Expanding transplant criteria for hepatocellular carcinoma: Small steps down a long road
Authors: William Sanchez
Journal: Hepatology (2009)

Hepatocellular carcinoma (HCC) remains a frequent complication among patients with cirrhosis and, as medical care for patients with chronic liver disease improves, an increasing proportion of patients with cirrhosis will die from HCC.1 Among carefully selected candidates, liver transplantation (LT) for HCC provides excellent outcomes with 5-year survival rates similar to patients undergoing LT for nonmalignant indications.2, 3 Many patients present with tumor burden beyond the currently accepted Milan criteria for deceased-donor organ allocation, yet they may potentially benefit from liver transplantation. Expanding the criteria for LT for patients with HCC remains an area of controversy and active investigation within the field of liver transplantation; however, the push for increased patient access to transplantation has to be carefully considered against the pull of obtaining the maximum long-term benefit from scarce donor organs. AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; LT, liver transplantation; SRTR, Scientific Registry of Transplant Recipients; TTV, total tumor volume. In the current issue of HEPATOLOGY, Toso and colleagues4 examine data from the Scientific Registry of Transplant Recipients (SRTR) and propose an expansion to the current allocation criteria for LT for the treatment of HCC. The authors propose inclusion criteria based upon calculated total tumor volume (TTV) and serum alpha-fetoprotein (AFP) level as opposed to the current Milan criteria based on the size (diameter) and number of lesions. In a retrospective analysis of 6478 adult patients undergoing primary LT for HCC, multivariate analysis revealed that only TTV > 115 cm3 and a serum AFP level > 400 ng/mL predicted mortality. The authors selected a TTV cut-off of 115 cm3 based on their recently published data suggesting that TTV predicts HCC recurrence following LT.5 Data on tumor size in the SRTR is reported by transplant centers based on imaging obtained closest to the date of transplantation. The imaging modalites used to obtain number and size of HCC nodules were reported in 80.5% of patients and included computed tomography in 58.7% and magnetic resonance in 42.5% of patients. The current study presents several strengths: analysis of the SRTR database provides a large cohort of patients for study and the proposed criteria are straightforward and readily incorporated into clinical practice. TTV is easily calculated from cross-sectional imaging studies and serum AFP is widely available and routinely measured. Notably, tumor radius (and therefore calculated TTV) was based on pre-LT imaging studies rather than explant pathology, strengthening the applicability of the proposed criteria as a selection tool for transplant candidates. Because volume is a cubic formula (v = 4/3Πr3), larger lesions—for which cross-sectional imaging is more accurate—are emphasized while the importance of smaller lesions and the total number of nodules is diminished. As with any study which proposes expanding the current transplant criteria for HCC, the key group of patients is those individuals who are beyond the Milan criteria but within the proposed criteria. Given the significant overlap between the existing and proposed criteria—96.8% of patients within the proposed tumor volume criteria met Milan criteria—overall favorable outcomes are expected. In the current study, 205 patients were transplanted under truly "expanded criteria" and had outcomes similar to those patients within Milan criteria. While this is a small percentage of the cases studied, it represents a large number of patients relative to other published studies. Many of the limitations of the current study are inherent to its retrospective nature, such as the lack of standardization of imaging modalities used and the variable use of pretransplant loco-regional therapy. Several important questions, however, remain unanswered. The primary endpoint of the current study was all-cause mortality. Unfortunately, the study did not assess the other main outcome of interest, namely recurrence-free survival. Furthermore, the median duration of follow-up after LT was relatively short at 13.4 months. The majority of HCCs will recur more than 1 year after LT and the median survival following recurrence has been reported to be on the order of 9 months.6 Whereas SRTR data may underestimate HCC recurrence rates due to underreporting, the lack of recurrence data coupled with a short follow-up period significantly limits the conclusions that can be drawn regarding the impact of the proposed expanded criteria on long-term outcomes following LT. Also, whether all small lesions portend the same favorable prognosis remains speculative (e.g., multiple, small "satellite" nodules surrounding a larger tumor mass may, in fact, predict a different clinical outcome than isolated small lesions). Lastly, it is unknown how well calculated tumor volumes correlate with measured tumor volumes (not all cancers are perfect spheres) and whether measured tumor volumes would be superior in predicting outcomes. It is likely that among patients with tumor burdens beyond the current transplant criteria, a subset of patients with favorable tumor biology exists and that these patients would have an acceptably low risk of post-transplant tumor recurrence. Overall, the tumor volume criteria proposed by Toso et al represents only a modest increase from the currently accepted Milan criteria and is, in fact, more restrictive than the University of California San Francisco criteria in terms of a single tumor (a TTV of 115 cm3 corresponds to a single lesion of approximately 6 cm in diameter).7 Excluding patients with elevated AFP serum levels would negatively affect a significant number of patients who currently meet Milan criteria. Ultimately, we need to define risk of HCC recurrence after LT on the basis of tumor biology rather than morphology. Diameter, especially when it is used as a static value, is a very crude predictor of tumor behavior. A patient with a slowly growing 5.1 cm tumor who would be currently excluded from LT may have a more favorable post-transplant outcome than a patient in whom a nodule increased in size from 3.5 cm to 4.8 cm over a short period of time. Tumor grade has been demonstrated to affect outcome, particularly in larger tumors, with patients who have poorly differentiated tumors demonstrating high rates of recurrence.8 Recent studies have identified molecular profiles associated with aggressive HCC behavior.9-11 Although tumor morphology can identify those patients who by virtue of limited disease burden will have favorable outcomes following LT, many more steps down a long road are necessary to identify those patients beyond the Milan criteria who will be best served by transplantation.