz M, Mandeli J, et al. Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet Oncol 2002;3:593–603.
[26] 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;334:693–9. [27] Marsh JW, Dvorchik I. Liver organ allocation for hepatocellular carcinoma: are we sure? Liver Transpl 2003;9:693–6. [28] Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394–403. [29] Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10:35–43. [30] Rimola A, Llovet JM, Navasa M, et al. Applicability of adult-to-adult living donor liver transplantation. J Hepatol 2005;43:104–9. [31] Kawasaki S. Living-donor liver transplantation for hepatocellular carcinoma. Hepatogastroenterology 2002;49:53–5. [32] Sugawara Y, Tamura S, Makuuchi M. Living donor liver transplantation for hepatocellular carcinoma: Tokyo University series. Dig Dis 2007;25:310–2. [33] Lee SG, Hwang S, Moon DB, et al. Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one large-volume center. Liver Transpl 2008;14:935–45. [34] Todo S, Furukawa H. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg 2004;240:451–459; discussion 459–61. [35] Berenguer M, Palau A, Aguilera V, et al. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation. Am J Transplant 2008;8:679–87. [36] Forman LM, Lewis JD, Berlin JA, et al. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122:889–96. [37] Carrion JA, Navasa M, Garcia-Retortillo M, et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology 2007;132:1746–56. [38] Sala M, Fuster J, Llovet JM, et al. High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation. Liver Transpl 2004;10:1294–300. [39] Shiina S, Teratani T, Obi S, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 2005;129:122–30. [40] Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 2003;228:235–40. [41] Livraghi T, Solbiati L, Meloni MF, et al. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology 2003;226:441–51. [42] Livraghi T, Meloni F, Di Stasi M, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology 2008;47:82–9. [43] Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology 2000;32:1224–9. [44] Sala M, Llovet JM, Vilana R, et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology 2004;40:1352–60. [45] Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 1995;197:101–8. [46] Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008;359:1995–2004. [47] Hoshida Y, Nijman SM, Kobayashi M, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009;69:7385–92.
Treatment of early hepatocellular carcinoma: Towards personalized therapy Silvia Tremosini, María Reig, Carlos Rodríguez de Lope, Alejandro Forner, Jordi Bruix * BCLC Group, Liver Unit, CIBEREHD, IDIBAPS, Hospital Clínic, Barcelona, Spain
Abstract In recent years, the wide implementation of surveillance programs has led to diagnose HCC at earlier stages, when curative options can be applied. In order to obtain the best results, treatment indication should take into account the estimation of baseline life expectancy. Patients at an early stage are those with single HCC or up to three nodules <3 cm with preserved liver function (Child-Pugh A–B) and no cancer related symptoms. These patients should be evaluated for any of the therapies that can offer complete responses with potential long-term cure, as reflected by a 5 years survival superior to 50–70%. These include surgical resection, liver transplantation and ablation. We briefly reviewed therapeutic management for early HCC, taking into account that any recommendation should be delivered in the clinical setting and based on an individualised evaluation of each patient. © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Ablation; Hepatocellular carcinoma; Personalized therapy; Surgical resection; Transplantation
1. Introduction Major advances have taken place during the last 20 years in the field of treatment for hepatocellular carcinoma (HCC) [1]. Years ago, the sole option available was surgical resection, but today, patients diagnosed with HCC can benefit from effective therapy at any evolutionary stage and hence, their survival has been unequivocally expanded. As in any clinical process, the key for optimal application of any health intervention is based on an individualised evaluation of the patient that ultimately should guide the decision making process, while never forgetting that evidence based data should be prime over personal wishful thinking. When considering treatment, the critical question to answer is what therapeutic intervention can be applied to benefit the patient, while a feasibility approach should be secondary. Frequently, clinical controversies revolve around the second concept putting major emphasis on technical potential (i.e., is * Correspondence to: Jordi Bruix, MD, BCLC Group, Liver Unit, CIBEREHD, IDIBAPS, Hospital Clínic, c/ Villarroel, 170. Escala 11, 4a planta, 08036 Barcelona, Spain. Tel.: +34 932279803, fax: +34 932275792. E-mail address: [email protected] (J. Bruix).
resection feasible?) rather than on impact on life expectancy (will outcome be significantly improved without incurring in risks of impairing it?). Thus, treatment indication should be based on the estimation of the baseline life expectancy [2] and its comparison with that offered by any intervention [3]. There are several systems aimed at estimating the life expectancy of HCC patients [4] unfortunately some of them do not offer a complete assessment of the patient as symptoms are neglected [5] while in other instances the evaluation of tumour burden and/or liver function [6,7] is done in a very coarse manner. As a whole, the usefulness in the clinical arena is limited. Only the Barcelona Clinic Liver Cancer (BCLC) staging and treatment strategy (Fig. 1) has gained wide acceptance and endorsement because of its stratification capacity and its linkage of staging with treatment indication [3,4]. According to this system, patients diagnosed with HCC are divided into four stages (BCLC 0/A: very early/early, BCLC B: intermediate, BCLC C: advanced and BCLC D: end-stage) (Fig. 1). Patients at BCLC 0/A are those with single HCC or up to three nodules <3 cm with preserved liver function (Child-Pugh A–B) and no cancer related symptoms. These patients should be evaluated for any of the therapies that can offer complete responses
1590-8658/$ – see front matter © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
S. Tremosini et al. / Digestive and Liver Disease 42S (2010) S242–S248
S243
Fig. 1. BCLC staging and treatment strategy. The figure shows the clinical decision making process applied to stratify patients diagnosed with HCC into very early/early, intermediate, advanced and end-stage. It links staging with treatment selection according to evidence based data (adapted from Llovet et al. [3]).
with potential long-term cure, as reflected by disease free survival exceeding 5 years in a relevant proportion of cases [4]. These include surgical resection, liver transplantation and ablation [3,4]. Patients at BCLC B are those with a preserved liver function and large/multifocal HCC without extrahepatic spread and/or cancer symptoms. In these patients transarterial chemoembolization is the preferred option if the liver function fits into Child-Pugh A [3]. Patients at BCLC C are those with extrahepatic spread and/or symptoms and the sole approach that has shown a positive impact in survival is sorafenib administration [8,9]. Finally, patients fitting into BCLC D (heavily impaired liver function, major physical impairment) should receive only symptomatic care and avoid unnecessary suffering. It is important to note that these recommendations apply to patients evaluated for HCC diagnosis and that evaluation of decompensated liver disease with major functional impairment is a different clinical scenario in which transplantation is the sole option with potential impact on survival. In this setting, the detection of liver cancer may become a contraindication for transplantation if too advanced (beyond the Milano criteria) and if transplant is not feasible, no option will be able to curb the grim life expectancy associated with extensive tumour stage and associated severe liver function impairment [10]. In this chapter we will review and discuss the criteria for the optimal selection of treatment for an individual patient diagnosed with very early/early HCC, while also exposing the limitations and potential areas of research that are currently ongoing and may have an impact in the next few years.
2. Definition of very early/early HCC As in all cancer types, there is a transition from an initial stage, where dissemination and risk of distant metastases is negligible, to a more invasive stage with vascular invasion spread to regional lymph nodes and other organs. This evolution has a correlation with tumour size, with a large set of data showing that the risk of vascular involvement and spread appears from a diameter of around 2 cm onwards and becomes almost universal beyond 5 cm [11–13] Indeed, while years ago small HCC was defined as being less than 5 cm, the cut-off and definition terms have changed over time to less than 4 cm, less than 3 and finally, less than 2 cm in size. The terms used to define this entity have included minute, subclinical and very early. The term “very early” was proposed a few years ago on the basis of pathology characterization of minute distinct nodules within a cirrhotic nodular liver ultimately leading to a consensus definition of the criteria to apply for a proper distinction between regenerative, dysplastic and malignant nodules [11]. It is important to note that even nodules <2 cm in size can be divided into two categories: the ill-defined indistinctly nodular type and the distinctly nodular type [11]. The indistinctly nodular type is composed of well differentiated hepatocytes. It has ill defined tumour boundaries and lacks vascular invasion or satellites. Contrarily, around 80% of small HCCs of distinctly nodular type are already moderately differentiated and microscopic vascular invasion in portal vein radicles or minute intrahepatic metastases (satellites) in the vicinity of the tumour can be observed in 27% and 10%
S244
S. Tremosini et al. / Digestive and Liver Disease 42S (2010) S242–S248
Fig. 2. MR showing a small nodule within a cirrhotic liver. The dynamic pattern is characteristic of HCC (intense arterial uptake – left panel – followed by venous washout in the venous phase – right panel).
of the cases, respectively [11]. Unfortunately, the accurate distinction between the very early HCC (corresponding to the carcinoma in situ entity) is not feasible as per today, since imaging criteria are not defined (very early HCC usually lacks arterial uptake on dynamic imaging [Fig. 2], but this may also occur in some already progressed HCC), and biopsy may not capture its specific profile. Hence, for treatment decision, both very early and early HCC within the BCLC staging classification share the same strategy. Thus, in the following paragraphs we will summarise the outcome data available for each of the options that may provide long-term cure, as this should serve as the background to establish the optimal therapy for each individual. In that sense, it has to be acknowledged that there are no large randomised controlled trials comparing the various options or each option to no treatment. Hence, any recommendation to be delivered in the clinical setting should be based on an individualised evaluation of each patient with an expert and sound assessment of the potential best outcome to be achieved by each of the options and even the decision to avoid treatment or to consider interventions that are first line options for more advanced stages, such as TACE or sorafenib.
3. Surgical resection Years ago this was the sole option to be considered and all efforts were aimed at increasing the resectability as per surgical technique and at avoiding liver failure and early postoperative death because of treatment related side effects. It is well known that patients with a normal liver tolerate large hepatectomy without significant risk of liver failure. However, in patients with chronic liver disease the tolerance to liver resection and long-term outcome is reduced in parallel to the degree of liver function impairment and appearance of portal hypertension [14,15]. Hemodynamic studies have shown that the presence of a hepatic vein pressure gradient greater than 10 mmHG is associated with a higher risk of postoperative liver decompensation and of poor long-term outcome [14]. Clinically relevant portal hypertension can also be detected
by the existence of esophageal varices or splenomegaly associated with reduced platelet count. The application of these criteria and the outcome correlation has been validated in both the East [16] and the West [17]. Thus, assessment of portal hypertension is a relevant step in risk assessment and outcome prediction. While 5 year survival in patients without portal hypertension exceeds 70%, those patients with such adverse profile present a reduction to 50–60%. If liver disease is decompensated (ascites, jaundice), survival is even further decreased. Obviously, higher risk does not translate into a full contraindication for resection, but the predicted outcome with surgery has to be confronted with that of applying alternative options. The best results are obtained in patients with small solitary tumours, while multifocality may not impede resection as regards technical feasibility, but all data show that long-term survival even in the absence of portal hypertension falls to around 50% with a high rate of disease recurrence [15]. This is the major drawback of surgical resection (as well as of ablation) and is due to two mechanisms. The most frequent is cell dissemination prior to treatment. This gives rise to metastatic nests and its incidence is higher in tumours exhibiting microscopic vascular invasion and/or satellites [18]. More than 80% of the patients with this profile will suffer recurrence within the first two years of follow-up and their prognosis is negatively affected. The second mechanism for recurrence is related to the oncogenic capacity of the underlying liver that can give rise to metachronous tumours [18,19]. They are more prevalent after the two years of followup and their potential to be successfully treated is higher as compared with early recurrence that is usually multifocal. Since the prevalence of vascular invasion/satellites increases along with tumour size, it is clear that the larger the tumour, the higher the risk of these and of recurrence. However, there are some infrequent patients with large solitary HCC in whom the expansive tumour growth has not been associated with development of additional tumour sites. Hence, if after proper staging of a large HCC there is no proven dissemination, surgery should not be contraindicated, but physicians and patients should be aware of the statistics showing that
S. Tremosini et al. / Digestive and Liver Disease 42S (2010) S242–S248
the likelihood of microscopic vascular invasion (and hence, early recurrence after surgery) parallels tumour size. Indeed, intraoperative ultrasound may disclose additional tumour sites not detected preoperatively and abort the proposed resection. Careful evaluation of the non-tumoural liver parenchyma to be resected and of the expected remaining volume is mandatory prior to operation. Preoperative portal vein embolization of the lobe free of disease may induce compensatory liver growth, but robust proof of benefit and safety needs assessment [20,21]. There are no strategies to effectively diminish the risk of recurrence. Antiviral treatment for the hepatitis B and C viruses may translate in the prevention of liver disease progression but does not act on the already disseminated tumour clones that will result in early recurrence. To what extent antiviral therapy may reduce metachronous HCC is still a matter of debate. Interferon administration has provided suggestive data, but of limited scientific strength [3]. Chemotherapy and preoperative chemoembolization have no benefits and may even induce severe side effects and impair outcome [22]. Promising results reported years ago with retinoid administration [23], adaptive immunotherapy [24] and intrarterial radiation [25] need proper evaluation and validation. Hence, major research is needed in this aspect and the proven activity of sorafenib in patients with HCC offers the rationale to test this antiangiogenic and antiproliferative multikinase inhibitor as an adjuvant to resection and ablation.
4. Transplantation This treatment is now part of the conventional armamentarium for the treatment of HCC. In the initial years of solid organ transplantation it was usually offered to patients with advanced HCC in whom the grim short-term prognosis due to cancer balanced the high risk of an experimental intervention. Refined surgical techniques and effective immune suppression permitted adequate survival and the analysis of the patients transplanted with incidental HCC allowed the establishment of limits of the tumour burden that could be accepted as an optimal indication because of long-term survival as good as that achieved in non-malignant conditions (70% at 5 years follow-up and around 50% at 10 years). The seminal study by Mazzaferro et al. [26] confirmed the validity of the so-called Milano criteria – single tumour ≤5 cm or 3 nodules ≤3 cm, with no vascular invasion or extrahepatic spread – and this has been widely accepted as the limit for candidate selection. Undoubtedly this definition excludes some patients with a slightly larger tumour burden that could achieve acceptable survival but significantly below the life expectancy of patients within Milano criteria. Suggestions for expansion [27–29] have been mostly based on the analysis of the explanted livers rather than on the radiology findings at the time of enlistment, use ill defined criteria to establish tumour burden, frequently dilute few patients with expanded criteria within a large group of conventional candidates, and finally, do not consider the impact of expanding the number of enlisted patients while it
S245
is well known that the major limitation for transplantation is the huge shortage of donors. The shortage varies according to countries and hence, every program/health system has to critically determine how many donors are available, how many candidates can be effectively treated within a fair system and the length of time patients will have to wait to be transplanted. During this period the HCC may progress and contraindicate transplantation and this impairs results according to intention to treat [3]. Priority policies have been established to transplant the sickest and diminish the risk of death while waiting. At the same time, it is common to treat the tumour upon enlistment as this may delay progression and reduce risk of exclusion. However, whatever is done to retain patients in the waiting list for longer or to advance those at higher risk, it is obvious that the number of livers is limited and that the sole effective approach to accommodate the demand is to increase the rate of donation. In this regard, living donation programs have become a valid possibility, but their applicability and impact in the West are still limited [30] as compared with data coming from countries where cadaveric donation is almost non-existent. Data from Asia [31–34] indicate a similar outcome using living donors, but despite technical refinements there is a 0.3–0.5% risk of death for the donor and this is likely the major reason for the limited applicability. Interestingly, the risk of HCC recurrence after transplantation is less than after resection or ablation even if stratifying for the same pathology risk profile. Hence, with similar survival and less recurrence, it would appear reasonable to consider transplantation as the first option as it would solve HCC and the underlying oncogenic liver. This consideration has to be tempered by the fact that liver transplantation is not a simple procedure. Morbidity and death rate in the early and intermediate follow-up period are higher than after resection surgery in optimal candidates. Finally, while recurrence of hepatitis B and alcoholic liver disease may be prevented, the status in patients infected with hepatitis C virus is not so encouraging [35–37]. Effective viral eradication is not common in cirrhotics (the underlying disease in most HCC), treatment pre and post-transplantation may have severe side effects, and, if not effective, reinfection of the graft is the rule and the long-term outcome is significantly impaired as compared to the other populations. All these facts have maintained surgical resection as the first line surgical option in patients with optimal profile as defined by solitary HCC in a liver without clinically relevant portal hypertension [14]. Operative risk is very low and analysis of the resected tumour will allow the classification of the tumor as at low risk for recurrence (no vascular invasion or satellites) (Fig. 3) [38] or as at high risk because of adverse pathology profile. If this is the case recurrence will impair prognosis and if the patient had been transplanted the risk and survival would have been significantly better. Based on this, the recommendation in these patients is to propose transplantation because of high risk of recurrence and not delay the decision to the appearance of recurrence as at that time multifocality will be the rule
S246
S. Tremosini et al. / Digestive and Liver Disease 42S (2010) S242–S248
Fig. 3. Small HCC with well defined limits and encapsulation. There is no evidence of microscopic vascular invasion or satellites. Hence, the risk of recurrence due to dissemination is low. If such adverse predictors were observed, the risk of recurrence after resection would be high and the patients would have to be considered for liver transplantation because of the risk of recurrence.
and transplantation will be contraindicated. By contrast, if the resected tumour does not have an invasive phenotype, the patient can avoid liver transplantation and the associated risks, while being under strict surveillance [38]. Recurrence will likely correspond to a metachronous tumour and benefit again of the same decision making process for treatment allocation.
5. Ablation This is the third therapy that can provide complete tumour elimination and long-term cure. To achieve this aim the patients have to fit into an optimal profile in terms of tumour burden and location. Ablation is based on inducing cell necrosis by either injecting agents that will induce cell death or by increasing or decreasing temperature, this also leading to cell death. The two most widely used techniques are ethanol injection and radiofrequency (RF), while other techniques such as laser, microwave, high intensity ultrasound, cryother-
Fig. 4. Small HCC treated by ethanol injection while waiting for liver transplantation. The nodule exhibits complete necrosis.
apy or acetic acid injection are less common or validated in terms of efficacy and safety. Ethanol injection at separate days until achieving complete tumour embedding (Fig. 4) was the standard technique until recently, but it has been replaced by RF. The needles for RF are thicker, but its advantage relies on its higher predictable antitumoral effect and the potential to treat successfully in one or two treatment sessions. Several studies have shown this higher disease control rate in a shorter time with RF and this is the basis for an improved outcome when it is compared against ethanol. However, the difference is apparent in nodules >2 cm while in lesions below this limit the efficacy and long-term outcome is very similar. Indeed, for any ablation technique the major limitations for efficacy is tumour size and even for RF, the long-term local disease control is significantly impaired when tumour size exceeds 3 cm. The extent of tumour necrosis is assessed by dynamic imaging, where absence of contrast uptake reflects successful necrosis (Fig. 5). While complete tumour necrosis exceeds 95% in nodules less than 2 cm, the success rate decreases to around 80% in HCC between 2 and 3 cm and to 50% at long
Fig. 5. Small hepatic nodule diagnosed as HCC and treated by radiofrequency ablation. While intense arterial uptake is recognised prior to treatment, the nodule appears avascular without any contrast uptake. This reflects tumor necrosis and hence, treatment success.
S. Tremosini et al. / Digestive and Liver Disease 42S (2010) S242–S248
term in larger tumours [39–42]. Initial response measured by tumour necrosis may appear successful in large lesions, but disease activity within the treated area is frequently detected during follow-up and this has given the basis for a combined treatment approach using chemoembolization followed by ablation. Up to now, there is no proof of its efficacy and application in practice should await data from research trials. Initial treatment with RF with later injection of ethanol to treat minute residual tumour foci is common practice and the two techniques should be seen as complementary rather than exclusive. Long-term studies indicate that Child-Pugh A patients with successful tumour necrosis may achieve a 50% survival at 5 years [43–45]. This compares well with the outcome of resection in those candidates who do not fit the optimal surgical profile [43].
6. Individualised decision making All the data exposed above should frame the rationale for the current treatment selection in an individual patient. The process has to take into account tumour extent, degree of liver function impairment and as in any other condition, the general health of the patient as reflected by age and associated comorbidities. If the underlying liver disease exhibits a preserved liver function without portal hypertension the first option to be considered is surgical resection. This provides optimal survival if the HCC is solitary. If high risk of recurrence is identified after resection, the patient will benefit from transplantation. However, if tumour staging has evidenced a multifocal HCC (up to three nodules <3 cm) resection might be feasible but the best outcome will be offered by transplantation. If this is not feasible because of any extrahepatic comorbidity, resection could again become an option. However, outcome may be similar to that offered by ablation if all tumours could be effectively ablated. Indeed, in solitary HCC <2 cm, ablation should be considered the first choice over transplant because the recurrence risk would not make the latter feasible. Then, resection would be considered if ablation should fail. If the same early HCC had appeared in a cirrhotic liver with portal hypertension, the best outcome would have been offered by transplantation, while resection and ablation may provide a lower life expectancy outcome if technically viable. Central tumour location may imply the need of large hepatectomy and thus, become too risky. The limiting factors for effective ablation are size and location: proximity to a large vessel impedes effective RF; subcapsular HCC may require direct puncture without a protective rim of non-tumoral liver and this increases the risk of seeding. Hence, if a solitary HCC is larger or unable to be ablated, surgery may become an option even in the presence of portal hypertension. Operative risk is increased, long-term outcome is not optimal, but even so it may compare positively with no treatment or TACE. Finally, if liver disease is decompensated, the sole option to improve survival is transplantation. Indeed, patients with advanced Child-Pugh stage or MELD >15
S247
should be considered for transplantation even in the absence of HCC and in such setting cancer detection may just become an exclusion criterion if the Milano criteria are exceeded.
7. Future perspectives The briefly reviewed therapeutic management for early HCC is valid for 2010. New data gathered in the next few years will surely change our understanding of cancer and specifically of HCC. The better knowledge of the molecular abnormalities leading to cancer and the specific profile associated to a better or worse prognosis will allow a biology-based prediction of the outcome of patients. This will also affect the treatment selection and the prediction of its long-term success [46]. Current data show that this refinement of the clinical evaluation of cancer is almost available [47] and the demonstration of the therapeutic activity of sorafenib [8] assures that this change in clinical practice based on cell biology is becoming a reality. The clinical management of patients according to robust clinical evidence and homogeneous decision making will provide the necessary setting to test if any serum or tissue marker is of any use to detect, diagnose and select treatment for HCC. In that way, serum and tissue banks with accurately annotated clinical data become a key tool for the generous and fruitful collaboration between clinicians and basic researchers, and this is the ultimate basis for a better care of our patients.
Conflict of interest JB has received a fee from Bayer HealthCare for his contribution to this supplement. Bayer HealthCare played no role in the preparation, review, or approval of the manuscript. ST, MR, CR and AF have no conflict of interest.
Financial support The BCLC group is supported by the Spanish Biomedical Research Network (CIBERehd) for the area of hepatic and digestive disorders of Ministry of Science and Innovation. This work was in part supported by a grant of the Instituto de Salud Carlos III (PI 08/0146). Silvia Tremosini and Carlos Rodriguez de Lope are funded by a grant of the BBVA foundation.
References [1] Bruix J, Llovet JM. Major achievements in hepatocellular carcinoma. Lancet 2009;373:614–6. [2] D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44:217–31. [3] Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints
S248
[4]
[5]
[6]
[7]
[8] [9]
[10] [11]
[12] [13] [14]
[15]
[16] [17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
S. Tremosini et al. / Digestive and Liver Disease 42S (2010) S242–S248 of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698–711. Forner A, Reig M, Rodrigruez de Lope C, et al. Current Strategy for Staging and Treatment : the BCLC Update and Future Prospects Semin Liver Dis 2010;30:61–74. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998;28:751–5. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646– 9. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001;33:464– 70. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia–Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25–34. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–36. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 2009;49:658–64. Kojiro M, Roskams T. Early hepatocellular carcinoma and dysplastic nodules. Semin Liver Dis 2005;25:133–42. Nakashima T, Kojiro M, editors. Hepatocellular carcinoma. Tokyo: Springer-Verlag; 1987. Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:1018–22. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30:1434–40. Cucchetti A, Ercolani G, Vivarelli M, et al. Is portal hypertension a contraindication to hepatic resection? Ann Surg 2009;250:922–8. Ishizawa T, Hasegawa K, Aoki T, et al. Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma. Gastroenterology 2008;134:1908–16. Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003;38:200–7. Chen YJ, Yeh SH, Chen JT, et al. Chromosomal changes and clonality relationship between primary and recurrent hepatocellular carcinoma. Gastroenterology 2000;119:431–40. Farges O, Belghiti J, Kianmanesh R, et al. Portal vein embolization before right hepatectomy: prospective clinical trial. Ann Surg 2003;237:208–17. Tanaka H, Hirohashi K, Kubo S, et al. Preoperative portal vein embolization improves prognosis after right hepatectomy for hepatocellular carcinoma in patients with impaired hepatic function. Br J Surg 2000;87:879–82. Yamasaki S, Hasegawa H, Kinoshita H, et al. A prospective randomized trial of the preventive effect of pre-operative transcatheter arterial embolization against recurrence of hepatocellular carcinoma. Jpn J Cancer Res 1996;87:206–11. Muto Y, Moriwaki H, Ninomiya M, et al. Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. Hepatoma Prevention Study Group. N Engl J Med 1996;334:1561–7. Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000;356:802–7. Schwartz JD, Schwartz M, Mandeli J, et al. Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet Oncol 2002;3:593–603.
[26] 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;334:693–9. [27] Marsh JW, Dvorchik I. Liver organ allocation for hepatocellular carcinoma: are we sure? Liver Transpl 2003;9:693–6. [28] Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33:1394–403. [29] Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10:35–43. [30] Rimola A, Llovet JM, Navasa M, et al. Applicability of adult-to-adult living donor liver transplantation. J Hepatol 2005;43:104–9. [31] Kawasaki S. Living-donor liver transplantation for hepatocellular carcinoma. Hepatogastroenterology 2002;49:53–5. [32] Sugawara Y, Tamura S, Makuuchi M. Living donor liver transplantation for hepatocellular carcinoma: Tokyo University series. Dig Dis 2007;25:310–2. [33] Lee SG, Hwang S, Moon DB, et al. Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one large-volume center. Liver Transpl 2008;14:935–45. [34] Todo S, Furukawa H. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg 2004;240:451–459; discussion 459–61. [35] Berenguer M, Palau A, Aguilera V, et al. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation. Am J Transplant 2008;8:679–87. [36] Forman LM, Lewis JD, Berlin JA, et al. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122:889–96. [37] Carrion JA, Navasa M, Garcia-Retortillo M, et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology 2007;132:1746–56. [38] Sala M, Fuster J, Llovet JM, et al. High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation. Liver Transpl 2004;10:1294–300. [39] Shiina S, Teratani T, Obi S, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 2005;129:122–30. [40] Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 2003;228:235–40. [41] Livraghi T, Solbiati L, Meloni MF, et al. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology 2003;226:441–51. [42] Livraghi T, Meloni F, Di Stasi M, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology 2008;47:82–9. [43] Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology 2000;32:1224–9. [44] Sala M, Llovet JM, Vilana R, et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology 2004;40:1352–60. [45] Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 1995;197:101–8. [46] Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 2008;359:1995–2004. [47] Hoshida Y, Nijman SM, Kobayashi M, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009;69:7385–92.