Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: An intention-to-treat analysis

Abstract

We previously reported encouraging results of down-staging of hepatocellular carcinoma (HCC) to meet conventional T2 criteria (one lesion 2–5 cm or two to three lesions <3 cm) for orthotopic liver transplantation (OLT) in 30 patients as a test of concept. In this ongoing prospective study, we analyzed longer-term outcome data on HCC down-staging in a larger cohort of 61 patients with tumor stage exceedingT2criteriawhowere enrolled between June 2002 and January 2007. Eligibility criteria for down-staging included: (1) one lesion >5 cm and up to 8 cm; (2) two to three lesions with at least one lesion >3 cm and not exceeding 5 cm, with total tumor diameter up to 8 cm; or (3) four to five lesions with none >3 cm, with total tumor diameter up to 8 cm. A minimum observation period of 3 months after down-staging was required before OLT. Tumor down-staging was successful in 43 patients (70.5%). Thirty-five patients (57.4%) had received OLT, including two who had undergone live-donor liver transplantation. Treatment failure was observed in 18 patients (29.5%), primarily due to tumor progression. In the explant of 35 patients who underwent OLT, 13 had complete tumor necrosis, 17 met T2 criteria, and five exceeded T2 criteria. The Kaplan-Meier intention-to-treat survival at 1 and 4 years after down-staging were 87.5% and 69.3%, respectively. The 1-year and 4-year posttransplantation survival rates were 96.2% and 92.1%, respectively. No patient had HCC recurrence after a median posttransplantation follow-up of 25 months. The only factor predicting treatment failure was pretreatment alpha-fetoprotein > 1,000 ng/mL. Conclusion Successful down-staging of HCC can be achieved in the majority of carefully selected patients and is associated with excellent posttransplantation outcome.

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

“…In addition, TACE can be performed in patients at the early stage in whom RFA cannot be performed because of tumor location (proximity to a gallbladder, biliary tree, or blood vessel) or medical comorbidities [198]. TACE is also the first-line therapy for downstaging tumors that exceed the criteria for transplantation [336][337][338]. Exclusion criteria in most trials are as follows: advanced liver disease (C-P class C), presence of vascular invasion or portal vein occlusion due to liver tumor, portosystemic shunt, hepatofugal blood flow, extrahepatic metastases, any contraindication to an arterial procedure (impaired clotting tests and renal failure), WHO performance stage 3 or 4, and end-stage tumorous disease (Okuda III) [339].…”

Does a patient qualify for liver transplantation after the down-staging of hepatocellular carcinoma?

“…Acceptable criteria are determined by the expectation of good survival after LT, and the same criteria are often used to limit access to deceased donor LT. The principle of down-staging involves the selection of patients whose tumors have a more favorable biology and who respond well to treatment and also do well after LT. 3 Thus, down-staging serves mainly as a selection tool for LT, but for the individual tumor, the down-staging treatment may not necessarily change the outcome of LT. The same principle of down-staging applies to living donor LT when the initial tumor burden exceeds the acceptable limits for the transplant center that is performing living donor LT. Clinically, the most relevant outcome parameters for down-staging are tumor recurrence after LT and survival, which includes posttransplant survival and intention-to-treat survival.…”

“…[3][4][5][6][7][8][9][10][11][12] This outcome measure starts from the time at which a patient with HCC is subjected to down-staging treatments before LT listing and takes into consideration tumor progression beyond acceptable limits (ie, changes in the tumor size or number, vascular invasion, or extrahepatic tumor dissemination) that leads to delisting or dropout from the LT waiting list. Dropout from the waiting list depends not only on the tumor biology but also on the time on the wait-list for deceased donor LT in a particular transplant center or region.…”

“…Most of the published reports have used the Milan criteria as the endpoint of down-staging. [3][4][5][6][7][8] The Response Evaluation Criteria in Solid Tumors (RECIST) [9][10][11] and other criteria 12,13 have also been used to define the response to tumor down-staging, especially when eligibility for LT is not restricted to patients meeting the Milan criteria. Because we are defining the response to down-staging according to measurements of only the viable tumor after locoregional therapy, the RECIST approach does not fit well into this scheme: it defines treatment responses according to the measurement of the entire tumor (including both the ablated or necrotic portion and the viable tumor).…”

“…Two subsequent studies have suggested that a response to locoregional therapy with transarterial chemoembolization (TACE) for HCC meeting or exceeding the Milan criteria could serve as a prognostic marker for improved posttransplant outcomes and for the selection of LT candidates. 10,11 A number of more recent studies have formally evaluated the intention-to-treat outcomes of HCC down-staging to the Milan criteria for LT eligibility [2][3][4][5][6][7][8] (Table 1). The endpoints of these studies include posttransplant survival, HCC recurrence, and dropout from the waiting list due to tumor progression or other causes.…”