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Volume: 19 Issue: 12 December 2021

FULL TEXT

ARTICLE
Validation of Risk Estimation of Tumor Recurrence After Transplant Score in Patients With Hepatocellular Carcinoma Treated by Liver Transplant

Abstract

Objectives: Recurrent hepatocellular carcinoma can occur after liver transplant in up to 15% of cases. Recurrent hepatocellular carcinoma is associated with a dismal prognosis and subsequently a futile liver transplant in most instances. A validated prognostic scoring system for recurrent hepatocellular carcinoma that combines both pretransplant factors and explant characteristics has not been available until lately. The Risk Estimation of Tumor Recurrence After Transplant (“RETREAT”) score was recently validated. In this study, we analyzed this score for patients treated by liver transplant at our institution.
Materials and Methods: Between August 2006 and December 2019, 73 adult patients within Milan criteria underwent liver transplant for hepatocellular carcinoma at our center. 
Results: Follow-up ranged from 24.3 to 149.9 months with a mean of 45.98 ± 33.3 months. The overall 5-year patient survival, graft survival, and tumor-free survival rates were 78.6%, 90.1%, and 86.3%, respectively. Recurrent hepatocellular carcinoma cases exclusively occurred in patients with score of 3 or more points, with incidence increasing from 0% in those who had scores of ?2 points to 30.8% in those who had scores of 3 to 5 points and to 66.7% in those who had >5 points (P < .001).
Conclusions: The Risk Estimation of Tumor Recurrence After Transplant (“RETREAT”) score predicted the occurrence of recurrent hepatocellular carcinoma in our patients and correlated significantly with its incidence. Patients with scores of >5 points were at a very high risk for recurrent hepatocellular carcinoma and should be closely monitored using laboratory and magnetic resonance imaging.


Key words : Microvascular invasion, Prognosis, RETREAT score, Tumor size

Introduction

While offering a treatment for underlying liver cirrhosis, liver transplantation (LT) offers a chance for cure in a subset of patients with hepatocellular carcinoma (HCC). Since the introduction of Milan criteria (MC) and its adoption by United Network for Organ Sharing, outcomes for patients with HCC who are treated by LT have dramatically improved.1-4

Despite that, recurrent HCC (rHCC) is still reported after LT in up to 15% of cases. Recurrent HCC is associated with a dismal prognosis and subsequently a futile LT in most instances.5,6 Currently, LT for HCC has increased four-fold since the early 2000s.7 This increase in transplant rates has been further compounded by a severe shortage of organs and the exponentially growing waiting list of patients with HCC. On the other hand, hepatic resection and ablative modalities offer 50% patient survival for rHCC.8,9

A validated prognostic scoring system for rHCC that combines both pre-LT factors and explant characteristics has not been available until lately. A large multicenter study recently developed and validated the Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score, which incorporates independent predictors of post-LT HCC recurrence.10 A 5-year risk for rHCC in patients within MC has been stratified using the RETREAT score; this risk is shown to range from <3% for those with a score of 0 to >75% for those with a score of 5 or more.10 In this study, we estimated and validated the RETREAT score for HCC patients treated with LT at our institution.

Materials and Methods

Between August 2006 and December 2019, 73 adult patients underwent LT for HCC within MC at our center. Cases of pediatric LT or liver retransplant were excluded from this study. Liver transplant was performed using both deceased donors and living donors. Living donor LT procedures were with first- and second-degree relatives of the respective recipients.

Hepatocellular carcinoma was diagnosed by contrast-enhanced computed tomography (CT) and/or abdominal magnetic resonance imaging. Staging was done by chest CT, cranial CT, and technetium-99m bone scintigraphy to exclude extrahepatic disease. Size, number, tumor grade, and lymph vascular invasion of HCC were diagnosed by an experienced pathologist.

The immunosuppression protocol utilized for LT recipients at our center involves the use of triple drug immunosuppression based mainly on calcineurin inhibitor (tacrolimus or cyclosporine) in addition to steroids and mycophenolate mofetil.

The RETREAT score is based on 3 variables: (1) alpha-fetoprotein (AFP) level, (2) the sum of maximum diameter of pathologically viable tumor tissue added to the number of HCC foci, and (3) the presence of microvascular invasion. The score is obtained by adding the total number of points scored in each of the 3 variables. If AFP level is between 0 and 20 ng/mL, the patient is given 0 points; at 21 to 99 mg/mL, the patient is given 1 point; at 100 to 999 mg/mL, the patient is given 2 points; and at AFP ?1000 mg/mL, the patient is given 3 points. The patient is given 0 points in the absence of vascular invasion and 2 points if there is evidence of microvascular invasion. For the sum of the number of HCC foci added to the maximum diameter of viable tumor, 0 points are given if the sum is 0, 1 point is given if the sum is less than 5, 2 points are given if the sum is 5 to less than 10, and 3 points are given if the sum is 10 or more (Figure 1 and Table 1).10 The score is then correlated with HCC recurrence.

Statistical analyses
Data were analyzed by using t tests and chi-square tests. P < .05 was considered statistically significant.

Results

Originally, 136 patients presented with HCC during the study period. Figure 2 illustrates their distribution according to their initial transplant criteria for HCC and whether they received LT directly or after downstaging.

Between August 2006 and December 2019, 73 patients underwent LT at our center for presence of HCC within MC. Table 2 shows the pretransplant variables for these patients. Follow-up ranged from 24.3 to 149.9 months with a mean of 45.98 ± 33.3 months. The overall 5-year patient survival, graft survival, and tumor-free survival rates were 78.6%, 90.1%, and 86.3%, respectively (Figure 3).

As shown in Table 3, most of our patients (73.1%) had RETREAT scores of ?2 points. Incidence of rHCC exclusively occurred in patients with RETREAT scores of 3 or more points. The incidence of rHCC increased from 0% in those with ?2 points to 30.8% in those with 3 to 5 points and to 66.7% in those who had more than 5 points. The RETREAT score predicted the occurrence of rHCC in our patients and correlated significantly with its occurrence (P < .001).

Discussion

When available, LT offers the best chance for cure for HCC patients within MC. Our data showed an excellent LT outcome for HCC patients within MC. We found that the incidence of rHCC was 8.2% in HCC patients within MC and treated with LT at our center. Recurrent HCC has been previously shown to occur in up to 15% of patients within MC. This marginally lower overall survival may be due to patients having HCC versus those transplanted without HCC.5,6

Furthermore, patients who are beyond the MC and receive transplants have been shown to have com-parable long-term outcomes versus those within MC.11 In other words, MC and other morphologically based criteria represent one of many aspects contributing to the ever-pursued excellent post-LT outcomes.10,12

Aspects affecting outcomes include biological tumor variables (namely, microvascular invasion and poor tumor differentiation). Tumor response to downstaging with locoregional treatment (LRT) has also been frequently quoted as a marker for tumor biology, especially in patients who require downstaging to LRT before LT.13-15 Unfortunately, these variables are dichotomous; when viewed alone, each variable roughly predicts tumor recurrence following LT.10 Until the introduction of the RETREAT score, a validated prognostic scoring system for HCC recurrence has been lacking.10 More studies are required to evaluate the power of the RETREAT score in predicting rHCC in patients transplanted beyond MC with or without downstaging to LRT.

A newly introduced prognostic nomogram from the University of California, Los Angeles, was able to predict rHCC.16 This system includes the 7 variables listed in Table 3.16 Compared with the RETREAT score, it is much more complex, and factors need to be mathematically computed. Moreover, more than one-third of patients included in this study were beyond MC.10,16 This factor would have affected the wide application of the University of California nomogram in the current, MC-favoring, organ allocation system.10

This predictive grading approach offers precise measurement for patients with specific risk for development of rHCC following LT and hence can assist in determining the frequency of HCC surveillance programs and immunosuppression protocols after LT. Some clinical implications that stemmed from the RETREAT score include a surveillance protocol for HCC recurrence that was recently endorsed by the University of California, San Francisco transplant center.10

We found that the RETREAT score accurately predicted the incidence of rHCC among MC patients treated by LT at our center. It also stratified the risk of rHCC incidence among those patients. We suggest applying a close surveillance program for patients with RETREAT score of more than 5 points.

Whether post-LT immunosuppression should be modulated according to the RETREAT score is an open-ended question. Some studies were in favor of the use of rapamycin over calcineurin inhibitor, as rapamycin was suggested to have an antineoplastic action.17-20 Unfortunately, the SiLVER trial showed no improvement on long-term recurrence-free survival with the use of rapamycin.21

Conclusions

The RETREAT score predicted the occurrence of rHCC in our patients and correlated significantly with its incidence. It also stratified the risk of rHCC incidence among those patients. Patients with RETREAT score of >5 points are at a very high risk for rHCC and should be subjected to close surveillance using laboratory and magnetic resonance imaging-based investigations.


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Volume : 19
Issue : 12
Pages : 1298 - 1302
DOI : 10.6002/ect.2021.0378


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From the 1Department of Surgery, University of Alexandria, Faculty of Medicine, Alexandria, Egypt; and the 2Organ Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Mohamed Rabei Abdelfattah, Department of Surgery, University of Alexandria, Faculty of Medicine, AL Khartoum Square, Azzaritta, PO Box 21131, Alexandria, Egypt
Phone: +20 1023061111
E-mail: Mohamad.rabie@gmail.com