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Comparison of treatment outcome between living donor liver transplantation and sorafenib for patients with hepatocellular carcinoma beyond the Milan criteria.

ABSTRACT: For patients with advanced hepatocellular carcinoma (HCC), sorafenib is the only systemic treatment recommended by international guidelines. We recently reported that HCC patients with a low MoRAL (model to predict tumor recurrence after LDLT) score (≤ 314.8) have excellent treatment outcomes after living-donor liver transplantation (LDLT), even though they are beyond the Milan criteria. In the present study, we investigated whether LDLT offers a better treatment outcome than sorafenib for patients with HCC beyond the Milan criteria according to the MoRAL score. A retrospective cohort study of 325 consecutive patients who were treated with either LDLT (n = 122) or sorafenib (n = 203) for HCC beyond the Milan criteria from 2005 to 2014 at a tertiary hospital was performed. The primary and secondary endpoints were overall survival (OS) and time-to-progression. When baseline characteristics were balanced using inverse probability weighting, OS was significantly longer in the LDLT group than in the sorafenib group (5-year OS rate, 71.9% vs. 4.9%; HR=0.1; P < 0.001). The LDLT group exhibited a significantly lower risk of tumor progression (5-year recurrence rate, 34.7% vs. 96%; HR=0.14; P < 0.001) than the sorafenib group. The increase in OS with LDLT was predominantly among patients with a low MoRAL score (5-year OS rate, 81.1% vs. 5.8%; HR=0.06; P < 0.001) compared with those with a high MoRAL score (5-year OS rate, 28.3% vs. 4.3%; HR = 0.42; P = 0.047). Patients with a low MoRAL score and without extrahepatic metastasis or hepatic vein invasion might be good candidates for LDLT instead of sorafenib treatment if there is a willing living related donor.

SUBMITTER: Cho Y

PROVIDER: S-EPMC5564586 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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Project description:Introduction: Several attempts have been made to expand the indications of liver transplantation for hepatocellular carcinoma (HCC) beyond Milan criteria. We aimed to define genomic features that enable the identification of patients with HCC beyond Milan criteria who have acceptable transplant outcomes. Methods: Among 770 consecutive HCC patients transplanted at Mount Sinai Hospital and Mayo Clinic between 1990 and 2013, 132 had tumors exceeding Milan criteria on pathology and were enrolled in the study. Explant tumors were analyzed to assess genomic signatures of poor prognosis and immunohistochemical markers associated with tumor recurrence and overall survival. Results: Most of the patients were males (80%) and HCV positive (71%) with a median age of 56. HCC beyond Milan criteria was defined pre-operative in 67%. On pathology, 44% of the patients satisfied the ‘up-to-7 rule’. At a median follow-up of 88 months, 64 patients had died and 45 recurred; the 5-year overall survival (OS) and recurrence rates were 57% and 35%, respectively. CK19 gene signature was independently associated with recurrence (HR=2.95, p<0.001), along with tumor size >5 cm (HR=3.37, p=0.023) and presence of satellite lesions (HR=2.98, p=0.001). S2 subclass signature, which is known to be associated with progenitor cell markers, was independently associated with poor OS (HR=3.18, p=0.001), along with tumor size >5 cm (HR=5.06, p<0.001) and outside up-to-seven rule (HR=2.50, p=0.002). Using the presence of markers of progenitor cells (either CK19 or S2 subclass signatures) patients may be classified into poor-prognosis (n=58; 5-year recurrence 53%, survival 45%) and good-prognosis subgroups (n=74; 5-year recurrence 19%, survival 67%) (HR=3.16, p<0.001 for recurrence, and HR=1.72, p=0.04 for OS). Conclusion: Gene signatures associated with progenitor cell markers (CK19 and S2 subclass signatures) define outcome of HCC patients beyond Milan criteria after transplantation. Patients without these signatures achieve survival rates similar as those patients within Milan criteria. Once prospectively validated, these markers may provide the rationale for a limited expansion of liver transplantation indications.

Project description:ObjectivesTo assess survival after liver resection and transplantation in patients with hepatocellular carcinoma (HCC) beyond Milan criteria.BackgroundThe role of liver resection and transplantation remains controversial for patients with HCC beyond Milan criteria. Resection of advanced tumors and transplantation using extended-criteria are pursued at select high-volume center.MethodsPatients from 5 liver cancer centers in the United States who had liver resection or transplantation for HCC beyond Milan criteria between 1990 and 2011 were included in the study. Multivariable and propensity-matching analyses estimated the effects of clinical factors and operative selection on survival.ResultsOf 608 patients beyond Milan without vascular invasion, 480 (79%) patients underwent resection and 128 (21%) underwent transplantation. Clinicopathologic profiles between resection and transplant patients differed significantly. Hepatitis C and cirrhosis were more prevalent in transplantation group (P < 0.001). Resection patients had larger tumors [median 9 cm, interquartile range (IQR): 6.5-12.9 cm vs. median 4.1, IQR: 3.4-5.3 cm, P < 0.001]; transplant patients were more likely to have multiple tumors (78% vs 28%, P < 0.001).Overall (OS) and disease-free survival (DFS) were both greater after tumor downstaging and transplantation than resection (all P < 0.001). OS did not differ between liver transplant recipients who were not pretreated or pretreated and failed to downstage compared with propensity-matched liver resection patients (P ≥ 0.176); DFS in this propensity matched cohort was greater after liver transplantation (P ≤ 0.017).ConclusionsLiver resection and transplantation provide curative options for patients with HCC beyond Milan criteria. Further treatment strategies aimed at the efficiency and durability of tumor downstaging and expansion of the role of transplantation among suitable candidates could improve outcomes in patients with large or multifocal HCC.

Project description:Background & aimsGood outcomes after liver transplantation (LT) have been reported after successfully downstaging to Milan criteria in more advanced hepatocellular carcinoma (HCC). We aimed to compare post-LT outcomes in patients receiving locoregional therapies (LRT) before LT according to Milan criteria and University of California San Francisco downstaging (UCSF-DS) protocol and 'all-comers'.MethodsThis multicentre cohort study included patients who received any LRT before LT from Europe and Latin America (2000-2018). We excluded patients with alpha-foetoprotein (AFP) above 1,000 ng/ml. Competing risk regression analysis for HCC recurrence was conducted, estimating subdistribution hazard ratios (SHRs) and corresponding 95% CIs.ResultsFrom 2,441 LT patients, 70.1% received LRT before LT (n = 1,711). Of these, 80.6% were within Milan, 12.0% within UCSF-DS, and 7.4% all-comers. Successful downstaging was achieved in 45.2% (CI 34.8-55.8) and 38.2% (CI 25.4-52.3) of the UCSF-DS group and all-comers, respectively. The risk of recurrence was higher for all-comers (SHR 6.01 [p <0.0001]) and not significantly higher for the UCSF-DS group (SHR 1.60 [p = 0.32]), compared with patients remaining within Milan. The all-comers presented more frequent features of aggressive HCC and higher tumour burden at explant. Among the UCSF-DS group, an AFP value of ≤20 ng/ml at listing was associated with lower recurrence (SHR 2.01 [p = 0.006]) and better survival. However, recurrence was still significantly high irrespective of AFP ≤20 ng/ml in all-comers.ConclusionsPatients within the UCSF-DS protocol at listing have similar post-transplant outcomes compared with those within Milan when successfully downstaged. Meanwhile, all-comers have a higher recurrence and inferior survival irrespective of response to LRT. Additionally, in the UCSF-DS group, an ALP of ≤20 ng/ml might be a novel tool to optimise selection of candidates for LT.Clinical trial numberThis study was registered as part of an open public registry (NCT03775863).Lay summaryPatients with more extended HCC (within the UCSF-DS protocol) successfully downstaged to the conventional Milan criteria do not have a higher recurrence rate after LT compared with the group remaining in the Milan criteria from listing to transplantation. Moreover, in the UCSF-DS patient group, an ALP value equal to or below 20 ng/ml at listing might be a novel tool to further optimise selection of candidates for LT.

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Comparison of treatment outcome between living donor liver transplantation and sorafenib for patients with hepatocellular carcinoma beyond the Milan criteria.

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