Outcomes of Sorafenib for Recurrent Hepatocellular Carcinoma After Liver Transplantation in the Era of Combined and Sequential Treatments : Transplantation

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Original Clinical Science—Liver

Outcomes of Sorafenib for Recurrent Hepatocellular Carcinoma After Liver Transplantation in the Era of Combined and Sequential Treatments

Tovoli, Francesco MD1,2; Pallotta, Dante Pio MD2; Sansone, Vito MD1; Iavarone, Massimo PhD, MD3; De Giorgio, Massimo PhD, MD4; Ielasi, Luca MD1; Di Costanzo, Giovan Giuseppe MD5; Giuffrida, Paolo MD4,6; Sacco, Rodolfo PhD, MD7,8; Pressiani, Tiziana MD9; Di Donato, Maria Francesca MD3; Trevisani, Franco PhD, MD2,10; Fagiuoli, Stefano MD4,11; Piscaglia, Fabio PhD, MD1,2; Granito, Alessandro MD1,2

Author Information
Transplantation 107(1):p 156-161, January 2023. | DOI: 10.1097/TP.0000000000004271
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Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is a serious event that tends to neglect the transplant benefit.1 Systemic treatments for this condition are still primarily based on sorafenib and other multitarget tyrosine kinase inhibitors (mTKIs), as immune checkpoint inhibitors have been associated with a non-negligible risk of graft rejection.2,3

Sorafenib is the most explored frontline systemic drug in patients with post-LT HCC recurrence. Since LT recipients were excluded from the registered SHARP and Asia-Pacific trials of sorafenib,4,5 current data derive from observational studies. Most of these studies are single-center trials with no control arm, with sample size and patients’ characteristics varying widely.6,7 Two different meta-analyses reported significant heterogeneity in outcome measures, with median overall survival (OS) ranging from 5.0 to 23.5 mo.6,7 The few studies that compared the OS of sorafenib-treated LT recipients with that of historic transplanted patients who had received the best supportive care in the presorafenib era reported a survival benefit of the systemic treatment.8-11 Still, the short OS reported in some papers12,13 led to suspicion that the immune suppression could hamper the antineoplastic benefits of sorafenib. The possible pharmaceutical interactions between sorafenib and antirejection drugs were also reported as a potential matter of concern.13-16

Still, most of the remaining studies reported median OS values, which were grossly comparable with or even superior to those described in non-LT patients.6,7 In a first meta-analysis,6 the pooled estimate of 1-y OS of LT patients who received sorafenib was 63.0% (95% confidence interval [CI], 47-78), a slightly better figure than that reported in the pretransplant setting.4,5,17 A most recently published analysis, instead, estimated a median OS of 12.8 mo (95% CI, 10.6-15.1) and a 1-y OS 56.8% (95% CI, 42.8-70.9).7 Both papers concluded that additional data from multicenter prospective studies were needed before drawing definite conclusions.

Establishing whether concurrent immune suppression actually leads to impaired survival is crucial in a therapeutic scenario in which immunotherapies are being increasingly explored.18 Also, verifying whether LT patients are relatively resistant to sorafenib can be helpful to patient informing, especially in the light of the availability of second- and third-line mTKIs, such as regorafenib and cabozantinib.19

In this study, we aimed to report the characteristics and outcome of a large multicenter cohort of LT recipients who experienced an HCC recurrence and received sorafenib as a first-line agent. The role of combined and sequential treatments is also discussed.


Design of the Study

This study was performed using medical records from the Archives of Patients with HCC treated with Sorafenib (ARPES) database. This prospective database was created in 2010 to collect data acquired in a real-life scenario of patients treated with sorafenib to identify clinical, laboratory, and imaging predictors of response to the drug. This database includes consecutive patients treated with sorafenib in 5 different Italian Centers (Bologna, Naples, Bergamo, Pisa, and Milan). Data were entered every 3–6 mo starting from January 2010 into electronic data files by co-investigators from each center and were checked at the data management center for internal consistency. For this study, we considered patients who were prescribed sorafenib from January 2010 to December 2019. The starting date coincided with the creation of the database and, therefore, with the possibility of obtaining prospective data from all the study centers. The closing date was chosen to allow an adequate follow-up of patients. The closing time for the last follow-up was January 31, 2021.

Baseline Evaluation

Parameters entailing the residual liver function according to the Child-Pugh score and ALBI grade,20 tumor staging according to the BCLC classification, baseline α-fetoprotein (AFP) value, and performance status according to the Eastern Cooperative Group Performance Status (ECOG-PS) were available for all patients. Information about concurrent medical conditions and medications was also available. For this study, we analyzed data about aspirin use (which has been recently reported as a possible factor related to a better outcome)21,22 and immune suppressant agents.

Management of Sorafenib

Sorafenib was started at a usual dosage of 400 mg twice a day. Dose modifications (including dose reductions and discontinuation) were performed in cases of intolerable adverse effects. Sorafenib was continued until (1) radiological and clinical progression (for patients eligible for second-line clinical trials or licensed drugs, radiological progression alone was considered sufficient for discontinuation); (2) unacceptable toxicity; and (3) clinically significant deterioration of liver function. The reason for the permanent discontinuation of sorafenib was categorized as previously proposed.23


The study protocol was reviewed and approved by the local ethics committees. All patients gave their written informed consent for their data to be included in the prospective observational registry. The study was conducted according to the ethical guidelines of the latest Declaration of Helsinki.

Statistical Analysis

Continuous variables are expressed as the median and interquartile range (IQR). Categorical variables are expressed as frequencies. Group comparisons were performed with the Mann-Whitney test. Categorical variables were evaluated using the 2-tailed Fisher test. OS was measured from the starting date of sorafenib until the date of death or the last visit. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analyzed with log-rank tests. To define the predictors of OS, we used a time-dependent covariates survival approach including statistically significant clinical variables (P < 0.05) from the univariate Cox analysis. Statistical analysis was performed using SPSS Statistics for Windows (version 24.0; IBM) and STATA/SE 14.1 (StataCorp).


Baseline Characteristics of the Study Population

Among the 632 cases included in the ARPES database, 81 (12.8%) were post-LT patients with a recurrent HCC (Table 1). Most of them (96.3%) had received at least 1 pre-LT treatment, which included: liver resection (n = 13), percutaneous ablation (n = 49), transarterial chemoembolization (n = 45), and selective internal radiation therapy (n = 1). The median time from LT to the first HCC recurrence was 19.2 mo (IQR 11.7–47.1). Six patients developed HCC after >5 y (ie. 60 mo). Among them, 4 patients were not cirrhotic at the time of recurrence. The remaining 2 patients had sign of chronic graft disease but had an extrahepatic-only recurrence. Consequently, the risk of misclassifying these patients as de novo HCC on cirrhotic graft was estimated as low. The median time from the first recurrence to the start of sorafenib was 4.0 mo (IQR 1.7–11.1). Following the first recurrence and before the start of sorafenib, 51 patients (63.0%) received at least 1 nonsystemic treatment, including: surgical resection (n = 34), percutaneous ablation (n = 17), transarterial chemoembolization (n = 6), and external beam radiation therapy (n = 4). Also, 3 patients who had received calcineurin inhibitors at the time of transplant had been switched to mammalian target of rapamycin (mTOR) inhibitors (mTORis) at the first recurrence (always before starting sorafenib). At the time of sorafenib start, 56 patients were receiving calcineurin inhibitors and 28 patients mTORi (with 5 patients receiving a combination of both classes and 2 patients treated with other drugs). A detailed description of antirejection regimens is reported in Table 2.

TABLE 1. - Characteristics of the study population (n = 81) at the start of sorafenib
Age (y) 57 (52–62)
Sex (male) 72 (88.9)
Liver disease etiology
 HBV 19 (23.5)
 HCV 49 (60.5)
 Nonviral 13 (16.0)
ALBI grade 1 29 (35.8)
AFP ≥400 ng/mL 13 (16.0)
ECOG-PS >0 9 (11.1)
Tumor >50% liver volume or main trunk PVT 0
Macrovascular invasion 10 (12.3)
Extrahepatic spread
- No lesions 14 (17.3)
- One organ 10 (12.3)
- Multiple organs 57 (70.4)
Aspirin treatment 66 (81.5)
Metformin treatment 11 (13.5)
AFP, alpha-fetoprotein; ECOG-PS, Eastern Cooperative Oncology Group – Performance Status; HBV, hepatitis B virus; HCV, hepatitis C virus; PVT, portal vein thrombosis.

TABLE 2. - Breakthrough of the immune-suppressive therapies among the 81 patients with hepatocellular carcinoma recurrence after liver transplant at the time of sorafenib start
Immune suppressive regimen N (%)
Everolimus 13 (16.0)
Sirolimus 8 (9.9)
Cyclosporine 14 (17.3)
Tacrolimus 35 (43.2)
Mycophenolate 2 (2.5)
Corticosteroids 1 (1.2)
Everolimus+mycophenolate 1 (1.2)
Tacrolimus+everolimus 5 (6.2)
Tacrolimus+corticosteroids 1 (1.2)
Everolimus+tacrolimus+corticosteroids 1 (1.2)
TOTAL exposed to mTORi 28 (34.6)
TOTAL exposed to CNI 56 (69.1)
CNI, calcineurin inhibitor; mTORi, mammalian target of rapamycin inhibitor.

Follow-up and Outcomes

Dermatological adverse events (including skin rash and hand-foot syndrome) occurred in 42 patients. A permanent dose reduction to 400 mg daily was required in 61.7% of the population. Median treatment duration was 8.4 mo. Combined treatments with surgical/locoregional procedures were relatively frequent (12.3%). These treatments included: tumor resections (n = 5), percutaneous ablation techniques (n = 3), transarterial chemoembolization (n = 3), and external beam radiation therapy (n = 3). Six patients received >1 concurrent treatment. Grade ≥3 bleeding events occurred in 3.7% of the population.

A total of 76 (93.8%) patients permanently discontinued sorafenib. The reasons were: progressive disease (72.4%), adverse events (23.7%), or liver failure (3.9%). After the permanent discontinuation of sorafenib, a relevant proportion of patients (34.2%) received second-line systemic drugs. The most frequently prescribed postsorafenib regimens in the LT group were: regorafenib (n = 8), cabozantinib (n = 5), metronomic capecitabine (n = 10), and conventional chemotherapy (n = 3).

The median OS and progression-free survival were 18.7 (95% CI, 13.0-25.4) and 6.7 (95% CI, 5.2-8.2) mo, respectively (Figure 1).

Kaplan-Mayer curve of overall survival. CI‚ confidence interval.

Predictors of Survival in the LT Cohort

The univariate analyses showed that ECOG-PS >0 and the presence of liver lesions were associated with worse survival, whereas dermatological adverse events had a protective role. The multivariable Cox regression confirmed ECOG-PS >0 and the presence of liver lesions as independent prognosticators of survival (Table 3).

TABLE 3. - Univariable and multivariable Cox regression analysis of factors associated with the overall survival
Univariable analysis Variable Multivariable analysis
HR 95% CI P HR 95% CI P
0.990 0.968 1.013 0.380 Age (y)
0.627 0.294 1.340 0.228 Male sex
Etiology (nonviral = reference)
1.785 0.800 3.982 0.157 HBV
1.514 0.766 2.996 0.233 HCV
1.125 0.625 2.026 0.695 Milan out
1.155 0.625 2.134 0.646 Recurrence <12 mo
0.840 0.427 1.654 0.615 mTORi treatment
1.043 0.568 1.916 0.892 Aspirin treatment
1.081 0.274 5.013 0.912 Metformin treatment
1.111 0.817 2.116 0.555 ALBI grade >1
1.803 1.122 2.897 0.015 Liver lesions (yes vs no) 1.710 1.058 2.761 0.028
1.167 0.593 2.298 0.655 Macrovascular invasion
Extrahepatic lesions (no = reference)
1.017 0.345 2.999 0.976 Single organ
0.928 0.333 2.588 0.887 Multiple organs
4.259 2.079 8.725 <0.001 ECOG-PS >0 3.513 1.612 7.657 0.002
1.321 0.674 2.589 0.418 AFP ≥400 ng/mL
0.545 0.331 0.897 0.017 Dermatological AEs a 0.729 0.432 1.231 0.237
aEvaluated with a time-dependent analysis.
AE, adverse event; AFP, alpha-fetoprotein; CI, confidence interval; ECOG-PS, Eastern Cooperative Oncology Group – Performance Status; HBV, hepatitis B virus; HCV, hepatitis C virus; mTORi, mammalian target of rapamycin inhibitor.


We described sorafenib efficacy and safety profile in a sizeable multicenter cohort of HCC patients with post-LT recurrence, answering the calls for large populations with prospectively collected data.6,24,25

We found that the LT patients reached a median OS of about 19 mo. This is similar to the data provided in LT patients by some authors,14,26-29 yet profoundly different from other reports.12,13,30-33 As the available meta-analyses mention, the baseline characteristics of LT patients and the centers’ policies are critical in understanding and interpreting the raw survival data.6,7

In our study, the remarkable OS of transplanted patients depended on multiple factors. First, LT patients had relatively favorable baseline characteristics. Indeed, the metastatic nature of the post-LT recurrence led to a very high rate of extrahepatic spread. However, this factor was counterbalanced by a low prevalence of liver dysfunction (due to the absence of liver cirrhosis) and low rates of symptomatic disease, massive liver neoplastic occupation, macrovascular invasion, and high AFP (due to an early diagnosis favored by strict controls with panoramic imaging during the first 1–2 y after LT).34 Chronic use of low-dose aspirin has been recently advocated as a positive predictive factor in sorafenib-treated patients.21,22 Its extensive use in LT patients to prevent the occlusion of the hepatic artery anastomosis34 could be another factor contributing to the OS values. Second, the preserved liver function and good performance status allowed a more frequent use of combined locoregional treatments during and after sorafenib. Also, a relevant number of LT patients were eligible for second-line systemic treatments after sorafenib discontinuation. This information is of particular interest as second- and third-line mTKIs have become available over time. An observational multicenter retrospective study of regorafenib in LT patients35 described outcomes similar to that reported in the registered RESORCE trial,36 which did not enroll transplant recipients. Notably, the median OS calculated from sorafenib start was 28.8 mo.35 A Phase 2 trial of cabozantinib in patients with recurring HCC after LT has been designed (NCT04204850), but no definite data are still available. Of note, a recent real-life study of cabozantinib in HCC patients included 10 LT recipients among a total of 96 patients; the median survival from the start of a frontline systemic therapy to death was 36 mo in patients who received the sorafenib–regorafenib–cabozantinib sequence.37 Under normal conditions, only a minority of patients can receive >1 therapeutic line, as general conditions and liver function worsen at the time of progression.38 However, since LT patients are more likely to receive postsorafenib treatments, they might also be one of the populations that will benefit more from sequential strategies. The possible postsorafenib treatments include both regorafenib and cabozantinib. Also, lenvatinib has become an alternative frontline treatment. Currently, sorafenib is the only available per-label second-line drug in lenvatinib pretreated patients. Third-line treatments will eventually include cabozantinib and regorafenib (the latter only in countries not limiting the possibility of prescription to the second-line setting).

Originally, we aimed to try and match LT patients with controls with similar baseline characteristics from the ARPES database. Unfortunately, the overt differences in the baseline characteristics of the patients did not allow such matches despite the numerosity of both cases and controls. Differently from the previous point, there are not much data in the literature that can be used to compare our findings. In the only study that explored the feasibility of matching, Lee et al39 examined 832 consecutive HCC patients treated with sorafenib (790 in the non-LT group and 42 in the LT group) between 2008 and 2019 at the liver unit of a Korean center. The enrolled population had similar characteristics to our study, except for a slightly higher prevalence of viral etiology of liver disease and Child-Pugh B patients.39 The authors reported higher median OS (16.8 versus 7.1 mo, P < 0.001) and time to progression in LT compared with non-LT patients in the entire study population.39 They also managed to match 42 pairs of patients using propensity scores, finding no significant survival differences in the matched population (18.2 versus 16.8 mo). Notably, performance status was not considered as a prognosticator nor as a matching factor. Also, liver function was categorized according to the Child-Pugh score, which is not entirely appropriate for noncirrhotic patients such as most LT recipients at the time of HCC recurrence (resulting in easier match as both populations have an overwhelming majority of Child-Pugh A patients). These discrepancies were likely responsible for the transition from a difficult match in Lee study39 (the liver lesions of the matched population had a median diameter of 8 mm, suggesting reduced generalizability) to an impossible one in our study.

Finally, we investigated the predictors of survival in the population of patients with post-LT recurrence of HCC who received sorafenib. The results of this analysis should be taken with caution as our sample size is one of largest in literature, but still suboptimal for multivariable regressions with a high number of covariates. With this limitation in mind, LT outside of the Milan criteria or concurrent therapy with calcineurin inhibitors were not associated with worse outcomes once sorafenib was started. This finding can be easily explained by the hypothesis that excessive pre-LT tumor burden or high level of exposure to calcineurin inhibitors might affect the time to recurrence,40 but not the response to sorafenib. Instead, we found that the presence of liver lesions was associated with a worse outcome. This finding cannot be justified by the risk of liver failure due to the neoplastic occupation of the liver, as most patients had noncirrhotic grafts when they started sorafenib (and were therefore unlikely to experience liver failure before very late stages). Instead, it could be hypothesized that hepatic and extrahepatic lesions have different pathogenic significance in the specific setting of post-LT recurrence. Although extrahepatic lesions can theoretically derive from circulating tumor cells or represent growth of preexisting metastasis undetected by imaging, neoplastic lesions of the graft are metastatic in nature (either from circulating cells or from extrahepatic sites) and therefore with a greater potential of biological aggressiveness. Clearly, this hypothesis is mainly academic and will need dedicated studies.

Our paper has some limitations deserving discussion. First, our analyses were retrospective in nature; however, the prospective collection of consecutive cases and the availability of all the requested information for every patient significantly reduced the possibility of selection biases. Second, a certain degree of intercenter variability in the management of both sorafenib and posttransplant therapies should be considered; still, we considered only centers that manage both patients with HCC and a native liver as well as an LT graft. Consequently, possible confounders derived by individual choices (such as the clinicians’ propensity to enroll cases with borderline eligibility and managing sorafenib toxicities41) should be limited. Third, the number of enrolled LT patients is the highest in the relevant literature but still not sufficiently high to compare the outcomes according to the concurrent antirejection treatment. The heterogeneity of the antirejection regimens partly depended on the evolving news cumulating during the enrollment. For instance, switching to mTOR inhibitors at the first HCC recurrence became less popular after the failure of the EVOLVE-1 trial for advanced HCC.42

In conclusion, we reported critical pieces of information. First, multimodal and sequential treatments are relatively frequent in patients with HCC recurring after LT. This factor, paired with a preserved liver function and more favorable baseline tumor characteristics, contributed to achieving considerable OS values in LT patients. This finding underlines the potentialities of both concurrent local treatments and mTKI sequences in the LT population. Second, even with the important limitations deriving from the absence of proper controls, we did not find poor OS and progression-free survival values in LT patients. This finding suggests that antirejection regimens do not automatically result in impaired survival. Clearly, an accurate and methodologically correct evaluation of the actual prognostic impact of antirejection drugs would require matched populations and homogeneous antirejection regimens. Still, our results crudely suggest that even potential detrimental effects on survival (if existent) do not seem to translate into an overtly impaired OS or response to sorafenib. Also, we did not find new signals of adverse events. This information can be used in clinical practice to inform and reassure patients about their outcomes. Equally important, the apparent lack of relevant deleterious effects derived from the inhibition of specific immune pathways might provide indirect yet valuable information in the era of checkpoint inhibitors.


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