The C statistic was 0.77 for the development cohort and 0.82 for the validation cohort. LT indicates liver transplant.
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Mehta N, Heimbach J, Harnois DM, et al. Validation of a Risk Estimation of Tumor Recurrence After Transplant (RETREAT) Score for Hepatocellular Carcinoma Recurrence After Liver Transplant. JAMA Oncol. 2017;3(4):493–500. doi:10.1001/jamaoncol.2016.5116
Copyright 2016 American Medical Association. All Rights Reserved.
What is an individual’s risk for recurrence of hepatocellular carcinoma (HCC) after liver transplant based on their tumor characteristics?
Using a multicenter retrospective cohort study approach, we have developed and validated a simple and novel score, the Risk Estimation of Tumor Recurrence After Transplant (RETREAT), that incorporates 3 variables: explant tumor burden, microvascular invasion, and α-fetoprotein level. The RETREAT score was highly predictive of HCC recurrence risk after liver transplantation.
The RETREAT risk score will help identify patients who would potentially derive benefit from future adjuvant therapies and also assist in determining posttransplant surveillance strategies.
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.
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.
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 α-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.
For 2 decades, the Milan criteria (1 lesion of ≤5 cm, 2-3 lesions of ≤3 cm)1 have been the benchmark for the selection of candidates with hepatocellular carcinoma (HCC) for liver transplantation (LT).2,3 Treatment of HCC now accounts for more than 20% of all LTs performed in the United States.4 Despite physician adherence to the Milan criteria, HCC recurrence still occurs in about 10% to 15% of patients,5-7 with a median survival of only about a year after HCC recurrence.2,3,8 Only 10% to 30% of recurrent HCCs are eligible for resection or ablation.8,9
The impact of tumor size and number on HCC recurrence risk is best illustrated in the “Metro-ticket forecast,”10 which follows the paradigm of “the further the distance (from conventional limits defined by Milan criteria), the higher the price (paid in terms of HCC recurrence).” Microvascular invasion is a well-established predictor of HCC recurrence after LT.5,11-13 Other factors implicated in HCC recurrence include elevated α-fetoprotein (AFP) levels14-17 and possibly des-gamma-carboxyprothrombin,18 poorly differentiated tumor grade,12 tumor progression despite locoregional therapy (LRT),19,20 as well as short waiting time before LT.21,22
Despite known risk factors for HCC recurrence after LT, no validated risk score is available to provide quantifiable and reliable measurements of an individual’s risk of post-LT HCC recurrence. The lack of a reliable model to estimate the risk for HCC recurrence after LT may explain why there is no standardized approach to HCC surveillance after LT2,5 and wide variation in this practice across LT centers.5 In the present large multicenter study, we aimed to develop and validate a recurrence risk score, the Risk Estimation of Tumor Recurrence After Transplant (RETREAT), for patients with HCC who meet the Milan criteria by imaging at the time of LT.
This multicenter study was approved by the institutional review boards of all participating institutions, and all boards waived patient written informed consent. The study included adult patients (age ≥18 years) with HCC always meeting Milan criteria on imaging who underwent LT with Model for End-Stage Liver Disease (MELD) score exception from June 2002 to December 2012. Patients requiring tumor downstaging to Milan criteria and those with intrahepatic cholangiocarcinoma or mixed HCC–cholangiocarcinoma on explant were excluded. Patients with incidental HCC were also excluded mainly because wait time to LT was 1 of the variables evaluated as a predictor of post-LT HCC recurrence. The development cohort consisted of 721 patients who underwent LT at 3 centers with different waiting times: short (Mayo Clinic, Jacksonville), medium (Mayo Clinic, Rochester), and long (University of California, San Francisco [UCSF]). The validation cohort consisted of 340 patients also within Milan criteria on imaging who underwent LT with MELD exception over the same time period at the University of Toronto.
The variables collected included age, sex, size and number of HCC tumors at time of diagnosis, AFP at time of listing and LT, LRT, cause of the liver disease, MELD score, and waiting time (defined as the time from HCC diagnosis to LT). All patients underwent contrast-enhanced computed tomography or magnetic resonance imaging at a minimum of once every 3 months after listing for LT.
Explant pathology reports were reviewed to determine histologic grade based on the modified Edmondson criteria,23 presence of vascular invasion, and tumor stage. Explant tumor staging was based on size and number of only viable tumors. The following categories of tumor stage were evaluated: within vs outside Milan criteria, total tumor diameter, number of viable lesions, and the sum of the largest diameter of viable tumor plus the number of viable tumors on explant.
The study end points were 5-year post-LT HCC recurrence and survival. Recurrence and survival probabilities were estimated by the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariable hazard ratios (HRs) for predictors of post-LT HCC recurrence were determined by Cox proportional hazards regression models and reported with 95% confidence intervals (CIs). Potential cutoffs were evaluated using the Akaike information criterion (AIC), with lower AIC values indicating better model fit. Predictors of HCC recurrence with a univariate P < .10 were included in the multivariable analysis, and the final model was selected by backward stepwise elimination (P > .05 for removal). The RETREAT score was then created based on the final multivariable model coefficients.24 Model coefficients were scaled to the coefficient for AFP and rounded to the nearest integer. This produced a simplified point scale reflecting the relative impact of model covariables. The integer value for each model component was then summed to calculate the RETREAT score.
In the validation cohort, the RETREAT score was tested and compared with Milan criteria (based on explant pathology findings). The overall C statistic was used to assess model discrimination, and net reclassification index25 to evaluate improvement in model performance by quantifying the proportion of correct risk reclassification for HCC recurrence. Net reclassification improvement was estimated using a priori 1- and 5-year recurrence risk groups (<5%, 5% to <10%, 10% to <20%, and ≥20%). Correct risk reclassification was indicated by RETREAT score predicted probabilities that reclassified patients with recurrence into higher risk groups and patients without recurrence into lower risk groups compared with predicted probabilities estimated by explant Milan criteria.
The baseline characteristics of the 721 patients in the development cohort and the 340 patients in the validation cohort are summarized in Table 1. Compared with the development cohort, the validation cohort was younger, had a higher percentage of men, and more frequently had hepatitis B or alcohol abuse as the cause of the liver disease. White patients made up 62.0% of the development cohort (n = 447); Asians, 19.1% (n = 138); Hispanics, 11.2% (n = 81); and African Americans 5.1% (n = 37). Patients in the validation cohort were more likely to have a single tumor and less likely to receive LRT prior to LT. Median wait time from HCC diagnosis to LT ranged from 4.3 months in the center with the shortest wait time to 12.9 months in the center with the longest wait time. Overall, wait time in the development cohort was shorter than in the validation cohort (8.1 vs 10.5 months).
Compared with the developmental cohort, the validation cohort had significantly higher proportions of microvascular invasion (23.8% [n = 81] vs 9.4% [n = 32]), moderately or poorly differentiated tumor grade (76.7% [n = 260] vs 44.0% [n = 150]), and explant tumor stage beyond Milan criteria (37.3% [n = 127] vs 22.1% [n = 75]). The median for the sum of the largest viable tumor diameter (cm) plus the number of viable tumors on explant was 4.5 in the validation cohort vs 3.5 in the development cohort (P < .001).
Median post-LT follow-up was 4.5 years (interquartile range [IQR], 2.5-6.8 years) in the development cohort. Follow-up included a combination of AFP and cross-sectional imaging every 4 to 6 months for the first 2 years after LT. This was performed in all HCC LT recipients at 2 centers and in patients deemed to be at high risk for HCC recurrence (AFP >300, explant tumor burden beyond Milan criteria, and/or microvascular invasion) at a third center. Overall post-LT survival was 93.1% (95% CI, 91.0%-94.8%) at 1 year and 77.0% (95% CI, 73.4%-80.1%) at 5 years. Recurrence of HCC was found in 11.6% (84 of 721) at a median of 13.0 months (IQR, 5.4-26.7 months) after LT. The most common sites of HCC recurrence were the lung (44.0% [n = 37]), bone (29.8% [n = 25]), liver (26.2% [n = 22]), and peritoneum (26.2% [n = 22]). The majority (75.0% [n = 63]) had a single site of HCC recurrence; 20.2% [n = 17] had 2 sites; and 4.8% [n = 4] had 3 or more sites of recurrence at diagnosis. Overall post-LT HCC recurrence at 1, 2, and 5 years was 5.7% (95% CI, 4.2%-7.8%), 8.7% (95% CI, 6.8%-11.1%), and 12.8% (95% CI, 10.3%-15.7%), respectively (Figure 1). There were no significant center-specific differences in rates of HCC recurrence.
Predictors of post-LT HCC recurrence in the development cohort on univariate analysis included microvascular invasion, moderately or poorly differentiated tumor grade, AFP at the time of LT as a continuous variable and at all tested cutoffs, and the sum of the largest diameter of viable tumor (cm) plus the number of tumors (Table 2). The tumor sum criterion had the lowest AIC compared with other assessments of tumor burden and therefore the best model fit. Age, sex, race/ethnicity, MELD score, cause of the liver disease, number of lesions at HCC diagnosis, and LRT (vs no LRT) were not predictive of HCC recurrence on univariate analysis. On multivariable analysis, predictors of HCC included (1) microvascular invasion, (2) sum of the largest diameter of viable tumor and number of viable tumors (at the following cutoffs: 1.1-4.9, 5-9.9, and ≥10), and (3) AFP at LT (at the following cutoffs: 20-99, 100-999, and ≥1000 ng/mL). The multivariable model coefficients for these 3 significant variables were then used to calculate a simplified RETREAT score. An individual patient’s RETREAT score is calculated by adding the individual points for each of the 3 variables (Table 3). The actual statistical model and the coefficients are also summarized in Table 3.
Calculated RETREAT scores ranged from 0 to 8, with the most common scores being 1 (31.9% [n = 220]) and 2 (22.5% [n = 149]). A patient with completely necrotic tumor on explant after LRT, no microvascular invasion on explant, and an AFP level lower than 20 ng/mL at LT would have a RETREAT score of 0 (21.6% of the cohort [n = 149]), predicting 1- and 5-year recurrence risk of only 1.0% (95% CI, 0.0%-2.1%) and 2.9% (95% CI, 0.0%-5.6%), respectively. Predicted risk of 1- and 5-year HCC recurrence rose with each point scored (Figure 2) such that a patient with a RETREAT score of 5 or higher (6.8% of the cohort [n = 47]) had a predicted 1- and 5-year recurrence risk of 39.3% (95% CI, 25.5%-50.5%) and 75.2% (95% CI, 56.7%-85.8%), respectively. The RETREAT score C statistic was 0.77 (95% CI, 0.71-0.82) in the development cohort for predicting HCC recurrence compared with 0.70 (95% CI, 0.63-0.76) for Milan criteria by explant. The C statistics for the individual components of RETREAT were 0.65 (95% CI, 0.58-0.72) for AFP, 0.74 (95% CI, 0.68-0.80) for the sum of the largest viable lesion plus number of lesions on explant, and 0.68 (95% CI, 0.64-0.73) for microvascular invasion.
For purposes of comparison, data for the development cohort are reported in the Post-LT Outcomes—Development Cohort subsection of the Results section. In the validation cohort, the median post-LT follow-up was 5.1 years (IQR, 2.6-7.7 years). The overall post-LT survival in this cohort was 91.8% (95% CI, 88.3%-94.2%) at 1 year and 71.5% (95% CI, 66.2%-76.2%) at 5 years (P = .06 vs development cohort). Higher HCC recurrence rates at 1 and 5 years after LT were observed in the validation cohort vs 8.7% (95% CI, 6.1%-7.8%) and 17.9% (95% CI, 14.0%-22.8%), respectively (P = .08 at 1 year, P = .03 at 5 years) (Figure 1). The RETREAT score performed well in the validation cohort with a C statistic of 0.82 (95% CI 0.77-0.86). Using the net reclassification index, we found that the RETREAT score improved prediction of HCC recurrence after LT compared with the Milan criteria at 1 year (0.40, P = .001) and 5 years after LT (0.31, P < .001).
There is a growing body of evidence that the Milan criteria represent just 1 of many factors that predict post-LT survival and HCC recurrence.26 Factors commonly used to define high risk for HCC recurrence after LT have included explant tumor stage beyond Milan criteria, tumor vascular invasion, and poorly differentiated tumor grade. These factors, however, are binary (yes or no), with each factor separately providing only a very crude estimation of HCC recurrence risk after LT. Even patients classified as low risk for HCC recurrence based on explant tumor burden within Milan criteria still carry an estimated 10% to 15% risk for HCC recurrence at 5 years after LT.5-7 A reliable and validated prognostic scoring system to provide an accurate quantification of individual HCC recurrence risk would be helpful to guide HCC surveillance strategies and determine the need for post-LT adjuvant therapy if available in the future.
In this large, multicenter study involving over 1000 patients with HCC always within Milan criteria by imaging before LT, we developed and validated the RETREAT score using 3 variables that were highly predictive of HCC recurrence: AFP at LT, microvascular invasion, and the sum of the largest diameter of viable tumor (cm) plus the number of viable tumors on explant (C statistic, 0.77). The RETREAT score was able to stratify 5-year HCC recurrence risks ranging from less than 3% in those with a risk score of 0 to higher than 75% with a risk score of 5 or higher. Despite higher rates of microvascular invasion, explant tumor burden, and overall HCC recurrence in the validation cohort, the RETREAT score still performed well with an even higher C statistic of 0.82.
One of the strengths of the RETREAT score is that it accounts for the effects of preoperative LRT, and only viable tumors are considered. Those with no viable tumors in the explant receive a score of 0 in assessing pathologic tumor burden, reflecting a very low risk for HCC recurrence. This finding is entirely consistent with 2 recent studies demonstrating a very low probability of HCC recurrence (0% to 2.4%) in patients who achieve complete response to LRT based on explant pathologic findings.27,28 In the present study, the sum of the largest diameter of viable tumor (cm) plus the number of viable tumors in the explant predicted HCC recurrence better than other categories in assessing tumor burden, namely tumors outside (vs within) Milan criteria and the total tumor diameter. Similarly, Mazzaferro et al10 proposed using a combination of the size of the largest tumor and the total number of tumors on explant to better estimate post-LT survival in the Metro-ticket forecast.10 Mazzaferro and colleagues used a web-based registry in their data collection and relied on overall patient survival rather than HCC recurrence as the end point. The present study used HCC recurrence as the primary end point and provided further evidence supporting the combination of maximum size and number of viable tumors as a reliable predictor of tumor recurrence after LT. The multicenter study design also allowed us to include a wide range of races/ethnicities and causes of liver disease. While viral hepatitis and non-white race appear to be strong risk factors for HCC development,29 we did not observe such an association in terms of increased post-LT HCC recurrence.
Recently, the University of California, Los Angeles (UCLA) group reported a prognostic nomogram for HCC recurrence after LT.12 This was constructed over a span of 30 years and did not include a validation set. One of the strengths of the RETREAT score is its simplicity in contrast to the UCLA nomogram, which involves 7 variables, including 1 that must be calculated. Furthermore, the UCLA study included 38% of patients with HCC either outside the Milan criteria by imaging or discovered incidentally in the explant, and participants an overall 5-year post-LT survival of only 60%. One would therefore question the generalizability of the UCLA nomogram in the current MELD era based on Milan criteria, with expected 5-year post-LT survival of 70% to 80%.2,5,30 We have included centers with short, medium, and long waiting times in our study, thus avoiding potential bias related to length of waiting time in a single-center study and improving the generalizability of our results.
How does the RETREAT score potentially affect clinical practice after LT? The RETREAT score helps determine whether HCC surveillance after LT is warranted, taking into consideration a recent study suggesting that long-term survival can be achieved with tumor-directed therapy in a subset with local HCC recurrence.9 Since the majority of HCC recurrence in the present study occurred within the first 2 years after LT, we propose the following guidelines for HCC surveillance strategy that has recently been instituted at UCSF: HCC surveillance every 6 months for 2 years for a RETREAT score of 1 to 3 and every 6 months for 5 years for a RETREAT score of 4. Patients with a RETREAT score of 5 or higher should undergo HCC surveillance every 3 to 4 months for 2 years followed by every 6 months for years 2 through 5. We further propose using multiphasic abdominal computed tomographic or magnetic resonance imaging, chest computed tomography, and AFP for surveillance at the recommended interval. Those with a RETREAT score of 0 should receive no surveillance, given their 5-year predicted recurrence risk of less than 3%. Identifying this subgroup (20% of study cohort [n = 149]) that does not require surveillance is cost saving.
The RETREAT score could potentially affect the use of post-LT immunosuppression. Calcineurin inhibitors may increase the risk for post-LT HCC recurrence,31,32 and the mammalian target of rapamycin (mTOR) inhibitors may have antineoplastic properties.33,34 A number of studies have evaluated post-LT outcomes with the mTOR-inhibitors sirolimus35-37 and everolimus.38-41 Despite early optimism, a prospective randomized controlled phase 3 international trial (SiLVER trial) failed to demonstrate an overall benefit of sirolimus in improving long-term recurrence-free survival beyond 5 years.42 Regarding possible adjuvant therapies, sorafenib is being investigated in a phase 1 trial to prevent post-LT HCC recurrence in high-risk candidates with tumors outside the Milan criteria or microvascular invasion and/or poorly differentiated tumor grade in the explant.43 Other potential therapies such as liver allograft-derived natural killer cells44 and radioimmunologic agents45 hold promise. The RETREAT score may be helpful in the design of future clinical trials—identifying candidates at high risk for HCC recurrence and providing a reference for the expected incidence of HCC recurrence. Patients with a RETREAT score of 4 or higher are at high risk for HCC recurrence and are therefore appropriate candidates for future adjuvant therapies.
There are limitations of the present study, including missing information on AFP at the time of LT in 4% of the developmental cohort [n = 29] and explant histologic tumor grade in 2% of the combined developmental and validation cohorts [n = 21]. We also did not assess lack of response to LRT or tumor progression despite LRT as potential risk factors for HCC recurrence. This analysis would have been difficult owing to multiple time points for evaluation in the center with prolonged LT waiting time and insufficient duration to observe the full effects of LRT in the center with short LT waiting time. Given the limitations of the retrospective study design, a multicenter study is planned to prospectively evaluate the application of RETREAT in post-LT HCC surveillance and to confirm the prognostic power of the RETREAT score.
In conclusion, we have developed and validated a novel score (RETREAT) for predicting post-LT HCC recurrence in patients always meeting the Milan criteria by pre-LT imaging. RETREAT stratifies 5-year HCC recurrence risk from less than 3% with a risk score of 0 to greater than 75% with a risk score of 5 or higher. The RETREAT score may help improve post-LT HCC surveillance strategies and identify patients who may benefit from future adjuvant therapies.
Corresponding Author: Francis Yao, MD, Division of Gastroenterology, Department of Medicine, University of California–San Francisco, 513 Parnassus Ave, Room S-357, San Francisco, CA 94143-0538 (firstname.lastname@example.org).
Accepted for Publication: September 7, 2016.
Published Online: November 13, 2016. doi:10.1001/jamaoncol.2016.5116
Author Contributions: Drs Mehta and Yao had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Mehta, Heimbach, Harnois, Sapisochin, Burns, Greig, Roberts, Yao.
Acquisition, analysis, or interpretation of data: Mehta, Heimbach, Harnois, Sapisochin, Dodge, Lee, Sanchez, Grant, Yao.
Drafting of the manuscript: Mehta, Harnois, Sapisochin, Dodge, Roberts, Yao.
Critical revision of the manuscript for important intellectual content: Mehta, Heimbach, Harnois, Sapisochin, Dodge, Lee, Burns, Sanchez, Greig, Grant, Yao.
Statistical analysis: Mehta, Harnois, Dodge.
Administrative, technical, or material support: Heimbach, Sapisochin, Sanchez, Grant.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by the Biostatistics Core of the UCSF Liver Center (P30 DK026473).
Role of the Funder/Sponsor: The funder played a role in the collection, management, analysis, and interpretation of the data. The funder had no role in the design and conduct of the study; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Previous Presentation: This research was presented at the American Association for the Study of Liver Diseases Liver Meeting; November 13, 2016; Boston, Massachusetts.