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Natural history and therapeutic management of recurrent hepatocellular carcinoma after liver transplantationHistoire naturelle et traitement de la récidive du carcinome hépatocellulaire après transplantation hépatique

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Summary

While the natural history and appropriate diagnostic and management practices are relatively well defined for hepatocellular carcinoma (HCC), data are scarce concerning the characteristic features and treatment modalities for recurrent HCC after liver transplantation. The time of recurrence appears to impact survival more significantly than localization, but to date, guidelines for therapeutic management of recurrent HCC have not been established. Data in the literature shows that late and unifocal recurrence has a better prognosis when treated by surgery or radiofrequency. In the event of early recurrence, surgery cannot be recommended due to the lack of evidence and the high risk of advanced disease. Systemic therapy can be discussed in a situation of multifocal recurrence. Proliferative signal inhibitors exhibit both immunosuppressive and antiproliferative properties and liver transplantation teams tend to introduce such treatment despite the lack of extensive data.

Résumé

Alors que l’histoire naturelle et la prise en charge thérapeutique du carcinome hépatocellulaire (CHC) sont mieux codifiées, il existe peu de données sur les caractéristiques et le traitement de la récidive du CHC après transplantation hépatique. Le délai de récidive semble plus influencer la survie que sa localisation et il n’existe actuellement pas de recommandation précise sur la prise en charge thérapeutique de la récidive du CHC post-transplantation hépatique. La récidive unifocale et tardive apparaît de meilleur prognostic si une résection chirurgicale ou une radiofréquence peuvent être proposées. En cas de récidive tumorale précoce, il ne semble pas licite de proposer la chirurgie d’emblée compte tenu du fort risque de maladie disséminée. La récidive multifocale fait discuter l’opportunité d’un traitement systémique. Actuellement les inhibiteurs du signal de prolifération ont l’avantage d’une activité immunosuppressive et antiproliférative et les équipes de transplantation hépatique introduisent volontiers cette nouvelle classe thérapeutique malgré le peu de données disponibles.

Introduction

Hepatocellular carcinoma (HCC) is the commonest primary malignant disease of the liver. Worldwide, it is the sixth leading cause of cancer and the third leading cause of cancer death [1]. Incidence has risen steadily in Europe, doubling in France in the last two decades [2].

Liver transplantation is the ideal treatment for HCC in cirrhosis because in addition to resection of the tumor, any malignant and/or pre-malignant foci, which could be present but not necessarily visible in the adjacent parenchyma, are removed. Until the early 1990s, the rate of disease recurrence following liver transplantation was high because transplantation was proposed for any stage of tumor dissemination. Indicators predictive of recurrence were then rapidly identified enabling an evidence-based selection of candidates with a low probability of recurrence. Using the Milan criteria, widely applied in Europe, the overall probability of survival at five years is relatively close to that observed for cirrhosis without HCC.

In France, the number of HCC patients waiting for liver transplantation has doubled in the last five years (135 candidates in 2002 and 323 in 2007). This indication is becoming one of the more prominent for liver transplantation (12.8% of the activity at enrolment in 2002 and 24% in 2007). At the present time, the rate of recurrence five years after liver transplantation is to the order of 10% to 20% [3], [4]. As the activity level for this indication increases, transplantation teams will be called upon to provide care for a growing number of patients with recurrent HCC. While the natural history and appropriate diagnostic and management practices are relatively well defined for HCC [5], data are scarce concerning the characteristic features and treatment modalities for recurrent HCC after liver transplantation.

Section snippets

Evolving risk of recurrence

In the past, the rates of recurrence after liver transplantation have varied greatly, depending on the series reported, but with a steady trend toward lower rates in recent years (Table 1). Before 1993, reported rates were high, to the order of 50%, and had a direct impact on survival. This situation arose because liver transplantation was proposed for patients with large or diffuse non-resectable tumors [6], [7]. As early as 1993, sensitivity analysis focusing on sub-groups of patients with

Adjuvant/neoadjuvant chemotherapy

Several adjuvant/neoadjuvant chemotherapy protocols, adjusted to the real stage of HCC dissemination found on the liver explant, offer attractive therapeutic potential. Considering the low rate of recurrence observed in recent series, it would be logical to propose such protocols for selected sub-populations with a high risk of recurrence. The main problem with this attitude is the safety aspect related to the cumulative toxicity of immunosuppressive and chemotherapy drugs.

Licartin, a

Conclusion

Within five years after their liver transplantation for HCC, 10% to 20% of the recipients with develop recurrent HCC. The overall prognosis of recurrent HCC is poor with fatal outcome within one year of diagnosis. An analysis of the natural history of recurrent HCC identifies several sub-populations with a better prognosis, defined more on the basis of time from liver transplantation to recurrence than on tumor localization. Expressed in terms of survival, the best prognosis is achieved with

Conflict of interests

None.

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