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Original Clinical Science—Liver

Surveillance for HCC After Liver Transplantation: Increased Monitoring May Yield Aggressive Treatment Options and Improved Postrecurrence Survival

Lee, David D. MD1,2; Sapisochin, Gonzalo MD, PhD, MSc3; Mehta, Neil MD4; Gorgen, Andre MD, MSc3; Musto, Kaitlyn R. PA-C2; Hajda, Hana BS5; Yao, Francis Y. MD4; Hodge, David O. MS6; Carter, Rickey E. PhD6; Harnois, Denise M. DO2

Author Information
doi: 10.1097/TP.0000000000003117
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Abstract

INTRODUCTION

Liver transplantation (LT) provides the most robust survival for carefully selected patients with hepatocellular carcinoma (HCC).1 Despite stringent inclusion criteria for LT access, recurrence of HCC after LT remains roughly between 6% and 20%.2-4 Patients who have recurrence of HCC after LT have significantly shortened survival, with a median survival after LT around 2 years.5 Due to the poor prognosis for patients who develop recurrence of HCC, many pre-LT prognostic scores have been developed to identify patients at risk for HCC recurrence after LT (Risk Estimation of Tumor Recurrence After Transplant [RETREAT], UCLA nomogram, Model of Recurrence after Liver Transplant, etc).2,6,7 Unfortunately, most of these scores are reliant on post-LT explant pathology information. Rather than identifying patients to be excluded from LT, the information generated from these predictive models have been proposed to provide guidance for post-LT management, either in the selection of patients to undergo adjuvant treatment, or to modify immunosuppression protocols, or to change the practice of surveillance imaging. Currently, no guidelines exist for post-LT surveillance imaging, due to a paucity of data.8 In many cases, the post-LT recurrence is multifocal and so aggressive that many groups have suggested that a poor prognosis is inevitable.9,10 And yet, some groups have suggested that aggressive intervention in selected patients can yield long-term posttransplant survival.5,11-15 To that end, we asked the question of whether or not increasing exposure to surveillance imaging can improve post-LT outcomes for patients who develop recurrence—that identifying early recurrent lesions allow for early disease to be identified, and potentially aggressive intervention to be pursued.

Using cumulative exposure to surveillance (CETS) as a marker for the benefit of screening intervals, we sought to determine if surveillance monitoring improves outcomes for patients with HCC recurrence after LT by finding recurrent disease amenable to treatment with curative intent.

MATERIALS AND METHODS

Study Design and Patient Population

Through a collaboration and Institutional Review Board approval with the University of California San Francisco (UCSF), University Health Network (UHN), Toronto, and Mayo Clinic Florida, data were collected from patients aged 18 years and older who underwent deceased-donor, whole-organ LT for HCC between October 2002 and February 2016 and developed recurrence. Median follow-up for all patients during this time was 4.5 years (interquartile range [IQR], 2.5–6.8 y). The following variables were included: demographic data (age, gender, race/ethnicity), tumor-related factors (size and number at the time of HCC diagnosis, α-feto-protein [AFP] at the time of listing and transplant, and RETREAT score), liver-related factors (etiology of liver disease and Model for End-Stage Liver Disease score), and post-LT management (imaging dates and findings, recurrence management, and treatment dates). RETREAT score was a post-LT recurrence prognostic tool using pre-LT and pathologic explant characteristics derived and validated with this same cohort of patients.7 The decisions regarding management of patients with HCC awaiting LT and post-LT HCC recurrence were made at each center’s multidisciplinary Liver Tumor Board, attended by transplant hepatologists, transplant surgeons, oncologists, interventional radiologists, and radiologists with an expertise in diagnostic abdominal imaging.

Immunosuppression Protocols

Immunosuppression was based on calcineurin inhibitor, mycophenolate, and corticosteroids with tapering of steroids within the first 3 months after transplant toward a lower maintenance dose. Mammalian target of rapamycin inhibitors were often initiated in patients with high risk for recurrence features but not routinely.

Imaging Protocol

Due to the lack of defined guidelines for screening, there was some variability of screening not only among the 3 centers but even within a given center over the 14-year study period. Despite these differences, there was enough similarity in the timing and modality of these programs to allow for combining all 3 experiences. Also, a sensitivity analysis was performed and showed that center effect did not influence either recurrence timing nor postrecurrence outcomes. Modality for screening included an intravenous contrast-enhanced chest computed tomography scan, intravenous contrast-enhanced magnetic resonance imaging or computed tomography of the abdomen, and bone scan with nuclear tracing. The most common timing interval for Mayo Clinic Florida was to monitor patients in the fourth, eighth, and 12th month after LT and annually thereafter. For UCSF, the usual timing was every 6 months following LT for the first 2 years. For the UHN, screening was most commonly performed every 6 months for the first 2 years. The diagnosis of HCC recurrence was based on imaging and confirmed with biopsy when feasible.

Treatments of HCC Recurrence

Surgical resection was the first-line treatment considered for all patients. Ablation was the treatment of choice in patients for whom the lesion was ≤3 cm, and surgical resection was not feasible. Transarterial therapies (either with chemoembolization or radioembolization) were pursued when neither surgical resection nor ablation was feasible. Stereotactic body radiation (SBRT) was pursued in cases not amenable for resection, ablation, or transarterial therapies. In many cases, patients received systemic chemotherapy; however, tolerance or completion of these regimens was not uniform. Sorafenib was also provided to many of these patients, but dose exposure was not reliable due to frequent disruption due to patient intolerance.

Determination of CETS

Screening protocols for cancer have been developed under a paradigm defined by 4 time points16 (Figure 1). The first point (T1) is the onset of disease, which is undetectable by screening. Before this time point (T0), there is no disease. The second point (T2) is when detectable disease allows for a screening test to identify a lesion. The third time point (T3) is when the cancer may progress to an asymptomatic invasive state, which may result in a detrimental change in prognosis. The fourth point (T4) is symptomatic and potentially beyond treatment. The time between T2 and T4 has been termed sojourn time, which is a window of opportunity when potential screening tests for preclinical disease may allow for detection and potential intervention. A screening test partitions sojourn time into the period before the screening test detects cancer (the delay time) and the time symptomatic and potentially incurable disease develops (lead time), ideally between T2 and T3. The goal of screening is to optimize the lead time to improve survival as well as to allow for intervention. With each negative screening test, a patient gains a period of protection during which either no disease is present or the disease is too small to be detected (the time from T0 and T2). Also, with each negative screening test, the probability for accurately detecting disease increases.16 For screening programs with HCC in a pre-LT population, the assigned protective interval is 6 months; however, as HCC has an estimated tumor doubling time of around 3–4 months, we have assigned 3 months for our protective interval in a population of post-LT patients with a history of HCC and risk for recurrence.17-20 For this study, we proposed the term CETS as a way to define the cumulative sum of all the protected intervals that each screening test provides. In our analysis, CETS has been treated as a continuous variable in months.

FIGURE 1.
FIGURE 1.:
Model of recurrence progression. A, An aggressive screening protocol which identifies disease early and amenable to potential treatment. B, A less frequent screening protocol which results in finding invasive disease, likely not amenable to potential treatment. CETS, cumulative exposure to surveillance; LT, liver transplant.

Study Outcome

The primary outcome was determined by postrecurrence survival. Treatment for curative intent was defined by treatment modalities that yielded the best postrecurrence survival and were labeled as aggressive treatment.

Statistical Analysis

Descriptive analyses consisting of means and SD; medians and IQRs; and frequencies and proportions were used to summarize the distribution of the data available. Comparisons of patients between the groups determined by that cutoff were completed using χ2 tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. Before conducting survival analyses on mortality after recurrence, the association of CETS with aggressive therapy, here defined as the use of resection or ablation, was considered. This association was summarized with the area under the receiver operating characteristic (ROC) curve. A cutoff that maximized both the sensitivity and specificity from that curve was used as a cutoff to illustrate the relationship of CETS to our long-term outcome of interest. Overall mortality after recurrence was estimated using the Kaplan-Meier method. Potential risk factors for that endpoint were evaluated using Cox proportional hazards models. The proportional hazards assumption was assessed using Schoenfeld residuals, and no statistical evidence against the assumption was found for the final model.

To account for the potential that time to recurrence could be an important confounding variable, a sensitivity analysis using time to recurrence as a stratification variable (<1 y, 1–3 y, >3 y) was performed. P values reported are 2-sided and have not been adjusted for multiple testing. P < 0.05 was used for statistical significance. Statistical analyses were conducted using both SAS 9.4 (Cary, NC) and STATA 13.1 (College Station, TX).

RESULTS

Of the 1764 HCC patients transplanted during this time interval, 223 (12.8%) patients developed recurrence following LT. Median follow-up after transplant was 32.3 months (IQR, 16.6–56.0 mo). One hundred sixty-five (74.3%) recurrences were identified through surveillance monitoring. At UCSF, 64.3% of the recurrences were found under their surveillance protocol, while 71.2% and 83.0% at Mayo, FL, and UHN, respectively. The remaining 58 (26.0%) patients were identified incidentally, through imaging for indications other than a concern for cancer. Median time to recurrence was 13.3 months (IQR, 6.6–25.6 mo) with a median RETREAT score of 3 (IQR, 2–5). There was a median surveillance of 3 CETS intervals (270 d) within the first 24 months post-LT. The median number of sites for recurrence at the time of diagnosis was 1 (IQR, 1–3). Intrahepatic recurrence occurred in 91 (40.8%) patients, either in the liver alone or in combination with extrahepatic sites. Fifty-eight (26.0%) patients underwent resection, either as primary treatment alone or in combination with ablation or SBRT. Ablation was pursued in 11 (4.9%) patients, many of whom received ablation in combination with SBRT, transarterial chemoembolization, or resection. One hundred one (45.3%) patients did not undergo any local regional treatment; however many of these patients did receive Sorafenib or other systemic therapies. Table 1 summarizes the demographics of patients in this study. Univariable cox modeling was performed to identify associations with postrecurrence mortality. The variables associated with reduced postrecurrence mortality included increased CETS (hazard ratio [HR], 0.93; 95% CI, 0.90-0.96; P < 0.001), longer time to recurrence (HR, 0.98; 95% confidence interval [CI], 0.97-0.99; P < 0.001), and treatment of recurrence with resection (HR, 0.29; 95% CI, 0.19-0.42; P < 0.001) or ablation (HR, 0.35; 95% CI, 0.13-0.95, P = 0.04). Having both extrahepatic and intrahepatic sites of recurrence was associated with postrecurrence mortality (HR, 1.91; 95% CI, 1.16-3.15; P = 0.01).

TABLE 1. - Patient with recurrence, demographics
Total (N = 223) HR (95% CI) P
Center (with UHN as reference variable)
 UCSF 70 (31.4%) 1.01 (0.72-1.42) 0.94
 Mayo clinic Florida 52 (23.3%) 1.25 (0.87-1.79) 0.23
 UHN 101 (45.3%) -
Age at transplant (y) 59.6 (54.6–63.9) 0.99 (0.97-1.01) 0.40
Gender (male) 182 (81.1%) 0.89 (0.62-1.28) 0.53
Time from diagnosis to transplant (mo) 12.2 (6.3–23.0) 1.00 (0.99-1.00) 0.48
Diagnosis (hepatitis C as reference variable)
 Hepatitis C 116 (52.0%) -
 Alcohol 28 (12.6%) 1.15 (0.74-1.78) 0.25
 Nonalcoholic steatohepatitis 21 (9.4%) 0.85 (0.51-1.41) 0.53
 Hepatitis B 49 (22.0%) 0.81 (0.56-1.17) 0.25
 Autoimmune 2 (0.9%) 0.30 (0.04-2.17) 0.23
 Other 7 (3.1%) 1.11 (0.45-2.73) 0.82
Raw MELD (transplant) 11.8 (8–14) 1.01 (0.98-1.04) 0.43
RETREAT score (as a continuous variable) 3 (2–5) 1.01 (0.98-1.04) 0.43
 0 6 (2.7%)
 1 40 (18.2%)
 2 28 (12.6%)
 3 54 (24.2%)
 4 31 (13.9%)
 ≥5 64 (28.7%)
Time to recurrence (mo) 13.3 (6.6–25.6) 0.98 (0.97-0.99) <0.001
Survival after recurrence (mo) 14.6 (7.6–27.8)
Total post-LT follow-up time (mo) 32.3 (16.6–56.0)
No. of surveillance images 3 (2–5) 0.86 (0.80-0.92) <0.001
No. of surveillance images in first 24 mo 3 (2–4) 0.86 (0.78-0.96) 0.005
CETS (with each increasing 30 d) 297 (193–464) 0.93 (0.90-0.96) <0.001
CETS in the first 24 mo 224 (112–311) 0.89 (0.86-0.93) <0.001
AFP at the time of recurrence 10.3 (4–290) 1.12 (1.06-1.19) <0.001
Site of recurrence (summarized) using liver recurrence as reference variable
 Extrahepatic 128 (57.4%) 0.88 (0.64-1.21) 0.44
 Both extrahepatic and intrahepatic 21 (9.4%) 1.91 (1.16-3.15) 0.01
Site of recurrence
 Abdomen (including adrenal, mesentery, lymph nodes, peritoneum) 34 (15.3%)
 Abdomen and bone 1 (0.5%)
 Abdomen and liver 4 (1.8%)
 Bone 36 (16.1%) 1.63 (1.15-2.33) <0.01
 Brain 6 (2.7%) 1.89 (0.83-4.27) 0.13
 Lung 53 (23.8%) 0.72 (0.52-1.00) 0.05
 Lung and brain 1 (0.5%)
 Lung and abdomen 1(0.5%)
 Liver 78 (35%) 1.02 (0.75-1.39) 0.88
 Liver and bone 2 (0.9%)
 Liver and lung 5 (2.2%)
 Liver, lung, and bone 2 (0.9%)
No. of sites 1 (1–3) 1.22 (0.91-1.65) 0.19
Management of recurrence
 Resection 36 (16.1%) 0.29 (0.19-0.42) <0.001
 Resection + ablation 4 (1.8%)
 Resection + SBRT 17 (7.6%)
 Resection + SBRT + ablation 1 (0.5%)
 Ablation 4 (1.8%) 0.35 (0.13-0.95) 0.04
 Ablation + SBRT 1 (0.5%)
 Ablation + TACE 1 (0.5%)
 SBRT 46 (20.6%) 1.24 (0.88-1.76) 0.22
 SBRT + TACE 3 (1.4%)
 TACE 8 (3.6%) 1.07 (0.61-1.89) 0.80
 TACE + TARE 1 (0.5%)
 Untreated 101 (45.2%)
No. of treatments for recurrence (as continuous variable) 1.04 (0.93-1.16) 0.47
 0 101 (45.2%)
 1 81 (36.3%)
 2 32 (14.4%)
 3 2 (0.9%)
 ≥4 7 (3.1%)
Cox proportional hazard models were performed to identify association with postrecurrence mortality. Total number and percentage in parentheses presented for categorical variables. Median with Interquartile range presented for continuous variables. – indicates variables that were reference variables for the regression.
AFP, α-fetoprotein; CETS, cumulative exposure to surveillance; CI, confidence interval; HR, hazard ratio; LT, liver transplant; MELD, Model for End-Stage Liver Disease; RETREAT, Risk Estimation of Tumor Recurrence After Transplant score; SBRT, stereotactic body radiation therapy; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; UCSF, University of California, San Francisco; UHN, University Health Network University of Toronto.

Because both resection and ablation are associated with reduced postrecurrence mortality and are often associated with aggressive treatment with the intention-to-cure, all instances of resection or ablation or both were combined as 1 variable—aggressive treatment. In multivariable analysis, the only statistically significant variables associated with reduced postrecurrence mortality were CETS (HR, 0.94; 95% CI, 0.91-0.98; P < 0.01) and aggressive treatment (HR, 0.31; 95% CI, 0.21-0.46; P < 0.001). Increasing lnAFP at the time of diagnosis was associated with an increased mortality (HR, 1.12; 95% CI, 1.06-1.19; P < 0.001; Table 2).

TABLE 2. - Multivariate Cox proportional hazard model for association with postrecurrence mortality
Multivariate analysis
Hazard ratio 95% confidence interval P
lnAFP at the time of diagnosis 1.12 1.06-1.19 <0.001
CETSa (increasing by 30 d) 0.94 0.91-0.98 <0.01
Time to recurrence (increasing by 30 d) 1.00 0.99-1.01 0.86
Aggressive treatment (surgery or ablation) 0.31 0.21-0.46 <0.001
Extrahepatic and intrahepatic recurrence 1.39 0.87-2.24 0.17
aProportion of time up-to-date with surveillance imaging; aggressive treatment, patients who received either resection or ablation or both for HCC recurrence.
AFP, α-fetoprotein; CETS, cumulative exposure to surveillance.

In order to ensure that time to recurrence was not contributing to the benefit of increasing CETS, a sensitivity analysis was performed to investigate the effect of CETS independent of time to recurrence. Time to recurrence was treated as a categorical variable defined by time to recurrence within the first year after transplant, 1–3 years, and the subsequent >3 years. Within each time group, CETS was independently shown to be associated with improved postrecurrence survival.

After controlling for the different underlying hazard in the 3 recurrence groups, CETS was significantly associated with reduced mortality (HR = 0.88; 95% CI, 0.80-0.96; P < 0.01).

Inevitably, the effect of surveillance is to identify disease that is amenable to aggressive treatment with the goal of improving postrecurrence survival. Using the first 24 months as our time window, we sought to determine if there was a certain amount of CETS associated with aggressive treatment. An ROC was then derived demonstrating that 252 days of CETS allowed for the highest sum of sensitivity and specificity for aggressive treatment (C statistic = 0.64). A Kaplan-Meier was then derived showing that patients who had at least the minimum 252 days of CETS showed improved postrecurrence survival (P < 0.001; Figure 2).

FIGURE 2.
FIGURE 2.:
Kaplan-Meier model for postrecurrence survival comparing patients who received either <252 days of cumulative exposure to surveillance (CETS) or ≥252 days of CETS.

DISCUSSION

Recurrence of HCC after LT has been associated with a bleak prognosis and performing LT for patients with high risk for recurrence has been deemed futile.9,10 Despite these concerns, survival benefit for patients with HCC has been demonstrated even for patients with the highest recurrence risk.21 Growing evidence shows that patients with recurrence can achieve improved survival with aggressive treatment.5,11,13-15,22,23 In this article, we investigated the impact of surveillance imaging after LT on postrecurrence survival. We demonstrate herein, that increased surveillance which is measured by CETS is actually independently associated with both improved postrecurrence survival and a higher probability toward aggressive treatment. We found that with every 1 month increased increment of CETS patients’ postrecurrence survival was improved. This analysis also confirms previously demonstrated reports that both ablation and resection were able to extend postrecurrence survival. In our analysis, we found that patients who achieved at least 252 days of CETS were more likely to undergo 1 or both of these potentially life-prolonging treatments. As expected, patients who had ≥252 days of CETS had a median survival of 20.4 months, which is significantly longer than those who did not (median, 11.2 mo).

This article affirms many well-established notions regarding HCC patients with recurrence after LT. Postrecurrence survival is mostly poor, with a median survival after recurrence around 14 months.5,11,14,15,24 Time to recurrence is a strong predictor for reduced postrecurrence survival.5,14,15,22 Among all the sites of recurrence, only bone recurrence is associated with the most significant reduced postrecurrence survival.5,14 While having intrahepatic disease compared with extrahepatic disease did not impact postrecurrence survival, having both extrahepatic and intrahepatic disease was associated with reduced postrecurrence survival.5,11 This would suggest that recurrence burden certainly impacts the postrecurrence survival. The number of sites involved with recurrence was not statistically significant, but we believe this lack of significance is largely due to the small overall range in the number of sites (only 1–3 sites for nearly all the patients). Surgical resection and ablation appear to extend postrecurrence survival.5,11,13-15,24 Interestingly, RETREAT score did not have any impact on postrecurrence survival.

The challenge with post-LT recurrence is balancing the aggressiveness of tumor biology with the opportunity to still intervene for improved postrecurrence survival. In many HCC recurrence prediction models, it is explant pathology features, response to locoregional treatment, and pre-LT AFP that suggest aggressive tumor biology. We were quite surprised to find that in our experience, RETREAT score was not predictive of postrecurrence survival. This finding suggests that more than just tumor biology features (as measured by pre-LT AFP, tumor size, and vascular invasion) predict postrecurrence survival. Most recently, Bodzin et al5 demonstrated that these tumor biology features plus neutrophil-lymphocyte ratio, donor sodium, and Model for End-Stage Liver Disease score at transplant could predict postrecurrence survival. This finding would suggest that not only the biology of the tumor but also the immunologic/biologic milieu of the recipient might impact postrecurrence survival as well. In their study, patients in the lowest risk group achieved >50% postrecurrence 5-year survival. It is not clear what percentage of the patients were treated with resection or aggressive treatment, but the authors seemed to suggest that tumor and patient biology, rather than treatment of recurrence modality, determined postrecurrence survival. Certainly, however, there is a role for aggressive treatment to change the course for patients with aggressive tumor biology. Many groups have demonstrated through small experiences (with 6–38 patients) that surgical resection of recurrent HCC has improved survival over those patients who were not resected. The unadjusted confounders of recurrence location, HCC biology, and patient medical comorbidity would also influence postrecurrence survival as well. Because the prognosis for patients with recurrence is so poor, any opportunity to extend postrecurrence survival beyond 1 year appears to be worthwhile; however, the effects of therapy remain difficult to study in isolation. In 1 study, Fields et al12 posit that an aggressive multimodality approach to treating HCC recurrence can yield the excellent result of a 40-month median postrecurrence survival. The problem with this article is that combined in their experience were patients who underwent ablation, transarterial radioembolization with y-90, or resection as primary treatment. Additionally, LT represented only a minority of these patients. Recurrence in the setting of these treatments is vastly different than in LT which addresses resection with the largest possible margins, elimination of the field defect associated with the primary liver disease as well as the burden of post-LT immunosuppression. It seems that the best approach toward patients with HCC recurrence after LT is to pursue aggressive treatment, if possible.

Other adjunct approaches to either reduce or manage HCC recurrence after LT include the modification of immunosuppression from calcineurin inhibitor-based protocols toward mammalian target of rapamycin inhibitors.25 At our centers, this approach was often initiated in the more recent experience but not routinely in the overall experience among the 3 centers. In many cases, patients received systemic chemotherapy; however, tolerance or completion of these protocols was not uniform. Sorafenib was also provided to many of these patients, but, again, tolerance and dose exposure were not reliable. While these may indeed impact the outcome for patients after recurrence, that impact is difficult to track in such a small subset of uncontrolled patients. For the intention of this study and screening frequency, we were not able to adjust for this impact, although the majority of studies would suggest that the impact might be subtle.10,26,27

In this analysis, we performed an ROC to determine that 252 days of CETS in the first 24 months would yield the best sensitivity and specificity for identifying disease treated with either resection or ablation. This recommendation would essentially require screening intervals be performed nearly every 6 months following transplant in the first 24 months. We acknowledge that the C statistic for this recommendation is only 0.64 and is not the strongest. We also concede that the decision to either resect or ablate a recurrent lesion after transplant is far more complex than simply when the last screening image was performed. An important finding in our analysis was that by increasing the screening interval, the probability for finding resectable or ablatable disease improved as did the postrecurrence survival. The only way to definitively assess the role of more frequent screening would be through a controlled trial—which our 3 sites plan to perform. Such a trial would also be critical in understanding the effectiveness for all HCC patients after transplant, not just for those in whom recurrence was found.

The role of retrospectively studying AFP in our analysis was problematic and not included in our recommendations for a number of reasons. First, AFP was elevated at the time of recurrence in only 50.2% of patients. Second, AFP was difficult to interpret following LT among the patients who recurred. Among the patients who developed recurrence, an isolated elevated AFP did not necessarily identify disease amenable to intervention. There were also many instances of elevated AFP without an identified lesion on imaging and only later the diagnosis of a recurrent lesion was made. Certainly, an elevated AFP at the time of recurrence diagnoses portended a poor prognosis; as a screening tool AFP, however, did not appear to be effective in our data set. Still, in moving forward toward a clinical trial, we would recommend screening of AFP at regular (perhaps monthly) intervals to understand what rising AFP and AFP trends after LT would mean for identifying early disease.

As a retrospective multicenter study, there are some inherent limitations in our findings. While all 3 centers had similar patient selection criteria, post-LT screening protocols, immunosuppression regimens, and approaches to the management of recurrence, some unmeasured differences may exist between the 3 centers. There was no difference in postrecurrence survival between any of the centers.

Despite these potential differences, the opportunity to pool 3 large experiences allows for us to draw conclusions that no single center could imply. A second criticism of this analysis is that not all imaging screening captures recurrent disease, as all radiologic tests are limited by their own sensitivity and specificity as noted above by the lag in elevated AFP and later recurrent lesion diagnosis. What is suggested from our data and the cancer screening epidemiology literature is that with each negative screening image, the probability of identifying earlier disease and capturing the true incidence of HCC recurrence increases.16 A third challenge to our analysis is separating the impact of time to recurrence from the cumulative total of CETS, as patients with very early recurrence would also have a very small CETS. To address this, we performed a stratified cox model fit to 3 groups of very early recurrence (<1 y), moderate timing of recurrence (1–3 y), and late recurrence (>3 y). After adjusting for time to recurrence, CETS still remained protective against postrecurrence mortality. Despite this adjustment, uncertainty, whether the effect of CETS is truly independent of time to recurrence, remains. This challenge highlights the difficulty of understanding tumor biology. For patients in whom very aggressive tumor biology recurs, it is likely that the prognosis is difficult to mitigate. Conversely, for patients in whom tumor biology is very slow and indolent, the opportunity to intervene is clearly obvious. For intermediate-risk patients, the ability to rescue from the fate of recurrence becomes least obvious. Certainly a randomized controlled trial, which we are pursuing, may elucidate the benefit of aggressively screening patients after LT and allow us to provide a stronger recommendation for their management.

In conclusion, this analysis of patients with HCC recurrence demonstrates that with increased screening, we can improve postrecurrence management and survival. We found that imaging every 6 months may provide the right amount of CETS months both to increase the probability of identifying disease which was able to be treated with aggressive surgical or ablative management and inevitably increase the postrecurrence survival. More data will be required to make a stronger recommendation. These data support an upcoming clinical trial which will hopefully identify a subset of patients in whom LT is not futile despite recurrence.

REFERENCES

1. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996; 334:693–699
2. Agopian VG, Harlander-Locke MP, Ruiz RM, et al. Impact of pretransplant bridging locoregional therapy for patients with hepatocellular carcinoma within milan criteria undergoing liver transplantation: analysis of 3601 patients from the US multicenter HCC transplant consortium. Ann Surg. 2017; 266:525–535
3. Ramanathan R, Sharma A, Lee DD, et al. Multimodality therapy and liver transplantation for hepatocellular carcinoma: a 14-year prospective analysis of outcomes. Transplantation. 2014; 98:100–106
4. Sharma P, Welch K, Hussain H, et al. Incidence and risk factors of hepatocellular carcinoma recurrence after liver transplantation in the MELD era. Dig Dis Sci. 2012; 57:806–812
5. Bodzin AS, Lunsford KE, Markovic D, et al. Predicting mortality in patients developing recurrent hepatocellular carcinoma after liver transplantation: impact of treatment modality and recurrence characteristics. Ann Surg. 2017; 266:118–125
6. Halazun KJ, Najjar M, Abdelmessih RM, et al. Recurrence after liver transplantation for hepatocellular carcinoma: A new MORAL to the story. Ann Surg. 2017; 265:557–564
7. 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; 3:493–500
8. Rubin J, Ayoub N, Kaldas F, et al. Management of recurrent hepatocellular carcinoma in liver transplant recipients: a systematic review. Exp Clin Transplant. 2012; 10:531–543
9. Viveiros A, Zoller H, Finkenstedt A. Hepatocellular carcinoma: when is liver transplantation oncologically futile? Transl Gastroenterol Hepatol. 2017; 2:63
10. de’Angelis N, Landi F, Carra MC, et al. Managements of recurrent hepatocellular carcinoma after liver transplantation: A systematic review. World J Gastroenterol. 2015; 21:11185–11198
11. Fernandez-Sevilla E, Allard MA, Selten J, et al. Recurrence of hepatocellular carcinoma after liver transplantation: is there a place for resection? Liver Transpl. 2017; 23:440–447
12. Fields TD, Philips P, Scoggins CR, et al. Multi-disciplinary concurrent management of recurrent hepatocellular therapy is superior to sequential therapy. World J Surg. 2017; 41:1331–1339
13. Kornberg A, Küpper B, Tannapfel A, et al. Long-term survival after recurrent hepatocellular carcinoma in liver transplant patients: clinical patterns and outcome variables. Eur J Surg Oncol. 2010; 36:275–280
14. Roayaie S, Schwartz JD, Sung MW, et al. Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis. Liver Transpl. 2004; 10:534–540
15. Sapisochin G, Goldaracena N, Astete S, et al. Benefit of treating hepatocellular carcinoma recurrence after liver transplantation and analysis of prognostic factors for survival in a large euro-american series. Ann Surg Oncol. 2015; 22:2286–2294
16. Walter SD, Day NE. Estimation of the duration of a pre-clinical disease state using screening data. Am J Epidemiol. 1983; 118:865–886
17. An C, Choi YA, Choi D, et al. Growth rate of early-stage hepatocellular carcinoma in patients with chronic liver disease. Clin Mol Hepatol. 2015; 21:279–286
18. Cucchetti A, Garuti F, Pinna AD, et al.; Italian Liver Cancer (ITA.LI.CA) group. Length time bias in surveillance for hepatocellular carcinoma and how to avoid it. Hepatol Res. 2016; 46:1275–1280
19. Goldberg DS, Valderrama A, Kamalakar R, et al. Hepatocellular carcinoma surveillance rates in commercially insured patients with noncirrhotic chronic hepatitis B. J Viral Hepat. 2015; 22:727–736
20. Kim JK, Kim HD, Jun MJ, et al. Tumor volume doubling time as a dynamic prognostic marker for patients with hepatocellular carcinoma. Dig Dis Sci. 2017; 62:2923–2931
21. Lai Q, Vitale A, Iesari S, et al.; European Hepatocellular Cancer Liver Transplant Study Group. Intention-to-treat survival benefit of liver transplantation in patients with hepatocellular cancer. Hepatology. 2017; 66:1910–1919
22. Kim SS, Kang TW, Song KD, et al. Radiofrequency ablation and transarterial chemoembolisation as first-line treatment for recurrent hepatocellular carcinoma or isolated intrahepatic recurrent hepatocellular carcinoma in transplanted livers. Clin Radiol. 2017; 72:141–149
23. Koh PS, Chan AC, Cheung TT, et al. Efficacy of radiofrequency ablation compared with transarterial chemoembolization for the treatment of recurrent hepatocellular carcinoma: a comparative survival analysis. HPB (Oxford). 2016; 18:72–78
24. Toso C, Cader S, Mentha-Dugerdil A, et al. Factors predicting survival after post-transplant hepatocellular carcinoma recurrence. J Hepatobiliary Pancreat Sci. 2013; 20:342–347
25. Lerut J, Iesari S, Foguenne M, et al. Hepatocellular cancer and recurrence after liver transplantation: what about the impact of immunosuppression? Transl Gastroenterol Hepatol. 2017; 2:80
26. Ge S, Huang D. Systemic therapies for hepatocellular carcinoma. Drug Discov Ther. 2015; 9:352–362
27. Tarantino G, Magistri P, Ballarin R, et al. Oncological impact of M-tor inhibitor immunosuppressive therapy after liver transplantation for hepatocellular carcinoma: review of the literature. Front Pharmacol. 2016; 7:387
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