Excellent Outcomes of Liver Transplantation Following Down-Staging of Hepatocellular Carcinoma to Within Milan Criteria: A Multicenter Study

doi:10.1016/j.cgh.2017.11.037

Clinical Gastroenterology and Hepatology

Volume 16, Issue 6, June 2018, Pages 955-964

https://doi.org/10.1016/j.cgh.2017.11.037 Get rights and content

Background & Aims

Single-center studies have reported excellent outcomes of patients who underwent liver transplantation for hepatocellular carcinoma (HCC) after successful down-staging (reduction of tumor burden with local-regional therapy), but multi-center studies are lacking. We performed a multi-center study, applying a uniform down-staging protocol, to assess outcomes of liver transplantation and performed an intention to treat analysis. We analyzed factors associated with treatment failure, defined as dropout from the liver transplant waitlist due to tumor progression, liver-related death without transplant, or recurrence of HCC after transplant.

Methods

We performed a retrospective multi-center study of 187 consecutive adults with HCC enrolled in the down-staging protocol at 3 liver transplant centers in California (Region 5), from 2002 through 2012. All patients underwent abdominal imaging 1 month after each local-regional treatment, and at a minimum of once every 3 months. The primary outcome was probability of treatment failure.

Results

Liver transplantation was performed after successful down staging in 109 patients (58%). Tumor explant from only 1 patient had poorly differentiated grade and 7 (6.4%) had vascular invasion. Based on Kaplan-Meier analysis of data collected a median 4.3 years after liver transplantation, 95% of patients would survive 1 year and 80% of patients would survive 5 years; probabilities of recurrence-free survival were 95% and 87%, respectively. There were no center-specific differences in survival in the intention to treat analysis (P = .62), in survival after liver transplantation (P = .95), or in recurrence of HCC (P = .99). Patients were removed from the liver transplantation waitlist due to tumor progression in (n = 59; 32%) or liver-related death without liver transplantation (n = 9; 5%). Factors associated with treatment failure, based on multivariable analysis, were pre-treatment levels of alpha-fetoprotein (AFP) >1000 ng/mL (hazard ratio, 3.3; P < .001) and Child Pugh class B or C (hazard ratio, 1.6; P < .001). The probability of treatment failure at 2 years from the first down-staging procedure was 100% for patients with levels of AFP >1000 and Child Pugh class B or C vs 29.4% for patients with neither risk factor (P < .001).

Conclusions

In a retrospective, multi-center study on HCC down staging under a uniform protocol, we found patients to have excellent outcomes following liver transplantation, with no center-specific effects. Our findings support application of the down-staging protocol on a broader scale. Patients with Child Pugh class B or C and AFP >1000 are unlikely to benefit from down staging.

Section snippets

Down-Staging Protocol

The United Network for Organ Sharing (UNOS) Region 5 down-staging protocol adopted from University of California, San Francisco has previously been described in detail (Table 1).¹² The present study included consecutive adult HCC patients enrolled in the down-staging protocol at 3 LT centers in Region 5 (University of California, San Francisco, California Pacific Medical Center, and Scripps Green Hospital) from 2002–2012. A minimum follow-up of 6 months after the first down-staging treatment

Baseline Characteristics and Local Regional Therapy

The baseline characteristics and details of LRT are presented in Table 2. Most of the cohort (69.5%) was from Center 1. At the time of first down-staging procedure, median MELD was 10, a total of 57.5% were Child’s class A (Child-Turcotte-Pugh [CTP] 5–6), 31.8% were Child’s B (CTP 7–9), and 10.6% were Child’s C (CTP 10–15). There were 38.0% with a single lesion, 51.3% with 2–3 lesions, and 10.7% with 4–5 lesions. Median baseline alpha-fetoprotein (AFP) was 24 (interquartile range [IQR], 8–154)

Discussion

In recent years there has been a paradigm shift in the selection of HCC patients for LT.17, 18, 19 Rather than relying solely on tumor size and number, there has been a greater emphasis on incorporating markers of tumor biology, including AFP20, 21 and response to LRT,22, 23 in the selection scheme. In this context, high AFP and tumor progression despite LRT identify more aggressive tumors with a substantially greater risk for HCC recurrence after LT. A period of observation is required for

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Cited by (98)

Multidisciplinary Treatment of Hepatocellular Carcinoma in 2023: Italian practice Treatment Guidelines of the Italian Association for the Study of the Liver (AISF), Italian Association of Medical Oncology (AIOM), Italian Association of Hepato-Bilio-Pancreatic Surgery (AICEP), Italian Association of Hospital Gastroenterologists (AIGO), Italian Association of Radiology and Clinical Oncology (AIRO), Italian Society of Pathological Anatomy and Diagnostic Cytology (SIAPeC-IAP), Italian Society of Surgery (SIC), Italian Society of Gastroenterology (SIGE), Italian Society of Medical and Interventional Radiology (SIRM), Italian Organ Transplant Society (SITO), and Association of Patients with Hepatitis and Liver Disease (EpaC) – Part I – Surgical treatments
2024, Digestive and Liver Disease
Worldwide, hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. The remarkable improvements in treating HCC achieved in the last years have increased the complexity of HCC management. Following the need to have updated guidelines on the multidisciplinary treatment management of HCC, the Italian Scientific Societies involved in the management of this cancer have promoted the drafting of a new dedicated document. This document was drawn up according to the GRADE methodology needed to produce guidelines based on evidence. Here is presented the first part of guidelines, focused on the multidisciplinary tumor board of experts and surgical treatments of HCC.
Liver-Directed Combined Radiation Therapy for Downstaging Beyond-Milan Hepatocellular Carcinoma to Liver Transplantation
2024, International Journal of Radiation Oncology Biology Physics
Curative surgery involving either resection or liver transplantation (LT) is indicated only for early-stage hepatocellular carcinoma (HCC). Over the years, numerous efforts have been made to downstage advanced HCC to curative surgery using various locoregional therapies. In this study, we investigated the role of liver-directed combined radiation therapy (LD-CRT) as a downstaging strategy for converting beyond-Milan advanced HCC to LT.
From January 2009 to February 2022, 53 patients with HCC who were initially beyond-Milan criteria were treated with LD-CRT and subsequent LT. These patients were compared with those who underwent upfront LT for within-Milan HCCs. The primary endpoint was overall survival (OS) and the secondary endpoint recurrence-free survival (RFS).
After LD-CRT, substantial downstaging was achieved in 35 patients (66%) who were initially beyond-Milan to within-Milan. At a median follow-up period of 47.6 months (range, 6.9-151.7 months), 5-year OS and 2-year RFS of the patients who received downstaging LD-CRT followed by LT were 66.9% and 63.2%, respectively. Patients who were successfully downstaged to within-Milan after LD-CRT had improved 5-year OS compared with their counterparts (81.9% vs 74.3%, P = .219). Recurrence after transplantation was observed in 18 patients (4 intrahepatic recurrences and 14 extrahepatic metastases).
LD-CRT achieved favorable oncological outcomes as a downstaging strategy for LT in patients with beyond-Milan HCC. The findings of this study suggest that the active adoption of LD-CRT needs full consideration for patients with beyond-Milan HCC, presenting the possibility of curing patients with advanced HCC.
Optimal Liver Transplantation Criteria for Hepatocellular Carcinoma
2024, Surgical Oncology Clinics of North America
Is hepatectomy feasible for hepatocellular carcinoma patients with clinically significant portal hypertension and beyond the Milan criteria?
2023, European Journal of Surgical Oncology
Hepatocellular carcinoma (HCC) patients with clinically significant portal hypertension (CSPH) and beyond the Milan criteria undergoing hepatectomy were previously considered to be at high risk and to have a poor prognosis, especially for major hepatectomy. The aim of this study was to investigate the safety and efficacy of hepatectomy in those patients.
Data were collected on HCC patients with CSPH treated at a single centre from January 2010 to October 2021. Propensity score-matched (PSM) analysis was used to balance the bias between groups.
Of the included patients, 556 underwent hepatectomy and 172 underwent transcatheter arterial chemoembolization (TACE). Comparison of patients beyond the Milan criteria and those with Milan criteria underwent hepatectomy, the 90-day mortality and complication rates were similar in the two groups. However, the overall survival (OS) and recurrence-free survival (RFS) of patients within the Milan criteria were significantly better than those beyond the Milan criteria (p < 0.001). In HCC patients beyond the Milan criteria, OS of performing hepatectomy was significantly longer than TACE (p < 0.001). Within HCC patients beyond the Milan criteria underwent hepatectomy, there was no significant difference in 90-day mortality and complications between minor and major hepatectomy in patients beyond the Milan criteria and no significant difference in RFS and OS after PSM.
Hepatectomy for HCC patients with CSPH and beyond the Milan criteria is safe and feasible, with an acceptable prognosis and no significant difference between minor and major hepatectomy.
Downstaging hepatocellular carcinoma before liver transplantation: A multicenter analysis of the “all-comers” protocol in the Multicenter Evaluation of Reduction in Tumor Size before Liver Transplantation (MERITS-LT) consortium
2023, American Journal of Transplantation
Patients with hepatocellular carcinoma meeting united network for organ sharing (UNOS)-downstaging (DS) criteria have excellent liver transplantation (LT) outcomes after DS. However, outcomes for “all-comers” (AC) patients with tumors initially exceeding UNOS-DS are poorly understood. Patients meeting AC (n = 82) or UNOS-DS (n = 229) at 7 LT centers in 4 UNOS regions were prospectively followed from 2015-2020. AC patients had a lower probability of successful DS (67% vs 83% within 12 months; P < .001). The 3-year survival was 69% for UNOS-DS vs 58% for AC (P = .05) and reduced to 30% in patients with Child-Pugh B/C cirrhosis or alpha-fetoprotein (AFP) ≥ 500. Five-year LT probability was 42% for AC vs 74% in UNOS-DS (P = .10). Thirty-eight percent were understaged on explant, with the increasing sum of the largest tumor diameter plus the number of lesions before LT (odds ratio 1.3; P = .01) and AFP ≥ 20 (odds ratio 5.9; P = .005) associated with understaging. Post-LT 3-year survival was 91% for AC vs 81% for UNOS-DS (P = .67). In this first prospective multiregional study of AC patients from the multicenter evaluation of reduction in tumor size before liver transplantation (MERITS-LT) consortium, we observed a 65% probability of successful DS. Three-year survival in AC was nearly 60%, though AC with Child-Pugh B/C or AFP ≥ 500 had poor survival. Explant pathology and 3-year post-LT outcomes were similar between cohorts, suggesting that LT is a reasonable goal in selected AC patients.
National Experience on Waitlist Outcomes for Down-Staging of Hepatocellular Carcinoma: High Dropout Rate in All-Comers
2023, Clinical Gastroenterology and Hepatology
The United Network for Organ Sharing (UNOS) grants priority listing for liver transplant for patients with hepatocellular carcinoma after successful down-staging to Milan criteria. We evaluated the national experience on down-staging by comparing 2 down-staging groups: tumor burden meeting UNOS down-staging (UNOS-DS) inclusion criteria, and all-comers (AC)-DS with initial tumor burden beyond UNOS-DS criteria vs patients always within Milan criteria.
We performed a retrospective analysis of the UNOS database of 23,398 patients listed for liver transplant who had submitted a hepatocellular carcinoma Model for End-Stage Liver Disease exception application from 2010 to 2019, classified as always within Milan (n = 20,579), UNOS-DS (n = 2151), and AC-DS (n = 668).
The 2-year cumulative probabilities of dropout were 19% for Milan, 25% for UNOS-DS (P < .001), and 30% for AC-DS (P < .001). In multivariate analysis of the down-staging groups, factors predicting dropout included Model for End-Stage Liver Disease at listing (hazard ratio [HR], 1.06; P < .001) and initial total tumor diameter (HR, 1.04; P = .002). Compared with α-fetoprotein (AFP) level ≤20 ng/mL, AFP levels of 21 to 100, 101 to 1000, and greater than 1000 ng/mL were associated with a higher risk of dropout (HRs, 1.63, 2.06, and 4.58, respectively; P < .001). A subset of all-comers with AFP levels greater than 100 ng/mL had a 2-year probability of dropout of 52% vs 26% for all others beyond Milan criteria (P < .001).
All-comers had a significantly higher risk for waitlist dropout compared with the UNOS-DS and Milan groups after initial successful down-staging to Milan criteria. In particular, the subgroup of AC-DS with an AFP level greater than 100 ng/mL had a greater than 50% probability of dropout in the next 2 years. These observations suggest a high likelihood of failure when expanding the indications for down-staging.

View all citing articles on Scopus

: Conflicts of interest The authors disclose no conflicts.

: Funding This work is supported in part by a grant from the National Institutes of Health to the University of California, San Francisco Liver Center (P01DK26743).

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Original articlePancreas, biliary tract, and liverExcellent Outcomes of Liver Transplantation Following Down-Staging of Hepatocellular Carcinoma to Within Milan Criteria: A Multicenter Study

Background & Aims

Methods

Results

Conclusions

Section snippets

Down-Staging Protocol

Baseline Characteristics and Local Regional Therapy

Discussion

Am J Transpl

Lancet Oncol

Hepatology

Lancet Oncol

Am J Transpl

Hepatocellular carcinoma

N Engl J Med

Standing the test of time: outcomes of a decade of prioritizing patients with hepatocellular carcinoma

Hepatology

Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis

N Engl J Med

Summary of candidate selection and expanded criteria for liver transplantation for hepatocellular carcinoma: a review and consensus statement

Liver Transpl

Reassessing the boundaries of liver transplantation for hepatocellular carcinoma: where do we stand with tumor down-staging?

Hepatology

Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States

Liver Transpl

Hepatocellular carcinoma: consensus recommendations of the National Cancer Institute Clinical Trials Planning Meeting

J Clin Oncol

Downstaging of hepatocellular cancer before liver transplant: Long-term outcome compared to tumors within Milan criteria

Hepatology

Original article
Pancreas, biliary tract, and liver
Excellent Outcomes of Liver Transplantation Following Down-Staging of Hepatocellular Carcinoma to Within Milan Criteria: A Multicenter Study