Neil Mehta

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

We report on the long‐term intention‐to‐treat (ITT) outcome of 118 patients with hepatocellular carcinoma (HCC) undergoing downstaging to within Milan/United Network for Organ Sharing T2 criteria before liver transplantation (LT) since 2002 and compare the results with 488 patients listed for LT with HCC meeting T2 criteria at listing in the same period. The downstaging subgroups include 1 lesion >5 and ≤8 cm (n = 43), 2 or 3 lesions at least one >3 and ≤5 cm with total tumor diameter ≤8 cm (n = 61), or 4‐5 lesions each ≤3 cm with total tumor diameter ≤8 cm (n = 14). In the downstaging group, 64 patients (54.2%) had received LT and 5 (7.5%) developed HCC recurrence. Two of the five patients with HCC recurrence had 4‐5 tumors at presentation. The 1‐ and 2‐year cumulative probabilities for dropout (competing risk) were 24.1% and 34.2% in the downstaging group versus 20.3% and 25.6% in the T2 group (P = 0.04). Kaplan‐Meiers 5‐year post‐transplant survival and recurrence‐free probabilities were 77.8% and 90.8%, respectively, in the downstaging group versus 81% and 88%, respectively, in the T2 group (P = 0.69 and P = 0.66, respectively). The 5‐year ITT survival was 56.1% in the downstaging group versus 63.3% in the T2 group (P = 0.29). Factors predicting dropout in the downstaging group included pretreatment alpha‐fetoprotein ≥1,000 ng/mL (multivariate hazard ratio [HR]: 2.42; P = 0.02) and Childs B versus Childs A cirrhosis (multivariate HR: 2.19; P = 0.04). Conclusion: Successful downstaging of HCC to within T2 criteria was associated with a low rate of HCC recurrence and excellent post‐transplant survival, comparable to those meeting T2 criteria without downstaging. Owing to the small number of patients with 4‐5 tumors, further investigations are needed to confirm the efficacy of downstaging in this subgroup. (Hepatology 2015;61:1968–1977)

Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria.

Serum alpha‐fetoprotein (AFP) has been increasingly recognized as a marker for a poor prognosis after liver transplantation (LT) for hepatocellular carcinoma (HCC). Many published reports, however, have included a large proportion of patients with HCC beyond the Milan criteria, and the effects of incorporating AFP as an exclusion criterion for LT remain unclear. We studied 211 consecutive patients undergoing LT for HCC within the Milan criteria according to imaging under the Model for End‐Stage Liver Disease organ allocation system between June 2002 and January 2009. The majority (93.4%) had locoregional therapy before LT. The median follow‐up was 4.5 years (minimum = 2 years). The Kaplan‐Meier 1‐ and 5‐year patient survival rates were 94.3% and 83.4%, respectively. In a univariate analysis, significant predictors of HCC recurrence included vascular invasion [hazard ratio (HR) = 10, 95% confidence interval (CI) = 3.9‐26, P < 0.001], a pathological tumor stage beyond the University of California San Francisco criteria (HR = 4.1, 95% CI = 1.36‐12.6, P = 0.01), an AFP level > 1000 ng/mL (HR = 4.5, 95% CI = 1.3‐15.3, P = 0.02), and an AFP level > 500 ng/mL (HR = 3.1, 95% CI = 1.04‐9.4, P = 0.04). In a multivariate analysis, vascular invasion was the only significant predictor of tumor recurrence (HR = 5.6, 95% CI = 1.9‐19, P = 0.02). An AFP level > 1000 ng/mL was the strongest pretransplant variable predicting vascular invasion (odds ratio = 6.8, 95% CI = 1.6‐19.1, P = 0.006). The 1‐ and 5‐year rates of survival without recurrence were 90% and 52.7%, respectively, for patients with an AFP level > 1000 ng/mL and 95% and 80.3%, respectively, for patients with an AFP level ≤ 1000 ng/mL (P = 0.026). Applying an AFP level > 1000 ng/mL as a cutoff would have resulted in the exclusion of 4.7% of the patients from LT and a 20% reduction in HCC recurrence. In conclusion, an AFP level > 1000 ng/mL may be a surrogate for vascular invasion and may be used to predict posttransplant HCC recurrence. Incorporating an AFP level > 1000 ng/mL as an exclusion criterion for LT within the Milan criteria may further improve posttransplant outcomes. Liver Transpl 20:945‐951, 2014.

Identification of liver transplant candidates with hepatocellular carcinoma and a very low dropout risk: Implications for the current organ allocation policy

It has been shown that patients with hepatocellular carcinoma (HCC) meeting the United Network for Organ Sharing T2 (Milan) criteria have an advantage in comparison with patients without HCC under the current organ allocation system for liver transplantation (LT). We hypothesized that within the T2 HCC group, there is a subgroup with a low risk of wait‐list dropout that should not receive the same listing priority. This study evaluated 398 consecutive patients with T2 HCC listed for LT with a Model for End‐Stage Liver Disease exception from March 2005 to January 2011 at our center. Competing risk (CR) regression was used to determine predictors of dropout. The probabilities of dropout due to tumor progression or death without LT according to the CR analysis were 9.4% at 6 months and 19.6% at 12 months. The median time from listing to LT was 8.8 months, and the median time from listing to dropout or death without LT was 7.2 months. Significant predictors of dropout or death without LT according to a multivariate CR regression included 1 tumor of 3.1 to 5 cm (versus 1 tumor of 3 cm or less), 2 or 3 tumors, a lack of a complete response to the first locoregional therapy (LRT), and a high alpha‐fetoprotein (AFP) level after the first LRT. A subgroup (19.9%) that met certain criteria (1 tumor of 2 to 3 cm, a complete response after the first LRT, and an AFP level ≤ 20 ng/mL after the first LRT) had 1‐ and 2‐year probabilities of dropout of 1.3% and 1.6%, respectively, whereas the probabilities were 21.6% and 26.5% for all other patients (P = 0.004). In conclusion, a combination of tumor characteristics and a complete response to the first LRT define a subgroup of patients with a very low risk of wait‐list dropout who do not require the same listing priority. Our results may have important implications for the organ allocation policy for HCC. Liver Transpl 19:1343‐1353, 2013.

Liver transplantation for “very early” intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment

The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that “very early” iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with “very early” iCCA and those with “advanced” disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the “very early” iCCA group and 33/48 (69%) the “advanced” group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the “advanced” group (3.1 [2.5‐4.4] versus 1.6 [1.5‐1.8]). After a median follow‐up of 35 (13.5‐76.4) months, the 1‐year, 3‐year, and 5‐year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1‐year, 3‐year, and 5‐year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. Conclusion: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178‐1188)

Moving past “One Size (and Number) Fits All” in the selection of candidates with hepatocellular carcinoma for liver transplantation

Liver transplantation (LT) is a cornerstone in the management of early-stage hepatocellular carcinoma (HCC). Despite favorable overall posttransplant survival with the restrictive Milan criteria, HCC recurrence still occurs in 10% to 15% of these patients. On the other hand, some patients with tumors beyond the Milan criteria may achieve survival similar to the survival of patients with tumors within the Milan criteria. Consequently, there are clearly factors beyond tumor size and number that are associated with worse tumor biology and thus a greater risk of HCC recurrence after LT. Microvascular invasion has been consistently shown to predict a poor prognosis after LT, but the presence of microvascular invasion cannot be ascertained before LT. In our ongoing efforts to refine current selection criteria and to further improve outcomes after LT, we are still searching for pretransplant tumor characteristics beyond size and number that can serve as surrogates for tumor aggressiveness and predict the likelihood of HCC recurrence after LT. Although a serum tumor marker that reliably predicts the presence of microvascular invasion or a high risk of HCC recurrence after LT remains elusive, there is a growing body of evidence indicating that a high alpha-fetoprotein (AFP) level is associated with worse outcomes after LT. However, the optimal AFP cutoff for predicting an unfavorable outcome has not yet been elucidated. In recent years, there has also been growing interest in further defining the role of locoregional therapy (LRT) in the selection of candidates with HCC for LT. Preliminary studies have suggested that a response to LRT based on the Response Evaluation Criteria in Solid Tumors may serve as a selection criterion for patients with HCC within or beyond the Milan criteria. The same principle has been applied to the down-staging of tumors by LRT within acceptable criteria based on tumor size and number, with the goal of achieving post-transplant survival similar to the survival of patients not requiring down-staging before LT. In this issue of Liver Transplantation, Lai and colleagues from 6 centers throughout Europe further explore the impact of AFP and responses to LRT on outcomes after LT for patients with HCC within or beyond the Milan criteria. In this large, multicenter cohort of 422 patients, the majority (73%) had HCC initially meeting the Milan criteria according to preoperative imaging, and the remaining patients were down-staged within the University of California San Francisco (UCSF) criteria. When the modified Response Evaluation Criteria in Solid Tumors (mRECIST) were used to assess responses to LRT, 29% exhibited a complete response, and 7% had progressive disease. HCC recurrence was observed in 14% of the study population. In a multivariate analysis of the entire population, patients with progressive disease had a 3.5-fold higher risk of HCC recurrence in comparison with patients with a complete response. The only stronger predictor of HCC recurrence was an AFP slope > 15 ng/mL/month, which was associated with a 5.4-fold increased risk of HCC recurrence. A

Hepatic artery and biliary complications in liver transplant recipients undergoing pretransplant transarterial chemoembolization.

Liver transplantation (LT) is the treatment of choice for patients with cirrhosis and hepatocellular carcinoma (HCC) not amenable to resection. Locoregional therapies for HCC are often used to reduce tumor burden, bridge patients to LT, and down‐stage HCC so that patients are eligible for LT. We hypothesized that prior endovascular antitumor therapy may increase the risk of hepatic artery (HA) and biliary complications after LT. The aim of this study was to compare HA and biliary complications in LT recipients with HCC who received transarterial chemoembolization (TACE) before LT with complications in LT recipients with HCC who did not receive TACE before LT. This was a retrospective cohort study of HCC patients at two transplant centers. The prevalence of HA complications (HA thrombosis, stenosis, or pseudoaneurysm) and biliary complications (nonanastomotic stricture, bile leak, and diffuse injury) were compared between patients treated with or without TACE. There were 456 HCC patients with a median age of 61 years (77% were male, and 63% had hepatitis C virus), and 328 (72%) received TACE before LT. The overall prevalence of HA complications was 4.7% in the no‐TACE group and 7.9% in the TACE group (P = 0.22). All HA stenosis complications (n = 14) occurred in the TACE group (P = 0.018 versus the no‐TACE group). An older donor age and a lower albumin level significantly increased the odds of HA complications. There was a nonstatistically significant increased odds of HA complications in the TACE group versus the no‐TACE group according to an adjusted analysis (odds ratio = 2.02, 95% confidence interval = 0.79‐5.16, P = 0.14). The overall prevalence of biliary complications was 16.4% in the no‐TACE group and 19.8% in the TACE group (P = 0.40). In conclusion, a lower pre‐LT albumin level and an older donor age were significantly associated with higher odds of HA complications after LT. TACE was not associated with higher odds of overall HA complications but was associated with a higher prevalence of HA stenosis. Further studies are warranted to confirm the HA stenosis findings and elucidate the pathogenesis. Liver Transpl 20:1221‐1228, 2014.

Factors Associated With Outcomes and Response to Therapy in Patients With Infiltrative Hepatocellular Carcinoma

BACKGROUND & AIMS Infiltrative hepatocellular carcinoma (iHCC) is characterized by its indistinct borders and lack of a typical pattern of contrast enhancement. There are few published data on iHCC. We assessed outcomes, effects of treatment, and prognostic factors in a large cohort of patients with iHCC. METHODS We analyzed data from 155 patients (median age, 60 years; 79% male; median level of α-fetoprotein, 347 ng/mL; median Model for End-Stage Liver Disease score, 13) with iHCC, on the basis of contrast-enhanced computed tomography or magnetic resonance imaging, from 2002-2010 at the University of California, San Francisco Medical Center. All imaging study results were independently reviewed by 2 investigators. RESULTS Most of the patients had tumors of Barcelona Clinic Liver Cancer stage C (70%) or D (22%). The median maximum tumor diameter was 11.3 cm; 41% of lesions were hypovascular, 82% had macrovascular invasion, and 52% had extrahepatic metastases. Median survival was 4.0 months, and rates of survival at 6 and 12 months were 30% and 10%, respectively. On multivariate analysis, predictors of 6-month mortality were Child-Pugh class B or C cirrhosis; lack of tumor-directed therapy with chemoembolization (transarterial chemoembolization), radiofrequency ablation, or sorafenib; α-fetoprotein level >1000 ng/mL; female sex; Model for End-Stage Liver Disease score; and maximum tumor diameter. The percentages of patients surviving 6 and 12 months were 17% and 2% for those who received no therapy (n = 109), 73% and 36% for those who received sorafenib (n = 11), and 45% and 17% for those who received transarterial chemoembolization (n = 18) (all P values <.01). CONCLUSIONS Infiltrative HCC is a radiographically distinct and advanced form of hepatocellular carcinoma with a poor prognosis. Therapy with transarterial chemoembolization or sorafenib appears to prolong survival and requires further investigation.

Validation of a Risk Estimation of Tumor Recurrence After Transplant (RETREAT) Score for Hepatocellular Carcinoma Recurrence After Liver Transplant.

Importance Several factors are associated with increased hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT), but no reliable risk score has been established to determine the individual risk for HCC recurrence. Objective We aimed to develop and validate a Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score for patients with HCC meeting Milan criteria by imaging. Design, Setting, and Participants Predictors of recurrence were tested in a development cohort of 721 patients who underwent LT between 2002 and 2012 at 3 academic transplant centers (University of California–San Francisco; Mayo Clinic, Rochester; and Mayo Clinic, Jacksonville) to create the RETREAT score. This was subsequently validated in a cohort of 341 patients also meeting Milan criteria by imaging who underwent LT at the University of Toronto transplant center using the C concordance statistic and net reclassification index. Main Outcomes and Measures Characteristics associated with post-LT HCC recurrence. Results A total of 1061 patients participated in the study; 77.8% (825) were men, and the median (IQR) age was 58.2 (53.3-63.9) years in the development cohort and 56.4 (51.7-61.0) years in the validation cohort (P < .001). In the development cohort of 721 patients (542 men), median &agr;-fetoprotein (AFP) level at the time of LT was 8.3 ng/mL; 9.4% had microvascular invasion (n = 68), and 22.1% were beyond Milan criteria on explant (n = 159) owing to understaging by pretransplantation imaging. Cumulative probabilities of HCC recurrence at 1 and 5 years were 5.7% and 12.8%, respectively. On multivariable Cox proportional hazards regression, 3 variables were independently associated with HCC recurrence: microvascular invasion, AFP at time of LT, and the sum of the largest viable tumor diameter and number of viable tumors on explant. The RETREAT score was created using these 3 variables, with scores ranging from 0 to 5 or higher that were highly predictive of HCC recurrence (C statistic, 0.77). RETREAT was able to stratify 5-year post-LT recurrence risk ranging from less than 3% with a score of 0 to greater than 75% with a score of 5 or higher. The validation cohort (n = 340; 283 men) had significantly higher microvascular invasion (23.8% [n = 81], P < .001), explant beyond Milan criteria (37.3% [n = 159], P < .001), and HCC recurrence at 5 years (17.9% [n = 159], P = .03). RETREAT showed good model discrimination (C statistic, 0.82; 95% CI, 0.77-0.86) and superior recurrence risk classification compared with explant Milan criteria (net reclassification index, 0.40; P = .001) in the validation cohort. Conclusions and Relevance We have developed and validated a simple and novel prognostic score that may improve post-LT HCC surveillance strategies and help identify patients who may benefit from future adjuvant therapies.

Intention to treat outcome of T1 hepatocellular carcinoma with the "wait and not ablate" approach until meeting T2 criteria for liver transplant listing.

Patients with T1 hepatocellular carcinoma (HCC; 1 lesion < 2 cm) are currently not eligible for priority listing for liver transplantation (LT). A common practice is to wait without locoregional therapy (LRT) until tumor growth occurs from T1 to T2 (1 lesion 2‐5 cm or 2‐3 lesions ≤ 3 cm) to be eligible for listing with Model for End‐Stage Liver Disease exception. We aimed to evaluate the intention to treat outcome of the “wait and not ablate” approach for nonresection candidates with T1 HCC until tumor growth to T2. The study included 114 patients with T1 HCC 1.0‐1.9 cm followed by serial imaging every 3 months. Two investigators performed independent imaging reviews to confirm the diagnosis. Median increase in total tumor diameter was 0.14 cm/month. Probabilities of progression from T1 to directly beyond T2 without LT listing were 4.4% at 6 months and 9.0% at both 12 and 24 months. The 1‐ and 3‐year survival was 94.5% and 75.5%. In multivariate analysis, predictors of rapid tumor progression, defined as a >1 cm increase in total tumor diameter over 3 months, included alcoholic liver disease (odds ratio [OR], 6.52; P = 0.02) and Hispanic race (OR, 3.86; P = 0.047), whereas hepatitis B appeared to be protective (OR, 0.09; P = 0.04). By competing risks regression, predictors of exclusion from LT (with or without listing for LT under T2) were alpha‐fetoprotein (AFP) ≥ 500 ng/mL (HR, 12.69; 95% confidence interval, 2.8‐57.0; P = 0.001) and rapid tumor progression (HR, 5.68; P < 0.001). In conclusion, the “wait and not ablate” approach until tumor growth from T1 to T2 before LT listing is associated with a <10% risk of tumor progression to directly beyond T2 criteria. However, patients with AFP ≥ 500 ng/mL and rapid tumor progression are at high risk for wait‐list dropout and should receive early LRT. Liver Transpl 22:178‐187, 2016.

Wait Time of Less Than 6 and Greater Than 18 Months Predicts Hepatocellular Carcinoma Recurrence After Liver Transplantation: Proposing a Wait Time “sweet Spot”

Background It has been postulated that short wait time before liver transplant (LT) for hepatocellular carcinoma (HCC) results in the inclusion of tumors with aggressive biology, but prolonged wait time could result in a shift to more aggressive tumor behavior. We therefore test the hypothesis that a wait time “sweet spot” exists with a lower risk for HCC recurrence compared with the other 2 extremes. Methods This multicenter study included 911 patients from 3 LT centers with short, medium, and long wait times (median of 4, 7, and 13 months, respectively) who received Model for End Stage Liver Disease exception listing for HCC from 2002 to 2012. Results Wait time, defined as time from initial HCC diagnosis to LT, was less than 6 months in 32.4%, 6 to 18 months in 53.7%, and greater than 18 months in 13.9%. Waitlist dropout was observed in 18.4% at a median of 11.3 months. Probability of HCC recurrence at 1 and 5 years were 6.4% and 15.5% with wait time of less than 6 or greater than 18 months (n = 343) versus 4.5% and 9.8% with wait time of 6 to 18 months (n = 397), respectively (P = 0.049). When only pre-LT factors were considered, wait time of less than 6 or greater than 18 months (HR, 1.6; P = 0.043) and AFP greater than 400 at HCC diagnosis (HR, 3.0; P < 0.001) predicted HCC recurrence in multivariable analysis. Conclusions This large multicenter study provides evidence of an association between very short (<6 months) or very long (>18 months) wait times and an increased risk for HCC recurrence post-LT. The so-called sweet spot of 6 to 18 months should be the target to minimize HCC recurrence.