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Treatment of recurrent hepatocellular carcinoma after liver transplantation

2011; Lippincott Williams & Wilkins; Volume: 17; Issue: S2 Linguagem: Inglês

10.1002/lt.22361

1527-6473

Eric G. Davis, Russell H. Wiesner, Juan Carlos García Valdecasas, Yoshiaki Kita, Massimo Rossi, Myron Schwartz,

Liver Disease and Transplantation

In an ever-expanding patient population, liver transplantation provides the best hope for long-term survival for many patients suffering from hepatocellular carcinoma (HCC) in the setting of cirrhosis. One study has even demonstrated superior 1- and 3-year survival rates for patients undergoing transplantation for HCC versus patients without HCC.1 Because of the shortage of deceased organ donors, the donor risk in living donor transplantation, the high cost of liver transplantation, and the poor outcomes of patients who develop recurrent HCC after transplantation, restrictive criteria have been widely adopted to minimize the likelihood of recurrence; despite careful selection, however, HCC recurrence remains the most important negative predictor of posttransplant survival and occurs in approximately 10% to 30% of patients. The literature describing the timing and sites of recurrence is summarized in Table 1. By definition, recurrent HCC following transplantation represents metastatic disease from the original tumor that either was not detectable before transplantation or was disseminated at the time of transplantation. Here we examine the treatment of recurrent HCC after transplantation, but we recognize at the outset that there is very limited evidence on which recommendations can be based. Apart from the systemic treatment of recurrent HCC with sorafenib, the evidence currently addressing this issue comprises observational studies and expert opinion (levels C and D). HCC, hepatocellular carcinoma; mTOR, mammalian target of rapamycin; TACE, transarterial chemoembolization. Isolated hepatic recurrence has been reported in 15% to 20% of the patients in most series, and it represents the pattern of recurrent HCC most amenable to locoregional therapy. In the nontransplant setting, the selection of treatments for HCC confined to the liver is fairly well standardized, although local experience and preferences result in some degree of variability; both the extent of the tumor and the condition of the underlying liver must be taken into account. There is essentially no literature that systematically analyzes this issue in the posttransplant setting. There are key differences between patients with posttransplant HCC recurrence and patients with primary HCC, and these differences must be considered when we are trying to apply standard treatment algorithms in the posttransplant setting. Unlike the large majority of livers harboring primary HCC, the liver in the patient with recurrent HCC is typically noncirrhotic, at least in the first 2 years after transplantation; during this time, the large majority of recurrences occur. When surgery is being considered for recurrent HCC, the technical issues inherent to reoperative surgery on the liver and related portal structures must be weighed. Recurrent HCC in the liver is by definition metastatic disease (except for those occasional late recurrences observed in the setting of recurrent cirrhosis, which are usually due to hepatitis C); local treatments in this setting do not offer the hope of treating the primary site before the onset of tumor dissemination. On this basis, retransplantation for recurrent HCC is virtually never considered. These various issues notwithstanding, the various treatments available for primary HCC have all been applied in the posttransplant setting, and the available literature is reviewed here. There is no controversy about the difference in the survival rates of patients whose recurrent HCC is surgically extirpated and patients who are treated nonsurgically. In fact, the Kyushu University group in 2010 reported 17 patients with HCC recurrence limited to the liver after transplantation; 9 of these patients were treated surgically and experienced survival approximating that of patients who did not experience HCC recurrence.9 All major series of HCC recurrence have substantiated the better survival of patients treated with resection; there is, however, an obvious case selection bias, so it is impossible to determine the extent to which surgery rather than favorable biology explains the difference. There is indirect evidence for a tumor biology explanation: vascular invasion was found during the original explant pathology examination in only 3 of 7 patients with surgically resectable recurrence but in all 9 patients whose recurrence pattern was unsuitable for surgery in 1 study.8 Liver resection after transplantation for a variety of indications, including recurrent HCC, has been shown to be safe.10 The literature concerning the results of surgical treatments for HCC recurrence is summarized in Table 2. Radiofrequency ablation, which is commonly used for both primary and metastatic liver cancers, can be applied in the posttransplant setting for both liver and pulmonary recurrences. In general, resection is preferred for these patients, but certain scenarios may make radiofrequency ablation more attractive (ie, large-volume ascites or hostile posttransplant adhesions that preclude safe surgical exploration and resection). In the New York City experience,2 half of the patients with isolated hepatic recurrences underwent liver resection, and each series reported a minority of patients treated in the same manner. When resection is intended, exploration also allows for the potential discovery and extirpation of small-volume peritoneal or nodal disease; most series have reported a few medium-term survivors. In a 2010 Korean study describing 28 recurrences after living donor liver transplantation, transarterial chemoembolization (TACE) was used initially for all isolated intrahepatic recurrences without any significant complications being reported.11 Despite early concerns about the safety and theoretical added risk of biliary ischemia in the transplanted liver parenchyma, each of the other large groups has reported the use of TACE in isolated patients with unresectable recurrent HCC. Fourteen patients who underwent lobaplatin-based TACE for unresectable recurrent HCC after transplantation were reported in early 2010; none of these patients developed major complications related to the therapy, and more than half demonstrated a partial response.12 Other local therapies with only short-term results that are not yet in widespread use have been described for both intrahepatic and extrahepatic recurrences. A distinction must be made here between the vast majority of posttransplant HCC recurrences, which result from the progression of tumors present at the time of transplantation, and those few cases of late recurrence, which represent the de novo development of HCC (most commonly in the setting of recurrent hepatitis C and advancing fibrosis). De novo HCC conceptually fits into the established framework of transplantation for patients with primary HCC; patients with unresectable de novo HCC that is within the Milan criteria are reasonable candidates for retransplantation.3, 13, 14 There are a few Asian reports of retransplantation for the early recurrence of HCC. These reports include a single patient from Korea with multifocal recurrence in the liver at 12.7 months who underwent retransplantation after TACE and was alive at 45 months11 and 5 patients from China who underwent retransplantation for HCC recurrence more than 6 months after the initial transplant (details about the timing of recurrence were not provided, and 3 of the patients subsequently died of recurrence).15 Nevertheless, the fact that early recurrence is a reflection of systemic tumor dissemination has led to the nearly universal view that retransplantation is not indicated for early HCC recurrence, just as transplantation in general is contraindicated for patients with systemic malignancies.16 In contrast to primary HCC, most studies of patients with recurrent HCC after transplantation have reported aggressive attempts at locoregional therapy of extrahepatic metastases. As with recurrence in the liver, multiple reports concerning extrahepatic recurrence have shown better survival rates for surgically treated patients, and the same issue of case selection has confounded attempts to relate surgery to outcomes. The common theme of these reports is the selection of patients for surgical treatment who have good functional status, a single site of recurrence, and a long interval from transplantation to recurrence. The resection of metastases to the regional lymph nodes, lungs, and adrenal glands has been reported. Five patients who underwent isolated lung resections for metastatic HCC after transplantation experienced survival similar to that of patients who underwent isolated liver resections.17 A case of sequential, bilateral adrenal metastases treated with resection has been reported with long-term survival.18 No reliable survival data are available for any of these approaches. Bone metastases are a common presentation of metastatic HCC after transplantation. Roayaie et al.2 reported especially poor survival for patients with bone metastases, and this was independent of other metastatic diseases. These metastases are commonly quite symptomatic and are treated with external beam radiation. Zoledronic acid is a bisphosphonate used for myeloma and metastatic bone tumors. In a case series of 17 patients with bone metastases from HCC, significant reductions in pain scores were achieved, and the use of narcotics seemed to decline.19 Fifty-one patients with painful HCC bone metastases who were treated with radiotherapy achieved effective palliation according to a pain questionnaire.20 mTOR inhibitors have shown efficacy as antineoplastic agents for some solid tumors, including neuroendocrine tumors and renal carcinomas; angiogenesis inhibition is one of the purported mechanisms of action. Calcineurin inhibitors have been shown to promote hepatic regeneration and are believed by some to predispose patients to earlier and more aggressive tumor recurrence by a similar mechanism (but not because of immunosuppression per se). The dual effects of antiangiogenesis and immunosuppression that are afforded by sirolimus, therefore, make sirolimus an attractive therapeutic option for posttransplant immunosuppression in the setting of HCC. Although there is a good deal of literature concerning the preemptive use of sirolimus in patients undergoing transplantation for HCC, sirolimus as a treatment for HCC recurrence is reported in only 1 significant series.21 This study documented the safety of the drug, but no outcomes for the 7 patients with recurrent HCC were described. It is unclear whether sirolimus should be added to calcineurin inhibitors or should replace them in this setting. Everolimus is an mTOR inhibitor marketed primarily as a cancer drug and used extensively for metastatic renal carcinoma. In 2010, the Bilbao group reported 2 patients with recurrent HCC; they were managed solely with a combination of everolimus and sorafenib and were alive at 18.5 (without recurrence) and 10 months (with recurrence)6; the Bilbao group has used this combination as its standard protocol for proven HCC recurrence since 2007. Sorafenib is an oral, multiple–tyrosine kinase inhibitor targeting molecular pathways different than those targeted by mTOR inhibitors. With the publication of the Sorafenib HCC Assessment Randomized Protocol trial results in 2008, sorafenib became the first and only drug licensed for treating unresectable, advanced HCC.22 Several case and series reports of sorafenib use in posttransplant patients with HCC recurrence have been published. So far, no evidence of increased sorafenib toxicity in posttransplant patients versus patients with primary HCC has emerged. A complete but temporary radiological response of a multifocal HCC recurrence after treatment with sorafenib and sirolimus has been reported,23 and an isolated complete radiological response of a lung metastasis after sorafenib therapy has been described as well.24 A 2010 retrospective series of 13 patients demonstrated no complete or partial responses, but disease stabilization was observed in approximately half of the studied patients.25 The literature on the posttransplant use of sorafenib is summarized in Table 3. First, locoregional therapy has a well-established role in the treatment of primary intrahepatic HCC and a proven survival benefit; however, the case selection bias renders all existing studies inconclusive with respect to the survival benefit of locoregional therapy for posttransplant HCC recurrence. Nevertheless, it remains reasonable to pursue the locoregional treatment of isolated sites of HCC recurrence either within or outside the liver in patients whose disease is limited, for whom the interval between transplantation and recurrence is long, and whose functional status is good as long the treatment can be performed with little risk. Retransplantation, except in cases of late recurrence thought to represent de novo HCC, is rarely, if ever, appropriate. Second, although firm evidence is lacking, it is nevertheless reasonable to use an mTOR inhibitor for immunosuppression in patients with recurrent HCC. It is unclear whether sirolimus or everolimus is preferable and whether mTOR inhibitors should be used in addition to (or instead of) calcineurin inhibitors. Third, sorafenib, the only drug with proven efficacy against HCC, appears to be safe in the posttransplant setting, even in conjunction with mTOR inhibitors, and should be used whenever a systemic treatment is warranted.