Journal of Liver: Disease & TransplantationISSN: 2325-9612

Research Article, J Liver Dis Transplant Vol: 3 Issue: 1

Sorafenib and Mammalian Target of Rapamycin Inhibitors after Liver Transplantation: A Single-Center Experience and Review of the Literature

Damiano Patrono1, Stefano Mirabella1, Elisabetta Magra1, Marco Palisi1, Renato Romagnoli1 and Mauro Salizzoni1,2*
1General Surgery 2U and Liver Transplantation Center, A.O. Città della Salute e della Scienza, Molinette Hospital, Corso Bramante 88-90-10126, Turin, Italy
2Professor of Surgery, University of Turin, Turin, Italy
Corresponding author : Prof. Mauro Salizzoni
Head of General Surgery 2U – Liver Transplantation Center, A. O. Città della Salute e della Scienza di Torino, University of Torino, Corso Bramante 88- 90, 10126, Torino, Italy
Tel: 00390116334374; Fax: 00390116336770
E-mail: [email protected]
Received: February 13, 2014 Accepted: June 20, 2014 Published: June 25, 2014
Citation: Patrono D, Mirabella S, Magra E, Palisi M, Romagnoli R (2014) Sorafenib and Mammalian Target of Rapamycin Inhibitors after Liver Transplantation: A Single-Center Experience and Review of the Literature. J Liver: Dis Transplant 3:1. doi:10.4172/2325-9612.1000119

Abstract

Sorafenib and Mammalian Target of Rapamycin Inhibitors after Liver Transplantation: A
Single-Center Experience and Review of the Literature

Hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) is observed in 10-15% of the patients and generally has a dismal prognosis. Little is known about the safety and efficacy of a therapeutic regimen including sorafenib and mammalian target of rapamycin inhibitors (mTORi) in this setting. The medical charts of the recipients of a LT presenting HCC recurrence and treated with sorafenib either alone
or in combination with mTORi were retrospectively reviewed.

Keywords: Sorafenib; Mammalian target of rapamycin inhibitors; Liver transplantation; Hepatocellular carcinoma

Keywords

Sorafenib; Mammalian target of rapamycin inhibitors; Liver transplantation; Hepatocellular carcinoma

Introduction

Liver transplantation (LT) is a widely accepted therapy for hepatocellular carcinoma (HCC). Patients fulfilling well-known selection criteria [1] exhibit survival similar to that of patients transplanted for other indications. HCC recurrence after LT is observed in 10 – 15% of the patients [2-19] and frequently has a dismal prognosis. Despite some patients amenable to radical resection may experience long term survival [5-7], HCC recurrence almost unavoidably leads to patient’s death. Because recurrence mostly presents as multifocal or metastatic disease [20,21], traditional therapeutic strategies against HCC are often not effective and there is a real interest for a therapeutic regimen that could improve the outcome of these patients.
Sorafenib (Nexavar, Bayer Pharma AG, Germany) is a multikinase inhibitor initially employed for the treatment of renal cell carcinoma [22], which has been proven effective in the treatment of advanced HCC in two controlled randomized phase III trials [23,24]. According to the Barcelona Clinic Liver Cancer (BCLC) staging system [25], sorafenib is the standard of care for advanced HCC in patients with a preserved hepatic function. The use of sorafenib after LT raises some concern due to the possibility of drug-to-drug interactions and hepatic function deterioration. In the setting of HCC recurrence after LT, the experience with sorafenib, alone or in association with mTORi, is limited to case reports and retrospective case series, showing that this combination therapy may achieve stabilization of disease in a consistent portion of patients, albeit its efficacy is limited by significant toxicity [4,9-11,14,17,18,26-31].
Sirolimus (Rapamune, Wyeth Europe Ltd, UK) and everolimus (Certican, Novartis International AG, Switzerland) are two immunosuppressant agents of the mammalian target of rapamycin (mTOR) inhibitors class. As activation of the mTOR pathway is observed in 15 – 41% of HCC [32], there is a strong rationale for using mTOR inhibitors (mTORi) in the setting of HCC recurrence after LT. Data from retrospective series show that the risk of HCC recurrence may be lower in patients treated with mTORi and suggest that their use should be implemented in patients at high risk of cancer after LT [2,12,16,33].
To date, the association of sorafenib and mTOR inhibitors in the setting of HCC recurrence after LT has been reported only in small retrospective series with conflicting results. Thus, the aim of this study was to review the current literature on the subject and to report our experience with the use of sorafenib +/- mTOR inhibitors in a consecutive series of patients treated for HCC recurrence after LT in our Institution.

Patients and Methods

Patient population and data collection
Recipients of LT for HCC were identified from a prospectively collected database including the patients transplanted in our Institution from May, 1991 to December, 2012; outpatient clinic charts were checked to identify patients with HCC recurrence and, among them, those treated with sorafenib alone or in association with a mTORi.
The data collected included demographic data and baseline patient and HCC characteristics at LT, timing and pattern of HCC recurrence, HCC treatment, sorafenib and mTORi dosing and toxicity, response to treatment and survival.
Pre-transplantation management and listing criteria
Pre-transplantation work-up included thoraco-abdominal computed tomography (CT) scan and alpha-fetoprotein (AFP) level measurement. Patients with multiple nodules or with a single nodule >2 cm were further studied by bone scintigraphy. Patients fulfilling Milan criteria were considered candidates for LT. After wait listing, HCC stage was re-assessed every three months by ultrasonography or CT scan. Loco-regional treatments (radiofrequency ablation, transarterial chemoembolization and percutaneous ethanol injection) were routinely performed as bridge procedures.
Post-transplantation follow-up and HCC recurrence diagnosis
The baseline immunosuppression protocol included a calcineurin inhibitor, steroids and mycophenolate mofetil, this last introduced as soon as white blood cells and platelets count was above 3,000/μL and 50,000/ μL, respectively. Induction therapy by basiliximab (Simulect®, Novartis Europharm Limited, UK) was administered exclusively to patients with cholestatic or autoimmune cirrhosis. With regards to the choice of the calcineurin inhibitors, cyclosporine A was preferred in HCV-positive patients, whereas tacrolimus was administered to all other patients.
After LT, Doppler ultrasonography and chest x-ray were performed every three months during the first year of follow up and yearly thereafter; AFP levels were obtained monthly during the first six months and every three months thereafter. Thoraco-abdominal CT scan, magnetic resonance imaging and bone scintigraphy were performed in case of AFP levels increase or clinical suspicion of HCC recurrence. Noninvasive HCC recurrence diagnosis was based on AASLD guidelines (i.e. lesions with a typical contrast enhancement pattern) [34,35] and was confirmed by histopathology whenever possible.
Treatment strategy
Unless otherwise contraindicated, all patients were switched to mTORi-based immunosuppression after HCC recurrence. Sirolimus (Sir) and Everolimus (Evl) target through levels were 4 – 8 ng/ml and 5 – 8 ng/ml, respectively. The choice of the mTORi was based on the attending physician personal preferences. Due to its pharmacodynamics, Evl was deemed more manageable in the LT setting and was generally preferred since 2006.
Sorafenib was administered in patients in good general conditions, with good hepatic function and not suitable for other locoregional treatments like surgical resection, radiofrequency ablation or transarterial chemoembolization. Starting daily dose was 800 mg or 400 mg, increased to 800 mg if tolerated. Sorafenib administration was discontinued in case of severe toxicity or disease progression.
Outcome
Response to treatment was assessed according to the Response Evaluation Criteria for Solid Tumors (RECIST) [36]. Toxicity was recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 [37].
The data were expressed as numbers of cases and percentages or medians and 95% confidence interval (95% CI), as appropriate. The Kaplan-Meier method was used for survival analysis. Cox proportional hazards method was used to identify factors associated with survival and progression-free survival after administration of sorafenib. Statistical analysis was performed with STATA 11 statistical software (StataCorp, Texas, USA).

Results

Patients characteristics and patterns of HCC recurrence
Among the 567 patients with HCC who underwent LT at our Institution, HCC recurrence was observed in 50 (8.8%). Fourteen patients were treated with sorafenib alone or in association with an mTORi. These patients had HCC recurrence in the period from June 2006 to December, 2012. In this time span, a total of 29 patients presented with HCC recurrence. Thus, sorafenib was administered to 48.3% (14/29) of the patients experiencing HCC recurrence during the study period (Figure 1). Median follow-up of the entire series from LT and from HCC recurrence was 35 (3 – 159) and 14 (1 – 59) months, respectively. Sorafenib was not administered in patients who experienced HCC recurrence and died before sorafenib became available (n = 2), in patients with a rapid disease progression (n = 4) or with a poor performance status (n = 2), in case of concomitant pathologies contraindicating sorafenib administration (n = 4) or concomitant HCV-related cirrhosis recurrence (n = 1), and in two patients with no residual disease after locoregional treatment, who are currently still alive (n = 2).
Figure 1: Study flowchart. Patients developing HCC recurrence before the study period (n = 21) were excluded from analysis due to inhomogeneous indications for LT, different immunosuppression protocols, possible changes in HCC recurrence management among different eras and data unavailability. Abbreviations: HCC, hepatocellular carcinoma; mTORi, mammalian target of rapamycin inhibitors.
Demographic data and baseline characteristics of the patients receiving sorafenib are summarized in Table 1. Median interval from LT to recurrence was 12.5 (95% CI: 11.7 – 26.2) months. Diagnosis of HCC recurrence was confirmed by histopathology in 12 (85%) cases. Performance status according to the Eastern Cooperative Oncology Group (ECOG) classification was 0 in all but one patient who was classified ECOG 1.
Table 1: Baseline Patients Characteristics and Response to Sorafenib.
Two patients (14%) presented an isolated hepatic HCC recurrence, whereas 12 (86%) presented systemic metastases. A mixed hepatic and systemic recurrence was observed in three (21%) patients. First site of recurrence was lung (n = 5), bones (n =5), liver allograft (n = 5), abdominal lymphnodes (n = 3), thoracic and abdominal wall (n = 1), mediastinum (n = 1) and pleura (n = 1).
Immunosuppression
At recurrence, twelve patients were receiving calcineurin inhibitors (Cyclosporine A: n = 6, Tacrolimus: n = 6) alone or in association with mycophenolate mofetil (n = 7). Two patients were already receiving a mTORi (Sir = 1, Evl = 1) due to advanced HCC stage at explant pathologic examination: one patient had approximately 20 small (diameter < 1 cm) bilobar lesions and another presented macrovascular invasion. Ten patients were switched to mTORi therapy (Sir = 2, Evl = 8) once HCC recurrence diagnosis was established. In two patients previous calcineurinbased immunosuppressive regimen was left unchanged because of proteinuria and hepatic function deterioration following HCV recurrence, respectively. In one further patient treatment with Evl was suspended for a one month period, due to a biliary complication requiring re-operation. Median duration of treatment with mTORi was 20.5 (95% CI: 13.3 – 47.5) months.
Sorafenib administration
According to current indications, a loco-regional treatment of HCC recurrence was always attempted before considering the indication for sorafenib. Consequently, in some patients sorafenib was administered late in the course of HCC recurrence, after a previous locoregional treatment had achieved a temporary stabilization of disease. Previous treatments included surgical resection, radiofrequency ablation, transarterial chemoembolization and external beam therapy, all of which were administered in 3 (21%) patients, respectively. In seven patients with systemic HCC recurrence, sorafenib alone (n = 2) or in association with mTORi (n = 5) was administered as a first-line treatment. Overall, sorafenib was started at a median interval of 4 (95% CI: 1 – 19.2) months from HCC recurrence and of 3 (95% CI: 1.1 – 18.1) months after the switch to mTORi. Maximum tolerated dose was 800 mg in 13 (93%) patients; in one patient (7%) the daily dose could not be raised over 400 mg. Median duration of treatment was 13.5 (95% CI: 5.8 – 19.3) months.
Treatment toxicity
Toxicity was invariably observed during sorafenib administration: all patients experienced some kind of adverse event (Table 2) leading to dose reduction, suspension or discontinuation in 71, 64, and 29% of the cases, respectively. Cutaneous toxicity was the most common but gastrointestinal adverse events were the most severe, including three cases of disabling diarrhea requiring dose suspension or adjustment and one case of hemorrhagic gastritis. Overall, grade 3 - 4 toxicity was observed in 6 (43%) patients. Hepatic function deterioration was observed in two patients and led to therapy discontinuation in both of them. One patient with a previously normal hepatic function developed a biopsy-proven acute cholestatic hepatitis (Figure 2), which subsided after treatment withdrawal; another patient with a previously documented HCV-related hepatitis recurrence presented hepatic function impairment during treatment with sorafenib. In this patient, sorafenib administration did not alter the expected course of HCV recurrence and no improvement was observed after sorafenib withdrawal. Thus, rather than sorafenib, HCV-recurrence was deemed responsible for liver function tests alteration.
Figure 2: Cholestatic hepatitis after sorafenib administration. Mild eosinophil infiltrate in the portal spaces (A, arrow) and frequent mitoses (B, arrowhead).
Table 2: Toxicity of Sorafenib.
Outcome
Crude survival of patients treated with sorafenib was significantly improved compared to patients not receiving sorafenib (Figure 3). The outcome of the patients who received sorafenib is summarized in Table 1: partial response and stabilization of disease was achieved in 1 (7%) and 6 (43%) patients, respectively. Six patients who achieved stable disease are currently receiving a combination therapy with sorafenib and Evl. Overall, disease control rate was 50%. Median time to progression was 6 months; median overall survival from LT, from HCC recurrence and from the start of sorafenib administration was 40, 27 and 19 months, respectively.
Figure 3: Kaplan-Meier survival curve from HCC recurrence of patients who did (n = 14) and did not (n = 15) receive sorafenib +/- mTORi during the same period. Hash marks represent censored patients. Median follow-up from HCC recurrence for the entire series was 14 (1 – 59) months. Median survival was 26 and 8 months in patients treated and not treated with sorafenib, respectively. The increased survival observed in the patients treated with sorafenib is most likely explained by the selection bias for which sorafenib was administered to patients with a more indolent recurrence.
An univariate Cox regression was carried out to identify the factors associated with survival after HCC recurrence. Survival analysis did not show any significant association with the timing and site of recurrence, the type of locoregional treatment, the treatment with mTORi or the timing, dosage, length and toxicity of the treatment with sorafenib. Progression-free survival was significantly shortened in patients who had to discontinue sorafenib for toxicity (p = 0.04; Figure 4A) and also in patients presenting bone metastases, although this second observation only approached statistical significance (p = 0.08; Figure 4B).
Figure 4: Progression free survival according to treatment toxicity (A) and to the presence of bone metastases (B) in patients receiving sorafenib. Square dots represent censored patients.

Discussion

Recurrence rate of hepatocellular carcinoma after LT is 10 - 15% and is influenced mainly by tumor stage and histological features. Although some patients may achieve occasionally long-term survival, the outcome is almost constantly death due to HCC recurrence. Indeed, median overall survival from HCC recurrence was 8.7 months in the series of Roayaie et al. [7]. Patients amenable to radical surgical resection seem to have a better prognosis and can rarely experience long-term disease-free survival, although it is not clear if this reflects more favorable tumor biology rather than an effect of treatment [5,6,13]. Unfortunately, patients frequently present with systemic recurrence not suitable for radical surgical resection, thus the search for an effective therapeutic regimen is of particular clinical interest. As recently pointed out in a review by Davis et al. [20], a pattern of systemic HCC recurrence is observed in 80 - 85% of the patients.
The rationale for using an association of sorafenib and mTORi is based on both clinical and experimental data. Studies evaluating the molecular response of hepatocarcinoma cells exposed to sorafenib and mTORi (Sir) suggest a possible synergistic effect of this combination: exposure to Sir reduces in vitro the sorafenib-induced phosphorylation of mTOR targets and cyclin B1 expression [38]. In the clinical setting, retrospective studies analyzing risk factors for HCC recurrence have shown a possible beneficial effect of mTORi immunosuppression [12,16]. On the other hand, sorafenib is the only systemic treatment with a documented effect on advanced HCC [23,24].
The clinical experience with the use of sorafenib +/- mTORi for HCC after LT is reviewed in Table 3 [4,9-11,14,17,18,26-29,31,39-44]. As it can be seen, response to treatment and related toxicity are inconstantly reported and vary considerably among different studies. Some Authors have observed improved outcomes in patients treated with sorafenib +/- mTORi and, with the limitations due to the treatment toxicity, advocate its application in the clinical setting [11,26-28,40-42]. Other Authors are more skeptical with regard to the results of the combination therapy and are concerned about the adverse events observed during the treatment that limit its feasibility [10,17,39,44].
Table 3: Experience with Sorafenib after liver transplantation.
As a whole, the results of our study are in line with the literature. Median overall survival from recurrence and time to progression was 27 and 6 months, respectively, which is comparable with that of a multicenter Spanish series, the largest reported to date [4]. Concerning toxicity, all patients experienced some degree of toxicity, which was severe in 43 % of the cases, leading to treatment discontinuation in 29% of the patients. However, no death due to an adverse event was observed in our series and toxicity was effectively managed in all cases.
Based on the current literature and on our results, however, it is difficult to assess the true efficacy of sorafenib +/- mTORi. This limitation is mainly due to the methodology of our study. Indeed, like most previous published articles, our study suffers from the selection bias due to its retrospective nature. The apparent improved survival exhibited by the patients treated with sorafenib (Figure 3) is most likely due to the fact that sorafenib could be administered to the patients with a more indolent HCC recurrence. It must be stressed that many patients achieving temporary disease control in our series received the combination of sorafenib + mTORi at a later stage, after previous locoregional treatments had allowed a temporary control of the disease. Thus, it is highly debatable if the relatively good outcome of some patients was due to the response to the treatment or to less aggressive tumor biology. The fact that progression-free survival was significantly shortened in patients having to discontinue sorafenib because of toxicity suggests that the treatment could have some beneficial effect. Unfortunately, we could not identify any clinical factor associated with survival after recurrence which may possibly help in choosing which subset of patients would benefit from the combination therapy, thus sparing unnecessary toxicity in patients in whom the course of the disease would likely be the same regardless of the treatment.
In conclusion, although the available evidence is weak, it seems justifiable to propose sorafenib associated with mTORi to the patients suffering from HCC recurrence after LT, as it is occasionally associated with a temporary disease control and improved survival. Given the price to pay in terms of toxicity, the decision to administer sorafenib + mTORi should be carefully evaluated on a case-by-case basis and the patients should be closely monitored. As a randomized controlled trial comparing different treatment protocols for HCC recurrence treatment would be difficult to realize and probably unethical [42], further studies based on large, multicenter patients series are needed to assess the benefit of this therapeutic strategy and, most importantly, to define the groups of patients to whom it should be proposed.

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