Time to transplantation as a predictor of hepatocellular carcinoma recurrence after liver transplantation

Abstract

In the United States, there are significant geographic disparities in the time to transplantation for patients with hepatocellular carcinoma (HCC); it is possible that rapid transplantation contributes to higher rates of posttransplant HCC recurrence because there is insufficient time for the tumor biology to manifest. In this study, we compared HCC recurrence in rapid transplant patients and their slower transplant counterparts. We identified adult liver transplantation (LT) candidates in the Organ Procurement and Transplantation Network/United Network for Organ Sharing (UNOS) data set who were granted an initial exception for an HCC diagnosis between January 1, 2006 and September 30, 2010 and underwent transplantation in the same time window. Patients were followed until HCC recurrence, non–HCC-related death, or last follow-up. The cumulative incidence of HCC recurrence was compared for patients waiting ≤120 days and patients waiting >120 days from an HCC exception to LT. The association between the risk of posttransplant recurrence and the wait time was further evaluated via competing risks regression with the Fine and Gray model. For 5002 LT recipients with HCC, the median wait time from an exception to LT was 77 days, and it varied from 30 to 169 days by UNOS region. The cumulative incidence of posttransplant HCC recurrence was 3.3% [95% confidence interval (CI) = 2.8%–3.8%] and 5.6% (95% CI = 5.0%–6.3%) within 1 and 2 years, respectively. The rate of observed recurrence within 1 year of transplantation was significantly lower for patients waiting >120 days versus patients waiting ≤120 days (2.2% versus 3.9%, P = 0.002); however, the difference did not persist at 2 years (5.0% versus 5.9%, P = 0.09). After we accounted for clinical factors, the HCC recurrence risk was reduced by 40% for patients waiting >120 days (subhazard ratio = 0.6, P = 0.005). In conclusion, the risk of HCC recurrence within the first year after transplantation may be lessened by the institution of a mandatory waiting time after an exception is granted.

Reply

“…1 These potentially important data demonstrate elevated circulating miRNAs, especially miR-122, in human subjects with ALI, which confirms published work from our group and elsewhere. 2 However, we have significant concerns about a number of the findings reported in this article.…”

“…3,4 Currently, it seems that lack of progression of tumor while waiting for a liver transplant, or successful down-staging of tumor, may be the best available biological marker, as demonstrated by the UCSF group and our article. 1,2,5 We agree that the development, and universal implementation of appropriate and reproducible biomarkers of tumor biology to allocation models of liver transplantation for HCC is required in order to optimize outcomes for HCC patients.…”

“…The lack of uniformity in organ allocation among regions has allowed us and others to examine the vast regional variation in waiting times to discover major differences in the outcomes of hepatocellular carcinoma (HCC) patients on the list, both with respect to recurrence and overall outcome. 1,2 It is clear that uniformity among transplant centers in the U.S. and worldwide in both access and treatment of these patients is required, and will allow the transplant community to better understand how to manage patients with HCC on the waiting list. While the Milan criteria are widely accepted despite having no specific tumor biology indices associated with them, many groups including our own have attempted to define markers of poor biology; however, none of these have been universally accepted or applied to organ allocation models.…”

Hepatocellular carcinoma: when is liver transplantation oncologically futile?

“…In contrast, longer recurrence free intervals after pre-LT treatment select patients with a low post-LT recurrence risk. In a large analysis of >5,000 HCC patients in the UNOS region those who remained on the waiting list without recurrence for >120 days had a 40% reduced risk of post-LT recurrence compared to those with a shorter waiting time (28). This "sweet spot" of 6-18 months waiting time has also been demonstrated by a very recent study (29).…”

Lack of Survival Benefit Following Liver Transplantation With MELD Exception Points for Hepatocellular Carcinoma: Beyond the Unblinding of Lady Justice

“…The potential importance of establishing tumor behavior and treatment response is highlighted by lesser rates of HCC recurrence seen in patients with longer waitlist time (>3-4 months). 14,15 In an analysis of UNOS data, higher MELD exception (ie, longer wait time) at transplant in patients with HCC was associated with better posttransplant survival, whereas higher calculated MELD in non-HCC cases was associated with worse posttransplant survival. 16 A recent study examined UNOS data for the impact of simulated 3-, 6-, and 9-month delays in exception MELD for T2 lesions.…”