In this issue of ONCOLOGY, Kim et al discuss adjuvant therapy after liver transplantation to decrease recurrence of hepatocellular carcinoma (HCC). Liver transplantation offers the best overall and recurrence-free survival for the treatment of stage I and II HCC. The landmark study in 1996 by Mazzaferro demonstrated that liver transplantation of patients with one lesion less than 5 cm or with up to three lesions but all less than 3 cm (the Milan criteria) resulted in low recurrence rates and similar survival to patients without HCC.[1] Subsequent studies have shown that the Milan criteria may be too stringent and that a significant number of patients with HCC beyond these criteria may still have relatively low recurrence rates and good outcomes after transplantation but are precluded from the procedure. Various groups have shown that liver transplantation may offer very good survival in patients with more advanced T3 or T4A lesions (summarized in reference 2).
The problem, of course, is that the incidence of tumor recurrence after transplantation increases with more advanced lesions, leading to poor outcomes. Because organs are a scarce and precious resource, the transplant community has been cautious in expanding the indications for liver transplantation in patients with HCC beyond the Milan criteria. Decreasing recurrence rates would improve organ utilization and outcomes and allow patients with more advanced HCC but with favorable tumor biology to be offered transplantation. Posttransplant adjuvant therapy is, therefore, an attractive and logical therapeutic option; however, the current dilemma is this: Not only are these options limited, but it is also unclear whether these treatments are effective in preventing recurrence.
Which patients are at highest risk for recurrence?
It is crucial to have more accurate methods of predicting which patients are at highest risk for HCC recurrence. Risk factors for HCC recurrence have been identified in numerous series and the most important tumor characteristics include size, number of lesions, presence of vascular invasion, and tumor differentiation. Tumors beyond the Milan criteria have recurrence rates of up to 42% (or even greater); it is difficult to ascertain more accurate rates as studies vary in follow-up and there is a wide range in transplanted patients’ tumor stages (with or without adjuvant therapy) between different series. Tumors within the Milan criteria have recurrence rates of 5% to 8%, indicating that size and number of lesions in a subgroup of patients do not always correlate with outcomes. It is impractical to offer adjuvant treatment to all patients with T1 and T2 tumors who undergo transplant. Therefore, there would be tremendous benefit if patients within the Milan criteria who have unfavorable tumor biology or, conversely, patients with larger tumors who have favorable tumor biology could be identified.
An example of the use of molecular techniques to assess tumor biology is demonstrated in work by Marsh et al.[3] These researchers analyzed 171 HCC patients who underwent transplantation and assessed their tumors for the presence or absence of mutations in a panel of tumor-suppressor genes. By determining the fractional allelic imbalance (FAI) rate index, defined as the number of mutated markers divided by the total number of informative markers, they demonstrated on multivariate analysis that FAI was the strongest predictor of recurrence, even more so than vascular invasion. The FAI was a powerful tool in distinguishing patients with lesions beyond the Milan criteria who did not develop recurrence and had good outcomes. This tool can potentially exclude patients at extreme risk of posttransplant HCC recurrence, but prospective validating studies need to be performed. A potential disadvantage to this technique is the requirement for tumors to be biopsied prior to transplantation.
Is posttransplant adjuvant therapy effective?
As Kim and coauthors point out, adjuvant therapy to prevent or decrease HCC recurrence after liver transplantation must be systemic, as the overall goal is to eradicate micrometastasis present at the time of transplantation. The allograft liver is the most common site of recurrence; however, the majority of recurrences (> 80%) also involve extrahepatic sites, most of which involve the lungs, followed by bone.[4] Currently, systemic chemotherapy is the most common form of posttransplant adjuvant treatment that has been extensively studied. Several groups have reported their experiences (Table 2 in the article by Kim et al), and the most commonly used agents in this setting include doxorubicin(Drug information on doxorubicin), cisplatin(Drug information on cisplatin), and gemcitabine(Drug information on gemcitabine) (Gemzar).
Despite the number of reports, the true efficacy of adjuvant chemotherapy to prevent recurrent HCC is unknown, though most studies have shown no significant gain. Most of the studies lack control groups, with the majority of patients having advanced disease (hence, the administration of adjuvant treatment). In addition, follow-up in many of the studies has been relatively short. It would seem to make logical sense to begin chemotherapy as soon as possible after the transplant; however, most patients are not medically fit to receive treatment in the early postoperative period. Most clinicians are, therefore, reluctant to administer chemotherapy to a liver transplant patient because of associated toxicities, in addition to the lack of any proven efficacy.
Two other promising agents that are unproven include the oral agent sorafenib(Drug information on sorafenib) (Nexavar), and the immunosuppressant sirolimus(Drug information on sirolimus) (Rapamune). Sorafenib, an oral tyrosine kinase inhibitor that is US Food and Drug Administration–approved for the treatment of unresectable HCC, appears to be a promising agent. However, no data have been published on the adjuvant use of sorafenib to prevent HCC recurrence after liver transplantation. A phase I safety trial in HCC patients who have undergone liver transplantation is currently being conducted by the National Cancer Institute. Sirolimus is an immunosuppressive agent that inhibits mammalian target of rapamycin (mTOR) and has been found to have antitumor effects in animal models of HCC. Several preliminary clinical studies have demonstrated that sirolimus may have modest survival benefits in HCC patients who have undergone liver transplantation.
Conclusions
Kim et al have aptly concluded that there is a pressing need for the development and use of more accurate prognostic markers to determine which patients are at highest risk for recurrence as well as a need for multicenter, randomized, and controlled studies to determine the efficacy of adjuvant therapy for the prevention of HCC recurrence after liver transplantation. Only with these efforts can we truly make further progress in decreasing HCC recurrence and safely expanding the indications for liver transplantation of patients with HCC.
