Hepatocellular Carcinoma: Neoadjuvant Therapy Reconsidered

August 1, 2007

Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in the setting of chronic liver disease and cirrhosis. The incidence of hepatocellular carcinoma is increasing in the United States and worldwide. Orthotopic liver transplantation (OLT) is a viable and potentially curative option for selected patients with HCC. Locoregional therapy has been used to control HCC before transplantation because of the limited number of donor organs, to prevent tumor progression, and to decrease the incidence of dropouts from the transplant waiting list. Traditionally, multiple investigational locoregional modalities such as tumor resection, radiofrequency ablation, transarterial chemoembolization, and systemic chemotherapy have been used as "bridging" therapies. While the investigation of novel neoadjuvant treatments is justified in an effort to prevent tumor progression, the absence of randomized controlled trials leaves uncertainty about the utility of these maneuvers in improving outcome. This review summarizes the current data on the different modalities used worldwide in the neoadjuvant treatment of hepatocellular carcinoma, the rationale for these approaches, efficacy, potential complications, and future prospects.

In this issue of ONCOLOGY, Almhanna et al review the current state of neoadjuvant therapy for hepatocellular carcinoma (HCC). In the management of transplantable HCC, through no fault of the authors, the term "neoadjuvant" is broad and poorly defined. The authors point out that the goals of neoadjuvant therapy for HCC are to prevent tumor progression and limit the dropout rate of transplant-listed patients due to tumor progression and, ideally, to minimize disease recurrence and improve survival. Nevertheless, the heterogeneity of the world literature undermines our ability to generate a consensus definition.

Defining "Neoadjuvant"

For instance, the "resection first when possible" approach is applied with no sense that transplantation is the ultimate goal—transplant is reserved for "resection failures." How can this be included in a discussion of "neoadjuvant therapy," when resection is actually the primary treatment? Although proponents propose that resection be used as primary therapy with salvage liver transplantation for recurrent disease, liver dysfunction, and positive margins, this aggressive approach is rarely utilized in the United States due to the added priority that patients receive when they are listed for transplantation in the setting of HCC. (More recently, the high recurrence rate of HCC after resection in the setting of hepatitis C virus has prompted even proponents of the "resection first when possible" approach to reevaluate this strategy.) Resection plays a limited role in the management of HCC, and should not be considered neoadjuvant therapy.

If one is to then define neoadjuvant as pretransplant treatment designed to limit tumor progression (and dropout rate) or to downstage tumor for those not listed for transplantation, then transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and chemotherapy are considerations. The authors comprehensively discuss these options; each of the modalities has limitations, and few have been assessed in prospective randomized trials that support their use.

Limited Evidence

TACE is an often used locoregional intervention. The primary effects of TACE are the actions of the chemotherapeutic agent, ischemia, and hypoxia. Although no randomized controlled trial has demonstrated the value of TACE for HCC in patients awaiting liver transplantation, these authors outline the papers that provide supportive evidence for the use of TACE in the neoadjuvant setting, which they acknowledge is weak and controversial at best.

For instance, the ability of TACE to downstage HCC has been considered in a retrospective study of 187 patients by Majno et al.[1] These investigators noted downstaging (42%) and total necrosis (50%) of tumor in those treated with TACE, and recurrence-free survival was improved in TACE patients who experienced downstaging as compared with those who did not respond to TACE. However, in the subgroup of patients who underwent liver transplantation, preoperative TACE did not improve survival.

Further, in a retrospective analysis by Saborido et al,[2] no significant benefit was found in the tumor recurrence rate after liver transplantation among patients who received TACE (16% with TACE vs 34% without TACE, P > .05). These investigators also noted identical recurrence patterns in both groups—that is, a > 60% extrahepatic relapse rate. The recent review from Clavien's group[3] summarizes worldwide efforts to date, pointing out that there is no established role for pretransplant TACE.

Evidence for pretransplant RFA is similarly weak, in that the reported series are small, with heterogeneous patient populations and a lack of standardized endpoints. The authors have developed this theme nicely in their paper. Chemotherapy has been ineffective to date, and while perhaps there is hope for the future with newer biologic agents, we must regard the newer studies with caution, as a significant confounding factor is the phenomenon of lead-time bias, due to earlier detection of HCC in patients with viral hepatitis.

Conclusions

In summary, there are no clear data that neoadjuvant therapy lowers the liver transplant dropout rate, decreases recurrence, or improves overall survival. Furthermore, we do not have good data regarding which modality is superior in the neoadjuvant setting. Current series usually report the modality for which their institution has the most expertise, and therefore, results are seldom consistent between centers. New chemotherapeutic options hold promise for efficacy and consistency in the future, but we all acknowledge that the gains will be incremental and achieved over years.

Going forward, randomized trials with the primary endpoints of dropout rate, disease recurrence, and overall survival are desperately needed. These studies will be difficult to conduct, not only because of the institutional biases already present among different transplantation centers, but also because of the challenges of funding trials of this magnitude. As Almhanna and colleagues point out, these studies will require a large number of patients and the support of multiple institutions across the continents.

The authors' concluding remarks, while intuitive, are an imperative, and bear repeating: "Efficient trial design, appropriate selection of correlative markers, and greater cooperation among hepatologists, surgeons, and medical oncologists, . . . will propel this field further" and improve what we can offer this challenging group of patients.

—Sunil K. Geevarghese, MD
—Ravi S. Chari, MD

Disclosures:

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.

References:

1. Majno PE, Sarasin FP, Mentha G, et al: Primary liver resection and salvage transplantation or primary liver transplantation in patients with single, small hepatocellular carcinoma and preserved liver function: An outcome-oriented decision analysis. Hepatology 31:899-906, 2000.

2. Saborido BP, Meneu JC, Moreno E, et al: Is transarterial chemoembolization necessary before liver transplantation for hepatocellular carcinoma? Am J Surg 190:383-387, 2005.

3. Lesurtel M, Mullhaupt B, Pestalozzi BC, et al: Transarterial chemoembolization as a bridge to liver transplantation for hepatocellular carcinoma: An evidence-based analysis. Am J Transplant 6:2644-2650, 2006.