Sorafenib is a multitargeted small molecule tyrosine kinase inhibitor that inhibits tumor growth and angiogenesis by inhibiting intracellular RAF kinases (CRAF, BRAF, and mutant BRAF), and cell surface kinase receptors (VEGFR-2, VEGFR-3, PDGFR-beta, cKIT, and FLT-3). It is currently the standard treatment of advanced unresectable HCC based on the Sorafenib(Drug information on sorafenib) HCC Assessment Randomized Protocol (SHARP), a multicenter double-blind, placebo-controlled trial that showed a statistically significant overall survival of 10.7 months in the sorafenib group compared to 7.9 months in the placebo group. A phase I trial by the National Cancer Institute (NCI) is currently recruiting patients to study the toxicity of sorafenib in patients with HCC after liver transplantation.
Promising results were obtained with the intravenous radioimmunologic agent licartin (a 131I-radiolabeled murine monoclonal antibody that targets an HCC-specific molecule, HAb18G/CD147) in a small placebo-controlled randomized double-blind study from China. Licartin specifically binds to HCC cells that express Hab18G/CD147 with a tumor/nontumor ratio > 1. The blood clearance fits a biphasic model, and its half-life is 63 to 90 hours. At 1-year follow-up, the HCC recurrence rate was significantly decreased by an absolute 30% (27% vs 57%), and the survival rate was increased from 62% to 83% in the treatment group compared to those in the control arm. Although results are promising, longer follow-up and further experience in a larger-scale study are needed to confirm these results and to establish the use of licartin in the adjuvant setting.
Patients who undergo liver transplantation are kept on lifelong immunosuppression. This poses an increased risk for recurrence with calcineurin inhibitors such as cyclosporine or tacrolimus(Drug information on tacrolimus) (Prograf, FK506). Sirolimus(Drug information on sirolimus) (Rapamune)-based immunosuppressants have gained popularity and interest recently in the adjuvant setting after OLT. Sirolimus is an mTOR inhibitor, and in addition to its immunosuppressive actions, it was shown to possess antitumor effects through its antiangiogenic actions. Zhou et al retrospectively examined 73 patients exceeding the Milan criteria after OLT; 27 received sirolimus-based therapy and the rest received tacrolimus. Mean overall survival was 594 ± 35 days and 480 ± 42 days, respectively. There was no difference in disease-free survival.
Another study by Zimmerman et al included 97 patients, of which 45 received sirolimus-based therapy after OLT. Overall survival at 1 and 5 years was 95.5% and 78.8%, respectively, and for those receiving sirolimus was 83% and 62%, respectively. It is not clear how many patients were within the Milan criteria. These studies have shown a possible survival advantage with sirolimus immunotherapy in the adjuvant setting without compromising engrafting.
Hepatocellular carcinoma recurrence after OLT remains a problem. Even with the implementation of the Milan criteria, recurrence rates have been shown to be 8% to 15% in most studies and even higher in patients who are beyond the Milan criteria. In this article, we have reviewed data on the role of systemic chemotherapy and combination of neoadjuvant local therapy and adjuvant systemic chemotherapy after OLT.
Since most recurrences after OLT are extrahepatic, systemic control of disease plays a vital role. In all adjuvant chemotherapy studies, the main toxicity has been bone marrow suppression requiring interruption of treatment or the use of granulocyte colony-stimulating factor (G-CSF, filgrastim(Drug information on filgrastim) [Neupogen])to overcome this problem. This complication is exacerbated by immunosuppressants used to reduce the risk of graft rejection after liver transplantation. Furthermore, the combined use of immunosuppressants and chemotherapy drugs can lead to drug interactions resulting in either decreased efficacy or increased toxicity.
Optimal timing of adjuvant systemic treatment has not been established. Theoretically, it seems reasonable to start systemic chemotherapy as early as possible after transplant at the time of maximal immunosuppression, during which micrometastases are most likely to grow. However, this is often difficult due to overlapping toxicities of chemotherapy and immunosuppressive medications, the need to recover from surgery, and the need for adequate hepatic, renal, and hemodynamic functions prior to initiation of treatment. In addition, there is also a concern about causing injury to the newly implanted liver by chemotherapy agents. Increased risk of viral reactivation with adjuvant chemotherapy has also been reported.
Many of the adjuvant trials reviewed in this article suffer from shared deficiencies. Most are uncontrolled studies with small numbers, heterogeneous inclusion criteria (eg, the Milan criteria were not used in older studies), and the omission of stratification by well-known prognostic factors. Furthermore some trials were not pure adjuvant trials, as some patients received local neoadjuvant therapy prior to liver transplantation.
It is difficult to design a trial with an endpoint of overall survival after OLT in patients who meet Milan criteria as they have a very good prognosis. Similar to the situation with stage II colon cancer, a few thousand patients need to be enrolled in order show an absolute benefit of 2% to 3%. Also, given the large financial burden these agents will put on patients and the health-care system, cost-effectiveness and cost-benefit are issues as well.
Instead, the focus of adjuvant trials should be on patients at a higher risk of recurrence, such as those with vascular invasion or tumor size beyond Milan or UCSF criteria, in order to match their survival with those who are within the criteria. Retrospective data by Mazaffero et al showed that overall prognosis was worse in patients who did not meet the Milan criteria, with a 5-year overall survival of 53.6%, compared to 73.3% in patients who met those criteria.
If future adjuvant trials show an improvement in overall survival for those who are at high risk or beyond recognized transplantation criteria, then transplant communities may be more receptive to expanding criteria for OLT and allow more patients to become eligible for the waiting list. A possible drawback to this is that if more patients are listed, the wait for an organ in an organ-shortage era will be longer and perhaps allow for disease progression while awaiting transplantation, or possibly deny an organ to a patient who does not have HCC. It is important to develop a scoring system to predict recurrence that can be applied in adjuvant studies after OLT. Chan et al developed the Predicting Cancer Recurrence Score (PCRS) tool using multiple prognostic factors such as histology, tumor size, and vascular invasion. Patients are stratified into low, intermediate, or high risk of recurrence. Molecular markers may play a bigger role in predicting reoccurrence in the future. As stated above, when FAI alone was compared to the Milan or UCSF criteria, it was found to be the stronger predictor of tumor-free survival. Similarly, Mazzaferro et al came up with the “up-to-seven” criteria, by which seven was defined as the result of the sum of the largest tumor size (in cm) and number of tumors for any given hepatocellular carcinoma. Patients who are beyond these criteria have a 5-year survival rate of only 48%. Therefore, it would be reasonable to conduct an adjuvant trial with patients who are beyond these criteria.
Data suggest that the presence and number of circulating tumor cells are associated with a worse survival. Studies should be developed to examine circulating tumor cells after OLT. In the era of novel agents, drugs like sorafenib should be studied in the adjuvant setting, provided there are safety data in terms of interactions with other immunosuppressants. The NCI is currently conducting a phase I trial to answer this question. Once safety profiles are established, then larger studies randomizing patients to agents of interest vs placebo should be performed in those with intermediate or high risk of recurrence.
In conclusion, there is a paucity of data concerning adjuvant treatments after liver transplantation for hepatocellular carcinoma. Adjuvant therapy is not currently recommended for any patient undergoing liver transplantation for HCC except in the context of a clinical trial. Effective adjuvant treatment should be systemic to tackle the circulating tumor cell burden. Novel agents should be developed and tried in randomized trials, especially in patients with intermediate and high risk of disease recurrence. Sirolimus-based immunotherapy after OLT may offer improved outcomes and should be studied in a controlled setting. In the era of organ shortage, it is imperative that we design trials to properly select patients and possibly use new molecular biomarkers or nomograms to improve the prognostic accuracy selection criteria for OLT. This will allow us to capture the potential benefits while maximizing our current resources.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.